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-[¹¹C]methyl-L-cysteine ([¹¹C]DCMC K _j, 3.1 nmol/L) and N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3- [¹²⁵I]iodo-L-tyrosine ([¹²⁵C]DCIT K_j, 1.5 nmol/L) were synthesized using [¹¹C]CH₃I and with [ ¹²⁵I]NaI/Iodogen, respectively. Results: At 30 minutes postinjection, [¹¹C]DCMC and [¹²⁵I]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 [¹¹C]DCMC or [¹²⁵I]DCIT. Conclusion: These results show the feasibility of imaging PSMA-positive prostate cancer using low molecular weight agents.