SEP-225289 serotonin and dopamine transporter occupancy: a PET study

Area of Science:

• Neuroscience
• Pharmacology
• Radiochemistry

Background:

• SEP-225289 is a novel compound with potential to inhibit dopamine, norepinephrine, and serotonin reuptake.
• Understanding transporter occupancy is crucial for drug development.

Purpose of the Study:

• To investigate the dopamine and serotonin transporter occupancy of SEP-225289 in humans using Positron Emission Tomography (PET).

Main Methods:

• An open-label PET study administered single doses of SEP-225289 (8, 12, 16 mg) to healthy volunteers.
• Dopamine transporter (DAT) occupancy was assessed using (11)C-PE2I PET, and serotonin transporter (SERT) occupancy using (11)C-DASB PET.
• Plasma concentrations and adverse events were monitored.

Main Results:

• Dopamine and serotonin transporter occupancies increased with SEP-225289 dose.
• Mean DAT occupancy ranged from 33% to 49%, while mean SERT occupancy ranged from 2% to 14%.
• Dopamine transporter IC(50) was 4.5 ng/mL, with extrapolated maximum occupancy of 85%.

Conclusions:

• Dopamine transporter occupancy was significantly higher than serotonin transporter occupancy at evaluated doses.
• PET occupancy studies are valuable tools in early drug development for assessing therapeutic potential and guiding dose selection.
• The findings support the utility of PET imaging in informing drug development decisions for novel compounds targeting neurotransmitter systems.