Imaging the Cannabinoid CB1 Receptor in Humans with [¹¹C] OMAR: Assessment of Kinetic Analysis Methods, Test–Retest Reproducibility, and Gender Differences

Abstract

The Radiotracer [ 11 C]OMAR was developed for positron emission tomography (PET) imaging of cannabinoid type-1 receptors (CB1R). The objectives of the present study were to evaluate kinetic analysis methods, determine test-retest reliability, and assess gender differences in receptor availability. Dynamic PET data were acquired in 10 human subjects, and analyzed with one-tissue (1T) and two-tissue (2T) compartment models and by the Logan and multilinear analysis (MA1) methods to estimate regional volume of distribution (V T ). The 2T model inclusive of a vascular component (2T V ) and MA1 were the preferred techniques. Test-retest reliability of V T was good (mean absolute deviation~9%; intraclass correlation coefficient~0.7). Tracer parent fraction in plasma was lower in women (P o 0.0001). Cerebral uptake normalized by body weight and injected dose was higher in men by 17% (P o0.0001), but V T was significantly greater in women by 23% (P o 0.0001). These findings show that [ 11 C]OMAR binding can be reliably quantified by the 2T model or MA1 method and demonstrate the utility of this tracer for in vivo imaging of CB1R. In addition, results from the present study indicate that gender difference in receptor binding should be taken into consideration when [ 11 C]OMAR is used to quantify CB1R availability in neuropsychiatric disorders.

Rapid Changes in Cannabinoid 1 Receptor Availability in Cannabis-Dependent Male Subjects After Abstinence From Cannabis

“…These measurements were performed by high pressure liquid chromatography. In addition, the fraction of plasma radioactivity unbound to protein ( f p ) was determined by ultrafiltration (22). …”

“…However, the characteristics of [ 18 F]MK-9470, which shows primarily irreversible receptor binding, poses challenges. Furthermore, the validity of the simplified data analysis technique (mSUV) used has been challenged by several groups (21, 22). …”

“…Finally, to rule out interscan variability as an explanation for any changes in CB1R availability in CDs, a small subset of HCs were scanned 4 weeks apart. CB1R availability was measured using the reversible ligand [ 11 C]OMAR (23) based on absolute quantification using arterial sampling with metabolite analysis and tracer kinetic modeling (22), a method that does not have the limitations associated with the mSUV outcome measure. CB1R availability was hypothesized to 1) be lower in CDs at baseline, 2) increase after 2 days of abstinence due to compensatory upregulation, and 3) recover to normal levels after 28 days of abstinence.…”

Cannabis Abusers Show Hypofrontality and Blunted Brain Responses to a Stimulant Challenge in Females but not in Males

“…Nevertheless, it has to be noted that some of these gender differences might reflect social and cultural factors influencing exposure and responses to cannabis rather than biological differences in the sensitivity to cannabis. A recent brain imaging study documented higher CB1 receptor levels in the brains of women compared with men (Neumeister et al, 2013;Normandin et al, 2015), and a preclinical study showed that THC altered CB1 receptor expression and function in females but not in males (Silva et al, 2016). This could provide a neurobiological basis for differences in sensitivity to the effects of cannabis between the genders.…”

“…Recent findings suggest higher expression of cannabinoid type-1 (CB1) receptors in the brain of women than men (Normandin et al, 2015). There is also evidence that women compared with men are less likely to be chronic cannabis users (Preston, 2006).…”