title: Synthesis and biochemical evaluation of a cyclic RGD oxorhenium complex as new ligand of alphaVbeta3 integrin.
abstract: We report the design of a new ligand of integrins that might be used for the molecular imaging of tumor neoangiogenesis. For this purpose, we designed a modified RGD tripeptide bearing a N-terminal N-bis(thioethyl)glycinate (NS(2)) motif and a thioethyl moiety at the C-terminus. Simultaneous coordination of an oxorhenium core by the NS(2) and thioethyl moieties led to peptide cyclization and gave the corresponding monomers 13a and b (major isomer) resulting from the syn/anti-isomerism, along with dimers' species 16a and b. Cyclometallated peptide 13b showed the most promising activity with an IC(50) of 86 nM for integrin alpha(V)beta(3) whereas it binds integrin alpha(IIb)beta(3) with an affinity lower by an order of magnitude. Labeling with [(99m)Tc]oxotechnetium gluconate led exclusively to complex 17, the equivalent of compound 13b, which displayed satisfactory stabilities in mice plasma and towards glutathione.
authors.affiliation: CEA/Saclay, iBiTec-S/SIMOPRO, Bâtiment 152, 91191 Gif-sur-Yvette, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Aufort
authors.forename: Marta
authors.initials: M
authors.lastname: Gonera
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chaignon
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Clainche
authors.forename: Christophe
authors.initials: C
authors.lastname: Dugave
mesh_terms: D000818:Animals; D005978:Glutathione / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010949:Plasma / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D012211:Rhenium / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D039302:Integrin alphaVbeta3; D008024:Ligands; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D012211:Rhenium; D005978:Glutathione