Design, Synthesis,
and Evaluation of 11C‑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
(9) exhibited potent inhibitory activity (IC50 = 30 nM) against DGKγ 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 DGKγ-deficient
mice and rats indicated that [11C]9 ([11C]T-278) specifically binds to DGKγ and
yields a high signal-to-noise ratio for DGKγ in rodent brains.