Synthesis and pharmacological evaluation of a series of fluoro-substituted 3-phenoxy-azetidines as cortical enhancers for the treatment of apathy.

We here report the discovery of a series of fluoro-substituted 3-phenoxy-azetidines useful for modulating levels of monoamines in cerebral cortical areas of the brain. The compounds were characterized by in vivo studies using, in particular, behavioural, and microdialysis methods. Furthermore, the compounds were tested in binding assays for the human serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters in order to assess the risk for addiction/dependency. Optimization of this class of compounds for improving cognitive functions while minimizing the effect on monoamine transporters resulted in the selection of a candidate drug 1 (IRL757). After 1 was successfully assessed in different animal models for motivation/goal-directed behaviour (unpublished data), it is currently being evaluated in humans for the treatment of apathy in neurological disorders in general, and in particular in Parkinson's disease (PD).