Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain

被引：1

作者：

Li, Wanqing ^{[1
]}

Zhang, Xiaojun ^{[2
]}

Ma, Jie ^{[3
,4
]}

Zhou, Jingyin ^{[1
]}

Di, Xuan ^{[1
]}

Huang, Donglan ^{[1
]}

Zhou, Kaixiang ^{[5
]}

Zhang, Jinming ^{[2
]}

Wang, Lu ^{[3
,4
]}

Fu, Hualong ^{[1
]}

Cui, Mengchao ^{[1
,5
]}

机构：

[1] Beijing Normal Univ, Coll Chem, Key Lab Radiopharmaceut, Minist Educ, Beijing 100875, Peoples R China

[2] Chinese Peoples Liberat Army Gen Hosp, Dept Nucl Med, Beijing 100853, Peoples R China

[3] Jinan Univ, Ctr Cyclotron & PET Radiopharmaceut, Dept Nucl Med, Guangzhou 510630, Peoples R China

[4] Jinan Univ, Affiliated Hosp 1, PET CT MRI Ctr, Guangzhou 510630, Peoples R China

[5] Beijing Normal Univ Zhuhai, Ctr Adv Mat Res, Zhuhai 519087, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 18期

基金：

中国国家自然科学基金;

关键词：

INFLAMMATION; NECROPTOSIS; INHIBITOR; NECROSTATIN-1; DISCOVERY;

D O I：

10.1021/acs.jmedchem.4c01263

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [F-18]WL1-3. Among these, [F-18]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain(2 min) = 4.89% ID/g) and rapid washout (brain(60 min) = 0.21% ID/g). PET studies in rat brains revealed that [F-18]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK ' 547. Notably, [F-18]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor alpha-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.

引用

页码：16403 / 16415

页数：13

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