A Series of Halogenated Heterodimeric Inhibitors of Prostate Specific Membrane Antigen (PSMA) as Radiolabeled Probes for Targeting Prostate Cancer

被引：257

作者：

Maresca, K. P. ^{[1
]}

Hillier, S. M. ^{[1
]}

Femia, F. J. ^{[1
]}

Keith, D. ^{[1
]}

Barone, C. ^{[1
]}

Joyal, J. L. ^{[1
]}

Zimmerman, C. N. ^{[1
]}

Kozikowski, A. P. ^{[2
]}

Barrett, J. A. ^{[1
]}

Eckelman, W. C. ^{[1
]}

Babich, J. W. ^{[1
]}

机构：

[1] Mol Insight Pharmaceut Inc, Cambridge, MA 02142 USA

[2] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 02期

基金：

美国国家卫生研究院;

关键词：

GLUTAMATE-CARBOXYPEPTIDASE-II; EXTRACELLULAR DOMAIN; FOLATE HYDROLASE; C-11-CHOLINE; THERAPY; TUMOR; TOMOGRAPHY; EXPRESSION; LIGANDS; DISEASE;

D O I：

10.1021/jm800994j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA were designed and synthesized where X = epsilon-N-(o-I, m-I, p-I, p-Br, o-C1, m-C1, p-C1, p-F, H)-benzyl-Lys and epsilon-(p-I, p-Br, p-C1, p-F, H)-phenylureido-Lys. The affinities for PSMA were determined by screening in a competitive binding assay. PSMA binding of the benzyllysine series was significantly affected by the nature of the halogen substituent (IC50 values, Cl < I = Br << F = H) and the ring position of the halogen atom (IC50 values, p-I < o-I << m-I). The halogen atom had little affect oil the binding affinity in the para substituted phenylureido-Lys series. Two lead iodine compounds were radiolabeled with I-123 and I-131 and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.

引用

页码：347 / 357

页数：11

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