Synthesis and Characterisation of a GRPR and PSMA Targeting Heterodimer for Theranostic Applications in Prostate Cancer

Abstract

Prostate cancer (PC) is the second most common cancer in the world for which diagnostic and therapeutic techniques require optimization. Currently the most used techniques for diagnosis are invasive digital rectal exams and blood prostate specific antigen (PSA) testing, which produces false negative and false positive results. In addition, PC overexpresses different biomarkers at different tumor stages making diagnosis and novel treatment difficult to perform. This report investigates the synthesis and characterization of PSMA and GRPR targeting heterodimers, used as a diagnostic for early and late-stage PC as well as targeted therapy. Two compounds were synthesized both containing NeoB, a PSMA targeting ligand and a DOTAGA chelator for complexing with diagnostic or therapeutic radionuclides. The platform for linking peptides utilizes a tetrazine functionality to achieve biorthogonal addition of chelators via an inverse electron demand Diels Alder (IEDDA) reaction. A cysteine on the N-terminus of the peptides allow for a biorthogonal cyano-thiol cycloaddition click reaction with the cyanopyrimidine. Two different lengths of the platform and the use of cyanopyrimidine functionalities were tested for stability. Unfortunately, the potential clinical application is limited by the poor stability of the cyanopyrimidine platform. Substituting the cyanopyrimidine functionality for tetrafluorophenyl (TFP) made the attachment of the peptides possible by increasing the stability of the platform. The reaction used to attach the peptides loses its biorthogonality but does result in the final heterodimers that can be used for further testing. The peptides were attached to a tetraflourophenyl activated platform via an amino hexanoic acid linker. Radiochemical yields and purities were determined for both final compounds.