Evaluation of a PET Radioligand to Image O-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 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.

• Authors: Soumen Paul, Mohammad B Haskali, Jeih-San Liow, Sami S Zoghbi, Vanessa N Barth, Marcy Comly Kolodrubetz, Michelle R Bond, Cheryl L Morse, Robert L Gladding, Michael P Frankland, Nancy Kant, Lawrence Slieker, Sergey Shcherbinin, Hugh N Nuthall, Paolo Zanotti-Fregonara, John A Hanover, Cynthia Jesudason, Victor W Pike, Robert B Innis
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 60 Issue 1 Pg. 129-134 (01 2019) ISSN: 1535-5667 [Electronic] United States
• PMID: 30213846 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Acetamides
• Ligands
• Piperidines
• Thiazoles
• lsn3316612
• hexosaminidase C
• beta-N-Acetylhexosaminidases

Topics

• Acetamides (pharmacokinetics)
• Animals
• Biological Transport
• Brain (diagnostic imaging, metabolism)
• Image Processing, Computer-Assisted
• Kinetics
• Ligands
• Macaca mulatta
• Mice
• Mice, Knockout
• Piperidines (pharmacokinetics)
• Positron-Emission Tomography (methods)
• Radiometry
• Thiazoles (pharmacokinetics)
• Tissue Distribution
• beta-N-Acetylhexosaminidases (metabolism)