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

• Published in: Journal of Nuclear Medicine Vol. 60; no. 1; pp. 129 - 134
• Main Authors: Paul, Soumen, Haskali, Mohammad B., Liow, Jeih-San, Zoghbi, Sami S., Barth, Vanessa N., Kolodrubetz, Marcy Comly, Bond, Michelle R., Morse, Cheryl L., Gladding, Robert L., Frankland, Michael P., Kant, Nancy, Slieker, Lawrence, Shcherbinin, Sergey, Nuthall, Hugh N., Zanotti-Fregonara, Paolo, Hanover, John A., Jesudason, Cynthia, Pike, Victor W., Innis, Robert B.
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.01.2019
• Subjects: Acetamides - pharmacokinetics; Alzheimer's disease; Amygdala; Animals; beta-N-Acetylhexosaminidases - metabolism; Biological Transport; Brain; Brain - diagnostic imaging; Brain - metabolism; Fluorine isotopes; Image Processing, Computer-Assisted; Kidneys; Kinetics; Laboratory animals; Ligands; Liver; Macaca mulatta; Medical imaging; Mice; Mice, Knockout; Monkeys; Neostriatum; Neurodegenerative diseases; Neuroimaging; Neurology; Organs; Pharmacokinetics; Pharmacology; Phosphorylation; Piperidines - pharmacokinetics; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Proteins; Radiation therapy; Radioactivity; Radioisotopes; Radiometry; Selectivity; Spleen; Tau protein; Thiazoles - pharmacokinetics; Tissue Distribution; Tomography; O-GlcNAcase; tau; Alzheimer disease; PET
• ISSN: 0161-5505; 1535-5667; 2159-662X; 1535-5667
• DOI: 10.2967/jnumed.118.213231

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 -GlcNAcase (OGA), which may subsequently decrease pathologic tau phosphorylation. Here, we report the pharmacokinetics of a novel PET radioligand, F-LSN3316612, which binds with high affinity and selectivity to OGA. 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. , a mouse brain-specific knockout of was also scanned to assess the specificity of the radioligand for its target enzyme. 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 mice, brain uptake of F-LSN3316612 was reduced by 82% compared with control mice. Peripheral organs were unaffected in mice, consistent with loss of OGA expression exclusively in the brain. The effective dose of F-LSN3316612 in humans was calculated to be 22 μSv/MBq, which is typical for F-labeled radioligands. These results show that F-LSN3316612 is an excellent radioligand for imaging and quantifying OGA in rhesus monkeys and mice. On the basis of these data, F-LSN3316612 merits evaluation in humans.