Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Autor:	Smith JA; 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., Bourdet DL, Daniels OT; 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)., Ding YS; 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)., Gallezot JD; 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)., Henry S; 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)., Kim KH; 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)., Kshirsagar S; 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)., Martin WJ; 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)., Obedencio GP; 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)., Stangeland E; 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)., Tsuruda PR; 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)., Williams W; 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)., Carson RE; 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)., Patil ST; 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).
Jazyk:	angličtina
Zdroj:	The international journal of neuropsychopharmacology [Int J Neuropsychopharmacol] 2014 Dec 13; Vol. 18 (2). Date of Electronic Publication: 2014 Dec 13.
DOI:	10.1093/ijnp/pyu027
Abstrakt:	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. (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
Databáze:	MEDLINE
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