title: SEP-225289 serotonin and dopamine transporter occupancy: a PET study.
abstract: SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy.
  
  
  METHODS
  Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events.
  
  
  RESULTS
  Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported.
  
  
  CONCLUSIONS
  At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about indication, dose, and therapeutic potential.
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, USA. cd2415@columbia.edu
authors.forename: Christine
authors.initials: C
authors.lastname: DeLorenzo
authors.forename: Sarah
authors.initials: S
authors.lastname: Lichenstein
authors.forename: Karen
authors.initials: K
authors.lastname: Schaefer
authors.forename: Judith
authors.initials: J
authors.lastname: Dunn
authors.forename: Randall
authors.initials: R
authors.lastname: Marshall
authors.forename: Lisa
authors.initials: L
authors.lastname: Organisak
authors.forename: Jahnavi
authors.initials: J
authors.lastname: Kharidia
authors.forename: Brigitte
authors.initials: B
authors.lastname: Robertson
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
mesh_terms: D000293:Adolescent; D000328:Adult; D000588:Amines / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D015331:Cohort Studies; D003503:Cyclobutanes / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014179:Neurotransmitter Uptake Inhibitors / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D021381:Protein Transport / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000588:Amines; D003503:Cyclobutanes; D050483:Dopamine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; C560745:SEP 225289; D050486:Serotonin Plasma Membrane Transport Proteins