Dataset Information

PET ligands [18F]LSN3316612 and [11C]LSN3316612 quantify O-linked-β-N-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]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.

SUBMITTER: Lu S

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

REPOSITORIES: biostudies-literature

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

Lu Shuiyu S Haskali Mohammad B MB Ruley Kevin M KM Dreyfus Nicolas J-F NJ DuBois Susan L SL Paul Soumen S Liow Jeih-San JS Morse Cheryl L CL Kowalski Aneta A Gladding Robert L RL Gilmore Jeremy J Mogg Adrian J AJ Morin S Michelle SM Lindsay-Scott Peter J PJ Ruble J Craig JC Kant Nancy A NA Shcherbinin Sergey S Barth Vanessa N VN Johnson Michael P MP Cuadrado Maria M Jambrina Enrique E Mannes Andrew J AJ Nuthall Hugh N HN Zoghbi Sami S SS Jesudason Cynthia D CD Innis Robert B RB Pike Victor W VW

Science translational medicine 20200501 543

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 ...[more]

PMID: 32404505

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Dataset Information

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

Publications

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

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