title: Effects of reduced endogenous 5-HT on the in vivo binding of the serotonin transporter radioligand 11C-DASB in healthy humans.
abstract: 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.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, New York 10032, USA. pst2001@columbia.edu
authors.forename: Peter S
authors.initials: PS
authors.lastname: Talbot
authors.forename: W Gordon
authors.initials: WG
authors.lastname: Frankle
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Suckow
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: 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
chemical_list: 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