sigma up 99m theta c-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel 99mTc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects. Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of 99mTc-MIP-1404 and 99mTc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Whole-body images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection. Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1-2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high-contrast images exhibited tumor-to-background ratios from 3:1 to 9:1 at 4 and 20 h. Compared with the standard-of-care bone scanning, 99mTc-MIP-1404 and 99mTc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.