The stereoselective synthesis of iodinated analogues of reboxetine : new imaging agents for the noradrenaline transporter

The noradrenaline reuptake transporter is located on the pre-synaptic membrane of noradrenic neurons. Its main function is to terminate the action of the neurotransmitter noradrenaline by reuptake back into the nerve terminal. Changes in the function and density of the noradrenaline reuptake transporter have been implicated in neurological disorders such as clinical depression and Alzheimer’s disease. In vivo imaging of the noradrenaline transporter using single photon emission computed tomography has been hampered by the lack of a suitable imaging agent. The information from imaging studies could lead to a better understanding of transporter function and the development of more efficient and faster acting drugs to treat the diseases associated it. For the first time, all four stereoisomers of an iodinated analogue of reboxetine were stereoselectively synthesised and biologically evaluated in an effort to understand the relationship between stereochemistry and potency. All four compounds were found to have nanomolar affinity for the noradrenaline transporter. Of most interest was the (2R,3S)-stereoisomer, which was identified as being as potent as the more studied (2S,3S)-stereoisomer. Therefore, a new series of iodoanalogues based on the (2R,3S)-stereochemical scaffold were synthesised and tested for their affinity with the noradrenaline transporter. This study revealed the derivative with ortho substitution on the phenoxy ring to be a potential lead for the development of a novel imaging agent for the noradrenaline transporter.