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Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Authors :
J-D Gallezot
Eric L. Stangeland
Richard E. Carson
Khs Kim
Jacqueline A.M. Smith
ST Patil
William J. Martin
DL Patil
S Kshirsagar
Wendol Williams
OT Daniels
Glenmar P. Obedencio
Y-S. Ding
Shannan Henry
PR Tsuruda
Source :
International Journal of Neuropsychopharmacology
Publication Year :
2015
Publisher :
Oxford University Press (OUP), 2015.

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.

Details

ISSN :
14695111 and 14611457
Volume :
18
Database :
OpenAIRE
Journal :
International Journal of Neuropsychopharmacology
Accession number :
edsair.doi.dedup.....d39d98640151d1678b20a9f62b1076c8
Full Text :
https://doi.org/10.1093/ijnp/pyu027