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-β-Hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoqu inoline ([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 V(T) ranged from 10 ± 2 mL/g in the cerebellum to 14 ± 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). Conclusion: 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.