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 [18F]WL1–3. Among these, [18F]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 (brain2 min = 4.89% ID/g)
and rapid washout (brain60 min = 0.21% ID/g). PET
studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed
by inhibition effects of unlabeled WL1 and GSK′547.
Notably, [18F]WL1 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.