Somatostatin receptor-binding peptides labeled with technetium-99m: chemistry and initial biological studies.

The synthesis of peptides which possess a high affinity for the somatostatin receptor and contain a chelator for the radionuclide technetium-99m is described. The target compounds were designed such that they would form stable, oxotechnetium(V) chelate complexes in which the Oxorhenium(V) chelate complexes of these peptides were prepared as nonradioactive surrogates for the technetium complexes. Peptide oxorhenium complexes and Tc-99m complexes eluted closely upon HPLC analysis. The receptor-binding affinities of both the free and rhenium-coordinated species were measured in vitro. The binding affinities of the free peptides (Ki's in the 0.25 - 10 nM range) compared favorably with [DTPA]octreotide (Ki = 1.6 nM), which, as the indium-111 complex, is already approved for somatostatin receptor (SSTR)-expressing tumor imaging in the United States and Europe. Furthermore, the rhenium-coordinated peptides had binding affinities which, in many cases, were higher than those of the corresponding free peptides, with several complexes having a Ki's of 0.1 nM. Some of the more potent SSTR-binding peptides were labeled with technetium-99m and assessed in an in vivo study with tumor-bearing rats. The 99m Tc-labeled peptides prepared in this study should be useful as SSTR-expressing tumor-imaging agents due to their high SSTR-binding affinities, ease of preparation, and, because they are low molecular weight peptides, expected pharmacokinetics characterized by rapid tracer excretion from the body resulting in high-contrast images.

Thrombus imaging using technetium-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 inhibitors of platelet aggregation and which contain a chelator for the radionuclide technetium-99m are described. The target compounds were designed such that stable, oxotechnetium(V) species could be prepared where the site of metal coordination was well defined. A strategy was employed where the pharmacophore-Arg-Gly-Asp-(RGD), or RGD mimetic, was constrained in a ring which was formed by the S-alkylation of a cysteine residue with an N-terminal chloroacetyl group. Binding affinities were enhanced by the replacement of arginine with the arginine mimetics S-(3-aminopropyl)cysteine and 4-amidinophenylalanine. Further enhancements could be obtained by the synthesis of oligomers which contained two or more rings containing receptor binding regions. The increase in binding affinity seen was more than that expected from a simple stoichiometric increase of pharmacophore. The most potent compounds described had IC50s of approximately 0.03 microM for the inhibition of human platelet aggregation. Two of the more potent peptides (P280 and P748) were labeled with technetium-99m and assessed in a canine thrombosis model. The 99m Tc complexes of the peptides prepared in this work hold promise as thrombus imaging agents due to their high receptor binding affinity, ease of preparation, and expected rapid pharmacokinetics.