Integration of DOTA as a bridging unit during solid-phase peptide synthesis

Abstract

A method for the introduction of bifunctionalized 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (DOTA) into the bridging unit of peptide-based radiopharmaceuticals has been developed. The method is executed in the context of Fmoc-based solid-phase peptide synthesis (SPPS) using standard coupling reagents (HOAt, TBTU, DIPEA) and was optimized to maximize yields (>99% conversion) and suppress the formation of side products (<25%). The bifunctionalized DOTA chelator can be used to integrate radioactive or non-radioactive Ga3+-isotopes. This facilitates novel and structurally simple PET tracer designs and the combination of other functional moieties, such as dyes, with Ga-DOTA-chelates in one hybrid tracer.