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

Abstract

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-5yl)oxy)-N-methylacetamide ( 9) exhibited potent inhibitory activity (IC 50 = 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 [ 11 C]9 ([ 11 C]T-278) specifically binds to DGKγ and yields a high signal-to-noise ratio for DGKγ in rodent brains.

BF3-Mediated Acetylation of Pyrazolo[1,5-a]pyrimidines and Other π-Excedent (N-Hetero)arenes

“…By the general procedure at 75 °C for 45 min with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1v, 174 mg, 1.0 mmol), pyrazol-5-yl acetate 2w was obtained as a pale yellow oil (104 mg, 48%). 1 4 -dioxaborinin-4-yl)-2-methyl-7phenylpyrazolo [1,5-a]pyrimidine 3a. A mixture of substrate 1a (105 mg, 0.50 mmol), acetic anhydride (AA, 0.5 mL ∼10 equiv), and BF 3 OEt 2 (0.5 mL, ∼8 equiv) was heated at 60 °C for 6.5 h using a heating mantle.…”

“…Acylation reaction is a fundamental and valuable transformation in organic synthesis and is often employed in manufacturing various pharmaceuticals, cosmetics, and agrochemicals. − Furthermore, acylated compounds are of great interest because they have demonstrated utility as functional substrates in constructing more complex structures with remarkable biological and physicochemical properties. − Many strategies have been developed to incorporate the acyl group into aromatic compounds, such as radical transformations, ,, metal acylation, − and the well-established Friedel–Crafts acylation. − However, except for formylation reactions, very few approaches are used to acetylate or acylate N -heteroaromatic rings. These scaffolds are of considerable interest due to their frequent biological and photophysical applications. − …”

Development of Specific PET Tracers for Central Nervous System Drug Targets

“…9 However, many CNS drug targets still lack the speci c or suitable PET tracers for clinical investigation. This report describes the design, synthesis, and characterization of the following speci c PET tracers for the CNS drug targets, monoacylglycerol lipase ([ 18 F]T ─ 401), 10,11 diacylglycerol kinase gamma ([ 11 C]T ─ 278), 12 lysine─ speci c demethylase 1 ([ 18 F]T ─ 914), 13,14 and cholesterol 24─ hydroxylase ([ 18 F]T ─ 008) 15,16 (Figure 1).…”