Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Roentgenweg 15, 72076 Tuebingen, Germany.
Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University, Roentgenweg 13, 72076 Tuebingen, Germany.
J Med Chem. 2021 Nov 11;64(21):15690-15701. doi: 10.1021/acs.jmedchem.1c00903. Epub 2021 Oct 21.
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 F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [F]talazoparib (RCY: 13 ± 3.4%; = 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). (8,9)-[F]Talazoparib demonstrated PARP binding in HCC1937 cells 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 [F]talazoparib exemplifies how DoE can enable the radiosyntheses of synthetically challenging radiolabeled compounds of high interest to the imaging community.
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，开发新型 PARP 成像探针，使其在药理学特征上优于已建立的 PARP 成像剂，是有必要的。在这里，我们提出了一种基于临床优势 PARP 抑制剂他拉唑帕尼的新型 F 标记的 PARP 放射性示踪剂。使用经过“实验设计”（DoE）优化的铜介导放射性氟代反应，实现了[F]他拉唑帕尼（RCY：13±3.4%； = 4）的自动化放射性合成。使用二维反相/手性放射性 HPLC（>99%ee）从反应混合物中分离出手性产物。（8,9）-[F]他拉唑帕尼在 HCC1937 细胞中显示出 PARP 结合，并在荷瘤小鼠中显示出优异的肿瘤与血液比（10.2±1.5）。此外，还观察到排泄、代谢和靶标结合方面的良好药理学特征。这种[F]他拉唑帕尼的合成示例说明了 DoE 如何能够实现对成像界具有高兴趣的合成具有挑战性的放射性标记化合物的放射性合成。
