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

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Science Translational Medicine  13 May 2020:
Vol. 12, Issue 543, eaau2939
DOI: 10.1126/scitranslmed.aau2939

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Targeting tauopathy with radioligands

Positron emission tomography (PET) can be useful for imaging the brain to study neurodegeneration but requires radioligands to identify and quantify specific proteins. Lu and colleagues developed two radioligands that detect an enzyme involved in posttranslational modifications of tau, a protein that accumulates in tangles in the brain during Alzheimer’s disease. The ligands imaged and quantified the target enzyme in rodent and monkey brain tissue and postmortem brain tissue from humans with Alzheimer’s disease. When delivered to healthy monkeys and humans, the radioligands showed uptake in the brain by PET imaging. These radioligands could be useful for drug development for tauopathies.

Abstract

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 (IC50) = 1.9 nM], emerged as a lead ligand after in silico analysis and in vitro evaluations. [3H]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 [18F]LSN3316612 and [11C]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. [18F]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 (VT) values by 110 min of scanning. Overall, [18F]LSN3316612 is preferred over [11C]LSN3316612 for future human studies, whereas either may be an effective positron emission tomography radioligand for quantifying brain OGA in rodent and monkey.

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