A novel approach for modeling <i>in vivo</i> enzyme turnover in the presence of a suicide inhibitor drug: A proof-of-concept brain PET study on MAG lipase.

ABSTRACT: PET imaging allows the study of enzyme concentration and activity in vivo. The enzyme natural turnover α, relevant for drug development, can be estimated if a suicide inhibitor drug is used. The main aim of this study was to develop a model for estimating α by accounting for the presence of residual inhibitor. We analyzed nonhuman primate PET data with monoacyglycerol lipase (MAGL) tracer [¹¹C]PF-06809247, and suicide inhibitor PF-06818883 (0.03-1.27 mg/kg, active compound PF-06807893). As [¹¹C]PF-06809247 is an irreversible tracer, we used simulations to evaluate the impact of flow limitation on identifiability of kinetic parameters. Based on this, MAGL activity estimates were obtained from three outcome parameters: K_i, k₃,

SUBMITTER: Volpi T 

PROVIDER: S-EPMC12081407 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature