In vivo quantification of brain serotonin transporters in humans using [C-11]McN 5652

Abnormal brain regional densities of serotonin (5-hydroxytryptamine [5-HT]) transporters have been reported in postmortem studies in several neuropsyc hiatric 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 ([C-11]McN 5652) is the first PET radioligand successfully developed to la bel 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 [C-11]McN 5652 in humans. Meth ods: The arterial input function and brain uptake of (+)-[C-11]McN 5652 and (-)-[C-11]McN 5652, the active and inactive enantiomers, respectively, wer e measured in 6 healthy volunteers. Results: (+)-[C-11]McN 5652 concentrate d in brain regions rich in 5-HT transporters (midbrain, thalamus, basal gan glia, and medial temporal lobe structures), whereas the uptake of (-)-[C-11 ]McN 5652 was more uniformly distributed. Total distribution volumes (VT) w ere derived using kinetic 2-compartment analysis and graphic analysis. VT d erived by both methods were highly correlated. (+)-[C-11]McN 5652 regional V-T ranged from 18 +/- 2 mL/g in the cerebellum to 46 +/- 13 mL/g in the mi dbrain. (-)-[C-11]McN 5652 regional V-T ranged from 10 +/- 2 mL/g in the ce rebellum to 14 +/- 3 mL/g in the thalamus. (+)-[C-11]McN 5652 V-T were high er than (-)-[C-11]McN 5652 V-T, in all regions, including the cerebellum, a region devoid of 5-HT transporters. Blocking experiments were also perform ed in baboons with saturating doses of citalopram and in humans with nonsat urating doses of paroxetine. Cerebellar and neocortical (+)-[C-11]McN 5652 V-T were unaffected by pretreatment with 5-HT transporter blockers. In area s of high receptor concentration (midbrain, caudate, and thalamus) 5-HT tra nsporter blockers decreased (+)-[C-11]McN 5652 V-T to the level of cerebell um (+)-[C-11]McN 5652 VT. Conclusion: These experiments indicate that the u se of the difference between (+)- and (-)-[C-11]McN 5652 V-T to define spec ific binding to 5-HT transporters leads to an overestimation of specific bi nding. 5-HT transporter BP was derived as the difference between the region al and cerebellar (+)-[C-11]McN 5652 V-T BP values were in good agreement w ith the distribution of 5-HT transporters in the human brain, except for re gions of relatively low 5-HT transporter concentration, such as the prefron tal cortex, where no specific binding was detected using (+)-[C-11]McN 5652 . (+)-[C-11]McN 5652 is an appropriate radiotracer to quantify 5-HT transpo rters in regions with relatively high concentration of 5-HT transporters, s uch as the midbrain, thalamus, and basal ganglia, and should prove useful i n elucidating abnormalities of 5-HT transmission in neuropsychiatric condit ions.