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Genz J, Berton C, Kichou S, Klingler S, Nolff MC, Braband H, Holland JP. Photoradiolabeling of onartuzumab with 99mTc and 188Re-tricarbonyl for radiotheranostics of gastric cancer. Chem Sci 2025; 16:6219-6230. [PMID: 40123688 PMCID: PMC11924949 DOI: 10.1039/d4sc08089k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/11/2025] [Indexed: 03/25/2025] Open
Abstract
The clinically relevant nuclear isomer of technetium-99 (99mTc) and the radionuclides rhenium-186/188 (186Re and 188Re) represent an almost ideal match for the development of radiotracers for applications in diagnostic imaging and molecularly targeted radionuclide therapy. Although the chemistry of Tc and Re is similar, important differences arise in both the synthesis and properties of their complexes. Here, we report the synthesis and characterization of 99mTc- and 188Re-onartuzumab by labeling of the cancer-specific mAb onartuzumab (MetMAb) with the corresponding metal-tricarbonyl complexes derived from a novel photoactivatable ligand. The acyclic tris-amine ligand L1, featuring a photoactive aryl azide (ArN3) group, was synthesized from N 1-(2-aminoethyl)ethane-1,2-diamine in 5 steps with an overall yield of 32%. Radiosynthesis of the [M(CO)3L1]+ (M = 99mTc or 188Re) photoactivatable complexes was accomplished via reduction of the [MVIIO4]- species to give the intermediate 99mTcI- and 188ReI-tricarbonyl-triaquo followed by ligand substitution with L1. The light-induced photoradiosynthesis of [M(CO)3L1-azepin]-onartuzumab (M-onartuzumab; M = 99mTc or 188Re) was achieved by irradiating the [M(CO)3L1]+ complexes in the presence of onartuzumab (formulated as MetMAb), with 395 nm light for 15 minutes at room temperature. Photoradiolabeling reactions produced M-onartuzumab radioimmunoconjugates in decay-corrected radiochemical yields of 20-30%, high radiochemical purities (RCP > 95%), and in molar activities of 1.026-4.146 MBq nmol-1. Cellular binding assays confirmed the specificity of radiotracer binding toward human hepatocyte growth-factor receptor (c-MET) expression on the surface of MNK-45 gastric adenocarcinoma cells. Subsequent planar γ-ray scintigraphy imaging and ex vivo biodistribution experiments in mouse models bearing subcutaneous MKN-45 xenografts revealed specific tumor targeting compared against competitive inhibition (blocking) controls performed at 24 hours (99mTc and 188Re) and 72 hours (188Re). Tumor uptake reached 20.20 ± 4.05 %ID g-1 for 99mTc-onartuzumab and 22.13 ± 3.11 %ID g-1 for 188Re-onartuzumab after 24 hours. Blocking experiments confirmed tumor specificity, with a reduction in tumor uptake of approximately 70% for both 99mTc-onartuzumab and 188Re-onartuzumab. Experimental data also revealed the biochemical equivalence of 99mTc-onartuzumab and 188Re-onartuzumab in terms of stability and pharmacokinetics in vivo. For 188Re-onartuzumab, activity was retained in the tumor for over 72 hours, with uptake levels at 20.21 ± 1.47 %ID g-1. Overall, the experiments demonstrated that photoradiosynthesis can be employed to develop a variety of rhenium based radioimmunoconjugates for future applications in tumor targeted radioimmunotherapy. Furthermore, these results underline the high potential of rhenium and technetium radioconjugates as theranostic platforms.
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Affiliation(s)
- Jonas Genz
- University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland +41 44 63 53 990 www.hollandlab.org
| | - Cesare Berton
- University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland +41 44 63 53 990 www.hollandlab.org
| | - Samy Kichou
- University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland +41 44 63 53 990 www.hollandlab.org
| | - Simon Klingler
- University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland +41 44 63 53 990 www.hollandlab.org
| | - Mirja C Nolff
- Klinik für Kleintierchirurgie, Vetsuisse-Fakultät, University of Zurich Winterthurerstrasse 260 CH-8057 Zurich Switzerland
| | - Henrik Braband
- University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland +41 44 63 53 990 www.hollandlab.org
| | - Jason P Holland
- University of Zurich, Department of Chemistry Winterthurerstrasse 190 CH-8057 Zurich Switzerland +41 44 63 53 990 www.hollandlab.org
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Kálmán-Szabó I, Képes Z, Fekete A, Vágner A, Nagy G, Szücs D, Gyuricza B, Arató V, Varga J, Kárpáti L, Garai I, Mándity I, Bruchertseifer F, Elek J, Szikra D, Trencsényi G. In Vivo evaluation of newly synthesized 213Bi-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptide analogues in melanocortin-1 receptor (MC1-R) positive experimental melanoma model. J Pharm Biomed Anal 2023; 229:115374. [PMID: 37001274 DOI: 10.1016/j.jpba.2023.115374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/27/2023] [Accepted: 03/27/2023] [Indexed: 03/30/2023]
Abstract
Given the rising pervasiveness of melanocortin-1 receptor (MC1-R) positive melanoma malignum (MM) and pertinent metastases, radiolabelled receptor-affine alpha-melanocyte stimulating hormone-analogue (α-MSH analogue) imaging probes would be of crucial importance in timely tumor diagnostic assessment. Herein we aimed at investigating the biodistribution and the MM targeting potential of newly synthesized 213Bi-conjugated MC1-R specific peptide-based radioligands with the establishment of MC1-R overexpressing MM preclinical model. DOTA-conjugated NAP, -HOLD, -FOLD, -and MARSamide were labelled with 213Bi. Ex vivo biodistribution studies were conducted post-administration of 3.81 ± 0.32 MBq [213Bi]Bi-DOTA conjugated deriva-tives into twenty B16-F10 tumor-bearing C57BL/6 J and healthy mice. Organ Level Internal Dose Assessment (OLINDA) and IDAC-Dose were used to calculate translational data-based absorbed radiation dose in human organs. Moderate or low %ID/g uptake of [213Bi]Bi-DOTA conjugated NAP, -HOLD, -and MARSamide and significantly increased [213Bi]Bi-DOTA-FOLDamide accumulation was observed in the thoracic and abdominal organs (p ≤ 0.01). High [213Bi]Bi-DOTA-NAP (%ID/g:3.76 ± 0.96), -and FOLDamide (%ID/g:3.28 ± 0.95) tumor tracer activity confirmed their MC1-R-affinity. The bladder wall received the highest radiation absorbed dose followed by the kidneys (bladder wall: 1.95·10-2 and 8.97·10-2 mSv/MBq; kidneys: 7.47·10-3 vs. 5.88·10-2 mSv/MBq measured by IDAC and OLINDA; respectively) indicating the suitability of the NAPamide derivative for clinical use. These novel [213Bi]Bi-DOTA-linked peptide probes displaying meaningful MC1-R affinity could be promising molecular probes in MM imaging.
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Affiliation(s)
- Ibolya Kálmán-Szabó
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Zita Képes
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
| | - Anikó Fekete
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Adrienn Vágner
- Scanomed Ltd., Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Gábor Nagy
- Scanomed Ltd., Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Dániel Szücs
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Department of Physical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem square 1, H-4032 Debrecen, Hungary; Doctoral School of Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem square 1, H-4032 Debrecen, Hungary
| | - Barbara Gyuricza
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Doctoral School of Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem square 1, H-4032 Debrecen, Hungary
| | - Viktória Arató
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - József Varga
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Levente Kárpáti
- Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre St. 7, H-1092 Budapest, Hungary
| | - Ildikó Garai
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Scanomed Ltd., Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - István Mándity
- Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre St. 7, H-1092 Budapest, Hungary; Artificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok boulevard 2, H-1117 Budapest, Hungary
| | | | - János Elek
- Department of Inorganic and Analytical Chemistry, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Science Port Ltd., Debrecen, Elek St. 166, H-4225 Debrecen, Hungary
| | - Dezs Szikra
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - György Trencsényi
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
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Melis DR, Burgoyne AR, Ooms M, Gasser G. Bifunctional chelators for radiorhenium: past, present and future outlook. RSC Med Chem 2022; 13:217-245. [PMID: 35434629 PMCID: PMC8942221 DOI: 10.1039/d1md00364j] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/14/2022] [Indexed: 01/16/2023] Open
Abstract
Targeted radionuclide therapy (TRNT) is an ever-expanding field of nuclear medicine that provides a personalised approach to cancer treatment while limiting toxicity to normal tissues. It involves the radiolabelling of a biological targeting vector with an appropriate therapeutic radionuclide, often facilitated by the use of a bifunctional chelator (BFC) to stably link the two entities. The radioisotopes of rhenium, 186Re (t 1/2 = 90 h, 1.07 MeV β-, 137 keV γ (9%)) and 188Re (t 1/2 = 16.9 h, 2.12 MeV β-, 155 keV γ (15%)), are particularly attractive for radiotherapy because of their convenient and high-abundance β--particle emissions as well as their imageable γ-emissions and chemical similarity to technetium. As a transition metal element with multiple oxidation states and coordination numbers accessible for complexation, there is great opportunity available when it comes to developing novel BFCs for rhenium. The purpose of this review is to provide a recap on some of the past successes and failings, as well as show some more current efforts in the design of BFCs for 186/188Re. Future use of these radionuclides for radiotherapy depends on their cost-effective availability and this will also be discussed. Finally, bioconjugation strategies for radiolabelling biomolecules with 186/188Re will be touched upon.
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Affiliation(s)
- Diana R Melis
- SCK CEN, Belgian Nuclear Research Centre Boeretang 200 BE-2400 Mol Belgium +1 865 341 1413 +32 14 33 32 83
- Chimie ParisTech, Laboratory for Inorganic Chemical Biology, PSL University F-75005 Paris France www.gassergroup.com +33 1 44 27 56 02
| | - Andrew R Burgoyne
- SCK CEN, Belgian Nuclear Research Centre Boeretang 200 BE-2400 Mol Belgium +1 865 341 1413 +32 14 33 32 83
| | - Maarten Ooms
- SCK CEN, Belgian Nuclear Research Centre Boeretang 200 BE-2400 Mol Belgium +1 865 341 1413 +32 14 33 32 83
| | - Gilles Gasser
- Chimie ParisTech, Laboratory for Inorganic Chemical Biology, PSL University F-75005 Paris France www.gassergroup.com +33 1 44 27 56 02
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Abbasi Gharibkandi N, Conlon JM, Hosseinimehr SJ. Strategies for improving stability and pharmacokinetic characteristics of radiolabeled peptides for imaging and therapy. Peptides 2020; 133:170385. [PMID: 32822772 DOI: 10.1016/j.peptides.2020.170385] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/13/2020] [Accepted: 08/13/2020] [Indexed: 02/07/2023]
Abstract
Tumor cells overexpress a variety of receptors that are emerging targets in cancer chemotherapy. Radiolabeled peptides with high affinity and selectivity for these overexpressed receptors have been designed for both imaging and therapy purposes. Such peptides display advantages such as high selectivity for tumor cells, rapid tumor tissue penetration, and rapid clearance from non-target tissues and the circulation. However, the very short in vivo half-life of radiolabeled peptides, arising from enzymatic degradation and/or efficient clearance by the kidney, limits their accumulation in tumors. This review presents various strategies that have been applied to extend the half-life extension and improve the pharmacokinetic characteristics of radiolabeled peptides. These include amino acid substitution, modification of the peptide termini, dimerization and multimerization of the peptide, cyclization, conjugation with polymers, sugars and albumin and use of peptidase inhibitors.
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Affiliation(s)
- Nasrin Abbasi Gharibkandi
- Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran; Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - J Michael Conlon
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Seyed Jalal Hosseinimehr
- Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
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5
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Structural modifications of amino acid sequences of radiolabeled peptides for targeted tumor imaging. Bioorg Chem 2020; 99:103802. [DOI: 10.1016/j.bioorg.2020.103802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/19/2020] [Accepted: 03/25/2020] [Indexed: 12/18/2022]
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Gao F, Sihver W, Bergmann R, Walther M, Stephan H, Belter B, Neuber C, Haase-Kohn C, Bolzati C, Pietzsch J, Pietzsch HJ. Radiochemical and radiopharmacological characterization of a 64 Cu-labeled α-MSH analog conjugated with different chelators. J Labelled Comp Radiopharm 2019; 62:495-509. [PMID: 30912594 DOI: 10.1002/jlcr.3728] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/01/2019] [Accepted: 03/08/2019] [Indexed: 02/06/2023]
Abstract
Radiolabeled α-melanocyte-stimulating hormone (α-MSH) derivatives have a high potential for diagnosis and treatment of melanoma, because of high specificity and binding affinity to the melanocortin-1 receptor (MC1R). Hence, the α-MSH-derived peptide NAP-NS1 with a β-Ala linker (ε-Ahx-β-Ala-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2 ) was conjugated to different chelators: either to NOTA (p-SCN-Bn-1,4,7-triazacyclononane-1,4,7-triacetic acid), to a hexadentate bispidine carbonate derivative (dimethyl-9-(((4-nitrophenoxy)carbonyl)oxy)-2,4-di(pyridin-2-yl)-3,7-bis(pyridin-2-ylmethyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate), or to DMPTACN (p-SCN-Ph-bis(2-pyridyl-methyl)-1,4,7-triaza-cyclononane), labeled with 64 Cu, and investigated in terms of radiochemical and radiopharmacological properties. For the three 64 Cu-labeled conjugates negligible transchelation, suitable buffer and serum stability, as well as appropriate water solubility, was determined. The three conjugates exhibited high binding affinity (low nanomolar range) in murine B16F10, human MeWo, and human TXM13 cells. The Bmax values of [64 Cu]Cu-bispidine-NAP-NS1 ([64 Cu]Cu-2) and [64 Cu]Cu-DMPTACN-NAP-NS1 ([64 Cu]Cu-3) were higher than those of [64 Cu]Cu-NOTA-NAP-NS1 ([64 Cu]Cu-1), implying that different charged chelate units might have an impact on binding capacity. Preliminary in vivo biodistribution studies suggested the main excretion pathway of [64 Cu]Cu-1 and [64 Cu]Cu-3 to be renal, while that of [64 Cu]Cu-2 seemed to be both renal and hepatobiliary. An initial moderate uptake in the kidney decreased clearly after 60 minutes. All three 64 Cu-labeled conjugates should be considered for further in vivo investigations using a suitable xenograft mouse model.
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Affiliation(s)
- Feng Gao
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Wiebke Sihver
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Ralf Bergmann
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Martin Walther
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Holger Stephan
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Birgit Belter
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Christin Neuber
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Cathleen Haase-Kohn
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Cristina Bolzati
- Italian National Research Council - CNR, Institute of Condensed Matter Chemistry and Energy Technologies ICMATE-CNR, Padova, Italy
| | - Jens Pietzsch
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Hans-Jürgen Pietzsch
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany
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Zhang C, Lin KS, Bénard F. Molecular Imaging and Radionuclide Therapy of Melanoma Targeting the Melanocortin 1 Receptor. Mol Imaging 2018; 16:1536012117737919. [PMID: 29182034 PMCID: PMC5714078 DOI: 10.1177/1536012117737919] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Melanoma is a deadly disease at late metastatic stage, and early diagnosis and accurate staging remain the key aspects for managing melanoma. The melanocortin 1 receptor (MC1 R) is overexpressed in primary and metastatic melanomas, and its endogenous ligand, the α-melanocyte-stimulating hormone (αMSH), has been extensively studied for the development of MC1 R-targeted molecular imaging and therapy of melanoma. Natural αMSH is not well suited for this purpose due to low stability in vivo. Unnatural amino acid substitutions substantially stabilized the peptide, while cyclization via lactam bridge and metal coordination further improved binding affinity and stability. In this study, we summarized the development and the in vitro and in vivo characteristics of the radiolabeled αMSH analogues, including 99mTc-, 111In-, 67 Ga-, or 125I-labeled αMSH analogues for imaging with single-photon emission computed tomography; 68Ga-, 64Cu-, or 18F-labeled αMSH analogues for imaging with positron emission tomography; and 188Re-, 177Lu-, 90Y-, or 212Pb-labeled αMSH analogues for radionuclide therapy. These radiolabeled αMSH analogues showed promising results with high tumor uptake and rapid normal tissue activity clearance in the preclinical model of B16F1 and B16F10 mouse melanomas. These results highlight the potential of using radiolabeled αMSH analogues in clinical applications for molecular imaging and radionuclide therapy of melanoma.
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Affiliation(s)
- Chengcheng Zhang
- 1 Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada
| | - Kuo-Shyan Lin
- 1 Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada.,2 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - François Bénard
- 1 Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada.,2 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada
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Feng Y, Phelps TE, Carroll V, Gallazzi F, Sieckman G, Hoffman TJ, Barnes CL, Ketring AR, Hennkens HM, Jurisson SS. Chemistry and radiochemistry of As, Re and Rh isotopes relevant to radiopharmaceutical applications: high specific activity radionuclides for imaging and treatment. Dalton Trans 2017; 46:14677-14690. [PMID: 28951905 DOI: 10.1039/c7dt02407j] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
The chemistry and radiochemistry of high specific activity radioisotopes of arsenic, rhenium and rhodium are reviewed with emphasis on University of Missouri activities over the past several decades, and includes recent results. The nuclear facilities at the University of Missouri (10 MW research reactor and 16.5 MeV GE PETtrace cyclotron) allow research and development into novel theranostic radionuclides. The production, separation, enriched target recovery, radiochemistry, and chelation chemistry of 72,77As, 186,188Re and 105Rh are discussed.
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Affiliation(s)
- Yutian Feng
- Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
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Torabizadeh SA, Abedi SM, Noaparast Z, Hosseinimehr SJ. Comparative assessment of a 99m Tc labeled H1299.2-HYNIC peptide bearing two different co-ligands for tumor-targeted imaging. Bioorg Med Chem 2017; 25:2583-2592. [DOI: 10.1016/j.bmc.2017.03.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 03/15/2017] [Indexed: 01/15/2023]
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Sabahnoo H, Noaparast Z, Abedi SM, Hosseinimehr SJ. New small 99mTc-labeled peptides for HER2 receptor imaging. Eur J Med Chem 2017; 127:1012-1024. [DOI: 10.1016/j.ejmech.2016.11.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 10/19/2016] [Accepted: 11/05/2016] [Indexed: 01/05/2023]
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Carta D, Salvarese N, Morellato N, Gao F, Sihver W, Pietzsch HJ, Biondi B, Ruzza P, Refosco F, Carpanese D, Rosato A, Bolzati C. Melanoma targeting with [ 99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analogs: Effects of cyclization on the radiopharmaceutical properties. Nucl Med Biol 2016; 43:788-801. [PMID: 27694057 DOI: 10.1016/j.nucmedbio.2016.08.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/23/2016] [Accepted: 08/26/2016] [Indexed: 11/16/2022]
Abstract
The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla3-c[Lys4-Glu-His-D-Phe-Arg-Trp-Glu10]-Arg11-Pro-Val-NH2 (NAP-NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2 (NAP-NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells. The consistent [99mTc(N)(PNP3)]-labeled compounds were readily obtained in high specific activity and their stability and biological properties were assessed. As an example, the chemical identity of [99mTc(N)(NAP-NS1)(PNP3)]+ was confirmed by carrier added experiments supported by radio/UV HPLC analysis combined with ESI(+)-MS. Compared with the linear peptide, cyclization negatively affected the biological properties of NAP-NS2 peptide by reducing its binding affinity for MC1R and by decreasing the overall excretion rate of the corresponding [99mTc(N)(PNP3)]-labeled peptide from the body as well as its in vivo stability. [99mTc(N)(NAP-NS1)(PNP3)]+ was evaluated for its potential as melanoma imaging probe in murine melanoma model. Data from in vitro and in vivo studies on B16/F10 melanoma model of [99mTc(N)(NAP-NS1)(PNP3)]+ clearly evidenced that the radiolabeled linear peptide keeps its biological properties up on the conjugation to the [99mTc(N)(PNP3)]-building block. The progressive increase of the tumor-to-nontarget ratios over the time indicates a quite stable interaction between the radio-complex and the MC1R.
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Affiliation(s)
- Davide Carta
- Dipartimento di Scienze del Farmaco, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | | | - Nicolò Morellato
- Dipartimento di Scienze del Farmaco, University of Padova, Via Marzolo 5, 35131 Padova, Italy
| | - Feng Gao
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany
| | - Wiebke Sihver
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany
| | - Hans Jurgen Pietzsch
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328, Dresden, Germany
| | | | | | | | - Debora Carpanese
- Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, University of Padova, Via Gattamelata, 64, 35138 Padova
| | - Antonio Rosato
- Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, University of Padova, Via Gattamelata, 64, 35138 Padova,; Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata, 64, 35128 Padova, Italy
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Lakić M, Sabo L, Ristić S, Savić A, Petričević S, Nikolić N, Vukadinović A, Janković D, Sabo TJ, Vranješ-Đurić S. Synthesis and biological evaluation of99mTc tricarbonyl complex ofO,O′-diethylethylenediamine-N,N′-di-3-propanoate as potential tumour diagnostic agent. Appl Organomet Chem 2015. [DOI: 10.1002/aoc.3401] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Mladen Lakić
- University of Belgrade, Vinča Institute of Nuclear Sciences; Laboratory for Radioisotopes; Belgrade Serbia
| | - Ljubica Sabo
- Department of Nuclear Medicine; Clinical Center of Serbia; Belgrade Serbia
| | - Slavica Ristić
- Biomedical Research, R&D Institute; Galenika a.d. Batajnički Drum b.b.; Belgrade Serbia
| | | | - Saša Petričević
- University of Belgrade; Faculty of Medicine; Belgrade Serbia
| | - Nadežda Nikolić
- University of Belgrade, Vinča Institute of Nuclear Sciences; Laboratory for Radioisotopes; Belgrade Serbia
| | - Aleksandar Vukadinović
- University of Belgrade, Vinča Institute of Nuclear Sciences; Laboratory for Radioisotopes; Belgrade Serbia
| | - Drina Janković
- University of Belgrade, Vinča Institute of Nuclear Sciences; Laboratory for Radioisotopes; Belgrade Serbia
| | - Tibor J. Sabo
- University of Belgrade; Faculty of Chemistry; Belgrade Serbia
| | - Sanja Vranješ-Đurić
- University of Belgrade, Vinča Institute of Nuclear Sciences; Laboratory for Radioisotopes; Belgrade Serbia
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Dash A, Chakraborty S, Pillai MRA, Knapp FFR. Peptide receptor radionuclide therapy: an overview. Cancer Biother Radiopharm 2015; 30:47-71. [PMID: 25710506 DOI: 10.1089/cbr.2014.1741] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) is a site-directed targeted therapeutic strategy that specifically uses radiolabeled peptides as biological targeting vectors designed to deliver cytotoxic levels of radiation dose to cancer cells, which overexpress specific receptors. Interest in PRRT has steadily grown because of the advantages of targeting cellular receptors in vivo with high sensitivity as well as specificity and treatment at the molecular level. Recent advances in molecular biology have not only stimulated advances in PRRT in a sustainable manner but have also pushed the field significantly forward to several unexplored possibilities. Recent decades have witnessed unprecedented endeavors for developing radiolabeled receptor-binding somatostatin analogs for the treatment of neuroendocrine tumors, which have played an important role in the evolution of PRRT and paved the way for the development of other receptor-targeting peptides. Several peptides targeting a variety of receptors have been identified, demonstrating their potential to catalyze breakthroughs in PRRT. In this review, the authors discuss several of these peptides and their analogs with regard to their applications and potential in radionuclide therapy. The advancement in the availability of combinatorial peptide libraries for peptide designing and screening provides the capability of regulating immunogenicity and chemical manipulability. Moreover, the availability of a wide range of bifunctional chelating agents opens up the scope of convenient radiolabeling. For these reasons, it would be possible to envision a future where the scope of PRRT can be tailored for patient-specific application. While PRRT lies at the interface between many disciplines, this technology is inextricably linked to the availability of the therapeutic radionuclides of required quality and activity levels and hence their production is also reviewed.
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Affiliation(s)
- Ashutosh Dash
- 1 Isotope Production and Applications Division, Bhabha Atomic Research Centre , Mumbai, India
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14
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Billaud EMF, Vidal A, Vincenot A, Besse S, Bouchon B, Debiton E, Miot-Noirault E, Miladi I, Rbah-Vidal L, Auzeloux P, Chezal JM. Development and Preliminary Evaluation of TFIB, a New Bimodal Prosthetic Group for Bioactive Molecule Labeling. ACS Med Chem Lett 2015; 6:168-72. [PMID: 25699145 DOI: 10.1021/ml500423v] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 11/24/2014] [Indexed: 11/29/2022] Open
Abstract
The new readily available prosthetic group, tetrafluorophenyl 4-fluoro-3-iodobenzoate (TFIB), designed for both molecular imaging and targeted radionuclide therapy purposes was radiolabeled either with fluorine or iodine radionuclides with excellent radiochemical yields and purities. These radiolabeled tags were conjugated to N,N-diethylethylenediamine to give melanin-targeting radiotracers [ (125) I]9 and [ (18) F]9, which were successfully evaluated by PET and gamma scintigraphic imaging in B16F0 pigmented melanoma-bearing C57BL/6J mice. Then, radiolabeled [ (125) I]/[ (18) F]TFIB was used to tag tumor-targeting peptides (i.e., PEG3[c(RGDyK)]2 and NDP-MSH targeting αvβ3 integrin and MC1R receptors, respectively) in mild conditions and with good radiochemical yields (47-83% d.c.) and purities (>99%). The resulting radiolabeled peptides were assessed both in vitro and by PET imaging in animal models.
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Affiliation(s)
- Emilie M. F. Billaud
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Aurélien Vidal
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Amélie Vincenot
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Sophie Besse
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Bernadette Bouchon
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Eric Debiton
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Elisabeth Miot-Noirault
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Imen Miladi
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Latifa Rbah-Vidal
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
| | - Philippe Auzeloux
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
- Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Jean-Michel Chezal
- Clermont Université, Université d’Auvergne, Laboratoire d’Imagerie Moléculaire et
Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
- INSERM, U990, F-63005 Clermont-Ferrand, France
- Centre Jean Perrin, F-63011 Clermont-Ferrand, France
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15
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Barkey NM, Preihs C, Cornnell HH, Martinez G, Carie A, Vagner J, Xu L, Lloyd MC, Lynch VM, Hruby VJ, Sessler JL, Sill KN, Gillies RJ, Morse DL. Development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor. J Med Chem 2013; 56:6330-8. [PMID: 23863078 DOI: 10.1021/jm4005576] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R.
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Affiliation(s)
- Natalie M Barkey
- Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States
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Guo H, Gallazzi F, Miao Y. Design and evaluation of new Tc-99m-labeled lactam bridge-cyclized alpha-MSH peptides for melanoma imaging. Mol Pharm 2013; 10:1400-8. [PMID: 23418722 DOI: 10.1021/mp3006984] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The purpose of this study was to examine the melanoma targeting and imaging properties of new (99m)Tc-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (α-MSH) peptides using bifunctional chelating agents. MAG3-GGNle-CycMSH(hex), AcCG3-GGNle-CycMSH(hex), and HYNIC-GGNle-CycMSH(hex) peptides were synthesized, and their melanocortin-1 (MC1) receptor binding affinities were determined in B16/F1 melanoma cells. The biodistribution of (99m)Tc-MAG3-GGNle-CycMSH(hex), (99m)Tc-AcCG3-GGNle-CycMSH(hex), (99m)Tc(CO)3-HYNIC-GGNle-CycMSH(hex), and (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) were determined in B16/F1 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) were further examined because of its high melanoma uptake and fast urinary clearance. The IC50 values of MAG3-GGNle-CycMSH(hex), AcCG3-GGNle-CycMSH(hex), and HYNIC-GGNle-CycMSH(hex) were 1.0 ± 0.05, 1.2 ± 0.19, and 0.6 ± 0.04 nM in B16/F1 melanoma cells, respectively. Among these four (99m)Tc-peptides, (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) exhibited the highest melanoma uptake (14.14 ± 4.90% ID/g) and fastest urinary clearance (91.26 ± 1.96% ID) at 2 h postinjection. (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) showed high tumor to normal organ uptake ratios except for the kidneys. The tumor/kidney uptake ratios of (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) were 2.50 and 3.55 at 4 and 24 h postinjection. The melanoma lesions were clearly visualized by SPECT/CT using (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) as an imaging probe at 2 h postinjection. Overall, high melanoma uptake coupled with fast urinary clearance of (99m)Tc(EDDA)-HYNIC-GGNle-CycMSH(hex) highlighted its potential for metastatic melanoma detection in the future.
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Affiliation(s)
- Haixun Guo
- College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, USA
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Taylor SR, Roberts MP, Wyatt NA, Pham TQ, Stark D, Bourdier T, Roselt P, Katsifis A, Greguric I. Synthesis and Radiosynthesis of a Novel PET Fluorobenzyl Piperazine for Melanoma Tumour Imaging; [18F]MEL054. Aust J Chem 2013. [DOI: 10.1071/ch12489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
2-{2-[4-(4-[18F]-Fluorobenzyl)piperazin-1-yl]-2-oxoethyl}isoindolin-1-one ([18F]MEL054), is a new potent indolinone-based melanin binder designed to target melanotic tumours. [18F]MEL054 was prepared by an automated two-step radiosynthesis, comprising of the preparation of 4-[18F]fluorobenzaldehyde from 4-formyl-N,N,N-trimethylanilinium triflate, followed by reductive alkylation with 2-(2-oxo-2-piperazin-1-ylethyl)isoindolin-1-one. 4-[18F]Fluorobenzaldehyde was prepared on a GE TRACERlab FXFN module in 68 ± 8 % radiochemical yield (RCY, non-decay corrected), purified by a Sep-Pak Plus C18 cartridge and eluted into the reactor of an in-house modified Nuclear Interface [18F]FDG synthesis module for the subsequent reductive alkylation reaction. HPLC purification produced [18F]MEL054 in a collected RCY of 34 ± 9 % (non-decay corrected), the total preparation time (including Sep-Pak Plus C18 and HPLC purification) did not exceed 105 min. The radiochemical purity of [18F]MEL054 was greater than 99 % with a specific radioactivity of 71–119 GBq μmol–1 and [18F]MEL054 remained stable in saline solution (>98 %) after 3 h.
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18
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Tsiapa I, Loudos G, Varvarigou A, Fragogeorgi E, Psimadas D, Tsotakos T, Xanthopoulos S, Mihailidis D, Bouziotis P, Nikiforidis GC, Kagadis GC. Biological evaluation of an ornithine-modified (99m)Tc-labeled RGD peptide as an angiogenesis imaging agent. Nucl Med Biol 2012; 40:262-72. [PMID: 23238128 DOI: 10.1016/j.nucmedbio.2012.10.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 10/23/2012] [Accepted: 10/24/2012] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Radiolabeled RGD peptides that specifically target integrin α(ν)β(3) have great potential in early tumor detection through noninvasive monitoring of tumor angiogenesis. Based on previous findings of our group on radiopeptides containing positively charged aminoacids, we developed a new cyclic cRGDfK derivative, c(RGDfK)-(Orn)(3)-CGG. This new peptide availing the polar linker (Orn)(3) and the (99m)Tc-chelating moiety CGG (Cys-Gly-Gly) is appropriately designed for (99m)Tc-labeling, as well as consequent conjugation onto nanoparticles. METHODS A tumor imaging agent, c(RGDfK)-(Orn)(3)-[CGG-(99m)Tc], is evaluated with regard to its radiochemical, radiobiological and imaging characteristics. RESULTS The complex c(RGDfK)-(Orn)(3)-[CGG-(99m)Tc] was obtained in high radiochemical yield (>98%) and was stable in vitro and ex vivo. It presented identical to the respective, fully analytically characterized (185/187)Re complex retention time in RP-HPLC. In contrary to other RGD derivatives, we showed that the new radiopeptide exhibits kidney uptake and urine excretion due to the ornithine linker. High tumor uptake (3.87±0.48% ID/g at 60 min p.i.) was observed and was maintained relatively high even at 24 h p.i. (1.83±0.05 % ID/g), thus providing well-defined scintigraphic imaging. Accumulation in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells. CONCLUSION Due to its relatively high tumor uptake, renal elimination and negligible abdominal localization, the new (99m)Tc-RGD peptide is considered promising in the field of imaging α(ν)β(3)-positive tumors. However, the preparation of multifunctional SPECT/MRI contrast agents (RGD-conjugated nanoparticles) for dual modality imaging of integrin expressing tumors should be further investigated.
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Affiliation(s)
- Irene Tsiapa
- Department of Medical Physics, School of Medicine, University of Patras, P.O. BOX: 132 73, GR 265 04, Rion, Greece
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Tafreshi NK, Huang X, Moberg VE, Barkey NM, Sondak VK, Tian H, Morse DL, Vagner J. Synthesis and characterization of a melanoma-targeted fluorescence imaging probe by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. Bioconjug Chem 2012; 23:2451-9. [PMID: 23116461 DOI: 10.1021/bc300549s] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The incidence of malignant melanoma is rising more rapidly than that of any other cancer in the United States. The melanocortin 1 receptor (MC1R) is overexpressed in most human melanoma metastases, thus making it a promising target for imaging and therapy of melanomas. We have previously reported the development of a peptidomimetic ligand with high specificity and affinity for MC1R. Here, we have conjugated near-infrared fluorescent dyes to the C-terminus of this ligand via lysine-mercaptopropionic acid linkers to generate MC1R specific optical probes (MC1RL-800, 0.4 nM K(i); and MC1RL-Cy5, 0.3 nM K(i)). Internalization of the imaging probe was studied in vitro by fluorescence microscopy using engineered A375/MC1R cells and B16F10 cells with endogenous MC1R expression. The in vivo tumor targeting of MC1RL-800 was evaluated by intravenous injection of probe into nude mice bearing bilateral subcutaneous A375 xenograft tumors with low MC1R expression and engineered A375/MC1R tumors with high receptor expression. Melanotic B16F10 xenografts were also studied. Fluorescence imaging showed that the agent has higher uptake values in tumors with high expression compared to low (p < 0.05), demonstrating the effect of expression levels on image contrast-to-noise. In addition, tumor uptake was significantly blocked by coinjection of excess NDP-α-MSH peptide (p < 0.05). In conclusion, the MC1R-specific imaging probe developed in this study displays excellent potential for the intraoperative detection of regional node involvement and for margin detection during melanoma metastasis resection.
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Affiliation(s)
- Narges K Tafreshi
- Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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20
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Lim JC, Hong YD, Kim JJ, Choi SM, Baek HS, Choi SJ. Synthesis and biological evaluation of a novel (177)Lu-DOTA-[Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) analogue for melanocortin-1 receptor-positive tumor targeting. Cancer Biother Radiopharm 2012; 27:464-72. [PMID: 22831553 DOI: 10.1089/cbr.2011.1140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In this study, a novel α-melanocyte stimulating hormone (α-MSH) analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled [Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) (DOTA-GMSH) for melanocortin-1 receptor (MC-1R) targeting was newly synthesized, radiolabeled with (177)Lu, and in vitro and in vivo characterized. (177)Lu-labeled peptides were prepared with a high radiolabeling yield (>98%), and its Log p value was -2.89. No degradation was observed not only by serum incubation at 37°C for 7 days but also by an HPLC analysis of radioactive metabolites in urine. A cell binding assay revealed that an inhibitory concentration of 50% (IC(50)) of the peptide was 3.80 nM. The tumor-to-blood ratio, which was 14.27 at 2 hours p.i., was increased to 56.37 at 24 hours p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and was rapidly cleared from the blood pool. We, therefore, conclude that (177)Lu-DOTA-GMSH has promising characteristics for application in nuclear medicine, namely for the diagnosis of MC-1R over-expressing tumors.
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Affiliation(s)
- Jae Cheong Lim
- Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute (KAERI) , Daejeon, Republic of Korea
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21
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Barkey NM, Tafreshi NK, Josan JS, De Silva CR, Sill KN, Hruby VJ, Gillies RJ, Morse DL, Vagner J. Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. J Med Chem 2011; 54:8078-84. [PMID: 22011200 DOI: 10.1021/jm201226w] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH(2)) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.
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Affiliation(s)
- Natalie M Barkey
- Department of Imaging, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States
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Correia JDG, Paulo A, Raposinho PD, Santos I. Radiometallated peptides for molecular imaging and targeted therapy. Dalton Trans 2011; 40:6144-67. [DOI: 10.1039/c0dt01599g] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Abstract
Because no effective cures are available for cutaneous malignant melanoma, early diagnosis and accurate staging are of the utmost importance in increasing patient survival. Fluorodeoxyglucose positron emission tomography (PET)/computed tomography is a functional imaging technique that has contributed to ameliorating surveillance of patients with melanoma. New PET probes are under evaluation, and many have been tried in in vivo imaging protocols based on the use of small animal PET and animal models of cutaneous melanoma. Those compounds are targeted to a-melanocyte-stimulating hormone receptor and to the intracellular biosynthesis of melanin, and all of them showed promising results.
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Affiliation(s)
- Cristina Nanni
- UO Medicina Nucleare, Azienda Ospedaliero Universitaria di Bologna Policlinico S.Orsola-Malpighi, Via Massarenti n.9, 40138 Bologna, Italy
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Garg S, Kothari K, Thopate SR, Doke AK, Garg PK. Design, synthesis, and preliminary in vitro and in vivo evaluation of N-(2-diethylaminoethyl)-4-[18F]fluorobenzamide ([18F]-DAFBA): a novel potential PET probe to image melanoma tumors. Bioconjug Chem 2010; 20:583-90. [PMID: 19222206 DOI: 10.1021/bc8005094] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In order to develop a PET radiopharmaceutical to image malignant melanoma, we synthesized N-(2-diethylaminoethyl)-4-[(18)F]fluorobenzamide ([(18)F]-DAFBA). In vitro studies show a high uptake of [(18)F]-DAFBA by the B16F1 melanoma cells. No significant binding was seen for DAFBA to the sigma-1 and sigma-2 receptors in vitro. The in vivo biodistribution studies performed in normal ICR mice showed a low uptake in the normal tissues followed by further elimination of radioactivity from these tissues with time. The biodistribution studies performed in C57 mice bearing the melanoma tumor xenograft showed a rapid uptake of radioactivity in the tumor that reached a plateau within 30 min postinjection. The F-18 uptake in the tumor was 7.00 +/- 2.76, 6.57 +/- 1.66, and 5.80 +/- 0.98%ID/g at 60, 120, and 180 min, respectively. A steady uptake of radioactivity in the tumor and low uptake in normal tissues resulted in high tumor to normal tissue ratios. For example, at 180 min postinjection, the tumor to tissue ratios were 14.90 +/- 6.47, 21.90 +/- 4.68, 32.91 +/- 6.11, 39.73 +/- 11.78, and 6.33 +/- 1.9, for the spleen, lungs, muscle, blood, and liver, respectively. The radioactivity rapidly cleared from the blood pool, and it decreased from 0.68 +/- 0.21%ID/g at 60 min to 0.13 +/- 0.03%ID/g at 180 min. The F-18 uptake in the bones at 60, 120, and 180 min was 0.91 +/- 0.27, 0.57 +/- 0.32, and 0.17 +/- 0.05%ID/g, respectively. This low uptake in the bones reflects its in vivo resistance toward defluorination. A low residual activity in normal tissues and a high tumor uptake signifies the superior imaging potential of this compound. Because of these positive traits, [(18)F]-DAFBA could help delineate the tumor and its metastases when used for imaging applications. Further in vivo studies are underway to assess the potential of [(18)F]-DAFBA as a promising PET imaging probe.
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Affiliation(s)
- Sudha Garg
- PET Center, Department of Radiological Sciences, Wake Forest University Medical Center, Winston Salem, NC 27157, USA.
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Lee S, Xie J, Chen X. Peptides and peptide hormones for molecular imaging and disease diagnosis. Chem Rev 2010; 110:3087-111. [PMID: 20225899 DOI: 10.1021/cr900361p] [Citation(s) in RCA: 259] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Seulki Lee
- Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 31 Center Drive, Suite 1C14, Bethesda, Maryland 20892-2281, USA
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Abstract
Targeted molecular imaging techniques have become indispensable tools in modern diagnostics because they provide accurate and specific diagnosis of disease information. Conventional nonspecific contrast agents suffer from low targeting efficiency; thus, the use of molecularly targeted imaging probes is needed depending on different imaging modalities. Although recent technologies have yielded various strategies for designing smart probes, utilization of peptide-based probes has been most successful. Phage display technology and combinatorial peptide chemistry have profoundly impacted the pool of available targeting peptides for the efficient and specific delivery of imaging labels. To date, selected peptides that target a variety of disease-related receptors and biomarkers are in place. These targeting peptides can be coupled with the appropriate imaging moieties or nanoplatforms on demand with the help of sophisticated bioconjugation or radiolabeling techniques. This review article examines the current trends in peptide-based imaging probes developed for in vivo applications. We discuss the advantage of and challenges in developing peptide-based probes and summarize current systems with respect to their unique design strategies and applications.
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Affiliation(s)
- Seulki Lee
- Laboratory for Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 31 Center Drive, Suite 1C14, Bethesda, Maryland 20892-2281, USA
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28
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Bartholomä M, Valliant J, Maresca KP, Babich J, Zubieta J. Single amino acid chelates (SAAC): a strategy for the design of technetium and rhenium radiopharmaceuticals. Chem Commun (Camb) 2009:493-512. [PMID: 19283279 DOI: 10.1039/b814903h] [Citation(s) in RCA: 168] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Mark Bartholomä
- Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
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29
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Abstract
Skin cancer is the most common form of cancer types. It is generally divided into two categories: melanoma (∼ 5%) and nonmelanoma (∼ 95%), which can be further categorized into basal cell carcinoma, squamous cell carcinoma, and some rare skin cancer types. Biopsy is still the gold standard for skin cancer evaluation in the clinic. Various anatomical imaging techniques have been used to evaluate different types of skin cancer lesions, including laser scanning confocal microscopy, optical coherence tomography, high-frequency ultrasound, terahertz pulsed imaging, magnetic resonance imaging, and some other recently developed techniques such as photoacoustic microscopy. However, anatomical imaging alone may not be sufficient in guiding skin cancer diagnosis and therapy. Over the last decade, various molecular imaging techniques (in particular single photon emission computed tomography and positron emission tomography) have been investigated for skin cancer imaging. The pathways or molecular targets that have been studied include glucose metabolism, integrin αvβ3, melanocortin-1 receptor, high molecular weight melanoma-associated antigen, and several other molecular markers. Preclinical molecular imaging is thriving all over the world, while clinical molecular imaging has not lived up to the expectations because of slow bench-to-bedside translation. It is likely that this situation will change in the near future and molecular imaging will truly play an important role in personalized medicine of melanoma patients.
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Affiliation(s)
- Hao Hong
- Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin, USA
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30
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Miao Y, Quinn TP. Peptide-targeted radionuclide therapy for melanoma. Crit Rev Oncol Hematol 2008; 67:213-28. [PMID: 18387816 PMCID: PMC3197246 DOI: 10.1016/j.critrevonc.2008.02.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 02/06/2008] [Accepted: 02/20/2008] [Indexed: 12/23/2022] Open
Abstract
Melanocortin-1 receptor (MC1-R) and melanin are two attractive melanoma-specific targets for peptide-targeted radionuclide therapy for melanoma. Radiolabeled peptides targeting MC1-R/melanin can selectively and specifically target cytotoxic radiation generated from therapeutic radionuclides to melanoma cells for cell killing, while sparing the normal tissues and organs. This review highlights the recent advances of peptide-targeted radionuclide therapy of melanoma targeting MC1-R and melanin. The promising therapeutic efficacies of 188Re-(Arg(11))CCMSH (188Re-[Cys(3,4,10), D-Phe(7),Arg(11)]-alpha-MSH(3-13)), 177Lu- and 212Pb-labeled DOTA-Re(Arg(11))CCMSH (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[ReO-(Cys(3,4,10), D-Phe(7), Arg(11))]-alpha-MSH(3-13)) and 188Re-HYNIC-4B4 (188Re-hydrazinonicotinamide-Tyr-Glu-Arg-Lys-Phe-Trp-His-Gly-Arg-His) in preclinical melanoma-bearing models demonstrate an optimistic outlook for peptide-targeted radionuclide therapy for melanoma. Peptide-targeted radionuclide therapy for melanoma will likely contribute in an adjuvant setting, once the primary tumor has been surgically removed, to treat metastatic deposits and for treatment of end-stage disease. The lack of effective treatments for metastatic melanoma and end-stage disease underscores the necessity to develop and implement new treatment strategies, such as peptide-targeted radionuclide therapy.
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Affiliation(s)
- Yubin Miao
- College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
- Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA
- Department of Dermatology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Thomas P. Quinn
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
- Department of Radiology, University of Missouri, Columbia, MO 65211, USA
- Harry S. Truman Memorial Veteran Hospital, Columbia, MO 65201, USA
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31
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Zwanziger D, Khan IU, Neundorf I, Sieger S, Lehmann L, Friebe M, Dinkelborg L, Beck-Sickinger AG. Novel Chemically Modified Analogues of Neuropeptide Y for Tumor Targeting. Bioconjug Chem 2008; 19:1430-8. [DOI: 10.1021/bc7004297] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Denise Zwanziger
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Irfan Ullah Khan
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Ines Neundorf
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Stephanie Sieger
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Lutz Lehmann
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Matthias Friebe
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Ludger Dinkelborg
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
| | - Annette G. Beck-Sickinger
- Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany, and Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany
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32
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Okarvi SM. Peptide-based radiopharmaceuticals and cytotoxic conjugates: potential tools against cancer. Cancer Treat Rev 2007; 34:13-26. [PMID: 17870245 DOI: 10.1016/j.ctrv.2007.07.017] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Revised: 06/28/2007] [Accepted: 07/25/2007] [Indexed: 02/08/2023]
Abstract
A hope for the diagnosis and treatment of cancer is the development of new tumor-specific peptide-based radiopharmaceuticals. The overexpression of many peptide receptors on human tumors makes such receptors an attractive potential target for diagnostic imaging and radiotherapy with specifically designed radiolabeled peptides. The use of solid-phase peptide synthesis, and the availability of a wide range of bifunctional chelating agents for the convenient radiolabeling of bioactive peptides with different radionuclides have produced a wide variety of medicinally useful peptide radiopharmaceuticals. A few of these peptides, such as somatostatin, bombesin, cholecystokinin/gastrin, neurotensin and vasoactive intestinal peptide are currently under investigation for their possible clinical applications in nuclear oncology. This article presents the recent development in radiolabeled small peptides, with major emphasis on somatostatin and bombesin analogs.
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Affiliation(s)
- S M Okarvi
- Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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Gallium-68-labeled DOTA-rhenium-cyclized alpha-melanocyte-stimulating hormone analog for imaging of malignant melanoma. Nucl Med Biol 2007; 34:945-53. [PMID: 17998097 DOI: 10.1016/j.nucmedbio.2007.07.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Revised: 06/07/2007] [Accepted: 07/03/2007] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Diagnosis of malignant melanoma is critical, since a patient's prognosis is poor. Previous studies have shown that 64Cu- and 86Y-DOTA-ReCCMSH(Arg11) have the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of positron emission tomography (PET). This encouraged us to investigate DOTA-ReCCMSH(Arg11) labeled with another beta+-emitting radionuclide, 68Ga. METHODS DOTA-ReCCMSH(Arg11) was successfully labeled with 68Ga at pH 3.8-4 at 85 degrees C. Acute biodistribution and small-animal PET imaging studies were performed in mice bearing B16/F1 melanoma tumor. RESULTS Biodistribution studies showed moderate receptor-mediated tumor uptake, fast nontarget organ clearance and high tumor to nontarget tissue ratios. Preadministration of d-lysine significantly reduced kidney uptake without affecting the uptake of the agent in the tumor. Small-animal PET images showed that the tumor could be clearly visualized at all time points examined (0.5-2 h) with the standardized uptake value analysis following a similar trend as the biodistribution data. CONCLUSIONS The preliminary data obtained suggest that 68Ga-DOTA-ReCCMSH(Arg11) is a promising PET imaging agent for early detection of malignant melanoma.
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Cantorias MV, Howell RC, Todaro L, Cyr JE, Berndorff D, Rogers RD, Francesconi LC. MO tripeptide diastereomers (M=99/99mTc, Re): models to identify the structure of 99mTc peptide targeted radiopharmaceuticals. Inorg Chem 2007; 46:7326-40. [PMID: 17691766 PMCID: PMC2270398 DOI: 10.1021/ic070077p] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals based on 99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptide targeting vectors through solid-phase peptide synthesis and form stable TcVO complexes. Upon complexation with [TcO]3+, two products form; these are syn and anti diastereomers, and they often have different biological behavior. This is the case with the approved radiopharmaceutical [99mTcO]depreotide ([99mTcO]P829, NeoTect) that is used to image lung cancer. [99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment of the product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult to crystallize for structural analysis. In this study, we isolated diastereomers of [99TcO] and [ReO] complexes of several tripeptide ligands that model the metal chelator region of [99mTcO]depreotide. Using X-ray crystallography, we observed that the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the opposite side of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. 1H NMR and circular dichroism (CD) spectroscopy report on the metal environment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic features from these techniques that can be used to assign the diastereomer profile in 99mTc peptide radiopharmaceuticals like [99mTcO]depreotide and in 188Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, and NMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexes where lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N1-M bond. The pKa measurements of the N1 amine (pKa approximately 5.6) suggested that this amine is rendered more acidic by both metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating a lysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metal center. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. The N1 amine group on non-lysine-containing metallopeptides is not as acidic (pKa approximately 6.8) and does not deprotonate and crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) were radiolabeled with 99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normal female nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compounds exhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially higher organ uptake and slower blood clearance than the anti compounds.
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Affiliation(s)
- Melchor V. Cantorias
- Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, 695 Park Avenue, New York, New York 10021
| | - Robertha C. Howell
- Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, 695 Park Avenue, New York, New York 10021
| | - Louis Todaro
- Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, 695 Park Avenue, New York, New York 10021
| | - John E. Cyr
- Research Laboratories of Schering AG, Radiopharmaceuticals Research, Berlin, Germany
| | - Dietmar Berndorff
- Research Laboratories of Schering AG, Radiopharmaceuticals Research, Berlin, Germany
| | - Robin D. Rogers
- Department of Chemistry, University of Alabama, Tuscaloosa, Alabama 35487
| | - Lynn C. Francesconi
- Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, 695 Park Avenue, New York, New York 10021
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Pham TQ, Greguric I, Liu X, Berghofer P, Ballantyne P, Chapman J, Mattner F, Dikic B, Jackson T, Loc'h C, Katsifis A. Synthesis and evaluation of novel radioiodinated benzamides for malignant melanoma. J Med Chem 2007; 50:3561-72. [PMID: 17602544 DOI: 10.1021/jm0701627] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The imaging potential of a series of [123I]benzamides was studied in mice bearing B16F0 melanoma tumors. Compound [123I]25 exhibited tumor uptake >8 %ID/g at 1 h, while that of [123I]14d and [123I]25 reached a maximum of 9-12 %ID/g at 6 h. Standardized uptake values of [123I]14d were higher than 100 between 24 and 72 h after injection. In haloperidol treated animals, the tumor uptake of [123I]14d was not significantly different to controls, while significant reduction of [123I]25 uptake was observed, supporting that [123I]14d uptake relates to melanin interaction, whereas part of the mechanism of [123I]25 uptake is related to its sigma 1-receptor affinity. Benzamides 14d and 25, which display rapid and high tumor uptake, appear to be promising imaging agents for melanoma detection, while 14d, which displays a long lasting and high melanoma/nontarget ratio, is more suitable for evaluation as a potential radiotherapeutic.
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Affiliation(s)
- Tien Q Pham
- Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, PMB 1 Menai N.S.W. 2234, Sydney, Australia
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Cheng Z, Zhang L, Graves E, Xiong Z, Dandekar M, Chen X, Gambhir SS. Small-animal PET of melanocortin 1 receptor expression using a 18F-labeled alpha-melanocyte-stimulating hormone analog. J Nucl Med 2007; 48:987-94. [PMID: 17504880 PMCID: PMC4154809 DOI: 10.2967/jnumed.107.039602] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
UNLABELLED (18)F-Labeled small synthetic peptides have emerged as attractive probes for imaging various molecular targets with PET. The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor (melanocortin type 1 receptor [MC1R]) is overexpressed in most murine and human melanomas. It is a promising molecular target for diagnosis and therapy of melanomas. However, (18)F compounds have not been successfully developed for imaging the MC1R. METHODS In this study, an alpha-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH(2) (NAPamide), was radiolabeled with N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB). The resulting radiopeptide was evaluated as a potential molecular probe for small-animal PET of melanoma and MC1R expression in melanoma xenografted mouse models. RESULTS The binding affinity of (19)F-SFB-conjugated NAPamide, (19)F-FB-NAPamide, was determined to be 7.2 +/- 1.2 nM (mean +/- SD) using B16/F10 cells and (125)I-(Tyr(2))-[Nle(4),D-Phe(7)]-alpha-MSH [(125)I-(Tyr(2))-NDP] as a radioligand. The biodistribution of (18)F-FB-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16/F10 melanoma tumors with high expression of MC1Rs and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Biodistribution experiments showed that tumor uptake values (percentage injected dose per gram of tumor [%ID/g]) of (18)F-FB-NAPamide were 1.19 +/- 0.11 %ID/g and 0.46 +/- 0.11 %ID/g, in B16/F10 and A375M xenografted melanoma at 1 h after injection, respectively. Furthermore, the B16/F10 tumor uptake was significantly inhibited by coinjection with excess alpha-MSH peptide (P < 0.05), indicating that (18)F-FB-NAPamide specifically recognizes the MC1R in living mice. Small-animal PET of (18)F-FB-NAPamide in mice bearing B16/F10 and A375M tumors at 1 h after tail vein injection revealed good B16/F10 tumor-to-background contrast and low A375M tumor-to-background ratios. CONCLUSION (18)F-FB-NAPamide is a promising molecular probe for alpha-MSH receptor-positive melanoma PET and warrants further study.
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Affiliation(s)
- Zhen Cheng
- Molecular Imaging Program at Stanford, Stanford University, Stanford, California 94305, USA.
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Cheng Z, Xiong Z, Subbarayan M, Chen X, Gambhir SS. 64Cu-labeled alpha-melanocyte-stimulating hormone analog for microPET imaging of melanocortin 1 receptor expression. Bioconjug Chem 2007; 18:765-72. [PMID: 17348700 PMCID: PMC4143155 DOI: 10.1021/bc060306g] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor (melanocortin type 1 receptor, or MC1R) plays an important role in the development and growth of melanoma cells. It was found that MC1R was overexpressed on most murine and human melanoma, making it a promising molecular target for melanoma imaging and therapy. Radiolabeled alpha-MSH peptide and its analogs that can specifically bind with MC1R have been extensively explored for developing novel agents for melanoma detection and radionuclide therapy. The goal of this study was to evaluate a 64Cu-labeled alpha-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys(DOTA)-NH2 (DOTA-NAPamide), as a potential molecular probe for microPET imaging of melanoma and MC1R expression in melanoma xenografted mouse models. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated NAPamide was synthesized and radiolabeled with 64Cu (t1/2=12 h) in NH4OAc (0.1 M; pH 5.5) buffered solution for 60 min at 50 degrees C. Cell culture studies reveal rapid and high uptake and internalization of 64Cu-DOTA-NAPamide in B16F10 cells. Over 90% of receptor-bound tracer is internalized at 3 h incubation. A cellular retention study demonstrates that the receptor-bound 64Cu-DOTA-NAPamide is slowly released from the B16F10 cells into the medium; 66% of the radioactivity is still associated with the cells even after 3 h incubation. The biodistribution of 64Cu-DOTA-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16F10 melanoma tumors with high capacity of MC1R and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Tumor uptake values of 64Cu-DOTA-NAPamide are found to be 4.63 +/- 0.45% and 2.49 +/- 0.31% ID/g in B16F10 and A375M xenografted melanoma at 2 h postinjection (pi), respectively. The B16F10 tumor uptake at 2 h pi is further inhibited to 2.29 +/- 0.24% ID/g, while A375M tumor uptake at 2 h pi remains 2.20 +/- 0.41% ID/g with a coinjection of excess alpha-MSH peptide. MicroPET imaging of 64Cu-DOTA-NAPamide in B16F10 tumor mice clearly shows good tumor localization. However, low A375M tumor uptake and poor tumor to normal tissue contrast were observed. This study demonstrates that 64Cu-DOTA-NAPamide is a promising molecular probe for alpha-MSH receptor positive melanoma PET imaging as well as MC1R expression imaging in living mice.
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Affiliation(s)
- Zhen Cheng
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, Stanford, California 94305-5344, USA.
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Banerjee SR, Maresca KP, Francesconi L, Valliant J, Babich JW, Zubieta J. New directions in the coordination chemistry of 99mTc: a reflection on technetium core structures and a strategy for new chelate design. Nucl Med Biol 2005; 32:1-20. [PMID: 15691657 DOI: 10.1016/j.nucmedbio.2004.09.001] [Citation(s) in RCA: 153] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2004] [Revised: 08/31/2004] [Accepted: 09/01/2004] [Indexed: 11/26/2022]
Abstract
Bifunctional chelates offer a general approach for the linking of radioactive metal cations to macromolecules. In the specific case of 99mTc, a variety of technologies have been developed for assembling a metal-chelate-biomolecule complex. An evaluation of these methodologies requires an appreciation of the coordination characteristics and preferences of the technetium core structures and oxidation states, which serve as platforms for the development of the imaging agent. Three technologies, namely, the MAG3-based bifunctional chelates, the N-oxysuccinimidylhydrazino-nicotinamide system and the recently described single amino acid chelates for the {Tc(CO)3}1+ core, are discussed in terms of the fundamental coordination chemistry of the technetium core structures. In assessing the advantages and disadvantages of these technologies, we conclude that the single amino acid analogue chelates (SAAC), which are readily conjugated to small peptides by solid-phase synthesis methods and which form robust complexes with the {Tc(CO)3}1+ core, offer an effective alternative to the previously described methods.
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Affiliation(s)
- Sangeeta Ray Banerjee
- Department of Chemistry, Syracuse University, Center for Science and Technology, Syracuse, NY 13244, USA
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Cheng Z, Chen J, Quinn TP, Jurisson SS. Radioiodination of Rhenium Cyclized α-Melanocyte-Stimulating Hormone Resulting in Enhanced Radioactivity Localization and Retention in Melanoma. Cancer Res 2004; 64:1411-8. [PMID: 14973076 DOI: 10.1158/0008-5472.can-03-0193] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Radiohalogenated alpha-melanocyte-stimulating hormone (alpha-MSH) analogs were proposed for melanoma imaging and potential radiotherapy because alpha-MSH receptors are overexpressed on both mouse and human melanoma cell lines. However, biodistribution studies in tumor-bearing mice with radiohalogenated alpha-MSH peptides showed very rapid tumor radioactivity wash out due to lysosomal degradation of the radiohalogenated complex after internalization, which decreased the therapeutic efficacy significantly (R. Stein et al., Cancer Res., 55: 3132-3139, 1995; P. K. Garg et al., Bioconjugate Chem., 6: 493-501, 1995.). The melanoma-targeting metallopeptide ReO[Cys(3,4,10),D-Phe(7)]alpha-MSH(3-13) (ReCCMSH) was shown to possess high tumor uptake and retention properties (J. Chen et al., Cancer Res., 60: 5649-5658, 2000). Therefore, three peptides, Ac-Lys-ReCCMSH(Arg(11)), Ac-D-Lys-ReCCMSH(Arg(11)), and [Nle(4),D-Phe(7)]alpha-MSH (NDP) (for comparison), labeled with N-succinimidyl 4-[(125)I]iodobenzoate ((125)I-PIB), were prepared and evaluated in vitro and in vivo to develop radiohalogenated alpha-MSH peptide analogs with high tumor uptake, retention, and favorable biodistribution characteristics. In vitro cell binding and internalization data showed that approximately 90% of radioiodinated peptides were internalized at 2 h in cultured B16/F1 melanoma cells. Cellular retention studies showed that the receptor-bound radioiodinated linear alpha-MSH analog NDP was released from the cells into the medium very quickly, whereas significant amounts of cell-associated radioactivity remained in the cells for Ac-Lys((125)I-3- or 4-iodobenzoate (IBA))-ReCCMSH(Arg(11)) and Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)). The in vitro data clearly demonstrate that rhenium cyclization significantly enhanced peptide trapping in the cells, as did D-amino acid incorporation. The combination of these two effects resulted in a 2.9-fold increase in the retention of radioactivity for Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) relative to (125)I-IBA-NDP at 4 h. In vivo studies also showed that Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) exhibited extremely high radioactivity accumulation and prolonged retention in the tumor. Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) and Ac-Lys((125)I-IBA)-ReCCMSH(Arg(11)) exhibited much higher tumor uptake at 24 h after injection compared with (125)I-IBA-NDP [7.18% injected dose/gram (ID/g), 4.92% ID/g, and 0.26% ID/g, respectively]. Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) also showed very fast whole body clearance and low nonspecific radioactivity accumulation in normal tissues compared with (125)I-IBA-NDP and Ac-Lys((125)I-IBA)-ReCCMSH(Arg(11)). A tumor:blood ratio of 34.3 was observed for Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) at 24 h postinjection, whereas values of 4.3 and 2.0 were observed for Ac-Lys((125)I-IBA)-ReCCMSH(Arg(11)) and (125)I-IBA-NDP, respectively. The biodistribution data clearly demonstrate that both rhenium cyclization and D-Lys incorporation enhanced the tumor localization and retention of the radiolabel. Therefore Ac-D-Lys-ReCCMSH(Arg(11)) is an excellent candidate for additional therapeutic studies.
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Affiliation(s)
- Zhen Cheng
- Department of Chemistry, Chemistry Building, University of Missouri-Columbia, Columbia, MO 65211, USA
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Okarvi SM. Peptide-based radiopharmaceuticals: Future tools for diagnostic imaging of cancers and other diseases. Med Res Rev 2004; 24:357-97. [PMID: 14994368 DOI: 10.1002/med.20002] [Citation(s) in RCA: 165] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Small synthetic receptor-binding peptides are the agents of choice for diagnostic imaging and radiotherapy of cancers due to their favorable pharmacokinetics. Molecular modification techniques permit the synthesis of a variety of bioactive peptides with chelating groups, without compromising biological properties. Various techniques have been developed that allow efficient and site-specific labeling of peptides with clinically useful radionuclides such as (99m)Tc, (123)I, (111)In, and (18)F. Among them, (99m)Tc is the radionuclide of choice because of its excellent chemical and imaging characteristics. Recently, many (99m)Tc-labeled peptides have proven to be useful imaging agents. Beside (99m)Tc-labeled peptides, several peptides radiolabeled with (111)In and (123)I have been prepared and characterized. In addition, (18)F-labeled peptides hold clinical potential due to their ability to quantitatively detect and characterize a variety of human diseases using positron-emission tomography. The availability of this wide range of peptides labeled with different radionuclides offers multiple diagnostic and therapeutic applications. Various receptors are over-expressed in particular tumor types and peptides binding to these receptors can be used to visualize tumor lesions scintigraphically. Thus, radiolabeled peptides have potential use as carriers for the delivery of radionuclides to tumors, infarcts, and infected tissues for diagnostic imaging and radiotherapy. Many radiolabeled peptides are currently under investigation to determine their potential as imaging agents. These peptides are designed mainly for thrombus, tumor, and infection/inflammation imaging. This article presents recent developments in small synthetic peptides for imaging of thrombosis, tumors, and infection/inflammation.
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Affiliation(s)
- Subhani M Okarvi
- Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia.
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Chen J, Cheng Z, Miao Y, Jurisson SS, Quinn TP. Alpha-melanocyte-stimulating hormone peptide analogs labeled with technetium-99m and indium-111 for malignant melanoma targeting. Cancer 2002; 94:1196-201. [PMID: 11877745 DOI: 10.1002/cncr.10284] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Previous studies have shown that the compact structure of a rhenium-cyclized alpha--melanocyte-stimulating hormone peptide analog, [Cys3410,D-Phe7]alpha-MSH(3--13), or Re-CCMSH, significantly enhanced its in vivo tumor uptake and retention. In this study, the metal chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to the N-terminus of Re-CCMSH in order to develop a melanoma-targeting peptide that could be labeled with a wider variety of imaging and therapeutic radionuclides. METHODS Biodistribution properties of indium-111 ((111)In)--labeled DOTA-Re-CCMSH were compared with the non-DOTA-containing technetium-99m ((99m)Tc)--CCMSH in murine melanoma--bearing C57 mice to determine the effects of DOTA on tumor uptake and whole-body clearance. The tumor targeting capacity and clearance kinetics of (111)In-DOTA-Re-CCMSH were also compared with other related cyclic and linear (111)In-labeled DOTA-alpha-MSH complexes. RESULTS The in vivo distribution data showed that the conjugation of DOTA to Re-CCMSH did not reduce its initial tumor uptake kinetics but did enhance its tumor retention and renal clearance properties. The tumor uptake of (111)In-DOTA-Re-CCMSH was significantly higher than the other (111)In-DOTA--coupled cyclic or linear alpha-MSH analogs used in this study. Moreover, (111)In-DOTA-Re-CCMSH displayed lower radioactivity accumulation in normal tissues of interest than its non-Re-cyclized counterpart, (111)In-DOTA-CCMSH; the disulfide bond--cyclized (111)In-DOTA-CMSH; or the linear (111)In-DOTA-NDP. CONCLUSIONS Peptide cyclization via rhenium coordination significantly enhanced the tumor targeting and renal clearance properties of DOTA-Re-CCMSH, making it an excellent candidate for melanoma radiodetection and radiotherapy.
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Affiliation(s)
- JianQing Chen
- Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
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Lou C, Chen ZN, Bian HJ, Li J, Zhou SB. Pharmacokinetics of radioimmunotherapeutic agent of direct labeling mAb 188Re-HAb18. World J Gastroenterol 2002; 8:69-73. [PMID: 11833074 PMCID: PMC4656629 DOI: 10.3748/wjg.v8.i1.69] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To label anti-hepatoma monoclonal antibody (mAb) fragment HAb18 F(ab’)2 was labeled with 188Re for the pharmacokinetic model of 188Re-HAb18 F(ab’)2 and to evaluate its pharmacokinetic parameters in hepatoma-bearing nude mice.
METHODS: HAb18 F(ab’)2 was directly labeled with 188Re using 2-mercaptoethanol (2-ME) as reducing agents. Labeling efficiency and immunoreactivity of 188Re-HAb18 F(ab’)2 were evaluated by Whatman 3MM paper chromatography and live cell assay, respectively. Biodistribution analysis was also conducted in nude mice bearing human hepatoma in which animals were sacrificed at different time points (1, 4, 18, 24 and 24 h) after 188Re-HAb18 F (ab’)2 was injected through tail-vein into hepatoma-bearing nude mice. The blood and radioactivity of organs and mass were measured. The concentrations of 188Re-HAb18 F(ab’)2 were evaluated with apharmacokinetic 3P97 software.
RESULTS: The optimum labeling efficiency and immunoreactive fraction were 91.7% and 0.78% respectively. The parameters of 188Re-HAb18 F(ab’)2 were: T1/2, 2.29 h; Vd,1.49 × 10-9 L·Bq-1; AUC, 20. 49 × 109 Bq·h·L-1;CL, 0.45 × 10-3 L·h-1. 188Re-HAb18 F(ab’)2 could locate specially in hepatoma with high selective reactivity of HAb18 F(ab’)2. 188Re-HAb18 F(ab’)2 was mainly eliminated by kidney. The maximal tumor to blood ratio was at 48 h, and maximal tumor to liver ratio was at 18 h.
CONCLUTION: The pharmacokinetics of 188Re-HAb18 F (ab’)2 fital-compartment model.188Re-HAb18 F(ab’)2 can be uptaken selectively at the hepatoma site.
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Affiliation(s)
- Chao Lou
- Department of Cell Engineering Research Centre, Fourth Military Medical University, Xi'an 710033, Shaanxi Province, China.
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Rao PS, Li H, Reddy KC, Thakur ML. Solid phase preparations of99mTc labeled radiopharmaceuticals. J Labelled Comp Radiopharm 2002. [DOI: 10.1002/jlcr.550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Hoffman TJ, Quinn TP, Volkert WA. Radiometallated receptor-avid peptide conjugates for specific in vivo targeting of cancer cells. Nucl Med Biol 2001; 28:527-39. [PMID: 11516698 DOI: 10.1016/s0969-8051(01)00209-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
New receptor-avid radiotracers are being developed for site-specific in vivo targeting of a myriad of receptors expressed on cancer cells. This review exemplifies strategies being used to design radiometallated peptide conjugates that maximize uptake in tumors and optimize their in vivo pharmacokinetic properties. Efforts to produce synthetic peptide analogues that target the following three receptor systems are highlighted: Gastrin releasing peptide (GRP), alpha-melanocyte stimulating hormone (alpha-MSH), and guanylate cyclase-C (GC-C) receptors.
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Affiliation(s)
- T J Hoffman
- Department of Internal Medicine, University of Missouri and Research Service, Columbia, MO 65211, USA
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