AbstractIn the present study, we have investigated the effects of a novel prolyl endopeptidase (EC 3.4.21.26, PEP) inhibitor, compound S 17092, on substance P (SP) and α‐melanocyte‐stimulating hormone (α‐MSH) metabolism in the rat brain. In vitro experiments revealed that S 17092 inhibits in a dose‐dependent manner PEP activity in rat cortical extracts (IC50 = 8.3 nm). In addition, S 17092 totally abolished the degradation of SP and α‐MSH induced by bacterial PEP. In vivo, a significant decrease in PEP activity was observed in the medulla oblongata after a single oral administration of S 17092 at doses of 10 and 30 mg/kg (−78% and −82%, respectively) and after chronic oral treatment with S 17092 at doses of 10 and 30 mg/kg per day (−75% and −88%, respectively). Concurrently, a single administration of S 17092 (30 mg/kg) caused a significant increase in SP‐ and α‐MSH‐like immunoreactivity (LI) in the frontal cortex (+41% and +122%, respectively) and hypothalamus (+84% and +49%, respectively). In contrast, chronic treatment with S 17092 did not significantly modify SP‐ and α‐MSH‐LI in the frontal cortex and hypothalamus. Collectively, the present results show that S 17092 elevates SP and α‐MSH concentrations in the rat brain by inhibiting PEP activity. These data suggest that the effect of S 17092 on memory impairment can be accounted for, at least in part, by inhibition of catabolism of promnesic neuropeptides such as SP and α‐MSH.