Global Drug Discovery, Bayer HealthCare, Müllerstrasse 178, 13353, Berlin, Germany.
J Med Chem. 2012 Nov 26;55(22):9510-20. doi: 10.1021/jm300710j. Epub 2012 Oct 24.
For prostate cancer, prostate specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target. Fluorinated derivatives of 2-(phosphonomethyl)pentanedioic acid were designed and synthesized to explore whether this fluorine-substituent is tolerated in the pentanedioic acid moiety that is common to almost all PSMA targeting small molecule inhibitors. The binding affinities of the racemic and individual stereoisomers of 2-fluoro-4-(phosphonomethyl)pentanedioic acid were determined and showed that the introduction of fluorine was well tolerated. The radiosynthesis of the analogous 2-[(18)F]fluoro-4-(phosphonomethyl)pentanedioic acid was developed and evaluated in vivo with the PSMA positive LNCaP human prostate cancer cell. The biological results demonstrated specific binding of the tracer to PSMA positive tumors in mice. These results warrant the further evaluation of this class of compounds as radiolabeled tracers for the detection and staging of prostate cancer.
对于前列腺癌，前列腺特异性膜抗原（PSMA）已被确定为一种诊断和治疗靶点。设计并合成了氟代衍生物 2-（膦酸甲基）戊二酸，以探讨氟取代基是否能在几乎所有针对小分子抑制剂的 PSMA 靶向的戊二酸部分中被容忍。确定了 2-氟-4-（膦酸甲基）戊二酸的外消旋和单个立体异构体的结合亲和力，结果表明引入氟是可以被容忍的。类似的 2-[(18)F]氟-4-（膦酸甲基）戊二酸的放射合成已开发，并在 PSMA 阳性 LNCaP 人前列腺癌细胞中进行了体内评估。生物学结果表明示踪剂与小鼠 PSMA 阳性肿瘤的特异性结合。这些结果证明了这类化合物作为放射性示踪剂用于检测和分期前列腺癌的进一步评估是合理的。
