Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans

Alterations of serotonin transporters (SERT) are implicated in a large number of psychiatric conditions. C-11-(+)-6beta-(4-Methylthiophenyl)-1,2,3,5,6alpha, 10beta-hexahydropyrrolo[2,1-a]isoquinoline (C-11-McN 5652) was the first PET radiotracer successfully developed as a SERT imaging agent. Recently, C-11-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile (C-11-DASB) was introduced as an alternative to C-11-McN 5652. Comparative evaluation of C-11-DASB and C-11-McN 5652 in baboons indicates that C-11-DASB is associated with (a) lower nonspecific binding in the brain, (b) higher plasma free fraction, and (c) faster plasma clearance and brain uptake kinetics, enabling measurement of SERT parameters in a shorter scanning time. The purpose of this study was to compare these 2 agents in healthy humans. Methods: Six healthy volunteers underwent 2 PET scans on the same day, one with C-11-DASB and one with C-11-McN 5652, in counterbalanced order. Regional distribution volumes (V-T) were derived for 16 brain regions by kinetic analysis using the arterial input function. Results: Both C-11-DASB and C-11-McN 5652 displayed similar patterns of accumulation: highest levels in the midbrain, thalamus and striatum; intermediate in the limbic regions; low in the neocortex; and lowest in the cerebellum. C-11-DASB cerebellar V-T (10.1 +/- 2.0 mL g(-1)) was lower than that of C-11-McN 5652 (20.8 +/- 3.6 mL g(-1)), indicating lower nonspecific binding. As a result, regional specific-to-nonspecific equilibrium partition coefficients (V-3") of C-11-DASB were higher compared with those of C-11-McN 5652 (for example, midbrain V-3" of C-11-DASB and C-11-McN 5652 were 2.04 +/- 0.44 and 1.20 +/- 0.34, respectively). The plasma free fraction was 8.9% +/- 1.6% for C-11-DASB and was not measurable for C-11-McN 5652. In contrast to the situation observed in baboons, plasma clearances of both compounds were similar in humans, and the minimal scanning times required to derive time-invariant distribution volumes in all regions were comparable for both tracers (95 min), Conclusion: With the exception of the scanning time, predictions from baboon studies were confirmed in humans. The higher specific-to-nonspecific ratios of C-11-DASB are a critical advantage. This property will be especially important for the measurement of SERT in regions with moderate density, such as the limbic regions, where alterations of serotonin transmission might be associated with anxiety and depression.