title: Inhibition of fatty acid amide hydrolase by BIA 10-2474 in rat brain.
abstract: In a recent clinical trial, the drug BIA 10-2474, a putative fatty acid amide hydrolase(FAAH) inhibitor, was responsible for severe adverse events (SAEs), including one death. To date, there has been little reliable information divulged about the potency of BIA 10-2474 at FAAH in the central nervous system. We synthesised BIA 10-2474 and determined its ability to inhibit FAAH ex vivo in rat brain using a FAAH selective radiotracer. BIA 10-2474 proved to be a potent FAAH inhibitor with IC50s of 50-70 µg/kg (i.p.) in various brain regions. This information may be useful for determining the cause of the SAEs.
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Junchao
authors.initials: J
authors.lastname: Tong
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Romina
authors.initials: R
authors.lastname: Mizrahi
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kish
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boileau
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Jose
authors.initials: J
authors.lastname: Nobrega
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Rusjan
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D003497:Cyclic N-Oxides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D011725:Pyridines; D019275:Radiopharmaceuticals; D000099252:Fatty Acid Amide Hydrolases; C000612073:BIA 10-2474
keywords: Animal models; brain imaging; clinical trials; positron emission tomography; receptor imaging