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Abstract: Background: [11C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [11C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [11C]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time–activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BP ND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BP ND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BP ND, which were highly correlated with 2TCM analyses (R 2 ≥0.86) although with negative bias (−29±27% at baseline across all ROI). NIGA was less biased (−19±16%) and better correlated with 2TCM (R 2 ≥0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed comparable mean biases (−11±27% vs. −7±47%) but correlation with 2TCM was higher for NIGA (R 2 =0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BP ND (−26±22%; R 2 ≥0.88) and Occ (−17±36%; R 2 =0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [11C]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies. [Copyright &y& Elsevier]