Evaluation of a PET Radioligand to Image <i>O</i>-GlcNAcase in Brain and Periphery of Rhesus Monkey and Knock-Out Mouse.

Abstract

Accumulation of hyperphosphorylated tau, a microtubule-associated protein, plays an important role in the progression of Alzheimer disease. Animal studies suggest that one strategy for treating Alzheimer disease and related tauopathies may be inhibition of <i>O</i>-GlcNAcase (OGA), which may subsequently decrease pathologic tau phosphorylation. Here, we report the pharmacokinetics of a novel PET radioligand, ¹⁸F-LSN3316612, which binds with high affinity and selectivity to OGA. <b>Methods:</b> PET imaging was performed on 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 using a 2-tissue-compartment model and serial concentrations of parent radioligand in arterial plasma. The radiation burden for future studies was based on whole-body imaging of monkeys. <i>Oga</i>^∆Br, a mouse brain-specific knockout of <i>Oga,</i> was also scanned to assess the specificity of the radioligand for its target enzyme. <b>Results:</b> 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 distribution volume. Whole-body imaging of rhesus monkeys showed high uptake in kidney, spleen, liver, and testes. In <i>Oga</i>^∆Br mice, brain uptake of ¹⁸F-LSN3316612 was reduced by 82% compared with control mice. Peripheral organs were unaffected in <i>Oga</i>^∆Br mice, consistent with loss of OGA expression exclusively in the brain. The effective dose of ¹⁸F-LSN3316612 in humans was calculated to be 22 μSv/MBq, which is typical for ¹⁸F-labeled radioligands. <b>Conclusion:</b> These results show that ¹⁸F-LSN3316612 is an excellent radioligand for imaging and quantifying OGA in rhesus monkeys and mice. On the basis of these data, ¹⁸F-LSN3316612 merits evaluation in humans.