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Departments of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons, New York
Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, New York, New York
Correspondence: For correspondence or reprints contact: Ramin V. Parsey, MD, PhD, New York State Psychiatric Institute, 1051 Riverside Dr., Box 42, New York, NY 10032.
ABSTRACT
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-ß-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 (VT) were derived using kinetic 2-compartment analysis and graphic analysis. VT derived by both methods were highly correlated. (+)-[11C]McN 5652 regional VT 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. (+)-[99mC]McN 5652 VT were higher than (–)-[l1C]McN 5652 VT 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 VT 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 VT to the level of cerebellum (+)-[11C]McN 5652 VT. Conclusion: These experiments indicate that the use of the difference between (+)- and (–)-[11C]McN 5652 VT 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 VT. 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. (+)-[1lC]McN 5652 is an appropriate radiotracerto 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.
Key Words: serotonin transporter • PET • [11C]McN 5652 • human brain • selective serotonin reuptake inhibitors
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