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