[¹⁸F]MK-9470, a positron emission tomography (PET) tracer forin vivohuman PET brain imaging of the cannabinoid-1 receptor

Abstract

[(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC(50), 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [(18)F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4-5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of [(18)F]MK-9470 very similar to that seen in monkeys, with very good test-retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in [(18)F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [(18)F]MK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

“…11,29 Other groups also showed that rimonabant occupies brain CB1R at doses that produce significant physiological effects. 30 There is only one report suggesting that central administration of rimonabant or endocannabinoids through intracerebroventricular (icv) injection did not affect food intake.…”

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

“…Kinetics of TACs was similar to that previously observed in nonhuman primates 12 with cerebral clearance generally faster than other CB1 ligands reported in humans. [8][9][10] Regional TACs averaged across scans are portrayed in Figure 3.…”

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

“…, which is characterized by high specificity and high affinity for the CB 1 receptor (rat IC 50 0.9 nM) [14]. The precursor for tracer synthesis was obtained from Merck Research Labs (West Point, PA, USA) and labelling was performed using an [ 18 F]ethylbromide procedure as described previously [14].…”

“…The precursor for tracer synthesis was obtained from Merck Research Labs (West Point, PA, USA) and labelling was performed using an [ 18 F]ethylbromide procedure as described previously [14]. The final product was obtained after high-performance liquid chromatography separation and had a radiochemical purity >95%.…”

“…Also unknown is whether CB 1 receptor levels are changed in vivo. In vivo imaging of CB 1 receptors in the rat brain has recently become feasible due to the development of a CB 1 -selective radioligand, [ 18 F] MK-9470 [14,15].…”