TY - JOUR
T1 - Evaluation of a PET radioligand to image O-GlcNAcase in brain and periphery of rhesus monkey and knock-out mouse
AU - Paul, Soumen
AU - Haskali, Mohammad B.
AU - Liow, Jeih San
AU - Zoghbi, Sami S.
AU - Barth, Vanessa N.
AU - Kolodrubetz, Marcy Comly
AU - Bond, Michelle R.
AU - Morse, Cheryl L.
AU - Gladding, Robert L.
AU - Frankland, Michael P.
AU - Kant, Nancy
AU - Slieker, Lawrence
AU - Shcherbinin, Sergey
AU - Nuthall, Hugh N.
AU - Zanotti-Fregonara, Paolo
AU - Hanover, John A.
AU - Jesudason, Cynthia
AU - Pike, Victor W.
AU - Innis, Robert B.
N1 - Funding Information:
This work was supported by the Intramural Research Programs of NIDDK and NIMH (ZIAMH002793; ZIAMH002795) and a research grant from Eli Lilly & Co. Vanessa Barth, Nancy Kant, Lawrence Slieker, Sergey Shcherbinin, Hugh Nuthall, and Cynthia Jesudason were employees of Eli Lilly and Co. at the time the study was conducted. No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
Copyright © 2019 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - O-GlcNAcase
KW - PET
KW - Tau
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U2 - 10.2967/jnumed.118.213231
DO - 10.2967/jnumed.118.213231
M3 - Article
C2 - 30213846
AN - SCOPUS:85059501197
SN - 0161-5505
VL - 60
SP - 129
EP - 134
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 1
ER -