Design, Synthesis, and Evaluation of 11 C-Labeled 3-Acetyl-Indole Derivatives as a Novel Positron Emission Tomography Imaging Agent for Diacylglycerol Kinase Gamma (DGKγ) in Brain

Diacylglycerol kinase gamma (DGKγ) is a subtype of DGK enzyme, which catalyzes ATP-dependent conversion of diacylglycerol to phosphatidic acid. DGKγ, 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 DGKγ validates target engagement of therapeutic DGKγ inhibitors and investigates DGKγ 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 DGKγ. Among the synthesized compounds, 2-((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide ( ) exhibited potent inhibitory activity (IC = 30 nM) against DGKγ and desirable physicochemical properties allowing efficient blood-brain barrier penetration and low levels of undesirable nonspecific binding. The radiolabeling of followed by PET imaging of wild-type and DGKγ-deficient mice and rats indicated that [ C] ([ C] ) specifically binds to DGKγ and yields a high signal-to-noise ratio for DGKγ in rodent brains.