Quantification of 11C-MADAM binding to the serotonin transporter in the human brain.
(11)C-N,N-Dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ((11)C-MADAM) is a newly synthesized radioligand with high selectivity and specificity for the serotonin transporter (5-HTT) in a monkey model. The purpose of this study in humans was to examine the suitability and potential of (11)C-MADAM for quantitative PET studies of 5-HTT in applied clinical studies on the pathophysiology and treatment of neuropsychiatric disorders.


METHODS
PET examination was performed on each of 9 male subjects after intravenous injection of (11)C-MADAM with high specific radioactivity. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. A metabolite-corrected arterial input function was used in kinetic 2- and 3-compartment analyses. Cerebellum was used as the reference region in a cross-validation of 6 reference tissue approaches.


RESULTS
The highest radioactivity concentration was detected in the raphe nuclei, followed consecutively by the striatum, hippocampal complex, cingulate cortex, neocortex, and cerebellum. The time-activity curve for the fraction of unchanged (11)C-MADAM in plasma was best described by a sigmoid function. After 50 min, the fraction was 40%. The labeled metabolites were more polar than the mother compound. The compartment model approaches converged, and could describe the time-activity curves in all regions. The total volume of distribution (V(t)) was similar to the regional distribution volumes obtained by the linear graphic analysis. The binding potentials (BPs) for 6 different approaches yielded similar values in all regions but the raphe nuclei, where the 2 equilibrium methods provided lower values.


CONCLUSIONS
The regional binding distribution of (11)C-MADAM is consistent with postmortem data acquired with (3)H-MADAM as well as with that of other reference ligands in vitro. The time-activity curves were well described by current major quantitative approaches. The suitability of the cerebellum as a reference region for nonspecific (11)C-MADAM binding could be confirmed, thus paving the way for experimentally less demanding approaches, such as the simplified reference tissue model, for applied clinical studies.
Lundberg
Johan
J
Department of Clinical Neuroscience, Section of Psychiatry, Karolinska Institutet, Stockholm, Sweden. johan.lundberg@cns.ki.se
Odano
Ikuo
I
Olsson
Hans
H
Halldin
Christer
C
Farde
Lars
L
D000328:Adult; D001596:Benzylamines / Q000493:pharmacokinetics*; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011865:Radioisotope Dilution Technique; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D014018:Tissue Distribution
D001596:Benzylamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C470437:N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins