title: Test-retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [¹¹C]MePPEP.
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 (CB1) 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 [(11)C]MePPEP in order to assess the stability of CB1-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 [(11)C]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).
  
  
  CONCLUSIONS
  Quantification of CB1 receptor availability using [(11)C]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. [(11)C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease.
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; MRC Clinical Sciences Centre Hammersmith Hospital, London, UK.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Riaño Barros
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; MRC Clinical Sciences Centre Hammersmith Hospital, London, UK.
authors.forename: Colm J
authors.initials: CJ
authors.lastname: McGinnity
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK.
authors.forename: Lula
authors.initials: L
authors.lastname: Rosso
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Neurodis Foundation, CERMEP, Imagerie du Vivant, Lyon. France.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Heckemann
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; MRC Clinical Sciences Centre Hammersmith Hospital, London, UK.
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Howes
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Institute of Clinical Medicine, Aarhus University, Denmark.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK; Epilepsy Society, Chalfont St Peter, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Duncan
authors.affiliation: Centre for Neuroimaging, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.affiliation: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK; Epilepsy Society, Chalfont St Peter, UK.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Koepp
authors.affiliation: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; MRC Clinical Sciences Centre Hammersmith Hospital, London, UK; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK; Epilepsy Society, Chalfont St Peter, UK; Neurodis Foundation, CERMEP, Imagerie du Vivant, Lyon. France. Electronic address: alexander.hammers@fondation-neurodis.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hammers
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D001810:Blood Volume; D001921:Brain / Q000000981:diagnostic imaging*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D011760:Pyrrolidinones; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: C526255:5-(3-methoxyphenyl)-3-(1-phenylethylamino)-1-(4-trifluoromethylphenyl)pyrrolidin-2-one; D011760:Pyrrolidinones; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1
keywords: CB(1); Intra-class correlation coefficient; Positron Emission Tomography; Reliability
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