title: 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: BACKGROUND
  Scanning properties and analytic methodology of the 5-HT2A receptor-selective positron emission tomography (PET) tracer 11C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects.
  
  
  METHODS
  64 11C-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-HT2A 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-HT2A 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 (BPP and BPND) 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-HT2A 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. 11C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BPND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT2A receptors was 14.0±5.0% per decade, and higher in prefrontal regions.
  
  
  CONCLUSIONS
  Our data confirm and extend support for 11C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT2A receptors in the human brain.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY 10032, USA. peter.talbot@manchester.ac.uk
authors.forename: Peter S
authors.initials: PS
authors.lastname: Talbot
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Erica
authors.initials: E
authors.lastname: Scher
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D044402:Receptor, Serotonin, 5-HT2A; D015203:Reproducibility of Results; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D005464:Fluorobenzenes; D010880:Piperidines; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; C079049:volinanserin