Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor
| Autor: | 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 |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Pharmacology
medicine.medical_specialty biology Chemistry Serotonin reuptake inhibitor TD-9855 Psychiatry and Mental health PET Endocrinology Monoamine neurotransmitter Internal medicine norepinephrine and serotonin transporter Serotonin Plasma Membrane Transport Proteins medicine biology.protein pain Pharmacology (medical) Norepinephrine Plasma Membrane Transport Proteins Serotonin Serotonin Uptake Inhibitors Reuptake inhibitor Serotonin transporter Research Article |
| Zdroj: | International Journal of Neuropsychopharmacology |
| ISSN: | 1469-5111 1461-1457 |
| DOI: | 10.1093/ijnp/pyu027 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|