Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic strategy for various neurodegenerative disorders. The development of a positron emission tomography (PET) probe for brain RIPK1 imaging could offer a valuable tool to assess therapeutic effectiveness and uncover the neuropathology associated with RIPK1. In this study, we present the development and characterization of two new PET radioligands, [C]PB218 and [C]PB220, which have the potential to facilitate brain RIPK1 imaging. [C]PB218 and [C]PB220 were successfully synthesized with a high radiochemical yield (34 % − 42 %) and molar activity (293 – 314 GBq/µmol). PET imaging characterization of two radioligands was conducted in rodents, demonstrating that both newly developed tracers have good brain penetration (maximum SUV = 0.9 – 1.0) and appropriate brain clearance kinetic profiles. Notably, [C]PB218 has a more favorable binding specificity than [C]PB220. A PET/MR study of [C]PB218 in a non-human primate exhibited good brain penetration, desirable kinetic properties, and a safe profile, thus supporting the translational applicability of our new probe. These investigations enable further translational exploration of [C]PB218 for drug discovery and PET probe development targeting RIPK1.

中文翻译：

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用于 RIPK1 正电子发射断层扫描成像的 11C 标记 7-Oxo-2,4,5,7-四氢-6H-吡唑并[3,4-c]吡啶放射性配体的合成和临床前评价

靶向受体相互作用蛋白激酶 1 (RIPK1) 已成为治疗各种神经退行性疾病的一种有前途的治疗策略。用于大脑 RIPK1 成像的正电子发射断层扫描 (PET) 探针的开发可以为评估治疗效果和揭示与 RIPK1 相关的神经病理学提供有价值的工具。在这项研究中，我们介绍了两种新型 PET 放射性配体 [C]PB218 和 [C]PB220 的开发和表征，它们具有促进大脑 RIPK1 成像的潜力。成功合成了[C]PB218和[C]PB220，具有高放射化学收率（34% - 42%）和摩尔活性（293 - 314 GBq/μmol）。在啮齿动物中对两种放射性配体进行了 PET 成像表征，证明两种新开发的示踪剂具有良好的脑穿透性（最大 SUV = 0.9 – 1.0）和适当的脑清除动力学曲线。值得注意的是，[C]PB218 比 [C]PB220 具有更有利的结合特异性。 [C]PB218 在非人类灵长类动物中的 PET/MR 研究表现出良好的大脑穿透性、理想的动力学特性和安全性，从而支持我们的新探针的转化适用性。这些研究使得 [C]PB218 能够进一步转化探索，用于针对 RIPK1 的药物发现和 PET 探针开发。