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

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]LSN3

SUBMITTER: Lu S 

PROVIDER: S-EPMC8494060 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature