P3‐062: effect of repeated administration of e2027, a novel phosphodiesterase‐9 inhibitor, on cyclic gmp levels in rat cerebrospinal fluid

Phosphodiesterase-9 (PDE9) is a cyclic guanosine monophosphate (cGMP) degrading enzyme that is widely expressed in the brain. Thus, PDE9 inhibition will increase cGMP levels in the brain. cGMP is involved in synaptic plasticity and cognitive function. Previously, we have showed that oral administration of E2027 increased cGMP levels in the CSF and improved memory performance in rats. A novel PDE9 inhibitor E2027 is being developed for long-term treatment of dementia with Lewy bodies. The purpose of this study was to examine the sustainability of the effects of repeated E2027 administration on cGMP level in the CSF of rats. E2027 was administrated orally to rats as single or repeated dose(s). For repeated administration, vehicle or E2027 (3 and 30 mg/kg) was administered to rats three times a day for 1, 2, or 6 weeks. CSF and plasma samples were collected 2 hours after the final administration in each dosing period. To confirm the E2027 plasma levels during dosing, satellite PK animals underwent serial plasma collection. The concentrations of CSF cGMP and plasma E2027 were measured by LC-MS/MS. Single administration of E2027 significantly increased cGMP levels in CSF at doses of 3 and 30 mg/kg in a dose-dependent manner. Repeated administration of E2027 for 1, 2, and 6 weeks also showed cGMP increases in CSF; with comparable effects across the time period studied. With repeated administration of E2027 at doses of 3 and 30 mg/kg, the plasma E2027 concentrations in rats were maintained at >300 ng/mL and >1500 ng/mL, respectively. These results demonstrated that repeated E2027 administration in rats achieved sustained cGMP levels in the brain (as measured in CSF) and suggest no significant tolerance to PDE9 inhibition develops over time.