PT - JOURNAL ARTICLE AU - Soumen Paul AU - Mohammad B. Haskali AU - Jeih-San Liow AU - Sami S. Zoghbi AU - Vanessa N. Barth AU - Marcy Comly Kolodrubetz AU - Michelle R. Bond AU - Cheryl L. Morse AU - Robert L. Gladding AU - Michael P. Frankland AU - Nancy Kant AU - Lawrence Slieker AU - Sergey Shcherbinin AU - Hugh N. Nuthall AU - Paolo Zanotti-Fregonara AU - John A. Hanover AU - Cynthia Jesudason AU - Victor W. Pike AU - Robert B. Innis TI - Evaluation of a PET Radioligand to Image <em>O</em>-GlcNAcase in Brain and Periphery of Rhesus Monkey and Knock-Out Mouse AID - 10.2967/jnumed.118.213231 DP - 2019 Jan 01 TA - Journal of Nuclear Medicine PG - 129--134 VI - 60 IP - 1 4099 - http://jnm.snmjournals.org/content/60/1/129.short 4100 - http://jnm.snmjournals.org/content/60/1/129.full SO - J Nucl Med2019 Jan 01; 60 AB - 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 O-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. Methods: 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. 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 distribution volume. Whole-body imaging of rhesus monkeys showed high uptake in kidney, spleen, liver, and testes. In Oga∆Br mice, brain uptake of 18F-LSN3316612 was reduced by 82% compared with control mice. Peripheral organs were unaffected in Oga∆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. Conclusion: 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.