Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer

Shawn M. Hillier, Kevin P. Maresca, Frank J. Femia, John C. Marquis, Catherine A. Foss, Nghi Nguyen, Craig N. Zimmerman, John A. Barrett, William C. Eckelman, Martin G. Pomper, John L. Joyal, John W. Babich

Research output: Contribution to journalArticlepeer-review

Abstract

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)-1-carboxy-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 (Ki = 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 (Kd = 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.

Original languageEnglish (US)
Pages (from-to)6932-6940
Number of pages9
JournalCancer Research
Volume69
Issue number17
DOIs
StatePublished - Sep 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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