Development and Preclinical Evaluation of Novel F‑18-Labeled Dihydropyrazole RIPK1 PET Tracers for Neuroinflammation Imaging

Receptor-interacting
protein kinase 1 (RIPK1) is a key mediator
of inflammation and cell death, making it a promising target for diagnosing
neurodegenerative diseases. In this study, we developed and evaluated
two novel dihydropyrazole-based PET tracers, [18F]PB833 and [18F]PB830, through structural
optimization of dihydropyrazole-based inhibitors. Both tracers demonstrated
good blood-brain barrier penetration in rodents. Notably, [18F]PB830 showed superior brain uptake, binding specificity,
and metabolic stability. In a mouse model of neuroinflammation, the
[18F]PB830 PET signal was significantly elevated,
which correlated with increased RIPK1 expression confirmed by immunofluorescence.
Furthermore, [18F]PB830 showed robust brain
uptake in nonhuman primates with a peak SUV of 2.6, indicating the
translational potential. Our findings establish [18F]PB830 as a promising PET radioligand for noninvasive assessment
of neuroinflammation and for preclinical studies of neurodegenerative
diseases.