title: Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.
abstract: BACKGROUND
  Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.
  
  
  METHODS
  We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.
  
  
  RESULTS
  TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open-label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL.
  
  
  CONCLUSIONS
  These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson). jsmith@theravance.com.
authors.forename: Jacqueline A M
authors.initials: JA
authors.lastname: Smith
authors.forename: D L
authors.initials: DL
authors.lastname: Bourdet
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: D L
authors.initials: DL
authors.lastname: Patil
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: O T
authors.initials: OT
authors.lastname: Daniels
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: Y-S
authors.initials: YS
authors.lastname: Ding
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: J-D
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: S
authors.initials: S
authors.lastname: Henry
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: K H S
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: S
authors.initials: S
authors.lastname: Kshirsagar
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: W J
authors.initials: WJ
authors.lastname: Martin
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: G P
authors.initials: GP
authors.lastname: Obedencio
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: E
authors.initials: E
authors.lastname: Stangeland
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: P R
authors.initials: PR
authors.lastname: Tsuruda
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: W
authors.initials: W
authors.lastname: Williams
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: R E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
authors.forename: S T
authors.initials: ST
authors.lastname: Patil
mesh_terms: D000328:Adult; D000814:Aniline Compounds; D000818:Animals; D001774:Blood Chemical Analysis; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008954:Models, Biological; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010647:Phenyl Ethers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013440:Sulfides
chemical_list: C412822:3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile; D000814:Aniline Compounds; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C524178:O-methyl reboxetine; D010647:Phenyl Ethers; D010880:Piperidines; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; D013440:Sulfides; C000601820:ampreloxetine; D000077593:Reboxetine
keywords: PET; TD-9855; norepinephrine and serotonin transporter; pain