2. Academic Validation
  3. Structure-based discovery of a 4,5-Dihydropyrazole-cored PET ligand for imaging of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the brain

Structure-based discovery of a 4,5-Dihydropyrazole-cored PET ligand for imaging of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the brain

  • Eur J Med Chem. 2024 Sep 2:279:116803. doi: 10.1016/j.ejmech.2024.116803.
Wanqing Li 1,  Xiaojun Zhang 2,  Jingyin Zhou 1,  Xuan Di 1,  Donglan Huang 1,  Jie Ma 3,  Kaixiang Zhou 4,  Jinming Zhang 5,  Lu Wang 6,  Hualong Fu 7,  Mengchao Cui 8
Affiliations

Affiliations

  • 1 Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, PR China.
  • 2 Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing, 100853, PR China.
  • 3 Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, PR China.
  • 4 Center for Advanced Materials Research & Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China.
  • 5 Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing, 100853, PR China. Electronic address: zhangjm301@163.com.
  • 6 Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, PR China. Electronic address: l_wang1009@jnu.edu.cn.
  • 7 Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, PR China. Electronic address: fuhualong@bnu.edu.cn.
  • 8 Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, PR China; Center for Advanced Materials Research & Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China.
PMID: 39255641 DOI: 10.1016/j.ejmech.2024.116803
Abstract

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates programmed cell death and inflammation, contributing to a wide range of human pathologies, including inflammatory disorders, neurodegenerative conditions, and Cancer. Despite this, no RIPK1 positron emission tomography (PET) ligand with significant in vivo specificity has been reported to date. In this work, we designed and synthesized a new family of dihydropyrazole-cored ligands suitable for 18F-labeling at the late stage. Among these, WL8 showed a strong binding affinity to RIPK1 (EC50 = 19.9 nM, Kd = 25 nM) and was successfully labeled with 18F in the 6-position of pyridine ring, yielding a high radiochemistry yield of 27.9 % (decay-corrected) and a high molar activity of 18.8-31.2 GBq/μmol. In in vitro autoradiography, [18F]WL8 showed some specific binding in the brain sections of rats and lipopolysaccharide (LPS) model mice. Preliminary PET studies in rat brains revealed that [18F]WL8 could efficiently penetrate the blood-brain barrier and was rapidly washed out. As anticipated, [18F]WL8 exhibited a high initial uptake (brain2min = 4.80 % ID/g) in mouse brains, followed by a rapid washout (brain60min = 0.14 % ID/g), although no clear specific binding to RIPK1 was observed. Moderate in vivo stability was noted for [18F]WL8 in mouse brains with 35.2 % of the parent fraction remaining after 30 min post-administration. Altogether, our work broadens the landscape and offers a new chemotype for RIPK1 PET ligand development.

Keywords

Brain kinetics; Dihydropyrazole-cored inhibitors; Necroptosis; PET imaging; RIPK1.

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