# Ascending single-dose study of the safety, pharmacokinetics, and pharmacodynamics of CSTI-500, a novel monoamine triple reuptake inhibitor, first-in-human

## TL;DR

This study tested a new drug, CSTI-500, in healthy volunteers to assess its safety and effects on brain chemicals.

## Contribution

The first-in-human evaluation of CSTI-500, a novel monoamine triple reuptake inhibitor, with PET-based pharmacodynamic measurements.

## Key findings

- CSTI-500 showed a maximum tolerable single dose of 100 mg with no serious adverse events.
- Striatal SERT occupancy was 72% at 4-6 hours post-dose and 62% at 24 hours.
- Pharmacokinetic data showed a median maximum concentration at 1-2 hours and a plasma half-life of 44-50 hours.

## Abstract

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

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).

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 [11C]MADAM and [11C]PE2I, respectively.

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.

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.

The online version contains supplementary material available at 10.1007/s00213-025-06861-4.