title: The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects.
abstract: BACKGROUND
  (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce >50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain.
  
  
  METHODS
  PET and [11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o.) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel.
  
  
  RESULTS
  DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed.
  
  
  CONCLUSIONS
  The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.
authors.affiliation: Brookhaven National Laboratory, Upton, NY 11973, USA. volkow@bnl.gov
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.forename: Susan
authors.initials: S
authors.lastname: Learned-Coughlin
authors.forename: Julia
authors.initials: J
authors.lastname: Yang
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: David
authors.initials: D
authors.lastname: Schlyer
authors.forename: John S
authors.initials: JS
authors.lastname: Gatley
authors.forename: Christopher
authors.initials: C
authors.lastname: Wong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Naomi
authors.initials: N
authors.lastname: Pappas
authors.forename: Michael
authors.initials: M
authors.lastname: Schueller
authors.forename: Millard
authors.initials: M
authors.lastname: Jayne
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.forename: Donald
authors.initials: D
authors.lastname: Warner
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D016642:Bupropion / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003042:Cocaine / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D012054:Reinforcement, Psychology; D018709:Statistics, Nonparametric; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; D016642:Bupropion; D014316:Tritium; D003042:Cocaine; C496215:radafaxine