Synthesis, characterization and in vitro evaluation of new oxorhenium- and oxotechnetium-CCK4 derivatives as molecular imaging agents for CCK2-receptor targeting.
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.
CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, SPCMIB, UMR 5068, 118 route de Narbonne, F-31062 Toulouse cedex 9, France.
Sandra
S
Dorbes
Béatrice
B
Mestre-Voegtlé
Yvon
Y
Coulais
Claude
C
Picard
Sandrine
S
Silvente-Poirot
Marc
M
Poirot
Eric
E
Benoist
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004355:Drug Stability; D006801:Humans; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015609:Organotechnetium Compounds / Q000737:chemistry*; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry*; D013758:Tetragastrin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D000090324:Tumor Protein, Translationally-Controlled 1
D015609:Organotechnetium Compounds; D043887:Receptor, Cholecystokinin B; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D013758:Tetragastrin; C015428:perrhenate; D012211:Rhenium