Metabolic Study of Stable Isotope Labeled Indolinone Derivative in Hepatocyte Cell by UPLC/Q TOF MS.

The aggregation process of α-synuclein (α-syn) is substantial in the pathogenesis of Parkinson's disease. Indolinone derivatives are inhibitors of α-syn aggregates and can be used as PET-based radiotracers for imaging α-syn fibrils. However, no investigations on the metabolism of indolinone derivatives have been reported until now. In the present research, a C and N isotope labeling strategy was developed to synthesize compound [C,N]-()-1-(4-aminobenzyl)-3-(()-(3-phenyl)allylidene)indolin-2-one (), which was then used in a study of metabolism in hepatocytes. The metabolites were characterized using accurate mass and characteristic ion measurements. In the metabolic system, compound was the main component (accounting for 97.5% of compound-related components) after incubation in hepatocytes for 3 h, which indicated that compound possessed great metabolic stability. Seven metabolites have been successfully verified by UPLC/Q TOF MS in metabolic studies, including hydroxyl (), hydroxyl and methylated (), -acetylated (), sulfate of hydroxyl (), the glucose conjugate of (), glucuronide conjugate of (), and glucuronide conjugate of hydroxyl (). The study on metabolism provides the important information to develop effective α-syn aggregate inhibitors and new PET-tracer-related indolinone derivatives.