Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

Abstract

Abstract[ 11 C]MePPEP is an inverse agonist and a radioligand developed to image cannabinoid CB 1 receptors with positron emission tomography (PET). It provides reversible, high specific signal in monkey brain. We assessed [ 11 C]MePPEP in rodent brain with regard to receptor selectivity, susceptibility to transport by P-glycoprotein (P-gp), sensitivity to displacement by agonists, and accumulation of radiometabolites. We used CB 1 receptor knockout mice and P-gp knockout mice to assess receptor selectivity and sensitivity to efflux transport, respectively. Using serial measurements of PET brain activity and plasma concentrations of [ 11 C]MePPEP, we estimated CB 1 receptor density in rat brain as distribution volume. CB 1 knockout mice showed only nonspecific brain uptake, and [ 11 C]MePPEP was not a substrate for P-gp. Direct acting agonists anandamide (10 mg/kg), methanandamide (10 mg/kg), CP 55,940 (1 mg/kg), and indirect agonist URB597 (0.3 and 0.6 mg/kg) failed to displace [ 11 C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg) displaced >65% of [ 11 C] MePPEP. Radiometabolites represented ∼13% of total radioactivity in brain between 30 and 120 min. [ 11 C]MePPEP was selective for the CB 1 receptor, was not a substrate for P-gp, and was more potently displaced by inverse agonists than agonists. The low potency of agonists suggests either a large receptor reserve or non-overlapping binding sites for agonists and inverse agonists. Radiometabolites of [ 11 C]MePPEP in brain caused distribution volume to be overestimated by ∼13%.

Quantification of Dopamine Transporter in Human Brain Using PET with 18F-FE-PE2I

“…To evaluate the effect of the possible accumulation of radiometabolites on the estimation of V T , we performed a time-stability analysis of V T . The increase in V T with an increase in scan length could be interpreted as evidence for the accumulation of radiometabolites in the brain (30). In the current study, V T values by the 2-TCM in the putamen and cerebellum with 60-min data were approximately 94% and 90% of terminal values with 90-min data (Fig.…”

PET Imaging Studies in Rhesus Monkey with the Cannabinoid-1 (CB1) Receptor Ligand [11C]CB-119

“…Most of the compounds to date produce small specific signals due to high lipophilicity and/or low affinity for CB1R, with the exception of [ 11 C] JHU75528 [3,4], [ 11 C]MePPEP [5,6], and [ 18 F]MK-9470 [7]. Applying the criteria of high affinity and selectivity for CB1R, appropriate lipophilicity for a CB1R radiotracer and synthesis via reliable radiochemistry suitable to a clinical setting, we labeled and carried out rhesus PET imaging studies with a number of potential CB1R PET tracers [9].…”

“…In addition to studying cannabinoid system biology, a CB1R SPECT or PET tracer could be used as a biomarker for target engagement to measure receptor occupancy of CB1R therapeutic compounds in preclinical as well as clinical studies and to guide dose selection in clinical trials. Recently, notable progress has been made in this area with the disclosure of [ 11 C] JHU75528 [3,4], [ 11 C]MePPEP [5,6], and [ 18 F]MK-9470 [7,8] (Fig. 1).…”

Effects of Aerobic Exercise on Mood and Human Opioidergic Activation Measured by Positron Emission Tomography

“…is that the tracer binds to the entire opioidergic system, thus providing a rather composite view of opioidergic neurotransmission evoked by exercise challenges. As the endocannabinoid system is also of great interest in the context of exercise research (Dietrich and McDaniel 2004 ;Sparling et al 2003 ) , future applications are awaited using novel compounds that label endocannabinoid receptors (Evens et al 2009 ;Terry et al 2008 ;Van Laere et al 2008 ) . For a detailed summary of the available opioidergic tracers, we refer to a recent review article from our group (Boecker et al 2008a ) .…”