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Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer

¹ Molecular Insight Pharmaceuticals, Cambridge, Massachusetts; and ² Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: John W. Babich, Molecular Insight Pharmaceuticals, 160 Second Street, Cambridge, MA. Phone: 617-492-5554; Fax: 617-492-5664; E-mail: jbabich{at}molecularinsight.com.

Key Words: prostate cancer • molecular imaging • prostate-specific membrane antigen • NAALADase • SPECT

Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (K_i = 4.6 ± 1.6 nmol/L and 0.24 ± 0.14 nmol/L, respectively) and, when radiolabeled with ¹²³I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (K_d = 3.8 ± 1.3 nmol/L and 0.81 ± 0.39 nmol/L, respectively). The association of [¹²³I]MIP-1072 and [¹²³I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [¹²³I]MIP-1072 and [¹²³I]MIP-1095 internalized into LNCaP cells at 37°C. Tissue distribution studies in mice showed 17.3 ± 6.3% (at 1 hour) and 34.3 ± 12.7% (at 4 hours) injected dose per gram of LNCaP xenograft tissue, for [¹²³I]MIP-1072 and [¹²³I]MIP-1095, respectively. [¹²³I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [¹²³I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [¹²³I]MIP-1072 and [¹²³I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer. [Cancer Res 2009;69(17):6932–40]