Given the clinical potential of poly(ADP-ribose) polymerases (PARP) imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacological profiles over established PARP imaging agents is warranted. Here, we present a novel ¹⁸F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [¹⁸F]talazoparib (RCY: 13 ± 3.4%; n = 4) was achieved using a “design of experiments” (DoE) optimized copper-mediated radiofluorination reaction. The chiral product was isolated from the reaction mixture using 2D reversed-phase/chiral radio-HPLC (>99% ee). (8S,9R)-[¹⁸F]Talazoparib demonstrated PARP binding in HCC1937 cells in vitro and showed an excellent tumor-to-blood ratio in xenograft-bearing mice (10.2 ± 1.5). Additionally, a favorable pharmacological profile in terms of excretion, metabolism, and target engagement was observed. This synthesis of [¹⁸F]talazoparib exemplifies how DoE can enable the radiosyntheses of synthetically challenging radiolabeled compounds of high interest to the imaging community.

中文翻译：

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DoE 优化支持对映体纯 [18F] Talazoparib 的自动制备及其作为 PARP 放射性示踪剂的体内评估

鉴于聚（ADP-核糖）聚合酶 (PARP) 成像在检测和分层各种癌症方面的临床潜力，有必要开发新的 PARP 成像探针，其药理学特征优于已建立的 PARP 成像剂。在这里，我们提出了一种基于临床上优越的 PARP 抑制剂 talazoparib的新型¹⁸ F 标记的 PARP 放射性示踪剂。使用“实验设计”(DoE) 优化的铜介导的放射性氟化反应实现了 [ ¹⁸ F] talazoparib (RCY: 13 ± 3.4%; n = 4) 的自动放射合成。使用二维反相/手性放射性 HPLC (>99% ee) 从反应混合物中分离手性产物。(8 S ,9 R )-[ ¹⁸F] Talazoparib在体外证明了HCC1937 细胞中的PARP 结合，并在异种移植小鼠中显示出极好的肿瘤与血液比率 (10.2 ± 1.5)。此外，观察到在排泄、代谢和靶标参与方面的有利药理学特征。[ ¹⁸ F] talazoparib 的这种合成举例说明了 DoE 如何使成像界高度感兴趣的具有合成挑战性的放射性标记化合物的放射性合成成为可能。