Radiolabeled Small-Molecule Ligands for Prostate-Specific Membrane Antigen: In vivo Imaging in Experimental Models of Prostate Cancer

• Published in: Clinical cancer research 2005-06, Vol.11 (11), p.4022-4028
• Main Authors: FOSS, Catherine A, MEASE, Ronnie C, HONG FAN, YUCHUAN WANG, RAVEN, Hayden T, DANNALS, Robert F, OLSZEWSKI, Rafal T, HESTON, Warren D, KOZIKOWSKI, Alan P, POMPER, Martin G
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Surface - metabolism; Antineoplastic agents; Binding, Competitive; Biological and medical sciences; Carbon Radioisotopes; Cell Line, Tumor; Female; Glutamate Carboxypeptidase II - metabolism; Gynecology. Andrology. Obstetrics; Humans; imaging; Iodine Radioisotopes; Ligands; Male; Male genital diseases; Medical sciences; Mice; Mice, SCID; Neoplasm Transplantation; Nephrology. Urinary tract diseases; PET; Pharmacology. Drug treatments; Positron-Emission Tomography - methods; prostate cancer; Prostatic Neoplasms - diagnosis; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - therapy; PSMA; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacokinetics; Tissue Distribution; Transplantation, Heterologous; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-2690

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