Radiolabeled small-molecule ligands for prostate-specific membrane antigen:: In vivo imaging in experimental models of prostate cancer

Purpose: Prostate-specific membrane antigen (PSMA) is a cell surface protein that is overexpressed in prostate cancer, including hormone-refractory and metastatic disease. Our goal in this study was to develop a series of PSMA-based imaging agents for clinical use. Experimental Design: We have synthesized and evaluated the in vivo biodistribution of two radiolabeled urea derivatives that have high affinity for PSMA in severe combined immunodeficient mice harboring MCF-7 (breast, PSMA-negative), PC-3 (prostate, PSMA-negative), and LNCaP (prostate, PSMA-positive) xenografts. Radiopharmaceutical binding selectivity and tumor uptake were also evaluated in vivo using dedicated small animal positron emission tomography, single photon emission computed tomography, and gamma scintigraphic imaging devices. N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[C-11]methyl-L-cysteine ([C-11]DCMC K-i, 3.1 nmol/L) and N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3- [I-125] iodo-L-tyrosine ([C-125] DCIT K-i, 1.5 nmol/L) were synthesized using [C-11] CH3] and with [I-125] NaI/Iodogen, respectively. Results: At 30 minutes postinjection, [C-11] DCMC and [I-125] DCIT showed tumor/muscle ratios of 10.8 and 4.7, respectively, with clear delineation of LNCaP-derived tumors on imaging. MCF-7-and PC-3-derived tumors showed significantly less uptake of [C-11] DCMC or [I-125] DCIT Conclusion: These results show the feasibility of imaging PSMA-positive prostate cancer using low molecular weight agents.