Abstract
Irsenontrine is a novel phosphodiesterase-9 inhibitor that has been developed for the treatment of cognitive dysfunction. To assess the pharmacokinetics, excretion, and distribution of the drug in humans, comprehensive assays for irsenontrine were developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) in three human matrices, including plasma, urine, and cerebrospinal fluid (CSF). Irsenontrine was extracted from the matrices by a straightforward protein precipitation method and subsequently separated on a reverse-phase column. The analytes, irsenontrine and the deuterated stable isotope as the internal standard, were detected by LC-MS/MS in multiple reaction monitoring. The assay demonstrated the quantifiable detection of irsenontrine in plasma, urine, and CSF samples at concentrations as low as 2 ng/mL, with a run time of only 4 min. The assays exhibited satisfactory reproducibility, with accuracy and precision within the acceptable limits. The assays were employed for the purpose of determining the concentrations of irsenontrine in the three matrices, in support of clinical trials. Furthermore, the incurred sample reanalysis further demonstrated the reproducibility of the assays.