Department of Nuclear Medicine, Saarland University-Medical Center, Kirrbergerstrasse, D-66421 Homburg, Germany.
Department of Nuclear Medicine, Medical Center-University of Freiburg, D-79106 Freiburg, Germany.
J Med Chem. 2021 Apr 22;64(8):4960-4971. doi: 10.1021/acs.jmedchem.1c00045. Epub 2021 Apr 7.
In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report on the formation of radioactive impurities formed during the clinical production of Lu-labeled PSMA-617. We provide compelling evidence that these impurities are the result of a spontaneous, thermally mediated condensation reaction of the Glu-CO-Lys moiety resulting in the formation of three different five-membered ring systems. Density functional theory (DFT) calculations show that the condensation and cyclization of the Glu-CO-Lys moiety is thermodynamically spontaneous. In cell experiments, no affinity of these cyclized compounds toward PSMA was observed. HPLC analyses of urine samples from patient studies showed rapid renal excretion of these radioactive cyclized species. Radiolabeling conditions were identified that significantly reduced the formation of cyclized side products yielding Lu-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements.
近年来，针对前列腺特异性膜抗原（PSMA）的放射性示踪剂在前列腺癌的管理中产生了巨大的影响。在这里，我们报告了在临床生产 Lu 标记的 PSMA-617 过程中形成的放射性杂质。我们提供了令人信服的证据，证明这些杂质是 Glu-CO-Lys 部分自发的、热介导的缩合反应的结果，导致形成了三种不同的五元环系统。密度泛函理论（DFT）计算表明，Glu-CO-Lys 部分的缩合和环化在热力学上是自发的。在细胞实验中，没有观察到这些环状化合物对 PSMA 的亲和力。来自患者研究的尿液样本的 HPLC 分析表明，这些放射性环状物质迅速经肾脏排泄。已经确定了放射性标记条件，可以显著减少环状副产物的形成，从而以高放射化学产率和纯度生成符合现行良好生产规范（cGMP）要求的 Lu 标记的 PSMA-617。
