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]<b>PB833</b> and [¹⁸F]<b>PB830</b>, through structural optimization of dihydropyrazole-based inhibitors. Both tracers demonstrated good blood-brain barrier penetration in rodents. Notably, [¹⁸F]<b>PB830</b> showed superior brain uptake, binding specificity, and metabolic stability. In a mouse model of neuroinflammation, the [¹⁸F]<b>PB830</b> PET signal was significantly elevated, which correlated with increased RIPK1 expression confirmed by immunofluorescence. Furthermore, [¹⁸F]<b>PB830</b> showed robust brain uptake in nonhuman primates with a peak SUV of 2.6, indicating the translational potential. Our findings establish [¹⁸F]<b>PB830</b> as a promising PET radioligand for noninvasive assessment of neuroinflammation and for preclinical studies of neurodegenerative diseases.