The PET radioligand [11C]MePPEP binds reversibly and with high specific signal to cannabinoid CB1 receptors in nonhuman primate brain.

The cannabinoid CB(1) receptor is one of the most abundant G protein-coupled receptors in the brain and is a promising target of therapeutic drug development. Success of drug development for neuropsychiatric indications is significantly enhanced with the ability to directly measure spatial and temporal binding of compounds to receptors in central compartments. We assessed the utility of a new positron emission tomography (PET) radioligand to image CB(1) receptors in monkey brain. [(11)C]MePPEP ((3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one) has high CB(1) affinity (K(b)=0.574+/-0.207 nM) but also moderately high lipophilicity (measured LogD(7.4)=4.8). After intravenous injection of [(11)C]MePPEP, brain activity reached high levels of almost 600% standardized uptake value (SUV) within 10-20 min. The regional uptake was consistent with the distribution of CB(1) receptors, with high radioactivity in striatum and cerebellum and low in thalamus and pons. Injection of pharmacological doses of CB(1)-selective agents confirmed that the tracer doses of [(11)C]MePPEP reversibly labeled CB(1) receptors. Preblockade or displacement with two CB(1) selective agents (ISPB; (4-(3-cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide) and rimonabant) showed that the majority (>89%) of brain uptake in regions with high receptor densities was specific and reversibly bound to CB(1) receptors in the high binding regions. [(11)C]MePPEP was rapidly removed from arterial plasma. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. The P-glycoprotein (P-gp) inhibitor DCPQ ((R)-4-[(1a,6,10b)-1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-[(5-quinolinyloxy)methyl]-1-piperazineethanol) did not significantly increase brain uptake of [(11)C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood-brain barrier. [(11)C]MePPEP is a radioligand with high brain uptake, high specific signal to CB(1) receptors, and adequately fast washout from brain that allows quantification with (11)C (half-life=20 min). These promising results in monkey justify studying this radioligand in human subjects.