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

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

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Accumulation of hyperphosphorylated tau, a microtubule-associ-ated 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, 18 F-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 ΔBr , 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 ΔBr mice, brain uptake of 18 F-LSN3316612 was reduced by 82% compared with control mice. Peripheral organs were unaffected in Oga ΔBr 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. On the basis of these data, 18 F-LSN3316612 merits evaluation in humans.

Original languageEnglish (US)
Pages (from-to)129-134
Number of pages6
JournalJournal of Nuclear Medicine
Volume60
Issue number1
DOIs
StatePublished - Jan 1 2019

Keywords

  • Alzheimer disease
  • O-GlcNAcase
  • PET
  • Tau

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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