The Fatty Acid Amide Hydrolase C385A Variant Affects Brain Binding of the Positron Emission Tomography Tracer [¹¹C]CURB

Abstract

The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [11 C]CURB ([ 11 C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n = 24) completed one [ 11 C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [11 C]CURB binding (λk 3 ) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [ 11 C]CURB measurement.

Fatty Acid Amide Hydrolase–morphine Interaction Influences Ventilatory Response to Hypercapnia and Postoperative Opioid Outcomes in Children

“…SNP rs324420 has an estimated mutation age of 114,425-177,525 years [42], and causes conversion of a conserved proline to threonine (p.Pro129Thr), resulting in an FAAH enzyme with enhanced sensitivity to proteolytic degradation and reduced cellular stability [43]. In addition, relative to C/C, A-allele carriers of rs324420 were found to have 23% lower in vivo binding of FAAH in brain using positron emission tomography probe [44]. Decreases in FAAH efficacy have been shown to increase sensitivity to anandamide in FAAH knockout mice (FAAH [ −/− ]) [45].…”

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

“…When appropriate, least significant difference t -tests, Bonferroni corrected, were applied to determine the significance of regional differences in [ 11 C]CURB binding between groups. Healthy controls (n=22) data were previously published as part of the genetic association study of FAAH rs324420 on [ 11 C]CURB binding (42). …”

“…Other studies showed that the C allele is associated with increased self-reported positive feeling during a marijuana challenge (38), craving during abstinence (39), cue-induced reward circuit activation (40), and negative mood symptoms linked to frontolimbic white matter abnormalities (41). Of note, we recently showed that the C/C genotype has higher levels of FAAH binding in brain using our positron emission tomography (PET) tracer [ 11 C]CURB (42). …”

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…1). 69–71 Pfizer’s urea-based irreversible FAAH inhibitor was radiolabeled as its direct isotopologue [ 11 C- carbonyl ]PF-04457845 by [ 11 C]CO 2 -fixation 72 in order to conduct biodistribution studies and confirm target engagement and irreversibility of binding to the enzyme in rats (Scheme 4B). Clinical translation of this tracer is also underway.…”