Design and Discovery of Novel NLRP3 Inhibitors and PET Imaging Radiotracers Based on a 1,2,3-Triazole-Bearing Scaffold

The
NOD-like receptor (NLR) family pyrin-domain-containing 3 (NLRP3)
inflammasome, an essential component of the innate immune system,
has been emerging as a viable drug target and a potential biomarker
for human diseases. In our efforts to develop novel small molecule
NLRP3 inhibitors, a 1-(5-chloro-2-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole
scaffold was designed via a rational approach based on our previous
leads. Structure–activity relationship studies and biophysical
studies identified a new lead compound 8 as a potent
(IC50: 0.55 ± 0.16 μM), selective, and direct
NLRP3 inhibitor. Positron emission tomography (PET) imaging studies
of [11C]8 demonstrated its rapid and high
brain uptake as well as fast washout in mice and rhesus macaque. Notably,
plasma kinetic analysis of this radiotracer from the PET/magnetic
resonance imaging studies in rhesus macaque suggested radiometabolic
stability. Collectively, our data not only encourage further studies
of this lead compound but also warrant further optimization to generate
additional novel NLRP3 inhibitors and suitable central nervous system
PET radioligands with translational promise.