Evaluation of a PET Radioligand to Image O-GlcNAcase in Brain and Periphery of Rhesus Monkey and Knock-Out Mouse

J Nucl Med. 2019 Jan;60(1):129-134. doi: 10.2967/jnumed.118.213231. Epub 2018 Sep 13.

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.

Keywords: Alzheimer disease; O-GlcNAcase; PET; tau.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / pharmacokinetics*
  • Animals
  • Biological Transport
  • Brain / diagnostic imaging*
  • Brain / 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*

Substances

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