RATIONALE

Monoamine triple reuptake inhibitors (TRIs) inhibit central dopamine, norepinephrine, and serotonin transporters, restoring functional monoamine neurotransmission.

OBJECTIVES

This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-ascending-doses (SAD) of the novel monoamine TRI CSTI-500. In addition, we estimated the peak and duration of striatal serotonin transporter (SERT) and dopamine transporter (DAT) occupancies, by using positron emission tomography (PET).

METHODS

Part A was a double-blinded, randomized, placebo-controlled, sequential SAD study with seven sequential dose panels (0.5-150 mg) where subjects in each panel received either a single oral dose of CSTI-500 (n=6) or placebo (n=2). Part B was an open-label, single-dose PET study to assess the peak and duration of SERT (n=4) and DAT (n=5) striatal occupancies, using the radioligands [C]MADAM and [C]PE2I, respectively.

RESULTS

The maximum tolerable acute single-dose of CSTI-500 was determined as 100 mg. No serious adverse events occurred. The median maximum CSTI-500 concentrations were attained at 1-2 hours post-dose (h pd); the estimated plasma elimination half-life was 44-50 h pd. Subsequent to a single-dose of 100 mg CSTI-500, mean striatal SERT occupancy was 72% and 62% at 4-6 and 24 h pd, respectively. Mean striatal DAT occupancy was 36% and 31% at 4-9 and 24 h pd, respectively.

CONCLUSIONS

CSTI-500 is a potent monoamine TRI with substantial striatal SERT and moderate DAT occupancies in healthy subjects. Together with promising safety-tolerability and pharmacokinetics profiles, the continued clinical development of CSTI-500 is strongly supported.