Radiopharmaceutical Design for GRPR Targeting in Prostate Cancer

Abstract

Molecular imaging is broadly defined as the characterization and measurement of biological processes in living animals at the cellular and molecular level. Bombesin (BBN), an amphibian 14-amino acid peptide, is a homologue of the 27-amino acid mammalian gastrin-releasing peptide (GRP). These peptides are mostly studied due to their implication in cancer cellular pathways. It has been proven that various cancer cell lines synthesize bombesin and GRP which in turn stimulate cancer growth through autocrine feedback mechanisms involving the expression of these peptides and that of their receptors in the tumor cells. During our research we have synthesized a library of GRP/BBN peptide analogs coupled to DOTA or acyclic tetraamines (N4) and have radiolabeled them with the diagnostic radionuclides 111In and 99mTc and/or the therapeutic radionuclides 90Y, 177Lu, and 188Re. Radiopeptides have been evaluated at the molecular and cellular level (competition, saturation binding assays, internalization-externalization experiments) as well as in experimental animals (metabolism, biodistribution and imaging in SCID/nude mice bearing human xenografts (human prostate or breast carcinomas). In the figure, the radioactivity uptake of four 111In-labeled truncated analogues of the human 27-mer GRP, conjugated with DOTA at the N-terminus of GRP(13/14/17/18-27) in crucial organs and human xenograft is illustrated.