Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan, 610041, China; State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Chengdu, Sichuan, 610041, China.
Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
Eur J Med Chem. 2024 Dec 5;279:116851. doi: 10.1016/j.ejmech.2024.116851. Epub 2024 Sep 6.
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a promising target for the diagnosis and treatment of various diseases, especially neurodegenerative disorders. Developing PET imaging probes targeting RIPK1 is beneficial for visualizing the connections between RIPK1 and diseases, as well as for related drug development. In this study, we report the design and synthesis of a series of novel RIPK1 inhibitors. Three potent inhibitors, 7i, 7k, and 8a, with good cell anti-necroptosis potency and physicochemical properties, were identified and selected for PET imaging probe development. Subsequently, three PET imaging radioligands ([C]7k, [F]7i, and [F]8a) were successfully synthesized. In mouse PET imaging studies, all three radioligands showed good brain uptake. Among them, probe [F]8a exhibited good binding specificity in both in vitro autoradiography and in vivo PET imaging studies. Additionally, [F]8a demonstrated good in vivo metabolic stability. This work highlights the potential of probe [F]8a for imaging brain RIPK1 in live animals, laying the groundwork for the future development of RIPK1 PET radioligands.
受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）是诊断和治疗各种疾病，特别是神经退行性疾病的有前途的靶点。开发针对 RIPK1 的 PET 成像探针有助于可视化 RIPK1 与疾病之间的联系，以及相关药物的开发。在这项研究中，我们报告了一系列新型 RIPK1 抑制剂的设计和合成。鉴定并选择了三种具有良好细胞抗坏死作用和理化性质的强效抑制剂 7i、7k 和 8a 用于 PET 成像探针的开发。随后，成功合成了三种 PET 成像放射性配体 [C]7k、[F]7i 和 [F]8a。在小鼠 PET 成像研究中，所有三种放射性配体均显示出良好的脑摄取。其中，探针 [F]8a 在体外放射自显影和体内 PET 成像研究中均表现出良好的结合特异性。此外，[F]8a 表现出良好的体内代谢稳定性。这项工作突出了探针 [F]8a 用于在活体动物中成像大脑 RIPK1 的潜力，为 RIPK1 PET 放射性配体的未来发展奠定了基础。
