Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [Lu-177]Lu-PSMA-617

Martin Sebastian; Tonnesmann Roswitha; Hierlmeier Ina; Maus Stephan; Rosar Florian; Ruf Juri; Holland Jason P.; Ezziddin Samer; Bartholoma Mark D.

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Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [Lu-177]Lu-PSMA-617

机译：在合成[LU-177] Lu-PSMA-617期间形成的侧产品的鉴定，表征和抑制

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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-177-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-177-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements.

机译：近年来，针对前列腺特异性膜抗原（PSMA）的放射性标记示踪剂对前列腺癌的治疗产生了巨大影响。在这里，我们报告了临床生产Lu-177标记的PSMA-617过程中形成的放射性杂质的形成。我们提供了令人信服的证据，证明这些杂质是Glu-CO-Lys部分自发热介导缩合反应的结果，导致形成三个不同的五元环系统。密度泛函理论（DFT）计算表明，Glu-CO-Lys部分的缩合和环化是热力学自发的。在细胞实验中，未观察到这些环化化合物对PSMA的亲和力。对患者研究的尿液样本进行的HPLC分析显示，这些放射性环化物在肾脏中迅速排泄。经鉴定，放射性标记条件可显著减少环化副产物的形成，产生Lu-177标记的PSMA-617，放射化学产率和纯度高，符合当前良好制造规范（cGMP）要求。

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《Journal of Medicinal Chemistry》 |2021年第8期|共12页
作者
Martin Sebastian; Tonnesmann Roswitha; Hierlmeier Ina; Maus Stephan; Rosar Florian; Ruf Juri; Holland Jason P.; Ezziddin Samer; Bartholoma Mark D.;
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Saarland Univ Dept Nucl Med Med Ctr D-66421 Homburg Germany;

Univ Freiburg Dept Nucl Med Med Ctr D-79106 Freiburg Germany;

Saarland Univ Dept Nucl Med Med Ctr D-66421 Homburg Germany;

Saarland Univ Dept Nucl Med Med Ctr D-66421 Homburg Germany;

Saarland Univ Dept Nucl Med Med Ctr D-66421 Homburg Germany;

Univ Freiburg Dept Nucl Med Med Ctr D-79106 Freiburg Germany;

Univ Zurich Dept Chem CH-8057 Zurich Switzerland;

Saarland Univ Dept Nucl Med Med Ctr D-66421 Homburg Germany;

Saarland Univ Dept Nucl Med Med Ctr D-66421 Homburg Germany;

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正文语种 eng
中图分类药学;
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Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [Lu-177]Lu-PSMA-617

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