Effects of reduced endogenous 5‐HT on the in vivo binding of the serotonin transporter radioligand 11C‐DASB in healthy humans

Although abnormal serotonin (5‐HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5‐HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as 11C‐raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5‐HT on the in vivo binding of the 5‐HT transporter (SERT) radioligand 11C‐DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with 11C‐DASB under control and reduced endogenous 5‐HT conditions, in a within‐subject, double‐blind, counterbalanced, crossover design. Regional distribution volumes (VT) were calculated using kinetic modeling and metabolite‐corrected arterial input function. 11C‐DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V  ′3 ), using the cerebellum as reference region. RTD caused small but significant mean reductions in 11C‐DASB VT (−6.1%) and BP (−4.5%) across brain regions, probably explained by a concomitant reduction in 11C‐DASB plasma free fraction (f1) of similar magnitude. No significant change in 11C‐DASB V  ′3 was observed between control and reduced 5‐HT conditions. Nor was there a significant relationship between the magnitude of tryptophan depletion and change in BP and V  ′3 across individual subjects. These results suggest that 11C‐DASB in vivo binding is not affected by reductions in endogenous 5‐HT. Synapse 55:164–175, 2005. © 2004 Wiley‐Liss, Inc.