THROMBUS IMAGING USING TC-99M-LABELED HIGH-POTENCY GPIIB IIIA RECEPTOR ANTAGONISTS - CHEMISTRY AND INITIAL BIOLOGICAL STUDIES/

Platelet-specific compounds which are radiolabeled with gamma-emitting radionuclides may be particularly useful for the noninvasive in vivo detection of thrombi. The synthesis of peptides which are potent inhib itors of platelet aggregation and which contain a chelator for the rad ionuclide technetium-99m are described. The target compounds were desi gned such that stable, oxotechnetium(V) species could be prepared wher e the site of metal coordination was well defined. A strategy was empl oyed where the pharmacophore-Arg-Gly-Asp-(RGD), or RGD mimetic, was co nstrained in a ring which was formed by the S-alkylation of a cysteine residue with an N-terminal chloroacetyl group. Binding affinities wer e enhanced by the replacement of arginine with the arginine mimetics S -(3-aminopropyl)cysteine and 4-amidinophenylalanine. Further enhanceme nts could be obtained by the synthesis of oligomers which contained tw o or more rings containing receptor binding regions. The increase in b inding affinity seen was more than that expected from a simple stoichi ometric increase of pharmacophore. The most potent compounds described had IC(50)s of approximately 0.03 mu M for the inhibition of human pl atelet aggregation. Two of the more potent peptides (P280 and P748) we re labeled with technetium-99m and assessed in a canine thrombosis mod el. The Tc-99m complexes of the peptides prepared in this work hold pr omise as thrombus imaging agents due to their high receptor binding af finity, ease of preparation, and expected rapid pharmacokinetics.