Spickschen_2026_ChemMedChem_21_e70320

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.