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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.
- Source :
-
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2015 Nov; Vol. 35 (11), pp. 1827-35. Date of Electronic Publication: 2015 Jun 17. - Publication Year :
- 2015
-
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.
- Subjects :
- Adult
Binding, Competitive drug effects
Brain drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors administration & dosage
Female
Healthy Volunteers
Humans
Image Processing, Computer-Assisted
Kinetics
Male
Middle Aged
Positron-Emission Tomography
Pyridazines administration & dosage
Reproducibility of Results
Urea administration & dosage
Urea pharmacology
Young Adult
Amidohydrolases antagonists & inhibitors
Biphenyl Compounds pharmacokinetics
Brain diagnostic imaging
Brain enzymology
Carbamates pharmacokinetics
Enzyme Inhibitors pharmacology
Pyridazines pharmacology
Radiopharmaceuticals pharmacokinetics
Urea analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1559-7016
- Volume :
- 35
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 26082009
- Full Text :
- https://doi.org/10.1038/jcbfm.2015.133