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

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)-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 (123)I, 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 [(123)I]MIP-1072 and [(123)I]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). [(123)I]MIP-1072 and [(123)I]MIP-1095 internalized into LNCaP cells at 37 degrees 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 [(123)I]MIP-1072 and [(123)I]MIP-1095, respectively. [(123)I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [(123)I]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 [(123)I]MIP-1072 and [(123)I]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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 17 Pg. 6932-40 (Sep 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19706750 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 2-(3-(1-carboxy-5-(3-(4-iodobphenyl)ureido)pentyl)ureido)pentanedioic acid
• 2-(3-(1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid
• Antigens, Surface
• Glutamates
• Iodine Radioisotopes
• Radiopharmaceuticals
• Urea
• FOLH1 protein, human
• Glutamate Carboxypeptidase II
• Lysine

Topics

• Animals
• Antigens, Surface (analysis, metabolism)
• Cell Line, Tumor
• Drug Evaluation, Preclinical
• Glutamate Carboxypeptidase II (analysis, antagonists & inhibitors, metabolism)
• Glutamates (chemistry, metabolism)
• Humans
• Iodine Radioisotopes
• Lysine (analogs & derivatives, metabolism)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prostatic Neoplasms (diagnosis, metabolism)
• Protein Binding
• Radiopharmaceuticals (metabolism)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon
• Urea (analogs & derivatives, metabolism)