Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions , 1550 Orleans Street, Baltimore, Maryland 21287, United States.
J Med Chem. 2014 Mar 27;57(6):2657-69. doi: 10.1021/jm401921j. Epub 2014 Mar 7.
Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five (64)Cu-labeled inhibitors of PSMA, [(64)Cu]3-7, which are based on the lysine-glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [(64)Cu]3-7 were prepared in high radiochemical yield (60-90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [(64)Cu]3-7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA- PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [(64)Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [(64)Cu]CB-TE2A as compared with [(64)Cu]NOTA, [(64)Cu]PCTA, [(64)Cu]Oxo-DO3A, and [(64)Cu]DOTA chelates in vivo.
前列腺特异性膜抗原（PSMA）是鉴定和治疗多种癌症的公认靶标。在这里，我们报告了五种（64）Cu 标记的 PSMA 抑制剂 [（64）Cu]3-7，它们基于赖氨酸-谷氨酸脲支架，并利用各种大环螯合剂，即 NOTA（3）、PCTA（4）、Oxo-DO3A（5）、CB-TE2A（6）和 DOTA（7），以确定哪种提供最适合体内 PET 成像的药代动力学。[（64）Cu]3-7 的制备具有高放射化学产率（60-90%）和纯度（>95%）。[（64）Cu]3-7 的正电子发射断层扫描（PET）成像研究表明，与同基因对照肿瘤（PSMA-PC3 flu）和背景组织相比，在表达 PSMA 的异种移植（PSMA+PC3 PIP）中特异性积累。CB-TE2A 螯合的[（64）Cu]6 提供的有利动力学和高图像对比度表明，它是测试候选物中最有前途的一种。这可能是由于与 NOTA、PCTA、Oxo-DO3A 和 DOTA 螯合物相比，[（64）Cu]CB-TE2A 在体内具有更高的稳定性。
