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Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators
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  • Yuliya Toporivska
    Yuliya Toporivska
    University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
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  • Andrzej Mular
    Andrzej Mular
    University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
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  • Karolina Piasta
    Karolina Piasta
    University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
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    Orcidhttps://orcid.org/0000-0003-0160-6920
  • Małgorzata Ostrowska
    Małgorzata Ostrowska
    University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
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  • Davide Illuminati
    Davide Illuminati
    University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
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  • Andrea Baldi
    Andrea Baldi
    University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
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  • Valentina Albanese
    Valentina Albanese
    University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
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    Orcidhttps://orcid.org/0000-0002-1947-2644
  • Salvatore Pacifico
    Salvatore Pacifico
    University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
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  • Igor O. Fritsky
    Igor O. Fritsky
    Taras Shevchenko National University of Kyiv, Department of Chemistry, 64 Volodymyrska Str., 01601 Kyiv, Ukraine
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  • Maurizio Remelli
    Maurizio Remelli
    University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
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  • Remo Guerrini
    Remo Guerrini
    University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
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  • Elzbieta Gumienna-Kontecka*
    Elzbieta Gumienna-Kontecka
    University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
    *Email for E.G.-K.: [email protected]
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Inorganic Chemistry

Cite this: Inorg. Chem. 2021, 60, 17, 13332–13347
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https://doi.org/10.1021/acs.inorgchem.1c01622
Published August 20, 2021

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Abstract

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Increasing attention has been recently devoted to 89Zr(IV) and 68Ga(III) radionuclides, due to their favorable decay characteristics for positron emission tomography (PET). In the present paper, a deep investigation is presented on Ga(III) and Zr(IV) complexes with a series of tri-(H3L1, H3L3, H3L4 and desferrioxamine E, DFOE) and tetrahydroxamate (H4L2) ligands. Herein, we describe the rational design and synthesis of two cyclic complexing agents (H3L1 and H4L2) bearing three and four hydroxamate chelating groups, respectively. The ligand structures allow us to take advantage of the macrocyclic effect; the H4L2 chelator contains an additional side amino group available for a possible further conjugation with a biomolecule. The thermodynamic stability of Ga(III) and Zr(IV) complexes in solution has been measured using a combination of potentiometric and pH-dependent UV–vis titrations, on the basis of metal–metal competition. The Zr(IV)-H4L2 complex is characterized by one of the highest formation constants reported to date for a tetrahydroxamate zirconium chelate (log β = 45.9, pZr = 37.0), although the complex-stability increase derived from the introduction of the fourth hydroxamate binding unit is lower than that predicted by theoretical calculations. Solution studies on Ga(III) complexes revealed that H3L1 and H4L2 are stronger chelators in comparison to DFOB. The complex stability obtained with the new ligands is also compared with that previously reported for other hydroxamate ligands. In addition to increasing the library of the thermodynamic stability data of Ga(III) and Zr(IV) complexes, the present work allows new insights into Ga(III) and Zr(IV) coordination chemistry and thermodynamics and broadens the selection of available chelators for 68Ga(III) and 89Zr(IV).

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Synopsis

Solution equilibria studies on Ga(III) and Zr(IV) complexes with a series of tri- and tetrahydroxamate ligands are presented. For this purpose, the rational design and synthesis of two cyclic complexing agents bearing three and four hydroxamate chelating groups was performed. The thermodynamic and speciation studies allow a discussion of the structure−complex stability dependence. The Zr(IV)-tetrahydroxamate complex is characterized by one of the highest formation constants reported to date for a hydroxamate zirconium chelator.

Introduction

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Recent research confirms an increasing interest in the use of gallium and zirconium radioiosotopes for medical diagnostic techniques such as PET or single-photon emission computed tomography (SPECT). (1−8)
The interest in the use of 68Ga (t1/2 = 1.13 h, Eβ+avg = 830 keV, 89%) for clinical PET comes from the accessibility of its production via an easily portable and long-lived 68Ge/68Ga generator system. (9) The favorable decay characteristics of 89Zr (t1/2 = 78.4 h, Eβ+avg = 395.5 keV, 23%) allow high PET image resolution to be obtained, since the sufficiently long half-life is an optimal match for the pharmacokinetics of most monoclonal antibodies. (10)
To be applied to molecular imaging, the metal isotope must be converted into a radiolabeled probe that can specifically reach the target of interest in vivo and remain there long enough to be detected. Therefore, the metal ion must be bound by an efficient chelator to overcome metal hydrolysis and transchelation, and linked to a biologically active targeting molecule, to be properly directed to the desirable molecular target in vivo.
To the best of our knowledge, the most widely used chelator for 68Ga is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). (11) In 2016 the FDA approved a 68Ga-DOTATATE (NETSPOT) kit for the preparation of a 68Ga-DOTATATE injection; (12) clinical trials revealed the superiority of 68Ga-DOTATATE with respect to 111In-pentetreotide in imaging neuroendocrine tumors. (13) Currently, the most successfully used 89Zr(IV) chelator is DFOB, but some decomposition has been observed over time in vivo, and 89Zr slowly accumulates in bones. (14−16)
Many chelators have been already suggested for 68Ga and 89Zr on the basis of in vivo assays. (14,17−23) While scientists are currently devoting considerable efforts toward the design of more efficient 89Zr and 68Ga chelators by increasing the in vivo stability of the corresponding complexes, the solution equilibrium chemistry, especially of Zr(IV) systems, has still rarely been investigated. (2,24−27) Solution studies on the coordination chemistry and formation constants of Zr(IV) complexes are not trivial for several reasons: an extremely high thermodynamic stability (requiring application of indirect competition methods with the use of other strong ligands with known stability constants), strong hydrolysis (occurring over almost the entire pH range), and the lack of spectral activity of the complexes. On the other hand, knowledge of the speciation of such complexes, especially at physiological pH, could provide information concerning the actual chemical form of the complex in biological media, and this can contribute to both a better understanding of the in vivo speciation and an explanation of the differences in the biological activity.
Our laboratory has recently reported the thermodynamic properties of Zr(IV)-DFOB complexes, suggesting the formation of three mononuclear complexes, i.e. [ZrHL]2+ [ZrL]+, and [ZrLH–1], over the pH range 1–11. (24) The stability constants and pZr value determined for the Zr(IV)-DFOB system place DFOB among the best Zr(IV) chelators, although the formation of six-coordinate unsaturated complexes (i.e., with the coordination sphere of Zr(IV) completed by two water molecules (28) or hydroxide ligands (29)) and the susceptibility of coordinated water molecules to deprotonation were suggested to be the reason for the in vivo lability of 89Zr(IV)-DFOB complexes. The thermodynamic stability of Zr(IV)-DFOB complexes is in line with in vivo research (15,16,30,31) and also with Holland’s recent DFT calculations, (32) indicating that our experimental approach was appropriate.
By capitalizing upon our earlier works on siderophore mimics, (33−36) in this work we have designed, synthesized, and fully characterized tri- and tetrahydroxamic H3L1 and H4L2 chelators (Scheme 1), analogues of DFOE, (37) and their Ga(III) and Zr(IV) complexes. In addition, the physicochemical properties of Zr(IV) complexes with three further trihydroxamic ligands, i.e. H3L3 (FOXE 2-5), (38)H3L4 (T4), (35) and DFOE (Scheme 1), were also investigated for the sake of comparison. The ligands employed here were selected to investigate the influence of some structural elements on the physicochemical properties of Zr(IV) complexes: i.e., (i) the number of binding groups required to complete the coordination sphere of the metal cation; (ii) the possible advantage of the macrocyclic effect; (iii) the size of the ligand cavity, which should be large enough to minimize ring strain; (iv) the symmetry of the ligand, which could limit the probability of a complex challenge. Ga(III) (and Fe(III)) binding to all of these ligands was also performed and will be discussed here, as the relation between the ligand structure and the stability of the complexes has been much more studied and is better understood for trivalent metal ions. Moreover, Fe(III) complexes are used as a tool to determine the thermodynamic stability of Ga(III) and Zr(IV) analogues.

Scheme 1

Scheme 1. Structures of the Ligands Investigated and Discussed in This Paper
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According to DFT studies, to minimize the ring strain, the cyclic tetrahydroxamic ligand should consist of a minimum of 36 atoms, which gives at least 7 chemical groups or 8 bonds. (39,40) The tetrahydroxamic ligand H4L2, designed to completely saturate the oxophilic coordination sphere of Zr(IV), meets this criterion, possessing at least 9 bonds between binding groups. Of note, H4L2 has been designed with the aim of introducing in the chelator a primary amine group, useful to improve the solubility of the ligand but, primarily, to allow the easy conjugation of the chelator to a targeting molecule for future in vivo studies. Trihydroxamic H3L1 is a symmetrical, macrocyclic ligand, comprising 9 bonds between binding groups; it allows the determination and direct comparison of the influence of the fourth binding group of H4L2 on Zr(IV) stability. This ligand also reveals the effect of the shortening of the chain in comparison to DFOE, H3L3, and DFOB, all with 10 bonds (Scheme 1). Tripodal H3L4, used earlier as a good mimic of a ferrichrome siderophore, was investigated here in order to compare its Zr(IV) binding capacity to those of other tri- and tetrahydroxamic ligands. (35) In H3L1, H4L2, and H3L3 (38) we have used retrohydroxamic units, with a reversed order with respect to the native hydroxamic moiety.
Until now, the stability constants for tetrahydroxamate Zr(IV) complexes have only been estimated from computational calculations (32) for linear DFO* (log β[Zr(DFO*)] = 51.56) and cyclic CTH36 (log β[Zr(CTH36)] = 52.84). DFO* (41) and CTH36 (39) possess 10 and 8 bonds between two hydroxamic groups, respectively.
Therefore, an experimental verification of the order of the stability increase between tri- and tetrahydroxamic chelators should be very useful. The same is true for examining the effects of a number of other variable structural elements, such as the symmetry of the structure and the length of the chain between the hydroxamate binding units. Although the thermodynamic formation constants do not predict in vivo stability and kinetic inertness, they are very useful and interesting parameters that may allow for a better design of efficient chelators for Zr(IV) ions.

Results and Discussion

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Design and Synthesis of the Ligands

The synthetic approaches for the preparation of H3L1 and H4L2 are depicted in Schemes 2 and 3, respectively. The hydroxamate-based monomers protected either at the carboxylic group as an ethyl ester (5) or at the amino function with Boc (6) were employed as common synthetic precursors of H3L1 and H4L2. The building blocks 5 and 6 were synthesized by starting from O-benzylhydroxylamine hydrochloride that was first reacted with di-tert-butyl dicarbonate to give compound 1 and then alkylated with ethyl 4-bromobutyrate in the presence of NaH to provide compound 2 (Scheme 2). Boc removal with TFA furnished the intermediate 3, which was coupled with Boc-protected γ-aminobutyric acid using HATU as a coupling reagent. This allowed us to obtain the orthogonally protected 4 as a suitable precursor of both 5 and 6, which were alternatively isolated after acidic and basic treatments, respectively.

Scheme 2

Scheme 2. Synthetic Pathway of the Ligand H3L1a
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aReagents and conditions: (i) (Boc)2O, K2CO3, H2O/dioxane; (ii) ethyl 4-bromobutyrate, NaH, DMF; (iii) TFA; (iv) Boc-γ-aminobutyric acid, HATU, DIPEA, DMF; (v) LiOH, H2O/dioxane; (vi) 5, HATU, DIPEA, DMF; (vii) 6, HATU, DIPEA, DMF; (viii) HATU, DIPEA, DMF; (ix) H2, Pd/C, MeOH.

Scheme 3

Scheme 3. Synthetic Pathway of the Ligand H4L2a
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aReagents and conditions: (i) TFA; (ii) Z-Lys(Boc)-OH, HATU, DIPEA, DMF; (iii) LiOH, H2O/dioxane; (iv) HATU, DIPEA, DMF; (v) H2, Pd/C, MeOH.

For the synthesis of H3L1, 5 and 6 were linked together via a standard amide coupling followed by TFA treatment to give 8. The reaction with another unit of 6 gave 9 as the linear protected precursor of H3L1. A head–tail HATU-mediated cyclization of 9 was realized under dilute conditions (0.5 mg/mL) after removal of the protection at the C and N terminal positions. A final Pd-catalyzed hydrogenolysis afforded the desired macrocycle H3L1 in good yields.
For the synthesis of the tetrahydroxamic derivative H4L2 (Scheme 3), an appropriate hydroxamate-bearing lysine derivative was first prepared as a building block (14). This was obtained by a coupling reaction between 5 and a residue of Z-Lys(Boc)-OH followed by saponification of the ester function. The monomeric unit 14 was coupled to 12, which resulted from TFA-mediated Boc deprotection of 9. The resulting intermediate 15 underwent head–tail HATU-mediated cyclization after removal of the protections at the C and N terminal positions as described above, leading to 16. In addition in this case, the final macrocycle was obtained after Pd-catalyzed removal of the benzyl functions from the hydroxamic groups. These conditions led also to CBz cleavage, leaving the free amino group suitable for future bioconjugation strategies.
H3L1, H4L2, and their precursors were fully characterized by 1H and 13C NMR (see the Supporting Information). The degree of purity of the final product was evaluated by analytical HPLC assays (see the Supporting Information), showing a purity of higher than 95%.

Thermodynamic Solution Studies

Ligand Protonation Constants

The metal affinity of a ligand depends on its acid–base properties; therefore, the protonation equilibria of H3L1 and H4L2 were first investigated. The proton-dissociation processes of the ligands were followed by potentiometric titrations in the pH range 2–11. The hydrolytic stability of the ligands was monitored by a second titration of the same sample with NaOH, following back-acidification of the initially titrated sample. The recorded titration curves were almost exactly superimposed; consequently, the protonation constants calculated from the two consecutive titrations were found to be equal within 0.05 log unit, which indicated that no decomposition occurred.
Data analysis allowed the determination of three protonation constants for H3L1 and four protonation constants for H4L2; all of them fall in the pH range 8–10 and can be attributed to the hydroxamate groups (Table 1). For each ligand, the protonation constants were assigned by comparing them with the known protonation constants of hydroxamate ligands. (24,35,37,42) When the changes in temperature, ionic strength, and ligand structures are allowed for, the protonation constants of H3L1 and H4L2 are in excellent agreement with the literature values of the cyclic hydroxamate siderophore DFOE (log K1 = 9.89, log K2 = 9.42, and log K3 = 8.65) reported by Anderegg et al. (37) The pH-dependent UV–vis titrations of H3L1 and H4L2 (Figure S1) revealed the development of a strong band with λmax = 230 nm, when the pH was increased from 7 to 11, which is usually observed for a hydroxamic group deprotonation process. (24,43) The amino group protonation of H4L2 was not detectable in the experimental pH range. We are aware that the electron-withdrawing character of both the −NH3+ and −NHOH groups affects the acidity of the other group in comparison with that in the related nonsubstituted compound H3L1. As was previously reported in the example of α- and β-alanine hydroxamic acids, the amino group may be more acidic than the hydroxamic group, or vice versa. According to the literature, the amino group may be more acidic than hydroxamic one, or vice versa. (44,45) On the basis of the protonation constant of the amino group of DFOB (log Kamine = 10.97 (24)), we assume for H4L2 that it is >11. However, we keep in mind that the deprotonation processes of amino and hydroxamate groups overlap and cannot be distinguished by potentiometry. To elucidate the protonation microequilibria of H4L2, 1H NMR titrations should be carried out. However, such a precise analysis is not needed for the determination of the stability of H4L2-metal complexes and therefore was not performed. The species distribution diagrams of H3L1 and H4L2 are presented in Figure S2. The protonation constants of H3L3 and H3L4 were reported elsewhere (Table 1). (35,38)
Table 1. Protonation Constants of Ligands and log β Values of Complexes Formed with Fe(III), Ga(III), and Zr(IV)a Ions
 H3L1H4L2H3L3 (FOXE 2–5) (38),bH3L4 (T4) (35),cDFOE (36,38),b
assigntlog βlog Klog βlog Klog βlog Klog βlog Klog βlog K
LH9.89(1)d9.89d10.06(1)d10.06d9.899.899.509.509.899.89
LH219.13(1)d9.24d19.65(1)d9.59d19.3119.3118.478.9719.319.42
LH327.44(1)d8.31d28.59(1)d8.94d27.9627.9626.738.2627.968.65
LH4  36.77(1)d8.18d      
 H3L1H4L2H3L3 (FOXE 2–5) (38),bH3L4 (T4) (35),cDFOE (36,38),b
 log βpKalog βpKalog βpKalog βpKalog βpKa
[FeH2L]  39.96(3)e3.00d      
    3.12d      
[FeHL]31.80(3)e3.21d36.96(7)e   29.822.48  
  3.1d36.82(6)d       
[FeL]28.59(2)e   32.4332.4327.34 32.43 
 28.7(1)d         
           
[GaH2L]  38.11(3)f2.20d      
    2.15(4)e      
[GaHL]29.44(7)f2.65d35.91(7)d8.13d  27.92(3)f2.36d  
  2.53(2)e     2.24(1)e  
[GaL]26.79(2)d9.79d27.60(6)d 29.7929.7925.56(1)d 29.79 
           
[ZrHL]  45.9(3)f2.6d  36.4(5)f2.15d  
    2.2(1)e   2.2(2)e  
[ZrL]34.8(2)f5.48d43.3(1)d 35.46(5)f7.03d34.25(5)d5.43d35.54(9)f 
  5.34(5)e   7.2(1)e 5.5(2)e  
[ZrLH–1]29.32(8)d   28.31(7)d 28.8(1)d   
a

Charges omitted for clarity.

b

The protonation constants of the ligands together and the stability constants of Fe(III) and Ga(III) complexes were taken from the literature.

c

The protonation constants of the ligands and the stability constants of Fe(III) complexes were taken from the literature.

d

Determined by potentiometric titrations.

e

Determined by pH-dependent UV–vis titrations.

f

Determined by metal–metal competition titrations; all measurements performed at 25 °C and I = 0.1 M NaClO4.

ESI-MS: Stoichiometry Evaluation

The stoichiometry of the complexes was evaluated by ESI-MS, frequently used as the first step in the determination of metal complex stoichiometry and already previously employed. (35,46,47) When the fact that ESI-MS is not able to distinguish the ionizable protons in the species is taken into account, this method can be successfully applied to evaluate the metal to ligand stoichiometry directly from the m/z values. For all of the investigated systems, an analysis of the ESI-MS data (collected for various metal to ligand molar ratios) revealed only mononuclear complexes (for details see Figure S3 and Table S1 in the Supporting Information).

Determination of Complex Stability

To evaluate the thermodynamic stability of Ga(III) and Zr(IV) complexes of the investigated ligands, the binding properties and speciation of Fe(III) complexes have first been determined (all the details are given in the Supporting Information). There are several reasons for this protocol. First, (i) the electron configuration of Ga(III) (d10) and Zr(IV) (d0) hinders the attainment of spectral information for most of the complexes. Furthermore, (ii) both metal ions are highly acidic and they are readily hydrolyzed over almost the entire pH range. In addition, (iii) the high charge to size ratio of the Zr(IV) ion implies the formation of complexes with an exceptional thermodynamic stability (already at very low pH); as a consequence, the stability constants cannot be directly determined using standard potentiometric titrations. Thus, the thermodynamic stability constants of the Fe(III)-H3L1 and Fe(III)-H4L2 systems were first determined (using a combination of potentiometric and pH-dependent UV–vis titrations), followed by Fe(III)–Ga(III) and Fe(III)–Zr(IV) metal–metal competition experiments. Of importance, in order to get accurate results, an experiment where two metal ions compete for a ligand must fulfill two basic requirements: (i) one of the metal chelates should have a strong absorption band in teither he visible or ultraviolet region of the spectrum, with an extinction coefficient much different from that of the free metal ion, while the second metal complex should not absorb in the same region of the spectrum; (ii) the equilibrium constant for the competition reaction must not be too small or too large. These requirements are fulfilled in the competition experiments between Fe(III) and Ga(III) for both ligands. In the case of Fe(III)–Zr(IV) competition, the difference between the stability constants of Fe(III) and Zr(IV) complexes was too high; thus, an additional competitor ligand—nitrilotriacetic acid (NTA)—was used in the titrations.
NTA is one of the most widely investigated and often used chelating agents. (48,49) It was selected for the current studies, as both Zr(IV)-NTA and Fe(III)-NTA complexes remain stable until pH 4, even at a metal to ligand molar ratio of 1:1. (27,48) Moreover, as an additional competing agent, NTA prevents the hydrolysis of the metal ions present in solution and weakens the transchelation observed in the case of H3L1 and H4L2 Fe(III) complexes titrated directly by Zr(IV) ions. The accuracy of the metal–metal competition titration with NTA was checked on the Zr(IV)-DFOB system, for which experimental data gave log β[ZrHDFOB] = 46.1(2) (see the Supporting Information), in very good agreement with our recently reported data (log β[ZrHDFOB] = 47.7, allowing for changes in the ionic strength). (24) Similar competition procedures are widely used for the evaluation of the stability constants of spectroscopically blind metal complexes. (25,50)

Ga(III) Complex Formation Equilibria

The evaluation of thermodynamic stability constants of Ga(III) and Zr(IV) complexes with H3L1, H4L2, and H3L4 started from pH-dependent UV–vis spectrophotometric titrations in the pH range 1–11 (Figure 1 and Figure S7, respectively). The spectral changes in the 200–300 nm range, corresponding to the hydroxamate group protonation state, were monitored. (51) The appearance of a band with a maximum at 225–230 nm with an increase in pH was observed and associated with complex formation.

Figure 1

Figure 1. UV spectra of Ga(III)-H3L1 (a, c) and Ga(III)-H4L2 (b, d) systems at a metal to ligand molar ratio of 1:1 in the pH range 1.0–11.0. Conditions: cL1 = 0.05 mM, cL2 = 0.05 mM, 0.1 M NaClO4, T = 25 °C.

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The pH-dependent UV–vis titration experiments for the Ga(III)-H3L1 system revealed an increase in a 230 nm transition band starting from pH 1 up to pH 4.4, with pKa = 2.53(2) (Figure 1 and Table 1). For the Ga(III)-H4L2 system, the 225 nm band development was observed starting from pH 1 up to pH 3.5, with pKa = 2.15(4) (Figure 1 and Table 1), while for Ga(III)-H3L4, it continued to increase up to pH 4.6 with pKa = 2.36(1) (Figure S7 and Table 1). Similar behavior was observed in the acidic range for Ga(III)-DFOB (and was assigned to two protonation constants of the complex, pKa1 = 0.78 and pKa2 = 1.10 (43)) and Th(IV)-DFOB (with pKa = 1.9 (42)) complexes. For the three investigated systems, UV spectra did not reveal any additional changes up to pH 9, indicating that the fully coordinated complex [GaL], in the case of the Ga(III)-H3L1 and Ga(III)-H3L4 systems, and the monoprotonated [GaHL2]+ complex, in the Ga(III)-H4L2 system, are the dominant species in solution. When the pH was increased to above 9, an increase in absorbance below 240 nm was observed (Figure 1 and Figure S7). Considering that the spectrophotometric titrations of the free ligands showed the same absorption curves at higher pH, we can suppose that the sharp band at 230–240 nm arises from unbound deprotonated hydroxamate chromophores. Most probably, at higher pH the complex is dissociated, yielding the hydrolyzed gallium species [Ga(OH)4]−. A similar observation has already been noted for hydroxamate ligands. (43,52)
Assuming the domination of the [GaHL1]+ complex below pH 2, its stability was determined by metal–metal competition titrations, (i) Fe(III)-H3L1 + Ga(III) and (ii) Ga(III)-H3L1 + Fe(III), both performed at pH 1.5. This pH was chosen in order to prevent the hydrolysis of the free metal ions and decomposition of the ligand, which is common for hydroxamic acids at a very acidic pH. (37,51) Upon addition of Ga(III) (up to 600 equiv) to the Fe(III)-H3L1 solution, the UV–vis band of [FeHL1]+ (λmax = 470 nm, Figure 2a) slowly disappeared as a result of the [GaHL1]+ complex formation. In the next competition experiment, the appearance of an LMCT transition band (λmax = 470 nm) upon addition of Fe(III) to the Ga(III)-H3L1 solution was observed (Figure 2b). The data refinement using H3L1 protonation constants (Table 1), Fe(III)-H3L1 stability constants (Table 1), and stability constants of hydroxocomplexes of both metals (see the Experimental Section) yielded a log β[GaHL1]+ value of 29.44(7) for Fe(III)-H3L1 + Ga(III) (Table 1) and of 28.3(6) in the case of Ga(III)-H3L1 + Fe(III) competition titrations.

Figure 2

Figure 2. UV–vis metal–metal competition experiment for (a) Fe(III)-H3L1+Ga(III) (cFe(III) = 0.075 mM, cL = 0.075 mM) and (b) Ga(III)-H3L1+Fe(III) (cFe(III) = 0.08 mM, cL1 = 0.08 mM) systems at pH 1.5, I = 0.1 M (NaClO4), and T = 25 °C.

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For the Ga(III)-H4L2 system, [GaH2L2]+ was assumed to be the most abundant species at pH 1.5, and its stability was again determined via (i) Fe(III)-H4L2 + Ga(III) and (ii) Ga(III)-H4L2 + Fe(III) titrations (Figure S8). The refinement of the titration data yielded log β[GaH2L2]+ = 38.11(3) and 39.06(4) for Fe(III)-H4L2 + Ga(III) and Ga(III)-H4L2 + Fe(III) competition titrations, respectively.
For the Ga(III)-H3L4 system, [GaHL4]+ was assumed to be the major complex at pH 1.5, and its stability was determined via an Fe(III)-H3L4 + Ga(III) competition titration (Figure S9). The refinement of the titration data yielded log β[GaHL4]+ = 27.92(3).
For the Ga(III)-H3L1 and Ga(III)-H4L2 systems, the constants obtained with the two types of titrations are not far from each other but are significantly different. Most likely, the constants measured by means of Ga(III)-H3L1/H4L2 + Fe(III) competition experiments are endowed with a greater error, attributable to the overlapping absorption of free iron, present in excess. Therefore, we retained the constants obtained from the Fe(III)-H3L1/H4L2 + Ga(III) competition experiments (log β[GaHL1]+ = 29.44(7) and log β[GaH2L2]+ = 38.11(3)) as fixed values in the subsequent potentiometric data calculations. The best-fitted speciation model for Ga(III)-H3L1 and Ga(III)-H3L4 systems revealed the presence of one additional complex, [GaL], with log β values of 26.79(2) and 25.56(1), respectively (pKa1 = 2.65 for Ga(III)-H3L1 and 2.36 for Ga(III)-H3L4; Table 1). For the Ga(III)-H4L2 system, in addition to [GaH2L2]+, [GaHL2] and [GaL2]− complexes were found with log β[GaHL2] = 35.91(7) and log β[GaL2]− = 27.60(6) (pKa1 = 2.20 and pKa2 = 8.13; Table 1). The pKa2 value of 8.13 is in good agreement with the pKa values of the free ligand (Table 1) and could be assigned to the deprotonation of an unbound hydroxamate group.

Zr(IV) Complex Formation Equilibria

The UV–vis titrations of Zr(IV)-H3L1 equimolar solution over the pH range 0.1–11 (Figure 3a,c) showed a well-defined absorbance band in the 200–300 nm range. The significant changes and the presence of an isosbestic point observed when the pH was increased from 0.1 to 0.9, allowed us to calculate a pKa1 value of 0.4(2); afterward, the observed 230 nm shoulder remained stable up to pH 4.6. When the pH was increased to 7.0, the development of a 220 nm shoulder with an isosbestic point at 230 nm was observed, characterized by pKa2 = 5.34(5). From pH 7.0, the spectra do not reveal any significant changes until pH 9.0, where the hydrolysis probably started. Since information about hydrolysis of the hydroxamate ligands at acidic pH has beenwidely described in the literature, (51,52) pKa1 = 0.4 indicates that the three hydroxamate groups are dissociated and therefore most probably bound to the Zr(IV) ion, already at pH <2.0. Assuming the formation of only monomeric complexes, the stability of [ZrL1]+ was determined via UV–vis competition batch experiments, using a Zr(IV)-NTA solution as a competing system for the Fe(III)-H3L1 complex (Figure 4a). The large LMCT band centered at 470 nm characteristic of dihydroxamate [FeHL1]+ species decreased gradually, and the refinement of the titration data, using the Fe(III)-H3L1 stability constants (Table 1) together with the Fe(III) and Zr(IV) hydrolysis constants, yielded a log β[ZrL1]+ value of 34.8(2).

Figure 3

Figure 3. UV spectra of the Zr(IV)-H3L1 (a, c) and Zr(IV)-H4L2 (b, d) systems at a metal to ligand molar ratio of 1:1 in the pH range 0.1–11 Conditions: cL1 = 0.05 mM, cL2 = 0.037 mM, 0.1 M NaClO4.

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Figure 4

Figure 4. UV–vis spectra of competition titrations of the Fe(III)-H3L1 + Zr(IV)-NTA (cFe(III) = 0.098 mM, cL1 = 0.098 mM) (a) and Fe(III)-H4L2 + Zr(IV)-NTA (cFe(III) = 0.055 mM, cL2 = 0.055 mM) (b) systems at pH 1.5 with 0.1 M NaClO4.

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The UV–vis titration data of the Zr(IV)-H4L2 system (Figure 3b,d) showed the development of a 230 nm shoulder upon an increse in pH from 0.1 to 3.0 and allowed us to calculate a pKa value of 2.2(1). Further, the spectra did not reveal any significant changes over the pH range 3.1–9.0, wherethe hydrolysis probably started. [ZrHL2]+ was assumed to be the major complex at pH 1.5, and its stability was determined via Fe(III)-H4L2 + Zr(IV)-NTA (Figure 4b) competition titrations. The refinement of the titration data yielded log β[ZrHL2]+ = 45.9(3).
The UV–vis spectra of the Zr(IV)-H3L3 and Zr(IV)-H3L4 systems were very similar to the spectra described above (Figure S11); at a pH of around 7 a slight blue shift of the 230 nm band appeared together with the isosbestic point, allowing us to calculate pKa = 7.2(1) for Zr(IV)-H3L3 and 5.5(2) for Zr(IV)-H3L4 (Table 1). For Zr(IV)-H3L4, an additional pKa = 2.2(2) was calculated, probably corresponding to the formation of the three-hydroxamate complex (Table 1). An evaluation of the competition titration data for Fe(III)-H3L3 + Zr(IV)-NTA revealed log β[ZrL3]+ = 35.46(5), while for Fe(III)-H3L4 + Zr(IV)-NTA log β[ZrHL4]2+ = 36.4(5) (Figure S12 and Table 1). Additionally, we have performed the same kind of titration for Fe(III)-DFOE + Zr(IV)-NTA, which gave log β[ZrDFOE]+ = 35.54(9) (Figure S12 and Table 1). It is worth noting that, during the competition titrations for the H3L3 ligand and DFOE, a decrease in the 430 nm (typical for three-hydroxamate iron complexes) band was observed, confirming that all three hydroxamate groups are bound already at pH <2. (38)
Using the constants obtained from competition titrations (log β[ZrL1]+ = 34.8(2) and log β[ZrHL2]+ = 45.9(3)) as fixed values, the potentiometric data were processed. The best-fitted speciation models revealed the presence of one additional complex for the Zr(IV)-H3L1 system ([ZrL1H–1], log β[ZrL1H–1] = 29.32(8)) and one additional complex for the Zr(IV)-H4L2 system ([ZrL2], log β[ZrL2] = 43.3(1)) (Table 1).
The [ZrL1]+ complex dominates the solution from pH 3 up to pH ∼5, where its deprotonation to [ZrL1H–1] occurs, with pKa = 5.48 (Figure S13a). These results are in line with the spectroscopic data (pKa = 5.34(5)) and could be ascribed to the dissociation of a water molecule from the coordination sphere of the Zr(IV) ion. For the Zr(IV)-EDTA system, the pKa attributed to the deprotonation of a water molecule is 6.2, (27) while for Zr(VI)-DFOB it is 6.36. (24)
The stability constants calculated for the Zr(IV)-H4L2 system reveal pKa = 2.6, which is in good agreement with the spectroscopic data (pKa = 2.2(1)) and could be assigned to the deprotonation of the hydroxamic group and the formation of a fully coordinated tetrahydroxamate complex. The [ZrL2] complex dominates the solution from pH 3 up to pH ∼9, when the dissociation of the complex probably occurs (Figure S13b).
An evaluation of the potentiometric data of Zr(IV)-H3L3 (with log β[ZrL3] = 35.46 fixed) revealed the presence of an additional complex, [ZrL3H–1] (log β[ZrL3H–1] = 28.35(5)) (Figure S13c), while for Zr(IV)-H3L4 (with log β[ZrHL4] = 36.4 fixed), there are two additional complexes, [ZrL4] (log β[ZrL4] = 34.25(5)) and [ZrL4H–1] (log β[ZrL4H–1] = 28.8(1)) (Figure S13d). For both systems, the pKa values calculated from potentiometric experiments are in excellent agreement with those from the pH-dependent UV–vis titrations (Table 1) and match the data obtained for the whole series of hydroxamate-based ligands. Of importance, the pKa value attributed to the deprotonation of a water molecule in the Zr(IV)-H3L3 system (pKa = 7.2) is higher than those for Zr(VI)-DFOB (pKa = 6.36) (24) and Zr(IV)-H3L1 (pKa = 5.48), suggesting that a longer linker between the binding groups is advantageous. In Zr(IV)-H3L4, this process is not observed, as all the coordinating positions of the Zr(IV) ion are occupied by four hydroxamate ligands.

Ligand Sequestering Ability

Despite a large variety of PET chelators synthesized and tested in order to provide strong coordination of Ga(III) and Zr(IV) in vivo, until now it is has been hard to avoid the release of these metal ions in the body. Here we report two new Ga(III) and Zr(IV) hydroxamate chelators, designed to achieve an efficient sequestering of these metal ions but also to understand how the cyclization and the introduction of an additional hydroxamate group influences the stability of Zr(IV) complexes. Therefore, it is important to evaluate and compare the Ga(III)- and Zr(IV)-sequestering abilities of H3L1 and H4L2 with those of other chelators. However, the direct comparison of the stability constants of metal complexes is not straightforward, and other tools taking into account all the physicochemical properties of the ligands, i.e. their denticity, coordination modes, and acid–base properties, should be used. (52) In order to reliably compare the chelating abilities of H3L1 and H4L2 toward Ga(III) and Zr(IV) ions, the pM values were calculated. pFe was originally introduced by Raymond for the comparison of iron-siderophore systems; (53) pGa = −log[Ga(III)free] and pZr = −log[Zr(IV)free] were calculated at pH 7.4 with cL = 10 μM and cGa(III)/Zr(IV) = 1 μM (Table 2).
Table 2. pGa and pZr Values for Various Synthetic and Natural Chelatorsa
ligandpGapZrchelating groups and ligand geometry
H3L122.532.43 hydroxamate groups in a cyclic arrangement
H4L222.337.04 hydroxamate groups in a linear arrangement
H3L325.431.53 hydroxamate groups in a cyclic arrangement
H3L421.932.63 hydroxamate groups in a linear arrangement
DFOB21.6 (43)32.2 (24)3 hydroxamate groups in a linear arrangement
DFOE25.2 (38)31.03 hydroxamate groups in a cyclic arrangement
DOTA20.5 (11) 4 macrocyclic amine groups and 4 carboxylate pendant arms
NOTA27.4 (54) 3 macrocyclic amine groups and 3 carboxylate pendant arms
H2hox28.4 (55) 2 8-hydroxyquinoline groups and 2 amino groups in a linear arrangement
PrP923.1 (56) 3 macrocyclic amine groups and 3 carboxylate pendant arms
HBED28.0 (57) 2 hydroxyaromatic donor groups and 2 carboxylate pendant arms
THPN 42.7 (2)4 3-hydroxy-4-pyridinone pendant arms
3,4,3-LI-HOPO 44.0 (25,58)4 1-hydroxy-2-pyridinonates in a linear arrangement
DTPA 32.3 (25,59)3 amino groups in linear arrangement and 4 carboxylate pendant arms
a

Values (re)calculated at pH 7.4 and cL = 10 μM and cGa(III)/Zr(IV) = 1 μM, on the basis of the protonation and stability constants given in original publications. The hydrolysis constants of Ga(III) and Zr(IV) ions were taken from the literature (60) and are given in the Experimental Section.

The pGa values for Ga(III)-H3L1 and Ga(III)-H4L2 systems are on the same order of magnitude as those of the well-known gallium chelators DFOB and PRP9 but are higher than that of the clinically used DOTA (Table 2). On the other hand, H2hox, (55) NOTA, (54) and HBED (57) present much higher Ga(III) chelating efficacy. The observed effect reflects the differences in the number and type of chelating groups present in the ligands (and therefore the number and type of donor atoms), as well as the ligand dimensions. Of importance, there is only about a 1 order of magnitude increase between pGa values for the linear trihydroxamate ligand DFOB and the cyclic tri- and tetrahydroxamates H3L1 and H4L2, respectively. This indicates that the cyclization of the structure only slightly influences the complex stability. It is worth underlining that H3L1 has shorter spacers between the hydroxamate groups (9 bonds) in comparison to those in DFOB and DFOE (10 bonds). In H3L3, the spacers have the same length of 10 bonds and the Ga(III) complexes reach the stability of DFOE. (38) Additionally, there is almost no difference in complex stability between Ga(III)-H3L1 and Ga(III)-H4L2, even though the cavity of H4L2 is much larger than that of H3L1, allowing higher flexibility and entropy of the complex structure.
For the Zr(IV) complexes of trihydroxamate H3L1, H3L3, and H3L4 systems, the pZr value is on the same order as those for DFOB (24) and DTPA (25) chelators. This suggests that ligand cyclization does not provide any increase in complex stability with respect to its linear analogue; for H3L3 and DFOE one may even claim a slight decrease in relation to DFOB. A similar conclusion was drawn from the comparison of Zr(IV) complexes of DFOB with fusarinine C (FCS, Scheme 1), where only minor differences in complex stability were observed in in vivo studies. (61) An elongation of the chain between hydroxamate binding units from 9 bonds in H3L1 to 10 in H3L3 is not reflected in the corresponding pZr values. The flexibility of the tripodal H3L4 ligand does not produce a higher stability of Zr(IV) complexes. Of importance, the pZr value for the tetrahydroxamate analogue H4L2 is >4 units higher than the values calculated for Zr(IV)-DFOB and Zr(IV)-H3L1 systems, reflecting the higher affinity of tetrahydroxamate H4L2 for Zr(IV), as expected. This feature was already observed in biological studies of other tetrahydroxamate chelators. (4,39,41) The high thermodynamic stability is certainly the result of the involvement of the fourth hydroxamate coordinating group of the ligand moiety.
The H3L1 and H4L2 ligands are very good examples to directly compare the stability of Zr(IV) complexes formed with tri- and tertrahydroxamate compounds. For these two ligands, we observe an increase in log β of 8.5 orders of magnitude for the Zr(IV)-H4L2 complex with respect to Zr(IV)-H3L1 (Table 1). However, this increase is lower than that predicted from the computational calculations performed by Holland (32) for tri- and tetrahydroxamate chelators: i.e., DFOB (log β[Zr(DFOB)] = 41.20) versus linear DFO* (41) (log β [Zr(DFO*)] = 51.56) and cyclic CTH36 (39) (log β[Zr(CTH36)] = 52.84). Also, log β[ZrL2] = 43.3(1) does not reach the values predicted from the above calculations for eight-coordinate Zr(IV)-DFO* and Zr(IV)-CTH36. Of note, the log β[ZrH(DFOB)OH] value previously determined by us for DFOB (40.04) (24) matches very well the computationally predicted log β[Zr(DFOB)] value (41.20). (32) Still, in the [ZrH(DFOB)OH]+ complex, dominating at pH 6.5–10.5, we have suggested the presence of an unbound protonated amino group and a hydrolyzed water molecule bound to Zr(IV). For the cyclic trihydroxamate ligand H3L1, characterized by 9-bond linkers between its hydroxamate units (Scheme 1), log β[ZrL1] = 34.8(2) is not far from the value estimated for the trihydroxamate cyclic siderophore FSC, (7,62) log β[Zr(FSC)] = 38.92; (32) this difference can be ascribed to the alterations in geometry and dimensions of the ligands. Zirconium is known to form complexes with a complicated geometry of a dodecahedron or square antiprism, (63,64) and numerous DFT studies have revealed that minor variations in ligand geometry (such as a pendant arm elongation or a modification of the ligand cavity size) could result in significant changes in the stability of Zr(IV) complexes. (39,65,66)H4L2 presented in this work possesses four hydroxamate units and amide units in the linker, but a larger cavity size and a significant asymmetry (coming from one much longer linker and with two amides and amino group) with respect to CTH36 (Scheme 1). (32,39) These structural alterations are most probably the reason for the lower thermodynamic stability of H4L2 complexes, as the coordination sphere might not be uniformly closed around the central ion. Unfortunately, the thermodynamic characterization of Zr(IV)-CTH36 complexes has not yey been reported; thus, the pZr value cannot be quantified. Another cyclic hydroxamic ligand, PPDDFOT1, that possesses four hydroxamic groups in a symmetrical arrangement and a cavity size even larger than that of H4L2 (11 bonds between hydroxamic groups) showed superior stability vs DFOB in EDTA challenging assays. (67) These results confirm that the Zr(IV) complex stability is strongly dependent on the ligand geometry and emphasize the demand for a thermodynamic solution study in order to understand this dependence. Other octadentate hydroxy-pyridinone chelators, such as THPN (2) and 3,4,3-LI-HOPO, (25) form the strongest complexes (Table 2). The reason could be not only the type of chelating groups present in the ligands but also the ligand architecture and dimensions.

Conclusions

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In the present work we have developed new chelating agents for the complete saturation of the coordination spheres of Ga(III) and Zr(IV) metals. The trihydroxamic (H3L1) and tetrahydroxamic (H4L2) ligands were successfully synthesized, and the thermodynamic properties of their Ga(III) and Zr(IV) complexes were evaluated. In addition, a series of other synthetic (H3L3, H3L4) and natural (DFOE) compounds was investigated. H3L1 proved to be an efficient Ga(III) chelator, but the stability of its Zr(IV) complexes is about 1 order of magnitude lower than that reported for the Zr(IV)-DFOB system. H4L2 is the first tetrahydroxamate ligand for which the formation constants and speciation with Zr(IV) were experimentally determined. Of importance, it revealed an enhanced stability of 8.5 orders of magnitude (log β[ZrL2]= 43.3, pZr = 37.0) with respect to Zr(IV)-H3L1 (log β[ZrL1]= 34.8, pZr = 32.4), as a consequence of the introduction of a fourth hydroxamate binding unit. However, the stability increase is lower than that predicted by computational calculations for the tetrahydroxamate chelators DFO* (log β[Zr(DFO*)] = 51.56) and CTH36 (log β[Zr(CTH36)] = 52.84), and this effect can be ascribed to the structural alterations of the H4L2 ligand.
Overall, the determination of the thermodynamic stability of metal complexes coupled with a suitable chelator design will help further developments of optimal chelators for PET imaging applications. However we are aware that there are still a great number of tests to do in order for these ligands to be used as a PET chelators, such as radiolabeling and kinetics studies, biodistribution assays, etc. Current efforts are focused on the design and studies of tetrapodal hydroxamate ligands, to interrogate how their shape and size tune the thermodynamic stability of Zr(IV) complexes.
According to the literature, the 89Zr radiolabeling strategies for hydroxamate ligands is usually simple, robust, and relatively rapid. They are performed under mild pH conditions, at room temperature, and take around 1 h for DFOB derivatives on their own without being attached to any targeting vectors and 1–3 h for DFO derivatives attached to targeting vectors, such as trastuzumab. (14,68,69) Cyclic hydroxamate ligands such as C7 (40) and CTH36 (39) (both with 8 bonds between hydroxamate groups) have demonstrated excellent complexation abilities at ambient temperature (>99% complexation after 120 min for C7 and >90% of the activity within 5 min reaction time for CTH36, respectively). The slightly smaller ligands C6 and C5, reported by Guerard et al., (40) appear to be less suitable for radiolabeling, with higher temperatures being required to obtain high complexation yields. The cyclic ligands reported in this paper possess a larger cavity size, with at least 9 bonds between hydroxamate groups, which allows us to assume that the radiolabeling process will be highly efficient and performed under mild conditions. Preliminary radiolabeling of artificial FOXE siderophores with 68Ga, represented here by FOXE 2–5, was achieved after 10 min at room temperature with moderate yields and high specific activities of 68Ga. (38) Further characterization is ongoing.

Experimental Section

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Synthesis

General Considerations

Unless stated otherwise, all commercially available reagents and solvents were of analytical grade. For the synthesis of H3L1 and H4L2, solvents and reagents were purchased from Bachem, BLDpharm, and Fluka. Crude products were purified via flash column chromatography on silica gel (Merck, 230–400 Mesh) or, for compounds 10, 11, 16, and 17, by semipreparative RP-HPLC using a Waters Prep 600 system equipped with a C18 Jupiter column (250 × 30 mm, 300 Å, 15 μm spherical particle size). Gradients were established each time by considering the analytical HPLC profile of the crude product. The column was perfused at a flow rate of 20 mL/min over 30 min with a binary system of solvent A (H2O + 0.1% v/v TFA) and solvent B (60% CH3CN in water +0.1% v/v TFA). Analytical RP-HPLC analyses were performed on a XBridge C18 column (4.6 × 150 mm, 5 μm particle size) using a flow rate of 0.7 mL/min and a linear gradient of acetonitrile (and 0.1% TFA) in water (and 0.1% TFA) from 0% to 100% over 25 min. The mass spectra were recorded on an ESI-Micromass ZMD 2000 instrument. TLC was performed on precoated plates of silica gel F254 (Merck, Darmstadt, Germany). 1H NMR analyses were obtained using a Varian spectrometer (400 MHz) and were referenced to residual 1H signals of the deuterated solvents (δ(1H) 7.26 for CDCl3; δ(1H) 2.50 for DMSO). The following abbreviations are used to describe the shape of the peaks: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet.

Synthesis of tert-Butyl(benzyloxy)carbamate (1)

To an ice-cooled solution of O-benzylhydroxylamine·HCl (4.00 g, 25 mmol) in a 1,4-dioxane/H2O mixture (60 mL, 1/1 v/v) was added K2CO3 (10.37 g, 75 mmol). Boc2O (8.18 g, 37.5 mmol), previously dissolved in dioxane, was then added dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the crude product extracted using ethyl acetate (30 mL) and water (3 × 15 mL). The organic phase was dried over Na2SO4, filtered, and evaporated. Compound 1 (4.86 g, 87% yield) was obtained as a colorless oil, which was used without any further purification. NMR data match those reported in the literature (PMID: 11906271). ESI-MS: calcd for C12H18NO3, 224.28 [M + H]+; found, 224.13 [M + H]+. TR = 19.70 min.

Synthesis of Ethyl 4-((Benzyloxy)(tert-butoxycarbonyl)amino)butanoate (2)

To a solution of 1 (4.86 g, 21.79 mmol) in DMF (15 mL) was added NaH (60% dispersion in mineral oil, 1.20 g, 23.94 mmol). The mixture was initially stirred at rt for 30 min, and then the reaction mixture was warmed to 60 °C and ethyl 4-bromobutyrate was added dropwise. At the completion of the reaction, the solvent was removed, and the residue was extracted with ethyl acetate and water (3 × 30 mL), dried over Na2SO4, and concentrated under vacuum. The product (2) was obtained as a yellowish oil (5.36 g, 73% yield). The NMR data correspond to those in the literature (PMID: 28715615). MS (ESI): calcd for C18H28NO5, 338.20 [M + H]+; found, 360.18 [M + Na]+, 697.37 [2M + Na]+. TR = 23.51 min.

Synthesis of Ethyl 4-(N-(Benzyloxy)-4-((tert-butoxycarbonyl)amino)butanamido)butanoate (4)

Compound 2 (5.36 g, 15.90 mmol) was dissolved in trifluoroacetic acid (TFA, 6 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was monitored by MS (ESI) before being concentrated under vacuum. The deprotected amino ester 3 was used without further purification in the next step. To an ice-cold solution of Boc-γ-aminobutiric acid (2.7 g, 13.45 mmol) in DMF (20 mL) were added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 5.6 g, 14.75 mmol) and DIPEA (2.6 mL, 14.75 mmol). A portion of 3 (3.5 g, 14.75 mmol) was dissolved in DMF (10 mL), and this solution was added dropwise to the first one. Then the reaction mixture was warmed to room temperature and stirred for 1 h. After removal of the solvent, the residue was dissolved in ethyl acetate and washed with a 5% aqueous solution of citric acid, a 10% aqueous solution of NaHCO3, and brine. The crude product was purified by column chromatography using ethyl acetate/petroleum ether (from 1/4 to 1/1 by volume) as an eluent mixture. Compound 4 was obtained as a slightly yellowish oil (4.35 g, 76.6% yield). ESI-MS: calcd for C22H35N2O6, 423.53 [M + H]+; found, 423.25 [M + H]+, 445.23 [M + Na]+, 867.47 [2M + Na]+. TR = 21.11 min. 1H NMR (400 MHz, CDCl3): δ 7.44–7.32 (m, 5H), 4.80 (s, 2H), 4.11 (qd, J = 7.1, 2.9 Hz, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.12 (t, J = 6.6 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.32 (t, J = 7.3 Hz, 2H), 1.99–1.91 (m, 2H), 1.80–1.73 (m, 2H), 1.42 (s, 9H), 1.26–1.20 (m, 3H).13C NMR (CDCl3): δ 172.9, 156.0, 134.3, 129.2, 129.0, 128.7, 79.1, 60.4, 44.6, 40.3, 31.4, 29.6, 28.4, 24.7, 22.3, 14.2.

Synthesis of Ethyl 10,20-Bis(benzyloxy)-2,2-dimethyl-4,9,14,19-tetraoxo-3-oxa-5,10,15,20-tetraazatetracosan-24-oate (7)

The Boc-deprotected derivative 5 (3.40 g, 7.8 mmol) was obtained as previously described for 3. Compound 6 was synthesized by dissolving the ethyl ester 4 (3.0 g, 7.1 mmol) in a 1,4-dioxane/H2O mixture in the presence of LiOH (1 M aqueous solution, 12.5 mmol). The mixture was stirred at rt for 20–30 min. Once the reaction was complete, dioxane was evaporated and the crude product was acidified using 1 M HCl to reach pH 6. Then, the aqueous phase was extracted using ethyl acetate. Compound 6 (0.91 g, 2.31 mmol) was used in the next step without further purification. The coupling reaction was conducted as previously described for 4, and derivative 7 was obtained as a yellowish oil (1.24 g, 77% yield) after column chromatography. ESI-MS: calcd for C37H55N4O9, 699.87 [M + H]+; found, 699.96 [M + H]+. TR = 21.18 min. 1H NMR (400 MHz, CDCl3): δ 7.50–7.31 (m, 10H), 7.04 (bs, 1H), 4.81 (d, J = 5.3 Hz, 4H), 4.12 (q, J = 7.1 Hz, 2H), 3.71–3.69 (m, 4H), 3.26 (dd, J = 11.9, 6.2 Hz, 2H), 3.17–3.09 (m, 2H), 2.53–2.39 (m, 4H), 2.33 (t, J = 7.3 Hz, 2H), 2.20 (t, J = 6.8 Hz, 2H), 1.98–1.92 (m, 4H), 1.84–1.73 (m, 4H), 1.42 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3): δ 174.7, 173.3, 173.0, 134.2, 129.3, 129.1, 129.1, 128.8, 60.5, 44.7, 44.3, 40.0, 39.6, 33.1, 31.4, 30.0, 29.4, 28.5, 24.8, 23.9, 23.2, 22.3, 14.3.

Synthesis of Ethyl 10,20,30-Tris(benzyloxy)-2,2-dimethyl-4,9,14,19,24,29-hexaoxo-3-oxa-5,10,15,20,25,30-hexaazatetratriacontan-34-oate (9)

Compound 9 was synthesized under the same coupling conditions used for 4 by starting from the acid derivative 6 (0.91 g, 2.31 mmol) and the amino derivative 8 (1.81 g, 2.54 mmol). The desired product was obtained as a colorless oil (1.89 g, 84% yield) after column chromatography. ESI-MS: calcd for C52H75N6O12, 976.20 [M + H]+; found, 975.94 [M + H]+. TR = 17.83.1H NMR (400 MHz, CDCl3): δ 7.39–7.35 (m, 15H), 5.05 (bs, 3H), 4.83–4.77 (m, 6H), 4.11 (q, J = 7.1 Hz, 2H), 3.72–3.67 (m, 6H), 3.34–3.19 (m, 4H), 3.16–3.11 (m, 2H), 2.49–2.45 (m, 6H), 2.32 (t, J = 7.3 Hz, 2H), 2.25–2.12 (m, 4H), 2.02–1.89 (m, 6H), 1.87–1.72 (m, 6H), 1.42 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3): δ 175.3, 174.1, 172.5, 157.3, 135.4, 128.9, 128.3, 128.2, 80.7, 73.8, 61.2, 48.6, 41.2, 40.4, 35.2, 31.8, 31.5, 28.4, 24.1, 21.7, 18.5, 14.7.

Synthesis of 1,11,21-Tris(benzyloxy)-1,6,11,16,21,26-hexaazacyclotriacontane-2,7,12,17,22,27-hexaone (10)

Compound 9 was Boc-deprotected as described for 3. Then, the ethyl group was hydrolyzed by LiOH as for 6. To a dilute solution of the fully deprotected trimer (1.92 g, 2.0 mmol) in DMF (100 mL) were added HATU (0.84 g, 2.2 mmol) and DIPEA (0.38 mL, 2.2 mmol) dropwise at 0 °C. The reaction mixture was stirred for 3 h. Then, the solvent was removed, and the residue was extracted with ethyl acetate and an aqueous solution of citric acid (10%), a solution of NaHCO3 (5%), and brine. The crude product was purified via semipreparative HPLC, giving the desired product as a colorless oil (0.70 g, 42% yield). ESI-MS: calcd for C45H61N6O9, 830.02 [M + H]+; found, 829.90 [M + H]+. TR = 21.47 min. 1H NMR (400 MHz, CDCl3): δ 7.39–7.31 (m, 18H), 4.77 (s, 6H), 3.69–3.67 (m, 6H), 3.25–3.23 (m, 6H), 2.46 (t, J = 6.7 Hz, 6H), 2.19 (t, J = 7.0 Hz, 6H), 1.97–1.91 (m, 6H), 1.85–1.70 (m, 6H). 13C NMR (CDCl3): δ 174.9, 173.8, 133.8, 129.3, 128.8, 44.2, 39.4, 33.0, 29.5, 23.7, 23.2.

Synthesis of 1,11,21-Trihydroxy-1,6,11,16,21,26-hexaazacyclotriacontane-2,7,12,17,22,27-hexaone (11, H3L1)

To a solution of the benzyl-protected derivative 10 (0.70 g, 0.84 mmol) in MeOH (30 mL) was added glacial acetic acid (1 mL). The mixture was treated with a catalytic amount (0.084 mmol) of palladium on activated charcoal (10% Pd basis) under a hydrogen atmosphere. After 24 h, the reaction mixture was filtered through Celite, concentrated under reduced pressure, diluted with water, and alkalinized with saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (4 × 10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Compound 11 was obtained as a light yellow oil after preparative HPLC purification (0.43 g, 91% yield). ESI-MS: calcd for C24H43N6O9, 559.64 [M + H]+; found, 559.79 [M + H]+. TR = 15.79 min. 1H NMR (400 MHz, CDCl3): δ 9.59 (bs, 3H), 7.83–7.81 (m, 3H), 3.53–3.38 (m, 6H), 3.15–2.93 (m, 6H), 2.40–2.24 (m, 5H), 2.20–2.16 (m, 2H), 2.02 (t, J = 7.1 Hz, 5H), 1.76–1.70 (m, 6H), 1.64–1.50 (m, 6H). 13C NMR (CDCl3): δ 174.5, 173.0, 172.2, 169.5, 158.9, 158.5, 129.9, 50.5, 47.3, 47.1, 38.7, 38.6, 33.0, 31.5, 31.2, 30.3, 29.7, 24.9, 24.8, 23.0, 22.3, 19.7. HR-ESI-MS m/z 559.30894; calcd for C24H43N6O9 ([M + H]+) 559.30860. Anal. Calcd for C24H42N6O9: C, 51.6; H, 7.6; N, 15.0. Found: C, 51.4; H, 7.5; N, 14.9.

Synthesis of Ethyl 17-(Benzyloxy)-10-(((benzyloxy)carbonyl)amino)-2,2-dimethyl-4,11,16-trioxo-3-oxa-5,12,17-triazahenicosan-21-oate (13)

Compound 13 was synthesized under the same coupling conditions used for compounds 4 and 9 bystarting from Z-Lys(Boc)-OH (1.05 g, 2.75 mmol) and the amino derivative 5 (1.09 g, 2.50 mmol). The desired product was obtained as a yellowish oil (1.40 g, 80% yield) after column chromatography. ESI-MS: calcd for C36H53N4O9, 685.84 [M + H]+; found, 685.73 [M + H]+. TR = 26.16 min. 1H NMR (400 MHz, CDCl3): δ 7.37–7.35 (m, 5H), 7.31–7.26 (m, 5H), 6.99 (s, 1H), 5.85 (d, J = 7.7 Hz, 1H), 5.13–4.96 (m, 2H), 4.76 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.73–3.59 (m, 2H), 3.28–3.13 (m, 2H), 3.03–2.97 (m, 2H), 2.47–2.40 (m, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.94–1.88 (m, 2H), 1.84–1.69 (m, 3H), 1.62–1.58 (m, 1H), 1.39 (s, 11H), 1.31 (dd, J = 19.1, 12.2 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3): δ 13C NMR (101 MHz, cdcl3) δ 174.3, 172.9, 172.0, 156.2, 136.2, 134.1, 129.2, 128.9, 128.6, 128.4, 128.0, 127.9, 78.9, 76.2, 66.8, 60.4, 54.8, 44.4, 39.9, 39.2, 38.5, 32.2, 31.2, 29.7, 29.4, 28.3, 23.7, 22.4, 22.1, 14.1.

Synthesis of Ethyl 17,27,37,47-Tetrakis(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-2,2-dimethyl-4,11,16,21,26,31,36,41,46-nonaoxo-3-oxa-5,12,17,22,27,32,37,42,47-nonaazahenpentacontan-51-oate (15)

The tetramer 15 was synthesized under the same coupling conditions used for compounds 4, 9, and 13 by starting from the acid derivative 14 (0.61 g, 0.93 mmol) and the amino derivative 12 (0.90 g, 1.02 mmol). The desired product was obtained as a colorless oil (0.97 g, 69% yield) after column chromatography. ESI-MS: calcd for C81H113N10O18, 1514.85 [M + H]+; found, 1514.16 [M + H]+, 775.95 [M + 2H]2+. TR = 25.88 min. 1H NMR (400 MHz, CDCl3): δ 7.47–7.28 (m, 25H), 5.13–4.96 (m, 2H), 4.86–4.65 (m, 8H), 4.09 (dd, J = 13.8, 6.8 Hz, 3H), 3.80–3.53 (m, 8H), 3.32–3.10 (m, 7H), 3.04–3.00 (m, 2H), 2.54–2.34 (m, 7H), 2.29 (t, J = 7.0 Hz, 2H), 2.23–2.05 (m, 6H), 1.96–1.90 (m, 8H), 1.82–1.68 (m, 8H), 1.66–1.53 (m, 2H), 1.40 (s, 12H), 1.25–1.19 (m, 4H), 0.94–0.85 (m, 2H). 13C NMR (CDCl3): δ 174.5, 172.9, 136.2, 134.0, 129.2, 129.1, 128.8, 128.5, 128.2, 128.0, 67.0, 60.5, 55.0, 44.1, 39.4, 39.0, 32.9, 32.0, 31.3, 29.8, 29.7, 29.5, 28.4, 23.9, 23.0, 22.5, 22.2, 14.2.

Synthesis of Benzyl (6,16,26,36-Tetrakis(benzyloxy)-2,7,12,17,22,27,32,37,42-nonaoxo-1,6,11,16,21,26,31,36,41-nonaazacycloheptatetracontan-43-yl)carbamate (16)

Compound 15 was Boc-deprotected as described for 3. Then, the ethyl group was hydrolyzed by LiOH as for 6. To a dilute solution of the fully deprotected tetramer (0.55 g, 0.367 mmol) in DMF (40 mL) were added HATU (0.154 g, 0.40 mmol) and DIPEA (0.07 mL, 0.40 mmol) dropwise at 0 °C. The reaction mixture was stirred for 3 h. Then, the solvent was removed, and the residue was extracted with ethyl acetate and an aqueous solution of citric acid (10%), a solution of NaHCO3 (5%), and brine. The crude product was purified via semipreparative HPLC, giving the desired product as a colorless oil (0.29 g, 57% yield). ESI-MS: calcd for C74H99N10O15, 1368.66 [M + H]+; found, 1368.36 [M + H]+, 684.74 [M+2H]2+. TR = 25.73 min. 1H NMR (400 MHz, DMSO-d6): δ 7.96–7.63 (m, 6H), 7.56–7.13 (m, 25H), 5.06–4.89 (m, 2H), 4.85–4.71 (m, 8H), 4.00–3.76 (m, 3H), 3.09–2.88 (m, 10H), 2.84–2.61 (m, 1H), 2.43–2.25 (m, 8H), 2.09–1.93 (m, 9H), 1.75–1.71 (m, 9H), 1.59–1.53 (m, 8H), 1.39–1.08 (m, 7H), 1.07–0.76 (m, 2H). 13C NMR (DMSO-d6): δ 171.8, 156.4, 135.2, 129.8, 129.1, 128.9, 128.7, 128.2, 128.1, 75.7, 65.8, 55.1, 44.5, 38.5, 33.0, 29.5, 24.7, 23.2.

Synthesis of (S)-43-Amino-6,16,26,36-tetrahydroxy-1,6,11,16,21,26,31,36,41-nonaazacycloheptatetracontane-2,7,12,17,22,27,32,37,42-nonaone (17, H4L2)

Compound 17 was synthesized as previously described for 11 by starting from derivative 16 (0.13 g, 71% yield). ESI-MS: calcd for C38H69N10O13, 874.03 [M + H]+; found, 873.75 [M + H]+. TR = 21.28 min. 1H NMR (400 MHz, DMSO-d6): δ 9.64–9.59 (m, 3H), 8.07–8.04 (m, 2H), 7.86–7.71 (m, 4H), 3.47–3.44 (m, 9H), 3.04–2.99 (m, 10H), 2.42–2.22 (m, 8H), 2.04–2.00 (m, 8H), 1.76–1.49 (m, 20H), 1.47–1.16 (m, 5H). 13C NMR (DMSO-d6): δ 172.9, 172.2, 168.7, 158., 56.5, 52.7, 47.2, 38.7, 33.0, 31.2, 29.7, 29.1, 24.8, 24.5, 23.0, 22.1. HR-ESI-MS m/z 873.50488; calcd for C38H69N10O13 ([M + H]+) 873.50401. Anal. Calcd for C38H68N10O13: C, 52.3; H, 7.9; N, 16.0. Found: C, 52.3; H, 7.8; N, 16.1.

Thermodynamic Solution Studies

General Considerations

Unless otherwise stated, all commercially available reagents and solvents were of analytical grade, were purchased from commercial suppliers (Sigma-Aldrich, Titripur, Merck, Fisher Scientific, Fluka), and were used as received without further purification. All solutions were prepared in doubly distilled water. A stock solution of Fe(III) was prepared immediately before use from Fe(ClO4)3·xH2O in 0.01 M HClO4 and standardized by an inductively coupled plasma–optical emission spectrometer (ICP-OES; iCAP 7400 Duo ICP-OES) along with spectrophotometric determination, on the basis of the molar extinction coefficient ε = 4160 M–1 cm–1 at 240 nm. (70,71) Stock solutions of Ga(III) and Zr(IV) were prepared immediately before use from Ga(ClO4)3·xH2O and anhydrous ZrCl4, respectively, in 0.1 M HClO4 to prevent hydrolysis and standardized by ICP-OES (iCAP 7400 Duo ICP-OES) along with direct titration with ethylenediaminetetraacetic acid (EDTA). (72,73) The HClO4 solutions were titrated with standardized NaOH (0.1 N). The carbonate-free NaOH solution was standardized by titration with potassium hydrogen phthalate (KHP). All stock solutions were prepared using a R200D Sartorius analytical balance (with 0.01 mg precision).
All measurements were performed at 0.1 M NaClO4 ionic strength, which was chosen instead of 1.0 M NaClO4 ionic strength in order to increase the solubility of the investigated ligands and their complexes. We are aware that some measurements were performed at a very acidic pH (<1), where the ionic strength 0.1 M is not enough to keep the ionic activity stable, but due to the decomposition of hydroxamate ligands in strong acids, (43,51) all measurements performed below pH 1 were assumed to be endowed with a large error and (i) were not taken into account during data evaluation or (ii) precluded from the discussion.

Electrospray Ionization Mass Spectrometry (ESI-MS)

ESI-MS data were recorded on a Bruker Q-FTMS spectrometer. The instrumental parameters were as follows: scan range, m/z 200–1600; dry gas, nitrogen; temperature, 170 °C; capillary voltage, 4500 V; ion energy, 5 eV. The capillary voltage was optimized to the highest signal to noise ratio. The spectra were recorded in the positive mode. Compounds were dissolved in a MeOH/H2O solution (80/20 by weight); the same solvent mixture was used to dilute the matrix solutions to the concentration range of 0.01 mM. The Fe(III), Ga(III), and Zr(IV) and stock solutions were prepared as described previously and added to the ligand solutions in 1/1, 2/1 and 1/3 mixtures for Fe(III) and Ga(III) and 1/1 and 1/3 mixtures for Zr(IV), all at pH 3 (the pH was adjusted by using acetic acid). The free hydrogen ion concentration was measured with a Mettler-Toledo InLab Semi-Micro combined glass electrode filled with NaCl in MeOH/H2O (80/20 by weight). Potential differences were measured with a Beckman ϕ72 pH meter, standardized according to the classical methods with buffers prepared according to reported procedures in MeOH/H2O solvent (80/20 by weight). (74,75)

Potentiometric Titrations

The potentiometric titrations of ligands and their complexes were carried out using a Titrando 905 (Metrohm) automatic titrator system, equipped with a combined glass electrode (Mettler Toledo, InLab Semi-Micro, with XEROLYT EXTRA Polymer filling) and a 800 Dosino dosing system, equipped with a a 2 mL micro buret. The ionic strength was fixed at I = 0.1 M with NaClO4. The electrode was calibrated daily in terms of hydrogen ion concentration using HClO4 (0.1 M) with CO2-free NaOH solutions (0.1 M). (76) A stream of high-purity argon, presaturated with water vapor, was passed over the surface of the solution cell, the cell was filled with 50 mL of the studied solution, and the system was thermostated at 25.0 ± 0.2 °C. At least three titrations were performed for each system, with a starting concentration of the ligand of 1 mM and a 1:1 metal to ligand molar ratio with a 10% excess of the ligand in the pH range 2–11. The purity and exact concentration of the ligand solutions were determined using the Gran method. (77) Special care was taken to ensure that complete equilibration was attained. The titration curves were carefully checked and did not display any pH fluctuations that often accompany the precipitation of metal hydroxides. The potentiometric data were refined with the SUPERQUAD (78) and HYPERQUAD (79) programs, which use nonlinear least-squares methods. The successive protonation constants of the ligand were calculated from the cumulative constants determined with the program and defined by eqs 1 and 2 (charges are omitted for clarity).
(1)
(2)
The stability constants calculated for metal complexes are defined by eqs 3 and 4:
(3)
(4)
The uncertainties in the log K values correspond to the added standard deviations in the cumulative constants.

pH-Dependent UV–Vis Titrations

The pH-dependent UV–vis spectrophotometric experiments for the Fe(III)-H3L1, Fe(III)-H4L2, Ga(III)-H3L1, Ga(III)-H4L2, Ga(III)-H3L4, Zr(IV)-H3L1, Zr(IV)-H4L2, Zr(IV)-H3L3, and Zr(IV)-H3L4 systems were carried out as a function of concentration with a Varian Cary 300 Bio spectrophotometer in the 300–700 nm range for iron complexes and 200–300 nm range for gallium and zirconium solutions using Hellma quartz optical cells with a 1 cm path length. To calculate the stability constants for investigated systems, two sets of pH-dependent UV–vis titrations were carried out: in the pH ranges (i) 0.1–2 and (ii) 2–11. In the (i) series, the experiments were performed by making 20 samples, differing by 0.1 pH unit, with a constant total volume of 0.7 mL and concentration of metal ion of ∼0.05–0.1 mM and metal to ligand molar ratio of 1:1; for all samples, the ionic strength was adjusted to 0.1 M by the addition of NaClO4 and the pH (range 0.1–2.0) was controlled by the concentration of HClO4. After preparation, each solution was allowed to equilibrate for about 1 h, and then its UV–vis spectrum was recorded. This was necessary to minimize the effects of hydroxamate ligand hydrolysis, which occurs in strong acid. (43,51) In the (ii) set of experiments, 3 mL of a solution containing a 1:1 Fe(III):ligand molar ratio, where the ferric concentration was around 0.20 mM, was introduced into a cell and the pH was adjusted by adding the proper microvolume of HClO4; the solutions were allowed to equilibrate (up to 30 min) and checked with a Mettler Toledo Super Easy pH meter with an accuracy of ±0.01, and then the spectra were recorded.

Metal Competition Batch UV–Vis Titrations

In order to calculate the stability constants of the investigated complexes, several competitive titrations were performed. All of them were carried out as a function of concentration with a Varian Cary 300 Bio spectrophotometer in the 300–650 nm range (with 1 nm precision) using Hellma quartz optical cells with a 1 cm path length. Spectrophotometric titrations were performed on samples with a concentration of the ligand of ∼0.05–0.1 mM and I = 0.1 M (completed by adding NaClO4), at 25.0 ± 0.1 °C; pH 1.5 or 2.0 was adjusted by adding the proper volume of HClO4. In general, the stock solution of the starting complex (Fe(III)-L, Ga(III)-L, or Zr(IV)-L, respectively) was divided into several aliquots to which an excess of titrant (Ga(III), Fe(III), or Zr(IV)-NTA, respectively) was added. After preparation, each solution was allowed to equilibrate for about 1 h, and then its UV–vis spectrum was recorded. The vials were kept in the dark, and the absorbance was measured again after 24, 48, and 120 h. Changes were observed only between the spectra collected after 1 and 24 h, indicating that an equilibrium was attained.
In order to determine the log β values of [GaHL]+ for H3L1 and H3L4 and of [GaH2L2]+, competition experiments at pH 1.5 of (i) Fe(III)-H3L + Ga(III) and (ii) Ga(III)-L + Fe(III) were performed. For (i) 15 samples with a constant concentration of Fe(III) ions and L (1:1) were titrated by up to 600 equiv of Ga(III) ions; for Ga(III)-L + Fe(III), 18 samples with a constant concentration of Ga(III) ions and H3L (1:1) were titrated by up to 4 equiv of Fe(III) ions.
In order to determine the log β values of [ZrL]+ for H3L1, H4L2, H3L3, H3L4, and DFOE and for [ZrHL2]+, competition experiments at pH 1.5 or 2, Fe(III)-L + Zr(IV)-NTA, were performed. In each experiment 18 samples with a constant concentration of Fe(III) ions and ligands were titrated by up to 50 equiv of a Zr(IV)-NTA solution with a metal to ligand molar ratio of 1:3, starting from 0 equiv.

Data Treatment

In the calculations of complex stability constants, the protonation constants of free ligands (Table 1) and the constants were related to hydrolytic species being taken into account: Ga(III), (60) Ga(OH)2+ log βGaH–1 = −3.11, Ga(OH)2+ log βGaH–2 = −7.66, Ga(OH)3 log βGaH–3 = −11.94, Ga(OH)4– logβGaH–4 = −15.66, to Fe(III), (80) Fe(OH)2+ log βFeH–1 = −2.56, Fe(OH)2+ log βFeH–2= −6.2, Fe(OH)3 log βFeH–3 = −11.44, Fe(OH)4– log βFeH–4 = −21.88, Fe(OH)52– log βFeH–5 = −2.74, Fe(OH)63–, and Zr(IV), (60) Zr(OH)3+ log βZrH–1 = −0.56, Zr(OH)22+ log βZrH–2 = −1.44, Zr(OH)4 log βZrH–4 = −8.85, Zr(OH)62– log βZrH–6 = −30.6, Zr3(OH)48+ log βZr3H–4 = −6.96, Zr4(OH)88+ log βZr4H–8 = 6.52, Zr3(OH)93+ log βZr3H–9 = 12.19. The Zr(IV) hydrolysis constants for the species Zr(OH)3+, Zr(OH)22+, Zr(OH)4, and Zr3(OH)48+ were recalculated for 0.1 M NaClO4 ionic strength according to literature parameters. (60) The pKw value used in the calculation at the 0.1 M NaClO4 ionic strength was −13.77. (81)
The UV–vis data were refined to obtain the overall binding constant using SPECFIT/32 software (82−84) that adjusts the absorptivity and the stability constants of the species formed at equilibrium. Specfit uses factor analysis to reduce the absorbance matrix and to extract the eigenvalues prior to the multiwavelength fit of the reduced data set according to the Marquardt algorithm. (82−84) Uncertainties in log β were calculated from the standard deviation.
The competition data were refined to obtain the overall binding constant using SPECFIT/32 software. (82−84) The protonation constants of ligands and formation constants for iron complexes (Table 1 and the literature (24)) were used as fixed parameters during data analysis. The concentration of iron complexes was calculated from the absorbance spectra (collected in the 300–700 nm range). Hydrolytic forms of the ferric ion in the studied pH range are characterized by an absorption band with a λmax value of below 300 nm, and therefore they are beyond the experimental wavelength window. However, the spectrum of Fe(III) in solution at the pH of the experiment was fixed in the calculations. (85,86) The stability constants of the Fe(III)-NTA (48) and Zr(IV)-NTA (27) complexes were taken from the literature and were used as fixed constants during the evaluation of the stability constants of the zirconium complexes.
The competition equilibrium is described by eqs 5 and 6:
(5)
(6)
The molecular charges are omitted for clarity. The data were processed using Origin 7.0. The species distribution diagrams were computed with the HYSS program. (79)

Supporting Information

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  • ESI-MS spectra and UV–vis spectroscopic data from solution studies, detail of the Fe(III) complex solution study, and 1H/13C NMR spectra and chromatograms of the synthesized compounds (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Yuliya Toporivska - University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
    • Andrzej Mular - University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
    • Karolina Piasta - University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland;  Orcidhttps://orcid.org/0000-0003-0160-6920
    • Małgorzata Ostrowska - University of Wroclaw, Faculty of Chemistry, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
    • Davide Illuminati - University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
    • Andrea Baldi - University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
    • Valentina Albanese - University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy;  Orcidhttps://orcid.org/0000-0002-1947-2644
    • Salvatore Pacifico - University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
    • Igor O. Fritsky - Taras Shevchenko National University of Kyiv, Department of Chemistry, 64 Volodymyrska Str., 01601 Kyiv, Ukraine;  Orcidhttps://orcid.org/0000-0002-1092-8035
    • Maurizio Remelli - University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
    • Remo Guerrini - University of Ferrara, Dipartimento di Scienze Chimiche, Farmaceutiche ed Agrarie, 46 Via Luigi Borsari, 44121 Ferrara, Italy
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This contribution is based upon work from COST Action CA18202, NECTAR–Network for Equilibria and Chemical Thermodynamics Advanced Research, supported by COST (European Cooperation in Science and Technology). We acknowledge the Polish National Science Centre (NCN, UMO 2015/19/B/ST5/00413) for financial support. A.M. was supported by the NCN (UMO-2017/26/A/ST5/00363).

References

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This article references 86 other publications.

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    Bioconjugate Chemistry (2017), 28 (9), 2211-2223CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Immuno-positron emission tomog. (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclin. studies have shown that DFO is not an ideal chelator because the 89Zr-DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochem., including novel chelators and site-specific conjugation methods.
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    Buchwalder, C.; Jaraquemada-Pelaez, M. D.; Rousseau, J.; Merkens, H.; Rodriguez-Rodriguez, C.; Orvig, C.; Benard, F.; Schaffer, P.; Saatchi, K.; Hafeli, U. O. Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular Zr-89-THPN-Conjugates. Inorg. Chem. 2019, 58 (21), 14667– 14681,  DOI: 10.1021/acs.inorgchem.9b02350
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    Buchwalder, Christian; Jaraquemada-Pelaez, Maria de Guadalupe; Rousseau, Julie; Merkens, Helen; Rodriguez-Rodriguez, Cristina; Orvig, Chris; Benard, Francois; Schaffer, Paul; Saatchi, Katayoun; Hafeli, Urs O.
    Inorganic Chemistry (2019), 58 (21), 14667-14681CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomog. (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclin. studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodn. stability was quantified in soln. titrn. studies, which revealed one of the highest formation consts. reported for a zirconium chelate (log βML 50.3(1), pM = 42.8). Soln. stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional deriv. of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-mol. wt. (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiol. stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIV for THPN. This finding contrasts with the exceptionally high thermodn. stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by d. functional theory (DFT) calcns. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiol. stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates. The tetrapodal octadentate chelating ligand THPN was investigated as an alternative chelator for 89Zr. Soln. studies with ZrIV and FeIII revealed exceptional thermodn. stabilities that are among the highest reported for these metal ions. The prepn. of a bifunctional deriv. of the ligand allowed a prolonged in vivo stability assessment employing a macromol. carrier that suggested a need for optimization of the conjugation strategy or of the kinetic inertness.
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    Buchwalder, C.; Rodriguez-Rodriguez, C.; Schaffer, P.; Karagiozov, S. K.; Saatchi, K.; Hafeli, U. O. A new tetrapodal 3-hydroxy-4-pyridinone ligand for complexation of (89)zirconium for positron emission tomography (PET) imaging. Dalton Trans. 2017, 46 (29), 9654– 9663,  DOI: 10.1039/C7DT02196H
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    A new tetrapodal 3-hydroxy-4-pyridinone ligand for complexation of 89zirconium for positron emission tomography (PET) imaging
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    Dalton Transactions (2017), 46 (29), 9654-9663CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    Zirconium-89 (89Zr) is an ideal radiometal isotope for antibody-based positron emission tomog. (immunoPET) as its phys. half-life (3.27 days) is a good match with the biol. half-life of larger mol. wt. targeting mols., such as antibodies (3-4 days), and its positron emission (BR = 100% EC/β+, Eβ+,avg = 395.5 keV) is suited for high resoln. PET imaging. Concerns over the in vivo stability of the most commonly used 89Zr-chelator, desferrioxamine B (DFO), have spurred efforts into the development of alternative 89Zr-chelators that withstand the release of osteophilic 89Zr4+. Herein we report the new chelator 1,3-propanediamine-N,N,N',N'-tetrakis[(2-(aminomethyl)-3-hydroxy-1,6-dimethyl-4(1H)-pyridinone)acetamide] (THPN) based on four 3-hydroxy-4-pyridinone (3,4-HOPO) coordinating groups, as a potentially superior chelator over DFO. THPN has been demonstrated to quant. form a monometallic complex with Zr4+ within 10 min at ambient temp. at as low as 10-6 M concns. of the chelator. The resulting complexes were studied in vitro and in vivo. The 89Zr-THPN complex was stable in serum and outperformed the 89Zr-DFO complex in a direct transchelation challenge. Healthy mice excreted 89Zr-THPN rapidly without signs of demetalation or residual organ uptake. This renders THPN as a promising alternative to DFO and introduces the first octadentate 3,4-HOPO chelator to the field.
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    Raave, R.; Sandker, G.; Adumeau, P.; Jacobsen, C. B.; Mangin, F.; Meyer, M.; Moreau, M.; Bernhard, C.; Da Costa, L.; Dubois, A.; Goncalves, V.; Gustafsson, M.; Rijpkema, M.; Boerman, O.; Chambron, J.-C.; Heskamp, S.; Denat, F. Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for Zr-89-immunoPET. Eur. J. Nucl. Med. Mol. Imaging 2019, 46 (9), 1966– 1977,  DOI: 10.1007/s00259-019-04343-2
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    Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET
    Raave, Rene; Sandker, Gerwin; Adumeau, Pierre; Jacobsen, Christian Borch; Mangin, Floriane; Meyer, Michel; Moreau, Mathieu; Bernhard, Claire; Da Costa, Laurene; Dubois, Adrien; Goncalves, Victor; Gustafsson, Magnus; Rijpkema, Mark; Boerman, Otto; Chambron, Jean-Claude; Heskamp, Sandra; Denat, Franck
    European Journal of Nuclear Medicine and Molecular Imaging (2019), 46 (9), 1966-1977CODEN: EJNMA6; ISSN:1619-7070. (Springer)
    The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO. Methods: The stability of 89Zr-labeled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The in vivo distribution was investigated in mice with s.c. HER2+ SKOV-3 or HER2- MDA-MB-231 xenografts by PET/CT imaging and quant. ex vivo tissue analyses 7 days after injection. Results: 89Zr-labeled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In vivo studies, HER2+ SKOV-3 tumor-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Conclusion: 89Zr-labeled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clin. used std. chelator for 89Zr immunoPET.
  5. 5
    Alnahwi, A. H.; Ait-Mohand, S.; Dumulon-Perreault, V.; Dory, Y. L.; Guerin, B. Promising Performance of 4HMS, a New Zirconium-89 Octadendate Chelator. ACS Omega 2020, 5 (19), 10731– 10739,  DOI: 10.1021/acsomega.0c00207
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    Promising Performance of 4HMS, a New Zirconium-89 Octadendate Chelator
    Alnahwi, Aiman H.; Ait-Mohand, Samia; Dumulon-Perreault, Veronique; Dory, Yves L.; Guerin, Brigitte
    ACS Omega (2020), 5 (19), 10731-10739CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    Over the last decade, the interest in zirconium-89 (89Zr) as a positron-emitting radionuclide increased considerably because of its standardized prodn. and its phys. half-life (78.41 h), which matches the biol. half-life of antibodies and its successful use in preclin. and clin. applications. So far, desferrioxamine (DFO), a com. available chelator, has been mainly used as a bifunctional chelating system. However, there are some concerns regarding the in vivo stability of the [89Zr]Zr-DFO complex. In this study, we report the synthesis of an acyclic N-hydroxy-N-Me succinamide-based chelator (4HMS) with 8 coordination sites and our first investigations into the use of this new chelator for 89Zr complexation. In vitro and in vivo comparative studies with [89Zr]Zr-4HMS and [89Zr]Zr-DFO are presented. The 4HMS chelator was synthesized in four steps starting with an excellent overall yield. Both chelators were quant. labeled with 89Zr within 5-10 min at pH 7 and room temp.; the molar activity of [89Zr]Zr-4HMS exceeded (>3 times) that of [89Zr]Zr-DFO. [89Zr]Zr-4HMS remained stable against transmetalation and transchelation and cleared from most tissues within 24 h. The kidney, liver, bone, and spleen uptakes were significantly low for this 89Zr-complex. Positron emission tomog. images were in accordance with the results of the biodistribution in healthy mice. Based on DFT calcns., a rationale is provided for the high stability of 89Zr-4HMS. This makes 4HMS a promising chelator for future development of 89Zr-radiopharmaceuticals.
  6. 6
    Kaeopookum, P.; Petrik, M.; Summer, D.; Klinger, M.; Zhai, C.; Rangger, C.; Haubner, R.; Haas, H.; Hajduch, M.; Decristoforo, C. Comparison of Ga-68-labeled RGD mono- and multimers based on a clickable siderophore-based scaffold. Nucl. Med. Biol. 2019, 78–79, 1– 10,  DOI: 10.1016/j.nucmedbio.2019.09.002
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    Comparison of 68Ga-labeled RGD mono- and multimers based on a clickable siderophore-based scaffold
    Kaeopookum, Piriya; Petrik, Milos; Summer, Dominik; Klinger, Maximilian; Zhai, Chuangyan; Rangger, Christine; Haubner, Roland; Haas, Hubertus; Hajduch, Marian; Decristoforo, Clemens
    Nuclear Medicine and Biology (2019), 78-79 (), 1-10CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
    Cyclic pentapeptides contg. the amino acid sequence arginine-glycine-aspartic (RGD) have been widely applied to target αvβ3 integrin, which is upregulated in various tumors during tumor-induced angiogenesis. Multimeric cyclic RGD peptides have been reported to be advantageous over monomeric counterparts for angiogenesis imaging. Here, we prepd. mono-, di-, and trimeric cyclic arginine-glycine-aspartic-D-phenylalanine-lysine (c (RGDfK)) derivs. by conjugation with the natural chelator fusarinine C (FSC) using click chem. based on copper (I)-catalyzed azide-alkyne cycloaddn. (CuAAC). In vitro internalization assays with human melanoma M21 (αvβ3-pos.) and M21-L (αvβ3-neg.) cell lines showed specific uptake of all derivs. and increased in the series: mono- < di- < trimeric peptide. The highest tumor uptake, tumor-to-background ratios, and image contrast were found for the dimeric [68Ga]GaMAFC(c(RGDfK)aza)2. In conclusion, we developed a novel strategy for direct, straight forward prepn. of mono-, di-, and trimeric c(RGDfK) conjugates based on the FSC scaffold. Interestingly, the best αvβ3 imaging properties were found for the dimeric [68Ga]GaMAFC(c(RGDfK)aza)2.
  7. 7
    Zhai, C. Y.; He, S. Z.; Ye, Y. J.; Rangger, C.; Kaeopookum, P.; Summer, D.; Haas, H.; Kremser, L.; Lindner, H.; Foster, J.; Sosabowski, J.; Decristoforo, C. Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89. Biomolecules 2019, 9 (3), 91– 105,  DOI: 10.3390/biom9030091
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    Rational design, synthesis and preliminary evaluation of novel fusarinine C-based chelators for radiolabeling with zirconium-89
    Zhai, Chuangyan; He, Shanzhen; Ye, Yunjie; Rangger, Christine; Kaeopookum, Piriya; Summer, Dominik; Haas, Hubertus; Kremser, Leopold; Lindner, Herbert; Foster, Julie; Sosabowski, Jane; Decristoforo, Clemens
    Biomolecules (2019), 9 (3), 91CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    Fusarinine C (FSC) has recently been shown to be a promising and novel chelator for 89Zr. Here, FSC has been further derivatized to optimize the complexation properties of FSC-based chelators for 89Zr-labeling by introducing addnl. carboxylic groups. These were expected to improve the stability of 89Zr-complexes by satg. the 8-coordination sphere of [89Zr] Zr4+, and also to introduce functionalities suitable for conjugation to targeting vectors such as monoclonal antibodies. For proof of concept, succinic acid derivatization at the amine groups of FSC was carried out, resulting in FSC(succ)2 and FSC(succ)3. FSC(succ)2 was further derivatized to FSC(succ)2 AA by reacting with acetic anhydride (AA). The Zr4+ complexation properties of these chelators were studied by reacting with ZrCl4. Partition coeff., protein binding, serum stability, acid dissocn., and transchelation studies of 89Zr-complexes were carried out in vitro and the results were compared with those for 89Zr-desferrioxamine B ([89Zr]Zr-DFO) and 89Zr-triacetylfusarinine C ([89Zr]Zr-TAFC). The in vivo properties of [89Zr]Zr-FSC(succ)3 were further compared with [89Zr]Zr-TAFC in BALB/c mice using micro-positron emission tomog./computer tomog. (microPET/CT) imaging. Fusarinine C (succ)2AA and FSC(succ)3 were synthesized with satisfactory yields. Complexation with ZrCl4 was achieved using a simple strategy resulting in high-purity Zr-FSC(succ)2AA and Zr-FSC(succ)3 with 1:1 stoichiometry. Distribution coeffs. of 89Zr-complexes revealed increased hydrophilic character compared to [89Zr]Zr-TAFC. All radioligands showed high stability in phosphate buffered saline (PBS) and human serum and low protein-bound activity over a period of seven days. Acid dissocn. and transchelation studies exhibited a range of in vitro stabilities following the order: [89Zr]Zr-FSC(succ)3 > [89Zr]Zr-TAFC > [89Zr]Zr-FSC(succ)2AA >> [89Zr]Zr-DFO. Biodistribution studies of [89Zr]Zr-FSC(succ)3 revealed a slower excretion pattern compared to [89Zr]Zr-TAFC. In conclusion, [89Zr]Zr-FSC(succ)3 showed the best stability and inertness. The promising results obtained with [89Zr]Zr-FSC(succ)2AA highlight the potential of FSC(succ)2 as a monovalent chelator for conjugation to targeted biomols., in particular, monoclonal antibodies.
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    Pandey, A.; Savino, C.; Ahn, S. H.; Yang, Z. Y.; Van Lanen, S. G.; Boros, E. Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency. J. Med. Chem. 2019, 62 (21), 9947– 9960,  DOI: 10.1021/acs.jmedchem.9b01388
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    Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency
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    Journal of Medicinal Chemistry (2019), 62 (21), 9947-9960CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Pathogenic bacteria scavenge ferric iron from the host for survival and proliferation using small-mol. chelators, siderophores. Here, we introduce and assess the gallium(III) complex of ciprofloxacin-functionalized desferrichrome (D2) as a potential therapeutic for bacterial infection using an in vitro assay and radiochem., tracer-based approach. Ga-D2 exhibits a min. inhibitory concn. of 0.23μM in Escherichia coli, in line with the parent fluoroquinolone antibiotic. Competitive and mutant strain assays show that Ga-D2 relies on FhuA-mediated transport for internalization. Ga-D2 is potent against Pseudomonas aeruginosa (3.8μM), Staphylococcus aureus (0.94μM), and Klebsiella pneumoniae (12.5μM), while Fe-D2 is inactive in these strains. Radiochem. expts. with E. coli reveal that 67Ga-D2 is taken up more efficiently than 67Ga-citrate. In naive mice, 67Ga-D2 clears renally and is excreted 13% intact in the urine. These pharmacokinetic and bacterial growth inhibitory properties qualify Ga-D2 for future investigations as a diagnosis and treatment tool for infection.
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    A review. Positron Emission Tomog. (PET) experienced accelerated development and has become an established method for medical research and clin. routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clin. PET. The future development of the 68Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, prodn. and availability of 68Ga, automation of the radiopharmaceutical prodn., progress of positron emission tomog. technologies and image anal. methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chem. The review presents the prospects of the 68Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents.
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    Molecular Imaging (2010), 9 (1), 1-20CODEN: MIOMBP; ISSN:1535-3508. (BC Decker Inc.)
    A review. Rapid and widespread growth in the use of nuclear medicine for both diagnosis and therapy of disease has been the driving force behind burgeoning research interests in the design of novel radiopharmaceuticals. Until recently, the majority of clin. and basic science research has focused on the development of 11C-, 13N-, 15O-, and 18F-radiopharmaceuticals for use with positron emission tomog. (PET) and 99mTc-labeled agents for use with single-photon emission computed tomog. (SPECT). With the increased availability of small, low-energy cyclotrons and improvements in both cyclotron targetry and purifn. chemistries, the use of "nonstandard" radionuclides is becoming more prevalent. This brief review describes the phys. characteristics of 60 radionuclides, including β+, β-, γ-ray, and α-particle emitters, which have the potential for use in the design and synthesis of the next generation of diagnostic and/or radiotherapeutic drugs. As the decay processes of many of the radionuclides described herein involve emission of high-energy γ-rays, relevant shielding and radiation safety issues are also considered. In particular, the properties and safety considerations assocd. with the increasingly prevalent PET nuclides 64Cu, 68Ga, 86Y, 89Zr, and 124I are discussed.
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    Kubicek, V.; Havlickova, J.; Kotek, J.; Gyula, T.; Hermann, P.; Toth, E.; Lukes, I. Gallium(III) Complexes of DOTA and DOTA-Monoamide: Kinetic and Thermodynamic Studies. Inorg. Chem. 2010, 49 (23), 10960– 10969,  DOI: 10.1021/ic101378s
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    Gallium(III) Complexes of DOTA and DOTA-Monoamide: Kinetic and Thermodynamic Studies
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    Inorganic Chemistry (2010), 49 (23), 10960-10969CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Given the practical advantages of the 68Ga isotope in positron emission tomog. applications, gallium complexes are gaining increasing importance in biomedical imaging. However, the strong tendency of Ga3+ to hydrolyze and the slow formation and very high stability of macrocyclic complexes altogether render Ga3+ coordination chem. difficult and explain why stability and kinetic data on Ga3+ complexes are rather scarce. Here the authors report soln. and solid-state studies of Ga3+ complexes formed with the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, (DOTA)4-, and its mono(n-butylamide) deriv., (DO3AMBu)3-. Thermodn. stability consts., log K(GaDOTA) = 26.05 and log K(GaDO3AMBu) = 24.64, were detd. by out-of-cell pH-potentiometric titrns. Due to the very slow formation and dissocn. of the complexes, equilibration times of up to ∼4 wk were necessary. The kinetics of complex dissocn. were followed by 71Ga NMR under both acidic and alk. conditions. The GaDOTA complex is significantly more inert (τ1/2 ∼12.2 d at pH = 0 and τ1/2 ∼6.2 h at pH = 10) than the GaDO3AMBu analog (τ1/2 ∼2.7 d at pH = 0 and τ1/2 ∼0.7 h at pH = 10). Nevertheless, the kinetic inertness of both chelates is extremely high and approves the application of Ga3+ complexes of such DOTA-like ligands in mol. imaging. The solid-state structure of the GaDOTA complex, crystd. from a strongly acidic soln. (pH < 1), evidenced a diprotonated form with protons localized on the free carboxylate pendants.
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    Holland, Jason P.; Divilov, Vadim; Bander, Neil H.; Smith-Jones, Peter M.; Larson, Steven M.; Lewis, Jason S.
    Journal of Nuclear Medicine (2010), 51 (8), 1293-1300CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
    89Zr (half-life, 78.41 h) is a positron-emitting radionuclide that displays excellent potential for use in the design and synthesis of radioimmunoconjugates for immunoPET. In the current study, we report the prepn. of 89Zr-desferrioxamine B (DFO)-J591, a novel 89Zr-labeled monoclonal antibody (mAb) construct for targeted immunoPET and quantification of prostate-specific membrane antigen (PSMA) expression in vivo. Methods: The in vivo behavior of 89Zr-chloride, 89Zr-oxalate, and 89Zr-DFO was studied using PET. High-level computational studies using d. functional theory calcns. have been used to investigate the electronic structure of 89Zr-DFO and probe the nature of the complex in aq. conditions. 89Zr-DFO-J591 was characterized both in vitro and in vivo. ImmunoPET in male athymic nu/nu mice bearing s.c. LNCaP (PSMA-pos.) or PC-3 (PSMA-neg.) tumors was conducted. The change in 89Zr-DFO-J591 tissue uptake in response to high- and low-specific-activity formulations in the 2 tumor models was measured using acute biodistribution studies and immunoPET. Results: The basic characterization of 3 important reagents-89Zr-chloride, 89Zr-oxalate, and the complex 89Zr-DFO-demonstrated that the nature of the 89Zr species dramatically affects the biodistribution and pharmacokinetics. D. functional theory calcns. provide a rationale for the obsd. high in vivo stability of 89Zr-DFO-labeled mAbs and suggest that in aq. conditions, 89Zr-DFO forms a thermodynamically stable, 8-coordinate complex by coordination of 2 water mols. 89Zr-DFO-J591 was produced in high radiochem. yield (>77%) and purity (>99%), with a specific activity of 181.7 ± 1.1 MBq/mg (4.91 ± 0.03 mCi/mg). In vitro assays demonstrated that 89Zr-DFO-J591 had an initial immunoreactive fraction of 0.95 ± 0.03 and remained active for up to 7 d. In vivo biodistribution expts. revealed high, target-specific uptake of 89Zr-DFO-J591 in LNCaP tumors after 24, 48, 96, and 144 h (34.4 ± 3.2 percentage injected dose per g [%ID/g], 38.0 ± 6.2 %ID/g, 40.4 ± 4.8 %ID/g, and 45.8 ± 3.2 %ID/g, resp.). ImmunoPET studies also showed that 89Zr-DFO-J591 provides excellent image contrast, with tumor-to-muscle ratios greater than 20, for the delineation of LNCaP xenografts between 48 and 144 h after administration. Conclusion: These studies demonstrate that 89Zr-DFO-labeled mAbs show exceptional promise as radiotracers for immunoPET of human cancers. 89Zr-DFO-J591 displays high tumor-to-background tissue contrast in immunoPET and can be used to delineate and quantify PSMA-pos. prostate tumors in vivo.
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    Boros, E.; Packard, A. B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev. 2019, 119 (2), 870– 901,  DOI: 10.1021/acs.chemrev.8b00281
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    Radioactive Transition Metals for Imaging and Therapy
    Boros, Eszter; Packard, Alan B.
    Chemical Reviews (Washington, DC, United States) (2019), 119 (2), 870-901CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    Nuclear medicine is composed of two complementary areas, imaging and therapy. Positron emission tomog. (PET) and single-photon imaging, including single-photon emission computed tomog. (SPECT), comprise the imaging component of nuclear medicine. These areas are distinct in that they exploit different nuclear decay processes and also different imaging technologies. In PET, images are created from the 511 keV photons produced when the positron emitted by a radionuclide encounters an electron and is annihilated. In contrast, in single-photon imaging, images are created from the γ rays (and occasionally X-rays) directly emitted by the nucleus. Therapeutic nuclear medicine uses particulate radiation such as Auger or conversion electrons or β- or α particles. All three of these technologies are linked by the requirement that the radionuclide must be attached to a suitable vector that can deliver it to its target. It is imperative that the radionuclide remain attached to the vector before it is delivered to its target as well as after it reaches its target or else the resulting image (or therapeutic outcome) will not reflect the biol. process of interest. Radiochem. is at the core of this process, and radiometals offer radiopharmaceutical chemists a tremendous range of options with which to accomplish these goals. They also offer a wide range of options in terms of radionuclide half-lives and emission properties, providing the ability to carefully match the decay properties with the desired outcome. This Review provides an overview of some of the ways this can be accomplished as well as several historical examples of some of the limitations of earlier metalloradiopharmaceuticals and the ways that new technologies, primarily related to radionuclide prodn., have provided solns. to these problems.
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    Kostelnik, T. I.; Orvig, C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev. 2019, 119 (2), 902– 956,  DOI: 10.1021/acs.chemrev.8b00294
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    Radioactive Main Group and Rare Earth Metals for Imaging and Therapy
    Kostelnik, Thomas I.; Orvig, Chris
    Chemical Reviews (Washington, DC, United States) (2019), 119 (2), 902-956CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    Radiometals possess an exceptional breadth of decay properties and have been applied to medicine with great success for several decades. The majority of current clin. use involves diagnostic procedures, which use either positron-emission tomog. (PET) or single-photon imaging to detect anat. abnormalities that are difficult to visualize using conventional imaging techniques (e.g., MRI and X-ray). The potential of therapeutic radiometals has more recently been realized and relies on ionizing radiation to induce irreversible DNA damage, resulting in cell death. In both cases, radiopharmaceutical development has been largely geared toward the field of oncol.; thus, selective tumor targeting is often essential for efficacious drug use. To this end, the rational design of four-component radiopharmaceuticals has become popularized. This Review introduces fundamental concepts of drug design and applications, with particular emphasis on bifunctional chelators (BFCs), which ensure secure consolidation of the radiometal and targeting vector and are integral for optimal drug performance. Also presented are detailed accounts of prodn., chelation chem., and biol. use of selected main group and rare earth radiometals.
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    Li, L. L.; Jaraquemada-Pelaez, M. D.; Sarden, N.; Kuo, H. T.; Sarduy, E. A.; Robertson, A.; Kostelnik, T.; Jermilova, U.; Ehlerding, E.; Merkens, H.; Radchenko, V.; Lin, K.-S.; Benard, F.; Engle, J.; Schaffer, P.; Orvig, C. New bifunctional chelators for theranostic applications. Nucl. Med. Biol. 2019, 62, S36– S42,  DOI: 10.1016/S0969-8051(19)30218-5
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    Nurchi, V. M.; Jaraquemada-Pelaez, M. D.; Crisponi, G.; Lachowicz, J. I.; Cappai, R.; Gano, L.; Santos, M. A.; Melchior, A.; Tolazzi, M.; Peana, M.; Medici, S.; Zoroddu, M.-A. A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays. J. Inorg. Biochem. 2019, 193, 152– 165,  DOI: 10.1016/j.jinorgbio.2019.01.012
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    A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays
    Nurchi, Valeria M.; de Guadalupe Jaraquemada-Pelaez, Maria; Crisponi, Guido; Lachowicz, Joanna I.; Cappai, Rosita; Gano, Lurdes; Santos, M. Amelia; Melchior, Andrea; Tolazzi, Marilena; Peana, Massimiliano; Medici, Serenella; Zoroddu, Maria Antonietta
    Journal of Inorganic Biochemistry (2019), 193 (), 152-165CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone mol. The protonation equil., together with the complex formation equil. of this ligand with Fe3+, Al3+, Cu2+ and Zn2+ ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of D. Functional Theory (DFT) calcns., has allowed a thorough characterization of the different species involved in equil. The stability of the formed complexes with Fe3+ and Al3+ are high enough to consider the new ligand for further studies for its clin. applications as a chelating agent. Biodistribution studies were carried out to assess the capacity the ligand for mobilization of gallium in 67Ga-citrate injected mice. These studies demonstrated that this ligand efficiently chelates the radiometal in our animal model, which suggests that it can be a promising candidate as sequestering agent of iron and other hard trivalent metal ions. Furthermore, the good zinc complexation capacity appears as a stimulating result taking into a potential use of this new ligand in anal. chem. as well as in agricultural and environmental applications.
  21. 21
    Richardson-Sanchez, T.; Tieu, W.; Gotsbacher, M. P.; Telfer, T. J.; Codd, R. Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium(IV) chelator. Org. Biomol. Chem. 2017, 15 (27), 5719– 5730,  DOI: 10.1039/C7OB01079F
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    Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium(IV) chelator
    Richardson-Sanchez, Tomas; Tieu, William; Gotsbacher, Michael P.; Telfer, Thomas J.; Codd, Rachel
    Organic & Biomolecular Chemistry (2017), 15 (27), 5719-5730CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    The water soly. of a natural product-inspired octadentate hydroxamic acid chelator designed to coordinate Zr(iv)-89 has been improved by using a combined microbiol.-chem. approach to engineer four ether oxygen atoms into the main-chain region of a methylene-contg. analog. First, an analog of the trimeric hydroxamic acid desferrioxamine B (DFOB) that contained three main-chain ether oxygen atoms (DFOB-O3) was generated from cultures of the native DFOB-producer Streptomyces pilosus supplemented with oxybis(ethanamine) (OBEA), which competed against the native 1,5-diaminopentane (DP) substrate during DFOB assembly. This precursor-directed biosynthesis (PDB) approach generated a suite of DFOB analogs contg. one (DFOB-O1), two (DFOB-O2) or three (DFOB-O3) ether oxygen atoms, with the latter produced as the major species. Log P measurements showed DFOB-O3 was about 45 times more water soluble than DFOB. Second, a peptide coupling chain-extension reaction between DFOB-O3 and the synthetic ether-containing endo-hydroxamic acid monomer 4-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-4-oxobutanoic acid (PBH-O1) gave the water soluble tetrameric hydroxamic acid DFOB-O3-PBH-O1 as an isostere of sparingly water soluble DFOB-PBH. The complex between DFOB-O3-PBH-O1 and natZr(iv), examined as a surrogate measure of the radiolabelling procedure, analysed by LC-MS as the protonated adduct ([M + H]+, m/zobs = 855.2; m/zcalc = 855.3), with supporting HRMS data. The use of a microbiol. system to generate a water-sol. analog of a natural product for downstream semi-synthetic chem. is an attractive pathway for developing new drugs and imaging agents. The improved water soly. of DFOB-O3-PBH-O1 could facilitate the synthesis and purification of downstream products, as part of the ongoing development of ligands optimised for Zr(iv)-89 immunological PET imaging.
  22. 22
    Brown, C. J. M.; Gotsbacher, M. P.; Codd, R. Improved Access to Linear Tetrameric Hydroxamic Acids with Potential as Radiochemical Ligands for Zirconium(IV)-89 PET Imaging. Aust. J. Chem. 2020, 73 (10), 969– 978,  DOI: 10.1071/CH19518
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    Improved Access to Linear Tetrameric Hydroxamic Acids with Potential as Radiochemical Ligands for Zirconium(iv)-89 PET Imaging
    Brown, Christopher J. M.; Gotsbacher, Michael P.; Codd, Rachel
    Australian Journal of Chemistry (2020), 73 (9 & 10), 969-978CODEN: AJCHAS; ISSN:0004-9425. (CSIRO Publishing)
    Two new linear tetrameric hydroxamic acid ligands (3 and 4) have been prepd. as potential radioligands for immunol. ZrIV-89 positron emission tomog. (PET) imaging. The ligands were prepd. by conjugating endo-hydroxamic acid amino carboxylic acid (endo-HXA) monomers 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (PPH) or 2-(2-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-2-oxoethoxy)acetic acid (PPHNOCO) to trimeric desferrioxamine B (DFOB). The properties of DFOB-PPH (3) and DFOB-PPHNOCO (4) were compared with the first-in-class ligand DFO* (named DFOB-PBH (2) in the present work) and DFOB (1). In the initial phase of an FeIII:ZrIV competition expt., 1 preferentially formed FeIII-1, with ZrIV-1 becoming dominant after 48h. Tetrameric 2-4 selected ZrIV above FeIII at all times. The initial rates of formation of ZrIV-3 and ZrIV-4 were greater than ZrIV -2, which could reflect a better match between the ZrIV ionic radius and the increased vol. of the coordination sphere provided by 3 and 4. In the presence of excess EDTA, ZrIV-4 dissocd. more rapidly than ZrIV-2 and ZrIV-3, which indicated that any beneficial increase in water soly. conferred by the presence of ether oxygen atoms in 4 could be offset by a redn. in complex stability. Outer-sphere solvation of the ether oxygen atoms in ZrIV-4 may increase the entropic contribution to the dissocn. of the complex. The rank order of the initial rate of ZrIV complexation in the presence of equimolar FeIII (highest to lowest) 4>3>2 >>> 1 together with the rate of the dissocn. of the ZrIV complex (lowest to highest) 2 ≈ 3>4 >>> 1 identifies 3 as a ligand with potential value for immunol. ZrIV-89 PET imaging.
  23. 23
    Sarbisheh, E. K.; Salih, A. K.; Raheem, S. J.; Lewis, J. S.; Price, E. W. A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89. Inorg. Chem. 2020, 59 (16), 11715– 11728,  DOI: 10.1021/acs.inorgchem.0c01629
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    A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89
    Sarbisheh, Elaheh Khozeimeh; Salih, Akam K.; Raheem, Shvan J.; Lewis, Jason S.; Price, Eric W.
    Inorganic Chemistry (2020), 59 (16), 11715-11727CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Herein the authors report a new high-denticity chelator based on the iron siderophore desferrioxamine (DFO). The authors' new chelator-DFO2-is acyclic and was designed and synthesized with the purpose of improving the coordination chem. and radiolabeling performance with radioactive zirconium-89. The radionuclide zirconium-89 ([89Zr]Zr4+) found wide use for positron emission tomog. (PET) imaging when it is coupled with proteins, antibodies, and nanoparticles. DFO2 has a potential coordination no. of 12, which uniquely positions this chelator for binding large, high-valent, and oxophilic metal ions. Following synthesis of the DFO2 chelator and the [natZr]Zr-(DFO2) complex the authors performed d. functional theory calcns. to study its coordination sphere, followed by zirconium-89 radiolabeling expts. for comparisons with the "gold std." chelator DFO. DFO (CN 6) can coordinate with zirconium in a hexadentate fashion, leaving two open coordination sites where water is thought to coordinate (total CN 8). DFO2 (potential CN 12, dodecadentate) can sat. the coordination sphere of zirconium with four hydroxamate groups (CN 8), with no room left for water to directly coordinate, and only binds a single atom of zirconium per chelate. Following quant. radiolabeling with zirconium-89, the preformed [89Zr]Zr-(DFO) and [89Zr]Zr-(DFO2) radiometal-chelate complexes were subjected to a battery of in vitro stability challenges, including human blood serum, apo-transferrin, serum albumin, iron, hydroxyapatite, and EDTA. One objective of these stability challenges was to det. if the increased denticity of DFO2 over that of DFO imparted improved complex stability, and another was to det. which of these assays is most relevant to perform with future chelators. In all of the assays DFO2 showed superior stability with zirconium-89, except for the iron challenge, where both DFO2 and DFO were identical. Substantial differences in stability were obsd. for human blood serum using a pptn. method of anal., apo-transferrin, hydroxyapatite, and EDTA challenges. These results suggest that DFO2 is a promising next-generation scaffold for zirconium-89 chelators and holds promise for radiochem. with even larger radionuclides, which the authors anticipate will expand the utility of DFO2 into theranostic applications. DFO2 is a new acyclic chelator contg. six hydroxamic acid moieties and a potential coordination no. of 12 (dodecadentate). This chelator presents double the potential coordination no. of desferrioxamine (DFO, hexadentate), providing interesting coordination options beyond the std. 6-8 coordination nos. that are typical for zirconium(IV). This addnl. coordinating ability has imbued DFO2 with radiochem. properties superior to those DFO, as demonstrated by zirconium-89 stability challenges, and should enable theranostic applications with even larger radiometal ions.
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    Toporivska, Y.; Gumienna-Kontecka, E. The solution thermodynamic stability of desferrioxamine B (DFO) with Zr(IV). J. Inorg. Biochem. 2019, 198, 110753– 110758,  DOI: 10.1016/j.jinorgbio.2019.110753
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    The solution thermodynamic stability of desferrioxamine B (DFO) with Zr(IV)
    Toporivska, Yuliya; Gumienna-Kontecka, Elzbieta
    Journal of Inorganic Biochemistry (2019), 198 (), 110753CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    Desferrioxamine B (DFO, [H4L]+, ligand) is currently the preferred chelator for 89Zr(IV), however the biol. studies suggest that it releases the metal ion in vivo. Herein, we present the soln. thermodn. of complexes formed between Zr(IV) and this hexadentate chelating agent, the data surprisingly not yet available in the literature. Several techniques including electrospray ionization mass spectrometry (ESI-MS), potentiometry, UV-Vis spectroscopy and isothermal titrn. calorimetry (ITC) were used to det. the stoichiometry and thermodn. stability of complexes formed in soln. over pH range 1-11, overcoming all the difficulties with the characterization of the aq. soln. chem. of Zr(IV) complexes, like strong hydrolysis and lack of spectral information. A model contg. only mononuclear complexes, i.e. [ZrHL]2+ [ZrL]+, [ZrLH-1] throughout the entire measured pH range is proposed. The stability consts. and pM (Zr(IV)) value detd. for Zr(IV)-DFO system, place DFO among good Zr(IV) chelators, however the formation of 6-coordinate unsatd. complexes (i.e. with coordination sphere of 8-coordinate Zr(IV) completed by water mols.), together with the susceptibility of coordinated water mol. to deprotonation, are suggested to be the reason of in vivo instability of 89Zr(IV)-DFO complexes.
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    Sturzbecher-Hoehne, M.; Choi, T. A.; Abergel, R. J. Hydroxypyridinonate Complex Stability of Group (IV) Metals and Tetravalent f-Block Elements: The Key to the Next Generation of Chelating Agents for Radiopharmaceuticals. Inorg. Chem. 2015, 54 (7), 3462– 3468,  DOI: 10.1021/acs.inorgchem.5b00033
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    Hydroxypyridinonate Complex Stability of Group(IV) Metals and Tetravalent f-Block Elements: The Key to the Next Generation of Chelating Agents for Radiopharmaceuticals
    Sturzbecher-Hoehne, Manuel; Choi, Taylor A.; Abergel, Rebecca J.
    Inorganic Chemistry (2015), 54 (7), 3462-3468CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    The soln. thermodn. of the water-sol. complexes formed between 3,4,3-LI(1,2-HOPO) and Zr(IV) or Pu(IV) were studied to establish the metal coordination properties of this octadentate chelating agent. Stability consts. log β110 = 43.1 ± 0.6 and 43.5 ± 0.7 were detd. for [Zr(IV)(3,4,3-LI(1,2-HOPO))] and [Pu(IV)(3,4,3-LI(1,2-HOPO))], resp., by spectrophotometric competition titrns. against Ce(IV). Such high thermodn. stabilities not only confirm the unparalleled Pu(IV) affinity of 3,4,3-LI(1,2-HOPO) as a decorporation agent but also corroborate the great potential of hydroxypyridinonate ligands as new 89Zr-chelating platforms for immuno-PET applications. These exptl. values are in excellent agreement with previous ests. and are discussed with respect to ionic radius and electronic configuration, in comparison with those of Ce(IV) and Th(IV). Also, a liq. chromatog. assay combined with mass spectrometric detection was developed to probe the sepn. of the neutral [M(IV)(3,4,3-LI(1,2-HOPO))] complex species (M = Zr, Ce, Th, and Pu), providing addnl. insight into the coordination differences between Group IV and tetravalent f-block metals and on the role of d and f orbitals in bonding interactions.
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    Intorre, B. I.; Martell, A. E. Zirconium complexes in aqueous solution. 1. Reaction with multidentate ligands. J. Am. Chem. Soc. 1960, 82 (2), 358– 364,  DOI: 10.1021/ja01487a027
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    Zirconium complexes in aqueous solution. I. Reaction with multidentate ligands
    Intorre, Benjamin I.; Martell, Arthur E.
    Journal of the American Chemical Society (1960), 82 (), 358-64CODEN: JACSAT; ISSN:0002-7863.
    A study of the interaction of Zr(IV) with a wide variety of chelating agents resulted in the discovery of a no. of chelates with multidentate O donor groups stable over a wide pH range. The most stable chelates were formed with di-Na 1,2-dihydroxybenzene-3,5-disulfonate, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, N-(hydroxyethyl)ethylenediaminetriacetic acid, N-(hydroxyethyl)iminodiacetic acid, and N,N-bis(hydroxyethyl)glycine. Ethylenediaminetetraacetic acid was less effective, and triethylenediaminetetraacetic acid did not lead to the formation of sol. complexes.
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    Intorre, B. J.; Martell, A. E. Zirconium complexes in aqueous solution. 3. Estimation of formation constants. Inorg. Chem. 1964, 3 (1), 81– 87,  DOI: 10.1021/ic50011a017
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    Zirconium complexes in aqueous solution. III. Estimation of formation constants
    Intorre, B. J.; Martell, A. E.
    Inorganic Chemistry (1964), 3 (1), 81-7CODEN: INOCAJ; ISSN:0020-1669.
    cf. CA 56, 11190b. Data obtained from potentiometric titration of the 1:1 Zr-EDTA chelate at different concns. were used to est. the dimerization const., KD, and hydrolysis const., Ka, of the monomeric chelate. Potentiometric data were used to det. equil. consts. for di-Na 1,2-dihydroxy-3,5-benzenedisulfonate(Tiron) with the Zr-EDTA 1:1 chelate to form the Zr-EDTA-Tiron 1:1:1 chelate. Spectrophotometric measurements were used to est. the formation const. of the Zr-Tiron 1:1 and Zr-nitrilotriacetate 1:1 chelates and to set limits on the Zr-EDTA 1:1 chelate formation const. Some data are reported for the corresponding Hf chelate systems.
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    Racow, E. E.; Kreinbih, J. J.; Cosby, A. G.; Yang, Y.; Pandey, A.; Boros, E.; Johnson, C. J. General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry. J. Am. Chem. Soc. 2019, 141 (37), 14650– 14660,  DOI: 10.1021/jacs.9b05874
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    General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry
    Racow, Emily E.; Kreinbihl, John J.; Cosby, Alexia G.; Yang, Yi; Pandey, Apurva; Boros, Eszter; Johnson, Christopher J.
    Journal of the American Chemical Society (2019), 141 (37), 14650-14660CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The formation of ternary aqua complexes of metal-based diagnostics and therapeutics is closely correlated to their in vivo efficacy but approaches to quantify the presence of coordinated water ligands are limited. We introduce a general and high-throughput method for characterizing the hydration state of para- and diamagnetic coordination complexes in the gas phase based on variable-temp. ion trap tandem mass spectrometry. Ternary aqua complexes are directly obsd. in the mass spectrum and quantified as a function of ion trap temp. We recover expected periodic trends for hydration across the lanthanides and distinguish complexes with several inner-sphere water ligands by inspection of temp.-dependent speciation curves. We derive gas-phase thermodn. parameters for discernible inner- and second-sphere hydration events, and discuss their application to predict soln.-phase behavior. The differences in temp. at which water binds in the inner and outer spheres arise primarily from entropic effects. The broad applicability of this method allows us to est. the hydration states of Ga, Sc, and Zr complexes under active preclin. and clin. study with as-yet undetd. hydration no. Variable-temp. mass spectrometry emerges as a general tool to characterize and quantitate trends in inner-sphere hydration across the periodic table.
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    Summers, K. L.; Sarbisheh, E. K.; Zimmerling, A.; Cotelesage, J. J. H.; Pickering, I. J.; George, G. N.; Price, E. W. Structural Characterization of the Solution Chemistry of Zirconium(IV) Desferrioxamine: A Coordination Sphere Completed by Hydroxides. Inorg. Chem. 2020, 59 (23), 17443– 17452,  DOI: 10.1021/acs.inorgchem.0c02725
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    Structural Characterization of the Solution Chemistry of Zirconium(IV) Desferrioxamine: A Coordination Sphere Completed by Hydroxides
    Summers, Kelly L.; Sarbisheh, Elaheh Khozeimeh; Zimmerling, Amanda; Cotelesage, Julien J. H.; Pickering, Ingrid J.; George, Graham N.; Price, Eric W.
    Inorganic Chemistry (2020), 59 (23), 17443-17452CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Positron emission tomog. (PET) using radiolabeled, monoclonal antibodies has become an effective, noninvasive method for tumor detection and is a crit. component of targeted radionuclide therapy. Metal ion chelator and bacterial siderophore desferrioxamine (DFO) is the gold std. compd. for incorporation of zirconium-89 in radiotracers for PET imaging because it is thought to form a stable chelate with [89Zr]Zr4+. However, DFO may not bind zirconium-89 tightly in vivo, with free zirconium-89 reportedly liberated into the bones of exptl. mouse models. Although high bone uptake has not been obsd. to date in humans, this potential instability has been proposed to be related to the unsatd. coordination sphere of [89Zr]Zr-DFO, which is thought to consist of the 3 hydroxamate groups of DFO and 1 or 2 water mols. In this study, we have used a combination of X-ray absorption spectroscopy and d. functional theory (DFT) geometry optimization calcns. to further probe the coordination chem. of this complex in soln. We find the extended X-ray absorption fine structure (EXAFS) curve fitting of an aq. soln. of Zr(IV)-DFO to be consistent with an 8-coordinate Zr with oxygen ligands. DFT calcns. suggest that the most energetically favorable Zr(IV) coordination environment in DFO likely consists of the 3 hydroxamate ligands from DFO, each with bidentate coordination, and 2 hydroxide ligands. Further EXAFS curve fitting provides addnl. support for this model. Therefore, we propose that the coordination sphere of Zr(IV)-DFO is most likely completed by 2 hydroxide ligands rather than 2 water mols., forming Zr(DFO)(OH)2. Zirconium desferrioxamine (DFO), specifically [89Zr]Zr4+(DFO), is a major component of many radiopharmaceuticals commonly used in positron emission tomog. for tumor detection, including theranostic applications. The Zr(IV) coordination sphere has been proposed to consist of the 3 hydroxamate groups from DFO and 2 water mols. Herein, we show evidence, from a combination of X-ray absorption spectroscopy and d. functional theory, to support the coordination of 2 hydroxides instead of water.
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    Holland, J. P.; Sheh, Y. C.; Lewis, J. S. Standardized methods for the production of high specific-activity zirconium-89. Nucl. Med. Biol. 2009, 36 (7), 729– 739,  DOI: 10.1016/j.nucmedbio.2009.05.007
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    Standardized methods for the production of high specific-activity zirconium-89
    Holland, Jason P.; Sheh, Yiauchung; Lewis, Jason S.
    Nuclear Medicine and Biology (2009), 36 (7), 729-739CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
    Zirconium-89 is an attractive metallo-radionuclide for use in immuno-PET due to favorable decay characteristics. Standardized methods for the routine prodn. and isolation of high-purity and high-specific-activity 89Zr using a small cyclotron are reported. Optimized cyclotron conditions reveal high av. yields of 1.52±0.11 mCi/μA·h at a proton beam energy of 15 MeV and current of 15 μA using a solid, com. available 89Y-foil target (0.1 mm, 100% natural abundance). 89Zr was isolated in high radionuclidic and radiochem. purity (>99.99%) as [89Zr]Zr-oxalate by using a solid-phase hydroxamate resin with >99.5% recovery of the radioactivity. The effective specific-activity of 89Zr was found to be in the range 5.28-13.43 mCi/μg (470-1195 Ci/mmol) of zirconium. New methods for the facile prodn. of [89Zr]Zr-chloride are reported. Radiolabeling studies using the trihydroxamate ligand desferrioxamine B (DFO) gave 100% radiochem. yields in <15 min at room temp., and in vitro stability measurements confirmed that [89Zr]Zr-DFO is stable with respect to ligand dissocn. in human serum for >7 days. Small-animal positron emission tomog. (PET) imaging studies have demonstrated that free 89Zr(IV) ions administered as [89Zr]Zr-chloride accumulate in the liver, while [89Zr]Zr-DFO is excreted rapidly via the kidneys within <20 min. These results have important implication for the anal. of immuno-PET imaging of 89Zr-labeled monoclonal antibodies. The detailed methods described can be easily translated to other radiochem. facilities and will facilitate the use of 89Zr in both basic science and clin. investigations.
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    Holland, J. P.; Vasdev, N. Charting the mechanism and reactivity of zirconium oxalate with hydroxamate ligands using density functional theory: implications in new chelate design. Dalton Trans. 2014, 43 (26), 9872– 9884,  DOI: 10.1039/C4DT00733F
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    Charting the mechanism and reactivity of zirconium oxalate with hydroxamate ligands using density functional theory: implications in new chelate design
    Holland, Jason P.; Vasdev, Neil
    Dalton Transactions (2014), 43 (26), 9872-9884CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    The reaction of [89Zr(C2O4)4]4- with the tris-hydroxamate ligand desferrioxamine B (DFO) provides the basis of radiolabelling biol. vectors such as antibodies and proteins with the radionuclide 89Zr for positron emission tomog. imaging. In this work, d. functional theory methods were used to investigate the mechanism of reaction from [Zr(C2O4)4]4- to Zr(MeAHA)4 by ligand substitution with N-Me acetohydroxamate (MeAHA). Calcns. were performed under simulated basic and acidic conditions. Ligand substitution under basic conditions was found to be thermodynamically feasible with an overall calcd. change in solvation free energy, ΔGsol = -97 kJ mol-1 using the B3LYP/DGDZVP methodol. and a water continuum solvation model. In contrast, an acid-mediated mechanism of ligand substitution was found to be thermodynamically non-feasible. MO anal. provides a rationale for the difference in thermodn. stability between [Zr(C2O4)4]4- and Zr(MeAHA)4. Overall, the DFT calcns. are consistent with obsd. exptl. 89Zr-radiolabelling reactions and suggest that computational methods may prove useful in designing novel chelates for increasing the thermodn. and kinetic stability of 89Zr-complexes in vivo.
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    Holland, J. P. Predicting the Thermodynamic Stability of Zirconium Radiotracers. Inorg. Chem. 2020, 59 (3), 2070– 2082,  DOI: 10.1021/acs.inorgchem.9b03515
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    Predicting the Thermodynamic Stability of Zirconium Radiotracers
    Holland, Jason P.
    Inorganic Chemistry (2020), 59 (3), 2070-2082CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    The thermodn. stability of a metal-ligand complex, as measured by the formation const. (log β) is one of the most important parameters that dets. metal ion selectivity and potential applications in, for example, radiopharmaceutical science. The stable coordination chem. of radioactive 89Zr4+ in aq. conditions is of paramount importance when developing positron-emitting radiotracers based on proteins (usually antibodies) for use with positron emission tomog. Desferrioxamine B (DFO) remains the chelate of choice for clin. applications of 89Zr-labeled proteins but the coordination of DFO to Zr4+ ions is suboptimal. Many alternative ligands have been reported but challenges in measuring very high log β value with metal ions like Zr4+ that tend to hydrolyze mean that accurate thermodn. data are scarce. In this work, d. functional theory (DFT) calcns. were used to predict the reaction energetics for metal ion complexation. Computed values of pseudo formation consts. (log β') are correlated with exptl. data and showed an excellent linear relationship (R2-value = 0.97). The model was then used to est. the abs. and relative formation consts. of 23 different Zr4+ complexes using a total of 17 different ligands, including many of the alternative bifunctional chelates that have been reported recently for use in 89Zr4+ radiochem. In addn., detailed computational studies were performed on the geometric isomerism and hydration state of Zr-desferrioxamine. Collectively, the results offer new insights into Zr4+ coordination chem. that will help guide the synthesis of future ligands. The computation model developed here is straightforward, reproducible, and can be readily applied in the design of other metal coordination compds. A simple computational approach is developed to predict the abs. and relative thermodn. stabilities of zirconium complexes. The model is used to evaluate the characteristics of 23 different complexes that have been designed for potential use in radiopharmaceutical synthesis.
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    Szebesczyk, A.; Olshvang, E.; Shanzer, A.; Carver, P. L.; Gumienna-Kontecka, E. Harnessing the power of fungal siderophores for the imaging and treatment of human diseases. Coord. Chem. Rev. 2016, 327, 84– 109,  DOI: 10.1016/j.ccr.2016.05.001
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    Harnessing the power of fungal siderophores for the imaging and treatment of human diseases
    Szebesczyk, Agnieszka; Olshvang, Evgenia; Shanzer, Abraham; Carver, Peggy L.; Gumienna-Kontecka, Elzbieta
    Coordination Chemistry Reviews (2016), 327-328 (), 84-109CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
    Innovative strategies are needed to address the current lack of clin. available antifungal drugs and for diagnostic techniques. 'Repurposing' of antifungal drugs, similar to techniques currently being utilized with 'older' antibacterial drugs in order to combat widespread resistance in the face of a dearth of new drugs, could prove beneficial. Although as yet very limited for fungi, a siderophore-based 'Trojan Horse' strategy, in the form of siderophore-antibiotic conjugates, siderophore-fluorescent probe conjugates, or Ga(III)-siderophore complexes, reveals potential clin. relevance and provides a strategy for targeting fungal infections through drug delivery, imaging, and in diagnostics. The application of siderophores against pathogenic fungi is evolving but is still far from its full potential, and further studies are needed to demonstrate their advantages and limitations. One of the biggest obstacles in developing fungus-specific diagnostics and side-effects-free therapeutics is that apart from the fungal cell wall, fungi are metabolically similar to mammalian cells; thus, pathogen-specific targets are extremely limited. One of the few fundamental differences between fungal and mammalian cells lies in the iron acquisition system. The most common mechanism is mediated by small org. chelators - siderophores, often essential for fungal virulence and pathogenicity. Fungi synthesize mainly hydroxamate-type siderophores, which are excreted into the environment, and bind ferric ions with high affinity and selectivity. Delivery of iron-loaded siderophores back to the pathogen occurs via specific membrane receptors and transport proteins. Natural siderophores are generally not species-specific; they exhibit broad-spectrum activity and can be recognized by various types of microorganisms. Moreover, they generally miss proper sites for incorporating addnl. functionalities; e.g. fluorescent probes, surface-adhesive moieties or drug mols., to be used for imaging and/or as therapeutic conjugates smuggled into microbial species via siderophore recognition and a 'Trojan Horse' strategy. Biomimetic analogs can overcome both these limitations and offer novel tools for both diagnostics and therapeutics. Siderophore mimics with a narrow spectrum of activity offer the possibility of developing selective diagnostic tools, while those with broad-spectrum activity may find therapeutic applications as antifungal drug delivery tools.
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    Kornreich-Leshem, H.; Ziv, C.; Gumienna-Kontecka, E.; Arad-Yellin, R.; Chen, Y.; Elhabiri, M.; Albrecht-Gary, A. M.; Hadar, Y.; Shanzer, A. Ferrioxamine B analogues: Targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica. J. Am. Chem. Soc. 2005, 127 (4), 1137– 1145,  DOI: 10.1021/ja035182m
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    Ferrioxamine B analogues: targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica
    Kornreich-Leshem, Hagit; Ziv, Carmit; Gumienna-Kontecka, Elzbieta; Arad-Yellin, Rina; Chen, Yona; Elhabiri, Mourad; Albrecht-Gary, Anne-Marie; Hadar, Yitzhak; Shanzer, Abraham
    Journal of the American Chemical Society (2005), 127 (4), 1137-1145CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A series of ferrioxamine B analogs that target the bacterium Yersinia enterocolitica was prepd. These Fe carriers are composed of 3 hydroxamate-contg. monomeric units. Two identical monomers consist of N-hydroxy-3-aminopropionic acid coupled with β-alanine, and a 3rd unit at the amino terminal is composed of N-hydroxy-3-aminopropionic acid and 1 of the following amino acids: β-alanine (1a), phenylalanine (1b), cyclohexylalanine (1c), or glycine (1d). Thermodn. results for representatives of the analogs have shown a strong destabilization (3-4 orders of magnitude) of the ferric complexes with respect to ferrioxamine B, probably due to shorter spacers and a more strained structure around the metal center. No significant effect of the variations at the N-terminal has been obsd. on the stability of the ferric complexes. By contrast, using in vivo radioactive uptake expts., we have found that these modifications have a substantial effect on the mechanism of Fe(III) uptake in Y. enterocolitica. Analogs 1a and 1d were utilized by the ferrioxamine B uptake system (FoxA), while 1b and 1c either used different uptake systems or were transported to the microbial cell nonspecifically by diffusion via the cell membrane. Transport via the FoxA system was also confirmed by uptake expts. with the FoxA deficient strain of Y. enterocolitica. A fluorescent marker, attached to 1a in a way that did not interfere with its biol. activity, provided addnl. means to monitor the uptake mechanism by fluorescence techniques. Of particular interest is the observation that 1a was utilized by the uptake system of ferrioxamine B in Y. enterocolitica (FoxA) but failed to use the ferrioxamine uptake route in Pseudomonas putida. Here, we present a case in which biomimetic siderophore analogs deliberately designed for a particular bacterium can distinguish between related uptake systems of different microorganisms.
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    Olshvang, E.; Szebesczyk, A.; Kozlowski, H.; Hadar, Y.; Gumienna-Kontecka, E.; Shanzer, A. Biomimetic ferrichrome: structural motifs for switching between narrow- and broad-spectrum activities in P. putida and E. coli. Dalton Trans. 2015, 44 (48), 20850– 20858,  DOI: 10.1039/C5DT02685G
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    Biomimetic ferrichrome: structural motifs for switching between narrow- and broad-spectrum activities in P. putida and E. coli
    Olshvang, Evgenia; Szebesczyk, Agnieszka; Kozlowski, Henryk; Hadar, Yitzhak; Gumienna-Kontecka, Elzbieta; Shanzer, Abraham
    Dalton Transactions (2015), 44 (48), 20850-20858CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    A series of novel ferrichrome (FC) analogs was designed based on the X-ray structure of FC in the FhuA transporter of Escherichia coli. Two strategies were employed: the first strategy optimized the overall size and relative orientation of H-bonding interactions. The second strategy increased H-bonding interactions by introducing external H-donors onto analogs' backbone. Tris-amino templates were coupled to succinic or aspartic acid, and the second carboxyl was used for hydroxamate construction. Succinic acid provided analogs without substituents, whereas aspartic acid generated analogs with external amines (i.e.H-donors). All analogs had similar physicochem. properties, yet the biol. activity in Pseudomonas putida and E. coli showed great variation. While some analogs targeted specifically P. putida, others were active in both strains thus exhibiting broad-spectrum activity (as in native FC). Narrow-spectrum or species-specificity might find application in microbial diagnostic kits, while broad-spectrum recognition may have advantages in therapeutics as siderophore-drug conjugates. The differences in the structure and range of microbial recognition helped us in formulating guidelines for minimal essential parameters required for inducing broad-spectrum activity.
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    Besserglick, J.; Olshvang, E.; Szebesczyk, A.; Englander, J.; Levinson, D.; Hadar, Y.; Gumienna-Kontecka, E.; Shanzer, A. Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets. Chem. - Eur. J. 2017, 23 (53), 13181– 13191,  DOI: 10.1002/chem.201702647
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    Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets
    Besserglick, Jenny; Olshvang, Evgenia; Szebesczyk, Agnieszka; Englander, Joseph; Levinson, Dana; Hadar, Yitzhak; Gumienna-Kontecka, Elzbieta; Shanzer, Abraham
    Chemistry - A European Journal (2017), 23 (53), 13181-13191CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Siderophores provide an established platform for studying mol. recognition principles in biol. systems. Herein, the prepn. of ferrichrome (FC) biomimetic analogs varying in length and polarity of the amino acid chain sepg. between the tripodal scaffold and the pendent FeIII chelating hydroxamic acid groups is reported. Spectroscopic and potentiometric titrns. detd. their iron affinity to be within the range of efficient chelators. Microbial growth promotion and iron uptake studies were conducted on E. coli, P. putida and U. maydis. A wide range of siderophore activity was obsd. in the current series: from a rare case of a species-specific growth promotor in P. putida to an analog matching FC in cross-phylum activity and uptake pathway. A fluorescent conjugate of the broad-range analog visualized siderophore destination in bacteria (periplasmic space) vs. fungi (cytosol) mapping new therapeutic targets. Quantum dots (QDs) decorated with the most potent FC analog provided a tool for immobilization of FC-recognizing bacteria. Bacterial clusters formed around QDs may provide a platform for their selection and concn.
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    Anderegg, G.; Leplatte, F.; Schwarzenbach, G. Hydroxamatkomplexe. 3. Eisen(iii)-austausch zwischen sideraminen und komplexonen - diskussion der bildungskonstanten der hydroxamatkomplexe. Helv. Chim. Acta 1963, 46 (4), 1409– 1422,  DOI: 10.1002/hlca.19630460436
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    Hydroxamate complexes. III. Iron(III)exchange between sideramines and complexones. A discussion of the formation constants of the hydroxamate complexes
    Anderegg, G.; L'Eplattenier, F.; Schwarzenbach, G.
    Helvetica Chimica Acta (1963), 46 (4), 1409-22CODEN: HCACAV; ISSN:0018-019X.
    Optical spectra were used to study the transfer of Fe(III) from complexes with the sideramines H4DFO+, N-acetyl-desferriferrioxamin B (H3AcDFO), H3NOC, desferriferrichrom (H3FChO), and desferriferrichrysin (H3FChY) to ligands such as ethylenediaminetetraacetic acid, diethylenetriamine-pentaacetic acid, etc. The equil. consts. for the exchange reactions were used to calc. equil. consts. in the Fe3+-sideramine systems. The equil. observed and the log K values obtained were Fe3+ + HAcDFO- .dblharw. Fe(HAcDFO)+ (21.6), Fe3+ + AcDFO3- .dblharw. Fe(AcDFO) (30.76), Fe3+ + HNOC- .dblharw. Fe(HNOC)+ (22.5), Fe3+ + HFChO- .dblharw. Fe(HFChO)+ (20.7), Fe3+ = FChO3- .dblharw. Fe(FChO) (29.07), and Fe3+ + FChY3- .dblharw. Fe(FChY) (29.96). The hydroxamic acid group behaves as a bidentate O donor very much like acetylacetone. There is a pronounced preference for Fe(III) over other metal ions.
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    Mular, A.; Shanzer, A.; Kozłowski, H.; Decristoforo, C.; Gumienna-Kontecka, E. Unpublished results.
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    Seibold, U.; Wangler, B.; Wangler, C. Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for Zr-89. ChemMedChem 2017, 12 (18), 1555– 1571,  DOI: 10.1002/cmdc.201700377
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    Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for 89Zr
    Seibold, Uwe; Waengler, Bjoern; Waengler, Carmen
    ChemMedChem (2017), 12 (18), 1555-1571CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Zirconium-89 is a positron-emitting radionuclide of high interest for medical imaging applications with positron emission tomog. (PET). For the introduction of this radiometal into biol. active targeting vectors, the chelating agent desferrioxamine B (DFO) is commonly applied. However, DFO is known to form 89Zr complexes of limited in vivo stability. Herein we describe the rational design and chem. development of a new macrocyclic four-hydroxamate-bearing chelating agent-1,10,19,28-tetrahydroxy-1,5,10,14,19,23,28,32-octaazacyclohexatriacontan-2,6,11,15,20,24,29,33-octaone (CTH36)-for the stable complexation of Zr4+. For this purpose, we first performed computational studies to det. the optimal chelator geometry before we developed different synthesis pathways toward the target structures. The best results were obtained using an efficient soln.-phase-based synthesis strategy toward the target chelating agent. To enable efficient and chemoselective conjugation to biomols., a tetrazine-modified variant of CTH36 was also developed. The excellent conjugation characteristics of the so-functionalized chelator were demonstrated on the example of the model peptide TCO-c(RGDfK). We detd. the optimal 89Zr radiolabeling parameters for CTH36 as well as its bioconjugate, and found that 89Zr radiolabeling proceeds efficiently under very mild reaction conditions. Finally, we performed comparative complex stability tests for 89Zr-CHT36-c(RGDfK) and 89Zr-DFO-c(RGDfK), showing improved complex stability for the newly developed chelator CTH36.
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    Guerard, F.; Lee, Y. S.; Brechbiel, M. W. Rational Design, Synthesis, and Evaluation of Tetrahydroxamic Acid Chelators for Stable Complexation of Zirconium(IV). Chem. - Eur. J. 2014, 20 (19), 5584– 5591,  DOI: 10.1002/chem.201304115
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    Rational Design, Synthesis, and Evaluation of Tetrahydroxamic Acid Chelators for Stable Complexation of Zirconium(IV)
    Guerard, Francois; Lee, Yong-Sok; Brechbiel, Martin W.
    Chemistry - A European Journal (2014), 20 (19), 5584-5591CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Metals of interest for biomedical applications often need to be complexed and assocd. in a stable manner with a targeting agent before use. Whereas the fundamentals of most transition-metal complexation processes have been thoroughly studied, the complexation of ZrIV has been somewhat neglected. This metal has received growing attention in recent years, esp. in nuclear medicine, using 89Zr, which a β+-emitter with near ideal characteristics for cancer imaging. However, the best chelating agent known for this radionuclide is the trishydroxamate desferrioxamine B (DFB), the ZrIV complex of which exhibits suboptimal stability, resulting in the progressive release of 89Zr in vivo. Based on a recent report demonstrating the higher thermodn. stability of the tetrahydroxamate complexes of ZrIV compared with the trishydroxamate complexes analogs to DFB, the authors designed a series of tetrahydroxamic acids of varying geometries for improved complexation of this metal. Three macrocycles differing in their cavity size (28 to 36-membered rings) were synthesized by using a ring-closing metathesis strategy, as well as their acyclic analogs. A soln. study with 89Zr showed the complexation to be more effective with increasing cavity size. Evaluation of the kinetic inertness of these new complexes in EDTA soln. showed significantly improved stabilities of the larger chelates compared with 89Zr-DFB, whereas the smaller complexes suffered from insufficient stabilities. These results were rationalized by a quantum chem. study. The lower stability of the smaller chelates was attributed to ring strain, whereas the better stability of the larger cyclic complexes was explained by the macrocyclic effect and by the structural rigidity. Overall, these new chelating agents open new perspectives for the safe and efficient use of 89Zr in nuclear imaging, with the best chelators providing dramatically improved stabilities compared with the ref. DFB.
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    Patra, M.; Bauman, A.; Mari, C.; Fischer, C. A.; Blacque, O.; Haussinger, D.; Gasser, G.; Mindt, T. L. An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes. Chem. Commun. 2014, 50 (78), 11523– 11525,  DOI: 10.1039/C4CC05558F
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    An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes
    Patra, Malay; Bauman, Andreas; Mari, Cristina; Fischer, Christiane A.; Blacque, Olivier; Haussinger, Daniel; Gasser, Gilles; Mindt, Thomas L.
    Chemical Communications (Cambridge, United Kingdom) (2014), 50 (78), 11523-11525CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    89Zr-based imaging agents hold great promise as novel radio-tracers in nuclear medicine. However, insufficient stability of currently used radiometal complexes in vivo is a safety concern for clin. applications. We herein report the first octadentate bifunctional chelating agent for the development of 89Zr-labeled (bio)conjugates with improved stability.
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    Whisenhunt, D. W.; Neu, M. P.; Hou, Z. G.; Xu, J.; Hoffman, D. C.; Raymond, K. N. Specific sequestering agents for the actinides. 29. Stability of the thorium(IV) complexes of desferrioxamine B (DFO) and three octadentate catecholate or hydroxypyridinonate DFO derivatives: DFOMTA, DFOCAMC, and DFO-1,2-HOPO. Comparative stability of the plutonium(IV) DFOMTA complex. Inorg. Chem. 1996, 35 (14), 4128– 4136,  DOI: 10.1021/ic951064r
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    Specific Sequestering Agents for the Actinides. 29. Stability of the Thorium(IV) Complexes of Desferrioxamine B (DFO) and Three Octadentate Catecholate or Hydroxypyridinonate DFO Derivatives: DFOMTA, DFOCAMC, and DFO-1,2-HOPO. Comparative Stability of the Plutonium(IV) DFOMTA Complex
    Whisenhunt, Donald W., Jr.; Neu, Mary P.; Hou, Zhiguo; Xu, Jide; Hoffman, Darleane C.; Raymond, Kenneth N.
    Inorganic Chemistry (1996), 35 (14), 4128-4136CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    The metal complex stability consts. of Th(IV) with desferrioxamine B (DFO) and three octadentate derivs. [N-(2,3-dihydroxy-4-carboxybenzoyl)desferrioxamine B (DFOCAMC), N-((1,2-dihydro-1-hydroxy-2-oxopyridin-6-yl)carbonyl)desferrioxamine B (DFO-1,2-HOPO) and N-(2,3-dihydroxy-4-(methylamido)benzoyl)desferrioxamine B (DFOMTA)] have been detd. The formation const. of the Pu(IV)/DFOMTA complex has also been detd., and the formation consts. have been estd. for the other Pu(IV) complexes of octadentate DFO derivs. The DFO derivs. form 1:1 complexes with Th(IV) in aq. soln. The soln. chem. of the Th(IV) complexes have been studied by spectrophotometric, potentiometric and proton NMR titrns. The Th(IV) formation consts. are as follows (log Kf values and ests.): DFO, 26.6(1); DFOMTA, 38.55(5); DFOCAMC, 37.2(3); DFO-1,2-HOPO, 33.7(4). The Pu(IV)/DFOMTA formation const., detd. by competitive spectrophotometric titrn. is (log Kf value) 41.7(2). The estn. of the other Pu(IV) formation consts. are as follows (log Kf values): DFOCAMC, 40.4; DFO-1,2-HOPO, 36.9. The selectivity of DFO and the three derivs. for actinide(IV) ions is discussed.
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    Borgias, B.; Hugi, A. D.; Raymond, K. N. Isomerization and solution structures of desferrioxamine-B complexes of aluminium (3+) and galium (3+). Inorg. Chem. 1989, 28 (18), 3538– 3545,  DOI: 10.1021/ic00317a029
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    Isomerization and solution structures of desferrioxamine B complexes of aluminum(3+) and gallium(3+)
    Borgias, Brandan; Hugi, Alain D.; Raymond, Kenneth N.
    Inorganic Chemistry (1989), 28 (18), 3538-45CODEN: INOCAJ; ISSN:0020-1669.
    The Ga(III) and Al(III) complexes of desferrioxamine B (H3DFO) were prepd. and purified by cation-exchange liq. chromatog. Both complexes elute as single bands, with elution rates comparable to those measured for the trans isomer(s) of kinetically inert Cr(HDFO)+. The soln. thermodn. of Ga(HDFO)+ show that the cationic complex is the only significant species at pH 2-9. Above pH 9 the complex undergoes hydrolysis. Its stability const., log KML, is 27.56 (compared to 30.60 for Fe(III)). The NMR spectra of both the Ga and Al complexes indicate the presence of 2 isomers in soln., whose rapid interconversion prevents chromatog. sepn. The kinetics of isomerization of Ga(HDFO)+ were studied by variable temp. 13C measurements in D2O, CD3OD, and DMSO-d6. The following kinetic parameters were obtained at 25°: k (s-1), ΔH⧧ (kcal mol-1) and ΔS⧧ (cal mol-1 K-1): 13(1), 13(1), -10(3) in water; 73(7), 17(2), and +8(8) in MeOH; 4.1(6) × 102, 17(5), and +10(15) in DMSO. These results, and the observation that in water isomerization is pH independent, are discussed in terms of a possible Id mechanism. Attempts to further characterize the isomers of Ga(HDFO)+ by 2D NMR were only partially successful, due to the complexity of the spectra. Ga is a good substitute metal for Fe in the M-DFO system. There are only 2 significant isomers in soln. of the labile Ga(III) complex, and these are most likely the N-cis,cis and C-trans,trans isomers.
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    Farkas, E.; Kiss, T.; Kurzak, B. Microscopic dissociation processes of alaninehydroxamic acids. J. Chem. Soc., Perkin Trans. 2 1990, (7), 1255– 1257,  DOI: 10.1039/p29900001255
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    Microscopic dissociation processes of alaninehydroxamic acids
    Farkas, Etelka; Kiss, Tamas; Kurzak, Barbara
    Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1990), (7), 1255-7CODEN: JCPKBH; ISSN:0300-9580.
    A pH-metric and 13C NMR study has been made of the proton complexes of L-α-alaninehydroxamic acid and β-alaninehydroxamic acid at 25° and I = 0.2 mol dm-3 and 1.0 mol dm-3 (KCl), to det. the macroscopic dissocn. consts. of the ligand. The NH3+ group is more acidic than the NHOH group for the α-deriv., while the acidity sequence is the opposite for the β-deriv.
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    Tegoni, M.; Ferretti, L.; Sansone, F.; Remelli, M.; Bertolasi, V.; Dallavalle, F. Synthesis, solution thermodynamics, and x-ray study of Cu-II 12 metallacrown-4 with GABA hydroxamic acid: An unprecedented crystal structure of a 12 MC-4 with a gamma-aminohydroxamate. Chem. - Eur. J. 2007, 13 (4), 1300– 1309,  DOI: 10.1002/chem.200601035
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    Synthesis, solution thermodynamics, and x-ray study of CuII [12]metallacrown-4 with GABA hydroxamic acid: an unprecedented crystal structure of a [12]MC-4 with a γ-aminohydroxamate
    Tegoni, Matteo; Ferretti, Luca; Sansone, Francesco; Remelli, Maurizio; Bertolasi, Valerio; Dallavalle, Francesco
    Chemistry - A European Journal (2007), 13 (4), 1300-1308CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The soln. equil. of γ-aminobutanehydroxamic acid (GABAha) with H+ and Cu2+ were studied by potentiometry, titrn. calorimetry, spectrophotometry, NMR spectroscopy, and ESI-MS. The thermodn. parameters of the CuII [12]metallacrown-4 obtained for GABAha were compared with those of the corresponding complexes of (S)-α-Alaha and β-Alaha. The stability (-ΔG0) sequence was β-Alaha » α-Alaha > GABAha, whereas the order of formation enthalpies (-ΔH0) was β-Alaha » GABAha > α-Alaha. These data were interpreted from the dimensions of the chelate rings and the planarity of the metallamacrocycles. The CuII [12]metallacrown-4 ([12]MC-4) complex of GABAha was isolated and its crystal structure, which is the 1st reported for a [12]MC-4 of a γ-aminohydroxamic acid, fully supports the structural features interpreted from the thermodn. data.
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    Piasta, K.; Dzielak, A.; Mucha, A.; Gumienna-Kontecka, E. Non-symmetrical bis(aminoalkyl) phosphinates: new ligands with enhanced binding of Cu(II) ions. New J. Chem. 2018, 42 (10), 7737– 7745,  DOI: 10.1039/C8NJ01094C
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    Non-symmetrical bis(aminoalkyl)phosphinates: new ligands with enhanced binding of Cu(II) ions
    Piasta, Karolina; Dzielak, Anna; Mucha, Artur; Gumienna-Kontecka, Elzbieta
    New Journal of Chemistry (2018), 42 (10), 7737-7745CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
    Three novel, non-sym. bis(aminoalkyl)phosphinic acids, L1-L3, have been synthesized and characterized. Soln. studies on the coordination abilities of the ligands showed that these compds. form various protonated mono- and bis-complexes, where copper(II) coordination is realized through the nitrogen atom(s) of the amino group(s), supported by oxygen(s) from the phosphinate unit(s). Potentiometric titrns. and a full spectroscopic anal. clarified the species distribution profiles and detailed coordination modes. L1-L3 ligands are efficient chelating agents for Cu(II) ions; their metal binding abilities were compared to structurally related compds. described earlier in the literature.
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    Ostrowska, M.; Toporivska, Y.; Golenya, I. A.; Shova, S.; Fritsky, I. O.; Pecoraro, V. L.; Gumienna-Kontecka, E. Explaining How alpha-Hydroxamate Ligands Control the Formation of Cu(II)-, Ni(II)-, and Zn(II)-Containing Metallacrowns. Inorg. Chem. 2019, 58 (24), 16642– 16659,  DOI: 10.1021/acs.inorgchem.9b02724
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    Explaining How α-Hydroxamate Ligands Control the Formation of Cu(II)-, Ni(II)-, and Zn(II)-Containing Metallacrowns
    Ostrowska, Malgorzata; Toporivska, Yuliya; Golenya, Irina A.; Shova, Sergiu; Fritsky, Igor O.; Pecoraro, Vincent L.; Gumienna-Kontecka, Elzbieta
    Inorganic Chemistry (2019), 58 (24), 16642-16659CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Four different crystal structures for quinolinehydroxamic acid (QuinHA) and picolinehydroxamic acid (PicHA) MCs with Cu(II) and Ni(II), and soln. studies on the formation of Cu(II), Ni(II), and Zn(II) MC complexes with QuinHA, PicHA, and pyrazylohydroxamic acid (PyzHA) are described. In polynuclear complex 1, [Cu5(QuinHA-2H)4(NO3)(DMSO)4](NO3), the metallamacrocyclic cavity is formed by four Cu(II) ions and four doubly deprotonated hydroximate ligands, and the center of the cavity is occupied by the fifth Cu(II) ion coordinated by four hydroximate oxygen atoms. The complex 2, [Cu10(PicHA-2H)8(H2O)4(ClO4)3](ClO4)·4H2O, exhibits a dimeric structure based on two pentanuclear collapsed 12-MC-4 Cu4(PicHA-2H)4 fragments united by two chiral capping Cu(II) ions exo-coordinated to the peripheral vacant (O,O') chelating units of each tetranuclear collapsed MC moiety. 3, [CaNi5(QuinHA-2H)5(H2O)2(Py)10](NO3)2, and 4, [CaNi5(PicHA-2H)5(DMF)2(Py)8](NO3)2, are planar 15-membered rings consisting of a PicHA or QuinHA ligand, resp. To understand fully the correlation between species isolated in the solid state and those presented in soln., the soln. equil. were investigated, showing the dependence of the MCs topologies and stability consts. (log β) on the ligand structure and metal ion. The formation of Cu(II), Ni(II), and Zn(II) metallacrown complexes of quinolinehydroxamic acid (QuinHA), picolinehydroxamic acid (PicHA), and pyrazylohydroxamic acid (PyzHA) were studied to understand the correlation between species isolated in solid state and those presented in soln. The strong preference of QuinHA for the formation of MCs was reflected esp. in the formation of Cu(II) MC, which is the first example of the system with the presence of only one, the 12-MC-4 complex, in soln.
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    Sanchiz, J.; Esparza, P.; Dominguez, S.; Brito, F.; Mederos, A. Solution studies of complexes of iron(III) with iminodiacetic, alkyl-substituted iminodiacetic and nitrilotriacetic acids by potentiometry and cyclic voltammetry. Inorg. Chim. Acta 1999, 291 (1–2), 158– 165,  DOI: 10.1016/S0020-1693(99)00125-5
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    Solution studies of complexes of iron(III) with iminodiacetic, alkyl-substituted iminodiacetic and nitrilotriacetic acids by potentiometry and cyclic voltammetry
    Sanchiz, Joaquin; Esparza, Pedro; Dominguez, Sixto; Brito, Felipe; Mederos, Alfredo
    Inorganica Chimica Acta (1999), 291 (1-2), 158-165CODEN: ICHAA3; ISSN:0020-1693. (Elsevier Science S.A.)
    Potentiometric studies were performed for the iminodiacetic (IDA), methyliminodiacetic (MIDA), ethyliminodiacetic (EIDA), propyliminodiacetic (PIDA), H2L, and nitrilotriacetic acids (NTA, H3L)-iron(III) systems at 25°C and I=0.5 mol dm-3 in KNO3. The stability consts. of the complexes formed were detd. Deprotonation and dimerization consts. were calcd., the species distribution diagrams were explained, the cyclic voltammetric studies were performed for IDA- and NTA-iron(III) systems.
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    Motekaitis, R. J.; Martell, A. E. The iron(III) and iron(II) complexes of nitrilotriacetic acid. J. Coord. Chem. 1994, 31 (1), 67– 78,  DOI: 10.1080/00958979408022546
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    The iron(III) and iron(II) complexes of nitrilotriacetic acid
    Motekaitis, Ramunas J.; Martell, Arthur E.
    Journal of Coordination Chemistry (1994), 31 (1), 67-78CODEN: JCCMBQ; ISSN:0095-8972.
    Because of conflicting and incomplete reports of the ferric and ferrous nitrilotriacetate (NTA, H3L) equil. in the literature, and uncertainties about the metal complex species present under various conditions, the system was investigated by potentiometric and spectrometric measurements, and the data were analyzed by simultaneous consideration of all species present. The new consts. for the ferric complexes at 25.0 °C and μ = 0.100 (KCl) are the stepwise formation const. log K(ML2) = 8.07, and the successive hydrolysis consts., logK[M(OH)L] = -4.36, logK[M(OH)2L] = -7.58, and logK[M(OH)3L] = -10.72. The first stepwise formation const., log K(ML) = 15.9, was not detd. in the present work since the value of 15.9 was considered accurate. For the ferrous complexes under the same conditions, the consts. reported are: logK(ML) = 8.90, logK(ML2) = 2.08, and logK[M(OH)L] = -10.82. The log protonation consts. of the ligand under these conditions are reported as 9.59, 2.52, and 1.47.
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    Deblonde, G. J. P.; Sturzbecher-Hoehne, M.; Abergel, R. J. Solution Thermodynamic Stability of Complexes Formed with the Octadentate Hydroxypyridinonate Ligand 3,4,3-LI(1,2-HOPO): A Critical Feature for Efficient Chelation of Lanthanide(IV) and Actinide(IV) Ions. Inorg. Chem. 2013, 52 (15), 8805– 8811,  DOI: 10.1021/ic4010246
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    Solution Thermodynamic Stability of Complexes Formed with the Octadentate Hydroxypyridinonate Ligand 3,4,3-LI(1,2-HOPO): A Critical Feature for Efficient Chelation of Lanthanide(IV) and Actinide(IV) Ions
    Deblonde, Gauthier J-P.; Sturzbecher-Hoehne, Manuel; Abergel, Rebecca J.
    Inorganic Chemistry (2013), 52 (15), 8805-8811CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    The soln. thermodn. of water-sol. complexes formed between Ce(III), Ce(IV), Th(IV) and the octadentate chelating agent 3,4,3-LI(1,2-HOPO) were investigated. Several techniques including spectrofluorimetric and automated spectrophotometric titrns. were used to overcome the slow spontaneous oxidn. of Ce(III) complexes yielding to stability consts. of log β110 = 17.4 ± 0.5, logβ11-1 = 8.3 ± 0.4 and logβ111 = 21.2 ± 0.4 for [Ce(III)(3,4,3-LI(1,2-HOPO))]-, [Ce(III)(3,4,3-LI(1,2-HOPO)(OH))]2-, and [Ce(III)(3,4,3-LI(1,2-HOPO)H)], resp. Using the spectral properties of the hydroxypyridinonate chelator in ligand competition titrns. against nitrilotriacetic acid, the stability const. log β110 = 41.5 ± 0.5 was detd. for [Ce(IV)(3,4,3-LI(1,2-HOPO))]. Finally, the extraordinarily stable complex [Ce(IV)(3,4,3-LI(1,2-HOPO))] was used in Th(IV) competition titrns., resulting in a stability const. of log β110 = 40.1 ± 0.5 for [Th(IV)3,4,3-LI(1,2-HOPO)]. These exptl. values are in excellent agreement with previous ests., they are discussed with respect to the ionic radius and oxidn. state of each cationic metal, and allow predictions on the stability of other actinide complexes including [U(IV)(3,4,3-LI(1,2-HOPO))], [Np(IV)(3,4,3-LI(1,2-HOPO))], and [Pu(IV)(3,4,3-LI(1,2-HOPO))]. Comparisons with the std. ligand diethylenetriamine pentaacetic acid (DTPA) provide a thermodn. basis for the obsd. significantly higher efficacy of 3,4,3-LI(1,2-HOPO) as an in vivo actinide decorporation agent.
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    Schwarzenbach, G.; Schwarzenbach, K. Hydroxamatkomplexe. 1. Die stabilitat der eisen(iii)-komplexe einfacher hydroxamsauren und des ferrioxamins B. Helv. Chim. Acta 1963, 46 (4), 1390– 1399,  DOI: 10.1002/hlca.19630460434
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    Hydroxamate complexes. I. The stabilities of the iron(III) complexes of simple hydroxamic acids and desferriferrioxamin B
    Schwarzenbach, G.; Schwarzenbach, K.
    Helvetica Chimica Acta (1963), 46 (4), 1390-1400CODEN: HCACAV; ISSN:0018-019X.
    The ionization consts. of Me-CONOH (I) (pK = 9.37), PhCONOH (II) (pK = 8.79), and desferriferrioxamin B (H4DFO+) (III) (pK1 = 8.39, pK2 = 9.03, pK3 = 9.70, and pK4 > 11), were measured by conventional pH techniques. The aq. equil. between Fe(III) and I, II, and III were investigated with the aid of oxidn.-redn. potentials, pH, and spectrophotometric measurements. Fe(III) forms the complexes FeA++, FeA2+, and FeA3, where A = the anion of I or II. The stepwise formation consts. (log K) for these species are 11.42, 9.68, and 7.2 for A = MeCONO- and 11.06, 9.37, 7.4 for A = PhCONO-. The log K values for the formation of Fe(H2DFO)++ (IV) and Fe(HDFO)+ are 21.84 and 30.60, resp. IV behaves like a dibasic acid with pK1 = 0.94 and pK2 > 10, resp.
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    Evers, A.; Hancock, R. D.; Martell, A. E.; Motekaitis, R. J. Metal-ion recognition in ligands with negatively charged oxygen donor groups - complexation of Fe(III), Ga(III), In(III), Al(III), and other highly charged metal-ions. Inorg. Chem. 1989, 28 (11), 2189– 2195,  DOI: 10.1021/ic00310a035
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    Metal ion recognition in ligands with negatively charged oxygen donor groups. Complexation of iron(III), gallium(III), indium(III), aluminum(III), and other highly charged metal ions
    Evers, Ann; Hancock, Robert D.; Martell, Arthur E.; Motekaitis, Ramunas J.
    Inorganic Chemistry (1989), 28 (11), 2189-95CODEN: INOCAJ; ISSN:0020-1669.
    The existence of good linear relations between the formation const. log value of complexes of ligands contg. neg. O donor groups only and log K1(OH-) values for the metal ions is demonstrated for a variety of ligands contg. phenolate, carboxylate, and hydroxamate donor groups. The formation consts. of DFB (desferriferrioxamine-B), BAMTPH (a synthetic trihydroxamate acid), and several dihydroxamic acids of the type HONHCO(CH2)nCONHOH (n = 4, 6, 7, and 8) with several metal ions are reported and used to demonstrate the general existence of linear relations of the above type. The DFB consts. are reported for Al(III), Ga(III), and In(III) and considered in relation to possible use of DFF for treating Al intoxication. The selectivity patterns of neg. charged O donor ligands for metal ions are discussed in relation to the effect of chain length of the bridging groups connecting the donor groups, the presence of sulfonic acid groups, and how the selectivity patterns might be altered by the inclusion of other donor groups such as neutral O and N donor groups.
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    Harris, W. R.; Carrano, C. J.; Raymond, K. N. Coordination chemistry of microbial iron transport compounds. 16. Isolation, characterization, and formation-constants of ferric aerobactin. J. Am. Chem. Soc. 1979, 101 (10), 2722– 2727,  DOI: 10.1021/ja00504a038
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    Coordination chemistry of microbial iron transport compounds. 16. Isolation, characterization, and formation constants of ferric aerobactin
    Harris, Wesley R.; Carrano, Carl J.; Raymond, Kenneth N.
    Journal of the American Chemical Society (1979), 101 (10), 2722-7CODEN: JACSAT; ISSN:0002-7863.
    Aerobactin, a dihydroxamate deriv. of citric acid, is a siderophore produced by Aerobacter aerogenes. The Fe complex was isolated from neutral aq. solns. as the trisodium salt. The high-spin octahedral complex was formed using the 2 bidentate hydroxamate groups and the central carboxylate and hydroxyl moieties of the citrate backbone. Ferric aerobactin exists predominantly as the Λ optical isomer in aq. solns. The stability consts. (logβ113 = 31.74, log β112 = 29.70, log β111 = 26.68, log β110 = 23.06, logβ11‾1 = 18.48) and redox potential also were detd. from spectroscopic, potentiometric titrn., and electrochem. techniques. The implication of these results to the mechanism of Fe uptake and release by A. aerogenes is discussed.
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    Clarke, E. T.; Martell, A. E. Stabilities of the Fe(III), Ga(III) and In(III) chelates of N,N′,N″-triazacyclononanetriacetic acid. Inorg. Chim. Acta 1991, 181 (2), 273– 280,  DOI: 10.1016/S0020-1693(00)86821-8
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    Stabilities of the iron(III), gallium(III) and indium(III) chelates of N,N',N"-triazacyclononanetriacetic acid
    Clarke, Eric T.; Martell, Arthur E.
    Inorganica Chimica Acta (1991), 181 (2), 273-80CODEN: ICHAA3; ISSN:0020-1693.
    The stability consts. of the complexes of Fe, Ga, and In (3+) ions with the sexadentate macrocyclic ligand 1,4,7-triazacyclonane-N,N',N''-triacetic acid (NOTA) were detd. in KCl supporting electrolyte (0.100 M) at 25.0°. The stability consts. (KML = [ML]/[L3-][M3+] of the Ga(III) and Fe(III) complexes with NOTA are high, 1030.98 and 1028.3, resp., and indicate preferential interaction of these small metal ions with NOTA. The stability const. of the In(III)-NOTA complex is somewhat lower (1026.2). Species distribution curves are presented to illustrate the conversion of the Ga(III) and In(III) chelates to the monohydroxo forms at p[H] 9.3 and 6.5, resp. The Fe(III)-NOTA complex dissocs. to form ferric hydroxide at and above p[H] 7.5, while the hydroxo In(III)-NOTA complex is converted to indium hydroxide at and above p[H] 7.5. The Ga(III)-NOTA system is sol. at all p[H] values, as a consequence of conversion of the hydroxo complex to the tetrahydroxo gallate ion at p[H] 10.4 and above.
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    Wang, X. Z.; Jaraquemada-Pelaez, M. D.; Cao, Y.; Pan, J. H.; Lin, K. S.; Patrick, B. O.; Orvig, C. H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for Ga-68 Radiopharmaceuticals. Inorg. Chem. 2019, 58 (4), 2275– 2285,  DOI: 10.1021/acs.inorgchem.8b01208
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    H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals
    Wang, Xiaozhu; Jaraquemada-Pelaez, Maria de Guadalupe; Cao, Yang; Pan, Jinhe; Lin, Kuo-Shyan; Patrick, Brian O.; Orvig, Chris
    Inorganic Chemistry (2019), 58 (4), 2275-2285CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    An acyclic hexadentate chelating ligand, H2hox, has been investigated as an alternative to current chelators for 68Ga. The straightforward prepn. of H2hox, involving only one or two steps, obviates the synthetic challenges assocd. with many reported 68Ga chelators; it forms a Ga3+ complex of great stability (log K = 34.4) with a remarkably high gallium scavenging ability (pM = 28.3). Moreover, H2hox coordinates 68Ga quant.-ly in 5 min at room temp. in ligand concns. as low as 10-7 M, achieving an unprecedented high molar activity of 11±1 mCi/nmol (407±3.7 MBq/nmol) without purifn., suggesting prospective kit-based convenience. [68Ga(hox)]+ showed no decompn. in a plasma challenge. Good in vivo stability and fast renal and hepatic clearance of the [68Ga(hox)]+ complex were demonstrated using dynamic PET/CT imaging. The intrinsic fluorescence of [Ga(hox)]+ allowed for direct fluorescence imaging of cellular uptake and distribution, demonstrating the dual channel detectability and intracellular stability of the metal complex.
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    Notni, J.; Hermann, P.; Havlickova, J.; Kotek, J.; Kubicek, V.; Plutnar, J.; Loktionova, N.; Riss, P. J.; Rosch, F.; Lukes, I. A. Triazacyclononane-Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric Ga-68 Tracers for Positron Emission Tomography. Chem. - Eur. J. 2010, 16 (24), 7174– 7185,  DOI: 10.1002/chem.200903281
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    A Triazacyclononane-Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric 68Ga Tracers for Positron Emission Tomography
    Notni, Johannes; Hermann, Petr; Havlickova, Jana; Kotek, Jan; Kubicek, Vojtech; Plutnar, Jan; Loktionova, Natalia; Riss, Patrick Johannes; Roesch, Frank; Lukes, Ivan
    Chemistry - A European Journal (2010), 16 (24), 7174-7185, S7174/1-S7174/11CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    For application in positron emission tomog. (PET), PrP9 (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]), a N,N',N''-trisubstituted triazacyclononane with methyl(2-carboxyethyl)phosphinic acid pendant arms, was developed as 68Ga3+ complexing agent. The synthesis is short and inexpensive. GaIII and FeIII complexes of PrP9 were characterized by single-crystal x-ray diffraction. Stepwise protonation consts. and thermodn. stabilities of metal complexes were detd. by potentiometry. The GaIII complex possesses a high thermodn. stability (log K[GaL] = 26.24) and a high degree of kinetic inertness. 68Ga labeling of PrP9 is possible at ambient temp. and in a wide pH range, also at pH values ≥1. For the 1st time, the neat eluate of a TiO2-based 68Ge/68Ga generator (consisting of 0.1M HCl) can be directly used for labeling purposes. The rate of 68Ga activity incorporation at pH 3.3 and 20° is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.
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    Motekaitis, R. J.; Sun, Y.; Martell, A. E.; Welch, M. J. Stabilities of gallium(III), iron(III), and indium(III) chelates of hydroxyaromatic ligands with different overall charges. Inorg. Chem. 1991, 30 (13), 2737– 2740,  DOI: 10.1021/ic00013a007
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    Stabilities of gallium(III), iron(III), and indium(III) chelates of hydroxyaromatic ligands with different overall charges
    Motekaitis, Ramunas, J.; Sun, Yizhen; Martell, Arthur E.; Welch, Michael J.
    Inorganic Chemistry (1991), 30 (13), 2737-40CODEN: INOCAJ; ISSN:0020-1669.
    The stability consts. of the Ga(III), In(III), and Fe (III) chelates of three new ligands, N-(2-hydroxybenzyl)-N'-(pyridoxyl)ethylenediamine-N,N'-diacetic acid (HBPLED), N-(2-hydroxy-3,5-dimethylbenyl)-N'-(3-hydroxy-1,2,5-trimethyl-4-pyridiniumyl)methyl)ethylenediamine-N,N'-diacetic acid (Me4HBPLED), and N,N'-bis(1,2-dimethyl-3-hydroxy-5-hydroxymethyl)-4-pyridiniumyl)methyl)ethylenediamine-N,N'-diacetic acid (DMPLED) are reported and compared with those of the parent ligands N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), N,N'-bis(2-hydroxy-3,5-dimethylbenzyl)ethylenediamine-N,N'-diacetic acid (TMHBED), and N,N'-bis(pyridoxyl)ethylenediamine-N,'-diacetic acid (PLED). This comparison shows the effect on chelate stability of the methylation of the pyridine nitrogens, which increases the overall charges of the complex mols. without changing the donor atoms in the coordination sphere. The data show that quaternization of the pyridine nitrogen decreases the stability consts. of the Fe(III) and Ga(III) chelates by about 2 orders of magnitude. A perturbation in the trends is seen in the chelates of Me4HBPLED, whereby methylation of the benzene ring tεnds to increase the metal chelate stabilities. The log K values are for HBPLED: Ga, 31.02; Fe, 31.01; In, 28.97.for Me4HBPLED: Ga, 31.85; Fe, 32.97; In, 27.82. For DMPLEd: Ga, 27.27; Fe, 27.20; In, 21.47.
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    Abergel, R. J.; D’Aleo, A.; Leung, C. N. P.; Shuh, D. K.; Raymond, K. N. Using the Antenna Effect as a Spectroscopic Tool: Photophysics and Solution Thermodynamics of the Model Luminescent Hydroxypyridonate Complex [EuIII(3,4,3-LI(1,2-HOPO))]−. Inorg. Chem. 2009, 48 (23), 10868– 10870,  DOI: 10.1021/ic9013703
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    Using the Antenna Effect as a Spectroscopic Tool: Photophysics and Solution Thermodynamics of the Model Luminescent Hydroxypyridonate Complex [EuIII(3,4,3-LI(1,2-HOPO))]-
    Abergel, Rebecca J.; D'Aleo, Anthony; Leung, Clara Ng Pak; Shuh, David K.; Raymond, Kenneth N.
    Inorganic Chemistry (2009), 48 (23), 10868-10870CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Although widely used in bioassays, the spectrofluorimetric method described here uses the antenna effect as a tool to probe the thermodn. parameters of ligands that sensitize lanthanide luminescence. The Eu3+ coordination chem., soln. thermodn. stability, and photophys. properties of the spermine-based hydroxypyridonate octadentate chelator 3,4,3-LI(1,2-HOPO) are reported. The complex [EuIII(3,4,3-LI(1,2-HOPO))]- luminesces with a long lifetime (805 μs) and a quantum yield of 7.0% in aq. soln., at pH 7.4. These remarkable optical properties were exploited to det. the high (and proton-independent) stability of the complex (log β110 = 20.2(2)) and to define the influence of the ligand scaffold on the stability and photophys. properties.
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    Anderegg, G.; Arnaud-Neu, F.; Delgado, R.; Felcman, J.; Popov, K. Critical evaluation of stability constants of metal complexes of complexones for biomedical and environmental applications (IUPAC Technical Report). Pure Appl. Chem. 2005, 77 (8), 1445– 1495,  DOI: 10.1351/pac200577081445
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    Critical evaluation of stability constants of metal complexes of complexones for biomedical and environmental applications
    Anderegg, Giorgio; Arnaud-Neu, Francoise; Delgado, Rita; Felcman, Judith; Popov, Konstantin
    Pure and Applied Chemistry (2005), 77 (8), 1445-1495CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)
    A review. Available exptl. data on stability consts. of proton (hydron) and metal complexes for seven complexones of particular biomedical and environmental interest: iminodiacetic acid (2,2'-azanediyldiacetic acid, IDA); (methylimino)diacetic acid (2,2'-(methylazanediyl)diacetic acid, MIDA); 2,2',2'',2'''-{[(carboxymethyl)azanediyl]bis[(ethane-1,2-diyl)nitrilo]}tetraacetic acid (DTPA); 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA); 2,2',2''-(1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA); 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA); 2,2',2'',2'''-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetraacetic acid (TETA), published in 1945-2000, have been critically evaluated. Some typical errors in stability const. measurements for particular complexones are summarized. Higher quality data are selected and presented as "Recommended" or "Provisional".
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    Summer, D.; Garousi, J.; Oroujeni, M.; Mitran, B.; Andersson, K. G.; Vorobyeva, A.; Lofblom, J.; Orlova, A.; Tolmachev, V.; Decristoforo, C. Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression. Mol. Pharmaceutics 2018, 15 (1), 175– 185,  DOI: 10.1021/acs.molpharmaceut.7b00787
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    Cyclic versus Noncyclic Chelating Scaffold for 89Zr-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression
    Summer, Dominik; Garousi, Javad; Oroujeni, Maryam; Mitran, Bogdan; Andersson, Ken G.; Vorobyeva, Anzhelika; Loefblom, John; Orlova, Anna; Tolmachev, Vladimir; Decristoforo, Clemens
    Molecular Pharmaceutics (2018), 15 (1), 175-185CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Zirconium-89 is an emerging radionuclide for positron emission tomog. (PET) esp. for biomols. with slow pharmacokinetics as due to its longer half-life, in comparison to fluorine-18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to-head as bifunctional chelators for 89Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temp. but radiochem. yields increased substantially at elevated temp., 85 °C. Both 89Zr-FSC-ZEGFR:2377 and 89Zr-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 °C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89Zr-DFO-ZEGFR:2377, radiolabeled at room temp., showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of 89Zr-FSC-ZEGFR:2377 as well as 89Zr-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomols. with zirconium-89. Furthermore, our findings indicate that 89Zr-radiolabeling of DFO conjugates at higher temp. reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.
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    Zhai, C. Y.; Summer, D.; Rangger, C.; Franssen, G. M.; Laverman, P.; Haas, H.; Petrik, M.; Haubner, R.; Decristoforo, C. Novel Bifunctional Cyclic Chelator for Zr-89 Labeling-Radiolabeling and Targeting Properties of RGD Conjugates. Mol. Pharmaceutics 2015, 12 (6), 2142– 2150,  DOI: 10.1021/acs.molpharmaceut.5b00128
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    Novel Bifunctional Cyclic Chelator for 89Zr Labeling-Radiolabeling and Targeting Properties of RGD Conjugates
    Zhai, Chuangyan; Summer, Dominik; Rangger, Christine; Franssen, Gerben M.; Laverman, Peter; Haas, Hubertus; Petrik, Milos; Haubner, Roland; Decristoforo, Clemens
    Molecular Pharmaceutics (2015), 12 (6), 2142-2150CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Within the last years 89Zr has attracted considerable attention as long-lived radionuclide for positron emission tomog. (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting αβ3 integrins were synthesized using different conjugation strategies and labeled with 89Zr. In vitro stability, biodistribution, and microPET/CT imaging were evaluated using [89Zr]FSC-RGD conjugates or [89Zr]triacetylfusarinine C (TAFC). Quant. 89Zr labeling was achieved within 90 min at room temp. The distribution coeffs. of the different radioligands indicate hydrophilic character. Compared to [89Zr]DFO, [89Zr]FSC derivs. showed excellent in vitro stability and resistance against transchelation in phosphate buffered saline (PBS), EDTA soln. (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging expts. showed efficient receptor-specific targeting of [89Zr]FSC-RGD conjugates. No bone uptake was obsd. analyzing PET images indicating high in vivo stability. These findings indicate that FSC is a highly promising chelator for the development of 89Zr-based PET imaging agents.
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    Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease. Chem. Rev. 2010, 110 (5), 2858– 2902,  DOI: 10.1021/cr900325h
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    Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease
    Wadas, Thaddeus J.; Wong, Edward H.; Weisman, Gary R.; Anderson, Carolyn J.
    Chemical Reviews (Washington, DC, United States) (2010), 110 (5), 2858-2902CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review.
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    Burdett, J. K.; Hoffmann, R.; Fay, R. C. Eigth-coordination. Inorg. Chem. 1978, 17 (9), 2553– 2568,  DOI: 10.1021/ic50187a041
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    Eight-coordination
    Burdett, Jeremy K.; Hoffmann, Roald; Fay, Robert C.
    Inorganic Chemistry (1978), 17 (9), 2553-68CODEN: INOCAJ; ISSN:0020-1669.
    A systematic MO anal. of 8-coordinate mols. is presented. The emphasis lies in appreciating the basic electronic structure, σ and π substituent site preferences, and relative bond lengths within a particular geometry for the following structures: dodecahedron (DD), square antiprism (SAP), C2v bicapped trigonal prism (BTP), cube (C), hexagonal bipyramid (HB), square prism (SP), bicapped trigonal antiprism (BTAP), and D3h bicapped trigonal prism (ETP). With respect to σ or electroneg. effects the better σ donor should lie in the A sites of the DD and the capping sites of the BTP, although the preferences are not very strong when viewed from the basis of ligand charges. For d2 π acceptors and d° π donors, π site preferences are .perp.B > .perp.A > ‖A,B (> means better than) for the DD (this is Orgel's rule), ‖ > .perp. for the SAP, (m‖ > b‖) > b.perp. > (c‖ ∼ c.perp. ∼ m.perp.) for the BTP (b, c, and m refer to ligands which are basal, are capping, or belong to the trigonal faces and lie on a verticle mirror plane) and eq‖ ∼ ax > eq.perp. for the HB. The reverse order holds for d2 donors. The obsd. site preferences in the DD are probably controlled by a mixt. of steric and electronic (σ, π) effects. An interesting crossover from r(M-A)/r(M-B) > 1 to β) < 1 is found as a function of geometry for the DD structure which is well matched by exptl. observations. Similar effects should occur in the BTP structure, but here exptl. data are scarce. The importance of electronic effects in the form of metal-ligand interactions in stabilizing a particular geometry is estd. by using perturbation theory in the form of the angular overlap method (AOM). In order of increasing energy ETP < BTP < SAP < DD « C ∼ HB ∼ BTAP. The importance of steric effects is estd. by calcg. the energy of an L88- species by mol. orbital methods. In order of increasing energy DD ∼ SAP < BTP ∼ C < HB ∼ BTAP « ETP. The combination of these 2 series leads to an explanation of the relative popularity of these structures, DD, SAP, BTP » C, HB, BTAP » ETP. The importance of the low-symmetry BTP as a low-energy structure for the d° configuration clearly emerges. The perturbation theory approach is also used to rationalize the relative bond lengths in the DD structure as a function of geometry and in the bipyramidal 5-, 7-, and 8-coordinate structures. Polytopal rearrangements are found to be barriers from MO calcns. on systems with nonchelating ligands for at least one pathway between DD and SAP or from either of these structures to the BTP geometry.
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    Rousseau, J.; Zhang, Z. X.; Wang, X. Z.; Zhang, C. C.; Lau, J.; Rousseau, E.; Colovic, M.; Hundal-Jabal, N.; Benard, F.; Lin, K. S. Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with Zr-89 for imaging with positron emission tomography. Bioorg. Med. Chem. Lett. 2018, 28 (5), 899– 905,  DOI: 10.1016/j.bmcl.2018.01.067
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    Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography
    Rousseau, Julie; Zhang, Zhengxing; Wang, Xiaozhu; Zhang, Chengcheng; Lau, Joseph; Rousseau, Etienne; Colovic, Milena; Hundal-Jabal, Navjit; Benard, Francois; Lin, Kuo-Shyan
    Bioorganic & Medicinal Chemistry Letters (2018), 28 (5), 899-905CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with 89Zr for positron emission tomog. imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, resp. Trastuzumab conjugates of 3 and 4 were efficiently labeled with 89Zr (>95% radiochem. yield). The in vitro plasma stability of 89Zr-4-Trastuzumab and esp. 89Zr-3-Trastuzumab was greatly improved over previously reported 89Zr-1-Trastuzumab and 89Zr-2-Trastuzumab, but their demetalation remained higher and faster than 89Zr-deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for 89Zr-4-Trastuzumab, followed by 89Zr-3-Trastuzumab, and to a lesser extent for 89Zr-DFO-Trastuzumab. Mol. modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr-complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability.
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    Boros, E.; Holland, J. P.; Kenton, N.; Rotile, N.; Caravan, P. Macrocycle-Based Hydroxamate Ligands for Complexation and Immunoconjugation of (89)Zirconium for Positron Emission Tomography (PET) Imaging. ChemPlusChem 2016, 81 (3), 274– 281,  DOI: 10.1002/cplu.201600003
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    Macrocycle-Based Hydroxamate Ligands for Complexation and Immunoconjugation of 89Zirconium for Positron Emission Tomography (PET) Imaging
    Boros, Eszter; Holland, Jason P.; Kenton, Nathaniel; Rotile, Nicholas; Caravan, Peter
    ChemPlusChem (2016), 81 (3), 274-281CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Four novel chelators (L1-L4) and their 89zirconium complexes were prepd. and compared with the 89zirconium desferrioxamine B (DFO) complex. The new chelates are based on 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) scaffolds and present either three or four hydroxamate arms for coordination with Zr4+ ions with coordination nos. between six and eight. The 89Zr-L4 complex showed similar stability to that of 89Zr-DFO when incubated in either rat blood plasma or EDTA challenge expts. Positron imaging and biodistribution studies in mice showed that 89Zr-L4 had similar pharmacokinetic behavior to that of 89Zr-DFO, with rapid renal elimination and low residual activity in background tissues. A bifunctional version of L4 (L5) was synthesized and conjugated to trastuzumab; an anti-HER2/neu antibody. Immunopositron emission tomog. imaging and biodistribution with 89Zr-L5-trastuzumab revealed high tumor to background ratios (tumor/blood ratio: 14.2±2.25) and a high tumor specificity that was comparable to the performance of 89Zr-DFO-trastuzumab.
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    Tieu, W.; Lifa, T.; Katsifis, A.; Codd, R. Octadentate Zirconium(IV)-Loaded Macrocycles with Varied Stoichiometry Assembled From Hydroxamic Acid Monomers using Metal-Templated Synthesis. Inorg. Chem. 2017, 56 (6), 3719– 3728,  DOI: 10.1021/acs.inorgchem.7b00362
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    Octadentate Zirconium(IV)-Loaded Macrocycles with Varied Stoichiometry Assembled From Hydroxamic Acid Monomers using Metal-Templated Synthesis
    Tieu, William; Lifa, Tulip; Katsifis, Andrew; Codd, Rachel
    Inorganic Chemistry (2017), 56 (6), 3719-3728CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) in a 1:4 stoichiometry in the presence of diphenylphosphoryl azide and triethylamine gave the octadentate Zr(IV)-loaded tetrameric hydroxamic acid macrocycle for-[Zr(DFOT1)] ([M + H]+ calc 887.3, obs 887.2). In this metal-templated synthesis (MTS) approach, the coordination preferences of Zr(IV) directed the preorganization of four oxygen-rich bidentate for-PBH ligands about the metal ion prior to ring closure under peptide coupling conditions. The replacement of for-PBH with 5-[(5-aminopentyl) (hydroxy)amino]-5-oxopentanoic acid (for-PPH), which contained an addnl. methylene group in the dicarboxylic acid region of the monomer, gave the analogous Zr(IV)-loaded macrocycle for-[Zr(PPDFOT1)] ([M + H]+ calc 943.4, obs 943.1). A second, well-resolved peak in the liq. chromatogram from the for-PPH MTS system also characterized as a species with [M + H]+ 943.3, and was identified as the octadentate complex between Zr(IV) and two dimeric tetradentate hydroxamic acid macrocycles for-[Zr(PPDFOT1D)2]. Treatment of for-[Zr(PPDFOT1)] or for-[Zr(PPDFOT1D)2] with EDTA at pH 4.0 gave the resp. hydroxamic acid macrocycles as free ligands: octadentate PPDFOT1 or two equiv. of tetradentate PPDFOT1D (homobisucaberin, HBC). At pH values closer to physiol., EDTA treatment of for-[Zr(DFOT1)], for-[Zr(PPDFOT1)], or Zr(IV) complexes with related linear tri- or tetrameric hydroxamic acid ligands showed the macrocycles were more resistant to the release of Zr(IV), which has implications for the design of ligands optimized for the use of Zr(IV)-89 in positron emission tomog. (PET) imaging of cancer.
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    Zeglis, B. M.; Mohindra, P.; Weissmann, G. I.; Divilov, V.; Hilderbrand, S. A.; Weissleder, R.; Lewis, J. S. Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels-Alder Click Chemistry. Bioconjugate Chem. 2011, 22 (10), 2048– 2059,  DOI: 10.1021/bc200288d
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    Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels-Alder Click Chemistry
    Zeglis, Brian M.; Mohindra, Priya; Weissmann, Gabriel I.; Divilov, Vadim; Hilderbrand, Scott A.; Weissleder, Ralph; Lewis, Jason S.
    Bioconjugate Chemistry (2011), 22 (10), 2048-2059CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    A modular system for the construction of radiometalated antibodies was developed based on the bioorthogonal cycloaddn. reaction between 3-(4-benzylamino)-1,2,4,5-tetrazine and the strained dienophile norbornene. The well-characterized, HER2-specific antibody trastuzumab and the positron emitting radioisotopes 64Cu and 89Zr were employed as a model system. The antibody was first covalently coupled to norbornene, and this stock of norbornene-modified antibody was then reacted with tetrazines bearing the chelators 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA) or desferrioxamine (DFO) and subsequently radiometalated with 64Cu and 89Zr, resp. The modification strategy is simple and robust, and the resultant radiometalated constructs were obtained in high specific activity (2.7-5.3 mCi/mg). For a given initial stoichiometric ratio of norbornene to antibody, the 64Cu-DOTA- and 89Zr-DFO-based probes were shown to be nearly identical in terms of stability, the no. of chelates per antibody, and immunoreactivity (>93% in all cases). In vivo PET imaging and acute biodistribution expts. revealed significant, specific uptake of the 64Cu- and 89Zr-trastuzumab bioconjugates in HER2-pos. BT-474 xenografts, with little background uptake in HER2-neg. MDA-MB-468 xenografts or other tissues. This modular system-one in which the divergent point is a single covalently modified antibody stock that can be reacted selectively with various chelators-will allow for both greater versatility and more facile cross-comparisons in the development of antibody-based radiopharmaceuticals.
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    Price, E. W.; Orvig, C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 2014, 43 (1), 260– 290,  DOI: 10.1039/C3CS60304K
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    Matching chelators to radiometals for radiopharmaceuticals
    Price, Eric W.; Orvig, Chris
    Chemical Society Reviews (2014), 43 (1), 260-290CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomog. (SPECT, e.g.67Ga, 99mTc, 111In, 177Lu) and positron emission tomog. (PET, e.g.68Ga, 64Cu, 44Sc, 86Y, 89Zr), as well as therapeutic applications (e.g.47Sc, 114mIn, 177Lu, 90Y, 212/213Bi, 212Pb, 225Ac, 186/188Re). A fundamental crit. component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable mol. target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochem., nuclear medicine, and mol. imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The exptl. methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents.
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    Bastian, R.; Weberling, R.; Palilla, F. Determination of iron by ultraviolet spectrophotometry. Anal. Chem. 1956, 28 (4), 459– 462,  DOI: 10.1021/ac50161a014
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    Determination of iron by ultraviolet spectrophotometry
    Bastian, Robert; Weberling, Richard; Palilla, Frank
    (1956), 28 (), 459-62CODEN: ANCHAM; ISSN:0003-2700.
    Fe+++ in HClO4 soln. gives an absorbance max. at 240 mμ (molar absorptivity 4.16 × 103 l. per mol. cm.). Less interference from other metals is encountered, however, at 260 mμ, which is the preferred wave length despite the lower absorption (molar absorptivity 2.88 × 103 l. per mol. cm.). Beer's law is followed up to an absorbance of at least 0.8. The absorbance rises with HClO4 concn. until 1 or 2 ml. of concd. HClO4 is present per 100 ml. of soln., and then remains nearly const. up to very high concns.; ten ml. of HClO4 in 100 ml. of soln. is recommended. The solns. are stable for long periods, no change in absorbance being noted in over 1 month. The temp. is not a crit. variable. Interferences of a no. of metals, and their elimination, are discussed.
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    Szebesczyk, A.; Olshvang, E.; Besserglick, J.; Gumienna-Kontecka, E. Influence of structural elements on iron(III) chelating properties in a new series of amino acid-derived monohydroxamates. Inorg. Chim. Acta 2018, 473, 286– 296,  DOI: 10.1016/j.ica.2017.06.020
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    Influence of structural elements on iron(III) chelating properties in a new series of amino acid-derived monohydroxamates
    Szebesczyk, Agnieszka; Olshvang, Evgenia; Besserglick, Jenny; Gumienna-Kontecka, Elzbieta
    Inorganica Chimica Acta (2018), 473 (), 286-296CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
    Amino acid-derived monohydroxamate compds. A1-A7 were synthesized and characterized for their coordination properties of Fe(III). The series varies in their skeletal lengths and compns.; some compds. lack external substituents, others are substituted with external functional amino or carboxylic groups, or alternatively inert Me. Undertaken investigations allowed the detn. of stoichiometry, stability consts. and spectroscopic parameters of formed ferric complexes. Incorporation of an external functional group with a dissociable proton affects the coordination behavior; the presence of carboxylic or amino groups hampers the formation of mono-, di- and trihydroxamate ferric complexes of presented compds. The differences in Fe(III) affinity of the monohydroxamates vs. trihydroxamates was reflected by the stability consts. and pFe, indicating the superior stability of hexadentate complexes.
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    Babko, A. K.; Gridchina, G. I. Vliyanie sostoyaniya tsirkoniya v rastvore na ego vzaimodeistvie s organicheskimi reaktivami. Zhur. Neorg. Khim. 1962, 7 (4), 889– 893
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    Effect of the state of zirconium in solution on its reaction with organic reagents
    Babko, A. K.; Gridchina, G. I.
    Zhurnal Neorganicheskoi Khimii (1962), 7 (), 889-95CODEN: ZNOKAQ; ISSN:0044-457X.
    The effect of the state of Zr in soln. on the rate of formation of colored complexes was studied with Xylenol Orange (I), Methylthymol Blue, Alizarin C, phenylfluorone, Arsenazo, and Stilbazo. Solns. of different concns. of Zr in 0.01-2N HCl, with a const. ionic strength μ = 1 maintained with NaCl, were allowed to stand 10 days. If necessary, the solns. were dild. with 2N HCl to a final HCl concn., CHCl = 2N and to a final [Zr] = 2 × 10-5M. I was added to a final concn. of 2.5 × 10-5M, and the optical d. was detd. at intervals. The results showed that the reactivity, α, of polyions of Zr was more dependent on CHCl than on [Zr]. Solns. aged with [Zr] >0.01M in 1N HCl exhibited low α. The structure of the polyions was of the type -Zr(OH)2-O-Zr(OH)2-O-. Preliminary pptn. of the hydroxide followed by soln. in N HCl lowered α. Heating soln. before the addn. of I, thus increasing hydrolysis, lowered α. The presence of Al or sulfates during the pptn. increased α. Complete restoration of α was obtained by heating with 2-5N HCl. Heating soln. of pH = 2 destroyed the reactivity, and 50 γ Th could be detd. in the presence of 50-100 γ Zr with I, and in the presence of 10 γ Al with aluminon.
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    Enyedy, E. A.; Primik, M. F.; Kowol, C. R.; Arion, V. B.; Kiss, T.; Keppler, B. K. Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study. Dalton Trans. 2011, 40 (22), 5895– 5905,  DOI: 10.1039/c0dt01835j
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    Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study
    Enyedy, Eva A.; Primik, Michael F.; Kowol, Christian R.; Arion, Vladimir B.; Kiss, Tamas; Keppler, Bernhard K.
    Dalton Transactions (2011), 40 (22), 5895-5905CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    The stoichiometries and stabilities of Ga3+, Fe3+, and Fe2+ complexes of Triapine and five related α-N heterocyclic thiosemicarbazones with potential antitumor activity were detd. by pH-potentiometry, UV-vis spectrophotometry, 1H NMR spectroscopy, and spectrofluorimetry in aq. soln. (with 30% DMSO), together with the characterization of the proton dissocn. processes. Addnl., the redox properties of the iron complexes were studied by cyclic voltammetry at various pH values. Formation of high stability bis-ligand complexes was found in all cases, which are predominant at physiol. pH with FeIII/FeII, while only at the acidic pH range with GaIII. The results show that among the thiosemicarbazones with various substituents the N-terminal dimethylation does not exert a measurable effect on the redox potential, but has the highest impact on the stability of the complexes as well as the cytotoxicity, esp. in the absence of a pyridine-NH2 group in the mol. In addn. the fluorescence properties of the ligands in aq. soln. and their changes caused by GaIII were studied.
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    Alfenaar, M.; Deligny, C. L. Universal ph-scale in methanol and methanol-water mixtures. Recl. Trav. Chim. Pays-Bas 1967, 86 (11), 1185– 1190,  DOI: 10.1002/recl.19670861104
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    Universal pH-scale in methanol and methanol-water mixtures
    Alfenaar, M.; De Ligny, C. L.
    Recueil des Travaux Chimiques des Pays-Bas (1967), 86 (12), 1185-90CODEN: RTCPA3; ISSN:0165-0513.
    An electrometric method was used to define a pH scale in terms of pHSt values of standard buffer solns. of 0.1M solns. of (COOH)2 and (NH4)2C2O4, of (CH2COOH)2 and LiHC4H4O4, and of o-C6H4(OH)(COOH) and o-HOC6H4COONa in MeOH or MeOH-H2O; in terms of pHSt of aq. standard buffer solns.; and for values of a correction term [Ej(H2O) - Ej(S)]/0.05916 added to the value of pHx (the unknown) detd. with a pH meter (Ej(H2O) and Ej(S) are the liq. junction potentials). Accuracy is 0.01-0.12 and 0.27 pH units in 0-90% MeOH and MeOH, resp.
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    Gelsema, W. J.; Deligny, C. L.; Remijnse, A. G.; Blijleve, H. pH-measurements in alcohol-water mixtures using aqueous standard buffer solutions for calibration. Recl. Trav. Chim. Pays-Bas 1966, 85 (7), 647– 660,  DOI: 10.1002/recl.19660850702
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    pH-measurements in alcohol-water mixtures, using aqueous standard buffer solutions for calibration
    Gelsema, W. J.; de Ligny, C. L.; Remijnse, A. G.; Blijleven, H. A.
    Recueil des Travaux Chimiques des Pays-Bas (1966), 85 (7), 647-60CODEN: RTCPA3; ISSN:0165-0513.
    Emf. detns. show that the influence of the solvent on the Liquid junction potential is the same for junctions formed in a capillary, a ground glass sleeve, and a fritted-glass disk. Also, the influence of the solvent on the standard potential of a glass electrode does not depend on the type of electrode. Thus, accurate pa*H.X detns. can be made in MeOH-H2O and EtOH-H2O mixts. by calibrating a pH-meter with aq. standard buffer solns. and subtracting from the meter readings pHx an amt. Δto account for the influence of the solvent. Δ-values are given for MeOH-H2O mixts. contg. up to 94% MeOH and for EtOH-H2O mixts. contg. up to 72% EtOH.
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    Gans, P.; O’Sullivan, B. GLEE, a new computer program for glass electrode calibration. Talanta 2000, 51 (1), 33– 37,  DOI: 10.1016/S0039-9140(99)00245-3
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    GLEE, a new computer program for glass electrode calibration
    Gans, P.; O'Sullivan, B.
    Talanta (2000), 51 (1), 33-37CODEN: TLNTA2; ISSN:0039-9140. (Elsevier Science B.V.)
    A new computer program (GLEE, glass electrode evaluation) was written for the calibration of a glass electrode by a strong acid-strong base titrn. This program provides an est. of the carbonate contamination of the base, the pseudo-Nernstian std. potential and slope of the electrode and, optionally, the concn. of the base and pKW. The program runs under the Windows 3.1x, 9x and NT operating systems.
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  • Abstract

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    Scheme 1

    Scheme 1. Structures of the Ligands Investigated and Discussed in This Paper
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    Scheme 2

    Scheme 2. Synthetic Pathway of the Ligand H3L1a
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    aReagents and conditions: (i) (Boc)2O, K2CO3, H2O/dioxane; (ii) ethyl 4-bromobutyrate, NaH, DMF; (iii) TFA; (iv) Boc-γ-aminobutyric acid, HATU, DIPEA, DMF; (v) LiOH, H2O/dioxane; (vi) 5, HATU, DIPEA, DMF; (vii) 6, HATU, DIPEA, DMF; (viii) HATU, DIPEA, DMF; (ix) H2, Pd/C, MeOH.

    Scheme 3

    Scheme 3. Synthetic Pathway of the Ligand H4L2a
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    aReagents and conditions: (i) TFA; (ii) Z-Lys(Boc)-OH, HATU, DIPEA, DMF; (iii) LiOH, H2O/dioxane; (iv) HATU, DIPEA, DMF; (v) H2, Pd/C, MeOH.

    Figure 1

    Figure 1. UV spectra of Ga(III)-H3L1 (a, c) and Ga(III)-H4L2 (b, d) systems at a metal to ligand molar ratio of 1:1 in the pH range 1.0–11.0. Conditions: cL1 = 0.05 mM, cL2 = 0.05 mM, 0.1 M NaClO4, T = 25 °C.

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    Figure 2

    Figure 2. UV–vis metal–metal competition experiment for (a) Fe(III)-H3L1+Ga(III) (cFe(III) = 0.075 mM, cL = 0.075 mM) and (b) Ga(III)-H3L1+Fe(III) (cFe(III) = 0.08 mM, cL1 = 0.08 mM) systems at pH 1.5, I = 0.1 M (NaClO4), and T = 25 °C.

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    Figure 3

    Figure 3. UV spectra of the Zr(IV)-H3L1 (a, c) and Zr(IV)-H4L2 (b, d) systems at a metal to ligand molar ratio of 1:1 in the pH range 0.1–11 Conditions: cL1 = 0.05 mM, cL2 = 0.037 mM, 0.1 M NaClO4.

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    Figure 4

    Figure 4. UV–vis spectra of competition titrations of the Fe(III)-H3L1 + Zr(IV)-NTA (cFe(III) = 0.098 mM, cL1 = 0.098 mM) (a) and Fe(III)-H4L2 + Zr(IV)-NTA (cFe(III) = 0.055 mM, cL2 = 0.055 mM) (b) systems at pH 1.5 with 0.1 M NaClO4.

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  • References

    This article references 86 other publications.

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      89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry
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      Bioconjugate Chemistry (2017), 28 (9), 2211-2223CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Immuno-positron emission tomog. (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclin. studies have shown that DFO is not an ideal chelator because the 89Zr-DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochem., including novel chelators and site-specific conjugation methods.
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      Buchwalder, C.; Jaraquemada-Pelaez, M. D.; Rousseau, J.; Merkens, H.; Rodriguez-Rodriguez, C.; Orvig, C.; Benard, F.; Schaffer, P.; Saatchi, K.; Hafeli, U. O. Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular Zr-89-THPN-Conjugates. Inorg. Chem. 2019, 58 (21), 14667– 14681,  DOI: 10.1021/acs.inorgchem.9b02350
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      Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular 89Zr-THPN-Conjugates
      Buchwalder, Christian; Jaraquemada-Pelaez, Maria de Guadalupe; Rousseau, Julie; Merkens, Helen; Rodriguez-Rodriguez, Cristina; Orvig, Chris; Benard, Francois; Schaffer, Paul; Saatchi, Katayoun; Hafeli, Urs O.
      Inorganic Chemistry (2019), 58 (21), 14667-14681CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomog. (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclin. studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodn. stability was quantified in soln. titrn. studies, which revealed one of the highest formation consts. reported for a zirconium chelate (log βML 50.3(1), pM = 42.8). Soln. stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional deriv. of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-mol. wt. (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiol. stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIV for THPN. This finding contrasts with the exceptionally high thermodn. stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by d. functional theory (DFT) calcns. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiol. stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates. The tetrapodal octadentate chelating ligand THPN was investigated as an alternative chelator for 89Zr. Soln. studies with ZrIV and FeIII revealed exceptional thermodn. stabilities that are among the highest reported for these metal ions. The prepn. of a bifunctional deriv. of the ligand allowed a prolonged in vivo stability assessment employing a macromol. carrier that suggested a need for optimization of the conjugation strategy or of the kinetic inertness.
    3. 3
      Buchwalder, C.; Rodriguez-Rodriguez, C.; Schaffer, P.; Karagiozov, S. K.; Saatchi, K.; Hafeli, U. O. A new tetrapodal 3-hydroxy-4-pyridinone ligand for complexation of (89)zirconium for positron emission tomography (PET) imaging. Dalton Trans. 2017, 46 (29), 9654– 9663,  DOI: 10.1039/C7DT02196H
      3
      A new tetrapodal 3-hydroxy-4-pyridinone ligand for complexation of 89zirconium for positron emission tomography (PET) imaging
      Buchwalder, Christian; Rodriguez-Rodriguez, Cristina; Schaffer, Paul; Karagiozov, Stoyan K.; Saatchi, Katayoun; Hafeli, Urs O.
      Dalton Transactions (2017), 46 (29), 9654-9663CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      Zirconium-89 (89Zr) is an ideal radiometal isotope for antibody-based positron emission tomog. (immunoPET) as its phys. half-life (3.27 days) is a good match with the biol. half-life of larger mol. wt. targeting mols., such as antibodies (3-4 days), and its positron emission (BR = 100% EC/β+, Eβ+,avg = 395.5 keV) is suited for high resoln. PET imaging. Concerns over the in vivo stability of the most commonly used 89Zr-chelator, desferrioxamine B (DFO), have spurred efforts into the development of alternative 89Zr-chelators that withstand the release of osteophilic 89Zr4+. Herein we report the new chelator 1,3-propanediamine-N,N,N',N'-tetrakis[(2-(aminomethyl)-3-hydroxy-1,6-dimethyl-4(1H)-pyridinone)acetamide] (THPN) based on four 3-hydroxy-4-pyridinone (3,4-HOPO) coordinating groups, as a potentially superior chelator over DFO. THPN has been demonstrated to quant. form a monometallic complex with Zr4+ within 10 min at ambient temp. at as low as 10-6 M concns. of the chelator. The resulting complexes were studied in vitro and in vivo. The 89Zr-THPN complex was stable in serum and outperformed the 89Zr-DFO complex in a direct transchelation challenge. Healthy mice excreted 89Zr-THPN rapidly without signs of demetalation or residual organ uptake. This renders THPN as a promising alternative to DFO and introduces the first octadentate 3,4-HOPO chelator to the field.
    4. 4
      Raave, R.; Sandker, G.; Adumeau, P.; Jacobsen, C. B.; Mangin, F.; Meyer, M.; Moreau, M.; Bernhard, C.; Da Costa, L.; Dubois, A.; Goncalves, V.; Gustafsson, M.; Rijpkema, M.; Boerman, O.; Chambron, J.-C.; Heskamp, S.; Denat, F. Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for Zr-89-immunoPET. Eur. J. Nucl. Med. Mol. Imaging 2019, 46 (9), 1966– 1977,  DOI: 10.1007/s00259-019-04343-2
      4
      Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET
      Raave, Rene; Sandker, Gerwin; Adumeau, Pierre; Jacobsen, Christian Borch; Mangin, Floriane; Meyer, Michel; Moreau, Mathieu; Bernhard, Claire; Da Costa, Laurene; Dubois, Adrien; Goncalves, Victor; Gustafsson, Magnus; Rijpkema, Mark; Boerman, Otto; Chambron, Jean-Claude; Heskamp, Sandra; Denat, Franck
      European Journal of Nuclear Medicine and Molecular Imaging (2019), 46 (9), 1966-1977CODEN: EJNMA6; ISSN:1619-7070. (Springer)
      The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO. Methods: The stability of 89Zr-labeled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The in vivo distribution was investigated in mice with s.c. HER2+ SKOV-3 or HER2- MDA-MB-231 xenografts by PET/CT imaging and quant. ex vivo tissue analyses 7 days after injection. Results: 89Zr-labeled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In vivo studies, HER2+ SKOV-3 tumor-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Conclusion: 89Zr-labeled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clin. used std. chelator for 89Zr immunoPET.
    5. 5
      Alnahwi, A. H.; Ait-Mohand, S.; Dumulon-Perreault, V.; Dory, Y. L.; Guerin, B. Promising Performance of 4HMS, a New Zirconium-89 Octadendate Chelator. ACS Omega 2020, 5 (19), 10731– 10739,  DOI: 10.1021/acsomega.0c00207
      5
      Promising Performance of 4HMS, a New Zirconium-89 Octadendate Chelator
      Alnahwi, Aiman H.; Ait-Mohand, Samia; Dumulon-Perreault, Veronique; Dory, Yves L.; Guerin, Brigitte
      ACS Omega (2020), 5 (19), 10731-10739CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      Over the last decade, the interest in zirconium-89 (89Zr) as a positron-emitting radionuclide increased considerably because of its standardized prodn. and its phys. half-life (78.41 h), which matches the biol. half-life of antibodies and its successful use in preclin. and clin. applications. So far, desferrioxamine (DFO), a com. available chelator, has been mainly used as a bifunctional chelating system. However, there are some concerns regarding the in vivo stability of the [89Zr]Zr-DFO complex. In this study, we report the synthesis of an acyclic N-hydroxy-N-Me succinamide-based chelator (4HMS) with 8 coordination sites and our first investigations into the use of this new chelator for 89Zr complexation. In vitro and in vivo comparative studies with [89Zr]Zr-4HMS and [89Zr]Zr-DFO are presented. The 4HMS chelator was synthesized in four steps starting with an excellent overall yield. Both chelators were quant. labeled with 89Zr within 5-10 min at pH 7 and room temp.; the molar activity of [89Zr]Zr-4HMS exceeded (>3 times) that of [89Zr]Zr-DFO. [89Zr]Zr-4HMS remained stable against transmetalation and transchelation and cleared from most tissues within 24 h. The kidney, liver, bone, and spleen uptakes were significantly low for this 89Zr-complex. Positron emission tomog. images were in accordance with the results of the biodistribution in healthy mice. Based on DFT calcns., a rationale is provided for the high stability of 89Zr-4HMS. This makes 4HMS a promising chelator for future development of 89Zr-radiopharmaceuticals.
    6. 6
      Kaeopookum, P.; Petrik, M.; Summer, D.; Klinger, M.; Zhai, C.; Rangger, C.; Haubner, R.; Haas, H.; Hajduch, M.; Decristoforo, C. Comparison of Ga-68-labeled RGD mono- and multimers based on a clickable siderophore-based scaffold. Nucl. Med. Biol. 2019, 78–79, 1– 10,  DOI: 10.1016/j.nucmedbio.2019.09.002
      6
      Comparison of 68Ga-labeled RGD mono- and multimers based on a clickable siderophore-based scaffold
      Kaeopookum, Piriya; Petrik, Milos; Summer, Dominik; Klinger, Maximilian; Zhai, Chuangyan; Rangger, Christine; Haubner, Roland; Haas, Hubertus; Hajduch, Marian; Decristoforo, Clemens
      Nuclear Medicine and Biology (2019), 78-79 (), 1-10CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
      Cyclic pentapeptides contg. the amino acid sequence arginine-glycine-aspartic (RGD) have been widely applied to target αvβ3 integrin, which is upregulated in various tumors during tumor-induced angiogenesis. Multimeric cyclic RGD peptides have been reported to be advantageous over monomeric counterparts for angiogenesis imaging. Here, we prepd. mono-, di-, and trimeric cyclic arginine-glycine-aspartic-D-phenylalanine-lysine (c (RGDfK)) derivs. by conjugation with the natural chelator fusarinine C (FSC) using click chem. based on copper (I)-catalyzed azide-alkyne cycloaddn. (CuAAC). In vitro internalization assays with human melanoma M21 (αvβ3-pos.) and M21-L (αvβ3-neg.) cell lines showed specific uptake of all derivs. and increased in the series: mono- < di- < trimeric peptide. The highest tumor uptake, tumor-to-background ratios, and image contrast were found for the dimeric [68Ga]GaMAFC(c(RGDfK)aza)2. In conclusion, we developed a novel strategy for direct, straight forward prepn. of mono-, di-, and trimeric c(RGDfK) conjugates based on the FSC scaffold. Interestingly, the best αvβ3 imaging properties were found for the dimeric [68Ga]GaMAFC(c(RGDfK)aza)2.
    7. 7
      Zhai, C. Y.; He, S. Z.; Ye, Y. J.; Rangger, C.; Kaeopookum, P.; Summer, D.; Haas, H.; Kremser, L.; Lindner, H.; Foster, J.; Sosabowski, J.; Decristoforo, C. Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89. Biomolecules 2019, 9 (3), 91– 105,  DOI: 10.3390/biom9030091
      7
      Rational design, synthesis and preliminary evaluation of novel fusarinine C-based chelators for radiolabeling with zirconium-89
      Zhai, Chuangyan; He, Shanzhen; Ye, Yunjie; Rangger, Christine; Kaeopookum, Piriya; Summer, Dominik; Haas, Hubertus; Kremser, Leopold; Lindner, Herbert; Foster, Julie; Sosabowski, Jane; Decristoforo, Clemens
      Biomolecules (2019), 9 (3), 91CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      Fusarinine C (FSC) has recently been shown to be a promising and novel chelator for 89Zr. Here, FSC has been further derivatized to optimize the complexation properties of FSC-based chelators for 89Zr-labeling by introducing addnl. carboxylic groups. These were expected to improve the stability of 89Zr-complexes by satg. the 8-coordination sphere of [89Zr] Zr4+, and also to introduce functionalities suitable for conjugation to targeting vectors such as monoclonal antibodies. For proof of concept, succinic acid derivatization at the amine groups of FSC was carried out, resulting in FSC(succ)2 and FSC(succ)3. FSC(succ)2 was further derivatized to FSC(succ)2 AA by reacting with acetic anhydride (AA). The Zr4+ complexation properties of these chelators were studied by reacting with ZrCl4. Partition coeff., protein binding, serum stability, acid dissocn., and transchelation studies of 89Zr-complexes were carried out in vitro and the results were compared with those for 89Zr-desferrioxamine B ([89Zr]Zr-DFO) and 89Zr-triacetylfusarinine C ([89Zr]Zr-TAFC). The in vivo properties of [89Zr]Zr-FSC(succ)3 were further compared with [89Zr]Zr-TAFC in BALB/c mice using micro-positron emission tomog./computer tomog. (microPET/CT) imaging. Fusarinine C (succ)2AA and FSC(succ)3 were synthesized with satisfactory yields. Complexation with ZrCl4 was achieved using a simple strategy resulting in high-purity Zr-FSC(succ)2AA and Zr-FSC(succ)3 with 1:1 stoichiometry. Distribution coeffs. of 89Zr-complexes revealed increased hydrophilic character compared to [89Zr]Zr-TAFC. All radioligands showed high stability in phosphate buffered saline (PBS) and human serum and low protein-bound activity over a period of seven days. Acid dissocn. and transchelation studies exhibited a range of in vitro stabilities following the order: [89Zr]Zr-FSC(succ)3 > [89Zr]Zr-TAFC > [89Zr]Zr-FSC(succ)2AA >> [89Zr]Zr-DFO. Biodistribution studies of [89Zr]Zr-FSC(succ)3 revealed a slower excretion pattern compared to [89Zr]Zr-TAFC. In conclusion, [89Zr]Zr-FSC(succ)3 showed the best stability and inertness. The promising results obtained with [89Zr]Zr-FSC(succ)2AA highlight the potential of FSC(succ)2 as a monovalent chelator for conjugation to targeted biomols., in particular, monoclonal antibodies.
    8. 8
      Pandey, A.; Savino, C.; Ahn, S. H.; Yang, Z. Y.; Van Lanen, S. G.; Boros, E. Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency. J. Med. Chem. 2019, 62 (21), 9947– 9960,  DOI: 10.1021/acs.jmedchem.9b01388
      8
      Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency
      Pandey, Apurva; Savino, Chloe; Ahn, Shin Hye; Yang, Zhaoyong; Van Lanen, Steven G.; Boros, Eszter
      Journal of Medicinal Chemistry (2019), 62 (21), 9947-9960CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Pathogenic bacteria scavenge ferric iron from the host for survival and proliferation using small-mol. chelators, siderophores. Here, we introduce and assess the gallium(III) complex of ciprofloxacin-functionalized desferrichrome (D2) as a potential therapeutic for bacterial infection using an in vitro assay and radiochem., tracer-based approach. Ga-D2 exhibits a min. inhibitory concn. of 0.23μM in Escherichia coli, in line with the parent fluoroquinolone antibiotic. Competitive and mutant strain assays show that Ga-D2 relies on FhuA-mediated transport for internalization. Ga-D2 is potent against Pseudomonas aeruginosa (3.8μM), Staphylococcus aureus (0.94μM), and Klebsiella pneumoniae (12.5μM), while Fe-D2 is inactive in these strains. Radiochem. expts. with E. coli reveal that 67Ga-D2 is taken up more efficiently than 67Ga-citrate. In naive mice, 67Ga-D2 clears renally and is excreted 13% intact in the urine. These pharmacokinetic and bacterial growth inhibitory properties qualify Ga-D2 for future investigations as a diagnosis and treatment tool for infection.
    9. 9
      Velikyan, I. Prospective of Ga-68-Radiopharmaceutical Development. Theranostics 2014, 4 (1), 47– 80,  DOI: 10.7150/thno.7447
      9
      Prospective of 68Ga-Radiopharmaceutical development
      Velikyan, Irina
      Theranostics (2014), 4 (1), 47-80CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
      A review. Positron Emission Tomog. (PET) experienced accelerated development and has become an established method for medical research and clin. routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clin. PET. The future development of the 68Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, prodn. and availability of 68Ga, automation of the radiopharmaceutical prodn., progress of positron emission tomog. technologies and image anal. methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chem. The review presents the prospects of the 68Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents.
    10. 10
      Holland, J. P.; Williamson, M. J.; Lewis, J. S. Unconventional Nuclides for Radiopharmaceuticals. Mol. Imaging 2010, 9 (1), 1– 20,  DOI: 10.2310/7290.2010.00008
      10
      Unconventional nuclides for radiopharmaceuticals
      Holland, Jason P.; Williamson, Matthew J.; Lewis, Jason S.
      Molecular Imaging (2010), 9 (1), 1-20CODEN: MIOMBP; ISSN:1535-3508. (BC Decker Inc.)
      A review. Rapid and widespread growth in the use of nuclear medicine for both diagnosis and therapy of disease has been the driving force behind burgeoning research interests in the design of novel radiopharmaceuticals. Until recently, the majority of clin. and basic science research has focused on the development of 11C-, 13N-, 15O-, and 18F-radiopharmaceuticals for use with positron emission tomog. (PET) and 99mTc-labeled agents for use with single-photon emission computed tomog. (SPECT). With the increased availability of small, low-energy cyclotrons and improvements in both cyclotron targetry and purifn. chemistries, the use of "nonstandard" radionuclides is becoming more prevalent. This brief review describes the phys. characteristics of 60 radionuclides, including β+, β-, γ-ray, and α-particle emitters, which have the potential for use in the design and synthesis of the next generation of diagnostic and/or radiotherapeutic drugs. As the decay processes of many of the radionuclides described herein involve emission of high-energy γ-rays, relevant shielding and radiation safety issues are also considered. In particular, the properties and safety considerations assocd. with the increasingly prevalent PET nuclides 64Cu, 68Ga, 86Y, 89Zr, and 124I are discussed.
    11. 11
      Kubicek, V.; Havlickova, J.; Kotek, J.; Gyula, T.; Hermann, P.; Toth, E.; Lukes, I. Gallium(III) Complexes of DOTA and DOTA-Monoamide: Kinetic and Thermodynamic Studies. Inorg. Chem. 2010, 49 (23), 10960– 10969,  DOI: 10.1021/ic101378s
      11
      Gallium(III) Complexes of DOTA and DOTA-Monoamide: Kinetic and Thermodynamic Studies
      Kubicek, Vojtech; Havlickova, Jana; Kotek, Jan; Tircso, Gyula; Hermann, Petr; Toth, Eva; Lukes, Ivan
      Inorganic Chemistry (2010), 49 (23), 10960-10969CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Given the practical advantages of the 68Ga isotope in positron emission tomog. applications, gallium complexes are gaining increasing importance in biomedical imaging. However, the strong tendency of Ga3+ to hydrolyze and the slow formation and very high stability of macrocyclic complexes altogether render Ga3+ coordination chem. difficult and explain why stability and kinetic data on Ga3+ complexes are rather scarce. Here the authors report soln. and solid-state studies of Ga3+ complexes formed with the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, (DOTA)4-, and its mono(n-butylamide) deriv., (DO3AMBu)3-. Thermodn. stability consts., log K(GaDOTA) = 26.05 and log K(GaDO3AMBu) = 24.64, were detd. by out-of-cell pH-potentiometric titrns. Due to the very slow formation and dissocn. of the complexes, equilibration times of up to ∼4 wk were necessary. The kinetics of complex dissocn. were followed by 71Ga NMR under both acidic and alk. conditions. The GaDOTA complex is significantly more inert (τ1/2 ∼12.2 d at pH = 0 and τ1/2 ∼6.2 h at pH = 10) than the GaDO3AMBu analog (τ1/2 ∼2.7 d at pH = 0 and τ1/2 ∼0.7 h at pH = 10). Nevertheless, the kinetic inertness of both chelates is extremely high and approves the application of Ga3+ complexes of such DOTA-like ligands in mol. imaging. The solid-state structure of the GaDOTA complex, crystd. from a strongly acidic soln. (pH < 1), evidenced a diprotonated form with protons localized on the free carboxylate pendants.
    12. 12
      NETSPOT (kit for the preparation of gallium Ga 68 DOTATATE injection); https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208547Orig1s000TOC.cfm (accessed April 1, 2018).
      There is no corresponding record for this reference.
    13. 13
      Calais, J.; Fendler, W.; Eiber, M.; Wolin, E.; Slavik, R.; Barrio, M.; Gupta, P.; Quon, A.; Schiepers, C.; Auerbach, M.; Czernin, J.; Herrmann, K. High degree of implementation of intended management changes after Ga-68-DOTATATE PET/CT imaging in patients with neuroendocrine tumors. J. Nucl. Med. 2017, 58, 172– 178
      There is no corresponding record for this reference.
    14. 14
      Dilworth, J. R.; Pascu, S. I. The chemistry of PET imaging with zirconium-89. Chem. Soc. Rev. 2018, 47 (8), 2554– 2571,  DOI: 10.1039/C7CS00014F
      14
      The chemistry of PET imaging with zirconium-89
      Dilworth, Jonathan R.; Pascu, Sofia I.
      Chemical Society Reviews (2018), 47 (8), 2554-2571CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      This Tutorial Review aims to provide an overview of the use of zirconium-89 complexes in biomedical imaging. Over the past decade there have been many new papers in this field, ranging from chem. through to preclin. and clin. applications. Here we attempt to summarise the main developments that have occurred in this period. The primary focus is on coordination chem. but other aspects such as isotope prodn., isotope properties, handling and radiochem. techniques and characterization of cold and labeled complexes are included. Selected results from animal and human clin. studies are presented in the context of the stabilities and properties of the labeled bioconjugates.
    15. 15
      Deri, M. A.; Abou Diane, S.; Francesconi, L. C.; Lewis, J. C. Physical, chemical, and biological insights into Zr-89 -DFO. J. Labelled. Comp. Radiopharm 2013, 56, S216
      There is no corresponding record for this reference.
    16. 16
      Holland, J. P.; Divilov, V.; Bander, N. H.; Smith-Jones, P. M.; Larson, S. M.; Lewis, J. S. Zr-89-DFO-J591 for ImmunoPET of Prostate-Specific Membrane Antigen Expression In Vivo. J. Nucl. Med. 2010, 51 (8), 1293– 1300,  DOI: 10.2967/jnumed.110.076174
      16
      89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo
      Holland, Jason P.; Divilov, Vadim; Bander, Neil H.; Smith-Jones, Peter M.; Larson, Steven M.; Lewis, Jason S.
      Journal of Nuclear Medicine (2010), 51 (8), 1293-1300CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
      89Zr (half-life, 78.41 h) is a positron-emitting radionuclide that displays excellent potential for use in the design and synthesis of radioimmunoconjugates for immunoPET. In the current study, we report the prepn. of 89Zr-desferrioxamine B (DFO)-J591, a novel 89Zr-labeled monoclonal antibody (mAb) construct for targeted immunoPET and quantification of prostate-specific membrane antigen (PSMA) expression in vivo. Methods: The in vivo behavior of 89Zr-chloride, 89Zr-oxalate, and 89Zr-DFO was studied using PET. High-level computational studies using d. functional theory calcns. have been used to investigate the electronic structure of 89Zr-DFO and probe the nature of the complex in aq. conditions. 89Zr-DFO-J591 was characterized both in vitro and in vivo. ImmunoPET in male athymic nu/nu mice bearing s.c. LNCaP (PSMA-pos.) or PC-3 (PSMA-neg.) tumors was conducted. The change in 89Zr-DFO-J591 tissue uptake in response to high- and low-specific-activity formulations in the 2 tumor models was measured using acute biodistribution studies and immunoPET. Results: The basic characterization of 3 important reagents-89Zr-chloride, 89Zr-oxalate, and the complex 89Zr-DFO-demonstrated that the nature of the 89Zr species dramatically affects the biodistribution and pharmacokinetics. D. functional theory calcns. provide a rationale for the obsd. high in vivo stability of 89Zr-DFO-labeled mAbs and suggest that in aq. conditions, 89Zr-DFO forms a thermodynamically stable, 8-coordinate complex by coordination of 2 water mols. 89Zr-DFO-J591 was produced in high radiochem. yield (>77%) and purity (>99%), with a specific activity of 181.7 ± 1.1 MBq/mg (4.91 ± 0.03 mCi/mg). In vitro assays demonstrated that 89Zr-DFO-J591 had an initial immunoreactive fraction of 0.95 ± 0.03 and remained active for up to 7 d. In vivo biodistribution expts. revealed high, target-specific uptake of 89Zr-DFO-J591 in LNCaP tumors after 24, 48, 96, and 144 h (34.4 ± 3.2 percentage injected dose per g [%ID/g], 38.0 ± 6.2 %ID/g, 40.4 ± 4.8 %ID/g, and 45.8 ± 3.2 %ID/g, resp.). ImmunoPET studies also showed that 89Zr-DFO-J591 provides excellent image contrast, with tumor-to-muscle ratios greater than 20, for the delineation of LNCaP xenografts between 48 and 144 h after administration. Conclusion: These studies demonstrate that 89Zr-DFO-labeled mAbs show exceptional promise as radiotracers for immunoPET of human cancers. 89Zr-DFO-J591 displays high tumor-to-background tissue contrast in immunoPET and can be used to delineate and quantify PSMA-pos. prostate tumors in vivo.
    17. 17
      Boros, E.; Packard, A. B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev. 2019, 119 (2), 870– 901,  DOI: 10.1021/acs.chemrev.8b00281
      17
      Radioactive Transition Metals for Imaging and Therapy
      Boros, Eszter; Packard, Alan B.
      Chemical Reviews (Washington, DC, United States) (2019), 119 (2), 870-901CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      Nuclear medicine is composed of two complementary areas, imaging and therapy. Positron emission tomog. (PET) and single-photon imaging, including single-photon emission computed tomog. (SPECT), comprise the imaging component of nuclear medicine. These areas are distinct in that they exploit different nuclear decay processes and also different imaging technologies. In PET, images are created from the 511 keV photons produced when the positron emitted by a radionuclide encounters an electron and is annihilated. In contrast, in single-photon imaging, images are created from the γ rays (and occasionally X-rays) directly emitted by the nucleus. Therapeutic nuclear medicine uses particulate radiation such as Auger or conversion electrons or β- or α particles. All three of these technologies are linked by the requirement that the radionuclide must be attached to a suitable vector that can deliver it to its target. It is imperative that the radionuclide remain attached to the vector before it is delivered to its target as well as after it reaches its target or else the resulting image (or therapeutic outcome) will not reflect the biol. process of interest. Radiochem. is at the core of this process, and radiometals offer radiopharmaceutical chemists a tremendous range of options with which to accomplish these goals. They also offer a wide range of options in terms of radionuclide half-lives and emission properties, providing the ability to carefully match the decay properties with the desired outcome. This Review provides an overview of some of the ways this can be accomplished as well as several historical examples of some of the limitations of earlier metalloradiopharmaceuticals and the ways that new technologies, primarily related to radionuclide prodn., have provided solns. to these problems.
    18. 18
      Kostelnik, T. I.; Orvig, C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev. 2019, 119 (2), 902– 956,  DOI: 10.1021/acs.chemrev.8b00294
      18
      Radioactive Main Group and Rare Earth Metals for Imaging and Therapy
      Kostelnik, Thomas I.; Orvig, Chris
      Chemical Reviews (Washington, DC, United States) (2019), 119 (2), 902-956CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      Radiometals possess an exceptional breadth of decay properties and have been applied to medicine with great success for several decades. The majority of current clin. use involves diagnostic procedures, which use either positron-emission tomog. (PET) or single-photon imaging to detect anat. abnormalities that are difficult to visualize using conventional imaging techniques (e.g., MRI and X-ray). The potential of therapeutic radiometals has more recently been realized and relies on ionizing radiation to induce irreversible DNA damage, resulting in cell death. In both cases, radiopharmaceutical development has been largely geared toward the field of oncol.; thus, selective tumor targeting is often essential for efficacious drug use. To this end, the rational design of four-component radiopharmaceuticals has become popularized. This Review introduces fundamental concepts of drug design and applications, with particular emphasis on bifunctional chelators (BFCs), which ensure secure consolidation of the radiometal and targeting vector and are integral for optimal drug performance. Also presented are detailed accounts of prodn., chelation chem., and biol. use of selected main group and rare earth radiometals.
    19. 19
      Li, L. L.; Jaraquemada-Pelaez, M. D.; Sarden, N.; Kuo, H. T.; Sarduy, E. A.; Robertson, A.; Kostelnik, T.; Jermilova, U.; Ehlerding, E.; Merkens, H.; Radchenko, V.; Lin, K.-S.; Benard, F.; Engle, J.; Schaffer, P.; Orvig, C. New bifunctional chelators for theranostic applications. Nucl. Med. Biol. 2019, 62, S36– S42,  DOI: 10.1016/S0969-8051(19)30218-5
      There is no corresponding record for this reference.
    20. 20
      Nurchi, V. M.; Jaraquemada-Pelaez, M. D.; Crisponi, G.; Lachowicz, J. I.; Cappai, R.; Gano, L.; Santos, M. A.; Melchior, A.; Tolazzi, M.; Peana, M.; Medici, S.; Zoroddu, M.-A. A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays. J. Inorg. Biochem. 2019, 193, 152– 165,  DOI: 10.1016/j.jinorgbio.2019.01.012
      20
      A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays
      Nurchi, Valeria M.; de Guadalupe Jaraquemada-Pelaez, Maria; Crisponi, Guido; Lachowicz, Joanna I.; Cappai, Rosita; Gano, Lurdes; Santos, M. Amelia; Melchior, Andrea; Tolazzi, Marilena; Peana, Massimiliano; Medici, Serenella; Zoroddu, Maria Antonietta
      Journal of Inorganic Biochemistry (2019), 193 (), 152-165CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
      This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone mol. The protonation equil., together with the complex formation equil. of this ligand with Fe3+, Al3+, Cu2+ and Zn2+ ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of D. Functional Theory (DFT) calcns., has allowed a thorough characterization of the different species involved in equil. The stability of the formed complexes with Fe3+ and Al3+ are high enough to consider the new ligand for further studies for its clin. applications as a chelating agent. Biodistribution studies were carried out to assess the capacity the ligand for mobilization of gallium in 67Ga-citrate injected mice. These studies demonstrated that this ligand efficiently chelates the radiometal in our animal model, which suggests that it can be a promising candidate as sequestering agent of iron and other hard trivalent metal ions. Furthermore, the good zinc complexation capacity appears as a stimulating result taking into a potential use of this new ligand in anal. chem. as well as in agricultural and environmental applications.
    21. 21
      Richardson-Sanchez, T.; Tieu, W.; Gotsbacher, M. P.; Telfer, T. J.; Codd, R. Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium(IV) chelator. Org. Biomol. Chem. 2017, 15 (27), 5719– 5730,  DOI: 10.1039/C7OB01079F
      21
      Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium(IV) chelator
      Richardson-Sanchez, Tomas; Tieu, William; Gotsbacher, Michael P.; Telfer, Thomas J.; Codd, Rachel
      Organic & Biomolecular Chemistry (2017), 15 (27), 5719-5730CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
      The water soly. of a natural product-inspired octadentate hydroxamic acid chelator designed to coordinate Zr(iv)-89 has been improved by using a combined microbiol.-chem. approach to engineer four ether oxygen atoms into the main-chain region of a methylene-contg. analog. First, an analog of the trimeric hydroxamic acid desferrioxamine B (DFOB) that contained three main-chain ether oxygen atoms (DFOB-O3) was generated from cultures of the native DFOB-producer Streptomyces pilosus supplemented with oxybis(ethanamine) (OBEA), which competed against the native 1,5-diaminopentane (DP) substrate during DFOB assembly. This precursor-directed biosynthesis (PDB) approach generated a suite of DFOB analogs contg. one (DFOB-O1), two (DFOB-O2) or three (DFOB-O3) ether oxygen atoms, with the latter produced as the major species. Log P measurements showed DFOB-O3 was about 45 times more water soluble than DFOB. Second, a peptide coupling chain-extension reaction between DFOB-O3 and the synthetic ether-containing endo-hydroxamic acid monomer 4-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-4-oxobutanoic acid (PBH-O1) gave the water soluble tetrameric hydroxamic acid DFOB-O3-PBH-O1 as an isostere of sparingly water soluble DFOB-PBH. The complex between DFOB-O3-PBH-O1 and natZr(iv), examined as a surrogate measure of the radiolabelling procedure, analysed by LC-MS as the protonated adduct ([M + H]+, m/zobs = 855.2; m/zcalc = 855.3), with supporting HRMS data. The use of a microbiol. system to generate a water-sol. analog of a natural product for downstream semi-synthetic chem. is an attractive pathway for developing new drugs and imaging agents. The improved water soly. of DFOB-O3-PBH-O1 could facilitate the synthesis and purification of downstream products, as part of the ongoing development of ligands optimised for Zr(iv)-89 immunological PET imaging.
    22. 22
      Brown, C. J. M.; Gotsbacher, M. P.; Codd, R. Improved Access to Linear Tetrameric Hydroxamic Acids with Potential as Radiochemical Ligands for Zirconium(IV)-89 PET Imaging. Aust. J. Chem. 2020, 73 (10), 969– 978,  DOI: 10.1071/CH19518
      22
      Improved Access to Linear Tetrameric Hydroxamic Acids with Potential as Radiochemical Ligands for Zirconium(iv)-89 PET Imaging
      Brown, Christopher J. M.; Gotsbacher, Michael P.; Codd, Rachel
      Australian Journal of Chemistry (2020), 73 (9 & 10), 969-978CODEN: AJCHAS; ISSN:0004-9425. (CSIRO Publishing)
      Two new linear tetrameric hydroxamic acid ligands (3 and 4) have been prepd. as potential radioligands for immunol. ZrIV-89 positron emission tomog. (PET) imaging. The ligands were prepd. by conjugating endo-hydroxamic acid amino carboxylic acid (endo-HXA) monomers 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (PPH) or 2-(2-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-2-oxoethoxy)acetic acid (PPHNOCO) to trimeric desferrioxamine B (DFOB). The properties of DFOB-PPH (3) and DFOB-PPHNOCO (4) were compared with the first-in-class ligand DFO* (named DFOB-PBH (2) in the present work) and DFOB (1). In the initial phase of an FeIII:ZrIV competition expt., 1 preferentially formed FeIII-1, with ZrIV-1 becoming dominant after 48h. Tetrameric 2-4 selected ZrIV above FeIII at all times. The initial rates of formation of ZrIV-3 and ZrIV-4 were greater than ZrIV -2, which could reflect a better match between the ZrIV ionic radius and the increased vol. of the coordination sphere provided by 3 and 4. In the presence of excess EDTA, ZrIV-4 dissocd. more rapidly than ZrIV-2 and ZrIV-3, which indicated that any beneficial increase in water soly. conferred by the presence of ether oxygen atoms in 4 could be offset by a redn. in complex stability. Outer-sphere solvation of the ether oxygen atoms in ZrIV-4 may increase the entropic contribution to the dissocn. of the complex. The rank order of the initial rate of ZrIV complexation in the presence of equimolar FeIII (highest to lowest) 4>3>2 >>> 1 together with the rate of the dissocn. of the ZrIV complex (lowest to highest) 2 ≈ 3>4 >>> 1 identifies 3 as a ligand with potential value for immunol. ZrIV-89 PET imaging.
    23. 23
      Sarbisheh, E. K.; Salih, A. K.; Raheem, S. J.; Lewis, J. S.; Price, E. W. A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89. Inorg. Chem. 2020, 59 (16), 11715– 11728,  DOI: 10.1021/acs.inorgchem.0c01629
      23
      A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89
      Sarbisheh, Elaheh Khozeimeh; Salih, Akam K.; Raheem, Shvan J.; Lewis, Jason S.; Price, Eric W.
      Inorganic Chemistry (2020), 59 (16), 11715-11727CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Herein the authors report a new high-denticity chelator based on the iron siderophore desferrioxamine (DFO). The authors' new chelator-DFO2-is acyclic and was designed and synthesized with the purpose of improving the coordination chem. and radiolabeling performance with radioactive zirconium-89. The radionuclide zirconium-89 ([89Zr]Zr4+) found wide use for positron emission tomog. (PET) imaging when it is coupled with proteins, antibodies, and nanoparticles. DFO2 has a potential coordination no. of 12, which uniquely positions this chelator for binding large, high-valent, and oxophilic metal ions. Following synthesis of the DFO2 chelator and the [natZr]Zr-(DFO2) complex the authors performed d. functional theory calcns. to study its coordination sphere, followed by zirconium-89 radiolabeling expts. for comparisons with the "gold std." chelator DFO. DFO (CN 6) can coordinate with zirconium in a hexadentate fashion, leaving two open coordination sites where water is thought to coordinate (total CN 8). DFO2 (potential CN 12, dodecadentate) can sat. the coordination sphere of zirconium with four hydroxamate groups (CN 8), with no room left for water to directly coordinate, and only binds a single atom of zirconium per chelate. Following quant. radiolabeling with zirconium-89, the preformed [89Zr]Zr-(DFO) and [89Zr]Zr-(DFO2) radiometal-chelate complexes were subjected to a battery of in vitro stability challenges, including human blood serum, apo-transferrin, serum albumin, iron, hydroxyapatite, and EDTA. One objective of these stability challenges was to det. if the increased denticity of DFO2 over that of DFO imparted improved complex stability, and another was to det. which of these assays is most relevant to perform with future chelators. In all of the assays DFO2 showed superior stability with zirconium-89, except for the iron challenge, where both DFO2 and DFO were identical. Substantial differences in stability were obsd. for human blood serum using a pptn. method of anal., apo-transferrin, hydroxyapatite, and EDTA challenges. These results suggest that DFO2 is a promising next-generation scaffold for zirconium-89 chelators and holds promise for radiochem. with even larger radionuclides, which the authors anticipate will expand the utility of DFO2 into theranostic applications. DFO2 is a new acyclic chelator contg. six hydroxamic acid moieties and a potential coordination no. of 12 (dodecadentate). This chelator presents double the potential coordination no. of desferrioxamine (DFO, hexadentate), providing interesting coordination options beyond the std. 6-8 coordination nos. that are typical for zirconium(IV). This addnl. coordinating ability has imbued DFO2 with radiochem. properties superior to those DFO, as demonstrated by zirconium-89 stability challenges, and should enable theranostic applications with even larger radiometal ions.
    24. 24
      Toporivska, Y.; Gumienna-Kontecka, E. The solution thermodynamic stability of desferrioxamine B (DFO) with Zr(IV). J. Inorg. Biochem. 2019, 198, 110753– 110758,  DOI: 10.1016/j.jinorgbio.2019.110753
      24
      The solution thermodynamic stability of desferrioxamine B (DFO) with Zr(IV)
      Toporivska, Yuliya; Gumienna-Kontecka, Elzbieta
      Journal of Inorganic Biochemistry (2019), 198 (), 110753CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
      Desferrioxamine B (DFO, [H4L]+, ligand) is currently the preferred chelator for 89Zr(IV), however the biol. studies suggest that it releases the metal ion in vivo. Herein, we present the soln. thermodn. of complexes formed between Zr(IV) and this hexadentate chelating agent, the data surprisingly not yet available in the literature. Several techniques including electrospray ionization mass spectrometry (ESI-MS), potentiometry, UV-Vis spectroscopy and isothermal titrn. calorimetry (ITC) were used to det. the stoichiometry and thermodn. stability of complexes formed in soln. over pH range 1-11, overcoming all the difficulties with the characterization of the aq. soln. chem. of Zr(IV) complexes, like strong hydrolysis and lack of spectral information. A model contg. only mononuclear complexes, i.e. [ZrHL]2+ [ZrL]+, [ZrLH-1] throughout the entire measured pH range is proposed. The stability consts. and pM (Zr(IV)) value detd. for Zr(IV)-DFO system, place DFO among good Zr(IV) chelators, however the formation of 6-coordinate unsatd. complexes (i.e. with coordination sphere of 8-coordinate Zr(IV) completed by water mols.), together with the susceptibility of coordinated water mol. to deprotonation, are suggested to be the reason of in vivo instability of 89Zr(IV)-DFO complexes.
    25. 25
      Sturzbecher-Hoehne, M.; Choi, T. A.; Abergel, R. J. Hydroxypyridinonate Complex Stability of Group (IV) Metals and Tetravalent f-Block Elements: The Key to the Next Generation of Chelating Agents for Radiopharmaceuticals. Inorg. Chem. 2015, 54 (7), 3462– 3468,  DOI: 10.1021/acs.inorgchem.5b00033
      25
      Hydroxypyridinonate Complex Stability of Group(IV) Metals and Tetravalent f-Block Elements: The Key to the Next Generation of Chelating Agents for Radiopharmaceuticals
      Sturzbecher-Hoehne, Manuel; Choi, Taylor A.; Abergel, Rebecca J.
      Inorganic Chemistry (2015), 54 (7), 3462-3468CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      The soln. thermodn. of the water-sol. complexes formed between 3,4,3-LI(1,2-HOPO) and Zr(IV) or Pu(IV) were studied to establish the metal coordination properties of this octadentate chelating agent. Stability consts. log β110 = 43.1 ± 0.6 and 43.5 ± 0.7 were detd. for [Zr(IV)(3,4,3-LI(1,2-HOPO))] and [Pu(IV)(3,4,3-LI(1,2-HOPO))], resp., by spectrophotometric competition titrns. against Ce(IV). Such high thermodn. stabilities not only confirm the unparalleled Pu(IV) affinity of 3,4,3-LI(1,2-HOPO) as a decorporation agent but also corroborate the great potential of hydroxypyridinonate ligands as new 89Zr-chelating platforms for immuno-PET applications. These exptl. values are in excellent agreement with previous ests. and are discussed with respect to ionic radius and electronic configuration, in comparison with those of Ce(IV) and Th(IV). Also, a liq. chromatog. assay combined with mass spectrometric detection was developed to probe the sepn. of the neutral [M(IV)(3,4,3-LI(1,2-HOPO))] complex species (M = Zr, Ce, Th, and Pu), providing addnl. insight into the coordination differences between Group IV and tetravalent f-block metals and on the role of d and f orbitals in bonding interactions.
    26. 26
      Intorre, B. I.; Martell, A. E. Zirconium complexes in aqueous solution. 1. Reaction with multidentate ligands. J. Am. Chem. Soc. 1960, 82 (2), 358– 364,  DOI: 10.1021/ja01487a027
      26
      Zirconium complexes in aqueous solution. I. Reaction with multidentate ligands
      Intorre, Benjamin I.; Martell, Arthur E.
      Journal of the American Chemical Society (1960), 82 (), 358-64CODEN: JACSAT; ISSN:0002-7863.
      A study of the interaction of Zr(IV) with a wide variety of chelating agents resulted in the discovery of a no. of chelates with multidentate O donor groups stable over a wide pH range. The most stable chelates were formed with di-Na 1,2-dihydroxybenzene-3,5-disulfonate, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, N-(hydroxyethyl)ethylenediaminetriacetic acid, N-(hydroxyethyl)iminodiacetic acid, and N,N-bis(hydroxyethyl)glycine. Ethylenediaminetetraacetic acid was less effective, and triethylenediaminetetraacetic acid did not lead to the formation of sol. complexes.
    27. 27
      Intorre, B. J.; Martell, A. E. Zirconium complexes in aqueous solution. 3. Estimation of formation constants. Inorg. Chem. 1964, 3 (1), 81– 87,  DOI: 10.1021/ic50011a017
      27
      Zirconium complexes in aqueous solution. III. Estimation of formation constants
      Intorre, B. J.; Martell, A. E.
      Inorganic Chemistry (1964), 3 (1), 81-7CODEN: INOCAJ; ISSN:0020-1669.
      cf. CA 56, 11190b. Data obtained from potentiometric titration of the 1:1 Zr-EDTA chelate at different concns. were used to est. the dimerization const., KD, and hydrolysis const., Ka, of the monomeric chelate. Potentiometric data were used to det. equil. consts. for di-Na 1,2-dihydroxy-3,5-benzenedisulfonate(Tiron) with the Zr-EDTA 1:1 chelate to form the Zr-EDTA-Tiron 1:1:1 chelate. Spectrophotometric measurements were used to est. the formation const. of the Zr-Tiron 1:1 and Zr-nitrilotriacetate 1:1 chelates and to set limits on the Zr-EDTA 1:1 chelate formation const. Some data are reported for the corresponding Hf chelate systems.
    28. 28
      Racow, E. E.; Kreinbih, J. J.; Cosby, A. G.; Yang, Y.; Pandey, A.; Boros, E.; Johnson, C. J. General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry. J. Am. Chem. Soc. 2019, 141 (37), 14650– 14660,  DOI: 10.1021/jacs.9b05874
      28
      General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry
      Racow, Emily E.; Kreinbihl, John J.; Cosby, Alexia G.; Yang, Yi; Pandey, Apurva; Boros, Eszter; Johnson, Christopher J.
      Journal of the American Chemical Society (2019), 141 (37), 14650-14660CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The formation of ternary aqua complexes of metal-based diagnostics and therapeutics is closely correlated to their in vivo efficacy but approaches to quantify the presence of coordinated water ligands are limited. We introduce a general and high-throughput method for characterizing the hydration state of para- and diamagnetic coordination complexes in the gas phase based on variable-temp. ion trap tandem mass spectrometry. Ternary aqua complexes are directly obsd. in the mass spectrum and quantified as a function of ion trap temp. We recover expected periodic trends for hydration across the lanthanides and distinguish complexes with several inner-sphere water ligands by inspection of temp.-dependent speciation curves. We derive gas-phase thermodn. parameters for discernible inner- and second-sphere hydration events, and discuss their application to predict soln.-phase behavior. The differences in temp. at which water binds in the inner and outer spheres arise primarily from entropic effects. The broad applicability of this method allows us to est. the hydration states of Ga, Sc, and Zr complexes under active preclin. and clin. study with as-yet undetd. hydration no. Variable-temp. mass spectrometry emerges as a general tool to characterize and quantitate trends in inner-sphere hydration across the periodic table.
    29. 29
      Summers, K. L.; Sarbisheh, E. K.; Zimmerling, A.; Cotelesage, J. J. H.; Pickering, I. J.; George, G. N.; Price, E. W. Structural Characterization of the Solution Chemistry of Zirconium(IV) Desferrioxamine: A Coordination Sphere Completed by Hydroxides. Inorg. Chem. 2020, 59 (23), 17443– 17452,  DOI: 10.1021/acs.inorgchem.0c02725
      29
      Structural Characterization of the Solution Chemistry of Zirconium(IV) Desferrioxamine: A Coordination Sphere Completed by Hydroxides
      Summers, Kelly L.; Sarbisheh, Elaheh Khozeimeh; Zimmerling, Amanda; Cotelesage, Julien J. H.; Pickering, Ingrid J.; George, Graham N.; Price, Eric W.
      Inorganic Chemistry (2020), 59 (23), 17443-17452CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Positron emission tomog. (PET) using radiolabeled, monoclonal antibodies has become an effective, noninvasive method for tumor detection and is a crit. component of targeted radionuclide therapy. Metal ion chelator and bacterial siderophore desferrioxamine (DFO) is the gold std. compd. for incorporation of zirconium-89 in radiotracers for PET imaging because it is thought to form a stable chelate with [89Zr]Zr4+. However, DFO may not bind zirconium-89 tightly in vivo, with free zirconium-89 reportedly liberated into the bones of exptl. mouse models. Although high bone uptake has not been obsd. to date in humans, this potential instability has been proposed to be related to the unsatd. coordination sphere of [89Zr]Zr-DFO, which is thought to consist of the 3 hydroxamate groups of DFO and 1 or 2 water mols. In this study, we have used a combination of X-ray absorption spectroscopy and d. functional theory (DFT) geometry optimization calcns. to further probe the coordination chem. of this complex in soln. We find the extended X-ray absorption fine structure (EXAFS) curve fitting of an aq. soln. of Zr(IV)-DFO to be consistent with an 8-coordinate Zr with oxygen ligands. DFT calcns. suggest that the most energetically favorable Zr(IV) coordination environment in DFO likely consists of the 3 hydroxamate ligands from DFO, each with bidentate coordination, and 2 hydroxide ligands. Further EXAFS curve fitting provides addnl. support for this model. Therefore, we propose that the coordination sphere of Zr(IV)-DFO is most likely completed by 2 hydroxide ligands rather than 2 water mols., forming Zr(DFO)(OH)2. Zirconium desferrioxamine (DFO), specifically [89Zr]Zr4+(DFO), is a major component of many radiopharmaceuticals commonly used in positron emission tomog. for tumor detection, including theranostic applications. The Zr(IV) coordination sphere has been proposed to consist of the 3 hydroxamate groups from DFO and 2 water mols. Herein, we show evidence, from a combination of X-ray absorption spectroscopy and d. functional theory, to support the coordination of 2 hydroxides instead of water.
    30. 30
      Holland, J. P.; Sheh, Y. C.; Lewis, J. S. Standardized methods for the production of high specific-activity zirconium-89. Nucl. Med. Biol. 2009, 36 (7), 729– 739,  DOI: 10.1016/j.nucmedbio.2009.05.007
      30
      Standardized methods for the production of high specific-activity zirconium-89
      Holland, Jason P.; Sheh, Yiauchung; Lewis, Jason S.
      Nuclear Medicine and Biology (2009), 36 (7), 729-739CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
      Zirconium-89 is an attractive metallo-radionuclide for use in immuno-PET due to favorable decay characteristics. Standardized methods for the routine prodn. and isolation of high-purity and high-specific-activity 89Zr using a small cyclotron are reported. Optimized cyclotron conditions reveal high av. yields of 1.52±0.11 mCi/μA·h at a proton beam energy of 15 MeV and current of 15 μA using a solid, com. available 89Y-foil target (0.1 mm, 100% natural abundance). 89Zr was isolated in high radionuclidic and radiochem. purity (>99.99%) as [89Zr]Zr-oxalate by using a solid-phase hydroxamate resin with >99.5% recovery of the radioactivity. The effective specific-activity of 89Zr was found to be in the range 5.28-13.43 mCi/μg (470-1195 Ci/mmol) of zirconium. New methods for the facile prodn. of [89Zr]Zr-chloride are reported. Radiolabeling studies using the trihydroxamate ligand desferrioxamine B (DFO) gave 100% radiochem. yields in <15 min at room temp., and in vitro stability measurements confirmed that [89Zr]Zr-DFO is stable with respect to ligand dissocn. in human serum for >7 days. Small-animal positron emission tomog. (PET) imaging studies have demonstrated that free 89Zr(IV) ions administered as [89Zr]Zr-chloride accumulate in the liver, while [89Zr]Zr-DFO is excreted rapidly via the kidneys within <20 min. These results have important implication for the anal. of immuno-PET imaging of 89Zr-labeled monoclonal antibodies. The detailed methods described can be easily translated to other radiochem. facilities and will facilitate the use of 89Zr in both basic science and clin. investigations.
    31. 31
      Holland, J. P.; Vasdev, N. Charting the mechanism and reactivity of zirconium oxalate with hydroxamate ligands using density functional theory: implications in new chelate design. Dalton Trans. 2014, 43 (26), 9872– 9884,  DOI: 10.1039/C4DT00733F
      31
      Charting the mechanism and reactivity of zirconium oxalate with hydroxamate ligands using density functional theory: implications in new chelate design
      Holland, Jason P.; Vasdev, Neil
      Dalton Transactions (2014), 43 (26), 9872-9884CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      The reaction of [89Zr(C2O4)4]4- with the tris-hydroxamate ligand desferrioxamine B (DFO) provides the basis of radiolabelling biol. vectors such as antibodies and proteins with the radionuclide 89Zr for positron emission tomog. imaging. In this work, d. functional theory methods were used to investigate the mechanism of reaction from [Zr(C2O4)4]4- to Zr(MeAHA)4 by ligand substitution with N-Me acetohydroxamate (MeAHA). Calcns. were performed under simulated basic and acidic conditions. Ligand substitution under basic conditions was found to be thermodynamically feasible with an overall calcd. change in solvation free energy, ΔGsol = -97 kJ mol-1 using the B3LYP/DGDZVP methodol. and a water continuum solvation model. In contrast, an acid-mediated mechanism of ligand substitution was found to be thermodynamically non-feasible. MO anal. provides a rationale for the difference in thermodn. stability between [Zr(C2O4)4]4- and Zr(MeAHA)4. Overall, the DFT calcns. are consistent with obsd. exptl. 89Zr-radiolabelling reactions and suggest that computational methods may prove useful in designing novel chelates for increasing the thermodn. and kinetic stability of 89Zr-complexes in vivo.
    32. 32
      Holland, J. P. Predicting the Thermodynamic Stability of Zirconium Radiotracers. Inorg. Chem. 2020, 59 (3), 2070– 2082,  DOI: 10.1021/acs.inorgchem.9b03515
      32
      Predicting the Thermodynamic Stability of Zirconium Radiotracers
      Holland, Jason P.
      Inorganic Chemistry (2020), 59 (3), 2070-2082CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      The thermodn. stability of a metal-ligand complex, as measured by the formation const. (log β) is one of the most important parameters that dets. metal ion selectivity and potential applications in, for example, radiopharmaceutical science. The stable coordination chem. of radioactive 89Zr4+ in aq. conditions is of paramount importance when developing positron-emitting radiotracers based on proteins (usually antibodies) for use with positron emission tomog. Desferrioxamine B (DFO) remains the chelate of choice for clin. applications of 89Zr-labeled proteins but the coordination of DFO to Zr4+ ions is suboptimal. Many alternative ligands have been reported but challenges in measuring very high log β value with metal ions like Zr4+ that tend to hydrolyze mean that accurate thermodn. data are scarce. In this work, d. functional theory (DFT) calcns. were used to predict the reaction energetics for metal ion complexation. Computed values of pseudo formation consts. (log β') are correlated with exptl. data and showed an excellent linear relationship (R2-value = 0.97). The model was then used to est. the abs. and relative formation consts. of 23 different Zr4+ complexes using a total of 17 different ligands, including many of the alternative bifunctional chelates that have been reported recently for use in 89Zr4+ radiochem. In addn., detailed computational studies were performed on the geometric isomerism and hydration state of Zr-desferrioxamine. Collectively, the results offer new insights into Zr4+ coordination chem. that will help guide the synthesis of future ligands. The computation model developed here is straightforward, reproducible, and can be readily applied in the design of other metal coordination compds. A simple computational approach is developed to predict the abs. and relative thermodn. stabilities of zirconium complexes. The model is used to evaluate the characteristics of 23 different complexes that have been designed for potential use in radiopharmaceutical synthesis.
    33. 33
      Szebesczyk, A.; Olshvang, E.; Shanzer, A.; Carver, P. L.; Gumienna-Kontecka, E. Harnessing the power of fungal siderophores for the imaging and treatment of human diseases. Coord. Chem. Rev. 2016, 327, 84– 109,  DOI: 10.1016/j.ccr.2016.05.001
      33
      Harnessing the power of fungal siderophores for the imaging and treatment of human diseases
      Szebesczyk, Agnieszka; Olshvang, Evgenia; Shanzer, Abraham; Carver, Peggy L.; Gumienna-Kontecka, Elzbieta
      Coordination Chemistry Reviews (2016), 327-328 (), 84-109CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      Innovative strategies are needed to address the current lack of clin. available antifungal drugs and for diagnostic techniques. 'Repurposing' of antifungal drugs, similar to techniques currently being utilized with 'older' antibacterial drugs in order to combat widespread resistance in the face of a dearth of new drugs, could prove beneficial. Although as yet very limited for fungi, a siderophore-based 'Trojan Horse' strategy, in the form of siderophore-antibiotic conjugates, siderophore-fluorescent probe conjugates, or Ga(III)-siderophore complexes, reveals potential clin. relevance and provides a strategy for targeting fungal infections through drug delivery, imaging, and in diagnostics. The application of siderophores against pathogenic fungi is evolving but is still far from its full potential, and further studies are needed to demonstrate their advantages and limitations. One of the biggest obstacles in developing fungus-specific diagnostics and side-effects-free therapeutics is that apart from the fungal cell wall, fungi are metabolically similar to mammalian cells; thus, pathogen-specific targets are extremely limited. One of the few fundamental differences between fungal and mammalian cells lies in the iron acquisition system. The most common mechanism is mediated by small org. chelators - siderophores, often essential for fungal virulence and pathogenicity. Fungi synthesize mainly hydroxamate-type siderophores, which are excreted into the environment, and bind ferric ions with high affinity and selectivity. Delivery of iron-loaded siderophores back to the pathogen occurs via specific membrane receptors and transport proteins. Natural siderophores are generally not species-specific; they exhibit broad-spectrum activity and can be recognized by various types of microorganisms. Moreover, they generally miss proper sites for incorporating addnl. functionalities; e.g. fluorescent probes, surface-adhesive moieties or drug mols., to be used for imaging and/or as therapeutic conjugates smuggled into microbial species via siderophore recognition and a 'Trojan Horse' strategy. Biomimetic analogs can overcome both these limitations and offer novel tools for both diagnostics and therapeutics. Siderophore mimics with a narrow spectrum of activity offer the possibility of developing selective diagnostic tools, while those with broad-spectrum activity may find therapeutic applications as antifungal drug delivery tools.
    34. 34
      Kornreich-Leshem, H.; Ziv, C.; Gumienna-Kontecka, E.; Arad-Yellin, R.; Chen, Y.; Elhabiri, M.; Albrecht-Gary, A. M.; Hadar, Y.; Shanzer, A. Ferrioxamine B analogues: Targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica. J. Am. Chem. Soc. 2005, 127 (4), 1137– 1145,  DOI: 10.1021/ja035182m
      34
      Ferrioxamine B analogues: targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica
      Kornreich-Leshem, Hagit; Ziv, Carmit; Gumienna-Kontecka, Elzbieta; Arad-Yellin, Rina; Chen, Yona; Elhabiri, Mourad; Albrecht-Gary, Anne-Marie; Hadar, Yitzhak; Shanzer, Abraham
      Journal of the American Chemical Society (2005), 127 (4), 1137-1145CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A series of ferrioxamine B analogs that target the bacterium Yersinia enterocolitica was prepd. These Fe carriers are composed of 3 hydroxamate-contg. monomeric units. Two identical monomers consist of N-hydroxy-3-aminopropionic acid coupled with β-alanine, and a 3rd unit at the amino terminal is composed of N-hydroxy-3-aminopropionic acid and 1 of the following amino acids: β-alanine (1a), phenylalanine (1b), cyclohexylalanine (1c), or glycine (1d). Thermodn. results for representatives of the analogs have shown a strong destabilization (3-4 orders of magnitude) of the ferric complexes with respect to ferrioxamine B, probably due to shorter spacers and a more strained structure around the metal center. No significant effect of the variations at the N-terminal has been obsd. on the stability of the ferric complexes. By contrast, using in vivo radioactive uptake expts., we have found that these modifications have a substantial effect on the mechanism of Fe(III) uptake in Y. enterocolitica. Analogs 1a and 1d were utilized by the ferrioxamine B uptake system (FoxA), while 1b and 1c either used different uptake systems or were transported to the microbial cell nonspecifically by diffusion via the cell membrane. Transport via the FoxA system was also confirmed by uptake expts. with the FoxA deficient strain of Y. enterocolitica. A fluorescent marker, attached to 1a in a way that did not interfere with its biol. activity, provided addnl. means to monitor the uptake mechanism by fluorescence techniques. Of particular interest is the observation that 1a was utilized by the uptake system of ferrioxamine B in Y. enterocolitica (FoxA) but failed to use the ferrioxamine uptake route in Pseudomonas putida. Here, we present a case in which biomimetic siderophore analogs deliberately designed for a particular bacterium can distinguish between related uptake systems of different microorganisms.
    35. 35
      Olshvang, E.; Szebesczyk, A.; Kozlowski, H.; Hadar, Y.; Gumienna-Kontecka, E.; Shanzer, A. Biomimetic ferrichrome: structural motifs for switching between narrow- and broad-spectrum activities in P. putida and E. coli. Dalton Trans. 2015, 44 (48), 20850– 20858,  DOI: 10.1039/C5DT02685G
      35
      Biomimetic ferrichrome: structural motifs for switching between narrow- and broad-spectrum activities in P. putida and E. coli
      Olshvang, Evgenia; Szebesczyk, Agnieszka; Kozlowski, Henryk; Hadar, Yitzhak; Gumienna-Kontecka, Elzbieta; Shanzer, Abraham
      Dalton Transactions (2015), 44 (48), 20850-20858CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      A series of novel ferrichrome (FC) analogs was designed based on the X-ray structure of FC in the FhuA transporter of Escherichia coli. Two strategies were employed: the first strategy optimized the overall size and relative orientation of H-bonding interactions. The second strategy increased H-bonding interactions by introducing external H-donors onto analogs' backbone. Tris-amino templates were coupled to succinic or aspartic acid, and the second carboxyl was used for hydroxamate construction. Succinic acid provided analogs without substituents, whereas aspartic acid generated analogs with external amines (i.e.H-donors). All analogs had similar physicochem. properties, yet the biol. activity in Pseudomonas putida and E. coli showed great variation. While some analogs targeted specifically P. putida, others were active in both strains thus exhibiting broad-spectrum activity (as in native FC). Narrow-spectrum or species-specificity might find application in microbial diagnostic kits, while broad-spectrum recognition may have advantages in therapeutics as siderophore-drug conjugates. The differences in the structure and range of microbial recognition helped us in formulating guidelines for minimal essential parameters required for inducing broad-spectrum activity.
    36. 36
      Besserglick, J.; Olshvang, E.; Szebesczyk, A.; Englander, J.; Levinson, D.; Hadar, Y.; Gumienna-Kontecka, E.; Shanzer, A. Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets. Chem. - Eur. J. 2017, 23 (53), 13181– 13191,  DOI: 10.1002/chem.201702647
      36
      Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets
      Besserglick, Jenny; Olshvang, Evgenia; Szebesczyk, Agnieszka; Englander, Joseph; Levinson, Dana; Hadar, Yitzhak; Gumienna-Kontecka, Elzbieta; Shanzer, Abraham
      Chemistry - A European Journal (2017), 23 (53), 13181-13191CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Siderophores provide an established platform for studying mol. recognition principles in biol. systems. Herein, the prepn. of ferrichrome (FC) biomimetic analogs varying in length and polarity of the amino acid chain sepg. between the tripodal scaffold and the pendent FeIII chelating hydroxamic acid groups is reported. Spectroscopic and potentiometric titrns. detd. their iron affinity to be within the range of efficient chelators. Microbial growth promotion and iron uptake studies were conducted on E. coli, P. putida and U. maydis. A wide range of siderophore activity was obsd. in the current series: from a rare case of a species-specific growth promotor in P. putida to an analog matching FC in cross-phylum activity and uptake pathway. A fluorescent conjugate of the broad-range analog visualized siderophore destination in bacteria (periplasmic space) vs. fungi (cytosol) mapping new therapeutic targets. Quantum dots (QDs) decorated with the most potent FC analog provided a tool for immobilization of FC-recognizing bacteria. Bacterial clusters formed around QDs may provide a platform for their selection and concn.
    37. 37
      Anderegg, G.; Leplatte, F.; Schwarzenbach, G. Hydroxamatkomplexe. 3. Eisen(iii)-austausch zwischen sideraminen und komplexonen - diskussion der bildungskonstanten der hydroxamatkomplexe. Helv. Chim. Acta 1963, 46 (4), 1409– 1422,  DOI: 10.1002/hlca.19630460436
      37
      Hydroxamate complexes. III. Iron(III)exchange between sideramines and complexones. A discussion of the formation constants of the hydroxamate complexes
      Anderegg, G.; L'Eplattenier, F.; Schwarzenbach, G.
      Helvetica Chimica Acta (1963), 46 (4), 1409-22CODEN: HCACAV; ISSN:0018-019X.
      Optical spectra were used to study the transfer of Fe(III) from complexes with the sideramines H4DFO+, N-acetyl-desferriferrioxamin B (H3AcDFO), H3NOC, desferriferrichrom (H3FChO), and desferriferrichrysin (H3FChY) to ligands such as ethylenediaminetetraacetic acid, diethylenetriamine-pentaacetic acid, etc. The equil. consts. for the exchange reactions were used to calc. equil. consts. in the Fe3+-sideramine systems. The equil. observed and the log K values obtained were Fe3+ + HAcDFO- .dblharw. Fe(HAcDFO)+ (21.6), Fe3+ + AcDFO3- .dblharw. Fe(AcDFO) (30.76), Fe3+ + HNOC- .dblharw. Fe(HNOC)+ (22.5), Fe3+ + HFChO- .dblharw. Fe(HFChO)+ (20.7), Fe3+ = FChO3- .dblharw. Fe(FChO) (29.07), and Fe3+ + FChY3- .dblharw. Fe(FChY) (29.96). The hydroxamic acid group behaves as a bidentate O donor very much like acetylacetone. There is a pronounced preference for Fe(III) over other metal ions.
    38. 38
      Mular, A.; Shanzer, A.; Kozłowski, H.; Decristoforo, C.; Gumienna-Kontecka, E. Unpublished results.
      There is no corresponding record for this reference.
    39. 39
      Seibold, U.; Wangler, B.; Wangler, C. Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for Zr-89. ChemMedChem 2017, 12 (18), 1555– 1571,  DOI: 10.1002/cmdc.201700377
      39
      Rational Design, Development, and Stability Assessment of a Macrocyclic Four-Hydroxamate-Bearing Bifunctional Chelating Agent for 89Zr
      Seibold, Uwe; Waengler, Bjoern; Waengler, Carmen
      ChemMedChem (2017), 12 (18), 1555-1571CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Zirconium-89 is a positron-emitting radionuclide of high interest for medical imaging applications with positron emission tomog. (PET). For the introduction of this radiometal into biol. active targeting vectors, the chelating agent desferrioxamine B (DFO) is commonly applied. However, DFO is known to form 89Zr complexes of limited in vivo stability. Herein we describe the rational design and chem. development of a new macrocyclic four-hydroxamate-bearing chelating agent-1,10,19,28-tetrahydroxy-1,5,10,14,19,23,28,32-octaazacyclohexatriacontan-2,6,11,15,20,24,29,33-octaone (CTH36)-for the stable complexation of Zr4+. For this purpose, we first performed computational studies to det. the optimal chelator geometry before we developed different synthesis pathways toward the target structures. The best results were obtained using an efficient soln.-phase-based synthesis strategy toward the target chelating agent. To enable efficient and chemoselective conjugation to biomols., a tetrazine-modified variant of CTH36 was also developed. The excellent conjugation characteristics of the so-functionalized chelator were demonstrated on the example of the model peptide TCO-c(RGDfK). We detd. the optimal 89Zr radiolabeling parameters for CTH36 as well as its bioconjugate, and found that 89Zr radiolabeling proceeds efficiently under very mild reaction conditions. Finally, we performed comparative complex stability tests for 89Zr-CHT36-c(RGDfK) and 89Zr-DFO-c(RGDfK), showing improved complex stability for the newly developed chelator CTH36.
    40. 40
      Guerard, F.; Lee, Y. S.; Brechbiel, M. W. Rational Design, Synthesis, and Evaluation of Tetrahydroxamic Acid Chelators for Stable Complexation of Zirconium(IV). Chem. - Eur. J. 2014, 20 (19), 5584– 5591,  DOI: 10.1002/chem.201304115
      40
      Rational Design, Synthesis, and Evaluation of Tetrahydroxamic Acid Chelators for Stable Complexation of Zirconium(IV)
      Guerard, Francois; Lee, Yong-Sok; Brechbiel, Martin W.
      Chemistry - A European Journal (2014), 20 (19), 5584-5591CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Metals of interest for biomedical applications often need to be complexed and assocd. in a stable manner with a targeting agent before use. Whereas the fundamentals of most transition-metal complexation processes have been thoroughly studied, the complexation of ZrIV has been somewhat neglected. This metal has received growing attention in recent years, esp. in nuclear medicine, using 89Zr, which a β+-emitter with near ideal characteristics for cancer imaging. However, the best chelating agent known for this radionuclide is the trishydroxamate desferrioxamine B (DFB), the ZrIV complex of which exhibits suboptimal stability, resulting in the progressive release of 89Zr in vivo. Based on a recent report demonstrating the higher thermodn. stability of the tetrahydroxamate complexes of ZrIV compared with the trishydroxamate complexes analogs to DFB, the authors designed a series of tetrahydroxamic acids of varying geometries for improved complexation of this metal. Three macrocycles differing in their cavity size (28 to 36-membered rings) were synthesized by using a ring-closing metathesis strategy, as well as their acyclic analogs. A soln. study with 89Zr showed the complexation to be more effective with increasing cavity size. Evaluation of the kinetic inertness of these new complexes in EDTA soln. showed significantly improved stabilities of the larger chelates compared with 89Zr-DFB, whereas the smaller complexes suffered from insufficient stabilities. These results were rationalized by a quantum chem. study. The lower stability of the smaller chelates was attributed to ring strain, whereas the better stability of the larger cyclic complexes was explained by the macrocyclic effect and by the structural rigidity. Overall, these new chelating agents open new perspectives for the safe and efficient use of 89Zr in nuclear imaging, with the best chelators providing dramatically improved stabilities compared with the ref. DFB.
    41. 41
      Patra, M.; Bauman, A.; Mari, C.; Fischer, C. A.; Blacque, O.; Haussinger, D.; Gasser, G.; Mindt, T. L. An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes. Chem. Commun. 2014, 50 (78), 11523– 11525,  DOI: 10.1039/C4CC05558F
      41
      An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes
      Patra, Malay; Bauman, Andreas; Mari, Cristina; Fischer, Christiane A.; Blacque, Olivier; Haussinger, Daniel; Gasser, Gilles; Mindt, Thomas L.
      Chemical Communications (Cambridge, United Kingdom) (2014), 50 (78), 11523-11525CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      89Zr-based imaging agents hold great promise as novel radio-tracers in nuclear medicine. However, insufficient stability of currently used radiometal complexes in vivo is a safety concern for clin. applications. We herein report the first octadentate bifunctional chelating agent for the development of 89Zr-labeled (bio)conjugates with improved stability.
    42. 42
      Whisenhunt, D. W.; Neu, M. P.; Hou, Z. G.; Xu, J.; Hoffman, D. C.; Raymond, K. N. Specific sequestering agents for the actinides. 29. Stability of the thorium(IV) complexes of desferrioxamine B (DFO) and three octadentate catecholate or hydroxypyridinonate DFO derivatives: DFOMTA, DFOCAMC, and DFO-1,2-HOPO. Comparative stability of the plutonium(IV) DFOMTA complex. Inorg. Chem. 1996, 35 (14), 4128– 4136,  DOI: 10.1021/ic951064r
      42
      Specific Sequestering Agents for the Actinides. 29. Stability of the Thorium(IV) Complexes of Desferrioxamine B (DFO) and Three Octadentate Catecholate or Hydroxypyridinonate DFO Derivatives: DFOMTA, DFOCAMC, and DFO-1,2-HOPO. Comparative Stability of the Plutonium(IV) DFOMTA Complex
      Whisenhunt, Donald W., Jr.; Neu, Mary P.; Hou, Zhiguo; Xu, Jide; Hoffman, Darleane C.; Raymond, Kenneth N.
      Inorganic Chemistry (1996), 35 (14), 4128-4136CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      The metal complex stability consts. of Th(IV) with desferrioxamine B (DFO) and three octadentate derivs. [N-(2,3-dihydroxy-4-carboxybenzoyl)desferrioxamine B (DFOCAMC), N-((1,2-dihydro-1-hydroxy-2-oxopyridin-6-yl)carbonyl)desferrioxamine B (DFO-1,2-HOPO) and N-(2,3-dihydroxy-4-(methylamido)benzoyl)desferrioxamine B (DFOMTA)] have been detd. The formation const. of the Pu(IV)/DFOMTA complex has also been detd., and the formation consts. have been estd. for the other Pu(IV) complexes of octadentate DFO derivs. The DFO derivs. form 1:1 complexes with Th(IV) in aq. soln. The soln. chem. of the Th(IV) complexes have been studied by spectrophotometric, potentiometric and proton NMR titrns. The Th(IV) formation consts. are as follows (log Kf values and ests.): DFO, 26.6(1); DFOMTA, 38.55(5); DFOCAMC, 37.2(3); DFO-1,2-HOPO, 33.7(4). The Pu(IV)/DFOMTA formation const., detd. by competitive spectrophotometric titrn. is (log Kf value) 41.7(2). The estn. of the other Pu(IV) formation consts. are as follows (log Kf values): DFOCAMC, 40.4; DFO-1,2-HOPO, 36.9. The selectivity of DFO and the three derivs. for actinide(IV) ions is discussed.
    43. 43
      Borgias, B.; Hugi, A. D.; Raymond, K. N. Isomerization and solution structures of desferrioxamine-B complexes of aluminium (3+) and galium (3+). Inorg. Chem. 1989, 28 (18), 3538– 3545,  DOI: 10.1021/ic00317a029
      43
      Isomerization and solution structures of desferrioxamine B complexes of aluminum(3+) and gallium(3+)
      Borgias, Brandan; Hugi, Alain D.; Raymond, Kenneth N.
      Inorganic Chemistry (1989), 28 (18), 3538-45CODEN: INOCAJ; ISSN:0020-1669.
      The Ga(III) and Al(III) complexes of desferrioxamine B (H3DFO) were prepd. and purified by cation-exchange liq. chromatog. Both complexes elute as single bands, with elution rates comparable to those measured for the trans isomer(s) of kinetically inert Cr(HDFO)+. The soln. thermodn. of Ga(HDFO)+ show that the cationic complex is the only significant species at pH 2-9. Above pH 9 the complex undergoes hydrolysis. Its stability const., log KML, is 27.56 (compared to 30.60 for Fe(III)). The NMR spectra of both the Ga and Al complexes indicate the presence of 2 isomers in soln., whose rapid interconversion prevents chromatog. sepn. The kinetics of isomerization of Ga(HDFO)+ were studied by variable temp. 13C measurements in D2O, CD3OD, and DMSO-d6. The following kinetic parameters were obtained at 25°: k (s-1), ΔH⧧ (kcal mol-1) and ΔS⧧ (cal mol-1 K-1): 13(1), 13(1), -10(3) in water; 73(7), 17(2), and +8(8) in MeOH; 4.1(6) × 102, 17(5), and +10(15) in DMSO. These results, and the observation that in water isomerization is pH independent, are discussed in terms of a possible Id mechanism. Attempts to further characterize the isomers of Ga(HDFO)+ by 2D NMR were only partially successful, due to the complexity of the spectra. Ga is a good substitute metal for Fe in the M-DFO system. There are only 2 significant isomers in soln. of the labile Ga(III) complex, and these are most likely the N-cis,cis and C-trans,trans isomers.
    44. 44
      Farkas, E.; Kiss, T.; Kurzak, B. Microscopic dissociation processes of alaninehydroxamic acids. J. Chem. Soc., Perkin Trans. 2 1990, (7), 1255– 1257,  DOI: 10.1039/p29900001255
      44
      Microscopic dissociation processes of alaninehydroxamic acids
      Farkas, Etelka; Kiss, Tamas; Kurzak, Barbara
      Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1990), (7), 1255-7CODEN: JCPKBH; ISSN:0300-9580.
      A pH-metric and 13C NMR study has been made of the proton complexes of L-α-alaninehydroxamic acid and β-alaninehydroxamic acid at 25° and I = 0.2 mol dm-3 and 1.0 mol dm-3 (KCl), to det. the macroscopic dissocn. consts. of the ligand. The NH3+ group is more acidic than the NHOH group for the α-deriv., while the acidity sequence is the opposite for the β-deriv.
    45. 45
      Tegoni, M.; Ferretti, L.; Sansone, F.; Remelli, M.; Bertolasi, V.; Dallavalle, F. Synthesis, solution thermodynamics, and x-ray study of Cu-II 12 metallacrown-4 with GABA hydroxamic acid: An unprecedented crystal structure of a 12 MC-4 with a gamma-aminohydroxamate. Chem. - Eur. J. 2007, 13 (4), 1300– 1309,  DOI: 10.1002/chem.200601035
      45
      Synthesis, solution thermodynamics, and x-ray study of CuII [12]metallacrown-4 with GABA hydroxamic acid: an unprecedented crystal structure of a [12]MC-4 with a γ-aminohydroxamate
      Tegoni, Matteo; Ferretti, Luca; Sansone, Francesco; Remelli, Maurizio; Bertolasi, Valerio; Dallavalle, Francesco
      Chemistry - A European Journal (2007), 13 (4), 1300-1308CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The soln. equil. of γ-aminobutanehydroxamic acid (GABAha) with H+ and Cu2+ were studied by potentiometry, titrn. calorimetry, spectrophotometry, NMR spectroscopy, and ESI-MS. The thermodn. parameters of the CuII [12]metallacrown-4 obtained for GABAha were compared with those of the corresponding complexes of (S)-α-Alaha and β-Alaha. The stability (-ΔG0) sequence was β-Alaha » α-Alaha > GABAha, whereas the order of formation enthalpies (-ΔH0) was β-Alaha » GABAha > α-Alaha. These data were interpreted from the dimensions of the chelate rings and the planarity of the metallamacrocycles. The CuII [12]metallacrown-4 ([12]MC-4) complex of GABAha was isolated and its crystal structure, which is the 1st reported for a [12]MC-4 of a γ-aminohydroxamic acid, fully supports the structural features interpreted from the thermodn. data.
    46. 46
      Piasta, K.; Dzielak, A.; Mucha, A.; Gumienna-Kontecka, E. Non-symmetrical bis(aminoalkyl) phosphinates: new ligands with enhanced binding of Cu(II) ions. New J. Chem. 2018, 42 (10), 7737– 7745,  DOI: 10.1039/C8NJ01094C
      46
      Non-symmetrical bis(aminoalkyl)phosphinates: new ligands with enhanced binding of Cu(II) ions
      Piasta, Karolina; Dzielak, Anna; Mucha, Artur; Gumienna-Kontecka, Elzbieta
      New Journal of Chemistry (2018), 42 (10), 7737-7745CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
      Three novel, non-sym. bis(aminoalkyl)phosphinic acids, L1-L3, have been synthesized and characterized. Soln. studies on the coordination abilities of the ligands showed that these compds. form various protonated mono- and bis-complexes, where copper(II) coordination is realized through the nitrogen atom(s) of the amino group(s), supported by oxygen(s) from the phosphinate unit(s). Potentiometric titrns. and a full spectroscopic anal. clarified the species distribution profiles and detailed coordination modes. L1-L3 ligands are efficient chelating agents for Cu(II) ions; their metal binding abilities were compared to structurally related compds. described earlier in the literature.
    47. 47
      Ostrowska, M.; Toporivska, Y.; Golenya, I. A.; Shova, S.; Fritsky, I. O.; Pecoraro, V. L.; Gumienna-Kontecka, E. Explaining How alpha-Hydroxamate Ligands Control the Formation of Cu(II)-, Ni(II)-, and Zn(II)-Containing Metallacrowns. Inorg. Chem. 2019, 58 (24), 16642– 16659,  DOI: 10.1021/acs.inorgchem.9b02724
      47
      Explaining How α-Hydroxamate Ligands Control the Formation of Cu(II)-, Ni(II)-, and Zn(II)-Containing Metallacrowns
      Ostrowska, Malgorzata; Toporivska, Yuliya; Golenya, Irina A.; Shova, Sergiu; Fritsky, Igor O.; Pecoraro, Vincent L.; Gumienna-Kontecka, Elzbieta
      Inorganic Chemistry (2019), 58 (24), 16642-16659CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Four different crystal structures for quinolinehydroxamic acid (QuinHA) and picolinehydroxamic acid (PicHA) MCs with Cu(II) and Ni(II), and soln. studies on the formation of Cu(II), Ni(II), and Zn(II) MC complexes with QuinHA, PicHA, and pyrazylohydroxamic acid (PyzHA) are described. In polynuclear complex 1, [Cu5(QuinHA-2H)4(NO3)(DMSO)4](NO3), the metallamacrocyclic cavity is formed by four Cu(II) ions and four doubly deprotonated hydroximate ligands, and the center of the cavity is occupied by the fifth Cu(II) ion coordinated by four hydroximate oxygen atoms. The complex 2, [Cu10(PicHA-2H)8(H2O)4(ClO4)3](ClO4)·4H2O, exhibits a dimeric structure based on two pentanuclear collapsed 12-MC-4 Cu4(PicHA-2H)4 fragments united by two chiral capping Cu(II) ions exo-coordinated to the peripheral vacant (O,O') chelating units of each tetranuclear collapsed MC moiety. 3, [CaNi5(QuinHA-2H)5(H2O)2(Py)10](NO3)2, and 4, [CaNi5(PicHA-2H)5(DMF)2(Py)8](NO3)2, are planar 15-membered rings consisting of a PicHA or QuinHA ligand, resp. To understand fully the correlation between species isolated in the solid state and those presented in soln., the soln. equil. were investigated, showing the dependence of the MCs topologies and stability consts. (log β) on the ligand structure and metal ion. The formation of Cu(II), Ni(II), and Zn(II) metallacrown complexes of quinolinehydroxamic acid (QuinHA), picolinehydroxamic acid (PicHA), and pyrazylohydroxamic acid (PyzHA) were studied to understand the correlation between species isolated in solid state and those presented in soln. The strong preference of QuinHA for the formation of MCs was reflected esp. in the formation of Cu(II) MC, which is the first example of the system with the presence of only one, the 12-MC-4 complex, in soln.
    48. 48
      Sanchiz, J.; Esparza, P.; Dominguez, S.; Brito, F.; Mederos, A. Solution studies of complexes of iron(III) with iminodiacetic, alkyl-substituted iminodiacetic and nitrilotriacetic acids by potentiometry and cyclic voltammetry. Inorg. Chim. Acta 1999, 291 (1–2), 158– 165,  DOI: 10.1016/S0020-1693(99)00125-5
      48
      Solution studies of complexes of iron(III) with iminodiacetic, alkyl-substituted iminodiacetic and nitrilotriacetic acids by potentiometry and cyclic voltammetry
      Sanchiz, Joaquin; Esparza, Pedro; Dominguez, Sixto; Brito, Felipe; Mederos, Alfredo
      Inorganica Chimica Acta (1999), 291 (1-2), 158-165CODEN: ICHAA3; ISSN:0020-1693. (Elsevier Science S.A.)
      Potentiometric studies were performed for the iminodiacetic (IDA), methyliminodiacetic (MIDA), ethyliminodiacetic (EIDA), propyliminodiacetic (PIDA), H2L, and nitrilotriacetic acids (NTA, H3L)-iron(III) systems at 25°C and I=0.5 mol dm-3 in KNO3. The stability consts. of the complexes formed were detd. Deprotonation and dimerization consts. were calcd., the species distribution diagrams were explained, the cyclic voltammetric studies were performed for IDA- and NTA-iron(III) systems.
    49. 49
      Motekaitis, R. J.; Martell, A. E. The iron(III) and iron(II) complexes of nitrilotriacetic acid. J. Coord. Chem. 1994, 31 (1), 67– 78,  DOI: 10.1080/00958979408022546
      49
      The iron(III) and iron(II) complexes of nitrilotriacetic acid
      Motekaitis, Ramunas J.; Martell, Arthur E.
      Journal of Coordination Chemistry (1994), 31 (1), 67-78CODEN: JCCMBQ; ISSN:0095-8972.
      Because of conflicting and incomplete reports of the ferric and ferrous nitrilotriacetate (NTA, H3L) equil. in the literature, and uncertainties about the metal complex species present under various conditions, the system was investigated by potentiometric and spectrometric measurements, and the data were analyzed by simultaneous consideration of all species present. The new consts. for the ferric complexes at 25.0 °C and μ = 0.100 (KCl) are the stepwise formation const. log K(ML2) = 8.07, and the successive hydrolysis consts., logK[M(OH)L] = -4.36, logK[M(OH)2L] = -7.58, and logK[M(OH)3L] = -10.72. The first stepwise formation const., log K(ML) = 15.9, was not detd. in the present work since the value of 15.9 was considered accurate. For the ferrous complexes under the same conditions, the consts. reported are: logK(ML) = 8.90, logK(ML2) = 2.08, and logK[M(OH)L] = -10.82. The log protonation consts. of the ligand under these conditions are reported as 9.59, 2.52, and 1.47.
    50. 50
      Deblonde, G. J. P.; Sturzbecher-Hoehne, M.; Abergel, R. J. Solution Thermodynamic Stability of Complexes Formed with the Octadentate Hydroxypyridinonate Ligand 3,4,3-LI(1,2-HOPO): A Critical Feature for Efficient Chelation of Lanthanide(IV) and Actinide(IV) Ions. Inorg. Chem. 2013, 52 (15), 8805– 8811,  DOI: 10.1021/ic4010246
      50
      Solution Thermodynamic Stability of Complexes Formed with the Octadentate Hydroxypyridinonate Ligand 3,4,3-LI(1,2-HOPO): A Critical Feature for Efficient Chelation of Lanthanide(IV) and Actinide(IV) Ions
      Deblonde, Gauthier J-P.; Sturzbecher-Hoehne, Manuel; Abergel, Rebecca J.
      Inorganic Chemistry (2013), 52 (15), 8805-8811CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      The soln. thermodn. of water-sol. complexes formed between Ce(III), Ce(IV), Th(IV) and the octadentate chelating agent 3,4,3-LI(1,2-HOPO) were investigated. Several techniques including spectrofluorimetric and automated spectrophotometric titrns. were used to overcome the slow spontaneous oxidn. of Ce(III) complexes yielding to stability consts. of log β110 = 17.4 ± 0.5, logβ11-1 = 8.3 ± 0.4 and logβ111 = 21.2 ± 0.4 for [Ce(III)(3,4,3-LI(1,2-HOPO))]-, [Ce(III)(3,4,3-LI(1,2-HOPO)(OH))]2-, and [Ce(III)(3,4,3-LI(1,2-HOPO)H)], resp. Using the spectral properties of the hydroxypyridinonate chelator in ligand competition titrns. against nitrilotriacetic acid, the stability const. log β110 = 41.5 ± 0.5 was detd. for [Ce(IV)(3,4,3-LI(1,2-HOPO))]. Finally, the extraordinarily stable complex [Ce(IV)(3,4,3-LI(1,2-HOPO))] was used in Th(IV) competition titrns., resulting in a stability const. of log β110 = 40.1 ± 0.5 for [Th(IV)3,4,3-LI(1,2-HOPO)]. These exptl. values are in excellent agreement with previous ests., they are discussed with respect to the ionic radius and oxidn. state of each cationic metal, and allow predictions on the stability of other actinide complexes including [U(IV)(3,4,3-LI(1,2-HOPO))], [Np(IV)(3,4,3-LI(1,2-HOPO))], and [Pu(IV)(3,4,3-LI(1,2-HOPO))]. Comparisons with the std. ligand diethylenetriamine pentaacetic acid (DTPA) provide a thermodn. basis for the obsd. significantly higher efficacy of 3,4,3-LI(1,2-HOPO) as an in vivo actinide decorporation agent.
    51. 51
      Schwarzenbach, G.; Schwarzenbach, K. Hydroxamatkomplexe. 1. Die stabilitat der eisen(iii)-komplexe einfacher hydroxamsauren und des ferrioxamins B. Helv. Chim. Acta 1963, 46 (4), 1390– 1399,  DOI: 10.1002/hlca.19630460434
      51
      Hydroxamate complexes. I. The stabilities of the iron(III) complexes of simple hydroxamic acids and desferriferrioxamin B
      Schwarzenbach, G.; Schwarzenbach, K.
      Helvetica Chimica Acta (1963), 46 (4), 1390-1400CODEN: HCACAV; ISSN:0018-019X.
      The ionization consts. of Me-CONOH (I) (pK = 9.37), PhCONOH (II) (pK = 8.79), and desferriferrioxamin B (H4DFO+) (III) (pK1 = 8.39, pK2 = 9.03, pK3 = 9.70, and pK4 > 11), were measured by conventional pH techniques. The aq. equil. between Fe(III) and I, II, and III were investigated with the aid of oxidn.-redn. potentials, pH, and spectrophotometric measurements. Fe(III) forms the complexes FeA++, FeA2+, and FeA3, where A = the anion of I or II. The stepwise formation consts. (log K) for these species are 11.42, 9.68, and 7.2 for A = MeCONO- and 11.06, 9.37, 7.4 for A = PhCONO-. The log K values for the formation of Fe(H2DFO)++ (IV) and Fe(HDFO)+ are 21.84 and 30.60, resp. IV behaves like a dibasic acid with pK1 = 0.94 and pK2 > 10, resp.
    52. 52
      Evers, A.; Hancock, R. D.; Martell, A. E.; Motekaitis, R. J. Metal-ion recognition in ligands with negatively charged oxygen donor groups - complexation of Fe(III), Ga(III), In(III), Al(III), and other highly charged metal-ions. Inorg. Chem. 1989, 28 (11), 2189– 2195,  DOI: 10.1021/ic00310a035
      52
      Metal ion recognition in ligands with negatively charged oxygen donor groups. Complexation of iron(III), gallium(III), indium(III), aluminum(III), and other highly charged metal ions
      Evers, Ann; Hancock, Robert D.; Martell, Arthur E.; Motekaitis, Ramunas J.
      Inorganic Chemistry (1989), 28 (11), 2189-95CODEN: INOCAJ; ISSN:0020-1669.
      The existence of good linear relations between the formation const. log value of complexes of ligands contg. neg. O donor groups only and log K1(OH-) values for the metal ions is demonstrated for a variety of ligands contg. phenolate, carboxylate, and hydroxamate donor groups. The formation consts. of DFB (desferriferrioxamine-B), BAMTPH (a synthetic trihydroxamate acid), and several dihydroxamic acids of the type HONHCO(CH2)nCONHOH (n = 4, 6, 7, and 8) with several metal ions are reported and used to demonstrate the general existence of linear relations of the above type. The DFB consts. are reported for Al(III), Ga(III), and In(III) and considered in relation to possible use of DFF for treating Al intoxication. The selectivity patterns of neg. charged O donor ligands for metal ions are discussed in relation to the effect of chain length of the bridging groups connecting the donor groups, the presence of sulfonic acid groups, and how the selectivity patterns might be altered by the inclusion of other donor groups such as neutral O and N donor groups.
    53. 53
      Harris, W. R.; Carrano, C. J.; Raymond, K. N. Coordination chemistry of microbial iron transport compounds. 16. Isolation, characterization, and formation-constants of ferric aerobactin. J. Am. Chem. Soc. 1979, 101 (10), 2722– 2727,  DOI: 10.1021/ja00504a038
      53
      Coordination chemistry of microbial iron transport compounds. 16. Isolation, characterization, and formation constants of ferric aerobactin
      Harris, Wesley R.; Carrano, Carl J.; Raymond, Kenneth N.
      Journal of the American Chemical Society (1979), 101 (10), 2722-7CODEN: JACSAT; ISSN:0002-7863.
      Aerobactin, a dihydroxamate deriv. of citric acid, is a siderophore produced by Aerobacter aerogenes. The Fe complex was isolated from neutral aq. solns. as the trisodium salt. The high-spin octahedral complex was formed using the 2 bidentate hydroxamate groups and the central carboxylate and hydroxyl moieties of the citrate backbone. Ferric aerobactin exists predominantly as the Λ optical isomer in aq. solns. The stability consts. (logβ113 = 31.74, log β112 = 29.70, log β111 = 26.68, log β110 = 23.06, logβ11‾1 = 18.48) and redox potential also were detd. from spectroscopic, potentiometric titrn., and electrochem. techniques. The implication of these results to the mechanism of Fe uptake and release by A. aerogenes is discussed.
    54. 54
      Clarke, E. T.; Martell, A. E. Stabilities of the Fe(III), Ga(III) and In(III) chelates of N,N′,N″-triazacyclononanetriacetic acid. Inorg. Chim. Acta 1991, 181 (2), 273– 280,  DOI: 10.1016/S0020-1693(00)86821-8
      54
      Stabilities of the iron(III), gallium(III) and indium(III) chelates of N,N',N"-triazacyclononanetriacetic acid
      Clarke, Eric T.; Martell, Arthur E.
      Inorganica Chimica Acta (1991), 181 (2), 273-80CODEN: ICHAA3; ISSN:0020-1693.
      The stability consts. of the complexes of Fe, Ga, and In (3+) ions with the sexadentate macrocyclic ligand 1,4,7-triazacyclonane-N,N',N''-triacetic acid (NOTA) were detd. in KCl supporting electrolyte (0.100 M) at 25.0°. The stability consts. (KML = [ML]/[L3-][M3+] of the Ga(III) and Fe(III) complexes with NOTA are high, 1030.98 and 1028.3, resp., and indicate preferential interaction of these small metal ions with NOTA. The stability const. of the In(III)-NOTA complex is somewhat lower (1026.2). Species distribution curves are presented to illustrate the conversion of the Ga(III) and In(III) chelates to the monohydroxo forms at p[H] 9.3 and 6.5, resp. The Fe(III)-NOTA complex dissocs. to form ferric hydroxide at and above p[H] 7.5, while the hydroxo In(III)-NOTA complex is converted to indium hydroxide at and above p[H] 7.5. The Ga(III)-NOTA system is sol. at all p[H] values, as a consequence of conversion of the hydroxo complex to the tetrahydroxo gallate ion at p[H] 10.4 and above.
    55. 55
      Wang, X. Z.; Jaraquemada-Pelaez, M. D.; Cao, Y.; Pan, J. H.; Lin, K. S.; Patrick, B. O.; Orvig, C. H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for Ga-68 Radiopharmaceuticals. Inorg. Chem. 2019, 58 (4), 2275– 2285,  DOI: 10.1021/acs.inorgchem.8b01208
      55
      H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals
      Wang, Xiaozhu; Jaraquemada-Pelaez, Maria de Guadalupe; Cao, Yang; Pan, Jinhe; Lin, Kuo-Shyan; Patrick, Brian O.; Orvig, Chris
      Inorganic Chemistry (2019), 58 (4), 2275-2285CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      An acyclic hexadentate chelating ligand, H2hox, has been investigated as an alternative to current chelators for 68Ga. The straightforward prepn. of H2hox, involving only one or two steps, obviates the synthetic challenges assocd. with many reported 68Ga chelators; it forms a Ga3+ complex of great stability (log K = 34.4) with a remarkably high gallium scavenging ability (pM = 28.3). Moreover, H2hox coordinates 68Ga quant.-ly in 5 min at room temp. in ligand concns. as low as 10-7 M, achieving an unprecedented high molar activity of 11±1 mCi/nmol (407±3.7 MBq/nmol) without purifn., suggesting prospective kit-based convenience. [68Ga(hox)]+ showed no decompn. in a plasma challenge. Good in vivo stability and fast renal and hepatic clearance of the [68Ga(hox)]+ complex were demonstrated using dynamic PET/CT imaging. The intrinsic fluorescence of [Ga(hox)]+ allowed for direct fluorescence imaging of cellular uptake and distribution, demonstrating the dual channel detectability and intracellular stability of the metal complex.
    56. 56
      Notni, J.; Hermann, P.; Havlickova, J.; Kotek, J.; Kubicek, V.; Plutnar, J.; Loktionova, N.; Riss, P. J.; Rosch, F.; Lukes, I. A. Triazacyclononane-Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric Ga-68 Tracers for Positron Emission Tomography. Chem. - Eur. J. 2010, 16 (24), 7174– 7185,  DOI: 10.1002/chem.200903281
      56
      A Triazacyclononane-Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric 68Ga Tracers for Positron Emission Tomography
      Notni, Johannes; Hermann, Petr; Havlickova, Jana; Kotek, Jan; Kubicek, Vojtech; Plutnar, Jan; Loktionova, Natalia; Riss, Patrick Johannes; Roesch, Frank; Lukes, Ivan
      Chemistry - A European Journal (2010), 16 (24), 7174-7185, S7174/1-S7174/11CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      For application in positron emission tomog. (PET), PrP9 (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]), a N,N',N''-trisubstituted triazacyclononane with methyl(2-carboxyethyl)phosphinic acid pendant arms, was developed as 68Ga3+ complexing agent. The synthesis is short and inexpensive. GaIII and FeIII complexes of PrP9 were characterized by single-crystal x-ray diffraction. Stepwise protonation consts. and thermodn. stabilities of metal complexes were detd. by potentiometry. The GaIII complex possesses a high thermodn. stability (log K[GaL] = 26.24) and a high degree of kinetic inertness. 68Ga labeling of PrP9 is possible at ambient temp. and in a wide pH range, also at pH values ≥1. For the 1st time, the neat eluate of a TiO2-based 68Ge/68Ga generator (consisting of 0.1M HCl) can be directly used for labeling purposes. The rate of 68Ga activity incorporation at pH 3.3 and 20° is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.
    57. 57
      Motekaitis, R. J.; Sun, Y.; Martell, A. E.; Welch, M. J. Stabilities of gallium(III), iron(III), and indium(III) chelates of hydroxyaromatic ligands with different overall charges. Inorg. Chem. 1991, 30 (13), 2737– 2740,  DOI: 10.1021/ic00013a007
      57
      Stabilities of gallium(III), iron(III), and indium(III) chelates of hydroxyaromatic ligands with different overall charges
      Motekaitis, Ramunas, J.; Sun, Yizhen; Martell, Arthur E.; Welch, Michael J.
      Inorganic Chemistry (1991), 30 (13), 2737-40CODEN: INOCAJ; ISSN:0020-1669.
      The stability consts. of the Ga(III), In(III), and Fe (III) chelates of three new ligands, N-(2-hydroxybenzyl)-N'-(pyridoxyl)ethylenediamine-N,N'-diacetic acid (HBPLED), N-(2-hydroxy-3,5-dimethylbenyl)-N'-(3-hydroxy-1,2,5-trimethyl-4-pyridiniumyl)methyl)ethylenediamine-N,N'-diacetic acid (Me4HBPLED), and N,N'-bis(1,2-dimethyl-3-hydroxy-5-hydroxymethyl)-4-pyridiniumyl)methyl)ethylenediamine-N,N'-diacetic acid (DMPLED) are reported and compared with those of the parent ligands N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), N,N'-bis(2-hydroxy-3,5-dimethylbenzyl)ethylenediamine-N,N'-diacetic acid (TMHBED), and N,N'-bis(pyridoxyl)ethylenediamine-N,'-diacetic acid (PLED). This comparison shows the effect on chelate stability of the methylation of the pyridine nitrogens, which increases the overall charges of the complex mols. without changing the donor atoms in the coordination sphere. The data show that quaternization of the pyridine nitrogen decreases the stability consts. of the Fe(III) and Ga(III) chelates by about 2 orders of magnitude. A perturbation in the trends is seen in the chelates of Me4HBPLED, whereby methylation of the benzene ring tεnds to increase the metal chelate stabilities. The log K values are for HBPLED: Ga, 31.02; Fe, 31.01; In, 28.97.for Me4HBPLED: Ga, 31.85; Fe, 32.97; In, 27.82. For DMPLEd: Ga, 27.27; Fe, 27.20; In, 21.47.
    58. 58
      Abergel, R. J.; D’Aleo, A.; Leung, C. N. P.; Shuh, D. K.; Raymond, K. N. Using the Antenna Effect as a Spectroscopic Tool: Photophysics and Solution Thermodynamics of the Model Luminescent Hydroxypyridonate Complex [EuIII(3,4,3-LI(1,2-HOPO))]−. Inorg. Chem. 2009, 48 (23), 10868– 10870,  DOI: 10.1021/ic9013703
      58
      Using the Antenna Effect as a Spectroscopic Tool: Photophysics and Solution Thermodynamics of the Model Luminescent Hydroxypyridonate Complex [EuIII(3,4,3-LI(1,2-HOPO))]-
      Abergel, Rebecca J.; D'Aleo, Anthony; Leung, Clara Ng Pak; Shuh, David K.; Raymond, Kenneth N.
      Inorganic Chemistry (2009), 48 (23), 10868-10870CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Although widely used in bioassays, the spectrofluorimetric method described here uses the antenna effect as a tool to probe the thermodn. parameters of ligands that sensitize lanthanide luminescence. The Eu3+ coordination chem., soln. thermodn. stability, and photophys. properties of the spermine-based hydroxypyridonate octadentate chelator 3,4,3-LI(1,2-HOPO) are reported. The complex [EuIII(3,4,3-LI(1,2-HOPO))]- luminesces with a long lifetime (805 μs) and a quantum yield of 7.0% in aq. soln., at pH 7.4. These remarkable optical properties were exploited to det. the high (and proton-independent) stability of the complex (log β110 = 20.2(2)) and to define the influence of the ligand scaffold on the stability and photophys. properties.
    59. 59
      Anderegg, G.; Arnaud-Neu, F.; Delgado, R.; Felcman, J.; Popov, K. Critical evaluation of stability constants of metal complexes of complexones for biomedical and environmental applications (IUPAC Technical Report). Pure Appl. Chem. 2005, 77 (8), 1445– 1495,  DOI: 10.1351/pac200577081445
      59
      Critical evaluation of stability constants of metal complexes of complexones for biomedical and environmental applications
      Anderegg, Giorgio; Arnaud-Neu, Francoise; Delgado, Rita; Felcman, Judith; Popov, Konstantin
      Pure and Applied Chemistry (2005), 77 (8), 1445-1495CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)
      A review. Available exptl. data on stability consts. of proton (hydron) and metal complexes for seven complexones of particular biomedical and environmental interest: iminodiacetic acid (2,2'-azanediyldiacetic acid, IDA); (methylimino)diacetic acid (2,2'-(methylazanediyl)diacetic acid, MIDA); 2,2',2'',2'''-{[(carboxymethyl)azanediyl]bis[(ethane-1,2-diyl)nitrilo]}tetraacetic acid (DTPA); 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA); 2,2',2''-(1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA); 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA); 2,2',2'',2'''-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetraacetic acid (TETA), published in 1945-2000, have been critically evaluated. Some typical errors in stability const. measurements for particular complexones are summarized. Higher quality data are selected and presented as "Recommended" or "Provisional".
    60. 60
      Brown, P. L.; Ekberg, C. Hydrolysis of Metal Ions; Wiley: 2016.
      There is no corresponding record for this reference.
    61. 61
      Summer, D.; Garousi, J.; Oroujeni, M.; Mitran, B.; Andersson, K. G.; Vorobyeva, A.; Lofblom, J.; Orlova, A.; Tolmachev, V.; Decristoforo, C. Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression. Mol. Pharmaceutics 2018, 15 (1), 175– 185,  DOI: 10.1021/acs.molpharmaceut.7b00787
      61
      Cyclic versus Noncyclic Chelating Scaffold for 89Zr-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression
      Summer, Dominik; Garousi, Javad; Oroujeni, Maryam; Mitran, Bogdan; Andersson, Ken G.; Vorobyeva, Anzhelika; Loefblom, John; Orlova, Anna; Tolmachev, Vladimir; Decristoforo, Clemens
      Molecular Pharmaceutics (2018), 15 (1), 175-185CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Zirconium-89 is an emerging radionuclide for positron emission tomog. (PET) esp. for biomols. with slow pharmacokinetics as due to its longer half-life, in comparison to fluorine-18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to-head as bifunctional chelators for 89Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temp. but radiochem. yields increased substantially at elevated temp., 85 °C. Both 89Zr-FSC-ZEGFR:2377 and 89Zr-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 °C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89Zr-DFO-ZEGFR:2377, radiolabeled at room temp., showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of 89Zr-FSC-ZEGFR:2377 as well as 89Zr-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomols. with zirconium-89. Furthermore, our findings indicate that 89Zr-radiolabeling of DFO conjugates at higher temp. reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.
    62. 62
      Zhai, C. Y.; Summer, D.; Rangger, C.; Franssen, G. M.; Laverman, P.; Haas, H.; Petrik, M.; Haubner, R.; Decristoforo, C. Novel Bifunctional Cyclic Chelator for Zr-89 Labeling-Radiolabeling and Targeting Properties of RGD Conjugates. Mol. Pharmaceutics 2015, 12 (6), 2142– 2150,  DOI: 10.1021/acs.molpharmaceut.5b00128
      62
      Novel Bifunctional Cyclic Chelator for 89Zr Labeling-Radiolabeling and Targeting Properties of RGD Conjugates
      Zhai, Chuangyan; Summer, Dominik; Rangger, Christine; Franssen, Gerben M.; Laverman, Peter; Haas, Hubertus; Petrik, Milos; Haubner, Roland; Decristoforo, Clemens
      Molecular Pharmaceutics (2015), 12 (6), 2142-2150CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Within the last years 89Zr has attracted considerable attention as long-lived radionuclide for positron emission tomog. (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting αβ3 integrins were synthesized using different conjugation strategies and labeled with 89Zr. In vitro stability, biodistribution, and microPET/CT imaging were evaluated using [89Zr]FSC-RGD conjugates or [89Zr]triacetylfusarinine C (TAFC). Quant. 89Zr labeling was achieved within 90 min at room temp. The distribution coeffs. of the different radioligands indicate hydrophilic character. Compared to [89Zr]DFO, [89Zr]FSC derivs. showed excellent in vitro stability and resistance against transchelation in phosphate buffered saline (PBS), EDTA soln. (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging expts. showed efficient receptor-specific targeting of [89Zr]FSC-RGD conjugates. No bone uptake was obsd. analyzing PET images indicating high in vivo stability. These findings indicate that FSC is a highly promising chelator for the development of 89Zr-based PET imaging agents.
    63. 63
      Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease. Chem. Rev. 2010, 110 (5), 2858– 2902,  DOI: 10.1021/cr900325h
      63
      Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease
      Wadas, Thaddeus J.; Wong, Edward H.; Weisman, Gary R.; Anderson, Carolyn J.
      Chemical Reviews (Washington, DC, United States) (2010), 110 (5), 2858-2902CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review.
    64. 64
      Burdett, J. K.; Hoffmann, R.; Fay, R. C. Eigth-coordination. Inorg. Chem. 1978, 17 (9), 2553– 2568,  DOI: 10.1021/ic50187a041
      64
      Eight-coordination
      Burdett, Jeremy K.; Hoffmann, Roald; Fay, Robert C.
      Inorganic Chemistry (1978), 17 (9), 2553-68CODEN: INOCAJ; ISSN:0020-1669.
      A systematic MO anal. of 8-coordinate mols. is presented. The emphasis lies in appreciating the basic electronic structure, σ and π substituent site preferences, and relative bond lengths within a particular geometry for the following structures: dodecahedron (DD), square antiprism (SAP), C2v bicapped trigonal prism (BTP), cube (C), hexagonal bipyramid (HB), square prism (SP), bicapped trigonal antiprism (BTAP), and D3h bicapped trigonal prism (ETP). With respect to σ or electroneg. effects the better σ donor should lie in the A sites of the DD and the capping sites of the BTP, although the preferences are not very strong when viewed from the basis of ligand charges. For d2 π acceptors and d° π donors, π site preferences are .perp.B > .perp.A > ‖A,B (> means better than) for the DD (this is Orgel's rule), ‖ > .perp. for the SAP, (m‖ > b‖) > b.perp. > (c‖ ∼ c.perp. ∼ m.perp.) for the BTP (b, c, and m refer to ligands which are basal, are capping, or belong to the trigonal faces and lie on a verticle mirror plane) and eq‖ ∼ ax > eq.perp. for the HB. The reverse order holds for d2 donors. The obsd. site preferences in the DD are probably controlled by a mixt. of steric and electronic (σ, π) effects. An interesting crossover from r(M-A)/r(M-B) > 1 to β) < 1 is found as a function of geometry for the DD structure which is well matched by exptl. observations. Similar effects should occur in the BTP structure, but here exptl. data are scarce. The importance of electronic effects in the form of metal-ligand interactions in stabilizing a particular geometry is estd. by using perturbation theory in the form of the angular overlap method (AOM). In order of increasing energy ETP < BTP < SAP < DD « C ∼ HB ∼ BTAP. The importance of steric effects is estd. by calcg. the energy of an L88- species by mol. orbital methods. In order of increasing energy DD ∼ SAP < BTP ∼ C < HB ∼ BTAP « ETP. The combination of these 2 series leads to an explanation of the relative popularity of these structures, DD, SAP, BTP » C, HB, BTAP » ETP. The importance of the low-symmetry BTP as a low-energy structure for the d° configuration clearly emerges. The perturbation theory approach is also used to rationalize the relative bond lengths in the DD structure as a function of geometry and in the bipyramidal 5-, 7-, and 8-coordinate structures. Polytopal rearrangements are found to be barriers from MO calcns. on systems with nonchelating ligands for at least one pathway between DD and SAP or from either of these structures to the BTP geometry.
    65. 65
      Rousseau, J.; Zhang, Z. X.; Wang, X. Z.; Zhang, C. C.; Lau, J.; Rousseau, E.; Colovic, M.; Hundal-Jabal, N.; Benard, F.; Lin, K. S. Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with Zr-89 for imaging with positron emission tomography. Bioorg. Med. Chem. Lett. 2018, 28 (5), 899– 905,  DOI: 10.1016/j.bmcl.2018.01.067
      65
      Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography
      Rousseau, Julie; Zhang, Zhengxing; Wang, Xiaozhu; Zhang, Chengcheng; Lau, Joseph; Rousseau, Etienne; Colovic, Milena; Hundal-Jabal, Navjit; Benard, Francois; Lin, Kuo-Shyan
      Bioorganic & Medicinal Chemistry Letters (2018), 28 (5), 899-905CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with 89Zr for positron emission tomog. imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, resp. Trastuzumab conjugates of 3 and 4 were efficiently labeled with 89Zr (>95% radiochem. yield). The in vitro plasma stability of 89Zr-4-Trastuzumab and esp. 89Zr-3-Trastuzumab was greatly improved over previously reported 89Zr-1-Trastuzumab and 89Zr-2-Trastuzumab, but their demetalation remained higher and faster than 89Zr-deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for 89Zr-4-Trastuzumab, followed by 89Zr-3-Trastuzumab, and to a lesser extent for 89Zr-DFO-Trastuzumab. Mol. modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr-complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability.
    66. 66
      Boros, E.; Holland, J. P.; Kenton, N.; Rotile, N.; Caravan, P. Macrocycle-Based Hydroxamate Ligands for Complexation and Immunoconjugation of (89)Zirconium for Positron Emission Tomography (PET) Imaging. ChemPlusChem 2016, 81 (3), 274– 281,  DOI: 10.1002/cplu.201600003
      66
      Macrocycle-Based Hydroxamate Ligands for Complexation and Immunoconjugation of 89Zirconium for Positron Emission Tomography (PET) Imaging
      Boros, Eszter; Holland, Jason P.; Kenton, Nathaniel; Rotile, Nicholas; Caravan, Peter
      ChemPlusChem (2016), 81 (3), 274-281CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Four novel chelators (L1-L4) and their 89zirconium complexes were prepd. and compared with the 89zirconium desferrioxamine B (DFO) complex. The new chelates are based on 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) scaffolds and present either three or four hydroxamate arms for coordination with Zr4+ ions with coordination nos. between six and eight. The 89Zr-L4 complex showed similar stability to that of 89Zr-DFO when incubated in either rat blood plasma or EDTA challenge expts. Positron imaging and biodistribution studies in mice showed that 89Zr-L4 had similar pharmacokinetic behavior to that of 89Zr-DFO, with rapid renal elimination and low residual activity in background tissues. A bifunctional version of L4 (L5) was synthesized and conjugated to trastuzumab; an anti-HER2/neu antibody. Immunopositron emission tomog. imaging and biodistribution with 89Zr-L5-trastuzumab revealed high tumor to background ratios (tumor/blood ratio: 14.2±2.25) and a high tumor specificity that was comparable to the performance of 89Zr-DFO-trastuzumab.
    67. 67
      Tieu, W.; Lifa, T.; Katsifis, A.; Codd, R. Octadentate Zirconium(IV)-Loaded Macrocycles with Varied Stoichiometry Assembled From Hydroxamic Acid Monomers using Metal-Templated Synthesis. Inorg. Chem. 2017, 56 (6), 3719– 3728,  DOI: 10.1021/acs.inorgchem.7b00362
      67
      Octadentate Zirconium(IV)-Loaded Macrocycles with Varied Stoichiometry Assembled From Hydroxamic Acid Monomers using Metal-Templated Synthesis
      Tieu, William; Lifa, Tulip; Katsifis, Andrew; Codd, Rachel
      Inorganic Chemistry (2017), 56 (6), 3719-3728CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) in a 1:4 stoichiometry in the presence of diphenylphosphoryl azide and triethylamine gave the octadentate Zr(IV)-loaded tetrameric hydroxamic acid macrocycle for-[Zr(DFOT1)] ([M + H]+ calc 887.3, obs 887.2). In this metal-templated synthesis (MTS) approach, the coordination preferences of Zr(IV) directed the preorganization of four oxygen-rich bidentate for-PBH ligands about the metal ion prior to ring closure under peptide coupling conditions. The replacement of for-PBH with 5-[(5-aminopentyl) (hydroxy)amino]-5-oxopentanoic acid (for-PPH), which contained an addnl. methylene group in the dicarboxylic acid region of the monomer, gave the analogous Zr(IV)-loaded macrocycle for-[Zr(PPDFOT1)] ([M + H]+ calc 943.4, obs 943.1). A second, well-resolved peak in the liq. chromatogram from the for-PPH MTS system also characterized as a species with [M + H]+ 943.3, and was identified as the octadentate complex between Zr(IV) and two dimeric tetradentate hydroxamic acid macrocycles for-[Zr(PPDFOT1D)2]. Treatment of for-[Zr(PPDFOT1)] or for-[Zr(PPDFOT1D)2] with EDTA at pH 4.0 gave the resp. hydroxamic acid macrocycles as free ligands: octadentate PPDFOT1 or two equiv. of tetradentate PPDFOT1D (homobisucaberin, HBC). At pH values closer to physiol., EDTA treatment of for-[Zr(DFOT1)], for-[Zr(PPDFOT1)], or Zr(IV) complexes with related linear tri- or tetrameric hydroxamic acid ligands showed the macrocycles were more resistant to the release of Zr(IV), which has implications for the design of ligands optimized for the use of Zr(IV)-89 in positron emission tomog. (PET) imaging of cancer.
    68. 68
      Zeglis, B. M.; Mohindra, P.; Weissmann, G. I.; Divilov, V.; Hilderbrand, S. A.; Weissleder, R.; Lewis, J. S. Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels-Alder Click Chemistry. Bioconjugate Chem. 2011, 22 (10), 2048– 2059,  DOI: 10.1021/bc200288d
      68
      Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels-Alder Click Chemistry
      Zeglis, Brian M.; Mohindra, Priya; Weissmann, Gabriel I.; Divilov, Vadim; Hilderbrand, Scott A.; Weissleder, Ralph; Lewis, Jason S.
      Bioconjugate Chemistry (2011), 22 (10), 2048-2059CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      A modular system for the construction of radiometalated antibodies was developed based on the bioorthogonal cycloaddn. reaction between 3-(4-benzylamino)-1,2,4,5-tetrazine and the strained dienophile norbornene. The well-characterized, HER2-specific antibody trastuzumab and the positron emitting radioisotopes 64Cu and 89Zr were employed as a model system. The antibody was first covalently coupled to norbornene, and this stock of norbornene-modified antibody was then reacted with tetrazines bearing the chelators 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA) or desferrioxamine (DFO) and subsequently radiometalated with 64Cu and 89Zr, resp. The modification strategy is simple and robust, and the resultant radiometalated constructs were obtained in high specific activity (2.7-5.3 mCi/mg). For a given initial stoichiometric ratio of norbornene to antibody, the 64Cu-DOTA- and 89Zr-DFO-based probes were shown to be nearly identical in terms of stability, the no. of chelates per antibody, and immunoreactivity (>93% in all cases). In vivo PET imaging and acute biodistribution expts. revealed significant, specific uptake of the 64Cu- and 89Zr-trastuzumab bioconjugates in HER2-pos. BT-474 xenografts, with little background uptake in HER2-neg. MDA-MB-468 xenografts or other tissues. This modular system-one in which the divergent point is a single covalently modified antibody stock that can be reacted selectively with various chelators-will allow for both greater versatility and more facile cross-comparisons in the development of antibody-based radiopharmaceuticals.
    69. 69
      Price, E. W.; Orvig, C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 2014, 43 (1), 260– 290,  DOI: 10.1039/C3CS60304K
      69
      Matching chelators to radiometals for radiopharmaceuticals
      Price, Eric W.; Orvig, Chris
      Chemical Society Reviews (2014), 43 (1), 260-290CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomog. (SPECT, e.g.67Ga, 99mTc, 111In, 177Lu) and positron emission tomog. (PET, e.g.68Ga, 64Cu, 44Sc, 86Y, 89Zr), as well as therapeutic applications (e.g.47Sc, 114mIn, 177Lu, 90Y, 212/213Bi, 212Pb, 225Ac, 186/188Re). A fundamental crit. component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable mol. target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochem., nuclear medicine, and mol. imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The exptl. methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents.
    70. 70
      Bastian, R.; Weberling, R.; Palilla, F. Determination of iron by ultraviolet spectrophotometry. Anal. Chem. 1956, 28 (4), 459– 462,  DOI: 10.1021/ac50161a014
      70
      Determination of iron by ultraviolet spectrophotometry
      Bastian, Robert; Weberling, Richard; Palilla, Frank
      (1956), 28 (), 459-62CODEN: ANCHAM; ISSN:0003-2700.
      Fe+++ in HClO4 soln. gives an absorbance max. at 240 mμ (molar absorptivity 4.16 × 103 l. per mol. cm.). Less interference from other metals is encountered, however, at 260 mμ, which is the preferred wave length despite the lower absorption (molar absorptivity 2.88 × 103 l. per mol. cm.). Beer's law is followed up to an absorbance of at least 0.8. The absorbance rises with HClO4 concn. until 1 or 2 ml. of concd. HClO4 is present per 100 ml. of soln., and then remains nearly const. up to very high concns.; ten ml. of HClO4 in 100 ml. of soln. is recommended. The solns. are stable for long periods, no change in absorbance being noted in over 1 month. The temp. is not a crit. variable. Interferences of a no. of metals, and their elimination, are discussed.
    71. 71
      Szebesczyk, A.; Olshvang, E.; Besserglick, J.; Gumienna-Kontecka, E. Influence of structural elements on iron(III) chelating properties in a new series of amino acid-derived monohydroxamates. Inorg. Chim. Acta 2018, 473, 286– 296,  DOI: 10.1016/j.ica.2017.06.020
      71
      Influence of structural elements on iron(III) chelating properties in a new series of amino acid-derived monohydroxamates
      Szebesczyk, Agnieszka; Olshvang, Evgenia; Besserglick, Jenny; Gumienna-Kontecka, Elzbieta
      Inorganica Chimica Acta (2018), 473 (), 286-296CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      Amino acid-derived monohydroxamate compds. A1-A7 were synthesized and characterized for their coordination properties of Fe(III). The series varies in their skeletal lengths and compns.; some compds. lack external substituents, others are substituted with external functional amino or carboxylic groups, or alternatively inert Me. Undertaken investigations allowed the detn. of stoichiometry, stability consts. and spectroscopic parameters of formed ferric complexes. Incorporation of an external functional group with a dissociable proton affects the coordination behavior; the presence of carboxylic or amino groups hampers the formation of mono-, di- and trihydroxamate ferric complexes of presented compds. The differences in Fe(III) affinity of the monohydroxamates vs. trihydroxamates was reflected by the stability consts. and pFe, indicating the superior stability of hexadentate complexes.
    72. 72
      Babko, A. K.; Gridchina, G. I. Vliyanie sostoyaniya tsirkoniya v rastvore na ego vzaimodeistvie s organicheskimi reaktivami. Zhur. Neorg. Khim. 1962, 7 (4), 889– 893
      72
      Effect of the state of zirconium in solution on its reaction with organic reagents
      Babko, A. K.; Gridchina, G. I.
      Zhurnal Neorganicheskoi Khimii (1962), 7 (), 889-95CODEN: ZNOKAQ; ISSN:0044-457X.
      The effect of the state of Zr in soln. on the rate of formation of colored complexes was studied with Xylenol Orange (I), Methylthymol Blue, Alizarin C, phenylfluorone, Arsenazo, and Stilbazo. Solns. of different concns. of Zr in 0.01-2N HCl, with a const. ionic strength μ = 1 maintained with NaCl, were allowed to stand 10 days. If necessary, the solns. were dild. with 2N HCl to a final HCl concn., CHCl = 2N and to a final [Zr] = 2 × 10-5M. I was added to a final concn. of 2.5 × 10-5M, and the optical d. was detd. at intervals. The results showed that the reactivity, α, of polyions of Zr was more dependent on CHCl than on [Zr]. Solns. aged with [Zr] >0.01M in 1N HCl exhibited low α. The structure of the polyions was of the type -Zr(OH)2-O-Zr(OH)2-O-. Preliminary pptn. of the hydroxide followed by soln. in N HCl lowered α. Heating soln. before the addn. of I, thus increasing hydrolysis, lowered α. The presence of Al or sulfates during the pptn. increased α. Complete restoration of α was obtained by heating with 2-5N HCl. Heating soln. of pH = 2 destroyed the reactivity, and 50 γ Th could be detd. in the presence of 50-100 γ Zr with I, and in the presence of 10 γ Al with aluminon.
    73. 73
      Enyedy, E. A.; Primik, M. F.; Kowol, C. R.; Arion, V. B.; Kiss, T.; Keppler, B. K. Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study. Dalton Trans. 2011, 40 (22), 5895– 5905,  DOI: 10.1039/c0dt01835j
      73
      Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study
      Enyedy, Eva A.; Primik, Michael F.; Kowol, Christian R.; Arion, Vladimir B.; Kiss, Tamas; Keppler, Bernhard K.
      Dalton Transactions (2011), 40 (22), 5895-5905CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      The stoichiometries and stabilities of Ga3+, Fe3+, and Fe2+ complexes of Triapine and five related α-N heterocyclic thiosemicarbazones with potential antitumor activity were detd. by pH-potentiometry, UV-vis spectrophotometry, 1H NMR spectroscopy, and spectrofluorimetry in aq. soln. (with 30% DMSO), together with the characterization of the proton dissocn. processes. Addnl., the redox properties of the iron complexes were studied by cyclic voltammetry at various pH values. Formation of high stability bis-ligand complexes was found in all cases, which are predominant at physiol. pH with FeIII/FeII, while only at the acidic pH range with GaIII. The results show that among the thiosemicarbazones with various substituents the N-terminal dimethylation does not exert a measurable effect on the redox potential, but has the highest impact on the stability of the complexes as well as the cytotoxicity, esp. in the absence of a pyridine-NH2 group in the mol. In addn. the fluorescence properties of the ligands in aq. soln. and their changes caused by GaIII were studied.
    74. 74
      Alfenaar, M.; Deligny, C. L. Universal ph-scale in methanol and methanol-water mixtures. Recl. Trav. Chim. Pays-Bas 1967, 86 (11), 1185– 1190,  DOI: 10.1002/recl.19670861104
      74
      Universal pH-scale in methanol and methanol-water mixtures
      Alfenaar, M.; De Ligny, C. L.
      Recueil des Travaux Chimiques des Pays-Bas (1967), 86 (12), 1185-90CODEN: RTCPA3; ISSN:0165-0513.
      An electrometric method was used to define a pH scale in terms of pHSt values of standard buffer solns. of 0.1M solns. of (COOH)2 and (NH4)2C2O4, of (CH2COOH)2 and LiHC4H4O4, and of o-C6H4(OH)(COOH) and o-HOC6H4COONa in MeOH or MeOH-H2O; in terms of pHSt of aq. standard buffer solns.; and for values of a correction term [Ej(H2O) - Ej(S)]/0.05916 added to the value of pHx (the unknown) detd. with a pH meter (Ej(H2O) and Ej(S) are the liq. junction potentials). Accuracy is 0.01-0.12 and 0.27 pH units in 0-90% MeOH and MeOH, resp.
    75. 75
      Gelsema, W. J.; Deligny, C. L.; Remijnse, A. G.; Blijleve, H. pH-measurements in alcohol-water mixtures using aqueous standard buffer solutions for calibration. Recl. Trav. Chim. Pays-Bas 1966, 85 (7), 647– 660,  DOI: 10.1002/recl.19660850702
      75
      pH-measurements in alcohol-water mixtures, using aqueous standard buffer solutions for calibration
      Gelsema, W. J.; de Ligny, C. L.; Remijnse, A. G.; Blijleven, H. A.
      Recueil des Travaux Chimiques des Pays-Bas (1966), 85 (7), 647-60CODEN: RTCPA3; ISSN:0165-0513.
      Emf. detns. show that the influence of the solvent on the Liquid junction potential is the same for junctions formed in a capillary, a ground glass sleeve, and a fritted-glass disk. Also, the influence of the solvent on the standard potential of a glass electrode does not depend on the type of electrode. Thus, accurate pa*H.X detns. can be made in MeOH-H2O and EtOH-H2O mixts. by calibrating a pH-meter with aq. standard buffer solns. and subtracting from the meter readings pHx an amt. Δto account for the influence of the solvent. Δ-values are given for MeOH-H2O mixts. contg. up to 94% MeOH and for EtOH-H2O mixts. contg. up to 72% EtOH.
    76. 76
      Gans, P.; O’Sullivan, B. GLEE, a new computer program for glass electrode calibration. Talanta 2000, 51 (1), 33– 37,  DOI: 10.1016/S0039-9140(99)00245-3
      76
      GLEE, a new computer program for glass electrode calibration
      Gans, P.; O'Sullivan, B.
      Talanta (2000), 51 (1), 33-37CODEN: TLNTA2; ISSN:0039-9140. (Elsevier Science B.V.)
      A new computer program (GLEE, glass electrode evaluation) was written for the calibration of a glass electrode by a strong acid-strong base titrn. This program provides an est. of the carbonate contamination of the base, the pseudo-Nernstian std. potential and slope of the electrode and, optionally, the concn. of the base and pKW. The program runs under the Windows 3.1x, 9x and NT operating systems.
    77. 77
      Gran, G. Determination of the equivalent point in potentiometric titrations. Acta Chem. Scand. 1950, 4 (4), 559– 577,  DOI: 10.3891/acta.chem.scand.04-0559
      77
      Determination of the equivalent point in potentiometric titrations
      Gran, Gunnar
      Acta Chemica Scandinavica (1950), 4 (), 559-77CODEN: ACHSE7; ISSN:0904-213X.
      In potentiometric titrations, the end point is generally found by plotting E (the measured potential) or pH as a function of V (the vol. of reagent added). Sometimes, however, the point of max. slope does not show the exact end point, as in the titration of very weak acids. In such cases, the value ΔE/Δ V or ΔpH/Δ V is often plotted as a function of V. There are some advantages to be gained by using ΔV/ΔE or ΔV/pH rather than the reciprocal relation. This idea is developed mathematically with the aid of 88 simple equations and shown by some empirical curves. The application of a correction factor for very accurate work is discussed.
    78. 78
      Gans, P.; Sabatini, A.; Vacca, A. Superquad - an improved general program for computation of formation-constants from potentiometric data. J. Chem. Soc., Dalton Trans. 1985, (6), 1195– 1200,  DOI: 10.1039/dt9850001195
      78
      SUPERQUAD: an improved general program for computation of formation constants from potentiometric data
      Gans, Peter; Sabatini, Antonio; Vacca, Alberto
      Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999) (1985), (6), 1195-200CODEN: JCDTBI; ISSN:0300-9246.
      The computer program SUPERQUAD was developed, in which formation consts. are detd. by minimization of an error-square sum based on measured electrode potentials. The program also permits refinement of any reactant concn. or std. electrode potential. The refinement is incorporated into a new procedure which can be used for model selection.
    79. 79
      Alderighi, L.; Gans, P.; Ienco, A.; Peters, D.; Sabatini, A.; Vacca, A. Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species. Coord. Chem. Rev. 1999, 184, 311– 318,  DOI: 10.1016/S0010-8545(98)00260-4
      79
      Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species
      Alderighi, Lucia; Gans, Peter; Ienco, Andrea; Peters, Daniel; Sabatini, Antonio; Vacca, Alberto
      Coordination Chemistry Reviews (1999), 184 (), 311-318CODEN: CCHRAM; ISSN:0010-8545. (Elsevier Science S.A.)
      A review is presented with 23 refs. describing hyperquad simulation and speciation (HySS) that is a computer program written for the Windows operating system on personal computers which provides (a) a system for simulating titrn. curves and (b) a system for providing speciation diagrams. The calcns. relate to equil. in soln. and also include the possibility of formation of a partially sol. ppt. There are no restrictions on the no. of reagents that may be present or on the no. of complexes that may be formed.
    80. 80
      Baes, C. F.; Mesmer, R. E. The thermodynamics of cation hydrolysis. Am. J. Sci. 1981, 281 (7), 935– 962,  DOI: 10.2475/ajs.281.7.935
      80
      The thermodynamics of cation hydrolysis
      Baes, C. F., Jr.; Mesmer, R. E.
      American Journal of Science (1981), 281 (7), 935-62CODEN: AJSCAP; ISSN:0002-9599.
      Data for the hydrolysis of aq. cations are critically reviewed, enthalpy and entropy values for the various kinds of reactions are complied, and correlations are derived for predicting behavior at elevated temps. Such information is essential for understanding the chem. and the transport of metallic elements in hydrothermal environments. Projections based on the correlations of hydrolysis behavior at elevated temp. depend on a knowledge of the stepwise hydrolysis consts. for mononuclear species, and more such information is badly needed.
    81. 81
      Zdyb, K.; Plutenko, M. O.; Lampeka, R. D.; Haukka, M.; Ostrowska, M.; Fritsky, I. O.; Gumienna-Kontecka, E. Cu(II), Ni(II) and Zn(II) mononuclear building blocks based on new polynucleating azomethine ligand: Synthesis and characterization. Polyhedron 2017, 137, 60– 71,  DOI: 10.1016/j.poly.2017.07.009
      81
      Cu(II), Ni(II) and Zn(II) mononuclear building blocks based on new polynucleating azomethine ligand: Synthesis and characterization
      Zdyb, Karolina; Plutenko, Maxym O.; Lampeka, Rostislav D.; Haukka, Matti; Ostrowska, Malgorzata; Fritsky, Igor O.; Gumienna-Kontecka, Elzbieta
      Polyhedron (2017), 137 (), 60-71CODEN: PLYHDE; ISSN:0277-5387. (Elsevier Ltd.)
      Five new mononuclear complexes formed by the polynucleating ligand 2-[1-(3,5-dimethyl)pyrazolyl]-2-hydroxyimino-N'-[1-(2-pyridyl)ethylidene]acetohydrazide (HL): [Ni(L)(HL)]ClO4·2CH3OH (1), [Ni(L)2]·CH3OH (2), [Zn(L)(HL)]ClO4·2CH3OH (3), [Zn(L)2]·CH3OH (4) and [Cu(L)2]·CH3OH (5) were synthesized and characterized by elemental anal., mass-spectrometry, IR-spectroscopy and x-ray anal. The complexes reveal distorted octahedral N4O2 coordination arrangement formed by both protonated and deprotonated (1, 3) or two deprotonated ligand mols. (2, 4, 5). The presence of noncoordinated oxime and pyrazole groups gave extensive systems of hydrogen bonds in the crystal packing of 1-5. Potentiometric titrns., ESI-MS and spectrophotometric studies of complex formation in MeOH/H2O solns. indicated the presence of mono- and polynuclear complexes with Cu(II), Ni(II) and Zn(II) ions. The soln. studies carried out for an excess of Cu(II) over HL ligand (2:1 and 3:2 M ratio) indicated also the formation of polynuclear Cu3L2Hx species, with an involvement of addnl. nitrogen donors in copper coordination. In binuclear [Cu2(L)2(DMF)2](ClO4)2·DMF (6) obtained in solid state, the Cu(II) coordination, analogous to the one in 1-5, was supported by pyrazole N atom.
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      Gampp, H.; Maeder, M.; Meyer, C. J.; Zuberbuhler, A. D. Calculation of equilibrium-constants from multiwavelength spectroscopic data. 1. Mathematical considerations. Talanta 1985, 32 (2), 95– 101,  DOI: 10.1016/0039-9140(85)80035-7
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      Calculation of equilibrium constants from multiwavelength spectroscopic data - I. Mathematical considerations
      Gampp, Harald; Maeder, Marcel; Meyer, Charles J.; Zuberbuehler, Andreas D.
      Talanta (1985), 32 (2), 95-101CODEN: TLNTA2; ISSN:0039-9140.
      An algorithm is derived for calcn. of stability consts. from multiwavelength spectrophotometric data using matrix algebra. Problems in finding the min. in a multidimensional parameter space are reduced by elimination of the molar absorptivities from the algorithm for the iterative refinement. Numerical accuracy and speed of calcn. are improved by use of anal. instead of numerical derivs. The no. of data to be fitted is decreased by principal-component anal.
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      Gampp, H.; Maeder, M.; Meyer, C. J.; Zuberbuhler, A. D. Calculation of equilibrium-constants from multiwavelength spectroscopic data. 2. Specfit - 2 user-friendly programs in basic and standard fortran-77. Talanta 1985, 32 (4), 257– 264,  DOI: 10.1016/0039-9140(85)80077-1
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      Calculation of equilibrium constants from multiwavelength spectroscopic data - II SPECFIT: two user-friendly programs in BASIC and standard FORTRAN 77
      Gampp, Harald; Maeder, Marcel; Meyer, Charles J.; Zuberbuehler, Andreas D.
      Talanta (1985), 32 (4), 257-64CODEN: TLNTA2; ISSN:0039-9140.
      A new program (SPECFIT), written in HP BASIC or FORTRAN 77, for the calcn. of stability consts. from spectroscopic data, is presented. Stability consts. were successfully calcd. from multiwavelength spectrophotometric and EPR data, but the program can be equally well applied to the numerical treatment of other spectroscopic measurements. The special features included in SPECFIT to improve convergence, increase numerical reliability, and minimize memory as well as computing time requirements, include (1) elimination of the linear parameters (i.e., molar absorptivities), (2) the use of anal. instead of numerical derivs. and (3) factor anal. Calcn. of stability consts. from spectroscopic data is then as straightforward as from potentiometric titrn. curves and gives results of analogous reproducibility. The spectroscopic method is, however, superior in discrimination between chem. models.
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      Rossotti, F. J.; Rossotti, H. S.; Whewell, R. J. Use of electronic computing techniques in calculation of stability constants. J. Inorg. Nucl. Chem. 1971, 33 (7), 2051– 2065,  DOI: 10.1016/0022-1902(71)80567-5
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      Use of electronic computing techniques in the calculation of stability constants
      Rossotti, F. J. C.; Rossotti, H. S.; Whewell, R. J.
      Journal of Inorganic and Nuclear Chemistry (1971), 33 (7), 2051-65CODEN: JINCAO; ISSN:0022-1902.
      The application of electronic computers to the calcn. of stability const. is reviewed. Simple nonstatistical programs, more sophisticated least-squares treatments, and highly complex nonlinear search techniques are discussed. Particular attention is given to the problems of the choice of a program for a given system, the introduction of weighting factors, and the reliability of the resulting stability const., and limits of error.
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      Milburn, R. M.; Vosburgh, W. C. A spectrophotometric study of the hydrolysis of iron(iii) ion 0.2. Polynuclear species. J. Am. Chem. Soc. 1955, 77 (5), 1352– 1355,  DOI: 10.1021/ja01610a084
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      Spectrophotometric study of the hydrolysis of iron(III) ion. II. Polynuclear species
      Milburn, Ronald M.; Vosburgh, W. C.
      Journal of the American Chemical Society (1955), 77 (), 1352-5CODEN: JACSAT; ISSN:0002-7863.
      cf. C.A. 45, 9340g. The hydrolysis of Fe(III) ion was investigated at 25° over a wide range of concns. and ionic strengths. Evidence is presented for polynuclear hydrolyzed Fe(III) species in 10-3 and 10-2M Fe(III) solns. The data as found indicate dimerization of the 1st hydrolysis product. Hydrolysis and dimerization consts. were detd. over the range studied. With increasing ionic strength, the dimerization const. increases and the 1st hydrolysis const. decreases in accord with the Debye-H.ovrddot.uckel theory. The absorption spectrum of the pure hydrated Fe(III) ion was redetd. through the range 320-360 mμ at concns. low enough to avoid interference by polynuclear species.
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      Milburn, R. M. A spectrophotometric study of the hydrolysis of iron(iii) ion 0.3. Heats and entropies of hydrolysis. J. Am. Chem. Soc. 1957, 79 (3), 537– 540,  DOI: 10.1021/ja01560a011
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      A spectrophotometric study of the hydrolysis of iron(III) ion. III. Heats and entropies of hydrolysis
      Milburn, Ronald M.
      Journal of the American Chemical Society (1957), 79 (), 537-40CODEN: JACSAT; ISSN:0002-7863.
      cf. C.A. 49, 12934f. The hydrolysis of iron(III) ion was studied over a range of ionic strengths up to 1.00 at temps. 18, 25, and 32°. Values of ΔF, ΔH, and ΔS are calcd. for the reactions Fe+++ + H2O ↹ FeOH ++ + H+ and 2FeOH ++ ↹ Fe(OH)2Fe4+. Increases in temp. and decreases in ionic strength shifted the 1st hydrolysis equil. to the right and the dimerization equil. to the left. A neg. ΔS° value found for the dimerization reaction was attributed to loss of independent motion that the monomeric ion experiences on combination and to a greater restrictive effect of an ion of +2n charge over surrounding H2O mols. than 2 monomeric ions of + n charge. For comparative purposes thermal quantities are calcd. for the derived reactions 2Fe3 + 2H2O ↹ Fe(OH)2Fe4+ + 2H+ and Fe+++ + OH- ↹ FeOH++. 20 references.

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    • ESI-MS spectra and UV–vis spectroscopic data from solution studies, detail of the Fe(III) complex solution study, and 1H/13C NMR spectra and chromatograms of the synthesized compounds (PDF)


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