2. Academic Validation
  3. Design, synthesis, and preclinical evaluation of 11C/18F-labeled inhibitors for RIPK1 PET imaging

Design, synthesis, and preclinical evaluation of 11C/18F-labeled inhibitors for RIPK1 PET imaging

  • Eur J Med Chem. 2024 Sep 6:279:116851. doi: 10.1016/j.ejmech.2024.116851.
Tianwen Luo 1,  Yanting Zhou 1,  Rui Wu 1,  Honghai Yin 2,  Weiyao Xie 1,  Hui Meng 1,  Chenyao Zhao 1,  Yanli Wang 3,  Yongle Wang 3,  Leyi Kang 3,  Xiaoai Wu 2,  Changning Wang 3,  Ping Bai 4
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States.
  • 4 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. Electronic address: pingbai@scu.edu.cn.
PMID: 39255644 DOI: 10.1016/j.ejmech.2024.116851
Abstract

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 ([11C]7k, [18F]7i, and [18F]8a) were successfully synthesized. In mouse PET imaging studies, all three radioligands showed good brain uptake. Among them, probe [18F]8a exhibited good binding specificity in both in vitro autoradiography and in vivo PET imaging studies. Additionally, [18F]8a demonstrated good in vivo metabolic stability. This work highlights the potential of probe [18F]8a for imaging brain RIPK1 in live Animals, laying the groundwork for the future development of RIPK1 PET radioligands.

Keywords

Necroptosis; Neuroinflammation; Positron emission tomography; RIPK1; Radioligands.

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