Design and Characterization of Squaramic Acid-Based Prostate-Specific Membrane Antigen Inhibitors for Prostate Cancer.

Prostate-specific membrane antigen (PSMA) overexpressed on prostate cancer (PCa) cells is a satisfactory theranostic target in PCa. To seek novel non-glutamate-urea-based PSMA inhibitors by the strategy of bioisosterism, 10 ligands were designed, synthesized, and characterized. Among them, ligands 17 , 18 , and 21-24 bearing the squaramic acid moiety proved to be potent PSMA inhibitors, with K i values ranging from 0.40 to 2.49 nM, which are comparable or higher in inhibitory potency compared to previously reported glutamate-urea-based inhibitors. Docking studies of 15 , 17 , and 19 were carried out to explore their binding mode in the active site of PSMA. Two near-infrared (NIR) probes, 23 (λ EM = 650 nm) and 24 (λ EM = 1088 nm), displayed favorable in vivo NIR imaging and successful NIR-II image-guided tumor resection surgery in PSMA-positive tumor-bearing mice, which demonstrated the effectiveness of these new squaramic acid-based inhibitors.