title: Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents.
abstract: [11C]MePPEP is an inverse agonist and a radioligand developed to image cannabinoid CB1 receptors with positron emission tomography (PET). It provides reversible, high specific signal in monkey brain. We assessed [11C]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 CB1 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 [11C]MePPEP, we estimated CB1 receptor density in rat brain as distribution volume. CB1 knockout mice showed only nonspecific brain uptake, and [11C]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 [11C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg) displaced >65% of [11C]MePPEP. Radiometabolites represented ~13% of total radioactivity in brain between 30 and 120 min. [11C]MePPEP was selective for the CB1 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 [11C]MePPEP in brain caused distribution volume to be overestimated by approximately 13%.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD 20892-2035, USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Terry
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Eyassu
authors.initials: E
authors.lastname: Chernet
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Lee
authors.initials: L
authors.lastname: Phebus
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.forename: Johannes
authors.initials: J
authors.lastname: Tauscher
authors.forename: John M
authors.initials: JM
authors.lastname: Schaus
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001667:Binding, Competitive; D001923:Brain Chemistry; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D063388:Endocannabinoids; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis*
chemical_list: C526255:5-(3-methoxyphenyl)-3-(1-phenylethylamino)-1-(4-trifluoromethylphenyl)pyrrolidin-2-one; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002250:Carbon Radioisotopes; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011760:Pyrrolidinones; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1; C088155:methanandamide; C078814:anandamide