Phosphinate or Urea? Synthesis and Biological Evaluation of Prostate Specific Membrane Antigen‐Targeted Fluorophores With Different Zinc‐Binding Motif

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Most prostate specific membrane antigen (PSMA)‐targeted drugs contain a urea‐based targeting vector, although high PSMA‐binding affinities have also been realized with other zinc‐binding motifs. This study describes the synthesis and evaluation of a hybrid compound containing a phosphinate motif (GPI) and a linker derived from an established urea‐based PSMA ligand (PSMA‐617). Fluorescent conjugates differing in their zinc‐binding motif only were synthesized and evaluated in vitro and in vivo. The phosphinate hybrid Cy5‐GPI617 ( 9 ) is more polar and has reduced binding affinity to human serum albumin (HSA) compared to its urea analog Cy5‐617 ( 10 ). At the same time, Cy5‐GPI617 ( 9 ) has an almost identical PSMA binding affinity (low nM) and leads to high, PSMA‐specific cellular uptake. In vivo, the phosphinate hybrid 9 showed reduced retention in nontumor tissues along with only moderately decreased tumor uptake compared to the urea analog 10 . These findings demonstrate that the previously performance‐limiting phosphate competition of GPI can be overcome by molecular engineering and highlight the potential of phosphinate‐based scaffolds for PSMA targeting.

This publication has 50 references indexed in Scilit: