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  3. Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease

Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease

  • Adv Sci (Weinh). 2024 Jun 25:e2309021. doi: 10.1002/advs.202309021.
Ping Bai 1,  Yu Lan 2 3,  Yan Liu 2,  Prasenjit Mondal 4,  Ashley Gomm 4,  Yulong Xu 2,  Yanli Wang 2,  Yongle Wang 2,  Leyi Kang 2,  Lili Pan 5,  Frederick A Bagdasarian 2,  Madelyn Hallisey 2,  Breanna Varela 2,  Se Hoon Choi 4,  Stephen N Gomperts 6,  Hsiao-Ying Wey 2,  Shiqian Shen 7,  Rudolph E Tanzi 4,  Changning Wang 2,  Can Zhang 4
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
  • 3 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 4 Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA.
  • 5 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 6 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA.
  • 7 Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
PMID: 38923244 DOI: 10.1002/advs.202309021
Abstract

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially Other RIPK1-related human studies.

Keywords

Alzheimer's disease; Necroptosis; Neuroinflammation; Positron emission tomography; RIPK1; Radioligand; [11C]CNY‐10.

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