Effects of tryptophan depletion on the binding of [ ¹¹C]-DASB to the serotonin transporter in baboons: Response to acute serotonin deficiency

The objective of this study was to evaluate the sensitivity of [ ¹¹C]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB) binding to the brain serotonin transporter (SERT) to changes in endogenous serotonin (5-hydroxytryptamine [5-HT]) levels. A ligand sensitive to endogenous competition (EC) would enable the measurement of fluctuations of intrasynaptic 5-HT. A ligand insensitive to EC can provide a measure of SERT unaffected by levels of 5-HT. Alternatively, serotonin depletion could accelerate internalization of SERT and reduce binding. Eighteen (14 baseline and 9 tryptophan-depleted) positron emission tomography (PET) scans were carried out in two baboons (Papio anubis). A metabolite-corrected arterial input function was used to estimate the binding potential (BP = B _max/K _D). Depletion of plasma tryptophan by a mean of 65% from the baseline (p =. 03) reduces [ ¹¹C]-DASB BP in the six brain regions of interest (ROI). Lower DASB binding correlated with lower plasma tryptophan levels in the ROIs with higher SERT density. [ ¹¹C]-DASB binding to SERT in vivo rapidly declines in response to acute reduction in serotonin availability, contrary to what is predicted by a simple competition model. This rapid reduction in SERT availability may be due to accelerated transporter internalization.