title: Blocking of fatty acid amide hydrolase activity with PF-04457845 in human brain: a positron emission tomography study with the novel radioligand [(11)C]CURB.
abstract: Positron emission tomography with [(11)C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test-retest reliability of [(11)C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test-retest [(11)C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n=2 each). The composite parameter λk3 (an index of FAAH activity, λ=K1/k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [(11)C]CURB injection. Oral administration of PF-04457845 reduced [(11)C]CURB binding to a homogeneous level at all three doses, with λk3 values decreased by ⩾91%. Excellent reproducibility and good reliability (test-retest variability=9%; intraclass correlation coefficient=0.79) were observed across all regions of interest investigated. Our findings suggest that λk3/[(11)C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Lab, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boileau
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Rusjan
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Lab, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Belinda
authors.initials: B
authors.lastname: Williams
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Lab, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Mansouri
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Romina
authors.initials: R
authors.lastname: Mizrahi
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Luca
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.affiliation: Human Brain Lab, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kish
authors.affiliation: Human Brain Lab, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Junchao
authors.initials: J
authors.lastname: Tong
mesh_terms: D000328:Adult; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000201:enzymology*; D002219:Carbamates / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002219:Carbamates; D004791:Enzyme Inhibitors; D011724:Pyridazines; D019275:Radiopharmaceuticals; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C560620:N-pyridazin-3-yl-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide; C555899:cyclohexyl carbonic acid 3'-carbamoyl-3-yl ester