Cannabinoid 1 receptor occupancy and neurovascular responses induced by agonist, antagonist/inverse-agonist, and potential modulator in non-human primate brains: PET/fMRI study

The cannabinoid 1 receptor (CB1R) is a key pharmacological target in the central nervous system, modulating emotions, cognition, and memory. Functional interactions between CB1R and mu-opioid receptors (MOR) in analgesia have been reported. This study investigated CB1R occupancy and neuronal activation in non-human primate brains following acute administration of a CB1R agonist (CP55,940), an antagonist/inverse-agonist (rimonabant), an MOR agonist (morphine) using simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). [¹¹C]OMAR, a CB1R-selective radiotracer, PET scans were acquired using bolus or bolus-plus-infusion protocols. Rimonabant (1, 3 mg/kg, <i>n</i> = 1 for each) reduced [¹¹C]OMAR non-displaceable binding potential by 25%-40% in CB1R-rich regions. To our knowledge, this is the first in vivo demonstration of CB1R occupancy by the agonist CP55,940 (0.05 mg/kg, <i>n</i> = 2), which displaced 15%-30% of [¹¹C]OMAR volume of distribution (V_T) in CB1R-rich regions. Although there was no clear dose-response relationship, CP55,940 increased cerebral blood volume (CBV), whereas rimonabant caused a biphasic response. Morphine administration (1 mg/kg, <i>n</i> = 2) reduced CBV in MOR-rich areas and modestly increased [¹¹C]OMAR V_T, suggesting a potential indirect modulation of CB1R availability. Given the small sample size and variability close to test-retest levels, these preliminary findings should be interpreted with caution.