2. Academic Validation
  3. Development and Preclinical Evaluation of Novel F-18-Labeled Dihydropyrazole RIPK1 PET Tracers for Neuroinflammation Imaging

Development and Preclinical Evaluation of Novel F-18-Labeled Dihydropyrazole RIPK1 PET Tracers for Neuroinflammation Imaging

  • J Med Chem. 2025 Dec 11;68(23):25590-25606. doi: 10.1021/acs.jmedchem.5c02770.
Hongyan Li 1 2 3,  Zeyi Qin 4,  Yanting Zhou 1 2 3,  Hui Meng 1 2 3,  Weiyao Xie 1 2 3,  Pan Yao 1 2 3,  Xinyu Yang 1 2 3,  Huawei Cai 5,  Lin Li 5,  Changning Wang 6,  Xiaoai Wu 5,  Ping Bai 1 2 3
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.
  • 2 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.
  • 3 Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4 Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, Maryland 21205, United States.
  • 5 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 6 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
PMID: 41266996 DOI: 10.1021/acs.jmedchem.5c02770
Abstract

Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation and cell death, making it a promising target for diagnosing neurodegenerative diseases. In this study, we developed and evaluated two novel dihydropyrazole-based PET tracers, [18F]PB833 and [18F]PB830, through structural optimization of dihydropyrazole-based inhibitors. Both tracers demonstrated good blood-brain barrier penetration in rodents. Notably, [18F]PB830 showed superior brain uptake, binding specificity, and metabolic stability. In a mouse model of neuroinflammation, the [18F]PB830 PET signal was significantly elevated, which correlated with increased RIPK1 expression confirmed by immunofluorescence. Furthermore, [18F]PB830 showed robust brain uptake in nonhuman primates with a peak SUV of 2.6, indicating the translational potential. Our findings establish [18F]PB830 as a promising PET radioligand for noninvasive assessment of neuroinflammation and for preclinical studies of neurodegenerative diseases.

Figures
Products