Abstract
The cannabinoid CB1 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 CB1 receptors in monkey brain. [11C]MePPEP ((3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one) has high CB1 affinity (Kb=0.574±0.207 nM) but also moderately high lipophilicity (measured LogD7.4=4.8). After intravenous injection of [11C]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 CB1 receptors, with high radioactivity in striatum and cerebellum and low in thalamus and pons. Injection of pharmacological doses of CB1-selective agents confirmed that the tracer doses of [11C]MePPEP reversibly labeled CB1 receptors. Preblockade or displacement with two CB1 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 CB1 receptors in the high binding regions. [11C]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 [11C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood–brain barrier. [11C]MePPEP is a radioligand with high brain uptake, high specific signal to CB1 receptors, and adequately fast washout from brain that allows quantification with 11C (half-life=20 min). These promising results in monkey justify studying this radioligand in human subjects.
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Acknowledgements
We thank Jonathan P Gourley, BS for help with radiometabolite analysis; Jeih-San Liow for assistance on image analysis; and the staff of the NIH PET Department for successful completion of the scanning studies, and Xenova Group, Ltd (UK) for providing tariquidar. This research was performed via a Cooperative Research and Development Agreement (CRADA) with Eli Lilly, Karolinska Institutet, and NIMH and was supported in part by the Intramural Program of NIMH (project Z01-MH-002795-04). FY was funded by Japanese Society for the Promotion of Sciences, Research Fellow in Biomedical and Behavioral Research at NIH (2005–2006). Eli Lilly provided research grant support to NIMH and the Karolinska Institutet as part of the current CRADA or other research agreements. RBI and VWP (NIMH) have received research support, but no personal income, from Eli Lilly and AstraZeneca. CH (Karolinska Institutet) has received research support and/or personal income from Eli Lilly and AstraZeneca.
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Yasuno, F., Brown, A., Zoghbi, S. et al. The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain. Neuropsychopharmacol 33, 259–269 (2008). https://doi.org/10.1038/sj.npp.1301402
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DOI: https://doi.org/10.1038/sj.npp.1301402
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