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 (11)C-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 (11)C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with (11)C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (V(T)) were calculated using kinetic modeling and metabolite-corrected arterial input function. (11)C-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 (11)C-DASB V(T) (-6.1%) and BP (-4.5%) across brain regions, probably explained by a concomitant reduction in (11)C-DASB plasma free fraction (f(1)) of similar magnitude. No significant change in (11)C-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 (11)C-DASB in vivo binding is not affected by reductions in endogenous 5-HT.
Talbot
Peter S
PS
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, New York 10032, USA. pst2001@columbia.edu
Frankle
W Gordon
WG
Hwang
Dah-Ren
DR
Huang
Yiyun
Y
Suckow
Raymond F
RF
Slifstein
Mark
M
Abi-Dargham
Anissa
A
Laruelle
Marc
M
D000328:Adult; D021542:Amino Acids, Neutral / Q000097:blood; D001596:Benzylamines / Q000378:metabolism* / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001931:Brain Mapping / Q000379:methods; D002250:Carbon Radioisotopes; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D010599:Pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D012016:Reference Values; D012039:Regional Blood Flow / Q000502:physiology; D012701:Serotonin / Q000032:analysis / Q000096:biosynthesis*; D050486:Serotonin Plasma Membrane Transport Proteins; D009435:Synaptic Transmission / Q000502:physiology; D014364:Tryptophan / Q000097:blood
D021542:Amino Acids, Neutral; D001596:Benzylamines; D002250:Carbon Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D014364:Tryptophan