1. ¹Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA
2. ²Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA
3. ³Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden

Correspondence: Dr RB Innis, Molecular Imaging Branch, National Institute of Mental Health, Building 31, Room B2B37, 31 Center Drive, Bethesda, MD 20892-2035, USA. Tel: +1 301 594 1368; Fax: +1 301 480 3610; E-mail: robert.innis@nih.gov

Received 28 December 2006; Revised 15 February 2007; Accepted 19 February 2007; Published online 28 March 2007.

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 (K_b=0.5740.207 nM) but also moderately high lipophilicity (measured LogD_7.4=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.