PET Imaging of P2X7 Receptor (P2X7R) for Neuroinflammation with Improved Radiosynthesis of Tracer [ 18 F]4A in Mice and Non-human Primates.

The P2X7 receptor (P2X7R) is a key neuroinflammation target in a variety of neurodegenerative diseases. Improved radiosynthesis was developed according to the previously reported P2X7R antagonist GSK1482160. Biodistribution, radiometabolite, and dynamic positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT-MRI) of the lipopolysaccharide (LPS) rat model and the transgenic mouse model of Alzheimer's disease (AD) revealed a stable, low uptake of [ 18 F]4A in the brain of healthy rats but a higher standardized uptake value ratio (SUVR) in LPS-treated rats (1.316 ± 0.062, n = 3) than in sham (1.093 ± 0.029, n = 3). There were higher area under curves (AUCs) in the neocortex (25.12 ± 1.11 vs 18.94 ± 1.47), hippocampus (22.50 ± 3.41 vs 15.90 ± 1.59), and basal ganglia (22.26 ± 0.81 vs 15.32 ± 1.76) of AD mice ( n = 3) than the controls ( n = 3) ( p < 0.05). Furthermore, 50 min dynamic PET in healthy nonhuman primates (NHPs) indicated [ 18 F]4A could penetrate the blood-brain barrier (BBB). In conclusion, [ 18 F]4A from this study is a potent P2X7R PET tracer that warrants further neuroinflammation quantification in human studies.