Blocking of fatty acid amide hydrolase activity with PF-04457845 in human brain: a positron emission tomography study with the novel radioligand |[lsqb]|11C|[rsqb]|CURB

Positron emission tomography with [C-11]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 [C-11]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 [C-11]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 k3 (an index of FAAH activity, lambda = 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 [C-11]CURB injection. Oral administration of PF-04457845 reduced [C-11] CURB binding to a homogeneous level at all three doses, with lambda 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 lambda k(3)/[C-11]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.