Synthesis, characterization and in vitro evaluation of new oxorhenium- and oxotechnetium-CCK4 derivatives as molecular imaging agents for CCK2-receptor targeting.

Abstract : The goal of this study is to design new (99m)Tc-radiolabelled shortened CCK derivatives that might be suitable for the molecular imaging of cholecystokinin-2 receptors (CCK2-R), these receptors being over-expressed in a number of neuroendocrine tumors such as medullary thyroid cancer and small-cell lung cancer. For this purpose, we designed several modified CCK4 analogs bearing an ON(2)S tetradentate chelating agent at the N-terminus, the CCK4 sequence representing the minimal peptide sequence that presents nanomolar affinity and activity towards the CCK2-R. Four peptide conjugates of general formula (Trt)SN(2)OPh-(X)(n)-CCK4 (X=beta-alanine or 6-aminohexanoic acid spacers; n=0, 2, 4) and their oxorhenium peptide conjugates have been synthesized and characterized. In vitro evaluation of these compounds showed a close relationship between the nature and the length of the spacer and the corresponding binding affinity values. The most promising oxorhenium complex 5-Re exhibited potent CCK2-receptor agonist properties in promoting the production of inositol phosphate in COS-7 cells (EC(50)=5.17nM). Preliminary (99m)Tc-radiolabelling studies with peptide conjugates 3 or 5 led exclusively to the corresponding (99m)TcO-complexes 3-Tc and 5-Tc, which exhibited high resistance towards an excess of cysteine and satisfactory stabilities in human serum. To conclude, the promising in vitro characteristics of compounds 5-Re, 5-Tc illustrate the feasibility to develop stable radiolabelled shortened CCK4 derivatives with a nanomolar CCK2-R affinity.
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European Journal of Medicinal Chemistry, Elsevier, 2010, 45 (2), pp.423-9. 〈10.1016/j.ejmech.2009.09.043〉
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http://www.hal.inserm.fr/inserm-00519153
Contributeur : Marc Poirot <>
Soumis le : samedi 18 septembre 2010 - 15:25:16
Dernière modification le : jeudi 11 janvier 2018 - 06:15:23

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Sandra Dorbes, Béatrice Mestre-Voegtlé, Yvon Coulais, Claude Picard, Sandrine Silvente-Poirot, et al.. Synthesis, characterization and in vitro evaluation of new oxorhenium- and oxotechnetium-CCK4 derivatives as molecular imaging agents for CCK2-receptor targeting.. European Journal of Medicinal Chemistry, Elsevier, 2010, 45 (2), pp.423-9. 〈10.1016/j.ejmech.2009.09.043〉. 〈inserm-00519153〉

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