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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]

Abstract: Drugs which inhibit the re-uptake of monoamines in the brain are effective in the treatment of depression; however, the neuropsychological mechanisms which lead to the resolution of depressive symptomatology are unclear. Behavioral studies in healthy volunteers suggest that acute administration of the selective norepinephrine reuptake inhibitor reboxetine modulates emotional processing. The current study therefore explored the neural basis of this effect. A single dose of reboxetine (4 mg) or placebo was administered to 24 healthy volunteers in a double-blind between-group design. Neural responses during categorisation and recognition of self-referent personality trait words were assessed using event-related functional Magnetic Resonance Imaging (fMRI). Reboxetine had no effect on neuronal response during self-referent categorisation of positive or negative personality trait words. However, in a subsequent memory test, reboxetine reduced neuronal activation in a fronto-parietal network during correct recognition of positive target words vs. matched distractors. This was combined with increased speed to recognize positive vs. negative words compared to control subjects and suggests facilitated memory for positive self-referent material. These results support the hypothesis that antidepressants have early effects on the neural processing of emotional material which may be important in their therapeutic actions. [Copyright &y& Elsevier]