In Vivo Cellular and Molecular Imaging Center

New imaging agents for prostate cancer

Brief Discription and findings:
Prostate-specific membrane antigen (PSMA) is a cell surface protein that is overexpressed in prostate cancer, including hormone-refractory and metastatic disease. This project supported the synthesis and evaluation of the in vivo biodistribution of two radiolabeled urea derivatives that have high affinity for PSMA in SCID mice bearing MCF7 (breast, PSMA-negative), PC3 (prostate, PSMA-negative) and LNCaP (prostate, PSMA-positive) xenografts (Fig. 3). Radiopharmaceutical binding selectivity and tumor uptake were also evaluated in vivo using dedicated small animal positron emission tomography (PET), single photon emission computed tomography (SPECT) and gamma scintigraphic imaging devices. N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-S-[11C]methyl-L-cysteine ([11C]DCMC, Ki = 3.1 nM) and N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[125I]iodo-L-tyrosine ([125I]DCIT, Ki = 1.5 nM) were synthesized as previously described using [11C]CH3I and with [125I]NaI/Iodogen, respectively. At 30min post-injection [11C]DCMC and [125I]DCIT demonstrated tumor/muscle ratios of 10.8 and 4.7, respectively, with clear delineation of LNCaP-derived tumors on imaging. MCF7- and PC3-derived tumors demonstrated significantly less uptake of [11C]DCMC or [125I]DCIT. These results demonstrate the feasibility of imaging PSMA-positive prostate cancer using low molecular weight agents. [11C]DCMC and [125I]DCIT demonstrated specific binding to PSMA-positive prostate tumor xenografts. These agents are easily synthesized and functionalized, and can be visualized with PET. Because PSMA is limited to relatively few structures, and due to their low molecular weight, images obtained with our compounds show only renal uptake (due to specific binding to PSMA) and excretion and uptake within PSMA-bearing tumors. The remainder of the tissue is devoid of significant activity on the images that we have obtained to date. We anticipate that by optimizing protocols we will see even better delineation of tumor/background. In addition, PSMA is present in the neovasculature of a variety of tumors including non-small cell lung cancer, colorectal carcinoma, and glioblastoma, suggesting that our agents may enable imaging of a wide variety of tumors.

Main publication: Foss, C. A., Mease, R. C., Fan, H., Wang, Y., Ravert, H. T., Dannals, R. F., Olszewski, R. T., Heston, W. D., Kozikowski, A. P., and Pomper, M. G. Radiolabeled Small-Molecule Ligands for Prostate-Specific MembraneAntigen: In vivo Imaging in Experimental Models of Prostate Cancer. Clin Cancer Res, 2005. 11(11): p. 4022-8.

Mease RC, Dusich CL, Foss CA, Ravert HT, Dannals RF, Seidel J, Prideaux A, Fox JJ, Sgouros G, Kozikowski AP, Pomper MG. Synthesis and in vivo evaluation of N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: a new imaging probe for prostate cancer. Clin Cancer Res 2007; 14:3036-3043.

Banerjee SR, Foss CA, Castanares M, Mease RC, Byun Y, Fox JJ, Hilton J, Lupold S, Kozikowski AP, Pomper MG. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA). J Med Chem 2008; 51:4504-4517.

Barinka C, Byun Y, Dusich CL, Ray S, Chen Y, Castanares M, Kozikowski AP, Mease RC, Pomper MG, Lubkowski J. Interactions between Human Glutamate Carboxypeptidase II and Urea-based Inhibitors: Structural Characterization. J Med Chem, in press.

Chen Y, Foss CA, Byun Y, Nimmagadda S, Pullambhatla M, Fox JJ, Castanares SE, Babich JW, Mease RC, Pomper MG. Radiohalogenated PSMA-based ureas as imaging agents for prostate cancer. J Med Chem, in press.

In Vivo Cellular Molecular Imaging Center (ICMIC)
Russell H. Morgan Department of Radiology and Radiological Science
Johns Hopkins University (JHU) School of Medicine
Baltimore, Maryland, USA