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      Test–retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [ 11C]MePPEP

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          Abstract

          Background

          Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The type 1 cannabinoid receptor (CB 1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test–retest reproducibility of measures of the PET ligand [ 11C]MePPEP in order to assess the stability of CB 1-receptor quantification in humans in vivo.

          Methods

          Fifteen healthy subjects (eight females; median age 32 years, range 25 to 65 years) had a 90-minute PET scan on two occasions after injection of a median dose of [ 11C]MePPEP of 364 MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~ 30–60 min after injection. Percentage test–retest change and between-subject variability were both assessed, and test–retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity.

          Results

          Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (> 0.75) or excellent (> 0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions ± standard deviation 0.83 ± 0.03), rank shaping regularised spectral analysis (0.82 ± 0.05), and the 2kbv model (0.82 ± 0.09), but mSUVs were also reliable for most regions (0.79 ± 0.13). Mean test–retest changes among the five well-performing methods ranged from 12 ± 10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32 ± 13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6).

          Conclusion

          Quantification of CB 1 receptor availability using [ 11C]MePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. [ 11C]MePPEP PET is well placed as a tool to investigate CB 1-receptor mediated neurotransmission in health and disease.

          Graphical abstract

          Cannabinoid receptor concentrations assessed with [ 11C]MePPEP-PET. Top, reliability (ICCs ± SDs) of different quantification strategies: blue, compartmental models; red, spectral analysis variants; green, SRTM; yellow, modified SUVs. Bottom, parametric V T map.

          Highlights

          • [11C]MePPEP is a PET tracer for cannabinoid receptors (CB1R).

          • Extensive evaluation of [11C]MePPEP data quantification strategies in large sample

          • We highlight successful methods to quantify CB1R in regions of interest.

          • Highly reliable parametric maps (ICC 0.83 ± 0.03) allow whole-brain surveys.

          • Modified standard uptake values also reliable, without arterial input functions

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          Most cited references58

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          Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

          Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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            Cannabinoid receptor localization in brain.

            [3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.
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              Determination and characterization of a cannabinoid receptor in rat brain.

              The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
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                Author and article information

                Contributors
                Journal
                Neuroimage
                Neuroimage
                Neuroimage
                Academic Press
                1053-8119
                1095-9572
                15 August 2014
                15 August 2014
                : 97
                : 151-162
                Affiliations
                [a ]Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
                [b ]MRC Clinical Sciences Centre Hammersmith Hospital, London, UK
                [c ]Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK
                [d ]Epilepsy Society, Chalfont St Peter, UK
                [e ]Neurodis Foundation, CERMEP, Imagerie du Vivant, Lyon. France
                [f ]Institute of Clinical Medicine, Aarhus University, Denmark
                [g ]Centre for Neuroimaging, Institute of Psychiatry, King's College London, London, UK
                Author notes
                [* ]Corresponding author at: Neurodis Foundation, c/o CERMEP — Imagerie du vivant, 59 boulevard Pinel, 69677 Lyon/Bron, France. Fax: + 33 4 72 68 86 10. alexander.hammers@ 123456fondation-neurodis.org
                Article
                S1053-8119(14)00275-4
                10.1016/j.neuroimage.2014.04.020
                4283194
                24736184
                5c55f421-af77-49e5-b040-a969816b690b
                Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
                History
                : 7 April 2014
                Categories
                Article

                Neurosciences
                cb1,positron emission tomography,reliability,intra-class correlation coefficient
                Neurosciences
                cb1, positron emission tomography, reliability, intra-class correlation coefficient

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