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

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.