Backbone metal-cyclization: a novel approach for simultaneous peptide cyclization and radiolabeling. Application to the combinatorial synthesis of rhenium-cyclic somatostatin analogs

A novel approach for the combinatorial synthesis of backbone-derived metal-cyclic peptide libraries is presented. In this approach the metalo-cyclic peptides are prepared from their linear precursors through complexation of a metal atom via two hemi-chelating arms located on the peptide backbone. Thus, cyclization and metal labeling of the peptides are achieved simultaneously. A library, composed of 48 rhenium-cyclic somatostatin analogs, was prepared. All rhenium somatostatin complexes exhibited high to moderate in vitro binding affinities toward cloned human somatostatin receptor subtype 2 (hsstr2). Five rhenium-cyclic peptides were found to be most potent with IC50 values between 1 and 3 nM making them promising leads for further development of tumor diagnostic and therapeutic radiolabeled agents. A 99mTc somatostatin cyclic analog was successfully prepared by the same method.