Design, Synthesis, And Evaluation Of C-11-Labeled 3-Acetyl-Indole Derivatives As A Novel Positron Emission Tomography Imaging Agent For Diacylglycerol Kinase Gamma (Dgk Gamma) In Brain

Diacylglycerol kinase gamma (DGK gamma) is a subtype of DGK enzyme, which catalyzes ATP-dependent conversion of diacylglycerol to phosphatidic acid. DGK gamma, localized in the brain, plays an important role in the central nervous system. However, its function has not been widely investigated. Positron emission tomography (PET) imaging of DGK gamma validates target engagement of therapeutic DGK gamma inhibitors and investigates DGK gamma levels under normal and disease conditions. In this study, we designed and synthesized a series of 3-acetyl indole derivatives as candidates for PET imaging agents for DGK gamma. Among the synthesized compounds, 2-((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide (9) exhibited potent inhibitory activity (IC50 = 30 nM) against DGK gamma and desirable physicochemical properties allowing efficient blood-brain barrier penetration and low levels of undesirable nonspecific binding. The radiolabeling of 9 followed by PET imaging of wild-type and DGK gamma-deficient mice and rats indicated that [C-11]9 ([C-11]T-278) specifically binds to DGK gamma and yields a high signal-to-noise ratio for DGK gamma in rodent brains.