Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in 64/67Cu RadiopharmaceuticalsClick to copy article linkArticle link copied!
- Marianna TosatoMarianna TosatoDepartment of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyMore by Marianna Tosato
- Marco Dalla TiezzaMarco Dalla TiezzaDepartment of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyMore by Marco Dalla Tiezza
- Nóra V. MayNóra V. MayCentre for Structural Science, Research Centre for Natural Sciences, Magyar tudósok Körútja 2, 1117 Budapest, HungaryMore by Nóra V. May
- Abdirisak Ahmed IsseAbdirisak Ahmed IsseDepartment of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyMore by Abdirisak Ahmed Isse
- Sonia NardellaSonia NardellaDepartment of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyDepartment of Pharmaceutical Sciences, University of Padova, via Marzolo 8, 35131 Padova, ItalyMore by Sonia Nardella
- Laura OrianLaura OrianDepartment of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyMore by Laura Orian
- Marco VeronaMarco VeronaDepartment of Pharmaceutical Sciences, University of Padova, via Marzolo 8, 35131 Padova, ItalyMore by Marco Verona
- Christian VaccarinChristian VaccarinDepartment of Pharmaceutical Sciences, University of Padova, via Marzolo 8, 35131 Padova, ItalyMore by Christian Vaccarin
- André AlkerAndré AlkerRoche Pharmaceutical Research and Early Development, Roche Innovation Center Basel F. Hoffmann-La Roche, Grenzacherstrasse 124, 4058 Basel, SwitzerlandMore by André Alker
- Helmut MäckeHelmut MäckeDepartment of Nuclear Medicine, University Hospital Freiburg, Hugstetterstrasse 55, D-79106 Freiburg, GermanyMore by Helmut Mäcke
- Paolo PastorePaolo PastoreDepartment of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyMore by Paolo Pastore
- Valerio Di Marco*Valerio Di Marco*Email: [email protected]Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, ItalyMore by Valerio Di Marco
Abstract
The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV–vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV–vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+–Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV–vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.
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Synopsis
A series of cyclen derivatives bearing sulfur- or mixed-sulfur-carboxylated pendant arms were considered as chelators for copper radioisotopes in radiopharmaceuticals. Stability and structure of their Cu2+ and Cu+ complexes were studied in aqueous solution using a multimethodological approach. The stability of both Cu2+ and Cu+ complexes should prevent the reductive-based copper demetallation observed in vivo for other copper chelators.
Introduction
Figure 1
Figure 1. Select state-of-the-art copper chelators (NOTA, DOTA, and TETA) and ligands investigated in this work (DO4S, DO3S, DO3SAm, and DO2A2S).
Results and Discussion
Protonation Properties of the Ligands
Complexation Kinetics of Cupric Complexes
Solution Thermodynamics of Cupric Complexes
Figure 2
Figure 2. Select UV–vis spectra at pH <2 of the Cu2+ complexes formed by (A) DO4S (CCu2+ = CDO4S = 1.5 × 10–4 mol/L), (B) DO3S (CCu2+ = CDO3S = 1.0 × 10–4 mol/L), (C) DO3SAm (CCu2+ = CDO3SAm = 1.1 × 10–4 mol/L), and (D) DO2A2S (CCu2+ = CDO2A2S = 0.9 × 10–4 mol/L) at I = 0.15 mol/L NaCl (for solutions at pH >0.8) and T = 25.0 °C.
ligand | equilibrium reactionb | logβ |
---|---|---|
DO4S | Cu2+ + L ⇋ CuL2+ | 19.8 ± 0.1c |
19.6 ± 0.4d | ||
DO3S | Cu2+ + L ⇋ CuL2+ | 20.34 ± 0.06c |
20.10 ± 0.08d | ||
DO3SAm | Cu2+ + L ⇋ CuL2+ | 19.8 ± 0.2c |
19.7 ± 0.2d | ||
DO2A2S | Cu2+ + H+ + L2– ⇋ CuHL+ | 24.22 ± 0.09c |
Cu2+ + L2– ⇋ CuL | 22.0 ± 0.3d | |
21.9 ± 0.2c | ||
DOTA | Cu2+ + 2H+ + L4– ⇋ CuH2L | 30.8e |
Cu2+ + H+ + L4– ⇋ CuHL– | 26.60e | |
Cu2+ + L4– ⇋ CuL2– | 22.30e |
The literature data for DOTA are reported for comparison.
L denotes the ligand in its totally deprotonated form.
Obtained by UV–vis spectrophotometric titrations.
Obtained by Ag+–Cu2+ competition (no ionic strength control).
From ref (44).
Figure 3
pCu2+ | |||
---|---|---|---|
ligand | pH 4.0 | pH 6.0 | pH 7.4 |
DO4S | 9.3 | 11.3 | 17.7 |
DO3S | 8.9 | 10.9 | 17.5 |
DO3SAm | 8.5 | 10.5 | 17.2 |
DO2A2S | 10.1 | 12.5 | 19.4 |
DOTA | 7.6 | 9.8 | 17.4 |
NOTA | 10.9 | 13.0 | 18.2 |
TETA | 7.3 | 9.6 | 16.2 |
Cyc4Me | 7.3 | 11.3 | 14.1 |
Structural Investigation of the Cupric Complexes
Figure 4
Figure 4. Measured (solid lines) and simulated (dotted lines) EPR spectra for solutions containing Cu2+ and (A) DO4S (CCu2+ = 1.0 × 10–3 mol/L; CDO4S = 1.3 × 10–3 mol/L) and (B) DO3S (CCu2+ = 1.0 × 10–3 mol/L; CDO3S = 1.1 × 10–3 mol/L) at room temperature (left) and 77 K (right). The component spectra obtained from the simulation are shown in the upper part.
isotropic parametersb | anisotropic parametersc | |||||||
---|---|---|---|---|---|---|---|---|
g0 | A0 (×10–4 cm–1) | g⊥ or gx, gy | g∥ or gz | A⊥ or Ax, Ay (×10–4 cm–1) | A∥ or Az (×10–4 cm–1) | calculateddg0,calc | suggested coordination | |
L = DO4S | ||||||||
CuL2+(1) | 2.091 | 71.7 | [4N] | |||||
CuL2+(2) | 2.103 | 63.6 | 2.048, 2.058 | 2.209 | 20.3, 23.5 | 171.2 | 2.105 | [4N]Sax |
L = DO3S | ||||||||
Cu2+ | 2.196 | 34.9 | 2.085 | 2.423 | 11.8 | 127.2 | 2.197 | |
CuL2+(1) | 2.093 | 74.0 | 2.036 | 2.184 | 15.6 | 179.3 | 2.085 | [4N] |
CuL2+(2) | 2.048, 2.058 | 2.209 | 20.3, 23.5 | 171.2 | 2.105 | [4N]Sax | ||
L = DO2A2S | ||||||||
Cu2+ | 2.085 | 2.423 | 11.8 | 127.2 | 2.197 | |||
CuLH22+(1) | 2.066 | 2.257 | 11.5 | 158.1 | 2.129 | [3N,S] | ||
CuLH22+(2) | 2.058 | 2.214 | 28.7 | 164,7 | 2.110 | [4N]Sax | ||
CuLH+ | 2.060 | 2.234 | 25.8 | 161,5 | 2.118 | [3N,O]Nax | ||
CuL | 2.075 | 2.272 | 24.5 | 142.8 | 2.141 | [2N,2O]2Nax | ||
L = Cyclene | ||||||||
CuL | 2.040, 2.055 | 2.197 | 16.9, 21.0 | 181.9 | 2.097 | [4N]H2Oax | ||
L = DOTAf | ||||||||
CuL2–(1) | 2.058 | 2.301 | 10.0 | 150.0 | 2.139 | [2N,2O]2Nax | ||
CuL2–(2) | 2.061 | 2.241 | 15.0 | 157.2 | 2.121 | [3N,O]Nax |
The literature data for Cu2+-DOTA and Cu2+-cyclen are reported for comparison.
The experimental error was ±0.001 for g0 and ±1 × 10–4 cm–1 for A0.
The experimental error was ±0.002 for gx and gy, ±0.001 for gz, and ±1 × 10–4 cm–1 for Ax, Ay, and Az.
Calculated by the equation g0,calc = (gx + gy + gz)/3 on the basis of anisotropic values.
From ref (41).
From ref (52).
gas phase | water | |||||
---|---|---|---|---|---|---|
M | ligand | coordination | ΔE | ΔG | ΔE | ΔG |
Cu2+ | DO4S | [4N] | –412.4 | –399.4 | –192.7 | –179.7 |
[4N,S] | –417.4 | –404.2 | –190.9 | –177.7 | ||
[4N,2S] | –410.1 | –396.6 | –179.8 | –166.2 | ||
DO3S | [4N] | –411.4 | –399.5 | –196.6 | –184.8 | |
[4N,S] | –418.1 | –403.8 | –197.4 | –183.1 | ||
[4N,2S] | –411.2 | –395.5 | –185.9 | –170.3 | ||
Cu+ | DO4S | [4N] | –117.3 | –104.7 | –60.6 | –48.0 |
[4N,S] | –128.3 | –115.4 | –68.9 | –56.0 | ||
[4N,2S] | –122.5 | –108.5 | –60.6 | –46.6 | ||
DO3S | [4N] | –119.7 | –108.6 | –63.4 | –52.4 | |
[4N,S] | –130.6 | –117.1 | –71.4 | –57.9 | ||
[4N,2S] | –126.2 | –111.4 | –63.9 | –49.0 |
All energies are in kilocalories per mole. Level of theory: (COSMO-)ZORA-OPBE/TZ2P//ZORA-OPBE/TZP.
Figure 5
Figure 5. ORTEP diagrams of (A) [Cu(DO4S)(NO3)]·NO3 and (B) [Cu(DO2A2S)] (Cu1 = molecule #1; Cu2 = molecule #2) with atom numbering. Thermal ellipsoids are drawn at the 50% probability level. Water molecules, hydrogen atoms, and nonbonded nitrate anions are omitted for the sake of clarity. The symmetry codes for molecules #1 and #2 in [Cu(DO2A2S)] are −x + 1, y, −z + 1 and −x + 2, y, −z + 1, respectively.
[Cu(DO2A2S)] | |||||
---|---|---|---|---|---|
[Cu(DO4S)(NO3)]·NO3 | molecule #1 | molecule #2 | |||
bond | distance (Å) | bond | distance (Å) | bond | distance (Å) |
Cu1–N5 | 2.03(7) | Cu1–O1 | 1.954(2) | Cu2–O3 | 1.955(2) |
Cu1–N3 | 2.04(7) | Cu1–N1 | 2.150(3) | Cu2–N3 | 2.110(3) |
Cu1–N2 | 2.05(7) | Cu1–N2 | 2.536(3) | Cu2–N4 | 2.336(3) |
Cu1–N4 | 2.06(7) | ||||
Cu1–O31 | 2.15(6) |
[Cu(DO2A2S)] | |||||
---|---|---|---|---|---|
[Cu(DO4S)(NO3)]·NO3 | molecule #1 | molecule #2 | |||
bond | angle (deg) | bond | angle (deg) | bond | angle (deg) |
N5–Cu1–N2 | 86.8(3) | O1–Cu1–N1 | 80.3(1) | O3–Cu2–N3 | 84.1(1) |
N5–Cu1–N3 | 151.9(3) | N1–Cu1–N1#1 | 117.2(2) | N3–Cu2–N3#2 | 103.3(2) |
N5–Cu1–N4 | 87.6(3) | N2–Cu1–N2#1 | 125.6(2) | N4–Cu2–N4#2 | 149.9(1) |
N5–Cu1–O31 | 104.6(3) | O1–Cu1–O1#1 | 87.0(1) | O3–Cu2–O3#2 | 89.6(1) |
N3–Cu1–O31 | 103.3(3) | O1–Cu1–N1#1 | 157.49(9) | O3–Cu2–N3#2 | 169.4(1) |
N2–Cu1–O31 | 110.5(3) | ||||
N4–Cu1–O31 | 98.7(3) |
See Figure 5 for atom labeling. Additional data are summarized in Tables S8, S9, S11, and S12. Symmetry codes: #1, −x + 1, y, −z + 1; #2, −x + 2, y, −z + 1.
Figure 6
Figure 6. Measured (solid lines) and simulated (dotted lines) spectra for solutions containing Cu2+ and DO2A2S (CCu2+ = 1.0 × 10–3 mol/L; CDO2AS = 1.1 × 10–3 mol/L) at 77 K. The component spectra obtained from the simulation are shown in the upper part.
gas phase | water | |||||
---|---|---|---|---|---|---|
M | coordination | formb | ΔE | ΔG | ΔE | ΔG |
Cu2+ | [4N,2O] | –698.8 | –684.7 | –220.8 | –206.7 | |
[4N,2O] | H+ | –563.3 | –548.3 | –202.6 | –187.6 | |
[4N,O] | H+ | –565.7 | –550.1 | –210.5 | –194.9 | |
[4N,O,S] | H+ | –563.8 | –546.4 | –201.0 | –183.7 | |
[4N,S] | H+ | –554.6 | –539.4 | –198.8 | –183.6 | |
[4N,2S] | H+ | –545.5 | –528.2 | –186.7 | –169.4 | |
Cu+ | [4N,2O] | –260.6 | –260.6 | –66.3 | –57.2 | |
[4N,O] | –257.7 | –257.7 | –75.5 | –66.0 | ||
[4N,O,S] | –253.1 | –253.1 | –71.4 | –61.0 | ||
[4N,S] | –248.1 | –248.1 | –77.8 | –67.8 | ||
[4N,2S] | –243.7 | –243.7 | –69.1 | –56.2 | ||
[4N,2O] | H+ | –193.4 | –193.4 | –63.1 | –50.5 | |
[4N,O] | H+ | –203.1 | –203.1 | –73.1 | –59.8 | |
[4N,O,S] | H+ | –199.6 | –199.6 | –68.7 | –54.1 | |
[4N,S] | H+ | –188.1 | –188.1 | –96.9 | –82.4 | |
[4N,2S] | H+ | –184.2 | –184.2 | –65.2 | –48.7 |
All of the energies are in kilocalories per mole. Level of theory: (COSMO-)ZORA-OPBE/TZ2P//ZORA-OPBE/TZP.
The two carboxylates were considered to be either deprotonated (−) or monoprotonated (H+).
Electrochemical Properties
Figure 7
Figure 7. Cyclic voltammograms of the copper complexes of (A) DO4S (C[Cu(DO4S)]2+ = 1.02 × 10–3 mol/L), (B) DO3S (C[Cu(DO3S)]2+ = 1.13 × 10–3 mol/L), and (C) DO2A2S (C[Cu(DO2A2S)] = 6.48 × 10–4 mol/L) in aqueous solution at pH 7, I = NaNO3 0.15 mol/L, and T = 25 °C. Scan rates: 0.1 V/s (A and B) and 0.01 V/s (C).
complex | Epc [V] vs SCEa | Epa [V] vs SCEa | ΔEp [V] vs SCEa | E1/2 [V] vs SCEa |
---|---|---|---|---|
Cu-DO4S | –0.182 ± 0.001 | –0.115 ± 0.003 | 0.067 | –0.149 ± 0.001 |
Cu-DO3S | –0.334 ± 0.004 | –0.252 ± 0.003 | 0.082 | –0.293 ± 0.005 |
Cu-DO2A2S | –0.496b | –0.341b | 0.155b | –0.421 ± 0.004 |
Average of the values measured at 0.01 V/s ≤ v ≤ 0.2 V/s.
Value at v = 0.01 V/s.
Solution Thermodynamics and Structural Investigation of the Cuprous Complexes
pCu+ | |||||
---|---|---|---|---|---|
ligand | equilibrium reaction | logβ | pH 4.0 | pH 6.0 | pH 7.4 |
DO4S | Cu+ + L ⇋ CuL+ | 19.8 ± 0.2 | 10.7 | 14.7 | 17.2 |
DO3S | Cu+ + L ⇋ CuL+ | 17.2 ± 0.2 | 7.9 | 11.9 | 14.5 |
DO2A2S | Cu+ + L2– ⇋ CuL– | 16.7 ± 0.1 | 7.3 | 11.3 | 14.1 |
pCu+ calculated at CCu+ = 10–6 mol/L and CL = 10–5 mol/L
Figure 8
Figure 8. LSV of Cu-DO4S before (blu) and after (gray) electrolysis at −0.35 V, performed with a rotating disk electrode at ω = 2000 rpm and v = 0.005 V/s, with I = NaNO3 0.15 mol/L and T = 25 °C.
Figure 9
Figure 9. 1H NMR spectra (400 MHz, room temperature, H2O + 10% D2O) of the in situ generated cuprous complexes: (A) DO4S (CCu= CDO4S = 1.6 × 10–3 mol/L) and (B) DO2A2S (CCu = CDO2A2S = 1.4 × 10–3 mol/L) at pH 7. The signal marked with an asterisk (2.22 ppm) is related to the acetone impurity.
Experimental Section
Materials
Complexation Kinetics
Thermodynamic Measurements
EPR Measurements
X-ray Crystal Structure
CV
Electrolysis and NMR
DFT Calculations


Conclusions
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c01550.
Structures of chelators proposed in the literature for copper-based radiopharmaceuticals, acidity constants and distribution diagrams of the free chelators (DO4S, DO3S, DO3SAm, DO2A2S, and DOTA), equilibration times required to reach equilibrium in Cu2+/chelator complex formation, UV–vis spectroscopic data and spectra of Cu2+/chelator complexes, EPR-derived isomeric dependence on the pH, extended crystallographic data and unit cell/packing arrangement pictures, DFT-computed free energy and structures of the Cu2+/chelator and Cu+/chelator complexes, cyclic voltammograms of free Cu, free chelators, and Cu/chelator complexes at various scan rates, and NMR data and spectra of Cu+/chelator complexes (PDF)
CCDC 2036253 and 2078038 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Acknowledgments
This research was supported by the ISOLPHARM_EIRA project funded by the Legnaro National Laboratories of the Italian Institute of Nuclear Physics (INFN) and by the National Research, Development and Innovation Office, NKFIA (Hungary), through Project K124544. The authors thank Dr. Thomas Gyr, Dr. Michael Henning, and students Marco Covolo and Eni Berberi for their work. Prof. Cristina Tubaro is also acknowledged for her assistance with the Schlenk line. M.D.T. is grateful to Fondazione CARIPARO for financial support (Ph.D. grant), and M.D.T. and L.O. thank INFN for access to cloud facilities.
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- 2Wadas, 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/cr900325hGoogle Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFChtro%253D&md5=674cf315a0df26fc4407445bd35595d6Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of DiseaseWadas, 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.
- 3Cai, Z.; Anderson, C. J. Chelators for Copper Radionuclides in Positron Emission Tomography Radiopharmaceuticals. J. Labelled Compd. Radiopharm. 2014, 57 (4), 224– 230, DOI: 10.1002/jlcr.3165Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFCjsLvI&md5=b804d4f3317d0c53978d3621a3b221ccChelators for copper radionuclides in positron emission tomography radiopharmaceuticalsCai, Zhengxin; Anderson, Carolyn J.Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (4), 224-230CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. The development of chelating agents for copper radionuclides in positron emission tomog. radiopharmaceuticals has been a highly active and important area of study in recent years. The rapid evolution of chelators has resulted in highly specific copper chelators that can be readily conjugated to biomols. and efficiently radiolabeled to form stable complexes in vivo. Chelators are not only designed for conjugation to monovalent biomols. but also for incorporation into multivalent targeting ligands such as theranostic nanoparticles. These advancements have strengthened the role of copper radionuclides in the fields of nuclear medicine and mol. imaging. This review emphasizes developments of new copper chelators that have most greatly advanced the field of copper-based radiopharmaceuticals over the past 5 years.
- 4Boros, E.; Cawthray, J. F.; Ferreira, C. L.; Patrick, B. O.; Adam, M. J.; Orvig, C. Evaluation of the H2dedpa Scaffold and Its CRGDyK Conjugates for Labeling with 64Cu. Inorg. Chem. 2012, 51 (11), 6279– 6284, DOI: 10.1021/ic300482xGoogle Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvFWqsr0%253D&md5=06aed6b5cecd6dc0224fa73f3070effeEvaluation of the H2dedpa Scaffold and its cRGDyK Conjugates for Labeling with 64CuBoros, Eszter; Cawthray, Jacqueline F.; Ferreira, Cara L.; Patrick, Brian O.; Adam, Michael J.; Orvig, ChrisInorganic Chemistry (2012), 51 (11), 6279-6284CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Studies of the acyclic ligand scaffold H2dedpa and its derivs. with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for 67/68Ga, the chelate is now shown to coordinate 64Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered soln.). The hexadentate, distorted octahedral coordination of H2dedpa is confirmed in the corresponding solid state X-ray crystal structure of [Cu(dedpa)]. Cyclic voltammetry detd. the redn. potential of [Cu(dedpa)] to be below values found for common bioreductants. Redn. and reoxidn. were irreversible but reproducible, indicating a potential change of coordination mode upon redn. of Cu(II) to Cu(I). The thermodn. stability const. log KCuL was detd. to be 19.16(5), comparable to other frequently used 64Cu chelates. Serum stability of the 64Cu labeled chelate revealed only 3% transchelation/assocn. to serum proteins after 2 h, while the conjugates reveal 10% ([Cu(RGD1)]) and 6% ([Cu(RGD2)]) transchelation at the same time point.
- 5Anderson, C. J.; Welch, M. J. Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging. Chem. Rev. 1999, 99 (9), 2219– 2234, DOI: 10.1021/cr980451qGoogle Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkvF2rurg%253D&md5=5e998fe68c5e014668482d56290411d0Radiometal-Labeled Agents (Non-Technetium) for Diagnostic ImagingAnderson, Carolyn J.; Welch, Michael J.Chemical Reviews (Washington, D. C.) (1999), 99 (9), 2219-2234CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review with 178 refs. of non-technetium-labeled radiometal-labeled agents used in gamma scintigraphy and positron emission tomog. Topics covered include prodn. of Ga, In, Cu and Y radionuclides, their chem., and detg. the optimal imaging agents for specific diseases.
- 6Shokeen, M.; Anderson, C. J. Molecular Imaging of Cancer with Copper-64 Radiopharmaceuticals and Positron Emission Tomography (PET). Acc. Chem. Res. 2009, 42 (7), 832– 841, DOI: 10.1021/ar800255qGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1Cmu7w%253D&md5=3cff4a2250ef2d284b06301c4abfe93fMolecular Imaging of Cancer with Copper-64 Radiopharmaceuticals and Positron Emission Tomography (PET)Shokeen, Monica; Anderson, Carolyn J.Accounts of Chemical Research (2009), 42 (7), 832-841CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Mol. imaging has evolved over the past several years into an important tool for diagnosing, understanding, and monitoring disease. Mol. imaging has distinguished itself as an interdisciplinary field, with contributions from chem., biol., physics, and medicine. The cross-disciplinary impetus has led to significant achievements, such as the development of more sensitive imaging instruments and robust, safer radiopharmaceuticals, thereby providing more choices to fit personalized medical needs. Mol. imaging is making steadfast progress in the field of cancer research among others. Cancer is a challenging disease, characterized by heterogeneity, uncontrolled cell division, and the ability of cancer cells to invade other tissues. Researchers are addressing these challenges by aggressively identifying and studying key cancer-specific biomarkers such as growth factor receptors, protein kinases, cell adhesion mols., and proteases, as well as cancer-related biol. processes such as hypoxia, apoptosis, and angiogenesis. Positron emission tomog. (PET) is widely used by clinicians in the United States as a diagnostic mol. imaging tool. Small-animal PET systems that can image rodents and generate reconstructed images in a noninvasive manner (with a resoln. as low as 1 mm) have been developed and are used frequently, facilitating radiopharmaceutical development and drug discovery. Currently, [18F]-labeled 2-fluorodeoxyglucose (FDG) is the only PET radiotracer used for routine clin. evaluation (primarily for oncol. imaging). There is now increasing interest in nontraditional positron-emitting radionuclides, particularly those of the transition metals, for imaging with PET because of increased prodn. and availability. Copper-based radionuclides are currently being extensively evaluated because they offer a varying range of half-lives and positron energies. For example, the half-life (12.7 h) and decay properties (β+, 0.653 MeV, 17.8%; β-, 0.579 MeV, 38.4 %; the remainder is electron capture) of 64Cu make it an ideal radioisotope for PET imaging and radiotherapy. In addn., the well-established coordination chem. of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to antibodies, proteins, peptides, and other biol. relevant mols. New chelators with greater in vivo stability, such as the cross-bridged (CB) versions of tetraazamacrocyclic 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), are now available. Finally, one of the major aspects of successful imaging is the identification and characterization of a relevant disease biomarker at the cellular and subcellular level and the ensuing development of a highly specific targeting moiety. In this Account, we discuss specific examples of PET imaging with new and improved 64Cu-based radiopharmaceuticals, highlighting the study of some of the key cancer biomarkers, such as epidermal growth-factor receptor (EGFR), somatostatin receptors (SSRs), and integrin αvβ3.
- 7Blower, P. J.; Lewis, J. S.; Zweit, J. Copper Radionuclides and Radiopharmaceuticals in Nuclear Medicine. Nucl. Med. Biol. 1996, 23 (8), 957– 980, DOI: 10.1016/S0969-8051(96)00130-8Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkslOqsQ%253D%253D&md5=39b9b14d56995b81d7c57f35e2fcdd82Copper radionuclides and radiopharmaceuticals in nuclear medicineBlower, Philip J.; Lewis, Jason S.; Zweit, JamalNuclear Medicine and Biology (1996), 23 (8), 957-980CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)The chem., radiochem., radiobiol., and radiopharmacol. of radiopharmaceuticals contg. copper radionuclides are reviewed, with 210 refs. Copper radionuclides offer application in positron emission tomog., targeted radiotherapy, and single photon imaging. The chem. of copper is relatively simple and well-suited to radiopharmaceutical application. Current radiopharmaceuticals include biomols. labeled via bifunctional chelators primarily based on cyclic polyaminocarboxylates and polyamines, and pyruvaldehyde-bis(N4-methylthiosemicarbazone) (PTSM) and its analogs. The chem. of copper, of which only a fraction has yet been exploited, is likely to be applied more fully in the future.
- 8Borgna, F.; Ballan, M.; Favaretto, C.; Verona, M.; Tosato, M.; Caeran, M.; Corradetti, S.; Andrighetto, A.; Di Marco, V.; Marzaro, G.; Realdon, N. Early Evaluation of Copper Radioisotope Production at ISOLPHARM. Molecules 2018, 23 (10), 2437, DOI: 10.3390/molecules23102437Google ScholarThere is no corresponding record for this reference.
- 9Srivastava, S. C.; Mausner, L. F. Therapeutic Radionuclides: Production, Physical Characteristics, and Applications. Therapeutic Nuclear Medicine; Springer-Verlag: Berlin, 2013; pp 11– 50.Google ScholarThere is no corresponding record for this reference.
- 10Ramogida, C.; Orvig, C. Tumour Targeting with Radiometals for Diagnosis and Therapy. Chem. Commun. 2013, 49 (42), 4720– 4739, DOI: 10.1039/c3cc41554fGoogle Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmvVegt7s%253D&md5=ea63aef48789cb3e1710af520c4542dbTumour targeting with radiometals for diagnosis and therapyRamogida, Caterina F.; Orvig, ChrisChemical Communications (Cambridge, United Kingdom) (2013), 49 (42), 4720-4739CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Use of radiometals in nuclear oncol. is a rapidly growing field and encompasses a broad spectrum of radiotracers for imaging via PET (positron emission tomog.) or SPECT (single-photon emission computed tomog.) and therapy via α, β-, or Auger electron emission. This feature article opens with a brief introduction to the imaging and therapy modalities exploited in nuclear medicine, followed by a discussion of the multi-component strategy used in radiopharmaceutical development, known as the bifunctional chelate (BFC) method. The modular assembly is dissected into its individual components and each is discussed sep. The concepts and knowledge unique to metal-based designs are outlined, giving insight into how these radiopharmaceuticals are evaluated for use in vivo. Imaging nuclides 64Cu, 68Ga, 86Y, 89Zr, and 111In, and therapeutic nuclides 90Y, 177Lu, 225Ac, 213Bi, 188Re, and 212Pb will be the focus herein. Finally, key examples have been extd. from the literature to give the reader a sense of breadth of the field.
- 11Liu, S. Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides. Adv. Drug Delivery Rev. 2008, 60 (12), 1347– 1370, DOI: 10.1016/j.addr.2008.04.006Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXoslWktr8%253D&md5=106b21e77e2ed4155f4a1c3781655612Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclidesLiu, ShuangAdvanced Drug Delivery Reviews (2008), 60 (12), 1347-1370CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Receptor-based radiopharmaceuticals are of great current interest in mol. imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomol. (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomol. serves as a "carrier" for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomols. with a metallic radionuclide. Different radiometals have significant difference in their coordination chem., and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on phys. and biol. properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chem. with technetium, copper, gallium, indium, yttrium and lanthanide radiometals.
- 12Fani, M.; Del Pozzo, L.; Abiraj, K.; Mansi, R.; Tamma, M. L.; Cescato, R.; Waser, B.; Weber, W. A.; Reubi, J. C.; Mäcke, H. R. PET of Somatostatin Receptor-Positive Tumors Using 64Cu- and 68Ga Somatostatin Antagonists: The Chelate Makes the Difference. J. Nucl. Med. 2011, 52 (7), 1110– 1118, DOI: 10.2967/jnumed.111.087999Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvVKltro%253D&md5=3225eb0d38a7e33658a8a5168e914497PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the differenceFani, Melpomeni; Del Pozzo, Luigi; Abiraj, Keelara; Mansi, Rosalba; Tamma, Maria Luisa; Cescato, Renzo; Waser, Beatrice; Weber, Wolfgang A.; Reubi, Jean Claude; Maecke, Helmut R.Journal of Nuclear Medicine (2011), 52 (7), 1110-1118CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-pos. tumors, esp. of subtype 2 (sst2). The clin. used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors detg. the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four 64Cu or 68Ga radioantagonists for PET of sst2-pos. tumors. Methods: The novel antagonist p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. 64/natCu- and 68/natGa-NODAGA-LM3 were prepd. at room temp., and 64/natCu-CB-TE2A-LM3 and 68/natGa-DOTA-LM3 were prepd. at 95°C. Binding affinity and antagonistic properties were detd. with receptor autoradiog. and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissocn. was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; 68/natGa-NODAGA-LM3 has the lowest half maximal inhibitory concn. (1.3 ± 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of 64Cu- and 68Ga-NODAGA-LM3 (∼40 percentage injected dose per g of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for 64Cu-NODAGA-LM3 (∼15 %ID/g, 24 h after injection) and almost negligible for 64Cu-CB-TE2A-LM3 (26.9 ± 3.3 %ID/g and 21.6 ± 2.1 %ID/g, 4 and 24 h after injection, resp.). Tumor-to-normal-tissue ratios were significantly higher for 64Cu-NODAGA-LM3 than for 64Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 ± 3.6 and 1.7 ± 0.3, resp.; tumor-to-muscle, 1,342 ± 115 and 75.2 ± 8.5, resp., at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, esp. for 64Cu- and 68Ga-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. 64Cu- and 68Ga-NODAGA-LM3 and 64Cu-CB-TE2A-LM3 are promising candidates for clin. translation because of their favorable pharmacokinetics and the high image contrast on PET scans.
- 13Litau, S.; Seibold, U.; Vall-Sagarra, A.; Fricker, G.; Wängler, B.; Wängler, C. Comparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and In Vivo Experiments. ChemMedChem 2015, 10 (7), 1200– 1208, DOI: 10.1002/cmdc.201500132Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXovVCktrk%253D&md5=e2b35e1f430df391e71e297217ca7d7fComparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and in vivo ExperimentsLitau, Shanna; Seibold, Uwe; Vall-Sagarra, Alicia; Fricker, Gert; Waengler, Bjoern; Waengler, CarmenChemMedChem (2015), 10 (7), 1200-1208CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)For 64Cu radiolabeling of biomols. to be used as in vivo positron emission tomog. (PET) imaging agents, various chelators are commonly applied. It has not yet been detd. which of the most potent chelators-NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl)diacetic acid), or CB-TE1A-GA (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl-8-acetic acid-1-glutaric acid)-forms the most stable complexes resulting in PET images of highest quality. We detd. the 64Cu complex stabilities for these three chelators by a combination of complex challenge and an in vivo approach. For this purpose, bioconjugates of the chelating agents with the gastrin-releasing peptide receptor (GRPR)-affine peptide PESIN and an integrin αvβ3-affine c(RGDfC) tetramer were synthesized and radiolabeled with 64Cu in excellent yields and specific activities. The 64Cu-labeled biomols. were evaluated for their complex stabilities in vitro by conducting a challenge expt. with the resp. other chelators as challengers. The in vivo stabilities of the complexes were also detd., showing the highest stability for the 64Cu-CB-TE1A-GA complex in both exptl. setups. Therefore, CB-TE1A-GA is the most appropriate chelating agent for *Cu-labeled radiotracers and in vivo imaging applications.
- 14Price, E. W.; Orvig, C. Matching Chelators to Radiometals for Radiopharmaceuticals. Chem. Soc. Rev. 2014, 43 (1), 260– 290, DOI: 10.1039/C3CS60304KGoogle Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVGktLzP&md5=30a847faed78cba5123ffca47bde5aa3Matching chelators to radiometals for radiopharmaceuticalsPrice, Eric W.; Orvig, ChrisChemical 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.
- 15Lima, L. M. P.; Halime, Z.; Marion, R.; Camus, N.; Delgado, R.; Platas-Iglesias, C.; Tripier, R. Monopicolinate Cross-Bridged Cyclam Combining Very Fast Complexation with Very High Stability and Inertness of Its Copper(II) Complex. Inorg. Chem. 2014, 53 (10), 5269– 5279, DOI: 10.1021/ic500491cGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmslGrtLw%253D&md5=e3dbf273c08b89d97e6cd94b9fa33841Monopicolinate Cross-Bridged Cyclam Combining Very Fast Complexation with Very High Stability and Inertness of Its Copper(II) ComplexLima, Luis M. P.; Halime, Zakaria; Marion, Ronan; Camus, Nathalie; Delgado, Rita; Platas-Iglesias, Carlos; Tripier, RaphaelInorganic Chemistry (2014), 53 (10), 5269-5279CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb-cyclam) deriv. bearing a picolinate arm (Hcb-te1pa) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid-base properties and coordination properties with Cu2+ and Zn2+ was studied. The x-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temp. and that demonstrated high thermodn. stability, which was measured by potentiometry (at 25° and 0.10 M in KNO3). Also the complex exists as a monopos. copper(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu2+ over Zn2+. The copper(II) complex was synthesized and studied in soln. using different spectroscopic techniques and DFT calcns. The kinetic inertness of the copper(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissocn. of the complex. The half-life of 96 days, in 5 M HClO4, and 465 min, in 5 M HCl at 25°, show the high kinetic stability of the copper(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Addnl., cyclic voltammetry expts. underlined the perfect electrochem. inertness of the complex as well as the quasi-reversible Cu2+/Cu+ redox system. The coordination geometry of the copper center in the complex was established in aq. soln. from UV-visible and EPR spectroscopies.
- 16Woodin, K. S.; Heroux, K. J.; Boswell, C. A.; Wong, E. H.; Weisman, G. R.; Niu, W.; Tomellini, S. A.; Anderson, C. J.; Zakharov, L. N.; Rheingold, A. L. Kinetic Inertness and Electrochemical Behavior of Copper(II) Tetraazamacrocyclic Complexes: Possible Implications for In Vivo Stability. Eur. J. Inorg. Chem. 2005, 2005 (23), 4829– 4933, DOI: 10.1002/ejic.200500579Google ScholarThere is no corresponding record for this reference.
- 17Cooper, M. S.; Ma, M. T.; Sunassee, K.; Shaw, K. P.; Williams, J. D.; Paul, R. L.; Donnelly, P. S.; Blower, P. J. Blower, P. J. Comparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and In Vitro/In Vivo Stability. Bioconjugate Chem. 2012, 23 (5), 1029– 1039, DOI: 10.1021/bc300037wGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvVyqurg%253D&md5=649071237104b7aaffb6d032acce51daComparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo StabilityCooper, Maggie S.; Ma, Michelle T.; Sunassee, Kavitha; Shaw, Karen P.; Williams, Jennifer D.; Paul, Rowena L.; Donnelly, Paul S.; Blower, Philip J.Bioconjugate Chemistry (2012), 23 (5), 1029-1039CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with 64Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p-SCN-Bn-Oxo-DO3A, p-SCN-NOTA, and p-SCN-PCTA), three DTPA derivs. (p-SCN-Bn-DTPA, p-SCN-CHX-A''-DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO2H) = (1-NH2-8-NHCO(CH2)3CO2H)sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane. Radiolabeling efficiency under various conditions, in vitro stability in serum at 37 °C, and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO2H were conjugated to rituximab by thiourea bond formation with an av. of 4.9 ± 0.9 chelators per antibody mol. Sar-CO2H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody mol. Efficiencies of 64Cu radiolabeling were dependent on the concn. of immunoconjugate. Notably, the 64Cu-NOTA-rituximab conjugate demonstrated the highest radiochem. yield (95%) under very dil. conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, contg. 1/10th the no. of chelators per antibody compared to that of other conjugates, retained high labeling efficiency (98%) at an antibody concn. of 250 nM. In contrast to the radioimmunoconjugates contg. DTPA derivs., which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6% dissocn. of 64Cu over 48 h. In vivo biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. While all the macrocyclic bifunctional chelators are suitable for mol. imaging using 64Cu-labeled antibody conjugates, NOTA and sar-CO2H show significant advantages over the others in that they can be radiolabeled rapidly at room temp., under dil. conditions, resulting in high specific activity.
- 18Boros, E.; Holland, J. P. Chemical Aspects of Metal Ion Chelation in the Synthesis and Application Antibody-based Radiotracers. J. Labelled Compd. Radiopharm. 2018, 61 (9), 652– 671, DOI: 10.1002/jlcr.3590Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1KhsLk%253D&md5=5197ae7bdc3a0c10c29f9ee8ddad2975Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracersBoros, Eszter; Holland, Jason P.Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61 (9), 652-671CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)Radiometals are becoming increasingly accessible and are utilized frequently in the design of radiotracers for imaging and therapy. Nuclear properties ranging from the emission of γ-rays and β+-particles (imaging) to Auger electron and β- and α-particles (therapy) in combination with long half-lives are ideally matched with the relatively long biol. half-life of monoclonal antibodies in vivo. Radiometal labeling of antibodies requires the incorporation of a metal chelate onto the monoclonal antibody. This chelate must coordinate the metal under mild conditions required for the handling of antibodies, as well as provide high kinetic, thermodn., and metabolic stability once the metal ion is coordinated to prevent release of the radionuclide before the target site is reached in vivo. Herein, we review the role of different radiometals that have found applications of the design of radiolabeled antibodies for imaging and radioimmunotherapy. Each radionuclide is described regarding its nuclear synthesis, coordinative preference, and radiolabeling properties with commonly used and novel chelates, as well as examples of their preclin. and clin. applications. An overview of recent trends in antibody-based radiopharmaceuticals is provided to spur continued development of the chem. and application of radiometals for imaging and therapy.
- 19Sharma, A. K.; Schultz, J. W.; Prior, J. T.; Rath, N. P.; Mirica, L. M. Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer’s Disease. Inorg. Chem. 2017, 56 (22), 13801– 13814, DOI: 10.1021/acs.inorgchem.7b01883Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslKqtL3F&md5=81e6fab97c8000cd43d6ee5a690077feCoordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer's DiseaseSharma, Anuj K.; Schultz, Jason W.; Prior, John T.; Rath, Nigam P.; Mirica, Liviu M.Inorganic Chemistry (2017), 56 (22), 13801-13814CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Positron emission tomog. (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, 11C and 18F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compds. (BFCs) based on macrocyclic 1,4,7-triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu2+ ions. In addn., these BFCs contain a 2-phenylbenzothiazole fragment that is known to interact tightly with amyloid β fibrillar aggregates. Detn. of the protonation consts. (pKa values) and stability consts. (log β values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallog., ESR spectroscopy, and electrochem. studies, suggests that these BFCs exhibit desirable properties for the development of novel 64Cu PET imaging agents for Alzheimer's disease.
- 20Bass, L. A.; Wang, M.; Welch, M. J.; Anderson, C. J. In Vivo Transchelation of Copper-64 from TETA-Octreotide to Superoxide Dismutase in Rat Liver. Bioconjugate Chem. 2000, 11 (4), 527– 532, DOI: 10.1021/bc990167lGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXktFOlurw%253D&md5=0468c443acdb8d77057188c715f1f76bIn Vivo Transchelation of Copper-64 from TETA-Octreotide to Superoxide Dismutase in Rat LiverBass, Laura A.; Wang, Mu; Welch, Michael J.; Anderson, Carolyn J.Bioconjugate Chemistry (2000), 11 (4), 527-532CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)An understanding of the metabolic fate of radiometal-labeled peptides is important due to their application in the areas of diagnostic imaging and targeted radiotherapy. Radioisotopes of copper (64Cu, T1/2 = 12.7 h; 67Cu, T1/2 = 62 h) have been labeled to monoclonal antibodies (mAbs) and peptides and have applications in the areas of PET imaging and targeted radiotherapy of cancer. Copper-64-TETA-D-Phe1-octreotide ([64Cu]TETA-OC) has been shown to bind to the somatostatin receptor, both in vitro and in vivo, and this agent inhibited the growth of somatostatin-receptor pos. tumors in rats. Copper-64-TETA-OC, however, showed a retention of activity in the blood, liver, and bone marrow, suggesting possible dissocn. of 64Cu from TETA-OC in vivo. The purpose of this study was to det. if 64Cu dissocs. from [64Cu]TETA-OC and binds to the protein, superoxide dismutase (SOD) in rat liver. The liver metab. of [64Cu]TETA-OC was examd. in normal rats using a gel-electrophoresis assay specific for SOD and size-exclusion chromatog. The major metabolite in rat liver at 20 h postinjection had a mol. wt. of 32 kDa as shown by size-exclusion chromatog. A gel electrophoresis assay specific for the detection of SOD [nitro-blue tetrazolium (NBT)] showed that a 64Cu-labeled protein isolated from rat liver homogenates comigrated with SOD. Evaluating the metabolic fate of copper radiopharmaceuticals demonstrated that Cu(II) dissocs. from macrocyclic chelators such as TETA and binds to proteins in high concns., namely SOD in rat liver.
- 21Dearling, J. L.; Voss, S. D.; Dunning, P.; Snay, E.; Fahey, F.; Smith, S. V.; Huston, J. S.; Meares, C. F.; Treves, S. T.; Packard, A. B. Imaging Cancer Using PET – the Effect of the Bifunctional Chelator on the Biodistribution of a 64Cu-Labeled Antibody. Nucl. Med. Biol. 2011, 38 (1), 29– 38, DOI: 10.1016/j.nucmedbio.2010.07.003Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkt1SlsA%253D%253D&md5=bbd504a87adbd65e8425527d33fbee27Imaging cancer using PET - the effect of the bifunctional chelator on the biodistribution of a 64Cu-labeled antibodyDearling, Jason L. J.; Voss, Stephan D.; Dunning, Patricia; Snay, Erin; Fahey, Frederic; Smith, Suzanne V.; Huston, James S.; Meares, Claude F.; Treves, S. Ted; Packard, Alan B.Nuclear Medicine and Biology (2011), 38 (1), 29-38CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodn. stability of the 64Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with 64Cu using these chelators in tumor-bearing mice. The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH2-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH2-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N,N',N",N"'-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with 64Cu and injected into mice bearing s.c. human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomog. images acquired at 1, 24 and 48 h post-injection, and at 48 h post-injection a full ex vivo biodistribution study was carried out. The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [64Cu]ch14.18-p-NH2-Bn-NOTA was 4.74 ± 0.77% of the injected dose per g of tissue (%ID/g), and for [64Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. The results of this study indicate that differences in the thermodn. stability of these chelator-Cu(II) complexes were not assocd. with significant differences in uptake of the tracer by the tumor. However, there were significant differences in tracer concn. in other tissues, including those involved in clearance of the radioimmunoconjugate (e.g., liver and spleen).
- 22Bhattacharyya, S.; Dixit, M. Metallic Radionuclides in the Development of Diagnostic and Therapeutic Radiopharmaceuticals. Dalt. Trans. 2011, 40 (23), 6112– 6128, DOI: 10.1039/c1dt10379bGoogle ScholarThere is no corresponding record for this reference.
- 23Schmidtke, A.; Läppchen, T.; Weinmann, C.; Bier-Schorr, L.; Keller, M.; Kiefer, Y.; Holland, J. P.; Bartholomä, M. D. Gallium Complexation, Stability, and Bioconjugation of 1,4,7- Triazacyclononane Derived Chelators with Azaheterocyclic Arms. Inorg. Chem. 2017, 56 (15), 9097– 9110, DOI: 10.1021/acs.inorgchem.7b01129Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Wks7%252FO&md5=e90e3f77013616603ec19593dc36b079Gallium Complexation, Stability, and Bioconjugation of 1,4,7-Triazacyclononane Derived Chelators with Azaheterocyclic ArmsSchmidtke, Alexander; Laeppchen, Tilman; Weinmann, Christian; Bier-Schorr, Lorenz; Keller, Manfred; Kiefer, Yvonne; Holland, Jason P.; Bartholomae, Mark D.Inorganic Chemistry (2017), 56 (15), 9097-9110CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)We have recently introduced a 1,4,7-triazacyclononane (TACN) based chelating system with addnl. five-membered azaheterocyclic substituents for complexation of radioactive Cu2+ ions. In this work, we investigated the complexation properties of these novel chelators with Ga3+. In labeling expts., we could show that the penta- and hexadentate imidazole derivs. NODIA-Me 4 and NOTI-Me 1 can be labeled with 68Ga in specific activities up to ∼30 MBq nmol-1, while the corresponding thiazole deriv. NOTThia 2 did not label satisfactorily under identical conditions. NMR studies on the Ga complexes of 1 and the model compd. NODIA-Me-NH-Me 5 revealed formation of rigid 1:1 chelates with a slow macrocyclic interconversion and inert Ga-N bonds to the methylimidazole residues on the NMR time scale. The TACN-derived bifunctional chelator NODIA-Me was furthermore conjugated to a prostate-specific membrane antigen (PSMA) targeting moiety to give the corresponding bioconjugate NODIA-Me-PSMA 7. Serum stability and ligand challenge expts. of 68Ga-7 confirmed formation of a stable complex for up to 4 h. The remaining coordination site of five-coordinate Ga complexes was found to be occupied by monodentate ligands including hydroxide and chloride anions depending on the conditions. According to d. functional theory calcns., coordination of monodentate ligands as well as of the amide group for the bioconjugated ligand are energetically plausible. Finally, the labeled bioconjugate 68Ga-7 exhibited rapid renal clearance in biodistribution studies performed by small animal PET imaging with no indication of transchelation/demetalation in vivo. Altogether, our results provide strong evidence for a stable Ga complexation of our novel TACN-based chelators bearing imidazole arms. Despite the formation of two complexes incorporating different monodentate ligands in vitro, the imidazole type ligands show promise as chelating agents for the future development of gallium based radiopharmaceuticals.
- 24Ramogida, C. F.; Boros, E.; Patrick, B. O.; Zeisler, S. K.; Kumlin, J.; Adam, M. J.; Schaffer, P.; Orvig, C. Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N’-Propyl-2-NI Ligands for 64Cu(II) Radiopharmaceuticals. Dalt. Trans. 2016, 45 (33), 13082– 13090, DOI: 10.1039/C6DT00932HGoogle ScholarThere is no corresponding record for this reference.
- 25Le Fur, M.; Beyler, M.; Le Poul, N.; Lima, L. M. P.; Le Mest, Y.; Delgado, R.; Platas-Iglesias, C.; Patinec, V.; Tripier, R. Improving the Stability and Inertness of Cu(II) and Cu(I) Complexes with Methylthiazolyl Ligands by Tuning the Macrocyclic Structure. Dalt. Trans. 2016, 45 (17), 7406– 7420, DOI: 10.1039/C6DT00385KGoogle ScholarThere is no corresponding record for this reference.
- 26Rylova, S. N.; Stoykow, C.; Del Pozzo, L.; Abiraj, K.; Tamma, M. L.; Kiefer, Y.; Fani, M.; Mäcke, H. R. The Somatostatin Receptor 2 Antagonist 64Cu-NODAGA-JR11 Outperforms 64Cu-DOTA-TATE in a Mouse Xenograft Model. PLoS One 2018, 13 (4), e0195802, DOI: 10.1371/journal.pone.0195802Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsl2gt77I&md5=fa3f63053b0633906e1af6bf6aef4964The somatostatin receptor 2 antagonist 64Cu- NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft modelRylova, Svetlana N.; Stoykow, Christian; Pozzo, Luigi Del; Abiraj, Keelara; Tamma, Maria Luisa; Kiefer, Yvonne; Fani, Melpomeni; Maecke, Helmut R.PLoS One (2018), 13 (4), e0195802/1-e0195802/16CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of 64Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7- acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH2), a somatostatin receptor 2 antagonist, with the clin. used sst2 agonist 64Cu-DOTA-TATE (TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated Kd values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist 64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist 64/natCu-DOTA-TATE. The tumor washout was slow or non-existent in the first 4 h, whereas kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Blood clearance was distinctly slower and persistent higher blood values were found at 24 h. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of 64Cu-NODAGAJR11 at 1 h, but release from tumor was very fast, particularly between 4 and 24 h. Tumor-to-normal organ ratios were distinctly lower after 1 h. This is indicative of insufficient in vivo stability. PET studies of 64Cu-NODAGA-JR11 reflected biodistribution data with nicely delineated tumor and low background. 64Cu-NODAGA-JR11 shows promising pharmacokinetic properties for further translation into the clinic.
- 27Smith, S. V. Molecular Imaging with Copper-64. J. Inorg. Biochem. 2004, 98 (11), 1874– 1901, DOI: 10.1016/j.jinorgbio.2004.06.009Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptlOktL0%253D&md5=b0972b1167a9b710b5c409d772941d95Molecular imaging with copper-64Smith, Suzanne V.Journal of Inorganic Biochemistry (2004), 98 (11), 1874-1901CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)A review. Mol. imaging is expected to change the face of drug discovery and development. The ability to link imaging to biol. for guiding therapy should improve the rate at which novel imaging technologies, probes, contrast agents, drugs and drug delivery systems can be transferred into clin. practice. Nuclear medicine imaging, in particular, positron emission tomog. (PET) allows the detection and monitoring of a variety of biol. and pathophysiol. processes, at tracer quantities of the radiolabeled target agents, and at doses free from pharmacol. effects. In the field of drug discovery and development, the use of radiotracers for radiolabelling target agents has now become one of the essential tools in identifying, screening and development of new target agents. In this regard, 64Cu (t1/2 = 12.7 h) has been identified as an emerging PET isotope. Its half-life is sufficiently long for radiolabelling a range of target agents and its ease of prodn. and adaptable chem. make it an excellent radioisotope for use in mol. imaging. This review describes recent advances, in the routes of 64Cu prodn., design and application of bi-functional ligands for use in radiolabelling with 64/67Cu2+, and their significance and anticipated impact on the field of mol. imaging and drug development.
- 28Jones-Wilson, T. M.; Deal, K. A.; Anderson, C. J.; McCarthy, D. W.; Kovacs, Z.; Motekaitis, R. J.; Sherry, A. D.; Martell, A. E.; Welch, M. J. The In Vivo Behavior of Copper-64-Labeled Azamacrocyclic Complexes. Nucl. Med. Biol. 1998, 25 (6), 523– 530, DOI: 10.1016/S0969-8051(98)00017-1Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlt1Wktrk%253D&md5=aa5cbc7f7ab5fb08f6659903f14f2fa3The in vivo behavior of copper-64-labeled azamacrocyclic complexesJones-Wilson, Teresa M.; Deal, Kim A.; Anderson, Carolyn J.; McCarthy, Deborah W.; Kovacs, Zoltan; Motekaitis, Ramunas J.; Sherry, A. Dean; Martell, Arthur E.; Welch, Michael J.Nuclear Medicine and Biology (1998), 25 (6), 523-530CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomols. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomol. conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biol. behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepd., and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivs., and cyclam, TETA, and et-cyclam were tetradecane backbone derivs. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compds. showed uptake and clearance through the liver and kidneys; however, the pos. charged 64Cu complexes showed significantly higher uptake in both of these organs than did the neg. charged or neutral complexes. 64Cu-TETA, a neg. charged complex with the tetradecane backbone, had the most efficient clearance by 24 h' postinjection. These data suggest that neg. charged complexes may have more favorable clearance properties when used as BFCs.
- 29Boswell, C. A.; Sun, X.; Niu, W.; Weisman, G. R.; Wong, E. H.; Rheingold, A. L.; Anderson, C. J. Comparative In Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes. J. Med. Chem. 2004, 47 (6), 1465– 1474, DOI: 10.1021/jm030383mGoogle Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFagtLw%253D&md5=542e8b853716a629b641740f102a48dbComparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic ComplexesBoswell, C. Andrew; Sun, Xiankai; Niu, Weijun; Weisman, Gary R.; Wong, Edward H.; Rheingold, Arnold L.; Anderson, Carolyn J.Journal of Medicinal Chemistry (2004), 47 (6), 1465-1474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biol. mols. The chelators most commonly utilized for labeling copper radionuclides to biomols. are analogs of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "cross-bridged" cyclam (CB-cyclam) derivs., form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogs in vivo. Herein we report results on the relative biol. stabilities and identification of the resulting radiolabeled metabolites of a series of 64Cu-labeled macrocyclic complexes. Metab. studies in normal rat liver have revealed that the 64Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (64Cu-CB-TE2A) resulted in significantly lower values of protein-assocd. 64Cu than 64Cu-TETA [13 ± 6% vs 75 ± 9% at 4 h]. A similar trend was obsd. for the corresponding cyclen derivs., with the 64Cu complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (64Cu-CB-DO2A) undergoing less transchelation than the 64Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (64Cu-DOTA) [61 ± 14% vs 90.3 ± 0.5% protein assocd. 64Cu at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged 64Cu complexes and that 64Cu-CB-TE2A is superior to 64Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator deriv. of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biol. mols. for diagnostic imaging and targeted radiotherapy.
- 30Wong, E. H.; Weisman, G. R.; Hill, D. C.; Reed, D. P.; Rogers, E. M.; Condon, J. P.; Fagan, M. A.; Calabrese, J. C.; Lam, K. C.; Guzei, I. A.; Rheingold, L. Synthesis and Characterization of Cross-Bridged Cyclams and Pendant-Armed Derivatives and Structural Studies of Their Copper(II) Complexes. J. Am. Chem. Soc. 2000, 122 (43), 10561– 10572, DOI: 10.1021/ja001295jGoogle Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXntlektb8%253D&md5=775e07e05132769aa54f7d81ba6c83d5Synthesis and Characterization of Cross-Bridged Cyclams and Pendant-Armed Derivatives and Structural Studies of Their Copper(II) ComplexesWong, Edward H.; Weisman, Gary R.; Hill, Daniel C.; Reed, David P.; Rogers, Mark E.; Condon, Jeffrey S.; Fagan, Maureen A.; Calabrese, Joseph C.; Lam, Kin-Chung; Guzei, Ilia A.; Rheingold, Arnold L.Journal of the American Chemical Society (2000), 122 (43), 10561-10572CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane ligands, including the parent compd., N,N'-dialkyl variants, and the 1st N,N'-di-pendant-arm derivs. were synthesized by a short, efficient, and conceptually novel approach. Their Cu(II) complexes were prepd., and four of these were structurally characterized by x-ray diffraction. In all four complexes, the cross-bridged tetraamine ligand is cis-folded, coordinating the metal cation within its mol. cleft using all four N lone pairs. Geometries intermediate between idealized square pyramidal and trigonal bipyramidal coordination were found for three of the complexes, whereas a distorted octahedral Cu coordination was found for the complex of a di-pendant-arm cross-bridged cyclam.
- 31Ferdani, R.; Stigers, D. J.; Fiamengo, A. L.; Wei, L.; Li, B. T. Y.; Golen, J. A.; Rheingold, A. L.; Weisman, G. R.; Wong, E. H.; Anderson, C. J. Synthesis, Cu(II) Complexation, 64Cu-Labeling and Biological Evaluation of Cross-Bridged Cyclam Chelators with Phosphonate Pendant Arms. Dalt. Trans. 2012, 41 (7), 1938– 1950, DOI: 10.1039/C1DT11743BGoogle ScholarThere is no corresponding record for this reference.
- 32Stigers, D. J.; Ferdani, R.; Weisman, G. R.; Wong, E. H.; Anderson, C. J.; Golen, J. A.; Moore, C.; Rheingold, A. L. A New Phosphonate Pendant-Armed Cross-Bridged Tetraamine Chelator Accelerates Copper(II) Binding for Radiopharmaceutical Applications. Dalt. Trans. 2010, 39 (7), 1699– 1701, DOI: 10.1039/B920871BGoogle ScholarThere is no corresponding record for this reference.
- 33Boros, E.; Packard, A. B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev. 2019, 119 (2), 870– 901, DOI: 10.1021/acs.chemrev.8b00281Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVKrsbnO&md5=729691dfe872671d502e0354b002a663Radioactive Transition Metals for Imaging and TherapyBoros, 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.
- 34Rodríguez-Rodríguez, A.; Halime, Z.; Lima, L. M. P.; Beyler, M.; Deniaud, D.; Le Poul, N.; Delgado, R.; Platas-Iglesias, C.; Patinec, V.; Tripier, R. Cyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) Coordination. Inorg. Chem. 2016, 55 (2), 619– 632, DOI: 10.1021/acs.inorgchem.5b01779Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlsVOnsQ%253D%253D&md5=57fe7bd81d2344a7eddfb744f32010aeCyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) CoordinationRodriguez-Rodriguez, Aurora; Halime, Zakaria; Lima, Luis M. P.; Beyler, Maryline; Deniaud, David; Le Poul, Nicolas; Delgado, Rita; Platas-Iglesias, Carlos; Patinec, Veronique; Tripier, RaphaelInorganic Chemistry (2016), 55 (2), 619-632CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Aiming to develop new copper chelates for application in nuclear medicine the authors report two new chelators, te1th and te2th, based on a cyclam backbone mono-N- or di-N1,N8-functionalized by methylthiazolyl arms. The acid-base properties of both ligands were studied as well as their coordination chem., esp. with Cu2+, when possible in aq. soln. and in the solid state. Single-crystal x-ray diffraction structures of complexes were detd. Stability consts. of the copper(II) and zinc(II) complexes showed that the complexes of both ligands with Cu2+ are thermodynamically very stable, and they exhibit an important selectivity for Cu2+ over Zn2+. The kinetic inertness in acidic medium of both copper(II) complexes was evaluated revealing a quite good resistance to dissocn. (the half-life times of complexes with te1th and te2th are 50.8 and 5.8 min, resp., in 5 M HCl and 30°). The coordination geometry of the metal center in the complexes was established in aq. soln. based on UV-visible, EPR spectroscopy, DFT studies, and NMR by using the zinc(II) complex analogs. The [Cu(te1th)]2+ and [Cu(te2th)]2+ complexes adopt trans-I and trans-III configurations both in the solid state and in soln., while the [Zn(te2th)]2+ complex crystallizes as the cis-V isomer but exists in soln. as a mixt. of trans-III and cis-V forms. Cyclic voltammetry expts. in acetonitrile point to a relatively easy redn. of [Cu(te2th)]2+ in acetonitrile soln. (Epc = -0.41 V vs. normal H electrode), but the reduced complex does not undergo dissocn. in the time scale of the authors' electrochem. expts. The results obtained in these studies revealed that despite the limited soly. of its copper(II) chelate, te2th is an attractive chelator for Cu2+ that provides a fast complexation process while forming a complex with a rather high thermodn. stability and kinetic inertness with respect to dissocn. even upon electrochem. redn.
- 35Bodio, E.; Boujtita, M.; Julienne, K.; Le Saec, P.; Gouin, S. G.; Hamon, J.; Renault, E.; Deniaud, D. Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical Applications. ChemPlusChem 2014, 79 (9), 1284– 1293, DOI: 10.1002/cplu.201402031Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFWjsrzF&md5=c7a390f621478ec35eb0da8020f8a505Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical ApplicationsBodio, Ewen; Boujtita, Mohammed; Julienne, Karine; Le Saec, Patricia; Gouin, Sebastien G.; Hamon, Jonathan; Renault, Eric; Deniaud, DavidChemPlusChem (2014), 79 (9), 1284-1293CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)A highly stable Cu(I) complex was obtained starting from a Cu(II) salt. This compd. was characterized by a combination of several anal. techniques (UV/visible spectroscopy, energy-dispersive x-ray spectroscopy, electrochem., and XPS) and was shown to present an N4Cu structure. These results were confirmed by a d. functional calcns. study of the binding energy and the electronic structure of model ligand and Cu complexes. Preliminary tests of complexation showed a high ability of the corresponding ligand to chelate 64Cu in very dild. medium, which is of interest for developing new positron emission tomog. imaging agents. The stability and the kinetic inertness of the complex are promising. In particular, it displayed good redox stability, which is important because in vivo redn. or oxidn. of the Cu of Cu complexes can lead to demetalation. The rapid microwave-assisted strategy used to synthesize the ligand was applied to the synthesis of more than ten ligands. One of these was functionalized by an amino group to form a bifunctional chelate for a future bioconjugation for applications in nuclear medicine.
- 36Shuvaev, S.; Suturina, E. A.; Rotile, N. J.; Astashkin, C. A.; Ziegler, C. J.; Ross, A. W.; Walker, T. L.; Caravan, P.; Taschner, I. S. Revisiting Dithiadiaza Macrocyclic Chelators for Copper-64 PET Imaging. Dalt. Trans. 2020, 49 (40), 14088– 14098, DOI: 10.1039/D0DT02787AGoogle ScholarThere is no corresponding record for this reference.
- 37Tosato, M.; Verona, M.; Doro, R.; Dalla Tiezza, M.; Orian, L.; Andrighetto, A.; Pastore, P.; Marzaro, G.; Di Marco, V. Toward Novel Sulphur-Containing Derivatives of Tetraazacyclododecane: Synthesis, Acid–Base Properties, Spectroscopic Characterization, DFT Calculations, and Cadmium(II) Complex Formation in Aqueous Solution. New J. Chem. 2020, 44 (20), 8337– 8350, DOI: 10.1039/D0NJ00310GGoogle Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsVWku7k%253D&md5=10503e6a59ba00101387227d97c2a542Toward novel sulphur-containing derivatives of tetraazacyclododecane: synthesis, acid-base properties, spectroscopic characterization, DFT calculations, and cadmium(II) complex formation in aqueous solutionTosato, Marianna; Verona, Marco; Doro, Riccardo; Dalla Tiezza, Marco; Orian, Laura; Andrighetto, Alberto; Pastore, Paolo; Marzaro, Giovanni; Di Marco, ValerioNew Journal of Chemistry (2020), 44 (20), 8337-8350CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)Macrocyclic ligands obtained by N-functionalization of 1,4,7,10-tetraazacyclododecane (cyclen) have been widely studied due to their remarkable complexing properties toward a variety of transition metals and lanthanides. Despite a plethora of cyclen-based mols. described in the literature, ones bearing sulfur-contg. functional groups have been almost ignored. Herein, a novel series of derivs. with hanging sulfide side-arms have been investigated: 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7,tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7,tris[2-(methylsulfanyl)ethyl]-10-methylacetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7,bis[2-(methylsulfanyl)ethyl]-4,10-diacetic-1,4,7,10-tetraazacyclododecane (DO2A2S). 1,4,7,10-Tetra-n-butyl-1,4,7,10-tetraazacyclododecane (DOT-n-Bu) was included as well in this study for comparison purposes. These compds. have been synthesized and then exptl. and theor. characterized. Their protonation consts. (pKa) have been detd. at 25°C in 0.15 M aq. NaNO3 and in 0.15 M aq. tetramethylammonium chloride by potentiometric titrns. and partly by UV-vis spectrophotometric measurements. D. functional theory (DFT) calcns. have been performed for cyclen, DO4S, and DO3S to investigate the conformations, the thermodn. of protonation equil. and to rationalize the relevant electronic transitions. Stability consts. of the Na+ complexes (log βNa) were computed for DO4S, DO3S, DO3SAm, and DO2A2S. For all compds., the monodimensional 1H-NMR and bidimensional (COSY, NOESY, and HMQC) spectra have been obtained in D2O as a function of pD. Results indicate that sulfur-contg. pendant arms induce partly unpredictable pKa, NMR, UV-Vis, and log βNa properties on the mols., and that these properties significantly differ from those of the corresponding compds. without sulfur (e.g. cyclen and DOT-n-Bu). Furthermore, potentiometric and 1H NMR titrns. were performed in order to evaluate the complexation ability of DO4S, DO3S and DO2A2S toward Cd2+ as a case-example of soft metal ions. The obtained complexes show remarkable stability and are stronger than those formed with cyclen and its most common deriv. DOTA esp. at acidic pH, thus demonstrating that these compds. can be promising chelators of soft metal ions.
- 38Tosato, M.; Asti, M.; Dalla Tiezza, M.; Orian, L.; Häussinger, D.; Vogel, R.; Köster, U.; Jensen, M.; Andrighetto, A.; Pastore, P.; Di Marco, V. Highly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled Radiopharmaceuticals. Inorg. Chem. 2020, 59 (15), 10907– 10919, DOI: 10.1021/acs.inorgchem.0c01405Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGksb3L&md5=0525c4e90bfa458285a90783d187f09fHighly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled RadiopharmaceuticalsTosato, Marianna; Asti, Mattia; Dalla Tiezza, Marco; Orian, Laura; Haussinger, Daniel; Vogel, Raphael; Koster, Ulli; Jensen, Mikael; Andrighetto, Alberto; Pastore, Paolo; Marco, Valerio DiInorganic Chemistry (2020), 59 (15), 10907-10919CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)With a half-life of 7.45 days, silver-111 (βmax 1.04 MeV, Eγ 245.4 keV [Iγ 1.24%], Eγ 342.1 keV [Iγ 6.7%]) is a promising candidate for targeted cancer therapy with β- emitters as well as for assocd. SPECT imaging. For its clin. use, the development of suitable ligands that form sufficiently stable Ag+-complexes in vivo is required. In this work, the following sulfur-contg. derivs. of tetraazacyclododecane (cyclen) have been considered as potential chelators for silver-111: 1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S), (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S4Me), 1,4,7-tris(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris(2-(methylsulfanyl)ethyl)-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis(2-(methylsulfanyl)ethyl)-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). Natural Ag+ was used in pH/Ag-potentiometric and UV-vis spectrophotometric studies to det. the metal speciation existing in aq. NaNO3 0.15 M at 25°C and the equil. consts. of the complexes, whereas NMR and DFT calcns. gave structural insights. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiol. pH. Furthermore, radiolabeling, stability in saline phosphate buffer, and metal-competition expts. using the two ligands forming the strongest complexes, DO4S and DO4S4Me, were carried out with [111Ag]Ag+ and promising results were obtained. Five cyclen derivs. bearing sulfide pendant arms were considered, and their Ag+ complex formation was studied in aq. soln. by potentiometry, UV-vis, NMR, radiolabeling expts. with 111Ag, and DFT calcns. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiol. pH. These ligands might be of interest for the setup of 111Ag labeled radiopharmaceuticals.
- 39Gyr, T.; Mäcke, H. R.; Hennig, M. A Highly Stable Silver(I) Complex of a Macrocycle Derived from Tetraazatetrathiacyclen. Angew. Chem., Int. Ed. Engl. 1997, 36 (24), 2786– 2788, DOI: 10.1002/anie.199727861Google ScholarThere is no corresponding record for this reference.
- 40Li, L.; Rousseau, J.; de Guadalupe Jaraquemada-Peláez, M.; Wang, X.; Robertson, A.; Radchenko, V.; Schaffer, P.; Lin, K.-S.; Bénard, F.; Orvig, C. 225Ac-H4py4pa for Targeted Alpha Therapy. Bioconjugate Chem. 2020. DOI: 10.1021/acs.bioconjchem.0c00171Google ScholarThere is no corresponding record for this reference.
- 41Lacerda, S.; Campello, M. P.; Santos, I. C.; Santos, I.; Delgado, R. Study of the Cyclen Derivative 2-[1,4,7,10-Tetraazacyclododecan-1-Yl]-Ethanethiol and Its Complexation Behaviour towards d-Transition Metal Ions. Polyhedron 2007, 26 (14), 3763– 3773, DOI: 10.1016/j.poly.2007.04.037Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpt1Cltbk%253D&md5=3c13fa0b8a4e4ddfecd90249326449e9Study of the cyclen derivative 2-[1,4,7,10-tetraazacyclododecan-1-yl]-ethanethiol and its complexation behavior towards d-transition metal ionsLacerda, Sara; Campello, Maria Paula; Santos, Isabel C.; Santos, Isabel; Delgado, RitaPolyhedron (2007), 26 (14), 3763-3773CODEN: PLYHDE; ISSN:0277-5387. (Elsevier B.V.)The compd. 2-[1,4,7,10-tetraazacyclododecan-1-yl]-ethanethiol (L2) has been synthesized and characterized by multinuclear NMR spectroscopy and mass spectrometry. Its thiol-protected precursor L1 has also been isolated and characterized, including by X-ray structural anal. The protonation consts. of L2 were detd. by potentiometric methods at 25.0 °C and 0.10 mol dm-3 KNO3 ionic strength. 3C NMR studies and 2D NMR spectra recorded at different pD values have been used to analyze its protonation scheme. Stability consts. of L2 with Cu2+, Zn2+ and Cd2+ were also detd. by potentiometry, and the Zn(II) and Cu(II) complexes were studied in soln. by NMR, UV-Vis, and EPR spectroscopies. The pM values (pH 7.4) calcd. for the metal complexes of L2 are higher than the corresponding values found for cyclen and cyclam, but the selectivity of L2 for Cu2+ is low.
- 42Ševčik, R.; Vanek, J.; Lubal, P.; Kotková, Z.; Kotek, J.; Hermann, P. Formation and Dissociation Kinetics of Copper(II) Complexes with Tetraphosphorus Acid DOTA Analogs. Polyhedron 2014, 67, 449– 455, DOI: 10.1016/j.poly.2013.09.024Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFWrtr%252FK&md5=75d8d129e68b0fc7679e44192061d69eFormation and dissociation kinetics of copper(II) complexes with tetraphosphorus acid DOTA analogsSevcik, Radek; Vanek, Jakub; Lubal, Premysl; Kotkova, Zuzana; Kotek, Jan; Hermann, PetrPolyhedron (2014), 67 (), 449-455CODEN: PLYHDE; ISSN:0277-5387. (Elsevier Ltd.)Thermodn. and kinetic properties of Cu(II) complexes with macrocyclic cyclen-based ligands having four phosphonic acid monoester (H4dotpOEt = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphonic acid monoethylester)) or four phosphinic acid (H4dotpH = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphinic acid) and H4dotpPh = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methyl(phenyl)phosphinic acid]) pendant arms were investigated. The formation kinetics carried out in pH range 1-5.5 (t = 25°C, I = 0.1 M KCl) shows that reactive species are (H2L)2- and (HL)3- anions and their reactivity differs by 4-5 orders of magnitude. Among studied ligands, H4dotpH is the most reactive one. Dissocn. of these copper(II) complexes was investigated in the presence of perchloric acid (I = 5 M (Na,H)ClO4, proton concn. range 0.1-5.0 M) and in temp. range 10-35°C. All studied complexes are less kinetically inert than the [Cu(dota)]2- complex and the Cu(II) complex of H4dotpH is the least kinetically inert among the studied complexes, probably due to the lowest thermodn. stability. These results show that the ligands probably cannot be employed for copper radioisotopes complexation but the data will be utilized in design of other macrocyclic ligands intended to be used in medicinal chem.
- 43Kasprzyk, S. P.; Wilkins, R. G. Kinetics of Interaction of Metal Ions with Two Tetraazatetraacetate Macrocycles. Inorg. Chem. 1982, 21 (9), 3349– 3352, DOI: 10.1021/ic00139a018Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XltFKjtbo%253D&md5=790b2cdb7d84b8e42bdc0f4696e57e97Kinetics of interaction of metal ions with two tetraazatetraacetate macrocyclesKasprzyk, Stanislaw P.; Wilkins, Ralph G.Inorganic Chemistry (1982), 21 (9), 3349-52CODEN: INOCAJ; ISSN:0020-1669.The kinetics of formation of metal complexes of the macrocyclic ligands 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetate (TETA) were measured by stopped-flow spectrophotometry. Observations were made at 25° and I = 0.25 M over a wide range of pH, and the reactive species was characterized as the monoprotonated form of the ligand. Metal ions examd. were Mg2+, Ca2+, Sr2+, Ba2+, Zn2+, Ni2+, and Cu2+. With a no. of systems, plots of the pseudo-1st-order rate const. kobsd vs. [M2+] in excess were hyperbolic conforming to the expression kobsd = (A[M2+])(1 + K[M2+])-1. K Is considered a const. for formation of a preassocn. complex. This may then proceed to a final complex (1st-order rate const. AK-1) or be a "dead-end" complex, with reactants reacting by a 2nd-order process, rate const. A. With the remaining systems, kobsd vs. [M2+] was linear as required for a 2nd-order reaction.
- 44Anderegg, 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. Pure Appl. Chem. 2005, 77 (8), 1445– 1495, DOI: 10.1351/pac200577081445Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXps1GrsLk%253D&md5=e3a5ede39f3959f9661890ee30ac6579Critical evaluation of stability constants of metal complexes of complexones for biomedical and environmental applicationsAnderegg, Giorgio; Arnaud-Neu, Francoise; Delgado, Rita; Felcman, Judith; Popov, KonstantinPure 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".
- 45Tosato, M.; Di Marco, V. Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs. Biomolecules 2019, 9 (7), 269, DOI: 10.3390/biom9070269Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1antbnM&md5=a5f65d72fd7f0b3eb8ec5df88ad4a038Metal chelation therapy and Parkinson's disease: a critical review on the thermodynamics of complex formation between relevant metal ions and promising or established drugsTosato, Marianna; Di Marco, ValerioBiomolecules (2019), 9 (7), 269CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)A review. The present review reports a list of approx. 800 compds. which have been used, tested or proposed for Parkinson's disease (PD) therapy in the year range 2014-2019 (Apr.): name(s), chem. structure and refs. are given. Among these compds., approx. 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compds. has been collected or, if not exptl. available, has been estd. from similar mols. Stoichiometries and stability consts. of the complexes have been reported; values of the cologarithm of the concn. of free metal ion at equil. (pM), and of the dissocn. const. Kd (both computed at pH = 7.4 and at total metal and ligand concns. of 10-6 and 10-5 mol/L, resp.), charge and stoichiometry of the most abundant metal-ligand complexes existing at physiol. conditions, have been obtained. A rigorous definition of the reported amts. is given, the possible usefulness of this data is described, and the need to characterize the metal-ligand speciation of PD drugs is underlined.
- 46Price, T. W.; Greenman, J.; Stasiuk, G. J. Current Advances in Ligand Design for Inorganic Positron Emission Tomography Tracers Ga-68, Cu-64, Zr-89 and Sc-44. Dalt. Trans. 2016, 45 (40), 15702– 15724, DOI: 10.1039/C5DT04706DGoogle ScholarThere is no corresponding record for this reference.
- 47Amundsen, A. R.; Whelan, J.; Bosnich, B. Biological Analogues. On the Nature of the Binding Sites of Copper-Containing Proteins. J. Am. Chem. Soc. 1977, 99 (20), 6730– 6739, DOI: 10.1021/ja00462a042Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXlsl2gsb8%253D&md5=809c857b403916da33563afec5e1803fBiological analogs. Nature of the binding sites of copper-containing proteinsAmundsen, Alan R.; Whelan, John; Bosnich, B.Journal of the American Chemical Society (1977), 99 (20), 6730-9CODEN: JACSAT; ISSN:0002-7863.An extended series of ligands and their Cu(II) complexes were prepd. as spectroscopic models for detg. the geometries and ligand coordinations of Cu proteins. The electronic properties of thioether, imidazole, amide anion, amine, phenolate anion, and thiolate anion coordination of Cu(II) were detd. In addn., the electronic spectra of some of these ligands in square-planar, square-pyramidal, and tetrahedral geometries about Cu(II) were obtained by appropriate ligand design. On the basis of these results and an anal. of the protein spectra, structures for the Cu coordination and geometry in (blue) type I Cu, Cu in galactose oxidase, type III Cu, and Cu in oxyhemocyanin are proposed.
- 48Hancock, R.; Wade, P.; Ngwenya, M.; De Sousa, A. S.; Damu, K. V. Ligand Design for Complexation in Aqueous Solution. Chelate Ring Size as a Basis for Control of Size-Based Selectivity for Metal Ions. Inorg. Chem. 1990, 29 (10), 1968– 1974, DOI: 10.1021/ic00335a039Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXit1Cgurc%253D&md5=b2730a78d0a3a83c15ebb0f75e944031Ligand design for complexation in aqueous solution. 2. Chelate ring size as a basis for control of size-based selectivity for metal ionsHancock, Robert D.; Wade, Peter W.; Ngwenya, M. Patrick; De Sousa, Alvaro S.; Damu, Kirty V.Inorganic Chemistry (1990), 29 (10), 1968-74CODEN: INOCAJ; ISSN:0020-1669.The role of chelate ring size in complex stability, and selectivity based on metal ion size, is examd. Formation consts. of pairs of ligands which differ in that one member of the pair forms a 5-membered chelate ring where the other forms a 6-membered chelate ring are reported with metal ions ranging in ionic radius from small (Be, Cu(II), Al) to medium sized (Zn, In(III)) and large (La(III), Pb(II)). Pairs of ligands studied whose formation consts. are combined with literature values already available) are 9-aneN2O (1-oxa-4,7-diazacyclononane) and 10-aneN2O (1-oxa-4,8-diazacyclodecane) 15-aneN4O (1-oxa-4,7,10,13-tetraazacyclopentadecane) and 16-aneN4O (1-oxa-4,7,11,14-tetraazacyclohexadecane), TIRON (4,5-dihydroxy-1,3-benzenedisulfonate) and CTA (chromotropic acid, 4,5-dihydroxynaphthalene-2,7-disulfonate), TM-cyclen (1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane) and TMC (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane). Except for the pair of rigid small macrocycles 9-aneN2O and 10-aneN2O, chelate ring size dominates macrocyclic ring size in controlling metal ion size-based selectivity so that complexes of larger metal ions are destabilized relative to those of smaller metal ions by an increase in chelate ring size from 5 to 6 membered. For the TIRON/CTA pair of ligands, rigidity introduced into the single chelate ring by arom. rings gave sharper size selectivity than for pairs of flexible ligands such as oxalate/malonate. With high levels of steric crowding, as in TM-cyclen and TMC, size selectivity still was controlled by chelate ring size. The strain energy (U) of 5- and 6-membered chelate rings of the ethylenediamine (EN) and 1,3-diaminopropane (TN) type was calcd. by mol. mechanics (MM) as a function of M-N bond length and N-M-N angle. The MM calcn. showed that min. U occurred for the EN chelate ring when the M-N bond length was 2.5 Å and the N-M-N angle was 70°, while for the TN chelate ring, U was a min. for M-N bond length 1.6 Å and N-M-N angle 109.5°. The MM studies on alkali metal ion complexes with crown ethers with different chelate ring sizes present showed that even with highly ionic M-L bonding, the effect of chelate ring size on metal ion selectivity should be present.
- 49Styka, M. C.; Smierciak, R. C.; Blinn, E. L.; DeSimone, R. E.; Passariello, J. V. Copper(II) Complexes Containing a 12-Membered Macrocyclic Ligand. Inorg. Chem. 1978, 17 (1), 82– 86, DOI: 10.1021/ic50179a018Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXjslOksg%253D%253D&md5=71a8cd94119e4e1bb1bfc6e29b349d02Copper(II) complexes containing a 12-membered macrocyclic ligandStyka, M. C.; Smierciak, R. C.; Blinn, E. L.; DeSimone, R. E.; Passariello, J. V.Inorganic Chemistry (1978), 17 (1), 82-6CODEN: INOCAJ; ISSN:0020-1669.Cu(II) complexes of 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane (tbcyclen) were prepd. They include Cu(cyclen)X2 (X = Cl, Br, NO3, Cu(tbcyclen)X2.nH2O (X = NO3, Cl, Br, NCS), Cu(tbcyclen)ClClO4.0.5H2O, and Cu(tbcyclen)ClBr.H2O. Substitution reactions, conductivity, ESR, and spectral data suggest that the complexes are 5-coordinate and approx. square-pyramidal geometry. The Cu(tbcyclen)X2 complexes have an absorption band in the 700-800-mμ range which has an unusually high extinction coeff. for a Cu(II) complex bonded to only N and O donor atoms.
- 50Gray, J. L.; Gerlach, D. L.; Papish, E. T. Crystal Structure of (Perchlorato-KO)(1,4,7,10-Tetraazacyclododecane-K4 N)Copper(II) Perchlorate. Acta Crystallogr. E Crystallogr. Commun. 2017, 73 (1), 31– 34, DOI: 10.1107/S2056989016019563Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkslGitw%253D%253D&md5=ab3e4ccfaaa8c0bb326b86c1fdfed2e2Crystal structure of (perchlorato-κO)(1,4,7,10-tetraazacyclododecane-κ4N)copper(II) perchlorateGray, Jessica L.; Gerlach, Deidra L.; Papish, Elizabeth T.Acta Crystallographica, Section E: Crystallographic Communications (2017), 73 (1), 31-34CODEN: ACSECI; ISSN:2056-9890. (International Union of Crystallography)The crystal structure of the title salt, [Cu(ClO4)(C8H20N4)]ClO4, is reported. The CuII ion exhibits a square-pyramidal geometry and is coordinated by the four N atoms of the neutral 1,4,7,10-tetraazacyclododecane (cyclen) ligand and an O atom from one perchlorate anion, with the second perchlorate ion hydrogen-bonded to one of the amine N atoms of the cyclen ligand. Addnl. N-H···O hydrogen bonds between the amine H atoms and the coordinating and non-coordinating perchlorate groups create a three-dimensional network structure. Crystals were grown from a concd. methanol soln. at ambient temp., resulting in no co-crystn. of solvent.
- 51Nikles, D. E.; Powers, M. J.; Urbach, F. L. Copper(II) Complexes with Tetradentate Bis(Pyridyl)-Dithioether and Bis(Pyridyl)-Diamine Ligands. Effect of Thioether Donors on the Electronic Absorption Spectra, Redox Behavior, and EPR Parameters of Copper(II) Complexes. Inorg. Chem. 1983, 22 (22), 3210– 3217, DOI: 10.1021/ic00164a009Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXls1ygtLk%253D&md5=3091904fe81131ba39a3747586ae43f3Copper(II) complexes with tetradentate bis(pyridyl)-dithioether and bis(pyridyl)-diamine ligands. Effect of thio ether donors on the electronic absorption spectra, redox behavior, and EPR parameters of copper(II) complexesNikles, D. E.; Powers, M. J.; Urbach, F. L.Inorganic Chemistry (1983), 22 (22), 3210-17CODEN: INOCAJ; ISSN:0020-1669.Eight Cu(II) chelates contg. a tetradentate R(CH2)xS(CH2)yS(CH2)xR (R = pyridyl) or R(CH2)xN(R1)(CH2)yN(R1)(CH2)xR (x = 1, 2, y = 2, 3, R1 = H, Me) were studied to det. the effect of thioether donors on the spectral and redox properties of the Cu complexes. The systematic variation of the chelate ring sizes (5-5-5, 5-6-5, 6-5-6, and 6-6-6) allowed stereochem. trends in the obsd. properties to be ascertained as well as the effect of thioether substitution for the amine donors. The electronic absorption spectra of the CuII[R2S2] complexes differed from those of the CuII[R2N2] series by the presence of a S(σ)→Cu(II) ligand-metal charge transfer (MLCT) region and an enhanced intensity in the visible (d-d) bands which was attributed to an intensity-borrowing mechanism from the low-energy charge-transfer band. The Cu(I) complexes of both series of ligands exhibited an absorption band at 300-350 nm corresponding to a Cu(I)→py(π*) MLCT transition. The Cu(II)/Cu(I) redn. potentials for the chelates typically showed little solvent dependence in CH3CN and aq. solns. as measured by cyclic and differential pulse voltammetry. The potentials for the R2S2 series are 400-660 mV vs. NHE, substantially higher than those exhibited by the R2N2 series (-170 to +320 mV vs. NHE). The redn. potentials for both series increase with increasing chelate ring size, suggesting that the larger chelate rings can more readily accommodate a pseudotetrahedral Cu(I) form. The anisotropic ESR parameters for the CuII[R2N2] series were nearly axial while the CuII[R2S2] series exhibited rhombic spectra representing the redn. in the effective donor atom symmetry of the complexes.
- 52Geraldes, C. F. G. C.; Marques, M. P.; de Castro, B.; Pereira, E. Study of Copper(II) Polyazamacrocyclic Complexes by Electronic Absorption Spectrophotometry and EPR Spectroscopy. Eur. Eur. J. Inorg. Chem. 2000, 2000 (3), 559– 565, DOI: 10.1002/(SICI)1099-0682(200003)2000:3<559::AID-EJIC559>3.0.CO;2-JGoogle ScholarThere is no corresponding record for this reference.
- 53Lima, L. M.; Esteban-Gomez, D.; Delgado, R.; Platas-Iglesias, C.; Tripier, R. Monopicolinate Cyclen and Cyclam Derivatives for Stable Copper(II) Complexation. Inorg. Chem. 2012, 51 (12), 6916– 6927, DOI: 10.1021/ic300784vGoogle Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvVSntrc%253D&md5=a01fe5223c102e75cf2b4b7497083c87Monopicolinate Cyclen and Cyclam Derivatives for Stable Copper(II) ComplexationLima, Luis M. P.; Esteban-Gomez, David; Delgado, Rita; Platas-Iglesias, Carlos; Tripier, RaphaelInorganic Chemistry (2012), 51 (12), 6916-6927CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) deriv. bearing a picolinate pendant arm (HL1), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analog HL2, were achieved by using two different selective-protection methods involving the prepn. of cyclen-bisaminal or phosphoryl cyclam derivs. The acid-base properties of both compds. were studied as well as their coordination chem., esp. with Cu2+, in aq. soln. and in solid state. The copper(II) complexes were synthesized, and the single crystal x-ray diffraction structures of compds. of formula [Cu(HL)](ClO4)2·H2O (L = L1 or L2), [CuL1](ClO4) and [CuL2]Cl·2H2O, were detd. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability consts. of the complexes were detd. at 25.0° and ionic strength 0.10 M in KNO3 using potentiometric titrns. Both ligands form complexes with Cu2+ that are thermodynamically very stable. Addnl., both HL1 and HL2 exhibit an important selectivity for Cu2+ over Zn2+. The kinetic inertness in acidic medium of both complexes of Cu2+ was evaluated by spectrophotometry revealing that [CuL2]+ is much more inert than [CuL1]+. The detd. half-life values also demonstrate the very high kinetic inertness of [CuL2]+ when compared to a list of copper(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aq. soln. from UV-visible and EPR spectroscopy, showing that the soln. structures of both complexes are in excellent agreement with those of crystallog. data. Cyclic voltammetry expts. point to a good stability of the complexes with respect to metal ion dissocn. upon redn. of the metal ion to Cu+ at about neutral pH. The authors' results revealed that the cyclam-based ligand HL2 is a very attractive receptor for copper(II), presenting a fast complexation process, a high kinetic inertness, and important thermodn. and electrochem. stability.
- 54Clay, R.; Murray-Rust, P.; Murray-Rust, J. Nitrato(1,4,7,10-Tetraazacyclododecane) Copper(II) Nitrate. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1979, 35 (8), 1894– 1895, DOI: 10.1107/S0567740879008013Google ScholarThere is no corresponding record for this reference.
- 55Riesen, A.; Zehnder, M.; Kaden, T. A. Metal Complexes of Macrocyclic Ligands. Part XXIII. Synthesis, Properties, and Structures of Mononuclear Complexes with 12- and 14-membered Tetraazamacrocycle-N,N′,N″,N‴-tetraacetic Acids. Helv. Chim. Acta 1986, 69 (8), 2067– 2073, DOI: 10.1002/hlca.19860690830Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXhtFamtbc%253D&md5=8b393179ce98b221e0c0c9e5eef24210Metal complexes of macrocyclic ligands. Part XXIII. Synthesis, properties, and structures of mononuclear complexes with 12- and 14-membered tetraazamacrocycle-N,N',N",N"'-tetraacetic acidsRiesen, Andreas; Zehnder, Margareta; Kaden, Thomas A.Helvetica Chimica Acta (1986), 69 (8), 2067-73CODEN: HCACAV; ISSN:0018-019X.I (R = (CH2)2 (H4dota, H4L), (CH2)3 (H4teta)) form with Ni2+, Cu2+, and Zn2+ (M2+) MLH2 and M'[ML], M' being an alk. earth ion. The structures of Ni(H2dota) and Cu(H2dota) were solved by x-ray structure anal. The metal ions are in a distorted octahedral geometry coordinated by 4 amino N-atoms and 2 carboxylates. In the case of Cu2+, the distortions are more pronounced than for Ni2+ indicating that the Jahn-Teller effect is operating. Starting from these 2 structures, the coordination geometry of the other complexes is discussed using visible and IR spectra.
- 56Ševčík, R.; Vaněk, J.; Michalicová, R.; Lubal, P.; Hermann, P.; Santos, I. C.; Santos, I.; Campello, M. P. C. Formation and Decomplexation Kinetics of Copper(II) Complexes with Cyclen Derivatives Having Mixed Carboxylate and Phosphonate Pendant Arms. Dalt. Trans. 2016, 45 (32), 12723– 12733, DOI: 10.1039/C6DT01127FGoogle ScholarThere is no corresponding record for this reference.
- 57Addison, A. W.; Carpenter, M.; Lau, L. K. M.; Wicholas, M. Coordination Sphere Flexibility at Copper: Chemistry of an Unipositive Copper(II) Macrocycle, [Cu(Cyclops)]+. Inorg. Chem. 1978, 17 (6), 1545– 1552, DOI: 10.1021/ic50184a032Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXitVagsLk%253D&md5=9e05d4264f9afd31ff330e7644c17e5dCoordination sphere flexibility at copper: chemistry of a unipositive copper(II) macrocycle, [Cu(cyclops)]+Addison, A. W.; Carpenter, M.; Lau, L. K. M.; Wicholas, M.Inorganic Chemistry (1978), 17 (6), 1545-52CODEN: INOCAJ; ISSN:0020-1669.The complex of Cu2+ with cyclops (I), an N4 macrocycle of 1- charge, was studied and square-pyramidal adducts of formal [Cu(cyclops)X] and [Cu(cyclops)L]ClO4 were isolated, where X represents a series of anionic Lewis bases and L represents a series of neutral Lewis bases. These adducts are notable for their strong axial interaction at the expense of the in-plane binding. The redox behavior of Cu(cyclops)+ and its adducts were studied by cyclic voltammetry, and equil. consts. were detd. for the 1:1 interactions of both oxidized and reduced Cu(cyclops)+ with pyridine, γ-picoline, Me Ph sulfide, and benzyl isocyanide. The relation of the chem. of Cu(cyclops+/0 to Cu biochem. is discussed.
- 58Taras-Goslinska, K.; Jonsson, M. Solvent Effect on the Redox Properties of Thioethers. J. Phys. Chem. A 2006, 110 (30), 9513– 9517, DOI: 10.1021/jp0623746Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmslWhu7s%253D&md5=7fb0a074cc06a81f0ad828b153b1a7bdSolvent Effects on the Redox Properties of ThioethersTaras-Goslinska, Katarzyna; Jonsson, MatsJournal of Physical Chemistry A (2006), 110 (30), 9513-9517CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The one-electron redn. potential of the radical cations of thioanisole (1), benzyl Me sulfide (2) and 2-hydroxyethyl benzyl sulfide (3) in water, formamide, acetonitrile, acetone, 1,1,1,3,3,3-hexafluoropropan-2-ol, methanol and 2-propanol was investigated by cyclic voltammetry. For comparison the one-electron redn. potentials in water were also measured using pulse radiolysis. The redox potential is strongly influenced by the nature of the solvent and the solvent sensitivity increases with charge localization. The present results have been used to evaluate solvent effects in view of the Kamlet-Taft relationship. The Kamlet-Taft expression quant. describes the solvent effects on the redox properties of 1-3 and gives the relative importance of the different solvent properties. The dominating contribution to the solvent effects is the solvent dipolarity/polarizability π*, whereas α appears to be of minor importance. Furthermore, the relationship between the π* and redn. potential of radical cations of 1-3 appear to be linear. It was also possible to find the same trend between the solvent dipole moment and peak potential of 1-3. These facts indicate that the nature of solvation is mainly nonspecific.
- 59Coleman, B. R.; Glass, R. S.; Setzer, W. N.; Prabhu, U. D. G.; Wilson, G. S. Electrochemistry of Aliphatic Thioethers as Models for Biological Electron Transfer. Adv. Chem. Ser. 1982, 201, 417– 441, DOI: 10.1021/ba-1982-0201.ch018Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXmslajtQ%253D%253D&md5=3f2f6fba24b61f5a156512ab8995874eElectrochemistry of aliphatic thioethers as models for biological electron transferColeman, Brian R.; Glass, Richard S.; Setzer, William N.; Prabhu, Usha Devi G.; Wilson, George S.Advances in Chemistry Series (1982), 201 (Electrochem. Spectrochem. Stud. Biol. Redox Compon.), 417-41CODEN: ADCSAJ; ISSN:0065-2393.A review and discussion with 71 refs.
- 60Houghton, D. S.; Humffray, A. A. Anodic Oxidation of Diaryl Sulphides—I. Diphenyl Sulphide in Sulphate and Perchlorate Media. Electrochim. Acta 1972, 17 (8), 1421– 1433, DOI: 10.1016/0013-4686(72)80086-0Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XltVyktrg%253D&md5=8a01c24a6e47a2db0c9ddabfe1ef5830Anodic oxidation of diaryl sulfides. I. Diphenyl sulfide in sulfate and perchlorate mediaHoughton, D. S.; Humffray, A. A.Electrochimica Acta (1972), 17 (8), 1421-33CODEN: ELCAAV; ISSN:0013-4686.Controlled-potential oxidn. at a Pt anode of Ph2S in 80% HOAc-H2O in the presence of ClO4- or SO42- produces Ph2SO in near quant. yield, with a coulombic efficiency close to 100%. At higher potentials, some further oxidn. to Ph2SO2 occurs. Single-sweep voltammetry is suitable for anal., provided that halide ions are absent. Possible mechanisms for the oxidn. to Ph2SO are discussed; 2 of these involve a transition state similar to that proposed for homogeneous oxidn. of sulfides to sulfoxides.
- 61Di Marco, V. Ph.D. Thesis, University of Padova, Padova, Italy, 1998.Google ScholarThere is no corresponding record for this reference.
- 62Baes, C. F. J.; Mesmer, R. E. The Hydrolysis of Cations; Wiley-Interscience: New York, 1976.Google ScholarThere is no corresponding record for this reference.
- 63Rockenbauer, A.; Korecz, L. Automatic Computer Simulations of ESR Spectra. Appl. Magn. Reson. 1996, 10 (1), 29– 43, DOI: 10.1007/BF03163097Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XltFehur8%253D&md5=7185bdaf5d33efaf5f8a347b568574dfAutomatic computer simulations of ESR spectraRockenbauer, Antal; Korecz, L.Applied Magnetic Resonance (1996), 10 (1-3), 29-43CODEN: APMREI; ISSN:0937-9347. (Springer)A versatility of automatic ESR simulation procedures was developed to obtain high quality of fitting and produce addnl. information. The following examples are treated: derivation of long-range proton hyperfine coupling consts. from unresolved lines; detn. of 13C hf couplings from the naturally abundant isotope satellites; analyzing chem. exchange phenomena with the 2-sites model (modified Bloch equation); decompn. of superimposed spectra consisting of poorly resolved components. To achieve best agreement between calcd. and exptl. spectra within a reasonable no. of iteration cycles, various approaches were combined, such as consecutive independent parameter optimization, least-square approach, optimization on "serpentines" and optimization of compd. parameters. The spectra can be computed both for liq. and solid state samples, for non-oriented, partially oriented and single crystal samples. Second order perturbation formulas are used for the spin Hamiltonian including g- and hyperfine tensors that have isotropic, axial and rhombic symmetry. Various lineshapes, including Lorentzian, Gaussian, mixed, modulation and dispersion distorted forms are applied. Third order parabolic interpolations are used for building up spectra from individual lines. To correct sweep non-linearity a 3rd order interpolation converts the spectrum to become equidistant. In the anal. of strongly overlapping superimposed spectra, simultaneous adjustment of 2 independent exptl. spectra can give an exact decompn. The inclusion of long-range couplings offers highly perfect fitting and allows one to resolve contributions of naturally abundant 13C isotopes.
- 64Higashi, T. Numerical Absorption Correction. NUMABS 2002.Google ScholarThere is no corresponding record for this reference.
- 65Sheldrick, G. M. Phase Annealing in Shelx-90: Direct Methods for Larger Structure. Acta Crystallogr., Sect. A: Found. Crystallogr. 1990, 46 (6), 467– 473, DOI: 10.1107/S0108767390000277Google ScholarThere is no corresponding record for this reference.
- 66CrystalClear-SM, version 1.4.0 SP1; Rigaku and Rigaku/MSC, 2008.Google ScholarThere is no corresponding record for this reference.
- 67Burla, M. C.; Caliandro, R.; Carrozzini, B.; Cascarano, G. L.; Cuocci, C.; Giacovazzo, C.; Mallamo, M.; Mazzone, A.; Polidori, G. Crystal Structure Determination and Refinement via SIR2014. J. Appl. Crystallogr. 2015, 48 (1), 306– 309, DOI: 10.1107/S1600576715001132Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVOmtrw%253D&md5=d2ef5d0634082b90c7fa0c2ef66b985eCrystal structure determination and refinement via SIR2014Burla, Maria Cristina; Caliandro, Rocco; Carrozzini, Benedetta; Cascarano, Giovanni Luca; Cuocci, Corrado; Giacovazzo, Carmelo; Mallamo, Mariarosaria; Mazzone, Annamaria; Polidori, GiampieroJournal of Applied Crystallography (2015), 48 (1), 306-309CODEN: JACGAR; ISSN:1600-5767. (International Union of Crystallography)SIR2014 is the latest program of the SIR suite for crystal structure soln. of small, medium and large structures. A variety of phasing algorithms have been implemented, both ab initio (std. or modern direct methods, Patterson techniques, Vive la Difference) and non-ab initio (simulated annealing, mol. replacement). The program contains tools for crystal structure refinement and for the study of three-dimensional electron-d. maps via suitable viewers.
- 68SHELXL-2013 Program for Crystal Structure Solution; University of Göttingen: Göttingen, Germany, 2013.Google ScholarThere is no corresponding record for this reference.
- 69Farrugia, L. J. WinGX and ORTEP for Windows: An Update. J. Appl. Crystallogr. 2012, 45 (4), 849– 854, DOI: 10.1107/S0021889812029111Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVKltbzK&md5=0b5b2b5facbaafdd6bbbb80e581bf3beWinGX and ORTEP for Windows: an updateFarrugia, Louis J.Journal of Applied Crystallography (2012), 45 (4), 849-854CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)The WinGX suite provides a complete set of programs for the treatment of small-mol. single-crystal diffraction data, from data redn. and processing, structure soln., model refinement and visualization, and metric anal. of mol. geometry and crystal packing, to final report prepn. in the form of a CIF. It includes several well known pieces of software and provides a repository for programs when the original authors no longer wish to, or are unable to, maintain them. It also provides menu items to execute external software, such as the SIR and SHELX suites of programs. The program ORTEP for Windows provides a graphical user interface (GUI) for the classic ORTEP program, which is the original software for the illustration of anisotropic displacement ellipsoids. The GUI code provides input capabilities for a wide variety of file formats, and extra functionality such as geometry calcns. and ray-traced outputs. The programs WinGX and ORTEP for Windows have been distributed over the internet for about 15 years, and this article describes some of the more modern features of the programs.
- 70Spek, A. L. Single-Crystal Structure Validation with the Program PLATON. J. Appl. Crystallogr. 2003, 36 (1), 7– 13, DOI: 10.1107/S0021889802022112Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltlChtw%253D%253D&md5=0a85de2407551632bb287508534904e2Single-crystal structure validation with the program PLATONSpek, A. L.Journal of Applied Crystallography (2003), 36 (1), 7-13CODEN: JACGAR; ISSN:0021-8898. (Blackwell Munksgaard)The results of a single-crystal structure detn. when in CIF format can now be validated routinely by automatic procedures. In this way, many errors in published papers can be avoided. The validation software generates a set of ALERTS detailing issues to be addressed by the experimenter, author, referee and publication journal. Validation was pioneered by the IUCr journal Acta Crystallographica Section C and is currently std. procedure for structures submitted for publication in all IUCr journals. The implementation of validation procedures by other journals is in progress. This paper describes the concepts of validation and the classes of checks that are carried out by the program PLATON as part of the IUCr check CIF facility. PLATON validation can be run at any stage of the structure refinement, independent of the structure detn. package used, and is recommended for use as a routine tool during or at least at the completion of every structure detn. Two examples are discussed where proper validation procedures could have avoided the publication of incorrect structures that had serious consequences for the chem. involved.
- 71Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. Mercury: Visualization and Analysis of Crystal Structures. J. Appl. Crystallogr. 2006, 39 (3), 453– 457, DOI: 10.1107/S002188980600731XGoogle Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkslehsbk%253D&md5=c9d7a3c38e1f27769e8578c861c11e3cMercury: visualization and analysis of crystal structuresMacrae, Clare F.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Shields, Greg P.; Taylor, Robin; Towler, Matthew; van de Streek, JaccoJournal of Applied Crystallography (2006), 39 (3), 453-457CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)Since its original release, the popular crystal structure visualization program Mercury has undergone continuous further development. Comparisons between crystal structures are facilitated by the ability to display multiple structures simultaneously and to overlay them. Improvements were made to many aspects of the visual display, including the addn. of depth cueing, and highly customizable lighting and background effects. Textual and numeric data assocd. with structures can be shown in tables or spreadsheets, the latter opening up new ways of interacting with the visual display. At. displacement ellipsoids, calcd. powder diffraction patterns and predicted morphologies can now be shown. Some limited mol.-editing capabilities were added. The object-oriented nature of the C++ libraries underlying Mercury makes it easy to re-use the code in other applications, and this has facilitated three-dimensional visualization in several other programs produced by the Cambridge Crystallog. Data Center.
- 72Allen, F. H.; Johnson, O.; Shields, G. P.; Smith, B. R.; Towler, M. CIF Applications. XV. EnCIFer: A Program for Viewing, Editing and Visualizing CIFs. J. Appl. Crystallogr. 2004, 37 (2), 335– 338, DOI: 10.1107/S0021889804003528Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitVagtbc%253D&md5=08ca1e807bede5d71d0157994759f3ccCIF applications. XV. enCIFer: a program for viewing, editing and visualizing CIFsAllen, Frank H.; Johnson, Owen; Shields, Gregory P.; Smith, Barry R.; Towler, MatthewJournal of Applied Crystallography (2004), 37 (2), 335-338CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)The enCIFer program permits the location, reporting and correction of syntax and format violations in single- or multi-block crystallog. information files (CIFs). The program also permits the editing of existing individual or looped data items and the addn. of new data in these categories, and provides data entry wizards for the addn. of two types of std. information for small mol. structural studies, namely publication data and chem. and phys. property information. Facilities for the graphical visualization and manipulation of structure(s) in a CIF are also provided.
- 73Hwang, T. L.; Shaka, A. J. Water Suppression That Works. Excitation Sculpting Using Arbitrary Wave-Forms and Pulsed-Field Gradients. J. Magn. Reson., Ser. A 1995, 112 (2), 275– 279, DOI: 10.1006/jmra.1995.1047Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjs1Wmsb0%253D&md5=f56de708de13417539d157c074ef3998Water suppression that works. Excitation sculpting using arbitrary waveforms and pulsed field gradientsHwang, Tsang-Lin; Shaka, A. J.Journal of Magnetic Resonance, Series A (1995), 112 (2), 275-9CODEN: JMRAE2; ISSN:1064-1858. (Academic)A water suppression technique which can applied to most NMR expts. is described. A simple echo sequence employing a pulsed field gradient before and after the refocusing element is applied. Theor. background and examples are gives.
- 74te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. Chemistry with ADF. J. Comput. Chem. 2001, 22 (9), 931– 967, DOI: 10.1002/jcc.1056Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjtlGntrw%253D&md5=314e7e942de9b28e664afc5adb2f574fChemistry with ADFTe Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T.Journal of Computational Chemistry (2001), 22 (9), 931-967CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)A review with 241 refs. We present the theor. and tech. foundations of the Amsterdam D. Functional (ADF) program with a survey of the characteristics of the code (numerical integration, d. fitting for the Coulomb potential, and STO basis functions). Recent developments enhance the efficiency of ADF (e.g., parallelization, near order-N scaling, QM/MM) and its functionality (e.g., NMR chem. shifts, COSMO solvent effects, ZORA relativistic method, excitation energies, frequency-dependent (hyper)polarizabilities, at. VDD charges). In the Applications section we discuss the phys. model of the electronic structure and the chem. bond, i.e., the Kohn-Sham MO (MO) theory, and illustrate the power of the Kohn-Sham MO model in conjunction with the ADF-typical fragment approach to quant. understand and predict chem. phenomena. We review the "Activation-strain TS interaction" (ATS) model of chem. reactivity as a conceptual framework for understanding how activation barriers of various types of (competing) reaction mechanisms arise and how they may be controlled, for example, in org. chem. or homogeneous catalysis. Finally, we include a brief discussion of exemplary applications in the field of biochem. (structure and bonding of DNA) and of time-dependent d. functional theory (TDDFT) to indicate how this development further reinforces the ADF tools for the anal. of chem. phenomena.
- 75Fonseca Guerra, C.; Snijders, J. G.; te Velde, G.; Baerends, E. J. Towards an Order-N DFT Method. Theor. Chem. Acc. 1998, 99 (6), 391– 403, DOI: 10.1007/s002140050353Google ScholarThere is no corresponding record for this reference.
- 76ADF2018; SCM, Theoretical Chemistry, Vrije Universiteit: Amsterdam: The Netherlands, 2018; http://www.scm.com.Google ScholarThere is no corresponding record for this reference.
- 77Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized Gradient Approximation Made Simple. Phys. Rev. Lett. 1996, 77 (18), 3865– 3868, DOI: 10.1103/PhysRevLett.77.3865Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmsVCgsbs%253D&md5=55943538406ee74f93aabdf882cd4630Generalized gradient approximation made simplePerdew, John P.; Burke, Kieron; Ernzerhof, MatthiasPhysical Review Letters (1996), 77 (18), 3865-3868CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)Generalized gradient approxns. (GGA's) for the exchange-correlation energy improve upon the local spin d. (LSD) description of atoms, mols., and solids. We present a simple derivation of a simple GGA, in which all parameters (other than those in LSD) are fundamental consts. Only general features of the detailed construction underlying the Perdew-Wang 1991 (PW91) GGA are invoked. Improvements over PW91 include an accurate description of the linear response of the uniform electron gas, correct behavior under uniform scaling, and a smoother potential.
- 78Handy, N. C.; Cohen, A. J. Left-Right Correlation Energy. Mol. Phys. 2001, 99 (5), 403– 412, DOI: 10.1080/00268970010018431Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhslGlur8%253D&md5=0c077bca407ca9c54d414391d60b8139Left-right correlation energyHandy, Nicholas C.; Cohen, Aron J.Molecular Physics (2001), 99 (5), 403-412CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)We first attempt to det. a local exchange functional Ex[ρ] which accurately reproduces the Hartree-Fock (HF) energies of the 18 first and second row atoms. Ex[ρ] is detd. from ρ and |gradρ|, and we find that we can improve significantly upon Becke's original generalized gradient approxn. functional (commonly called B88X) by allowing the coeff. of the Dirac exchange term to be optimized (it is argued that mols. do not behave like the uniform electron gas). We call this new two parameter exchange functional OPTX. We find that neither Δρ or τ = Σ|gradφi|2 improve the fit to these at. energies. These exchange functionals include not only exchange, but also left-right correlation. It is therefore proposed that this functional provides a definition for exchange energy plus left-right correlation energy when used in Kohn-Sham (KS) calcns. We call this energy the Kohn-Sham exchange (or KSX) energy. It is shown that for nearly all mols. studied these KSX energies are lower than the corresponding HF energies, thus giving values for the non-dynamic correlation energy. At stretched geometries, the KSX energies are always lower than the HF energies, and often substantially so. Furthermore all bond lengths from the KSX calcns. are longer than HF bond lengths and exptl. bond lengths, which again demonstrates the inclusion of left-right correlation effects in the functional. For these reasons we prefer to split the correlation energy into two parts: left-right correlation energy and dynamic correlation energy, arguing that the usage of the words "non-dynamic" or "static" or "near-degeneracy" is less meaningful. We recognize that this definition of KSX is not precise, because the definition of a local Ex[ρ] can never be precise. We also recognize that these ideas are not new, but we think that their importance has been insufficiently recognized in functional detn. When we include third row atoms in our anal., we are unable to find a local exchange functional which is a substantial improvement over B88X for the reprodn. of HF energies. This must arise from the effects of the core orbitals, and therefore we do not consider that this detracts from the improved accuracy of OPTX. We report some MCSCF calcns. constructed from bonding-antibonding configurations, from which we attempt to calc. ab initio left-right correlation. There is only moderate agreement between the two approaches. Finally we combine the OPTX functional with established correlation functionals (LYP, P86, P91) to form OLYP, OP86 and OP91; OLYP is a great improvement on BLYP for both energy and structure, and OP86, OP91 are an improvement over BP86, BP91 for structure. The importance of the exchange functional for mol. structure is therefore underlined.
- 79Swart, M.; Ehlers, A. W.; Lammertsma, K. Performance of the OPBE Exchange-Correlation Functional. Mol. Phys. 2004, 102 (23–24), 2467– 2474, DOI: 10.1080/0026897042000275017Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFGmu7rK&md5=ab48b6ca8a51335ab2105808c28b809bPerformance of the OPBE exchange-correlation functionalSwart, Marcel; Ehlers, Andreas W.; Lammertsma, KoopMolecular Physics (2004), 102 (23-24), 2467-2474CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)In a recent evaluation of d. functional theory (DFT) functionals OPBE, which combines Handy's optimized exchange (OPTX) with the PBE correlation, was shown to correctly predict the spin states (singlet through sextet) of seven different iron complexes (2004, J. Phys. Chem. A, 108, 5479). The present study provides a further test of OPBE as well as that of the OPerdew and OLYP functionals, in which OPTX is combined with the Perdew and LYP correlations, resp. These three are compared to other pure DFT functionals for their performance in calcg. the atomization energies for the G2-set of up to 148 mols., six reaction barriers of SN2 reactions, geometry optimizations of 19 small mols. and four metallocenes, and zero-point vibrational energies for 13 small mols. OPBE performs exceptional well in all cases.
- 80van Lenthe, E.; Baerends, E. J.; Snijders, J. G. Relativistic Total Energy Using Regular Approximations. J. Chem. Phys. 1994, 101 (11), 9783– 9792, DOI: 10.1063/1.467943Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXisFChu7g%253D&md5=4b0c97a476c22d4e3f783f0b97c72581Relativistic total energy using regular approximationsvan Lenthe, E.; Baerends, E. J.; Snijders, J. G.Journal of Chemical Physics (1994), 101 (11), 9783-92CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)In this paper we will discuss relativistic total energies using the zeroth order regular approxn. (ZORA). A simple scaling of the ZORA one-electron Hamiltonian is shown to yield energies for the hydrogenlike atom that are exactly equal to the Dirac energies. The regular approxn. is not gauge invariant in each order, but the scaled ZORA energy can be shown to be exactly gauge invariant for hydrogenic ions. It is practically gauge invariant for many-electron systems and proves superior to the (unscaled) first order regular approxn. for at. ionization energies. The superior to the (unscaled) first order regular approxn. for at. ionization energies. The regular approxn., if scaled, can therefore be applied already in zeroth order to mol. bond energies. Scalar relativistic d. functional all-electron and frozen core calcns. on diatomics, consisting of copper, silver, and gold and their hydrides are presented. We used exchange-correlation energy functionals commonly used in nonrelativistic calcns.; both in the local-d. approxn. (LDA) and including d.-gradient ("nonlocal") corrections (NLDA). At the NLDA level the calcd. dissocn. energies are all within 0.2 eV from expt., with an av. of 0.1 eV. All-electron calcns. for Au2 and AuH gave results within 0.05 eV of the frozen core calcns. Ag2 and AgCu and CuH.
- 81Allinger, N. L.; Zhou, X.; Bergsma, J. Molecular Mechanics Parameters. J. Mol. Struct.: THEOCHEM 1994, 312 (1), 69– 83, DOI: 10.1016/S0166-1280(09)80008-0Google ScholarThere is no corresponding record for this reference.
- 82Ho, J.; Klamt, A.; Coote, M. L. Comment on the Correct Use of Continuum Solvent Models. J. Phys. Chem. A 2010, 114 (51), 13442– 13444, DOI: 10.1021/jp107136jGoogle Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFaktL3I&md5=ffa1aa6c6f5f321292fcf8d4a843c037Comment on the Correct Use of Continuum Solvent ModelsHo, Junming; Klamt, Andreas; Coote, Michelle L.Journal of Physical Chemistry A (2010), 114 (51), 13442-13444CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)There is no expanded citation for this reference.
- 83Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113 (18), 6378– 6396, DOI: 10.1021/jp810292nGoogle Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXksV2is74%253D&md5=54931a64c70d28445ee53876a8b1a4b9Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface TensionsMarenich, Aleksandr V.; Cramer, Christopher J.; Truhlar, Donald G.Journal of Physical Chemistry B (2009), 113 (18), 6378-6396CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)We present a new continuum solvation model based on the quantum mech. charge d. of a solute mol. interacting with a continuum description of the solvent. The model is called SMD, where the "D" stands for "d." to denote that the full solute electron d. is used without defining partial at. charges. "Continuum" denotes that the solvent is not represented explicitly but rather as a dielec. medium with surface tension at the solute-solvent boundary. SMD is a universal solvation model, where "universal" denotes its applicability to any charged or uncharged solute in any solvent or liq. medium for which a few key descriptors are known (in particular, dielec. const., refractive index, bulk surface tension, and acidity and basicity parameters). The model separates the observable solvation free energy into two main components. The first component is the bulk electrostatic contribution arising from a self-consistent reaction field treatment that involves the soln. of the nonhomogeneous Poisson equation for electrostatics in terms of the integral-equation-formalism polarizable continuum model (IEF-PCM). The cavities for the bulk electrostatic calcn. are defined by superpositions of nuclear-centered spheres. The second component is called the cavity-dispersion-solvent-structure term and is the contribution arising from short-range interactions between the solute and solvent mols. in the first solvation shell. This contribution is a sum of terms that are proportional (with geometry-dependent proportionality consts. called at. surface tensions) to the solvent-accessible surface areas of the individual atoms of the solute. The SMD model has been parametrized with a training set of 2821 solvation data including 112 aq. ionic solvation free energies, 220 solvation free energies for 166 ions in acetonitrile, methanol, and DMSO, 2346 solvation free energies for 318 neutral solutes in 91 solvents (90 nonaq. org. solvents and water), and 143 transfer free energies for 93 neutral solutes between water and 15 org. solvents. The elements present in the solutes are H, C, N, O, F, Si, P, S, Cl, and Br. The SMD model employs a single set of parameters (intrinsic at. Coulomb radii and at. surface tension coeffs.) optimized over six electronic structure methods: M05-2X/MIDI!6D, M05-2X/6-31G*, M05-2X/6-31+G**, M05-2X/cc-pVTZ, B3LYP/6-31G*, and HF/6-31G*. Although the SMD model has been parametrized using the IEF-PCM protocol for bulk electrostatics, it may also be employed with other algorithms for solving the nonhomogeneous Poisson equation for continuum solvation calcns. in which the solute is represented by its electron d. in real space. This includes, for example, the conductor-like screening algorithm. With the 6-31G* basis set, the SMD model achieves mean unsigned errors of 0.6-1.0 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 4 kcal/mol on av. for ions with either Gaussian03 or GAMESS.
- 84Pye, C. C.; Ziegler, T. An Implementation of the Conductor-like Screening Model of Solvation within the Amsterdam Density Functional Package. Theor. Chem. Acc. 1999, 101 (6), 396– 408, DOI: 10.1007/s002140050457Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktVSqt7k%253D&md5=ff0f000eb1217a8d117a1be17e02ac1fAn implementation of the conductor-like screening model of solvation within the Amsterdam density functional packagePye, Cory C.; Ziegler, TomTheoretical Chemistry Accounts (1999), 101 (6), 396-408CODEN: TCACFW; ISSN:1432-881X. (Springer-Verlag)The conductor-like screening model (COSMO) of solvation was implemented in the Amsterdam d. functional program with max. flexibility in mind. Four cavity definitions were incorporated. Several iterative schemes were tested for solving the COSMO equations. The biconjugate gradient method proves to be both robust and memory-conserving. The interaction between the surface charges and the electron d. may be calcd. by integrating over either the fitted or exact d., or by calcg. the mol. potential. A disk-smearing algorithm is applied in the former case to avoid singularities. Several SCF/COSMO coupling schemes were examd. in an attempt to reduce computational effort. A gradient-preserving algorithm for removing outlying charge was implemented. Preliminary optimized radii are given. Applications to the benzene oxide-oxepin valence tautomerization and to glycine conformation are presented.
- 85Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed. 2017, 56 (34), 10070– 10086, DOI: 10.1002/anie.201701486Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOlt7nL&md5=6e86c7cfaf7b09e58c0a50a589601578Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain ModelBickelhaupt, F. Matthias; Houk, Kendall N.Angewandte Chemie, International Edition (2017), 56 (34), 10070-10086CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The activation strain or distortion/interaction model is a tool to analyze activation barriers that det. reaction rates. For bimol. reactions, the activation energies are the sum of the energies to distort the reactants into geometries they have in transition states plus the interaction energies between the two distorted mols. The energy required to distort the mols. is called the activation strain or distortion energy. This energy is the principal contributor to the activation barrier. The transition state occurs when this activation strain is overcome by the stabilizing interaction energy. Following the changes in these energies along the reaction coordinate gives insights into the factors controlling reactivity. This model has been applied to reactions of all types in both org. and inorg. chem., including substitutions and eliminations, cycloaddns., and several types of organometallic reactions.
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Abstract
Figure 1
Figure 1. Select state-of-the-art copper chelators (NOTA, DOTA, and TETA) and ligands investigated in this work (DO4S, DO3S, DO3SAm, and DO2A2S).
Figure 2
Figure 2. Select UV–vis spectra at pH <2 of the Cu2+ complexes formed by (A) DO4S (CCu2+ = CDO4S = 1.5 × 10–4 mol/L), (B) DO3S (CCu2+ = CDO3S = 1.0 × 10–4 mol/L), (C) DO3SAm (CCu2+ = CDO3SAm = 1.1 × 10–4 mol/L), and (D) DO2A2S (CCu2+ = CDO2A2S = 0.9 × 10–4 mol/L) at I = 0.15 mol/L NaCl (for solutions at pH >0.8) and T = 25.0 °C.
Figure 3
Figure 4
Figure 4. Measured (solid lines) and simulated (dotted lines) EPR spectra for solutions containing Cu2+ and (A) DO4S (CCu2+ = 1.0 × 10–3 mol/L; CDO4S = 1.3 × 10–3 mol/L) and (B) DO3S (CCu2+ = 1.0 × 10–3 mol/L; CDO3S = 1.1 × 10–3 mol/L) at room temperature (left) and 77 K (right). The component spectra obtained from the simulation are shown in the upper part.
Figure 5
Figure 5. ORTEP diagrams of (A) [Cu(DO4S)(NO3)]·NO3 and (B) [Cu(DO2A2S)] (Cu1 = molecule #1; Cu2 = molecule #2) with atom numbering. Thermal ellipsoids are drawn at the 50% probability level. Water molecules, hydrogen atoms, and nonbonded nitrate anions are omitted for the sake of clarity. The symmetry codes for molecules #1 and #2 in [Cu(DO2A2S)] are −x + 1, y, −z + 1 and −x + 2, y, −z + 1, respectively.
Figure 6
Figure 6. Measured (solid lines) and simulated (dotted lines) spectra for solutions containing Cu2+ and DO2A2S (CCu2+ = 1.0 × 10–3 mol/L; CDO2AS = 1.1 × 10–3 mol/L) at 77 K. The component spectra obtained from the simulation are shown in the upper part.
Figure 7
Figure 7. Cyclic voltammograms of the copper complexes of (A) DO4S (C[Cu(DO4S)]2+ = 1.02 × 10–3 mol/L), (B) DO3S (C[Cu(DO3S)]2+ = 1.13 × 10–3 mol/L), and (C) DO2A2S (C[Cu(DO2A2S)] = 6.48 × 10–4 mol/L) in aqueous solution at pH 7, I = NaNO3 0.15 mol/L, and T = 25 °C. Scan rates: 0.1 V/s (A and B) and 0.01 V/s (C).
Figure 8
Figure 8. LSV of Cu-DO4S before (blu) and after (gray) electrolysis at −0.35 V, performed with a rotating disk electrode at ω = 2000 rpm and v = 0.005 V/s, with I = NaNO3 0.15 mol/L and T = 25 °C.
Figure 9
Figure 9. 1H NMR spectra (400 MHz, room temperature, H2O + 10% D2O) of the in situ generated cuprous complexes: (A) DO4S (CCu= CDO4S = 1.6 × 10–3 mol/L) and (B) DO2A2S (CCu = CDO2A2S = 1.4 × 10–3 mol/L) at pH 7. The signal marked with an asterisk (2.22 ppm) is related to the acetone impurity.
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- 2Wadas, 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/cr900325h2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFChtro%253D&md5=674cf315a0df26fc4407445bd35595d6Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of DiseaseWadas, 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.
- 3Cai, Z.; Anderson, C. J. Chelators for Copper Radionuclides in Positron Emission Tomography Radiopharmaceuticals. J. Labelled Compd. Radiopharm. 2014, 57 (4), 224– 230, DOI: 10.1002/jlcr.31653https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFCjsLvI&md5=b804d4f3317d0c53978d3621a3b221ccChelators for copper radionuclides in positron emission tomography radiopharmaceuticalsCai, Zhengxin; Anderson, Carolyn J.Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (4), 224-230CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. The development of chelating agents for copper radionuclides in positron emission tomog. radiopharmaceuticals has been a highly active and important area of study in recent years. The rapid evolution of chelators has resulted in highly specific copper chelators that can be readily conjugated to biomols. and efficiently radiolabeled to form stable complexes in vivo. Chelators are not only designed for conjugation to monovalent biomols. but also for incorporation into multivalent targeting ligands such as theranostic nanoparticles. These advancements have strengthened the role of copper radionuclides in the fields of nuclear medicine and mol. imaging. This review emphasizes developments of new copper chelators that have most greatly advanced the field of copper-based radiopharmaceuticals over the past 5 years.
- 4Boros, E.; Cawthray, J. F.; Ferreira, C. L.; Patrick, B. O.; Adam, M. J.; Orvig, C. Evaluation of the H2dedpa Scaffold and Its CRGDyK Conjugates for Labeling with 64Cu. Inorg. Chem. 2012, 51 (11), 6279– 6284, DOI: 10.1021/ic300482x4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvFWqsr0%253D&md5=06aed6b5cecd6dc0224fa73f3070effeEvaluation of the H2dedpa Scaffold and its cRGDyK Conjugates for Labeling with 64CuBoros, Eszter; Cawthray, Jacqueline F.; Ferreira, Cara L.; Patrick, Brian O.; Adam, Michael J.; Orvig, ChrisInorganic Chemistry (2012), 51 (11), 6279-6284CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Studies of the acyclic ligand scaffold H2dedpa and its derivs. with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for 67/68Ga, the chelate is now shown to coordinate 64Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered soln.). The hexadentate, distorted octahedral coordination of H2dedpa is confirmed in the corresponding solid state X-ray crystal structure of [Cu(dedpa)]. Cyclic voltammetry detd. the redn. potential of [Cu(dedpa)] to be below values found for common bioreductants. Redn. and reoxidn. were irreversible but reproducible, indicating a potential change of coordination mode upon redn. of Cu(II) to Cu(I). The thermodn. stability const. log KCuL was detd. to be 19.16(5), comparable to other frequently used 64Cu chelates. Serum stability of the 64Cu labeled chelate revealed only 3% transchelation/assocn. to serum proteins after 2 h, while the conjugates reveal 10% ([Cu(RGD1)]) and 6% ([Cu(RGD2)]) transchelation at the same time point.
- 5Anderson, C. J.; Welch, M. J. Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging. Chem. Rev. 1999, 99 (9), 2219– 2234, DOI: 10.1021/cr980451q5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkvF2rurg%253D&md5=5e998fe68c5e014668482d56290411d0Radiometal-Labeled Agents (Non-Technetium) for Diagnostic ImagingAnderson, Carolyn J.; Welch, Michael J.Chemical Reviews (Washington, D. C.) (1999), 99 (9), 2219-2234CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review with 178 refs. of non-technetium-labeled radiometal-labeled agents used in gamma scintigraphy and positron emission tomog. Topics covered include prodn. of Ga, In, Cu and Y radionuclides, their chem., and detg. the optimal imaging agents for specific diseases.
- 6Shokeen, M.; Anderson, C. J. Molecular Imaging of Cancer with Copper-64 Radiopharmaceuticals and Positron Emission Tomography (PET). Acc. Chem. Res. 2009, 42 (7), 832– 841, DOI: 10.1021/ar800255q6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1Cmu7w%253D&md5=3cff4a2250ef2d284b06301c4abfe93fMolecular Imaging of Cancer with Copper-64 Radiopharmaceuticals and Positron Emission Tomography (PET)Shokeen, Monica; Anderson, Carolyn J.Accounts of Chemical Research (2009), 42 (7), 832-841CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Mol. imaging has evolved over the past several years into an important tool for diagnosing, understanding, and monitoring disease. Mol. imaging has distinguished itself as an interdisciplinary field, with contributions from chem., biol., physics, and medicine. The cross-disciplinary impetus has led to significant achievements, such as the development of more sensitive imaging instruments and robust, safer radiopharmaceuticals, thereby providing more choices to fit personalized medical needs. Mol. imaging is making steadfast progress in the field of cancer research among others. Cancer is a challenging disease, characterized by heterogeneity, uncontrolled cell division, and the ability of cancer cells to invade other tissues. Researchers are addressing these challenges by aggressively identifying and studying key cancer-specific biomarkers such as growth factor receptors, protein kinases, cell adhesion mols., and proteases, as well as cancer-related biol. processes such as hypoxia, apoptosis, and angiogenesis. Positron emission tomog. (PET) is widely used by clinicians in the United States as a diagnostic mol. imaging tool. Small-animal PET systems that can image rodents and generate reconstructed images in a noninvasive manner (with a resoln. as low as 1 mm) have been developed and are used frequently, facilitating radiopharmaceutical development and drug discovery. Currently, [18F]-labeled 2-fluorodeoxyglucose (FDG) is the only PET radiotracer used for routine clin. evaluation (primarily for oncol. imaging). There is now increasing interest in nontraditional positron-emitting radionuclides, particularly those of the transition metals, for imaging with PET because of increased prodn. and availability. Copper-based radionuclides are currently being extensively evaluated because they offer a varying range of half-lives and positron energies. For example, the half-life (12.7 h) and decay properties (β+, 0.653 MeV, 17.8%; β-, 0.579 MeV, 38.4 %; the remainder is electron capture) of 64Cu make it an ideal radioisotope for PET imaging and radiotherapy. In addn., the well-established coordination chem. of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to antibodies, proteins, peptides, and other biol. relevant mols. New chelators with greater in vivo stability, such as the cross-bridged (CB) versions of tetraazamacrocyclic 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), are now available. Finally, one of the major aspects of successful imaging is the identification and characterization of a relevant disease biomarker at the cellular and subcellular level and the ensuing development of a highly specific targeting moiety. In this Account, we discuss specific examples of PET imaging with new and improved 64Cu-based radiopharmaceuticals, highlighting the study of some of the key cancer biomarkers, such as epidermal growth-factor receptor (EGFR), somatostatin receptors (SSRs), and integrin αvβ3.
- 7Blower, P. J.; Lewis, J. S.; Zweit, J. Copper Radionuclides and Radiopharmaceuticals in Nuclear Medicine. Nucl. Med. Biol. 1996, 23 (8), 957– 980, DOI: 10.1016/S0969-8051(96)00130-87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkslOqsQ%253D%253D&md5=39b9b14d56995b81d7c57f35e2fcdd82Copper radionuclides and radiopharmaceuticals in nuclear medicineBlower, Philip J.; Lewis, Jason S.; Zweit, JamalNuclear Medicine and Biology (1996), 23 (8), 957-980CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)The chem., radiochem., radiobiol., and radiopharmacol. of radiopharmaceuticals contg. copper radionuclides are reviewed, with 210 refs. Copper radionuclides offer application in positron emission tomog., targeted radiotherapy, and single photon imaging. The chem. of copper is relatively simple and well-suited to radiopharmaceutical application. Current radiopharmaceuticals include biomols. labeled via bifunctional chelators primarily based on cyclic polyaminocarboxylates and polyamines, and pyruvaldehyde-bis(N4-methylthiosemicarbazone) (PTSM) and its analogs. The chem. of copper, of which only a fraction has yet been exploited, is likely to be applied more fully in the future.
- 8Borgna, F.; Ballan, M.; Favaretto, C.; Verona, M.; Tosato, M.; Caeran, M.; Corradetti, S.; Andrighetto, A.; Di Marco, V.; Marzaro, G.; Realdon, N. Early Evaluation of Copper Radioisotope Production at ISOLPHARM. Molecules 2018, 23 (10), 2437, DOI: 10.3390/molecules23102437There is no corresponding record for this reference.
- 9Srivastava, S. C.; Mausner, L. F. Therapeutic Radionuclides: Production, Physical Characteristics, and Applications. Therapeutic Nuclear Medicine; Springer-Verlag: Berlin, 2013; pp 11– 50.There is no corresponding record for this reference.
- 10Ramogida, C.; Orvig, C. Tumour Targeting with Radiometals for Diagnosis and Therapy. Chem. Commun. 2013, 49 (42), 4720– 4739, DOI: 10.1039/c3cc41554f10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmvVegt7s%253D&md5=ea63aef48789cb3e1710af520c4542dbTumour targeting with radiometals for diagnosis and therapyRamogida, Caterina F.; Orvig, ChrisChemical Communications (Cambridge, United Kingdom) (2013), 49 (42), 4720-4739CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. Use of radiometals in nuclear oncol. is a rapidly growing field and encompasses a broad spectrum of radiotracers for imaging via PET (positron emission tomog.) or SPECT (single-photon emission computed tomog.) and therapy via α, β-, or Auger electron emission. This feature article opens with a brief introduction to the imaging and therapy modalities exploited in nuclear medicine, followed by a discussion of the multi-component strategy used in radiopharmaceutical development, known as the bifunctional chelate (BFC) method. The modular assembly is dissected into its individual components and each is discussed sep. The concepts and knowledge unique to metal-based designs are outlined, giving insight into how these radiopharmaceuticals are evaluated for use in vivo. Imaging nuclides 64Cu, 68Ga, 86Y, 89Zr, and 111In, and therapeutic nuclides 90Y, 177Lu, 225Ac, 213Bi, 188Re, and 212Pb will be the focus herein. Finally, key examples have been extd. from the literature to give the reader a sense of breadth of the field.
- 11Liu, S. Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides. Adv. Drug Delivery Rev. 2008, 60 (12), 1347– 1370, DOI: 10.1016/j.addr.2008.04.00611https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXoslWktr8%253D&md5=106b21e77e2ed4155f4a1c3781655612Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclidesLiu, ShuangAdvanced Drug Delivery Reviews (2008), 60 (12), 1347-1370CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Receptor-based radiopharmaceuticals are of great current interest in mol. imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomol. (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomol. serves as a "carrier" for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomols. with a metallic radionuclide. Different radiometals have significant difference in their coordination chem., and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on phys. and biol. properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chem. with technetium, copper, gallium, indium, yttrium and lanthanide radiometals.
- 12Fani, M.; Del Pozzo, L.; Abiraj, K.; Mansi, R.; Tamma, M. L.; Cescato, R.; Waser, B.; Weber, W. A.; Reubi, J. C.; Mäcke, H. R. PET of Somatostatin Receptor-Positive Tumors Using 64Cu- and 68Ga Somatostatin Antagonists: The Chelate Makes the Difference. J. Nucl. Med. 2011, 52 (7), 1110– 1118, DOI: 10.2967/jnumed.111.08799912https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvVKltro%253D&md5=3225eb0d38a7e33658a8a5168e914497PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the differenceFani, Melpomeni; Del Pozzo, Luigi; Abiraj, Keelara; Mansi, Rosalba; Tamma, Maria Luisa; Cescato, Renzo; Waser, Beatrice; Weber, Wolfgang A.; Reubi, Jean Claude; Maecke, Helmut R.Journal of Nuclear Medicine (2011), 52 (7), 1110-1118CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-pos. tumors, esp. of subtype 2 (sst2). The clin. used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors detg. the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four 64Cu or 68Ga radioantagonists for PET of sst2-pos. tumors. Methods: The novel antagonist p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. 64/natCu- and 68/natGa-NODAGA-LM3 were prepd. at room temp., and 64/natCu-CB-TE2A-LM3 and 68/natGa-DOTA-LM3 were prepd. at 95°C. Binding affinity and antagonistic properties were detd. with receptor autoradiog. and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissocn. was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; 68/natGa-NODAGA-LM3 has the lowest half maximal inhibitory concn. (1.3 ± 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of 64Cu- and 68Ga-NODAGA-LM3 (∼40 percentage injected dose per g of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for 64Cu-NODAGA-LM3 (∼15 %ID/g, 24 h after injection) and almost negligible for 64Cu-CB-TE2A-LM3 (26.9 ± 3.3 %ID/g and 21.6 ± 2.1 %ID/g, 4 and 24 h after injection, resp.). Tumor-to-normal-tissue ratios were significantly higher for 64Cu-NODAGA-LM3 than for 64Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 ± 3.6 and 1.7 ± 0.3, resp.; tumor-to-muscle, 1,342 ± 115 and 75.2 ± 8.5, resp., at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, esp. for 64Cu- and 68Ga-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. 64Cu- and 68Ga-NODAGA-LM3 and 64Cu-CB-TE2A-LM3 are promising candidates for clin. translation because of their favorable pharmacokinetics and the high image contrast on PET scans.
- 13Litau, S.; Seibold, U.; Vall-Sagarra, A.; Fricker, G.; Wängler, B.; Wängler, C. Comparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and In Vivo Experiments. ChemMedChem 2015, 10 (7), 1200– 1208, DOI: 10.1002/cmdc.20150013213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXovVCktrk%253D&md5=e2b35e1f430df391e71e297217ca7d7fComparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and in vivo ExperimentsLitau, Shanna; Seibold, Uwe; Vall-Sagarra, Alicia; Fricker, Gert; Waengler, Bjoern; Waengler, CarmenChemMedChem (2015), 10 (7), 1200-1208CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)For 64Cu radiolabeling of biomols. to be used as in vivo positron emission tomog. (PET) imaging agents, various chelators are commonly applied. It has not yet been detd. which of the most potent chelators-NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl)diacetic acid), or CB-TE1A-GA (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl-8-acetic acid-1-glutaric acid)-forms the most stable complexes resulting in PET images of highest quality. We detd. the 64Cu complex stabilities for these three chelators by a combination of complex challenge and an in vivo approach. For this purpose, bioconjugates of the chelating agents with the gastrin-releasing peptide receptor (GRPR)-affine peptide PESIN and an integrin αvβ3-affine c(RGDfC) tetramer were synthesized and radiolabeled with 64Cu in excellent yields and specific activities. The 64Cu-labeled biomols. were evaluated for their complex stabilities in vitro by conducting a challenge expt. with the resp. other chelators as challengers. The in vivo stabilities of the complexes were also detd., showing the highest stability for the 64Cu-CB-TE1A-GA complex in both exptl. setups. Therefore, CB-TE1A-GA is the most appropriate chelating agent for *Cu-labeled radiotracers and in vivo imaging applications.
- 14Price, E. W.; Orvig, C. Matching Chelators to Radiometals for Radiopharmaceuticals. Chem. Soc. Rev. 2014, 43 (1), 260– 290, DOI: 10.1039/C3CS60304K14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVGktLzP&md5=30a847faed78cba5123ffca47bde5aa3Matching chelators to radiometals for radiopharmaceuticalsPrice, Eric W.; Orvig, ChrisChemical 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.
- 15Lima, L. M. P.; Halime, Z.; Marion, R.; Camus, N.; Delgado, R.; Platas-Iglesias, C.; Tripier, R. Monopicolinate Cross-Bridged Cyclam Combining Very Fast Complexation with Very High Stability and Inertness of Its Copper(II) Complex. Inorg. Chem. 2014, 53 (10), 5269– 5279, DOI: 10.1021/ic500491c15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmslGrtLw%253D&md5=e3dbf273c08b89d97e6cd94b9fa33841Monopicolinate Cross-Bridged Cyclam Combining Very Fast Complexation with Very High Stability and Inertness of Its Copper(II) ComplexLima, Luis M. P.; Halime, Zakaria; Marion, Ronan; Camus, Nathalie; Delgado, Rita; Platas-Iglesias, Carlos; Tripier, RaphaelInorganic Chemistry (2014), 53 (10), 5269-5279CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb-cyclam) deriv. bearing a picolinate arm (Hcb-te1pa) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid-base properties and coordination properties with Cu2+ and Zn2+ was studied. The x-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temp. and that demonstrated high thermodn. stability, which was measured by potentiometry (at 25° and 0.10 M in KNO3). Also the complex exists as a monopos. copper(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu2+ over Zn2+. The copper(II) complex was synthesized and studied in soln. using different spectroscopic techniques and DFT calcns. The kinetic inertness of the copper(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissocn. of the complex. The half-life of 96 days, in 5 M HClO4, and 465 min, in 5 M HCl at 25°, show the high kinetic stability of the copper(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Addnl., cyclic voltammetry expts. underlined the perfect electrochem. inertness of the complex as well as the quasi-reversible Cu2+/Cu+ redox system. The coordination geometry of the copper center in the complex was established in aq. soln. from UV-visible and EPR spectroscopies.
- 16Woodin, K. S.; Heroux, K. J.; Boswell, C. A.; Wong, E. H.; Weisman, G. R.; Niu, W.; Tomellini, S. A.; Anderson, C. J.; Zakharov, L. N.; Rheingold, A. L. Kinetic Inertness and Electrochemical Behavior of Copper(II) Tetraazamacrocyclic Complexes: Possible Implications for In Vivo Stability. Eur. J. Inorg. Chem. 2005, 2005 (23), 4829– 4933, DOI: 10.1002/ejic.200500579There is no corresponding record for this reference.
- 17Cooper, M. S.; Ma, M. T.; Sunassee, K.; Shaw, K. P.; Williams, J. D.; Paul, R. L.; Donnelly, P. S.; Blower, P. J. Blower, P. J. Comparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and In Vitro/In Vivo Stability. Bioconjugate Chem. 2012, 23 (5), 1029– 1039, DOI: 10.1021/bc300037w17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvVyqurg%253D&md5=649071237104b7aaffb6d032acce51daComparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo StabilityCooper, Maggie S.; Ma, Michelle T.; Sunassee, Kavitha; Shaw, Karen P.; Williams, Jennifer D.; Paul, Rowena L.; Donnelly, Paul S.; Blower, Philip J.Bioconjugate Chemistry (2012), 23 (5), 1029-1039CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with 64Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p-SCN-Bn-Oxo-DO3A, p-SCN-NOTA, and p-SCN-PCTA), three DTPA derivs. (p-SCN-Bn-DTPA, p-SCN-CHX-A''-DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO2H) = (1-NH2-8-NHCO(CH2)3CO2H)sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane. Radiolabeling efficiency under various conditions, in vitro stability in serum at 37 °C, and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO2H were conjugated to rituximab by thiourea bond formation with an av. of 4.9 ± 0.9 chelators per antibody mol. Sar-CO2H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody mol. Efficiencies of 64Cu radiolabeling were dependent on the concn. of immunoconjugate. Notably, the 64Cu-NOTA-rituximab conjugate demonstrated the highest radiochem. yield (95%) under very dil. conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, contg. 1/10th the no. of chelators per antibody compared to that of other conjugates, retained high labeling efficiency (98%) at an antibody concn. of 250 nM. In contrast to the radioimmunoconjugates contg. DTPA derivs., which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6% dissocn. of 64Cu over 48 h. In vivo biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. While all the macrocyclic bifunctional chelators are suitable for mol. imaging using 64Cu-labeled antibody conjugates, NOTA and sar-CO2H show significant advantages over the others in that they can be radiolabeled rapidly at room temp., under dil. conditions, resulting in high specific activity.
- 18Boros, E.; Holland, J. P. Chemical Aspects of Metal Ion Chelation in the Synthesis and Application Antibody-based Radiotracers. J. Labelled Compd. Radiopharm. 2018, 61 (9), 652– 671, DOI: 10.1002/jlcr.359018https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1KhsLk%253D&md5=5197ae7bdc3a0c10c29f9ee8ddad2975Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracersBoros, Eszter; Holland, Jason P.Journal of Labelled Compounds and Radiopharmaceuticals (2018), 61 (9), 652-671CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)Radiometals are becoming increasingly accessible and are utilized frequently in the design of radiotracers for imaging and therapy. Nuclear properties ranging from the emission of γ-rays and β+-particles (imaging) to Auger electron and β- and α-particles (therapy) in combination with long half-lives are ideally matched with the relatively long biol. half-life of monoclonal antibodies in vivo. Radiometal labeling of antibodies requires the incorporation of a metal chelate onto the monoclonal antibody. This chelate must coordinate the metal under mild conditions required for the handling of antibodies, as well as provide high kinetic, thermodn., and metabolic stability once the metal ion is coordinated to prevent release of the radionuclide before the target site is reached in vivo. Herein, we review the role of different radiometals that have found applications of the design of radiolabeled antibodies for imaging and radioimmunotherapy. Each radionuclide is described regarding its nuclear synthesis, coordinative preference, and radiolabeling properties with commonly used and novel chelates, as well as examples of their preclin. and clin. applications. An overview of recent trends in antibody-based radiopharmaceuticals is provided to spur continued development of the chem. and application of radiometals for imaging and therapy.
- 19Sharma, A. K.; Schultz, J. W.; Prior, J. T.; Rath, N. P.; Mirica, L. M. Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer’s Disease. Inorg. Chem. 2017, 56 (22), 13801– 13814, DOI: 10.1021/acs.inorgchem.7b0188319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslKqtL3F&md5=81e6fab97c8000cd43d6ee5a690077feCoordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer's DiseaseSharma, Anuj K.; Schultz, Jason W.; Prior, John T.; Rath, Nigam P.; Mirica, Liviu M.Inorganic Chemistry (2017), 56 (22), 13801-13814CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Positron emission tomog. (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, 11C and 18F, have short half-lives, and their usage is thus somewhat limited. By comparison, the 64Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compds. (BFCs) based on macrocyclic 1,4,7-triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu2+ ions. In addn., these BFCs contain a 2-phenylbenzothiazole fragment that is known to interact tightly with amyloid β fibrillar aggregates. Detn. of the protonation consts. (pKa values) and stability consts. (log β values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallog., ESR spectroscopy, and electrochem. studies, suggests that these BFCs exhibit desirable properties for the development of novel 64Cu PET imaging agents for Alzheimer's disease.
- 20Bass, L. A.; Wang, M.; Welch, M. J.; Anderson, C. J. In Vivo Transchelation of Copper-64 from TETA-Octreotide to Superoxide Dismutase in Rat Liver. Bioconjugate Chem. 2000, 11 (4), 527– 532, DOI: 10.1021/bc990167l20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXktFOlurw%253D&md5=0468c443acdb8d77057188c715f1f76bIn Vivo Transchelation of Copper-64 from TETA-Octreotide to Superoxide Dismutase in Rat LiverBass, Laura A.; Wang, Mu; Welch, Michael J.; Anderson, Carolyn J.Bioconjugate Chemistry (2000), 11 (4), 527-532CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)An understanding of the metabolic fate of radiometal-labeled peptides is important due to their application in the areas of diagnostic imaging and targeted radiotherapy. Radioisotopes of copper (64Cu, T1/2 = 12.7 h; 67Cu, T1/2 = 62 h) have been labeled to monoclonal antibodies (mAbs) and peptides and have applications in the areas of PET imaging and targeted radiotherapy of cancer. Copper-64-TETA-D-Phe1-octreotide ([64Cu]TETA-OC) has been shown to bind to the somatostatin receptor, both in vitro and in vivo, and this agent inhibited the growth of somatostatin-receptor pos. tumors in rats. Copper-64-TETA-OC, however, showed a retention of activity in the blood, liver, and bone marrow, suggesting possible dissocn. of 64Cu from TETA-OC in vivo. The purpose of this study was to det. if 64Cu dissocs. from [64Cu]TETA-OC and binds to the protein, superoxide dismutase (SOD) in rat liver. The liver metab. of [64Cu]TETA-OC was examd. in normal rats using a gel-electrophoresis assay specific for SOD and size-exclusion chromatog. The major metabolite in rat liver at 20 h postinjection had a mol. wt. of 32 kDa as shown by size-exclusion chromatog. A gel electrophoresis assay specific for the detection of SOD [nitro-blue tetrazolium (NBT)] showed that a 64Cu-labeled protein isolated from rat liver homogenates comigrated with SOD. Evaluating the metabolic fate of copper radiopharmaceuticals demonstrated that Cu(II) dissocs. from macrocyclic chelators such as TETA and binds to proteins in high concns., namely SOD in rat liver.
- 21Dearling, J. L.; Voss, S. D.; Dunning, P.; Snay, E.; Fahey, F.; Smith, S. V.; Huston, J. S.; Meares, C. F.; Treves, S. T.; Packard, A. B. Imaging Cancer Using PET – the Effect of the Bifunctional Chelator on the Biodistribution of a 64Cu-Labeled Antibody. Nucl. Med. Biol. 2011, 38 (1), 29– 38, DOI: 10.1016/j.nucmedbio.2010.07.00321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkt1SlsA%253D%253D&md5=bbd504a87adbd65e8425527d33fbee27Imaging cancer using PET - the effect of the bifunctional chelator on the biodistribution of a 64Cu-labeled antibodyDearling, Jason L. J.; Voss, Stephan D.; Dunning, Patricia; Snay, Erin; Fahey, Frederic; Smith, Suzanne V.; Huston, James S.; Meares, Claude F.; Treves, S. Ted; Packard, Alan B.Nuclear Medicine and Biology (2011), 38 (1), 29-38CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodn. stability of the 64Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with 64Cu using these chelators in tumor-bearing mice. The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH2-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH2-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N,N',N",N"'-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with 64Cu and injected into mice bearing s.c. human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomog. images acquired at 1, 24 and 48 h post-injection, and at 48 h post-injection a full ex vivo biodistribution study was carried out. The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [64Cu]ch14.18-p-NH2-Bn-NOTA was 4.74 ± 0.77% of the injected dose per g of tissue (%ID/g), and for [64Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. The results of this study indicate that differences in the thermodn. stability of these chelator-Cu(II) complexes were not assocd. with significant differences in uptake of the tracer by the tumor. However, there were significant differences in tracer concn. in other tissues, including those involved in clearance of the radioimmunoconjugate (e.g., liver and spleen).
- 22Bhattacharyya, S.; Dixit, M. Metallic Radionuclides in the Development of Diagnostic and Therapeutic Radiopharmaceuticals. Dalt. Trans. 2011, 40 (23), 6112– 6128, DOI: 10.1039/c1dt10379bThere is no corresponding record for this reference.
- 23Schmidtke, A.; Läppchen, T.; Weinmann, C.; Bier-Schorr, L.; Keller, M.; Kiefer, Y.; Holland, J. P.; Bartholomä, M. D. Gallium Complexation, Stability, and Bioconjugation of 1,4,7- Triazacyclononane Derived Chelators with Azaheterocyclic Arms. Inorg. Chem. 2017, 56 (15), 9097– 9110, DOI: 10.1021/acs.inorgchem.7b0112923https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Wks7%252FO&md5=e90e3f77013616603ec19593dc36b079Gallium Complexation, Stability, and Bioconjugation of 1,4,7-Triazacyclononane Derived Chelators with Azaheterocyclic ArmsSchmidtke, Alexander; Laeppchen, Tilman; Weinmann, Christian; Bier-Schorr, Lorenz; Keller, Manfred; Kiefer, Yvonne; Holland, Jason P.; Bartholomae, Mark D.Inorganic Chemistry (2017), 56 (15), 9097-9110CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)We have recently introduced a 1,4,7-triazacyclononane (TACN) based chelating system with addnl. five-membered azaheterocyclic substituents for complexation of radioactive Cu2+ ions. In this work, we investigated the complexation properties of these novel chelators with Ga3+. In labeling expts., we could show that the penta- and hexadentate imidazole derivs. NODIA-Me 4 and NOTI-Me 1 can be labeled with 68Ga in specific activities up to ∼30 MBq nmol-1, while the corresponding thiazole deriv. NOTThia 2 did not label satisfactorily under identical conditions. NMR studies on the Ga complexes of 1 and the model compd. NODIA-Me-NH-Me 5 revealed formation of rigid 1:1 chelates with a slow macrocyclic interconversion and inert Ga-N bonds to the methylimidazole residues on the NMR time scale. The TACN-derived bifunctional chelator NODIA-Me was furthermore conjugated to a prostate-specific membrane antigen (PSMA) targeting moiety to give the corresponding bioconjugate NODIA-Me-PSMA 7. Serum stability and ligand challenge expts. of 68Ga-7 confirmed formation of a stable complex for up to 4 h. The remaining coordination site of five-coordinate Ga complexes was found to be occupied by monodentate ligands including hydroxide and chloride anions depending on the conditions. According to d. functional theory calcns., coordination of monodentate ligands as well as of the amide group for the bioconjugated ligand are energetically plausible. Finally, the labeled bioconjugate 68Ga-7 exhibited rapid renal clearance in biodistribution studies performed by small animal PET imaging with no indication of transchelation/demetalation in vivo. Altogether, our results provide strong evidence for a stable Ga complexation of our novel TACN-based chelators bearing imidazole arms. Despite the formation of two complexes incorporating different monodentate ligands in vitro, the imidazole type ligands show promise as chelating agents for the future development of gallium based radiopharmaceuticals.
- 24Ramogida, C. F.; Boros, E.; Patrick, B. O.; Zeisler, S. K.; Kumlin, J.; Adam, M. J.; Schaffer, P.; Orvig, C. Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N’-Propyl-2-NI Ligands for 64Cu(II) Radiopharmaceuticals. Dalt. Trans. 2016, 45 (33), 13082– 13090, DOI: 10.1039/C6DT00932HThere is no corresponding record for this reference.
- 25Le Fur, M.; Beyler, M.; Le Poul, N.; Lima, L. M. P.; Le Mest, Y.; Delgado, R.; Platas-Iglesias, C.; Patinec, V.; Tripier, R. Improving the Stability and Inertness of Cu(II) and Cu(I) Complexes with Methylthiazolyl Ligands by Tuning the Macrocyclic Structure. Dalt. Trans. 2016, 45 (17), 7406– 7420, DOI: 10.1039/C6DT00385KThere is no corresponding record for this reference.
- 26Rylova, S. N.; Stoykow, C.; Del Pozzo, L.; Abiraj, K.; Tamma, M. L.; Kiefer, Y.; Fani, M.; Mäcke, H. R. The Somatostatin Receptor 2 Antagonist 64Cu-NODAGA-JR11 Outperforms 64Cu-DOTA-TATE in a Mouse Xenograft Model. PLoS One 2018, 13 (4), e0195802, DOI: 10.1371/journal.pone.019580226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsl2gt77I&md5=fa3f63053b0633906e1af6bf6aef4964The somatostatin receptor 2 antagonist 64Cu- NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft modelRylova, Svetlana N.; Stoykow, Christian; Pozzo, Luigi Del; Abiraj, Keelara; Tamma, Maria Luisa; Kiefer, Yvonne; Fani, Melpomeni; Maecke, Helmut R.PLoS One (2018), 13 (4), e0195802/1-e0195802/16CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of 64Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7- acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH2), a somatostatin receptor 2 antagonist, with the clin. used sst2 agonist 64Cu-DOTA-TATE (TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated Kd values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist 64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist 64/natCu-DOTA-TATE. The tumor washout was slow or non-existent in the first 4 h, whereas kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Blood clearance was distinctly slower and persistent higher blood values were found at 24 h. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of 64Cu-NODAGAJR11 at 1 h, but release from tumor was very fast, particularly between 4 and 24 h. Tumor-to-normal organ ratios were distinctly lower after 1 h. This is indicative of insufficient in vivo stability. PET studies of 64Cu-NODAGA-JR11 reflected biodistribution data with nicely delineated tumor and low background. 64Cu-NODAGA-JR11 shows promising pharmacokinetic properties for further translation into the clinic.
- 27Smith, S. V. Molecular Imaging with Copper-64. J. Inorg. Biochem. 2004, 98 (11), 1874– 1901, DOI: 10.1016/j.jinorgbio.2004.06.00927https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptlOktL0%253D&md5=b0972b1167a9b710b5c409d772941d95Molecular imaging with copper-64Smith, Suzanne V.Journal of Inorganic Biochemistry (2004), 98 (11), 1874-1901CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)A review. Mol. imaging is expected to change the face of drug discovery and development. The ability to link imaging to biol. for guiding therapy should improve the rate at which novel imaging technologies, probes, contrast agents, drugs and drug delivery systems can be transferred into clin. practice. Nuclear medicine imaging, in particular, positron emission tomog. (PET) allows the detection and monitoring of a variety of biol. and pathophysiol. processes, at tracer quantities of the radiolabeled target agents, and at doses free from pharmacol. effects. In the field of drug discovery and development, the use of radiotracers for radiolabelling target agents has now become one of the essential tools in identifying, screening and development of new target agents. In this regard, 64Cu (t1/2 = 12.7 h) has been identified as an emerging PET isotope. Its half-life is sufficiently long for radiolabelling a range of target agents and its ease of prodn. and adaptable chem. make it an excellent radioisotope for use in mol. imaging. This review describes recent advances, in the routes of 64Cu prodn., design and application of bi-functional ligands for use in radiolabelling with 64/67Cu2+, and their significance and anticipated impact on the field of mol. imaging and drug development.
- 28Jones-Wilson, T. M.; Deal, K. A.; Anderson, C. J.; McCarthy, D. W.; Kovacs, Z.; Motekaitis, R. J.; Sherry, A. D.; Martell, A. E.; Welch, M. J. The In Vivo Behavior of Copper-64-Labeled Azamacrocyclic Complexes. Nucl. Med. Biol. 1998, 25 (6), 523– 530, DOI: 10.1016/S0969-8051(98)00017-128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlt1Wktrk%253D&md5=aa5cbc7f7ab5fb08f6659903f14f2fa3The in vivo behavior of copper-64-labeled azamacrocyclic complexesJones-Wilson, Teresa M.; Deal, Kim A.; Anderson, Carolyn J.; McCarthy, Deborah W.; Kovacs, Zoltan; Motekaitis, Ramunas J.; Sherry, A. Dean; Martell, Arthur E.; Welch, Michael J.Nuclear Medicine and Biology (1998), 25 (6), 523-530CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomols. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomol. conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biol. behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepd., and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivs., and cyclam, TETA, and et-cyclam were tetradecane backbone derivs. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compds. showed uptake and clearance through the liver and kidneys; however, the pos. charged 64Cu complexes showed significantly higher uptake in both of these organs than did the neg. charged or neutral complexes. 64Cu-TETA, a neg. charged complex with the tetradecane backbone, had the most efficient clearance by 24 h' postinjection. These data suggest that neg. charged complexes may have more favorable clearance properties when used as BFCs.
- 29Boswell, C. A.; Sun, X.; Niu, W.; Weisman, G. R.; Wong, E. H.; Rheingold, A. L.; Anderson, C. J. Comparative In Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes. J. Med. Chem. 2004, 47 (6), 1465– 1474, DOI: 10.1021/jm030383m29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFagtLw%253D&md5=542e8b853716a629b641740f102a48dbComparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic ComplexesBoswell, C. Andrew; Sun, Xiankai; Niu, Weijun; Weisman, Gary R.; Wong, Edward H.; Rheingold, Arnold L.; Anderson, Carolyn J.Journal of Medicinal Chemistry (2004), 47 (6), 1465-1474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biol. mols. The chelators most commonly utilized for labeling copper radionuclides to biomols. are analogs of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "cross-bridged" cyclam (CB-cyclam) derivs., form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogs in vivo. Herein we report results on the relative biol. stabilities and identification of the resulting radiolabeled metabolites of a series of 64Cu-labeled macrocyclic complexes. Metab. studies in normal rat liver have revealed that the 64Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (64Cu-CB-TE2A) resulted in significantly lower values of protein-assocd. 64Cu than 64Cu-TETA [13 ± 6% vs 75 ± 9% at 4 h]. A similar trend was obsd. for the corresponding cyclen derivs., with the 64Cu complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (64Cu-CB-DO2A) undergoing less transchelation than the 64Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (64Cu-DOTA) [61 ± 14% vs 90.3 ± 0.5% protein assocd. 64Cu at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged 64Cu complexes and that 64Cu-CB-TE2A is superior to 64Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator deriv. of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biol. mols. for diagnostic imaging and targeted radiotherapy.
- 30Wong, E. H.; Weisman, G. R.; Hill, D. C.; Reed, D. P.; Rogers, E. M.; Condon, J. P.; Fagan, M. A.; Calabrese, J. C.; Lam, K. C.; Guzei, I. A.; Rheingold, L. Synthesis and Characterization of Cross-Bridged Cyclams and Pendant-Armed Derivatives and Structural Studies of Their Copper(II) Complexes. J. Am. Chem. Soc. 2000, 122 (43), 10561– 10572, DOI: 10.1021/ja001295j30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXntlektb8%253D&md5=775e07e05132769aa54f7d81ba6c83d5Synthesis and Characterization of Cross-Bridged Cyclams and Pendant-Armed Derivatives and Structural Studies of Their Copper(II) ComplexesWong, Edward H.; Weisman, Gary R.; Hill, Daniel C.; Reed, David P.; Rogers, Mark E.; Condon, Jeffrey S.; Fagan, Maureen A.; Calabrese, Joseph C.; Lam, Kin-Chung; Guzei, Ilia A.; Rheingold, Arnold L.Journal of the American Chemical Society (2000), 122 (43), 10561-10572CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane ligands, including the parent compd., N,N'-dialkyl variants, and the 1st N,N'-di-pendant-arm derivs. were synthesized by a short, efficient, and conceptually novel approach. Their Cu(II) complexes were prepd., and four of these were structurally characterized by x-ray diffraction. In all four complexes, the cross-bridged tetraamine ligand is cis-folded, coordinating the metal cation within its mol. cleft using all four N lone pairs. Geometries intermediate between idealized square pyramidal and trigonal bipyramidal coordination were found for three of the complexes, whereas a distorted octahedral Cu coordination was found for the complex of a di-pendant-arm cross-bridged cyclam.
- 31Ferdani, R.; Stigers, D. J.; Fiamengo, A. L.; Wei, L.; Li, B. T. Y.; Golen, J. A.; Rheingold, A. L.; Weisman, G. R.; Wong, E. H.; Anderson, C. J. Synthesis, Cu(II) Complexation, 64Cu-Labeling and Biological Evaluation of Cross-Bridged Cyclam Chelators with Phosphonate Pendant Arms. Dalt. Trans. 2012, 41 (7), 1938– 1950, DOI: 10.1039/C1DT11743BThere is no corresponding record for this reference.
- 32Stigers, D. J.; Ferdani, R.; Weisman, G. R.; Wong, E. H.; Anderson, C. J.; Golen, J. A.; Moore, C.; Rheingold, A. L. A New Phosphonate Pendant-Armed Cross-Bridged Tetraamine Chelator Accelerates Copper(II) Binding for Radiopharmaceutical Applications. Dalt. Trans. 2010, 39 (7), 1699– 1701, DOI: 10.1039/B920871BThere is no corresponding record for this reference.
- 33Boros, E.; Packard, A. B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev. 2019, 119 (2), 870– 901, DOI: 10.1021/acs.chemrev.8b0028133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVKrsbnO&md5=729691dfe872671d502e0354b002a663Radioactive Transition Metals for Imaging and TherapyBoros, 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.
- 34Rodríguez-Rodríguez, A.; Halime, Z.; Lima, L. M. P.; Beyler, M.; Deniaud, D.; Le Poul, N.; Delgado, R.; Platas-Iglesias, C.; Patinec, V.; Tripier, R. Cyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) Coordination. Inorg. Chem. 2016, 55 (2), 619– 632, DOI: 10.1021/acs.inorgchem.5b0177934https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlsVOnsQ%253D%253D&md5=57fe7bd81d2344a7eddfb744f32010aeCyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) CoordinationRodriguez-Rodriguez, Aurora; Halime, Zakaria; Lima, Luis M. P.; Beyler, Maryline; Deniaud, David; Le Poul, Nicolas; Delgado, Rita; Platas-Iglesias, Carlos; Patinec, Veronique; Tripier, RaphaelInorganic Chemistry (2016), 55 (2), 619-632CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Aiming to develop new copper chelates for application in nuclear medicine the authors report two new chelators, te1th and te2th, based on a cyclam backbone mono-N- or di-N1,N8-functionalized by methylthiazolyl arms. The acid-base properties of both ligands were studied as well as their coordination chem., esp. with Cu2+, when possible in aq. soln. and in the solid state. Single-crystal x-ray diffraction structures of complexes were detd. Stability consts. of the copper(II) and zinc(II) complexes showed that the complexes of both ligands with Cu2+ are thermodynamically very stable, and they exhibit an important selectivity for Cu2+ over Zn2+. The kinetic inertness in acidic medium of both copper(II) complexes was evaluated revealing a quite good resistance to dissocn. (the half-life times of complexes with te1th and te2th are 50.8 and 5.8 min, resp., in 5 M HCl and 30°). The coordination geometry of the metal center in the complexes was established in aq. soln. based on UV-visible, EPR spectroscopy, DFT studies, and NMR by using the zinc(II) complex analogs. The [Cu(te1th)]2+ and [Cu(te2th)]2+ complexes adopt trans-I and trans-III configurations both in the solid state and in soln., while the [Zn(te2th)]2+ complex crystallizes as the cis-V isomer but exists in soln. as a mixt. of trans-III and cis-V forms. Cyclic voltammetry expts. in acetonitrile point to a relatively easy redn. of [Cu(te2th)]2+ in acetonitrile soln. (Epc = -0.41 V vs. normal H electrode), but the reduced complex does not undergo dissocn. in the time scale of the authors' electrochem. expts. The results obtained in these studies revealed that despite the limited soly. of its copper(II) chelate, te2th is an attractive chelator for Cu2+ that provides a fast complexation process while forming a complex with a rather high thermodn. stability and kinetic inertness with respect to dissocn. even upon electrochem. redn.
- 35Bodio, E.; Boujtita, M.; Julienne, K.; Le Saec, P.; Gouin, S. G.; Hamon, J.; Renault, E.; Deniaud, D. Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical Applications. ChemPlusChem 2014, 79 (9), 1284– 1293, DOI: 10.1002/cplu.20140203135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFWjsrzF&md5=c7a390f621478ec35eb0da8020f8a505Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical ApplicationsBodio, Ewen; Boujtita, Mohammed; Julienne, Karine; Le Saec, Patricia; Gouin, Sebastien G.; Hamon, Jonathan; Renault, Eric; Deniaud, DavidChemPlusChem (2014), 79 (9), 1284-1293CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)A highly stable Cu(I) complex was obtained starting from a Cu(II) salt. This compd. was characterized by a combination of several anal. techniques (UV/visible spectroscopy, energy-dispersive x-ray spectroscopy, electrochem., and XPS) and was shown to present an N4Cu structure. These results were confirmed by a d. functional calcns. study of the binding energy and the electronic structure of model ligand and Cu complexes. Preliminary tests of complexation showed a high ability of the corresponding ligand to chelate 64Cu in very dild. medium, which is of interest for developing new positron emission tomog. imaging agents. The stability and the kinetic inertness of the complex are promising. In particular, it displayed good redox stability, which is important because in vivo redn. or oxidn. of the Cu of Cu complexes can lead to demetalation. The rapid microwave-assisted strategy used to synthesize the ligand was applied to the synthesis of more than ten ligands. One of these was functionalized by an amino group to form a bifunctional chelate for a future bioconjugation for applications in nuclear medicine.
- 36Shuvaev, S.; Suturina, E. A.; Rotile, N. J.; Astashkin, C. A.; Ziegler, C. J.; Ross, A. W.; Walker, T. L.; Caravan, P.; Taschner, I. S. Revisiting Dithiadiaza Macrocyclic Chelators for Copper-64 PET Imaging. Dalt. Trans. 2020, 49 (40), 14088– 14098, DOI: 10.1039/D0DT02787AThere is no corresponding record for this reference.
- 37Tosato, M.; Verona, M.; Doro, R.; Dalla Tiezza, M.; Orian, L.; Andrighetto, A.; Pastore, P.; Marzaro, G.; Di Marco, V. Toward Novel Sulphur-Containing Derivatives of Tetraazacyclododecane: Synthesis, Acid–Base Properties, Spectroscopic Characterization, DFT Calculations, and Cadmium(II) Complex Formation in Aqueous Solution. New J. Chem. 2020, 44 (20), 8337– 8350, DOI: 10.1039/D0NJ00310G37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsVWku7k%253D&md5=10503e6a59ba00101387227d97c2a542Toward novel sulphur-containing derivatives of tetraazacyclododecane: synthesis, acid-base properties, spectroscopic characterization, DFT calculations, and cadmium(II) complex formation in aqueous solutionTosato, Marianna; Verona, Marco; Doro, Riccardo; Dalla Tiezza, Marco; Orian, Laura; Andrighetto, Alberto; Pastore, Paolo; Marzaro, Giovanni; Di Marco, ValerioNew Journal of Chemistry (2020), 44 (20), 8337-8350CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)Macrocyclic ligands obtained by N-functionalization of 1,4,7,10-tetraazacyclododecane (cyclen) have been widely studied due to their remarkable complexing properties toward a variety of transition metals and lanthanides. Despite a plethora of cyclen-based mols. described in the literature, ones bearing sulfur-contg. functional groups have been almost ignored. Herein, a novel series of derivs. with hanging sulfide side-arms have been investigated: 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7,tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7,tris[2-(methylsulfanyl)ethyl]-10-methylacetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7,bis[2-(methylsulfanyl)ethyl]-4,10-diacetic-1,4,7,10-tetraazacyclododecane (DO2A2S). 1,4,7,10-Tetra-n-butyl-1,4,7,10-tetraazacyclododecane (DOT-n-Bu) was included as well in this study for comparison purposes. These compds. have been synthesized and then exptl. and theor. characterized. Their protonation consts. (pKa) have been detd. at 25°C in 0.15 M aq. NaNO3 and in 0.15 M aq. tetramethylammonium chloride by potentiometric titrns. and partly by UV-vis spectrophotometric measurements. D. functional theory (DFT) calcns. have been performed for cyclen, DO4S, and DO3S to investigate the conformations, the thermodn. of protonation equil. and to rationalize the relevant electronic transitions. Stability consts. of the Na+ complexes (log βNa) were computed for DO4S, DO3S, DO3SAm, and DO2A2S. For all compds., the monodimensional 1H-NMR and bidimensional (COSY, NOESY, and HMQC) spectra have been obtained in D2O as a function of pD. Results indicate that sulfur-contg. pendant arms induce partly unpredictable pKa, NMR, UV-Vis, and log βNa properties on the mols., and that these properties significantly differ from those of the corresponding compds. without sulfur (e.g. cyclen and DOT-n-Bu). Furthermore, potentiometric and 1H NMR titrns. were performed in order to evaluate the complexation ability of DO4S, DO3S and DO2A2S toward Cd2+ as a case-example of soft metal ions. The obtained complexes show remarkable stability and are stronger than those formed with cyclen and its most common deriv. DOTA esp. at acidic pH, thus demonstrating that these compds. can be promising chelators of soft metal ions.
- 38Tosato, M.; Asti, M.; Dalla Tiezza, M.; Orian, L.; Häussinger, D.; Vogel, R.; Köster, U.; Jensen, M.; Andrighetto, A.; Pastore, P.; Di Marco, V. Highly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled Radiopharmaceuticals. Inorg. Chem. 2020, 59 (15), 10907– 10919, DOI: 10.1021/acs.inorgchem.0c0140538https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGksb3L&md5=0525c4e90bfa458285a90783d187f09fHighly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled RadiopharmaceuticalsTosato, Marianna; Asti, Mattia; Dalla Tiezza, Marco; Orian, Laura; Haussinger, Daniel; Vogel, Raphael; Koster, Ulli; Jensen, Mikael; Andrighetto, Alberto; Pastore, Paolo; Marco, Valerio DiInorganic Chemistry (2020), 59 (15), 10907-10919CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)With a half-life of 7.45 days, silver-111 (βmax 1.04 MeV, Eγ 245.4 keV [Iγ 1.24%], Eγ 342.1 keV [Iγ 6.7%]) is a promising candidate for targeted cancer therapy with β- emitters as well as for assocd. SPECT imaging. For its clin. use, the development of suitable ligands that form sufficiently stable Ag+-complexes in vivo is required. In this work, the following sulfur-contg. derivs. of tetraazacyclododecane (cyclen) have been considered as potential chelators for silver-111: 1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S), (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S4Me), 1,4,7-tris(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris(2-(methylsulfanyl)ethyl)-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis(2-(methylsulfanyl)ethyl)-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). Natural Ag+ was used in pH/Ag-potentiometric and UV-vis spectrophotometric studies to det. the metal speciation existing in aq. NaNO3 0.15 M at 25°C and the equil. consts. of the complexes, whereas NMR and DFT calcns. gave structural insights. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiol. pH. Furthermore, radiolabeling, stability in saline phosphate buffer, and metal-competition expts. using the two ligands forming the strongest complexes, DO4S and DO4S4Me, were carried out with [111Ag]Ag+ and promising results were obtained. Five cyclen derivs. bearing sulfide pendant arms were considered, and their Ag+ complex formation was studied in aq. soln. by potentiometry, UV-vis, NMR, radiolabeling expts. with 111Ag, and DFT calcns. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiol. pH. These ligands might be of interest for the setup of 111Ag labeled radiopharmaceuticals.
- 39Gyr, T.; Mäcke, H. R.; Hennig, M. A Highly Stable Silver(I) Complex of a Macrocycle Derived from Tetraazatetrathiacyclen. Angew. Chem., Int. Ed. Engl. 1997, 36 (24), 2786– 2788, DOI: 10.1002/anie.199727861There is no corresponding record for this reference.
- 40Li, L.; Rousseau, J.; de Guadalupe Jaraquemada-Peláez, M.; Wang, X.; Robertson, A.; Radchenko, V.; Schaffer, P.; Lin, K.-S.; Bénard, F.; Orvig, C. 225Ac-H4py4pa for Targeted Alpha Therapy. Bioconjugate Chem. 2020. DOI: 10.1021/acs.bioconjchem.0c00171There is no corresponding record for this reference.
- 41Lacerda, S.; Campello, M. P.; Santos, I. C.; Santos, I.; Delgado, R. Study of the Cyclen Derivative 2-[1,4,7,10-Tetraazacyclododecan-1-Yl]-Ethanethiol and Its Complexation Behaviour towards d-Transition Metal Ions. Polyhedron 2007, 26 (14), 3763– 3773, DOI: 10.1016/j.poly.2007.04.03741https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpt1Cltbk%253D&md5=3c13fa0b8a4e4ddfecd90249326449e9Study of the cyclen derivative 2-[1,4,7,10-tetraazacyclododecan-1-yl]-ethanethiol and its complexation behavior towards d-transition metal ionsLacerda, Sara; Campello, Maria Paula; Santos, Isabel C.; Santos, Isabel; Delgado, RitaPolyhedron (2007), 26 (14), 3763-3773CODEN: PLYHDE; ISSN:0277-5387. (Elsevier B.V.)The compd. 2-[1,4,7,10-tetraazacyclododecan-1-yl]-ethanethiol (L2) has been synthesized and characterized by multinuclear NMR spectroscopy and mass spectrometry. Its thiol-protected precursor L1 has also been isolated and characterized, including by X-ray structural anal. The protonation consts. of L2 were detd. by potentiometric methods at 25.0 °C and 0.10 mol dm-3 KNO3 ionic strength. 3C NMR studies and 2D NMR spectra recorded at different pD values have been used to analyze its protonation scheme. Stability consts. of L2 with Cu2+, Zn2+ and Cd2+ were also detd. by potentiometry, and the Zn(II) and Cu(II) complexes were studied in soln. by NMR, UV-Vis, and EPR spectroscopies. The pM values (pH 7.4) calcd. for the metal complexes of L2 are higher than the corresponding values found for cyclen and cyclam, but the selectivity of L2 for Cu2+ is low.
- 42Ševčik, R.; Vanek, J.; Lubal, P.; Kotková, Z.; Kotek, J.; Hermann, P. Formation and Dissociation Kinetics of Copper(II) Complexes with Tetraphosphorus Acid DOTA Analogs. Polyhedron 2014, 67, 449– 455, DOI: 10.1016/j.poly.2013.09.02442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFWrtr%252FK&md5=75d8d129e68b0fc7679e44192061d69eFormation and dissociation kinetics of copper(II) complexes with tetraphosphorus acid DOTA analogsSevcik, Radek; Vanek, Jakub; Lubal, Premysl; Kotkova, Zuzana; Kotek, Jan; Hermann, PetrPolyhedron (2014), 67 (), 449-455CODEN: PLYHDE; ISSN:0277-5387. (Elsevier Ltd.)Thermodn. and kinetic properties of Cu(II) complexes with macrocyclic cyclen-based ligands having four phosphonic acid monoester (H4dotpOEt = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphonic acid monoethylester)) or four phosphinic acid (H4dotpH = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphinic acid) and H4dotpPh = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methyl(phenyl)phosphinic acid]) pendant arms were investigated. The formation kinetics carried out in pH range 1-5.5 (t = 25°C, I = 0.1 M KCl) shows that reactive species are (H2L)2- and (HL)3- anions and their reactivity differs by 4-5 orders of magnitude. Among studied ligands, H4dotpH is the most reactive one. Dissocn. of these copper(II) complexes was investigated in the presence of perchloric acid (I = 5 M (Na,H)ClO4, proton concn. range 0.1-5.0 M) and in temp. range 10-35°C. All studied complexes are less kinetically inert than the [Cu(dota)]2- complex and the Cu(II) complex of H4dotpH is the least kinetically inert among the studied complexes, probably due to the lowest thermodn. stability. These results show that the ligands probably cannot be employed for copper radioisotopes complexation but the data will be utilized in design of other macrocyclic ligands intended to be used in medicinal chem.
- 43Kasprzyk, S. P.; Wilkins, R. G. Kinetics of Interaction of Metal Ions with Two Tetraazatetraacetate Macrocycles. Inorg. Chem. 1982, 21 (9), 3349– 3352, DOI: 10.1021/ic00139a01843https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XltFKjtbo%253D&md5=790b2cdb7d84b8e42bdc0f4696e57e97Kinetics of interaction of metal ions with two tetraazatetraacetate macrocyclesKasprzyk, Stanislaw P.; Wilkins, Ralph G.Inorganic Chemistry (1982), 21 (9), 3349-52CODEN: INOCAJ; ISSN:0020-1669.The kinetics of formation of metal complexes of the macrocyclic ligands 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetate (TETA) were measured by stopped-flow spectrophotometry. Observations were made at 25° and I = 0.25 M over a wide range of pH, and the reactive species was characterized as the monoprotonated form of the ligand. Metal ions examd. were Mg2+, Ca2+, Sr2+, Ba2+, Zn2+, Ni2+, and Cu2+. With a no. of systems, plots of the pseudo-1st-order rate const. kobsd vs. [M2+] in excess were hyperbolic conforming to the expression kobsd = (A[M2+])(1 + K[M2+])-1. K Is considered a const. for formation of a preassocn. complex. This may then proceed to a final complex (1st-order rate const. AK-1) or be a "dead-end" complex, with reactants reacting by a 2nd-order process, rate const. A. With the remaining systems, kobsd vs. [M2+] was linear as required for a 2nd-order reaction.
- 44Anderegg, 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. Pure Appl. Chem. 2005, 77 (8), 1445– 1495, DOI: 10.1351/pac20057708144544https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXps1GrsLk%253D&md5=e3a5ede39f3959f9661890ee30ac6579Critical evaluation of stability constants of metal complexes of complexones for biomedical and environmental applicationsAnderegg, Giorgio; Arnaud-Neu, Francoise; Delgado, Rita; Felcman, Judith; Popov, KonstantinPure 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".
- 45Tosato, M.; Di Marco, V. Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs. Biomolecules 2019, 9 (7), 269, DOI: 10.3390/biom907026945https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1antbnM&md5=a5f65d72fd7f0b3eb8ec5df88ad4a038Metal chelation therapy and Parkinson's disease: a critical review on the thermodynamics of complex formation between relevant metal ions and promising or established drugsTosato, Marianna; Di Marco, ValerioBiomolecules (2019), 9 (7), 269CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)A review. The present review reports a list of approx. 800 compds. which have been used, tested or proposed for Parkinson's disease (PD) therapy in the year range 2014-2019 (Apr.): name(s), chem. structure and refs. are given. Among these compds., approx. 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compds. has been collected or, if not exptl. available, has been estd. from similar mols. Stoichiometries and stability consts. of the complexes have been reported; values of the cologarithm of the concn. of free metal ion at equil. (pM), and of the dissocn. const. Kd (both computed at pH = 7.4 and at total metal and ligand concns. of 10-6 and 10-5 mol/L, resp.), charge and stoichiometry of the most abundant metal-ligand complexes existing at physiol. conditions, have been obtained. A rigorous definition of the reported amts. is given, the possible usefulness of this data is described, and the need to characterize the metal-ligand speciation of PD drugs is underlined.
- 46Price, T. W.; Greenman, J.; Stasiuk, G. J. Current Advances in Ligand Design for Inorganic Positron Emission Tomography Tracers Ga-68, Cu-64, Zr-89 and Sc-44. Dalt. Trans. 2016, 45 (40), 15702– 15724, DOI: 10.1039/C5DT04706DThere is no corresponding record for this reference.
- 47Amundsen, A. R.; Whelan, J.; Bosnich, B. Biological Analogues. On the Nature of the Binding Sites of Copper-Containing Proteins. J. Am. Chem. Soc. 1977, 99 (20), 6730– 6739, DOI: 10.1021/ja00462a04247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXlsl2gsb8%253D&md5=809c857b403916da33563afec5e1803fBiological analogs. Nature of the binding sites of copper-containing proteinsAmundsen, Alan R.; Whelan, John; Bosnich, B.Journal of the American Chemical Society (1977), 99 (20), 6730-9CODEN: JACSAT; ISSN:0002-7863.An extended series of ligands and their Cu(II) complexes were prepd. as spectroscopic models for detg. the geometries and ligand coordinations of Cu proteins. The electronic properties of thioether, imidazole, amide anion, amine, phenolate anion, and thiolate anion coordination of Cu(II) were detd. In addn., the electronic spectra of some of these ligands in square-planar, square-pyramidal, and tetrahedral geometries about Cu(II) were obtained by appropriate ligand design. On the basis of these results and an anal. of the protein spectra, structures for the Cu coordination and geometry in (blue) type I Cu, Cu in galactose oxidase, type III Cu, and Cu in oxyhemocyanin are proposed.
- 48Hancock, R.; Wade, P.; Ngwenya, M.; De Sousa, A. S.; Damu, K. V. Ligand Design for Complexation in Aqueous Solution. Chelate Ring Size as a Basis for Control of Size-Based Selectivity for Metal Ions. Inorg. Chem. 1990, 29 (10), 1968– 1974, DOI: 10.1021/ic00335a03948https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXit1Cgurc%253D&md5=b2730a78d0a3a83c15ebb0f75e944031Ligand design for complexation in aqueous solution. 2. Chelate ring size as a basis for control of size-based selectivity for metal ionsHancock, Robert D.; Wade, Peter W.; Ngwenya, M. Patrick; De Sousa, Alvaro S.; Damu, Kirty V.Inorganic Chemistry (1990), 29 (10), 1968-74CODEN: INOCAJ; ISSN:0020-1669.The role of chelate ring size in complex stability, and selectivity based on metal ion size, is examd. Formation consts. of pairs of ligands which differ in that one member of the pair forms a 5-membered chelate ring where the other forms a 6-membered chelate ring are reported with metal ions ranging in ionic radius from small (Be, Cu(II), Al) to medium sized (Zn, In(III)) and large (La(III), Pb(II)). Pairs of ligands studied whose formation consts. are combined with literature values already available) are 9-aneN2O (1-oxa-4,7-diazacyclononane) and 10-aneN2O (1-oxa-4,8-diazacyclodecane) 15-aneN4O (1-oxa-4,7,10,13-tetraazacyclopentadecane) and 16-aneN4O (1-oxa-4,7,11,14-tetraazacyclohexadecane), TIRON (4,5-dihydroxy-1,3-benzenedisulfonate) and CTA (chromotropic acid, 4,5-dihydroxynaphthalene-2,7-disulfonate), TM-cyclen (1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane) and TMC (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane). Except for the pair of rigid small macrocycles 9-aneN2O and 10-aneN2O, chelate ring size dominates macrocyclic ring size in controlling metal ion size-based selectivity so that complexes of larger metal ions are destabilized relative to those of smaller metal ions by an increase in chelate ring size from 5 to 6 membered. For the TIRON/CTA pair of ligands, rigidity introduced into the single chelate ring by arom. rings gave sharper size selectivity than for pairs of flexible ligands such as oxalate/malonate. With high levels of steric crowding, as in TM-cyclen and TMC, size selectivity still was controlled by chelate ring size. The strain energy (U) of 5- and 6-membered chelate rings of the ethylenediamine (EN) and 1,3-diaminopropane (TN) type was calcd. by mol. mechanics (MM) as a function of M-N bond length and N-M-N angle. The MM calcn. showed that min. U occurred for the EN chelate ring when the M-N bond length was 2.5 Å and the N-M-N angle was 70°, while for the TN chelate ring, U was a min. for M-N bond length 1.6 Å and N-M-N angle 109.5°. The MM studies on alkali metal ion complexes with crown ethers with different chelate ring sizes present showed that even with highly ionic M-L bonding, the effect of chelate ring size on metal ion selectivity should be present.
- 49Styka, M. C.; Smierciak, R. C.; Blinn, E. L.; DeSimone, R. E.; Passariello, J. V. Copper(II) Complexes Containing a 12-Membered Macrocyclic Ligand. Inorg. Chem. 1978, 17 (1), 82– 86, DOI: 10.1021/ic50179a01849https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXjslOksg%253D%253D&md5=71a8cd94119e4e1bb1bfc6e29b349d02Copper(II) complexes containing a 12-membered macrocyclic ligandStyka, M. C.; Smierciak, R. C.; Blinn, E. L.; DeSimone, R. E.; Passariello, J. V.Inorganic Chemistry (1978), 17 (1), 82-6CODEN: INOCAJ; ISSN:0020-1669.Cu(II) complexes of 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane (tbcyclen) were prepd. They include Cu(cyclen)X2 (X = Cl, Br, NO3, Cu(tbcyclen)X2.nH2O (X = NO3, Cl, Br, NCS), Cu(tbcyclen)ClClO4.0.5H2O, and Cu(tbcyclen)ClBr.H2O. Substitution reactions, conductivity, ESR, and spectral data suggest that the complexes are 5-coordinate and approx. square-pyramidal geometry. The Cu(tbcyclen)X2 complexes have an absorption band in the 700-800-mμ range which has an unusually high extinction coeff. for a Cu(II) complex bonded to only N and O donor atoms.
- 50Gray, J. L.; Gerlach, D. L.; Papish, E. T. Crystal Structure of (Perchlorato-KO)(1,4,7,10-Tetraazacyclododecane-K4 N)Copper(II) Perchlorate. Acta Crystallogr. E Crystallogr. Commun. 2017, 73 (1), 31– 34, DOI: 10.1107/S205698901601956350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkslGitw%253D%253D&md5=ab3e4ccfaaa8c0bb326b86c1fdfed2e2Crystal structure of (perchlorato-κO)(1,4,7,10-tetraazacyclododecane-κ4N)copper(II) perchlorateGray, Jessica L.; Gerlach, Deidra L.; Papish, Elizabeth T.Acta Crystallographica, Section E: Crystallographic Communications (2017), 73 (1), 31-34CODEN: ACSECI; ISSN:2056-9890. (International Union of Crystallography)The crystal structure of the title salt, [Cu(ClO4)(C8H20N4)]ClO4, is reported. The CuII ion exhibits a square-pyramidal geometry and is coordinated by the four N atoms of the neutral 1,4,7,10-tetraazacyclododecane (cyclen) ligand and an O atom from one perchlorate anion, with the second perchlorate ion hydrogen-bonded to one of the amine N atoms of the cyclen ligand. Addnl. N-H···O hydrogen bonds between the amine H atoms and the coordinating and non-coordinating perchlorate groups create a three-dimensional network structure. Crystals were grown from a concd. methanol soln. at ambient temp., resulting in no co-crystn. of solvent.
- 51Nikles, D. E.; Powers, M. J.; Urbach, F. L. Copper(II) Complexes with Tetradentate Bis(Pyridyl)-Dithioether and Bis(Pyridyl)-Diamine Ligands. Effect of Thioether Donors on the Electronic Absorption Spectra, Redox Behavior, and EPR Parameters of Copper(II) Complexes. Inorg. Chem. 1983, 22 (22), 3210– 3217, DOI: 10.1021/ic00164a00951https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXls1ygtLk%253D&md5=3091904fe81131ba39a3747586ae43f3Copper(II) complexes with tetradentate bis(pyridyl)-dithioether and bis(pyridyl)-diamine ligands. Effect of thio ether donors on the electronic absorption spectra, redox behavior, and EPR parameters of copper(II) complexesNikles, D. E.; Powers, M. J.; Urbach, F. L.Inorganic Chemistry (1983), 22 (22), 3210-17CODEN: INOCAJ; ISSN:0020-1669.Eight Cu(II) chelates contg. a tetradentate R(CH2)xS(CH2)yS(CH2)xR (R = pyridyl) or R(CH2)xN(R1)(CH2)yN(R1)(CH2)xR (x = 1, 2, y = 2, 3, R1 = H, Me) were studied to det. the effect of thioether donors on the spectral and redox properties of the Cu complexes. The systematic variation of the chelate ring sizes (5-5-5, 5-6-5, 6-5-6, and 6-6-6) allowed stereochem. trends in the obsd. properties to be ascertained as well as the effect of thioether substitution for the amine donors. The electronic absorption spectra of the CuII[R2S2] complexes differed from those of the CuII[R2N2] series by the presence of a S(σ)→Cu(II) ligand-metal charge transfer (MLCT) region and an enhanced intensity in the visible (d-d) bands which was attributed to an intensity-borrowing mechanism from the low-energy charge-transfer band. The Cu(I) complexes of both series of ligands exhibited an absorption band at 300-350 nm corresponding to a Cu(I)→py(π*) MLCT transition. The Cu(II)/Cu(I) redn. potentials for the chelates typically showed little solvent dependence in CH3CN and aq. solns. as measured by cyclic and differential pulse voltammetry. The potentials for the R2S2 series are 400-660 mV vs. NHE, substantially higher than those exhibited by the R2N2 series (-170 to +320 mV vs. NHE). The redn. potentials for both series increase with increasing chelate ring size, suggesting that the larger chelate rings can more readily accommodate a pseudotetrahedral Cu(I) form. The anisotropic ESR parameters for the CuII[R2N2] series were nearly axial while the CuII[R2S2] series exhibited rhombic spectra representing the redn. in the effective donor atom symmetry of the complexes.
- 52Geraldes, C. F. G. C.; Marques, M. P.; de Castro, B.; Pereira, E. Study of Copper(II) Polyazamacrocyclic Complexes by Electronic Absorption Spectrophotometry and EPR Spectroscopy. Eur. Eur. J. Inorg. Chem. 2000, 2000 (3), 559– 565, DOI: 10.1002/(SICI)1099-0682(200003)2000:3<559::AID-EJIC559>3.0.CO;2-JThere is no corresponding record for this reference.
- 53Lima, L. M.; Esteban-Gomez, D.; Delgado, R.; Platas-Iglesias, C.; Tripier, R. Monopicolinate Cyclen and Cyclam Derivatives for Stable Copper(II) Complexation. Inorg. Chem. 2012, 51 (12), 6916– 6927, DOI: 10.1021/ic300784v53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvVSntrc%253D&md5=a01fe5223c102e75cf2b4b7497083c87Monopicolinate Cyclen and Cyclam Derivatives for Stable Copper(II) ComplexationLima, Luis M. P.; Esteban-Gomez, David; Delgado, Rita; Platas-Iglesias, Carlos; Tripier, RaphaelInorganic Chemistry (2012), 51 (12), 6916-6927CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) deriv. bearing a picolinate pendant arm (HL1), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analog HL2, were achieved by using two different selective-protection methods involving the prepn. of cyclen-bisaminal or phosphoryl cyclam derivs. The acid-base properties of both compds. were studied as well as their coordination chem., esp. with Cu2+, in aq. soln. and in solid state. The copper(II) complexes were synthesized, and the single crystal x-ray diffraction structures of compds. of formula [Cu(HL)](ClO4)2·H2O (L = L1 or L2), [CuL1](ClO4) and [CuL2]Cl·2H2O, were detd. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability consts. of the complexes were detd. at 25.0° and ionic strength 0.10 M in KNO3 using potentiometric titrns. Both ligands form complexes with Cu2+ that are thermodynamically very stable. Addnl., both HL1 and HL2 exhibit an important selectivity for Cu2+ over Zn2+. The kinetic inertness in acidic medium of both complexes of Cu2+ was evaluated by spectrophotometry revealing that [CuL2]+ is much more inert than [CuL1]+. The detd. half-life values also demonstrate the very high kinetic inertness of [CuL2]+ when compared to a list of copper(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aq. soln. from UV-visible and EPR spectroscopy, showing that the soln. structures of both complexes are in excellent agreement with those of crystallog. data. Cyclic voltammetry expts. point to a good stability of the complexes with respect to metal ion dissocn. upon redn. of the metal ion to Cu+ at about neutral pH. The authors' results revealed that the cyclam-based ligand HL2 is a very attractive receptor for copper(II), presenting a fast complexation process, a high kinetic inertness, and important thermodn. and electrochem. stability.
- 54Clay, R.; Murray-Rust, P.; Murray-Rust, J. Nitrato(1,4,7,10-Tetraazacyclododecane) Copper(II) Nitrate. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1979, 35 (8), 1894– 1895, DOI: 10.1107/S0567740879008013There is no corresponding record for this reference.
- 55Riesen, A.; Zehnder, M.; Kaden, T. A. Metal Complexes of Macrocyclic Ligands. Part XXIII. Synthesis, Properties, and Structures of Mononuclear Complexes with 12- and 14-membered Tetraazamacrocycle-N,N′,N″,N‴-tetraacetic Acids. Helv. Chim. Acta 1986, 69 (8), 2067– 2073, DOI: 10.1002/hlca.1986069083055https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXhtFamtbc%253D&md5=8b393179ce98b221e0c0c9e5eef24210Metal complexes of macrocyclic ligands. Part XXIII. Synthesis, properties, and structures of mononuclear complexes with 12- and 14-membered tetraazamacrocycle-N,N',N",N"'-tetraacetic acidsRiesen, Andreas; Zehnder, Margareta; Kaden, Thomas A.Helvetica Chimica Acta (1986), 69 (8), 2067-73CODEN: HCACAV; ISSN:0018-019X.I (R = (CH2)2 (H4dota, H4L), (CH2)3 (H4teta)) form with Ni2+, Cu2+, and Zn2+ (M2+) MLH2 and M'[ML], M' being an alk. earth ion. The structures of Ni(H2dota) and Cu(H2dota) were solved by x-ray structure anal. The metal ions are in a distorted octahedral geometry coordinated by 4 amino N-atoms and 2 carboxylates. In the case of Cu2+, the distortions are more pronounced than for Ni2+ indicating that the Jahn-Teller effect is operating. Starting from these 2 structures, the coordination geometry of the other complexes is discussed using visible and IR spectra.
- 56Ševčík, R.; Vaněk, J.; Michalicová, R.; Lubal, P.; Hermann, P.; Santos, I. C.; Santos, I.; Campello, M. P. C. Formation and Decomplexation Kinetics of Copper(II) Complexes with Cyclen Derivatives Having Mixed Carboxylate and Phosphonate Pendant Arms. Dalt. Trans. 2016, 45 (32), 12723– 12733, DOI: 10.1039/C6DT01127FThere is no corresponding record for this reference.
- 57Addison, A. W.; Carpenter, M.; Lau, L. K. M.; Wicholas, M. Coordination Sphere Flexibility at Copper: Chemistry of an Unipositive Copper(II) Macrocycle, [Cu(Cyclops)]+. Inorg. Chem. 1978, 17 (6), 1545– 1552, DOI: 10.1021/ic50184a03257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXitVagsLk%253D&md5=9e05d4264f9afd31ff330e7644c17e5dCoordination sphere flexibility at copper: chemistry of a unipositive copper(II) macrocycle, [Cu(cyclops)]+Addison, A. W.; Carpenter, M.; Lau, L. K. M.; Wicholas, M.Inorganic Chemistry (1978), 17 (6), 1545-52CODEN: INOCAJ; ISSN:0020-1669.The complex of Cu2+ with cyclops (I), an N4 macrocycle of 1- charge, was studied and square-pyramidal adducts of formal [Cu(cyclops)X] and [Cu(cyclops)L]ClO4 were isolated, where X represents a series of anionic Lewis bases and L represents a series of neutral Lewis bases. These adducts are notable for their strong axial interaction at the expense of the in-plane binding. The redox behavior of Cu(cyclops)+ and its adducts were studied by cyclic voltammetry, and equil. consts. were detd. for the 1:1 interactions of both oxidized and reduced Cu(cyclops)+ with pyridine, γ-picoline, Me Ph sulfide, and benzyl isocyanide. The relation of the chem. of Cu(cyclops+/0 to Cu biochem. is discussed.
- 58Taras-Goslinska, K.; Jonsson, M. Solvent Effect on the Redox Properties of Thioethers. J. Phys. Chem. A 2006, 110 (30), 9513– 9517, DOI: 10.1021/jp062374658https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmslWhu7s%253D&md5=7fb0a074cc06a81f0ad828b153b1a7bdSolvent Effects on the Redox Properties of ThioethersTaras-Goslinska, Katarzyna; Jonsson, MatsJournal of Physical Chemistry A (2006), 110 (30), 9513-9517CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The one-electron redn. potential of the radical cations of thioanisole (1), benzyl Me sulfide (2) and 2-hydroxyethyl benzyl sulfide (3) in water, formamide, acetonitrile, acetone, 1,1,1,3,3,3-hexafluoropropan-2-ol, methanol and 2-propanol was investigated by cyclic voltammetry. For comparison the one-electron redn. potentials in water were also measured using pulse radiolysis. The redox potential is strongly influenced by the nature of the solvent and the solvent sensitivity increases with charge localization. The present results have been used to evaluate solvent effects in view of the Kamlet-Taft relationship. The Kamlet-Taft expression quant. describes the solvent effects on the redox properties of 1-3 and gives the relative importance of the different solvent properties. The dominating contribution to the solvent effects is the solvent dipolarity/polarizability π*, whereas α appears to be of minor importance. Furthermore, the relationship between the π* and redn. potential of radical cations of 1-3 appear to be linear. It was also possible to find the same trend between the solvent dipole moment and peak potential of 1-3. These facts indicate that the nature of solvation is mainly nonspecific.
- 59Coleman, B. R.; Glass, R. S.; Setzer, W. N.; Prabhu, U. D. G.; Wilson, G. S. Electrochemistry of Aliphatic Thioethers as Models for Biological Electron Transfer. Adv. Chem. Ser. 1982, 201, 417– 441, DOI: 10.1021/ba-1982-0201.ch01859https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXmslajtQ%253D%253D&md5=3f2f6fba24b61f5a156512ab8995874eElectrochemistry of aliphatic thioethers as models for biological electron transferColeman, Brian R.; Glass, Richard S.; Setzer, William N.; Prabhu, Usha Devi G.; Wilson, George S.Advances in Chemistry Series (1982), 201 (Electrochem. Spectrochem. Stud. Biol. Redox Compon.), 417-41CODEN: ADCSAJ; ISSN:0065-2393.A review and discussion with 71 refs.
- 60Houghton, D. S.; Humffray, A. A. Anodic Oxidation of Diaryl Sulphides—I. Diphenyl Sulphide in Sulphate and Perchlorate Media. Electrochim. Acta 1972, 17 (8), 1421– 1433, DOI: 10.1016/0013-4686(72)80086-060https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XltVyktrg%253D&md5=8a01c24a6e47a2db0c9ddabfe1ef5830Anodic oxidation of diaryl sulfides. I. Diphenyl sulfide in sulfate and perchlorate mediaHoughton, D. S.; Humffray, A. A.Electrochimica Acta (1972), 17 (8), 1421-33CODEN: ELCAAV; ISSN:0013-4686.Controlled-potential oxidn. at a Pt anode of Ph2S in 80% HOAc-H2O in the presence of ClO4- or SO42- produces Ph2SO in near quant. yield, with a coulombic efficiency close to 100%. At higher potentials, some further oxidn. to Ph2SO2 occurs. Single-sweep voltammetry is suitable for anal., provided that halide ions are absent. Possible mechanisms for the oxidn. to Ph2SO are discussed; 2 of these involve a transition state similar to that proposed for homogeneous oxidn. of sulfides to sulfoxides.
- 61Di Marco, V. Ph.D. Thesis, University of Padova, Padova, Italy, 1998.There is no corresponding record for this reference.
- 62Baes, C. F. J.; Mesmer, R. E. The Hydrolysis of Cations; Wiley-Interscience: New York, 1976.There is no corresponding record for this reference.
- 63Rockenbauer, A.; Korecz, L. Automatic Computer Simulations of ESR Spectra. Appl. Magn. Reson. 1996, 10 (1), 29– 43, DOI: 10.1007/BF0316309763https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XltFehur8%253D&md5=7185bdaf5d33efaf5f8a347b568574dfAutomatic computer simulations of ESR spectraRockenbauer, Antal; Korecz, L.Applied Magnetic Resonance (1996), 10 (1-3), 29-43CODEN: APMREI; ISSN:0937-9347. (Springer)A versatility of automatic ESR simulation procedures was developed to obtain high quality of fitting and produce addnl. information. The following examples are treated: derivation of long-range proton hyperfine coupling consts. from unresolved lines; detn. of 13C hf couplings from the naturally abundant isotope satellites; analyzing chem. exchange phenomena with the 2-sites model (modified Bloch equation); decompn. of superimposed spectra consisting of poorly resolved components. To achieve best agreement between calcd. and exptl. spectra within a reasonable no. of iteration cycles, various approaches were combined, such as consecutive independent parameter optimization, least-square approach, optimization on "serpentines" and optimization of compd. parameters. The spectra can be computed both for liq. and solid state samples, for non-oriented, partially oriented and single crystal samples. Second order perturbation formulas are used for the spin Hamiltonian including g- and hyperfine tensors that have isotropic, axial and rhombic symmetry. Various lineshapes, including Lorentzian, Gaussian, mixed, modulation and dispersion distorted forms are applied. Third order parabolic interpolations are used for building up spectra from individual lines. To correct sweep non-linearity a 3rd order interpolation converts the spectrum to become equidistant. In the anal. of strongly overlapping superimposed spectra, simultaneous adjustment of 2 independent exptl. spectra can give an exact decompn. The inclusion of long-range couplings offers highly perfect fitting and allows one to resolve contributions of naturally abundant 13C isotopes.
- 64Higashi, T. Numerical Absorption Correction. NUMABS 2002.There is no corresponding record for this reference.
- 65Sheldrick, G. M. Phase Annealing in Shelx-90: Direct Methods for Larger Structure. Acta Crystallogr., Sect. A: Found. Crystallogr. 1990, 46 (6), 467– 473, DOI: 10.1107/S0108767390000277There is no corresponding record for this reference.
- 66CrystalClear-SM, version 1.4.0 SP1; Rigaku and Rigaku/MSC, 2008.There is no corresponding record for this reference.
- 67Burla, M. C.; Caliandro, R.; Carrozzini, B.; Cascarano, G. L.; Cuocci, C.; Giacovazzo, C.; Mallamo, M.; Mazzone, A.; Polidori, G. Crystal Structure Determination and Refinement via SIR2014. J. Appl. Crystallogr. 2015, 48 (1), 306– 309, DOI: 10.1107/S160057671500113267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVOmtrw%253D&md5=d2ef5d0634082b90c7fa0c2ef66b985eCrystal structure determination and refinement via SIR2014Burla, Maria Cristina; Caliandro, Rocco; Carrozzini, Benedetta; Cascarano, Giovanni Luca; Cuocci, Corrado; Giacovazzo, Carmelo; Mallamo, Mariarosaria; Mazzone, Annamaria; Polidori, GiampieroJournal of Applied Crystallography (2015), 48 (1), 306-309CODEN: JACGAR; ISSN:1600-5767. (International Union of Crystallography)SIR2014 is the latest program of the SIR suite for crystal structure soln. of small, medium and large structures. A variety of phasing algorithms have been implemented, both ab initio (std. or modern direct methods, Patterson techniques, Vive la Difference) and non-ab initio (simulated annealing, mol. replacement). The program contains tools for crystal structure refinement and for the study of three-dimensional electron-d. maps via suitable viewers.
- 68SHELXL-2013 Program for Crystal Structure Solution; University of Göttingen: Göttingen, Germany, 2013.There is no corresponding record for this reference.
- 69Farrugia, L. J. WinGX and ORTEP for Windows: An Update. J. Appl. Crystallogr. 2012, 45 (4), 849– 854, DOI: 10.1107/S002188981202911169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVKltbzK&md5=0b5b2b5facbaafdd6bbbb80e581bf3beWinGX and ORTEP for Windows: an updateFarrugia, Louis J.Journal of Applied Crystallography (2012), 45 (4), 849-854CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)The WinGX suite provides a complete set of programs for the treatment of small-mol. single-crystal diffraction data, from data redn. and processing, structure soln., model refinement and visualization, and metric anal. of mol. geometry and crystal packing, to final report prepn. in the form of a CIF. It includes several well known pieces of software and provides a repository for programs when the original authors no longer wish to, or are unable to, maintain them. It also provides menu items to execute external software, such as the SIR and SHELX suites of programs. The program ORTEP for Windows provides a graphical user interface (GUI) for the classic ORTEP program, which is the original software for the illustration of anisotropic displacement ellipsoids. The GUI code provides input capabilities for a wide variety of file formats, and extra functionality such as geometry calcns. and ray-traced outputs. The programs WinGX and ORTEP for Windows have been distributed over the internet for about 15 years, and this article describes some of the more modern features of the programs.
- 70Spek, A. L. Single-Crystal Structure Validation with the Program PLATON. J. Appl. Crystallogr. 2003, 36 (1), 7– 13, DOI: 10.1107/S002188980202211270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltlChtw%253D%253D&md5=0a85de2407551632bb287508534904e2Single-crystal structure validation with the program PLATONSpek, A. L.Journal of Applied Crystallography (2003), 36 (1), 7-13CODEN: JACGAR; ISSN:0021-8898. (Blackwell Munksgaard)The results of a single-crystal structure detn. when in CIF format can now be validated routinely by automatic procedures. In this way, many errors in published papers can be avoided. The validation software generates a set of ALERTS detailing issues to be addressed by the experimenter, author, referee and publication journal. Validation was pioneered by the IUCr journal Acta Crystallographica Section C and is currently std. procedure for structures submitted for publication in all IUCr journals. The implementation of validation procedures by other journals is in progress. This paper describes the concepts of validation and the classes of checks that are carried out by the program PLATON as part of the IUCr check CIF facility. PLATON validation can be run at any stage of the structure refinement, independent of the structure detn. package used, and is recommended for use as a routine tool during or at least at the completion of every structure detn. Two examples are discussed where proper validation procedures could have avoided the publication of incorrect structures that had serious consequences for the chem. involved.
- 71Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. Mercury: Visualization and Analysis of Crystal Structures. J. Appl. Crystallogr. 2006, 39 (3), 453– 457, DOI: 10.1107/S002188980600731X71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkslehsbk%253D&md5=c9d7a3c38e1f27769e8578c861c11e3cMercury: visualization and analysis of crystal structuresMacrae, Clare F.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Shields, Greg P.; Taylor, Robin; Towler, Matthew; van de Streek, JaccoJournal of Applied Crystallography (2006), 39 (3), 453-457CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)Since its original release, the popular crystal structure visualization program Mercury has undergone continuous further development. Comparisons between crystal structures are facilitated by the ability to display multiple structures simultaneously and to overlay them. Improvements were made to many aspects of the visual display, including the addn. of depth cueing, and highly customizable lighting and background effects. Textual and numeric data assocd. with structures can be shown in tables or spreadsheets, the latter opening up new ways of interacting with the visual display. At. displacement ellipsoids, calcd. powder diffraction patterns and predicted morphologies can now be shown. Some limited mol.-editing capabilities were added. The object-oriented nature of the C++ libraries underlying Mercury makes it easy to re-use the code in other applications, and this has facilitated three-dimensional visualization in several other programs produced by the Cambridge Crystallog. Data Center.
- 72Allen, F. H.; Johnson, O.; Shields, G. P.; Smith, B. R.; Towler, M. CIF Applications. XV. EnCIFer: A Program for Viewing, Editing and Visualizing CIFs. J. Appl. Crystallogr. 2004, 37 (2), 335– 338, DOI: 10.1107/S002188980400352872https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitVagtbc%253D&md5=08ca1e807bede5d71d0157994759f3ccCIF applications. XV. enCIFer: a program for viewing, editing and visualizing CIFsAllen, Frank H.; Johnson, Owen; Shields, Gregory P.; Smith, Barry R.; Towler, MatthewJournal of Applied Crystallography (2004), 37 (2), 335-338CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)The enCIFer program permits the location, reporting and correction of syntax and format violations in single- or multi-block crystallog. information files (CIFs). The program also permits the editing of existing individual or looped data items and the addn. of new data in these categories, and provides data entry wizards for the addn. of two types of std. information for small mol. structural studies, namely publication data and chem. and phys. property information. Facilities for the graphical visualization and manipulation of structure(s) in a CIF are also provided.
- 73Hwang, T. L.; Shaka, A. J. Water Suppression That Works. Excitation Sculpting Using Arbitrary Wave-Forms and Pulsed-Field Gradients. J. Magn. Reson., Ser. A 1995, 112 (2), 275– 279, DOI: 10.1006/jmra.1995.104773https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjs1Wmsb0%253D&md5=f56de708de13417539d157c074ef3998Water suppression that works. Excitation sculpting using arbitrary waveforms and pulsed field gradientsHwang, Tsang-Lin; Shaka, A. J.Journal of Magnetic Resonance, Series A (1995), 112 (2), 275-9CODEN: JMRAE2; ISSN:1064-1858. (Academic)A water suppression technique which can applied to most NMR expts. is described. A simple echo sequence employing a pulsed field gradient before and after the refocusing element is applied. Theor. background and examples are gives.
- 74te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. Chemistry with ADF. J. Comput. Chem. 2001, 22 (9), 931– 967, DOI: 10.1002/jcc.105674https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjtlGntrw%253D&md5=314e7e942de9b28e664afc5adb2f574fChemistry with ADFTe Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T.Journal of Computational Chemistry (2001), 22 (9), 931-967CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)A review with 241 refs. We present the theor. and tech. foundations of the Amsterdam D. Functional (ADF) program with a survey of the characteristics of the code (numerical integration, d. fitting for the Coulomb potential, and STO basis functions). Recent developments enhance the efficiency of ADF (e.g., parallelization, near order-N scaling, QM/MM) and its functionality (e.g., NMR chem. shifts, COSMO solvent effects, ZORA relativistic method, excitation energies, frequency-dependent (hyper)polarizabilities, at. VDD charges). In the Applications section we discuss the phys. model of the electronic structure and the chem. bond, i.e., the Kohn-Sham MO (MO) theory, and illustrate the power of the Kohn-Sham MO model in conjunction with the ADF-typical fragment approach to quant. understand and predict chem. phenomena. We review the "Activation-strain TS interaction" (ATS) model of chem. reactivity as a conceptual framework for understanding how activation barriers of various types of (competing) reaction mechanisms arise and how they may be controlled, for example, in org. chem. or homogeneous catalysis. Finally, we include a brief discussion of exemplary applications in the field of biochem. (structure and bonding of DNA) and of time-dependent d. functional theory (TDDFT) to indicate how this development further reinforces the ADF tools for the anal. of chem. phenomena.
- 75Fonseca Guerra, C.; Snijders, J. G.; te Velde, G.; Baerends, E. J. Towards an Order-N DFT Method. Theor. Chem. Acc. 1998, 99 (6), 391– 403, DOI: 10.1007/s002140050353There is no corresponding record for this reference.
- 76ADF2018; SCM, Theoretical Chemistry, Vrije Universiteit: Amsterdam: The Netherlands, 2018; http://www.scm.com.There is no corresponding record for this reference.
- 77Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized Gradient Approximation Made Simple. Phys. Rev. Lett. 1996, 77 (18), 3865– 3868, DOI: 10.1103/PhysRevLett.77.386577https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmsVCgsbs%253D&md5=55943538406ee74f93aabdf882cd4630Generalized gradient approximation made simplePerdew, John P.; Burke, Kieron; Ernzerhof, MatthiasPhysical Review Letters (1996), 77 (18), 3865-3868CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)Generalized gradient approxns. (GGA's) for the exchange-correlation energy improve upon the local spin d. (LSD) description of atoms, mols., and solids. We present a simple derivation of a simple GGA, in which all parameters (other than those in LSD) are fundamental consts. Only general features of the detailed construction underlying the Perdew-Wang 1991 (PW91) GGA are invoked. Improvements over PW91 include an accurate description of the linear response of the uniform electron gas, correct behavior under uniform scaling, and a smoother potential.
- 78Handy, N. C.; Cohen, A. J. Left-Right Correlation Energy. Mol. Phys. 2001, 99 (5), 403– 412, DOI: 10.1080/0026897001001843178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhslGlur8%253D&md5=0c077bca407ca9c54d414391d60b8139Left-right correlation energyHandy, Nicholas C.; Cohen, Aron J.Molecular Physics (2001), 99 (5), 403-412CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)We first attempt to det. a local exchange functional Ex[ρ] which accurately reproduces the Hartree-Fock (HF) energies of the 18 first and second row atoms. Ex[ρ] is detd. from ρ and |gradρ|, and we find that we can improve significantly upon Becke's original generalized gradient approxn. functional (commonly called B88X) by allowing the coeff. of the Dirac exchange term to be optimized (it is argued that mols. do not behave like the uniform electron gas). We call this new two parameter exchange functional OPTX. We find that neither Δρ or τ = Σ|gradφi|2 improve the fit to these at. energies. These exchange functionals include not only exchange, but also left-right correlation. It is therefore proposed that this functional provides a definition for exchange energy plus left-right correlation energy when used in Kohn-Sham (KS) calcns. We call this energy the Kohn-Sham exchange (or KSX) energy. It is shown that for nearly all mols. studied these KSX energies are lower than the corresponding HF energies, thus giving values for the non-dynamic correlation energy. At stretched geometries, the KSX energies are always lower than the HF energies, and often substantially so. Furthermore all bond lengths from the KSX calcns. are longer than HF bond lengths and exptl. bond lengths, which again demonstrates the inclusion of left-right correlation effects in the functional. For these reasons we prefer to split the correlation energy into two parts: left-right correlation energy and dynamic correlation energy, arguing that the usage of the words "non-dynamic" or "static" or "near-degeneracy" is less meaningful. We recognize that this definition of KSX is not precise, because the definition of a local Ex[ρ] can never be precise. We also recognize that these ideas are not new, but we think that their importance has been insufficiently recognized in functional detn. When we include third row atoms in our anal., we are unable to find a local exchange functional which is a substantial improvement over B88X for the reprodn. of HF energies. This must arise from the effects of the core orbitals, and therefore we do not consider that this detracts from the improved accuracy of OPTX. We report some MCSCF calcns. constructed from bonding-antibonding configurations, from which we attempt to calc. ab initio left-right correlation. There is only moderate agreement between the two approaches. Finally we combine the OPTX functional with established correlation functionals (LYP, P86, P91) to form OLYP, OP86 and OP91; OLYP is a great improvement on BLYP for both energy and structure, and OP86, OP91 are an improvement over BP86, BP91 for structure. The importance of the exchange functional for mol. structure is therefore underlined.
- 79Swart, M.; Ehlers, A. W.; Lammertsma, K. Performance of the OPBE Exchange-Correlation Functional. Mol. Phys. 2004, 102 (23–24), 2467– 2474, DOI: 10.1080/002689704200027501779https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFGmu7rK&md5=ab48b6ca8a51335ab2105808c28b809bPerformance of the OPBE exchange-correlation functionalSwart, Marcel; Ehlers, Andreas W.; Lammertsma, KoopMolecular Physics (2004), 102 (23-24), 2467-2474CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)In a recent evaluation of d. functional theory (DFT) functionals OPBE, which combines Handy's optimized exchange (OPTX) with the PBE correlation, was shown to correctly predict the spin states (singlet through sextet) of seven different iron complexes (2004, J. Phys. Chem. A, 108, 5479). The present study provides a further test of OPBE as well as that of the OPerdew and OLYP functionals, in which OPTX is combined with the Perdew and LYP correlations, resp. These three are compared to other pure DFT functionals for their performance in calcg. the atomization energies for the G2-set of up to 148 mols., six reaction barriers of SN2 reactions, geometry optimizations of 19 small mols. and four metallocenes, and zero-point vibrational energies for 13 small mols. OPBE performs exceptional well in all cases.
- 80van Lenthe, E.; Baerends, E. J.; Snijders, J. G. Relativistic Total Energy Using Regular Approximations. J. Chem. Phys. 1994, 101 (11), 9783– 9792, DOI: 10.1063/1.46794380https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXisFChu7g%253D&md5=4b0c97a476c22d4e3f783f0b97c72581Relativistic total energy using regular approximationsvan Lenthe, E.; Baerends, E. J.; Snijders, J. G.Journal of Chemical Physics (1994), 101 (11), 9783-92CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)In this paper we will discuss relativistic total energies using the zeroth order regular approxn. (ZORA). A simple scaling of the ZORA one-electron Hamiltonian is shown to yield energies for the hydrogenlike atom that are exactly equal to the Dirac energies. The regular approxn. is not gauge invariant in each order, but the scaled ZORA energy can be shown to be exactly gauge invariant for hydrogenic ions. It is practically gauge invariant for many-electron systems and proves superior to the (unscaled) first order regular approxn. for at. ionization energies. The superior to the (unscaled) first order regular approxn. for at. ionization energies. The regular approxn., if scaled, can therefore be applied already in zeroth order to mol. bond energies. Scalar relativistic d. functional all-electron and frozen core calcns. on diatomics, consisting of copper, silver, and gold and their hydrides are presented. We used exchange-correlation energy functionals commonly used in nonrelativistic calcns.; both in the local-d. approxn. (LDA) and including d.-gradient ("nonlocal") corrections (NLDA). At the NLDA level the calcd. dissocn. energies are all within 0.2 eV from expt., with an av. of 0.1 eV. All-electron calcns. for Au2 and AuH gave results within 0.05 eV of the frozen core calcns. Ag2 and AgCu and CuH.
- 81Allinger, N. L.; Zhou, X.; Bergsma, J. Molecular Mechanics Parameters. J. Mol. Struct.: THEOCHEM 1994, 312 (1), 69– 83, DOI: 10.1016/S0166-1280(09)80008-0There is no corresponding record for this reference.
- 82Ho, J.; Klamt, A.; Coote, M. L. Comment on the Correct Use of Continuum Solvent Models. J. Phys. Chem. A 2010, 114 (51), 13442– 13444, DOI: 10.1021/jp107136j82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFaktL3I&md5=ffa1aa6c6f5f321292fcf8d4a843c037Comment on the Correct Use of Continuum Solvent ModelsHo, Junming; Klamt, Andreas; Coote, Michelle L.Journal of Physical Chemistry A (2010), 114 (51), 13442-13444CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)There is no expanded citation for this reference.
- 83Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113 (18), 6378– 6396, DOI: 10.1021/jp810292n83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXksV2is74%253D&md5=54931a64c70d28445ee53876a8b1a4b9Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface TensionsMarenich, Aleksandr V.; Cramer, Christopher J.; Truhlar, Donald G.Journal of Physical Chemistry B (2009), 113 (18), 6378-6396CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)We present a new continuum solvation model based on the quantum mech. charge d. of a solute mol. interacting with a continuum description of the solvent. The model is called SMD, where the "D" stands for "d." to denote that the full solute electron d. is used without defining partial at. charges. "Continuum" denotes that the solvent is not represented explicitly but rather as a dielec. medium with surface tension at the solute-solvent boundary. SMD is a universal solvation model, where "universal" denotes its applicability to any charged or uncharged solute in any solvent or liq. medium for which a few key descriptors are known (in particular, dielec. const., refractive index, bulk surface tension, and acidity and basicity parameters). The model separates the observable solvation free energy into two main components. The first component is the bulk electrostatic contribution arising from a self-consistent reaction field treatment that involves the soln. of the nonhomogeneous Poisson equation for electrostatics in terms of the integral-equation-formalism polarizable continuum model (IEF-PCM). The cavities for the bulk electrostatic calcn. are defined by superpositions of nuclear-centered spheres. The second component is called the cavity-dispersion-solvent-structure term and is the contribution arising from short-range interactions between the solute and solvent mols. in the first solvation shell. This contribution is a sum of terms that are proportional (with geometry-dependent proportionality consts. called at. surface tensions) to the solvent-accessible surface areas of the individual atoms of the solute. The SMD model has been parametrized with a training set of 2821 solvation data including 112 aq. ionic solvation free energies, 220 solvation free energies for 166 ions in acetonitrile, methanol, and DMSO, 2346 solvation free energies for 318 neutral solutes in 91 solvents (90 nonaq. org. solvents and water), and 143 transfer free energies for 93 neutral solutes between water and 15 org. solvents. The elements present in the solutes are H, C, N, O, F, Si, P, S, Cl, and Br. The SMD model employs a single set of parameters (intrinsic at. Coulomb radii and at. surface tension coeffs.) optimized over six electronic structure methods: M05-2X/MIDI!6D, M05-2X/6-31G*, M05-2X/6-31+G**, M05-2X/cc-pVTZ, B3LYP/6-31G*, and HF/6-31G*. Although the SMD model has been parametrized using the IEF-PCM protocol for bulk electrostatics, it may also be employed with other algorithms for solving the nonhomogeneous Poisson equation for continuum solvation calcns. in which the solute is represented by its electron d. in real space. This includes, for example, the conductor-like screening algorithm. With the 6-31G* basis set, the SMD model achieves mean unsigned errors of 0.6-1.0 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 4 kcal/mol on av. for ions with either Gaussian03 or GAMESS.
- 84Pye, C. C.; Ziegler, T. An Implementation of the Conductor-like Screening Model of Solvation within the Amsterdam Density Functional Package. Theor. Chem. Acc. 1999, 101 (6), 396– 408, DOI: 10.1007/s00214005045784https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktVSqt7k%253D&md5=ff0f000eb1217a8d117a1be17e02ac1fAn implementation of the conductor-like screening model of solvation within the Amsterdam density functional packagePye, Cory C.; Ziegler, TomTheoretical Chemistry Accounts (1999), 101 (6), 396-408CODEN: TCACFW; ISSN:1432-881X. (Springer-Verlag)The conductor-like screening model (COSMO) of solvation was implemented in the Amsterdam d. functional program with max. flexibility in mind. Four cavity definitions were incorporated. Several iterative schemes were tested for solving the COSMO equations. The biconjugate gradient method proves to be both robust and memory-conserving. The interaction between the surface charges and the electron d. may be calcd. by integrating over either the fitted or exact d., or by calcg. the mol. potential. A disk-smearing algorithm is applied in the former case to avoid singularities. Several SCF/COSMO coupling schemes were examd. in an attempt to reduce computational effort. A gradient-preserving algorithm for removing outlying charge was implemented. Preliminary optimized radii are given. Applications to the benzene oxide-oxepin valence tautomerization and to glycine conformation are presented.
- 85Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed. 2017, 56 (34), 10070– 10086, DOI: 10.1002/anie.20170148685https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOlt7nL&md5=6e86c7cfaf7b09e58c0a50a589601578Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain ModelBickelhaupt, F. Matthias; Houk, Kendall N.Angewandte Chemie, International Edition (2017), 56 (34), 10070-10086CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The activation strain or distortion/interaction model is a tool to analyze activation barriers that det. reaction rates. For bimol. reactions, the activation energies are the sum of the energies to distort the reactants into geometries they have in transition states plus the interaction energies between the two distorted mols. The energy required to distort the mols. is called the activation strain or distortion energy. This energy is the principal contributor to the activation barrier. The transition state occurs when this activation strain is overcome by the stabilizing interaction energy. Following the changes in these energies along the reaction coordinate gives insights into the factors controlling reactivity. This model has been applied to reactions of all types in both org. and inorg. chem., including substitutions and eliminations, cycloaddns., and several types of organometallic reactions.
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c01550.
Structures of chelators proposed in the literature for copper-based radiopharmaceuticals, acidity constants and distribution diagrams of the free chelators (DO4S, DO3S, DO3SAm, DO2A2S, and DOTA), equilibration times required to reach equilibrium in Cu2+/chelator complex formation, UV–vis spectroscopic data and spectra of Cu2+/chelator complexes, EPR-derived isomeric dependence on the pH, extended crystallographic data and unit cell/packing arrangement pictures, DFT-computed free energy and structures of the Cu2+/chelator and Cu+/chelator complexes, cyclic voltammograms of free Cu, free chelators, and Cu/chelator complexes at various scan rates, and NMR data and spectra of Cu+/chelator complexes (PDF)
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