Norepinephrine transporter inhibitors and their therapeutic potential

The norepinephrine transporter (NET) is located in the plasma membrane of noradrenergic neurons, where it functions to take up synaptically released norepinephrine (NE). The NET thus serves as the primary mechanism for the inactivation of noradrenergic signaling. Some potent and selective or mixed NET inhibitors (e.g., reboxetine and atomoxetine) have been successfully developed to treat a variety of mental disorders such as depression and attention deficit hyperactivity disorder (ADHD). However, to date, only a very limited number of NET-selective inhibitors are available. New potent and selective NET inhibitors may find application in the treatment of mental disorders or in PET imaging, and may enhance our basic understanding of these illnesses. In the present review, both previously reported and newly designed NET inhibitors, as well as their therapeutic and imaging potential, will be discussed. Two types of molecules, the conformationally constrained tropanes and the piperidine-based nocaine/modafinil hybrid ligands, represent new leads and provide good opportunities for discovering novel potent and selective NET inhibitors that are useful as therapies and imaging agents for the NET.