99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen for Molecular Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and small-molecule radiopharmaceuticals target-ing PSMA rapidly detect the location and extent of disease. Here we evaluated preclinically 4 novel 99mTc-labeled small-molecule inhibitors of PSMA with the potential for clinical translation for mo-lecular imaging of prostate cancer in humans. Methods: Four PSMA inhibitors derived from the glutamate-urea-glutamate or glutamate-urea-lysine pharmacophores conjugated to CIM or TIM chelators were radiolabeled with 99mTc and evaluated in vitro and in vivo. Results: High-affinity, saturable binding to PSMA on LNCaP cells was observed with Kd values of 0.64 6 0.46 nM for 99mTc-MIP-1427, 1.07 6 0.89 nM for 99mTc-MIP-1404, 1.75 6 0.32 nM for 99mTc-MIP-1428, and 4.35 6 0.35 nM for 99mTc-MIP-1405. 99mTc-labeled PSMA inhibitors did not bind human prostate cancer PC3 cells, which lack PSMA, demonstrating specificity