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We aimed to develop effective radioligands for quantifying brain O -linked-β- N -acetyl-glucosamine ( O -GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools for evaluating drug target engagement. Posttranslational modifications of tau, a biomarker of Alzheimer's disease, by O -GlcNAc through the enzyme pair OGA and O -GlcNAc transferase (OGT) are inversely related to the amounts of its insoluble hyperphosphorylated form. Increase in tau O -GlcNAcylation by OGA inhibition is believed to reduce tau aggregation. LSN3316612, a highly selective and potent OGA ligand [half-maximal inhibitory concentration (IC 50 ) = 1.9 nM], emerged as a lead ligand after in silico analysis and in vitro evaluations. [ 3 H]LSN3316612 imaged and quantified OGA in postmortem brains of rat, monkey, and human. The presence of fluorine and carbonyl functionality in LSN3316612 enabled labeling with positron-emitting fluorine-18 or carbon-11. Both [ 18 F]LSN3316612 and [ 11 C]LSN3316612 bound reversibly to OGA in vivo, and such binding was blocked by pharmacological doses of thiamet G, an OGA inhibitor of different chemotype, in monkeys. [ 18 F]LSN3316612 entered healthy human brain avidly (~4 SUV) without radiodefluorination or adverse effect from other radiometabolites, as evidenced by stable brain total volume of distribution (V T ) values by 110 min of scanning. Overall, [ 18 F]LSN3316612 is preferred over [ 11 C]LSN3316612 for future human studies, whereas either may be an effective positron emission tomography radioligand for quantifying brain OGA in rodent and monkey.

science translational medicine

PET ligands [ 18 F]LSN3316612 and [ 11 C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain