Versatile Diphosphine Chelators for Radiolabeling Peptides with ^99mTc and ⁶⁴Cu

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1. 1

   Jackson, J. A.; Hungnes, I. N.; Ma, M. T.; Rivas, C. Bioconjugates of Chelators with Peptides and Proteins in Nuclear Medicine: Historical Importance, Current Innovations, and Future Challenges. Bioconjugate Chem. 2020, 31, 483– 491,  DOI: 10.1021/acs.bioconjchem.0c00015

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   Bioconjugates of Chelators with Peptides and Proteins in Nuclear Medicine: Historical Importance, Current Innovations, and Future Challenges

   Jackson, Jessica A.; Hungnes, Ingebjoerg N.; Ma, Michelle T.; Rivas, Charlotte

   Bioconjugate Chemistry (2020), 31 (3), 483-491CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

   A review. Mol. radiopharmaceuticals based on bioconjugates of chelators with peptides and proteins have had significant clin. impact in the diagnosis and treatment of several types of cancers. In the 1990s, indium-111 and yttrium-90 labeled chelator-peptide/protein conjugates established the clin. utility of these radiopharmaceuticals for receptor-targeted γ-scintigraphy imaging and systemic radiotherapy. Second-generation bioconjugates based on peptides targeting the somatostatin II receptor and the prostate-specific membrane antigen are now widely used for management of neuroendocrine and prostate cancer, resp. These bioconjugates are typically radiolabeled with gallium-68 for imaging of target receptor expression with positron emission tomog., and the β--emitter, lutetium-177, for targeted radiotherapy. Innovations in radioisotope technol. and biomol. therapies are likely to drive the future clin. development of radiopharmaceuticals based on radiometals. New chelator-peptide and chelator-protein bioconjugates will underpin nuclear medicine advances in mol. imaging and radiotherapy.
2. 2

   Maurer, T.; Robu, S.; Schottelius, M.; Schwamborn, K.; Rauscher, I.; van den Berg, N. S.; van Leeuwen, F. W. B.; Haller, B.; Horn, T.; Heck, M. M.; Gschwend, J. E.; Schwaiger, M.; Wester, H. J.; Eiber, M. ^99mTechnetium-Based Prostate-Specific Membrane Antigen–Radioguided Surgery in Recurrent Prostate Cancer. Eur. Urol. 2019, 75, 659– 666,  DOI: 10.1016/j.eururo.2018.03.013

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   (99m)Technetium-based Prostate-specific Membrane Antigen-radioguided Surgery in Recurrent Prostate Cancer

   Maurer Tobias; Robu Stephanie; Schottelius Margret; Wester Hans-Jurgen; Schwamborn Kristina; Rauscher Isabel; Schwaiger Markus; Eiber Matthias; van den Berg Nynke S; van Leeuwen Fijs W B; Haller Bernhard; Horn Thomas; Heck Matthias M; Gschwend Jurgen E

   European urology (2019), 75 (4), 659-666 ISSN:.

   BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging. OBJECTIVE: To describe the technique, feasibility, and short-term outcomes of (99m)Technetium ((99m)Tc)-based PSMA-radioguided surgery ((99m)Tc-PSMA-RGS) for removal of recurrent PC lesions. DESIGN, SETTING, AND PARTICIPANTS: Thirty-one consecutive patients with evidence of recurrent PC on (68)Ga-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid ((68)Ga-PSMA-11) PET after radical prostatectomy undergoing (99m)Tc-PSMA-RGS were retrospectively analyzed. SURGICAL PROCEDURE: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of (99m)Tc-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7h). MEASUREMENTS: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated. RESULTS AND LIMITATIONS: In total, 132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5-96.7%). With (99m)Tc-PSMA-RGS, all lesions visualized on preoperative (68)Ga-PSMA-11 PET could be removed. Moreover, (99m)Tc-PSMA-RGS detected additional metastases as small as 3mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6-18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo. CONCLUSIONS: As a new technique for surgical guidance, (99m)Tc-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated. PATIENT SUMMARY: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo).
3. 3

   Schmidkonz, C.; Hollweg, C.; Beck, M.; Reinfelder, J.; Goetz, T. I.; Sanders, J. C.; Schmidt, D.; Prante, O.; Bäuerle, T.; Cavallaro, A.; Uder, M.; Wullich, B.; Goebell, P.; Kuwert, T.; Ritt, P. ^99mTc-MIP-1404-SPECT/CT for the Detection of PSMA-Positive Lesions in 225 Patients with Biochemical Recurrence of Prostate Cancer. Prostate 2018, 78, 54– 63,  DOI: 10.1002/pros.23444

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   99mTc-MIP-1404-SPECT/CT for the detection of PSMA-positive lesions in 225 patients with biochemical recurrence of prostate cancer

   Schmidkonz, Christian; Hollweg, Claudia; Beck, Michael; Reinfelder, Julia; Goetz, Theresa I.; Sanders, James C.; Schmidt, Daniela; Prante, Olaf; Baeuerle, Tobias; Cavallaro, Alexander; Uder, Michael; Wullich, Bernd; Goebell, Peter; Kuwert, Torsten; Ritt, Philipp

   Prostate (Hoboken, NJ, United States) (2018), 78 (1), 54-63CODEN: PRSTDS; ISSN:0270-4137. (Wiley-Blackwell)

   Whole-body planar and SPECT/CT images of the lower abdomen and thorax were obtained 3-4 h p.i. of 710 ± 64 MBq 99mTc-MIP-1404. Images were visually analyzed for presence and location of abnormal uptake. In addn., quant. anal. of the SPECT/CT data was carried out on a subset of 125 patients. Tracer-pos. lesions were detected in 77% (174/225) of all patients. Detections occurred at the area of local recurrence in the prostate in 25% of patients (or a total of 56), with metastases in lymph nodes in 47% (105), bone in 27% (60), lung in 5% (12), and other locations in 2% (4) of patients. Detection rates were 90% at PSA levels ≥2 ng/mL and 54% below that threshold. Lesional SUVmax values were, on av., 32.2 ± 29.6 (0.8-142.2), and tumor-to-normal ratios 146.6 ± 160.5 (1.9-1482.4). The PSA level correlated significantly with total uptake of MIP-1404 in tumors (P < 0.001). Furthermore, total tumor uptake was significantly higher in patients with Gleason scores ≥8 compared to those with Gleason scores ≤7 (P < 0.05). In patients with androgen deprivation therapy, the detection rate was significantly higher compared to patients without androgen deprivation therapy (86% vs 71%, P < 0.001). SPECT/CT with 99mTc-labeled MIP-1404 has a high probability in detecting PSMA-pos. lesions in patients with elevated PSA.
4. 4

   Hicks, R. J.; Jackson, P.; Kong, G.; Ware, R. E.; Hofman, M. S.; Pattison, D. A.; Akhurst, T.; Drummond, E.; Roselt, P.; Callahan, J.; Price, R.; Jeffery, C. M.; Hong, E.; Noonan, W.; Herschtal, A.; Hicks, L. J.; Hedt, A.; Harris, M.; Paterson, B. M.; Donnelly, P. S. First-in-Human Trial of ⁶⁴Cu-SARTATE PET Imaging of Patients with Neuroendocrine Tumours Demonstrates High Tumor Uptake and Retention, Potentially Allowing Prospective Dosimetry for Peptide Receptor Radionuclide Therapy. J. Nucl. Med. 2019, 60, 777– 785,  DOI: 10.2967/jnumed.118.217745

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   64Cu-SARTATE PET imaging of patients with neuroendocrine tumors demonstrates high tumor uptake and retention, potentially allowing prospective dosimetry for peptide receptor radionuclide therapy

   Hicks, Rodney J.; Jackson, Price; Kong, Grace; Ware, Robert E.; Hofman, Michael S.; Pattison, David A.; Akhurst, Timothy A.; Drummond, Elizabeth; Roselt, Peter; Callahan, Jason; Price, Roger; Jeffery, Charmaine M.; Hong, Emily; Noonan, Wayne; Herschtal, Alan; Hicks, Lauren J.; Hedt, Amos; Harris, Matthew; Paterson, Brett M.; Donnelly, Paul S.

   Journal of Nuclear Medicine (2019), 60 (6), 777-785CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)

   Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and detg. the suitability of patients for peptide receptor radionuclide therapy. Based on promising preclin. studies, we have performed a first-time-in-humans trial of 64Cu- MeCOSar-Tyr3-octreotate (64Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. In a prospective trial, 10 patients with known neuroendocrine neoplasia and pos. for uptake on 68Ga-DOTA-octreotate (68Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of 64Cu-SARTATE. 64Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. Comparison of 64Cu-SARTATE PET/CT obtained at 4 h to 68Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, esp. in the liver. The highest early physiol. organ uptake was in the kidneys, liver, and spleen. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for 67Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of 64Cu would also facilitate good-manufg.-practice prodn. and distribution to sites without access to 68Ga.
5. 5

   Rivas, C.; Jackson, J. A.; Hungnes, I. N.; Ma, M. T. Radioactive Metals in Imaging and Therapy. Comprehensive Coordination Chemistry III; Elsevier, 2021; Vol. 9, pp 706– 740.

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6. 6

   Liu, S.; Chakraborty, S. ^99mTc-Centered One-Pot Synthesis for Preparation of ^99mTc Radiotracers. Dalton Trans. 2011, 40, 6077– 6086,  DOI: 10.1039/c0dt01462a

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   99mTc-centered one-pot synthesis for preparation of 99mTc radiotracers

   Liu, Shuang; Chakraborty, Sudipta

   Dalton Transactions (2011), 40 (23), 6077-6086CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)

   A review. Nuclear medicine relies on two main imaging modalities: single photon emission computed tomog. (SPECT) and positron emission tomog. (PET). Radiopharmaceuticals (or radiotracers) are the blood stream of nuclear medicine for the diagnosis or therapy of diseases. Diagnostic radiotracers that are small mols. labeled with a gamma-emitter for SPECT or positron-emitter for PET provide a non-invasive method to assess the disease or disease states and monitor the therapeutic efficacy of a specific treatment regime. Over the past four decades, radiopharmaceutical research has been practising one-pot synthesis at the tracer level (10-7-10-6 M). Many 99mTc radiotracers currently used in nuclear medicine are routinely prepd. by following the basic principles of one-pot synthesis. Unlike traditional org. one-pot synthesis, which often involves the formation of multiple C-C and C-heteroatom bonds in a single step, the 99mTc-centered one-pot synthesis requires the formation of multiple coordination bonds between Tc and various donor atoms, such as N, O, S and P. This review will illustrate how the 99mTc-centered one-pot synthesis is utilized for routine prepns. of different 99mTc radiotracers.
7. 7

   Ma, M. T.; Blower, P. J. Chelators for Diagnostic Molecular Imaging with Radioisotopes of Copper, Gallium and Zirconium. Metal Chelation in Medicine; Royal Society of Chemistry: Cambridge, U.K., 2016; Chapter 8, pp 260– 312.

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   Kelly, J. D.; Forster, A. M.; Higley, B.; Archer, C. M.; Booker, F. S.; Canning, L. R.; Wai Chiu, K.; Edwards, B.; Gill, H. K.; McPartlin, M.; Nagle, K. R.; Latham, I. A.; Pickett, R. D.; Storey, A. E.; Webbon, P. M. Technetium-99m-Tetrofosmin as a New Radiopharmaceutical for Myocardial Perfusion Imaging. J. Nucl. Med. 1993, 34, 222– 227

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   Technetium-99m-tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging

   Kelly, J. Duncan; Forster, Alan M.; Higley, Brian; Archer, Colin M.; Booker, Fong S.; Canning, Lewis R.; Chiu, K. Wai; Edwards, Barbara; Gill, Harjit K.; et al.

   Journal of Nuclear Medicine (1993), 34 (2), 222-7CODEN: JNMEAQ; ISSN:0161-5505.

   A new cationic complex, [99mTc(tetrofosmin)2O2]+, where tetrofosmin is the ether functionalized diphosphine ligand 1,2-bis[bis(2-ethoxyethyl)phosphino]ethane, has been synthesized and evaluated for potential use in myocardial perfusion imaging. The structure of the complex has been detd. by x-ray crystallog. of the 99Tc analog. In comparison with previously reported 99mTc complexes of alkylphosphines, the tetrofosmin species shows substantially increased clearance from nontarget tissue, esp. blood and liver. A freeze-dried kit formulation has been developed. The kit provides a product of high radiochem. purity up to 8 h after reconstitution at room temp.
9. 9

   Amersham Health. Myoview Kit for the Preparation of Technetium Tc^99m Tetrofosmin for Injection. www.accessdata.fda.gov/drugsatfda_docs/label/2003/20372slr015_myoview_lbl.pdf (accessed Jan 20, 2023).

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10. 10

    Bolzati, C.; Malagò, E.; Boschi, A.; Cagnolini, A.; Porchia, M.; Bandoli, G. Symmetric Bis-Substituted and Asymmetric Mono-Substituted Nitridotechnetium Complexes with Heterofunctionalized Phosphinothiolate Ligands. New J. Chem. 1999, 23, 807– 809,  DOI: 10.1039/a903679b

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    Symmetric bis-substituted and asymmetric mono-substituted nitridotechnetium complexes with heterofunctionalized phosphinothiolate ligands

    Bolzati, Cristina; Malago, Erica; Boschi, Alessandra; Cagnolini, Aldo; Porchia, Marina; Bandoli, Giuliano

    New Journal of Chemistry (1999), 23 (8), 807-809CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)

    The mixed bidentate ligand 2-(dicyclohexylphosphino)ethanethiol (HL) reacts with labile nitrido-Tc precursors to afford a rare example of an asym. monosubstituted species [TcN(L)Cl(PPh3)] (1), along with the sym. bis-substituted complex [TcN(L)2] (2). The latter compd., as assessed by TLC and HPLC chromatog., possesses the same mol. structure as the agent produced at the 'non-carrier added' level using the 99mTc nuclear isomer. The mol. structures of 1 and 2 were detd. by x-ray crystallog.
11. 11

    Bolzati, C.; Caporale, A.; Agostini, S.; Carta, D.; Cavazza-Ceccato, M.; Refosco, F.; Tisato, F.; Schievano, E.; Bandoli, G. Avidin-Biotin System: A Small Library of Cysteine Biotinylated Derivatives Designed for the [^99mTc(N)(PNP)]²⁺ Metal Fragment. Nucl. Med. Biol. 2007, 34, 511– 522,  DOI: 10.1016/j.nucmedbio.2007.04.006

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    Avidin-biotin system: A small library of cysteine biotinylated derivatives designed for the [99mTc(N)(PNP)]2+ metal fragment

    Bolzati, Cristina; Caporale, Andrea; Agostini, Stefania; Carta, Davide; Cavazza-Ceccato, Mario; Refosco, Fiorenzo; Tisato, Francesco; Schievano, Elisabetta; Bandoli, Giuliano

    Nuclear Medicine and Biology (2007), 34 (5), 511-522CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)

    Using the avidin-biotin system as model, we investigate here the effective application of [Tc(N)L(PNP)]+/0 technol. (L=N-functionalized cysteine [O-,S-]; PNP=aminodiphosphine) to the prepn. of target-specific radiopharmaceuticals. A series of 99mTc-nitrido complexes contg. functionalized biotin ligands was prepd. and their biol. profile was detd. To minimize the steric and the electronic influences of the Tc-carrying complex on the biotin-avidin receptor interaction, the following N-functionalized cysteine-biotin derivs. were synthesized: (1) Biot-CysOSH; (2) Biot-Abu-CysOSH; (3) Biot-Abz-CysOSH; (4) Biot--(Ac)Lys-CysOSH; (5) Biot--(Ac)Lys-CysOSH; (6) Biot-Glu-CysOSH. The asym. nitrido-Tc(V) 99g/99mTc(N)(Biot-X-CysOS)(PNP3) (X=spacer) complexes, where PNP3 was N,N-bis-[(dimethoxypropyl)phosphinoethyl] methoxy-ethylamine, were obtained by simultaneous addn. of PNP3 and the relevant biotinylated ligand to a soln. contg. a 99mTc-nitrido precursor (yields >95%). In all cases, a mixt. of syn- and anti isomers was obsd. In vitro challenge expts. with glutathione and cysteine indicated that no transchelation reactions occurred. Assessment of the in vitro binding to avidin of the complexes revealed that only the complexes contg. Biot-Abu-CysOS and Biot-Glu-CysOS ligand maintained a good affinity for the concentrator. Stability studies carried out in human and mouse plasma as well as in rat and mouse liver homogenate evidenced a rapid enzymic degrdn. for the 99mTc(N)(Biot-Abu-CysOS)(PNP3) complex, whereas the 99mTc(N)(Biot-Glu-CysOS)(PNP3) one was stable in all conditions. Tissue biodistribution in normal Balb/C mice of the most stable candidate showed a rapid clearance both from the blood and the other tissues. The activity was eliminated both through the hepatobiliary system and the urinary tract.
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    Kannan, R.; Pillarsetty, N.; Gali, H.; Hoffman, T. J.; Barnes, C. L.; Jurisson, S. S.; Smith, C. J.; Volkert, W. A. Design and Synthesis of a Bombesin Peptide-Conjugated Tripodal Phosphino Dithioether Ligand Topology for the Stabilization of the fac-[M(CO)₃]⁺ Core (M = 99 MTc or Re). Inorg. Chem. 2011, 50, 6210– 6219,  DOI: 10.1021/ic200491z

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    Design and Synthesis of a Bombesin Peptide-Conjugated Tripodal Phosphino Dithioether Ligand Topology for the Stabilization of the fac-[M(CO)3]+ Core (M = 99 mTc or Re)

    Kannan, Raghuraman; Pillarsetty, Nagavarakishore; Gali, Hariprasad; Hoffman, Timothy J.; Barnes, Charles L.; Jurisson, Silvia S.; Smith, Charles J.; Volkert, Wynn A.

    Inorganic Chemistry (2011), 50 (13), 6210-6219CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)

    A new tumor-seeking tridentate topol. consisting of a phosphino dithioether ((HOCH2)2PCH2CH2S(CH2)nCH2SR; PS2) ligand framework for the prodn. of kinetically inert and in vivo stable facial [99mTc(CO)3(PS2)]+ or [Re(CO)3(PS2)]+ is described. The x-ray crystal structure of fac-Re(CO)3(PS2)PF6 is reported. The bioconjugation strategies for incorporating bombesin (BBN) peptides on to the PS2 tripodal framework and, thereby, de novo designing of GRP receptor-seeking Tc(PS2-BBN)(CO)3 are developed.
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    Kothari, K. K.; Raghuraman, K.; Pillarsetty, N. K.; Hoffman, T. J.; Owen, N. K.; Katti, K. V.; Volkert, W. A. Syntheses, in vitro and in vivo Characterization of a ^99mTc-(I)-Tricarbonyl-Benzylamino-Dihydroxymethyl Phosphine (NP₂) Chelate. Appl. Radiat. Isot. 2003, 58, 543– 549,  DOI: 10.1016/S0969-8043(03)00030-7

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    Syntheses, in vitro and in vivo characterization of a 99mTc-(I)-tricarbonyl-benzylamino-dihydroxymethyl phosphine (NP2) chelate

    Kothari, K. K.; Raghuraman, K.; Pillarsetty, N. K.; Hoffman, T. J.; Owen, N. K.; Katti, K. V.; Volkert, W. A.

    Applied Radiation and Isotopes (2003), 58 (5), 543-549CODEN: ARISEF; ISSN:0969-8043. (Elsevier Science Ltd.)

    Studies were performed to study the complexation chem. of 99mTc(CO)+3 with a new tridentate amino-dihydroxymethyl phosphine (NP2) ligand with the 99mTc(CO)3(OH2)+3 synthon at tracer levels. A single, well-defined 99mTc(CO)3NP2 complex is formed at pH 7.5 within 10 min at 60°C that exhibits high in vitro and in vivo stability.
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    Gali, H.; Hoffman, T. J.; Sieckman, G. L.; Owen, N. K.; Katti, K. V.; Volkert, W. A. Synthesis, Characterization, and Labeling with ^99mTc/¹⁸⁸Re of Peptide Conjugates Containing a Dithia-Bisphosphine Chelating Agent. Bioconjugate Chem. 2001, 12, 354– 363,  DOI: 10.1021/bc000077c

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    Synthesis, Characterization, and Labeling with 99mTc/188Re of Peptide Conjugates Containing a Dithia-bisphosphine Chelating Agent

    Gali, Hariprasad; Hoffman, Timothy J.; Sieckman, Gary L.; Owen, Nellie K.; Katti, Kattesh V.; Volkert, Wynn A.

    Bioconjugate Chemistry (2001), 12 (3), 354-363CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    Radiolabeling of small receptor-avid peptides at specific predetd. chelation sites with radioactive metals was an effective approach for prodn. of target-specific radiopharmaceuticals for diagnosis and therapy of diseases. Among various electron-donating groups found on chelator frameworks, phosphines are unique because they display versatile coordination chem. with a wide range of transition metals. The authors have recently reported the utility of a dithia-bis(hydroxymethyl)phosphine-based (P2S2) bifunctional chelating agent (BFCA) contg. air-stable primary phosphine groups to form 99mTc-labeled receptor-avid peptides by the preconjugation approach. Here the authors report a novel strategy for labeling small peptides with both 99mTc and 188Re using the P2S2-COOH (6,8-bis[3-(bis(hydroxymethyl)phosphanyl)propylsulfanyl]octanoic acid) BFCA by a postconjugation radiolabeling approach. The 1st step in this approach involves the coupling of the corresponding (PH2)2S2-COOH intermediate to the N-terminus of the peptide(s). Formylation of P-H bonds with aq. formaldehyde in the presence of HCl in EtOH affords the corresponding (hydroxymethyl)phosphine-P2S2-peptide conjugates as an oxidatively stable phosphonium salt. The P2S2-peptide conjugates are generated (the PH2 groups are converted to P(CH2OH)2 groups) by treatment of the P2S2-peptide phosphonium salt(s) with 1 M Na bicarbonate soln. at pH 8.5. Complexation of BFCA conjugates with 99mTc is achieved by direct redn. with Sn(II) tartrate to yield the 99mTc-P2S2-peptide conjugate in near quant. yields. Complexation of the BFCA conjugates with 188Re is achieved by transchelation with 188Re citrate in yields of ≥90%. (PH2)2S2-COOH BFCA was conjugated to model peptides. The glycylglycine Et ester (GlyGlyOEt)-(PH2)2S2-COOH BFCA conjugate was converted to the hydroxymethyl phosphine form and complexed with 99mTc to produce the 99mTcO2-P2S2-GlyGlyOEt conjugate in RCPs of ≥95%. This singular 99mTc product is stable over 24 h in aq. soln. as confirmed by HPLC. Identical retention times of the 99mTcO2-P2S2-GlyGlyOEt complex and its cold Re analog (ReO2-P2S2-GlyGlyOEt) on HPLC indicates similarity in structures at the macroscopic and the tracer levels. The utility of this postconjugation strategy was further demonstrated by synthesizing a P2S2-D-Lys6-LHRH conjugate and producing its corresponding 99mTc complex in RCPs of ≥88%. Finally, the P2S2-5-Ava-BBN[7-14]NH2 bombesin (BBN) analog was synthesized, the PH2 groups converted to P(CH2OH)2 groups and subsequently labeled with 188Re to yield a 188Re-labeled bombesin analog with a RCP of ≥90%. The biol. integrity of this conjugate was demonstrated in both in vitro and in vivo. The results of this study demonstrate that the (PH2)2S2-COOH BFCA can be conveniently used as a precursor for labeling small receptor-avid peptides with diagnostic (99mTc) and therapeutic (188Re) radionuclides via the postconjugation approach in high yields.
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    Karra, S. R.; Schibli, R.; Gali, H.; Katti, K. V.; Hoffman, T. J.; Higginbotham, C.; Sieckman, G. L.; Volkert, W. A. ^99mTc-Labeling and in vivo Studies of a Bombesin Analogue with a Novel Water-Soluble Dithiadiphosphine-Based Bifunctional Chelating Agent. Bioconjugate Chem. 1999, 10, 254– 260,  DOI: 10.1021/bc980096a

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    99mTc-Labeling and in Vivo Studies of a Bombesin Analog with a Novel Water-Soluble Dithiadiphosphine-Based Bifunctional Chelating Agent

    Karra, Srinivasa R.; Schibli, Roger; Gali, Hariprasad; Katti, Kattesh V.; Hoffman, Timothy J.; Higginbotham, Chris; Sieckman, Gary L.; Volkert, Wynn A.

    Bioconjugate Chemistry (1999), 10 (2), 254-260CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    Recent progress in the synthesis of water-sol. phosphine ligand systems and their corresponding 99mTc complexes prompted the development of a new bifunctional chelating agent (BFCA) based on a tetradentate dithiadiphosphine framework (P2S2-COOH). The detailed synthesis of this new BFCA is described. The corresponding 99mTc complex, 99mTc-P2S2-COOH, can be formed in >95% yield. To demonstrate the potential of this chelate to efficiently label peptides, 99mTc-P2S2-COOH was coupled to the N-terminal region of the truncated nine-amino acid bombesin analog, 5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 [BBN(7-14)], to form 99mTc-P2S2-BBN(7-14). Conjugation to the peptide was performed in borate buffer (pH 8.5) by applying the prelabeling approach in yields of >60%. In competitive binding assays, using Swiss 3T3 mouse fibroblast cells against [125I-Tyr4]bombesin, Re-P2S2-BBN(7-14) exhibited an IC50 value of 0.8 ± 0.4 nM. The pharmacokinetic studies of 99mTc-P2S2-BBN(7-14) and its ability to target tissue expressing gastrin-releasing peptide (GRP) receptors were performed in normal mice. The 99mTc-P2S2-BBN(7-14) exhibited fast and efficient clearance from the blood pool (0.6 ± 0.1% ID, 4 h postinjection) and excretion through the renal and hepatobiliary pathways (56.4 ± 8.2 and 28.1 ± 7.9% ID, 4 h postinjection, resp.). Significant uptake in the pancreas was obsd. (pancreatic acini cells express bombesin/GRP receptors), producing pancreas:blood and pancreas:muscle ratios of ca. 22 and 80, resp., at 4 h postinjection.
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    Hungnes, I. N.; Al-Salemee, F.; Gawne, P. J.; Eykyn, T.; Atkinson, R. A.; Terry, S. Y. A.; Clarke, F.; Blower, P. J.; Pringle, P. G.; Ma, M. T. One-Step, Kit-Based Radiopharmaceuticals for Molecular SPECT Imaging: A Versatile Diphosphine Chelator for ^99mTc Radiolabelling of Peptides. Dalton Trans. 2021, 50, 16156– 16165,  DOI: 10.1039/D1DT03177E

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    16

    One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for 99mTc radiolabelling of peptides

    Hungnes, Ingebjoerg N.; Al-Salemee, Fahad; Gawne, Peter J.; Eykyn, Thomas; Atkinson, R. Andrew; Terry, Samantha Y. A.; Clarke, Fiona; Blower, Philip J.; Pringle, Paul G.; Ma, Michelle T.

    Dalton Transactions (2021), 50 (44), 16156-16165CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)

    Radiotracers labeled with technetium-99m (99mTc) enable accessible diagnostic imaging of disease, provided that radiotracer prepn. is simple. While 99mTc radiopharmaceuticals for imaging perfusion are routinely prepd. from kits, and regularly used in healthcare, there are no 99mTc-labeled receptor-targeted radiopharmaceuticals in widespread clin. use. This is in part due to the multistep radiosyntheses required for the latter. We demonstrate that the diphosphine, 2,3-bis(diphenylphosphino)maleic anhydride (BMA), is an excellent platform for prepn. of kit-based, receptor-targeted 99mTc-labeled radiotracers: its conjugates are simple to prep. and can be easily labeled with 99mTc using one-step, kit-based protocols. Here, reaction of BMA with the αvβ3-integrin receptor targeted cyclic peptide, Arg-Gly-Asp-DPhe-Lys (RGD), provided the first diphosphine-peptide conjugate, DP-RGD. DP-RGD was incorporated into a "kit", and addn. of a saline soln. contg. 99mTcO4- to this kit, followed by heating, furnished the radiotracer [99mTcO2(DP-RGD)2]+ in consistently high radiochem. yields (>90%). The analogous [ReO2(DP-RGD)2]+ compd. was prepd. and characterised, revealing that both [99mTcO2(DP-RGD)2]+ and [ReO2(DP-RGD)2]+ consist of a mixt. of cis and trans geometric isomers. Finally, [99mTcO2(DP-RGD)2]+ exhibited high metabolic stability, and selectively targeted αvβ3-integrin receptors, enabling in vivo SPECT imaging of αvβ3-integrin receptor expression in mice.
17. 17

    Nuttall, R. E.; Pham, T. T.; Chadwick, A. C.; Hungnes, I. N.; Firth, G.; Heckenast, M. A.; Sparkes, H. A. M.; Galan, C.; Ma, M. T.; Pringle, P. G. Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules. Inorg. Chem. 2023,  DOI: 10.1021/acs.inorgchem.2c04008

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    There is no corresponding record for this reference.
18. 18

    Lewis, J. S.; Zweit, J.; Blower, P. J. Effect of Ligand and Solvent on Chloride Ion Coordination in Anti-Tumour Copper(I) Diphosphine Complexes: Synthesis of [Cu(dppe)₂]Cl and Analogous Complexes (dppe = 1,2-Bis(Diphenylphosphino)Ethane). Polyhedron 1998, 17, 513– 517,  DOI: 10.1016/S0277-5387(97)00343-4

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    18

    Effect of ligand and solvent on chloride ion coordination in anti-tumor copper(I) diphosphine complexes: synthesis of [Cu(dppe)2]Cl and analogous complexes (dppe = 1,2-bis(diphenylphosphino)ethane)

    Lewis, Jason S.; Zweit, Jamal; Blower, Philip J.

    Polyhedron (1998), 17 (4), 513-517CODEN: PLYHDE; ISSN:0277-5387. (Elsevier Science Ltd.)

    Complexes formed between Cu(I) and 1,2-bis(diphenylphosphino)ethane (L1) were previously isolated as salts of the [CuL12]+ cation if only noncoordinating anions are present, or as [Cu2Cl2L13] if chloride is present. The authors describe the synthesis of [CuL12]Cl, the stoichiometry of which is confirmed by elemental anal., FAB mass spectroscopy and cond. Polar solvents (water-EtOH mixts.) give the latter, whereas solvents of lower polarity (CHCl3, CH2Cl2) give the complexes contg. coordinated chloride. The related ligands cis-1,2-bis(diphenylphosphino)ethene, 1,2-bis(diethylphosphino)ethane, 1,2-bis(dimethylphosphino)ethane and 1,2-bis(hydroxymethylphosphino)ethane also form [CuL2]Cl. This behavior, and that of other 1,2-bisphosphine ligands, is rationalized in terms of competition between chloride and phosphine ligands for binding sites on the metal, with the equil. position detd. by solvent polarity, ligand structure and rigidity, and steric and electronic properties of the ligands.
19. 19

    Lewis, J. S.; Dearling, J. L. J.; Sosabowski, J. K.; Zweit, J.; Carnochan, P.; Kelland, L. R.; Coley, H. M.; Blower, P. J. Copper Bis(Diphosphine) Complexes: Radiopharmaceuticals for the Detection of Multi-Drug Resistance in Tumours by PET. Eur. J. Nucl. Med. 2000, 27, 638– 646,  DOI: 10.1007/s002590050557

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    19

    Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumors by PET

    Lewis, Jason S.; Dearling, Jason L. J.; Sosabowski, Jane K.; Zweit, Jamal; Carnochan, Paul; Kelland, Lloyd R.; Coley, Helen M.; Blower, Philip J.

    European Journal of Nuclear Medicine (2000), 27 (6), 638-646CODEN: EJNMD9; ISSN:0340-6997. (Springer-Verlag)

    Experience with imaging of the multi-drug resistance (MDR) phenotype in tumors using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp) transporter, suggests that better quantification of images and sepn. of MDR from other variables affecting tracer uptake in tumors are required. One approach to these problems is the development of short half-life positron-emitting tracers which are substrates of Pgp. Several lipophilic cationic copper(I) bis(diphosphine) complexes labeled with copper-64 have been synthesized and evaluated in vitro as substrates for Pgp. The synthesis is rapid and efficient with no need for purifn. steps. The chem. is suitable for use with very short half-life radionuclides such as copper-62 (9.7 min) and copper-60 (23.7 min). Incubation of the complexes with human serum in vitro showed that they are sufficiently stable in serum to support clin. imaging, and the more lipophilic members of the series are taken up rapidly by cells (Chinese hamster ovary and human ovarian carcinoma) in vitro with great avidity. Uptake in human ovarian carcinoma cells is significantly reduced after several months of conditioning in the presence of doxorubicin, which induces increased Pgp expression. Uptake in hooded rat sarcoma (HSN) cells, which express Pgp, is significantly increased in the presence of the MDR modulator cyclosporin A. Biodistribution studies in hooded rats show rapid blood clearance, excretion through both kidneys and liver, and low uptake in other tissues. The one complex investigated in HSN tumor-bearing rats showed uptake in tumor increasing up to 30 min p.i. while it was decreasing in other tissues. We conclude that diphosphine ligands offer a good basis for development of radiopharmaceuticals contg. copper radionuclides, and that this series of complexes should undergo further evaluation in vivo as positron emission tomog. imaging agents for MDR.
20. 20

    Lewis, J. S.; Zweit, J.; Dearling, J. L. J.; Rooney, B. C.; Blower, P. J. Copper(I) Bis(Diphosphine) Complexes as a Basis for Radiopharmaceuticals for Positron Emission Tomography and Targeted Radiotherapy. Chem. Commun. 1996, 1093– 1094,  DOI: 10.1039/cc9960001093

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    20

    Copper(I) bis(diphosphine) complexes as a basis for radiopharmaceuticals for positron emission tomography and targeted radiotherapy

    Lewis, Jason S.; Zweit, Jamal; Dearling, Jason L. J.; Rooney, Barrie C.; Blower, Philip J.

    Chemical Communications (Cambridge) (1996), (10), 1093-1094CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    Copper(I) bis(diphosphine) complexes provide an excellent basis for development of short/medium-lived PET (positron emission tomog.) imaging and therapy agents contg. copper radioisotopes, because of their extreme facility of synthesis and scope for derivatization and bioconjugate formation.
21. 21

    Lewis, J. S.; Heath, S. L.; Powell, A. K.; Zweit, J.; Blower, P. J. Diphosphine Bifunctional Chelators for Low-Valent Metal Ions. Crystal Structures of the Copper(I) Complexes [CuClL¹₂]and [CuL¹₂][PF₆][L¹ = 2,3-Bis(diphenylphosphino)maleic anhydride]. J. Chem. Soc. Dalt. Trans. 1997, 855– 862,  DOI: 10.1039/a607203h

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    There is no corresponding record for this reference.
22. 22

    Fei, M.; Sur, S. K.; Tyler, D. R. Reaction of (η₅-C₅Ph₅)₂Mo₂(CO)₆ with a Chelating Phosphine Ligand: Generation of Stable 17- and 19-Electron Complexes. Dynamic Equilibrium of (η₅-C₅Ph₅)₂Mo₂(CO)₆ and (η₅-C₅Ph₅)Mo(CO)₃. Organometallics 1991, 10, 419– 423,  DOI: 10.1021/om00048a017

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    22

    Reaction of (η5-C5Ph5)2Mo2(CO)6 with a chelating phosphine ligand: generation of stable 17- and 19-electron complexes. Dynamic equilibrium of (η5-C5Ph5)2Mo2(CO)6 and (η5-C5Ph5)Mo(CO)3

    Fei, Mao; Sur, Sandip K.; Tyler, David R.

    Organometallics (1991), 10 (2), 419-23CODEN: ORGND7; ISSN:0276-7333.

    The synthesis of (η5-C5Ph5)2Mo2(CO)6 is described. In soln., the dimer is in equil. with 2 17-electron (η5-C5Ph5)Mo(CO)3 monomers. The equil. const. for the dimer-monomer equil., as detd. by electronic absorption spectroscopy, is 8.7 (±5.1) × 10-5 at 23°. A 1 × 10-4M soln. of the dimer is thus 40% ± 15% dissocd. (η5-C5Ph5)2Mo2(CO)6 reacts with L2 [L2 = chelating phosphine ligand 2,3-bis(diphenylphosphino)maleic anhydride] to form the 19-electron (18 + δ) (η5-C5Ph5)Mo(CO)2(L2-P,P') (I) and the 17-electron (η5-C5Ph5)Mo(CO)2(L2-P) complexes. Variable-temp. ESR (ESR) showed a dynamic equil. between these 19- and 17-electron complexes with lower temp. favoring the 19-electron complex. Complex I has two magnetically equiv. P atoms, and the room-temp. ESR spectrum is a 1:2:1 triplet. This spectrum and its temp.-dependent behavior are compared with the spectrum of (η5-C5Ph4H)Mo(CO)2(L2-P,P'). IR, ESR, and electronic spectroscopic data are reported for all complexes generated in this study.
23. 23

    Mao, F.; Tyler, D. R.; Bruce, M. R. M.; Bruce, A. E.; Rieger, A. L.; Rieger, P. H. Solvent Effects on Electron Delocalization in Paramagnetic Organometallic Complexes: Solvent Manipulation of the Amount of 19-Electron Character in Co(CO)₃L₂ (L₂ = a Chelating Phosphine). J. Am. Chem. Soc. 1992, 114, 6418– 6424,  DOI: 10.1021/ja00042a019

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    23

    Solvent effects on electron delocalization in paramagnetic organometallic complexes: solvent manipulation of the amount of 19-electron character in Co(CO)3L2 (L2 = a chelating phosphine)

    Mao, Fei; Tyler, David R.; Bruce, Mitchell R. M.; Bruce, Alice E.; Rieger, Anne L.; Rieger, Philip H.

    Journal of the American Chemical Society (1992), 114 (16), 6418-24CODEN: JACSAT; ISSN:0002-7863.

    IR, ESR, and electronic absorption spectroscopic studies are reported on the 18 + δ Co(CO)3L2 complex where L2 is the chelating phosphine ligand 2,3-bis(diphenylphosphino)maleic anhydride. 18 + δ Complexes are 19-electron complexes in which the unpaired electron is primarily localized on a ligand. The spectra are solvent dependent and are interpreted in terms of increased delocalization of the unpaired electron from an L2(π*) orbital onto the Co(CO)3 portion of the mol. with decreasing solvent polarity. The relationship between the extent of delocalization onto the Co(CO)3 and the substitution reactivity of the mol. was studied. Increased delocalization increases the rate of CO loss (and hence dissociatively activated substitution) because the acceptor MO on the Co(CO)3 fragment is Co-CO antibonding (k(benzene, 25°) = (7.46 ± 0.04) × 10-2 s-1; k(CH2Cl2, 25°) = (5.47 ± 0.03) × 10-3 s-1). These substitution results are an exception to the rule of thumb which states that the lability of M-CO bonds decreases as the ν(C≡O) frequencies decrease. An SCF-Xα-SW calcn. on the Co(CO)3L2' complex (L2' = 2,3-bis(phosphino)maleic anhydride; i.e. L2' is L2 with the Ph groups replaced by H atoms) confirmed previous ESR spectroscopic results which showed that the SOMO on the Co(CO)3L2 complex is primarily an L2-based π* orbital.
24. 24

    Fenske, D.; Becher, H. J. 2,3-Bis(diphenylphosphino)maleinsäureanhydrid und Diphenylphosphinoderivate des Cyclobutendions als Liganden in Metallcarbonylen. Chem. Ber. 1974, 107, 117– 122,  DOI: 10.1002/cber.19741070114

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    24

    2,3-Bis(diphenylphosphino)maleic anhydride and diphenylphosphino derivatives of cyclobutenedione as ligands in metal carbonyls

    Fenske, Dieter; Becher, Hermann J.

    Chemische Berichte (1974), 107 (107), 117-22CODEN: CHBEAM; ISSN:0009-2940.

    2,3-Bis(diphenylphosphino)maleic anhydride (L) is prepd. from 2,3-dichloromaleic anhydride and Me3SiPPh2. With this compd. as a bidentate ligand, the complexes Ni(CO)2L and M(CO)4L (M = Cr, Mo, or W) are obtained. These are stable and deeply colored, due to an absorption band in the region of 17,500 cm-1 which shows a strong solvatochromic effect. With 1,2 - bis(diphenylphosphino)cyclobutenedione as ligand L, only the complex Ni(CO)2L could be prepd., which immediately decomposes in light. 1-(Diphenylphosphino)-2-phenylcyclobutenedione as an monodentate ligand, forms stable complexes of the type M(CO)5L (M = Cr or Mo).
25. 25

    Tolman, C. A. Steric Effects of Phosphorus Ligands in Organometallic Chemistry and Homogeneous Catalysis. Chem. Rev. 1977, 77, 313– 348,  DOI: 10.1021/cr60307a002

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    25

    Steric effects of phosphorus ligands in organometallic chemistry and homogeneous catalysis

    Tolman, Chadwick A.

    Chemical Reviews (Washington, DC, United States) (1977), 77 (3), 313-48CODEN: CHREAY; ISSN:0009-2665.

    A review, with 298 refs.
26. 26

    Tolman, C. A. Electron Donor-Acceptor Properties of Phosphorus Ligands. Substituent Additivity. J. Am. Chem. Soc. 1970, 92, 2953– 2956,  DOI: 10.1021/ja00713a006

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    26

    Electron donor-acceptor properties of phosphorus ligands. Substituent additivity

    Tolman, Chadwick A.

    Journal of the American Chemical Society (1970), 92 (10), 2953-6CODEN: JACSAT; ISSN:0002-7863.

    A rapid method is described for detg. electron donor-acceptor properties of triply connected P ligands based on the A1 carbonyl stretching frequency of Ni(CO)3L in CH2Cl2. Data are given for 70 ligands and a substituent additivity rule is proposed. Forty-seven substituent parameters χi are derived and found to correlate well with Kabachnik's σ parameters, based on ionization consts. of P acids.
27. 27

    Anton, D. R.; Crabtree, R. H. Metalation-Resistant Ligands: Some Properties of Dibenzocyclooctatetraene Complexes of Molybdenum, Rhodium, and Iridium. Organometallics 1983, 2, 621– 627,  DOI: 10.1021/om00077a009

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    27

    Metalation-resistant ligands: some properties of dibenzocyclooctatetraene complexes of molybdenum, rhodium and iridium

    Anton, Douglas R.; Crabtree, Robert H.

    Organometallics (1983), 2 (5), 621-7CODEN: ORGND7; ISSN:0276-7333.

    The chelating diolefinic ligand dibenzo[a,e]cyclooctatetraene (dct) displaces 1,5-cyclooctadiene (cod) from [Ir(cod)Cl]2 to give [Ir(dct)Cl]2. This reacts with AgBF4 and PPh3 to give [Ir(dct)L2]+ BF4-. Addn. of H at -80° gives cis-[IrH2(dct)L2]+ BF4-, which is stable at 20° in CH2Cl2 but rearranges with MeOH catalysis at -30° to cis,trans-[IrH2(dct)L2]BF4. This is the 1st case of such a catalyzed rearrangement and occurs via a deprotonation-reprotonation sequence. The intermediate [IrH(dct)L2] can be obtained from the cis,trans-dihydride and t-BuOK. Where L2 is (Ph2PCH2)2CH2 (dpp), a cis-dihydride is obtained at -80°, which rearranges with MeOH catalysis to a new trans isomer. The analogous Rh complex [Rh(dct)L2]+ PF6- (L = PPh3) does not react with H2, but [RhH2(dct)L2]+ PF6-, the 1st Rh dihydride olefin complex, can be obtained from dct and [RhH2(Me2CO)2L2]+ PF6-. The strongly electrophilic character imparted to its complexes by the dct ligand is discussed with ref. to the IR of (dct)Mo(CO)4, which suggests that dct is substantially more electron-withdrawing than cod. A Tolman-type electronic parameter for both monodentate and chelating ligands is proposed. The substitution of dct for cod makes the complex cis,trans-[IrH2(diene)(PPh3)2]+ BF4- more acidic by ≥8 pK units.
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    Berners-Price, S. J.; Sadler, P. J.; Brevard, C.; Pagelot, A. [Cu(Ph₂PCH₂CH₂PEt₂)₂]Cl: A Chelated Copper(I) Complex with Tetrahedral Stereochemistry. Rate of Inversion Compared with Those of Isostructural Silver(I) and Gold(I) Complexes. Inorg. Chem. 1986, 25, 596– 599,  DOI: 10.1021/ic00225a004

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    There is no corresponding record for this reference.
29. 29

    Berners-Price, S. J.; Johnson, R. K.; Mirabelli, C. K.; Faucette, L. F.; McCabe, F. L.; Sadler, P. J. Copper(I) Complexes with Bidentate Tertiary Phosphine Ligands: Solution Chemistry and Antitumor Activity. Inorg. Chem. 1987, 26, 3383– 3387,  DOI: 10.1021/ic00267a034

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    29

    Copper(I) complexes with bidentate tertiary phosphine ligands: solution chemistry and antitumor activity

    Berners-Price, Susan J.; Johnson, Randall K.; Mirabelli, Christopher K.; Faucette, Leo F.; McCabe, Francis L.; Sadler, Peter J.

    Inorganic Chemistry (1987), 26 (20), 3383-7CODEN: INOCAJ; ISSN:0020-1669.

    Cu may play an important role in the antitumor activity of diphosphines. [CuI(dppey)2]Cl and [CuI(dppp)2]Cl (dppey = Ph2PCH:CHPPh2; dppp = Ph2P(CH2)3PPh2) were prepd. and characterized. (CuCl)2(dppe)3 (dppe = Ph2P(CH2)2PPh2) underwent dissociative equil. in CDCl3 and CD2Cl2 solns., as detd. by temp.-dependent 1H and 31P NMR studies. One of the products was [Cu(dppe)2]+, the proportion of which increased on adding excess dppe. The complex was also a product from the reaction of Cu2+ with excess dppe in DMA. [Cu(P-P)2]Cl (P-P = dppey, dppp) and (CuCl)2(dppe)3 were all active against P388 leukemia, M5076 reticulum cell sarcoma, and B16 melanoma. [Cu(eppe)2]Cl (eppe = Et2P(CH2)2PPh2) was active only against P388 leukemia. The activities were comparable to those of the analogous Au(I) complexes, and complexes were more potent than the free ligands.
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    Imberti, C.; Terry, S. Y. A.; Cullinane, C.; Clarke, F.; Cornish, G. H.; Ramakrishnan, N. K.; Roselt, P.; Cope, A. P.; Hicks, R. J.; Blower, P. J.; Ma, M. T. Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(Hydroxypyridinone) Conjugates for Molecular Imaging of α_vβ₃ Integrin Expression with Gallium-68. Bioconjugate Chem. 2017, 28, 481– 495,  DOI: 10.1021/acs.bioconjchem.6b00621

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    30

    Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of αvβ3 Integrin Expression with Gallium-68

    Imberti, Cinzia; Terry, Samantha Y. A.; Cullinane, Carleen; Clarke, Fiona; Cornish, Georgina H.; Ramakrishnan, Nisha K.; Roselt, Peter; Cope, Andrew P.; Hicks, Rodney J.; Blower, Philip J.; Ma, Michelle T.

    Bioconjugate Chemistry (2017), 28 (2), 481-495CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (68Ga) under mild conditions, and the resulting radiotracers can delineate peptide receptor expression at sites of diseased tissue in vivo. We have synthesized a dendritic bifunctional chelator contg. nine 1,6-dimethyl-3-hydroxypyridin-4-one groups (SCN-HP9) that can coordinate up to three Ga3+ ions. This deriv. has been conjugated to a trimeric peptide (RGD3) contg. three peptide groups that target the αvβ3 integrin receptor. The resulting dendritic compd., HP9-RGD3, can be radiolabeled in 97% radiochem. yield at a 3-fold higher specific activity than its homologues HP3-RGD and HP3-RGD3 that contain only a single metal binding site. PET scanning and biodistribution studies show that [68Ga(HP9-RGD3)] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress αvβ3 integrin than [68Ga(HP3-RGD)] and [68Ga(HP3-RGD3)]. However, concomitant nontarget organ retention of [68Ga(HP9-RGD3)] results in low tumor to nontarget organ contrast in PET images. On the other hand, the trimeric peptide homolog contg. a single tris(hydroxypyridinone) chelator, [68Ga(HP3-RGD3)], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [68Ga(HP3-RGD3)] enables clear delineation of αvβ3 integrin receptor expression in vivo.
31. 31

    Frei, A.; Fischer, E.; Childs, B. C.; Holland, J. P.; Alberto, R. Two Is Better than One: Difunctional High-Affinity PSMA Probes Based on a [CpM(CO)₃] (M = Re/ ^99mTc) Scaffold. Dalt. Trans. 2019, 48, 14600– 14605,  DOI: 10.1039/C9DT02506E

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    There is no corresponding record for this reference.
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    Zia, N. A.; Cullinane, C.; Van Zuylekom, J. K.; Waldeck, K.; McInnes, L. E.; Buncic, G.; Haskali, M. B.; Roselt, P. D.; Hicks, R. J.; Donnelly, P. S. A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention. Angew. Chemie Int. Ed. 2019, 58, 14991– 14994,  DOI: 10.1002/anie.201908964

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    32

    A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention

    Zia, Nicholas A.; Cullinane, Carleen; Van Zuylekom, Jessica K.; Waldeck, Kelly; McInnes, Lachlan E.; Buncic, Gojko; Haskali, Mohammad B.; Roselt, Peter D.; Hicks, Rodney J.; Donnelly, Paul S.

    Angewandte Chemie, International Edition (2019), 58 (42), 14991-14994CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Mols. contg. lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prep. copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepd. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temp. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 h post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.
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    Tsionou, M. I.; Knapp, C. E.; Foley, C. A.; Munteanu, C. R.; Cakebread, A.; Imberti, C.; Eykyn, T. R.; Young, J. D.; Paterson, B. M.; Blower, P. J.; Ma, M. T. Comparison of Macrocyclic and Acyclic Chelators for Gallium-68 Radiolabelling. RSC Adv. 2017, 7, 49586– 49599,  DOI: 10.1039/C7RA09076E

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    33

    Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling

    Tsionou, Maria Iris; Knapp, Caroline E.; Foley, Calum A.; Munteanu, Catherine R.; Cakebread, Andrew; Imberti, Cinzia; Eykyn, Thomas R.; Young, Jennifer D.; Paterson, Brett M.; Blower, Philip J.; Ma, Michelle T.

    RSC Advances (2017), 7 (78), 49586-49599CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)

    Gallium-68 (68Ga) is a positron-emitting isotope used for clin. PET imaging of peptide receptor expression. 68Ga radiopharmaceuticals used in mol. PET imaging consist of disease-targeting biomols. tethered to chelators that complex 68Ga3+. Ideally, the chelator will rapidly, quant. and stably coordinate 68Ga3+ at room temp., near neutral pH and low chelator concn., allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based 68Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with 68Ga3+ is reported. Radiochem. yields have been measured under conditions of varying chelator concns., pH (3.5 and 6.5) and temp. (25 and 90°C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) contg. three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for 68Ga3+ under different pH and temp. conditions. Performing radiolabelling reactions at pH 6.5, 25°C and 5-50μM chelator concn. resulted in near quant. radiochem. yields for all chelators, except DOTA. Radiochem. yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temp., except in the case of DOTA. THP and DFO were the most effective 68Ga3+ chelators at near-neutral pH and 25°C, rapidly providing near-quant. radiochem. yields at very low chelator concns. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for 68Ga3+ complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of 68Ga-biomols. for mol. PET imaging. LC-MS and 1H, 13C{1H} and 71Ga NMR studies of HBED complexes of Ga3+ showed that under the anal. conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solns. contained octahedral [Ga(HBED)(H2O)], with HBED coordinated in a pentadentate N2O3 mode, with only one phenolic group coordinated to Ga3+, and the remaining coordination site occupied by a water mol.
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    Eder, M.; Neels, O.; Müller, M.; Bauder-Wüst, U.; Remde, Y.; Schäfer, M.; Hennrich, U.; Eisenhut, M.; Afshar-Oromieh, A.; Haberkorn, U.; Kopka, K. Novel Preclinical and Radiopharmaceutical Aspects of [⁶⁸Ga]Ga-PSMA-HBED-CC: A New PET Tracer for Imaging of Prostate Cancer. Pharmaceuticals 2014, 7, 779– 796,  DOI: 10.3390/ph7070779

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    Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer

    Eder, Matthias; Neels, Oliver; Mueller, Miriam; Bauder-Wuest, Ulrike; Remde, Yvonne; Schaefer, Martin; Hennrich, Ute; Eisenhut, Michael; Afshar-Oromieh, Ali; Haberkorn, Uwe; Kopka, Klaus

    Pharmaceuticals (2014), 7 (7), 779-796CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)

    The detection of prostate cancer lesions by PET imaging of the prostate-specific membrane antigen (PSMA) has gained highest clin. impact during the last years. 68Ga-labeled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) represents a successful novel PSMA inhibitor radiotracer which has recently demonstrated its suitability in individual first-in-man studies. The radiometal chelator HBED-CC used in this mol. represents a rather rarely used acyclic complexing agent with chem. characteristics favorably influencing the biol. functionality of the PSMA inhibitor. The simple replacement of HBED-CC by the prominent radiometal chelator DOTA was shown to dramatically reduce the in vivo imaging quality of the resp. 68Ga-labeled PSMA-targeted tracer proving that HBED-CC contributes intrinsically to the PSMA binding of the Glu-urea-Lys(Ahx) pharmacophore. Owing to the obvious growing clin. impact, this work aims to reflect the properties of HBED-CC as acyclic radiometal chelator and presents novel preclin. data and relevant aspects of the radiopharmaceutical prodn. process of [68Ga]Ga-PSMA-HBED-CC.
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    Bernal, P.; Raoul, J.-L.; Stare, J.; Sereegotov, E.; Sundram, F. X.; Kumar, A.; Jeong, J.-M.; Pusuwan, P.; Divgi, C.; Zanzonico, P.; Vidmar, G.; Buscombe, J.; Chau, T. T. M.; Saw, M. M.; Chen, S.; Ogbac, R.; Dondi, M.; Padhy, A. K. International Atomic Energy Agency-Sponsored Multination Study of Intra-Arterial Rhenium-188-Labeled Lipiodol in the Treatment of Inoperable Hepatocellular Carcinoma: Results With Special Emphasis on Prognostic Value of Dosimetric Study. Semin. Nucl. Med. 2008, 38, S40– S45,  DOI: 10.1053/j.semnuclmed.2007.10.006

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    Shinto, A. Rhenium 188: The Poor Man’s Yttrium. World J. Nucl. Med. 2017, 16, 1– 2,  DOI: 10.4103/1450-1147.198225

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    Rhenium 188: The Poor Man's Yttrium

    Shinto Ajit

    World journal of nuclear medicine (2017), 16 (1), 1-2 ISSN:1450-1147.

    There is no expanded citation for this reference.
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    Davison, A.; Orvig, C.; Trop, H. S.; Sohn, M.; DePamphilis, B. V.; Jones, A. G. Preparation of Oxobis(Dithiolato) Complexes of Technetium(V) and Rhenium(V). Inorg. Chem. 1980, 19, 1988– 1992,  DOI: 10.1021/ic50209a031

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    Preparation of oxobis(dithiolato) complexes of technetium(V) and rhenium(V)

    Davison, Alan; Orvig, Chris; Trop, Harvey S.; Sohn, Miriam; DePamphilis, Bruno V.; Jones, Alun G.

    Inorganic Chemistry (1980), 19 (7), 1988-92CODEN: INOCAJ; ISSN:0020-1669.

    A series of oxobis(dithiolato)metalate(V) complexes of Te and Re were prepd. and studied by various phys. techniques, including IR and optical spectroscopy and cyclic voltammetry. Phys. properties of the complexes are compared with respect to periodicity and the substituents on the ligand backbones. The stability of these five-coordinate complexes contradicts the current notion that Tc(V) and Re(V) complexes are inherently unstable in aq. soln.
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    Cooper, M. S.; Ma, M. T.; Sunassee, K.; Shaw, K. P.; Williams, J. D.; Paul, R. L.; Donnelly, P. S.; 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, 1029– 1039,  DOI: 10.1021/bc300037w

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    Comparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability

    Cooper, 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.
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    Jauregui-Osoro, M.; De Robertis, S.; Halsted, P.; Gould, S. M.; Yu, Z.; Paul, R. L.; Marsden, P. K.; Gee, A. D.; Fenwick, A.; Blower, P. J. Production of Copper-64 Using a Hospital Cyclotron: Targetry, Purification and Quality Analysis. Nucl. Med. Commun. 2021, 42, 1024– 1038,  DOI: 10.1097/MNM.0000000000001422

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    Production of copper-64 using a hospital cyclotron: targetry, purification and quality analysis

    Jauregui-Osoro, Maite; De Robertis, Simona; Halsted, Philip; Gould, Sarah-May; Yu, Zilin; Paul, Rowena L.; Marsden, Paul K.; Gee, Antony D.; Fenwick, Andrew; Blower, Philip J.

    Nuclear Medicine Communications (2021), 42 (9), 1024-1038CODEN: NMCODC; ISSN:0143-3636. (Lippincott Williams & Wilkins)

    To construct and evaluate a 64Cu prodn. system that minimises the amt. of costly 64Ni, radionuclidic impurities and nonradioactive metal contamination and maximises radiochem. and radionuclidic purity and molar activity; and to report anal. and quality control methods that can be used within typical PET radiochem. prodn. facilities to measure metal ion concns. and radiometal molar activities. Low vol. was ensured by dissolving the irradiated nickel in a low vol. of hydrochloric acid ( mL) using the concave gold target backing as a reaction vessel in a custom-built target holder. Removal of contaminating 55Co and nonradioactive trace metals was ensured by adding an intermediate hydrochloric acid concn. step during the conventional ion-exchange elution process. The radionuclidic purity of the product was detd. by half-life measurements, gamma spectroscopy and ion radiochromatog. Trace metal contamination and molar activity were detd. by ion chromatog. On a small scale, suitable for preclin. research, the process produced typically 3.2 GBq 64Cu in 2 mL soln. from 9.4 ± 2.1 mg nickel-64 electroplated onto a gold target backing. The product had high molar activity (121.5 GBq/μmol), was free of trace metal contamination detectable by ion chromatog. and has been used for many preclin. and clin. PET imaging applications.