Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: Quantitative analysis, test–retest reproducibility, and vulnerability to endogenous 5-HT tone

Abstract Introduction Scanning properties and analytic methodology of the 5-HT 2A receptor-selective positron emission tomography (PET) tracer 11 C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. Methods 64 11 C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18–55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test–retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT 2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT 2A receptors. Results Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BP P and BP ND ) test–retest variability was very good (7–11%) in neocortical regions other than orbitofrontal, and moderately good (14–20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT 2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 μg to remain below 5% receptor occupancy. 11 C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BP ND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT 2A receptors was 14.0 ± 5.0% per decade, and higher in prefrontal regions. Conclusions Our data confirm and extend support for 11 C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT 2A receptors in the human brain.