Combinatorial synthesis of rhenium-cyclic somatostatin analogs using the novel peptide Backbone Metal-Cyclization(BMC)method

摘要

Labeling peptides,antibodies,or steroid hormones with radioactive isotopes is a known approach for in vivo tumor imaging or therapy.The most frequently used route for the generation of this kind of agents is that connecting the radioisotope to the biomolecule through a chelating group,e.g.diethylenetriamine pentaacetic acid(DTPA),1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraaceticacid(DOTA),which is covalently linked to the tumor targeting molecule.We present here a method for simultaneous peptide backbone cyclization and radiolabeling:Backbone Metal-Cyclization(BMC).According to this approach,two chelating moieties are positioned flanking the peptide pharmacophore as handles for simultaneous metal entrapment and peptide cyclization.This method introduces the ability to synthesize combinatorial libraries of metal cyclic peptides with conformational diversity,which to the best of our knowledge were previously unreported,by offering several points of diversity:the position of the chelating arms on the peptide backbone,the nature and length of the linkers connecting them to the peptide backbone,the stereochemical configuration of the ligands and the nature of their donor atoms.In order to demonstrate the applicability of BMC to the combinatorial synthesis of libraries of cyclic metalo peptides with potential clinical applications,we aimed towards the synthesis of a library of novel somatostatin analogs,that retain high binding to the human somatostatin receptor subtype 2(hsstr2)and can accordingly serve as lead compounds in the development of new imaging and therapeutic agents.