Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses.
BACKGROUND
[(11)C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT(2A) receptor quantification in vivo. Studies suggest that [(11)C]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 [(11)C]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)>or=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)>or=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)>or=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 [(11)C]MDL100,907 PET studies, yielding estimates of 5-HT(2A) receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT(2A) receptor PET studies.
Meyer
Philipp T
PT
Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany. philipp.meyer@uniklinik-freiburg.de
Bhagwagar
Zubin
Z
Cowen
Philip J
PJ
Cunningham
Vincent J
VJ
Grasby
Paul M
PM
Hinz
Rainer
R
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping / Q000379:methods; D002250:Carbon Radioisotopes; D005260:Female; D005464:Fluorobenzenes; D006801:Humans; D007700:Kinetics; D016014:Linear Models; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives / Q000494:pharmacology; D008875:Middle Aged; D000078785:Mirtazapine; D008959:Models, Neurological; D010880:Piperidines; D049268:Positron-Emission Tomography / Q000379:methods*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D012815:Signal Processing, Computer-Assisted
D002250:Carbon Radioisotopes; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D008803:Mianserin; D000078785:Mirtazapine; C079049:volinanserin