Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [¹¹C]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 λk 3 (an index of FAAH activity, λ = 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 λk 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 λk 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 (495% inhibition at 1 mg) in living human brain.

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

“…Currently a clinical trial with the Pfizer FAAH inhibitor PF-04457845 (71–73) is on-going for cannabis withdrawal (NCT01618656 at ClinicalTrials.gov). Our recent human blocking study with the Pfizer compound and [ 11 C]CURB PET provided crucial information on the dosing regimen that produces sufficient FAAH inhibition in the human brain (44). …”

“…The recently developed PET tracer [ 11 C]CURB ([ 11 C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)) (43) is an effective PET radioligand, which binds selectively and irreversibly to FAAH (44). We recently reported that FAAH binding can be estimated reliably and reproducibly (44) using a two-tissue compartment model with irreversible trapping (2-TCMi) that fitted regional time-activity curves, with the composite parameter λ k 3 (λ= K 1 /k 2 ) as the preferred index of FAAH binding (45). …”

New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals

“…Moreover, two potent and irreversible fatty acid amide hydrolase (FAAH) inhibitors, [ 11 C]PF-04457845 [41] and [ 11 C]CURB [42], have also been prepared. The latter, [ 11 C]CURB, have recently been translated to a clinical setting for reginal quantification of FAAH activity in human brain [43]. Furthermore, the reversible monoamine oxidase B (MAO-B) radioligand, [ 11 C]SL25.1188, previously prepared using the technical demanding [ 11 C]phosgene approach, was radiolabeled in high yield via 11 CO 2 -fixation [44, 45].…”

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies

“…[ 11 C]CURB is an irreversible FAAH inhibitor that shows high brain uptake in rodents, with highest uptake levels in the cortex and cerebellum [24]. As with radiotracers targeting CB 1 , imaging with [ 11 C]CURB has been demonstrated to have good test-retest reliability [25]. There are several lines of evidence suggesting that [ 11 C]CURB provides an index of FAAH activity.…”