Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents.
[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%.
Terry
Garth
G
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD 20892-2035, USA.
Liow
Jeih-San
JS
Chernet
Eyassu
E
Zoghbi
Sami S
SS
Phebus
Lee
L
Felder
Christian C
CC
Tauscher
Johannes
J
Schaus
John M
JM
Pike
Victor W
VW
Halldin
Christer
C
Innis
Robert B
RB
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*
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