In vivo quantification of brain serotonin transporters in humans using [11C]McN 5652.
Abnormal brain regional densities of serotonin (5-hydroxytryptamine [5-HT]) transporters have been reported in postmortem studies in several neuropsychiatric conditions, such as major depression and schizophrenia. trans-1,2,3,5,6,10-beta-Hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([11C]McN 5652) is the first PET radioligand successfully developed to label 5-HT transporters in the living human brain. The purpose of this study was to develop an imaging protocol and analytic method to measure regional 5-HT transporter binding potential (BP) with [11C]McN 5652 in humans.


METHODS
The arterial input function and brain uptake of (+)-[11C]McN 5652 and (-)-[11C]McN 5652, the active and inactive enantiomers, respectively, were measured in 6 healthy volunteers.


RESULTS
(+)-[11C]McN 5652 concentrated in brain regions rich in 5-HT transporters (midbrain, thalamus, basal ganglia, and medial temporal lobe structures), whereas the uptake of (-)-[11C]McN 5652 was more uniformly distributed. Total distribution volumes (V(T)) were derived using kinetic 2-compartment analysis and graphic analysis. V(T) derived by both methods were highly correlated. (+)-[11C]McN 5652 regional V(T) ranged from 18 +/- 2 mL/g in the cerebellum to 46 +/- 13 mL/g in the midbrain. (-)-[11C]McN 5652 regional VT ranged from 10 +/- 2 mL/g in the cerebellum to 14 +/- 3 mL/g in the thalamus. (+)-[11C]McN 5652 V(T) were higher than (-)-[11C]McN 5652 V(T) in all regions, including the cerebellum, a region devoid of 5-HT transporters. Blocking experiments were also performed in baboons with saturating doses of citalopram and in humans with nonsaturating doses of paroxetine. Cerebellar and neocortical (+)-[11C]McN 5652 V(T) were unaffected by pretreatment with 5-HT transporter blockers. In areas of high receptor concentration (midbrain, caudate, and thalamus) 5-HT transporter blockers decreased (+)-[11C]McN 5652 V(T) to the level of cerebellum (+)-[11C]McN 5652 V(T).


CONCLUSIONS
These experiments indicate that the use of the difference between (+)- and (-)-[11C]McN 5652 V(T) to define specific binding to 5-HT transporters leads to an overestimation of specific binding. 5-HT transporter BP was derived as the difference between the regional and cerebellar (+)-[11C]McN 5652 V(T). BP values were in good agreement with the distribution of 5-HT transporters in the human brain, except for regions of relatively low 5-HT transporter concentration, such as the prefrontal cortex, where no specific binding was detected using (+)-[11C]McN 5652. (+)-[11C]McN 5652 is an appropriate radiotracer to quantify 5-HT transporters in regions with relatively high concentration of 5-HT transporters, such as the midbrain, thalamus, and basal ganglia, and should prove useful in elucidating abnormalities of 5-HT transmission in neuropsychiatric conditions.
Parsey
R V
RV
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Kegeles
L S
LS
Hwang
D R
DR
Simpson
N
N
Abi-Dargham
A
A
Mawlawi
O
O
Slifstein
M
M
Van Heertum
R L
RL
Mann
J J
JJ
Laruelle
M
M
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007546:Isoquinolines / Q000493:pharmacokinetics*; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000000981:diagnostic imaging / Q000378:metabolism; D009419:Nerve Tissue Proteins; D012016:Reference Values; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*; D050486:Serotonin Plasma Membrane Transport Proteins; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C058079:McN 5652