Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [11C]CURB

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 γ k 3 (an index of FAAH activity, γ = K 1 / k 2 ) 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 γ k 3 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 γ k 3 /[ 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.