Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer.
Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer.
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DOI：
10.1158/0008-5472.can-09-1682
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Babich JW
中科院分区：
文献类型：
--
作者：
Hillier SM;Maresca KP;Femia FJ;Marquis JC;Foss CA;Nguyen N;Zimmerman CN;Barrett JA;Eckelman WC;Pomper MG;Joyal JL;Babich JW
前列腺特异性膜抗原（PSMA）在正常人前列腺上皮中表达，并且在前列腺癌中高度上调。我们以前报道了一系列针对PSMA的新型小分子抑制剂。选择两种化合物MIP-1072（（S）-2-（3-（（S）-1-羧基-5-（4-碘苄基氨基）戊基）脲基）戊二酸）和MIP-1095（（S）-2-（3-（（S）-1-羧基-5-（3-（4-碘苯基）脲基）戊基）脲基）戊二酸）进行进一步评价。MIP-1072和MIP-1095有效抑制PSMA的谷氨酸羧肽酶活性（Ki分别为4.6 ± 1.6和0.24 ± 0.14 nM），并且当用123 I放射性标记时，对人前列腺癌LNCaP细胞上的PSMA表现出高亲和力（Kd分别为3.8 ± 1.3和0.81 ± 0.39 nM）。[123 I]MIP-1072和[123 I]MIP-1095与PSMA的结合是特异性的;与缺乏PSMA的人前列腺癌PC 3细胞没有结合，并且通过与结构上不相关的NAALADase抑制剂2-（膦酰基甲基）戊二酸（PMPA）共孵育消除了结合。[123 I]MIP-1072和[123 I]MIP-1095在37 °C内化到LNCaP细胞中。小鼠组织分布研究表明，[123 I]MIP-1072和[123 I]MIP-1095分别为17.3 ± 6.3（1小时）和34.3 ± 12.7（4小时）%注射剂量/克组织。与[123 I]MIP-1072相比，[123 I] MIP-1095表现出更大的肿瘤摄取，但从血液和非靶组织中洗脱较慢。通过在LNCaP异种移植物中与PMPA竞争以及在PC 3异种移植物中不存在摄取来证明与PSMA的体内特异性结合。SPECT/CT显像证实了荷瘤小鼠对[123 I]MIP-1072和[123 I]MIP-1095的摄取。PSMA特异性放射性药物应该为前列腺癌的检测和分期提供一种新的分子靶向选择。
Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly upregulated 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 and 0.24 ± 0.14 nM, respectively), and when radiolabeled with 123I exhibited high affinity for PSMA on human prostate cancer LNCaP cells (Kd = 3.8 ± 1.3 and 0.81 ± 0.39 nM, 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 co-incubation 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 demonstrated 17.3 ± 6.3 (at 1 hr) and 34.3 ± 12.7 (at 4 hr) % injected dose per gram of tissue, for [123I]MIP-1072 and [123I]MIP-1095, respectively. [123I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and non-target tissues compared to [123I]MIP-1072. Specific binding to PSMA in vivo was demonstrated 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 SPECT/CT imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.