Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing 100853, P. R. China.
J Med Chem. 2024 Sep 26;67(18):16403-16415. doi: 10.1021/acs.jmedchem.4c01263. Epub 2024 Sep 11.
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]-. Among these, [F] showed specific binding to RIPK1 in mouse brain sections through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain = 4.89% ID/g) and rapid washout (brain = 0.21% ID/g). PET studies in rat brains revealed that [F] could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled and GSK'547. Notably, [F] showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.
受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）已成为病理性细胞死亡和炎症的重要调节剂，并与各种中枢神经系统疾病的病理学有关。在这项研究中，我们报道了三种有效的二氢吡唑核心 RIPK1 正电子发射断层扫描（PET）配体 [F]-的开发。在这些配体中，[F]-通过放射自显影显示出与小鼠脑切片中 RIPK1 的特异性结合，并在小鼠中表现出良好的脑动力学特性，其特征为高初始摄取（脑 = 4.89% ID/g）和快速洗脱（脑 = 0.21% ID/g）。在大鼠脑中的 PET 研究表明，[F]-可以很容易地穿透大脑，其特异性结合通过未标记的 [F] 和 GSK'547 的抑制作用得到证实。值得注意的是，[F]-在成像肿瘤坏死因子 α 诱导的全身性炎症反应综合征模型中大鼠脑中 RIPK1 的改变方面显示出显著的潜力。这些发现可能为未来设计有效的 RIPK1 PET 配体铺平道路。
