Synthesis and preclinical evaluation of 11C-labeled 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine radioligands for RIPK1 positron emission tomography imaging

Tianwen Luo; Na Sang; Yan Liu; Yanting Zhou; Rui Wu; Frederick A Bagdasarian; Hsiao-Ying Wey; Jinyi Lang; Changning Wang; Ping Bai

doi:10.1016/j.bioorg.2024.107279

Synthesis and preclinical evaluation of ¹¹C-labeled 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine radioligands for RIPK1 positron emission tomography imaging

Bioorg Chem. 2024 May:146:107279. doi: 10.1016/j.bioorg.2024.107279. Epub 2024 Mar 9.

Authors

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 Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
³ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States.
⁴ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: cwang15@mgh.harvard.edu.
⁵ 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: 38513325
DOI: 10.1016/j.bioorg.2024.107279

Abstract

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, [¹¹C]PB218 and [¹¹C]PB220, which have the potential to facilitate brain RIPK1 imaging. [¹¹C]PB218 and [¹¹C]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, [¹¹C]PB218 has a more favorable binding specificity than [¹¹C]PB220. A PET/MR study of [¹¹C]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 [¹¹C]PB218 for drug discovery and PET probe development targeting RIPK1.

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

MeSH terms

Animals
Brain* / diagnostic imaging
Brain* / metabolism
Positron-Emission Tomography* / methods
Pyridines / metabolism
Radiochemistry
Radiopharmaceuticals / chemistry

Substances

Radiopharmaceuticals
Pyridines