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

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 (CM 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 [C-11]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 [C-11]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 similar to 30-60 mm 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 2kby. 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 CBI receptor availability using [C-11]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. [C-11] MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease. Crown Copyright (C) 2014 Published by Elsevier Inc.