Jalkanen_2011_Basic.Clin.Pharmacol.Toxicol_109_443

Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P(app) ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed. Then, the in vivo brain/blood ratio was determined for the total brain and plasma concentrations and also for the unbound extracellular drug concentrations after a single dose (50 micromol/kg i.p.). KYP-2047 had a significantly higher P(app) than JTP-4819. In vivo, KYP-2047 had higher total and unbound brain/blood ratios. KYP-2047 was equally distributed between the cortex, hippocampus and striatum. In the case of JTP-4819, the unbound brain extracellular concentrations could not be readily predicted from the unbound blood levels, probably because of its poor membrane penetration properties. KYP-2047 displayed a better ability to reach the intracellularly located brain PREP, and it inhibited this enzyme more effectively than JTP-4819 after an equimolar single dose. In conclusion, KYP-2047 showed better brain penetration characteristics than JTP-4819 both in vitro and in vivo. KYP-2047 is a brain-penetrating, potent and long-acting PREP inhibitor; thus, it represents a convenient pharmacological tool for assessing the potential of PREP as a drug target.