Positron emission tomography imaging of the P2X7 receptor with a novel tracer, [¹⁸F]GSK1482160, in a transgenic mouse model of Alzheimer's disease and healthy non-human primates

This study aimed to evaluate [¹⁸F]GSK1482160 Positron emission tomography imaging for targeting P2X7R, a biomarker for neuroinflammation. Studies of acute neuroinflammation in rodents and transgenic mice with Alzheimer's disease (AD), as well as wild-type (WT) controls, were conducted via PET-CT-MRI scans after tail vein injection of [¹⁸F]GSK1482160. Imaging was quantified based on the time-activity curve, the standardized uptake value ratio, and the binding kinetics distribution volume ratio (DVR) to assess the expression of P2X7R. Tissues were collected post-PET for immunofluorescence staining. Correlation analysis was performed between DVR and Morris water maze test results. Finally, dynamic Positron Emission Tomography-Magnetic Resonance Imaging (PET-MRI) scans were performed in healthy non-human primates (NHPs). Our study demonstrated that AD mice had a significantly higher DVR than WT mice in the hippocampus (0.92 ± 0.06 vs. 0.79 ± 0.02, p < 0.05), cortex (1.09 ± 0.03 vs. 0.88 ± 0.04, p < 0.05), and striatum (1.02 ± 0.10 vs. 0.83 ± 0.1, p < 0.05). Immunofluorescence staining showed increased expression of P2X7R in the AD, along with its colocalization with activated microglia and astrocytes. Correlation analysis indicated that brain regions with higher binding of [¹⁸F]GSK1482160 (i.e., the cortex, striatum, and hippocampus) were more vulnerable to cognitive impairment. PET-MRI scans of healthy NHPs demonstrated the feasibility of brain penetration and P2X7R target engagement for the translation of [¹⁸F]GSK1482160 in human studies.