Evaluation of a novel PET radioligand to image O-GlcNAcase in brain and periphery of rhesus monkey and knock-out mouse.

Accumulation of hyper-phosphorylated tau, a microtubule-associated protein, plays an important role in the progression of Alzheimer's disease (AD). Animal studies suggest that one strategy for treating AD and related tauopathies may be inhibition of O-GlcNAcase (OGA), which may subsequently decrease pathological tau phosphorylation Here, we report the pharmacokinetics of a novel positron emission tomography (PET) radioligand, 18 F-LSN3316612, which binds with high affinity and selectivity to OGA. Methods: PET imaging was performed in rhesus monkeys at baseline and after administration of either thiamet G, a potent OGA inhibitor, or nonradioactive LSN3316612. The density of the enzyme was calculated as distribution volume (VT) using a two-tissue compartment model and serial concentrations of parent radioligand in arterial plasma. The radiation burden for future studies was calculated based on whole-body imaging of monkeys. Oga∆Br, a mouse brain-specific knockout of Oga, was also scanned to assess the specificity of the radioligand for its target enzyme. Results: Uptake of radioactivity in monkey brain was high (~5 SUV) and followed by slow washout. The highest uptake was in the amygdala, followed by striatum and hippocampus. Pretreatment with thiamet G or nonradioactive LSN3316612 reduced brain uptake to a low and uniform concentration in all regions, corresponding to an approximately 90% decrease in VT. Whole-body imaging in rhesus monkeys showed high uptake in kidney, spleen, liver, and testes. In Oga∆Br mice, brain uptake of 18 F-LSN3316612 was reduced by 82% compared to control mice. Peripheral organs were unaffected in Oga∆Br mice, consistent with loss of OGA expression exclusively in the brain. The effective dose of 18 F- LSN3316612 in humans was calculated to be 22 µSv/MBq, which is typical for 18 F-labeled radioligands. Conclusion: These results show that 18 F-LSN3316612 is an excellent radioligand for imaging and quantifying OGA in rhesus monkeys and mice. Based on these data, 18 F-LSN3316612 merits evaluation in humans.