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
  • 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.

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