Incorporation of PeT fluorescent units into the pharmacophore of atypical dopamine transporter inhibitors.

Dopamine signaling dysregulation is an important feature of numerous central nervous system (CNS) diseases and disorders including psychostimulant use disorder (PUD). Atypical dopamine transporter (DAT) inhibitors have been developed as potential candidates for PUD treatment. Herein, we develop eight new pH sensitive chemical probes with potential of an atypical DAT inhibition profile by incorporating fluorescent anthracene units into the pharmacophore of either modafinil or benztropine. Five new anthracene analogues showed significantly higher affinity for wildtype DAT compared to the outward-facing biased DAT mutant Y156F, which is a characteristic of atypical inhibitors. Additionally, the compounds generally showed higher affinities for DAT over the serotonin transporter (SERT). These novel probes may be used to assess the degree of amine protonation upon protein binding, hence the de facto pH in the active site and consequently if a pH difference between classical and atypical binding exists.