TY - JOUR
T1 - Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer
AU - Hillier, Shawn M.
AU - Maresca, Kevin P.
AU - Femia, Frank J.
AU - Marquis, John C.
AU - Foss, Catherine A.
AU - Nguyen, Nghi
AU - Zimmerman, Craig N.
AU - Barrett, John A.
AU - Eckelman, William C.
AU - Pomper, Martin G.
AU - Joyal, John L.
AU - Babich, John W.
PY - 2009/9/1
Y1 - 2009/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70149094319&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70149094319&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-09-1682
DO - 10.1158/0008-5472.CAN-09-1682
M3 - Article
C2 - 19706750
AN - SCOPUS:70149094319
SN - 0008-5472
VL - 69
SP - 6932
EP - 6940
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -