Design and synthesis of a novel photoaffinity ligand for the dopamine and serotonin transporters based on 2β-carbomethoxy-3β-biphenyltropane

Tropane-based photoaffinity ligands covalently bind to discrete points of attachment on the dopamine transporter (DAT). To further explore structure-activity relations, a ligand in which the photoactivated group was extended from the 3-position of the tropane ring was synthesized from cocaine via a Stille or Suzuki coupling strategy. 3-(4′-Azido-3′-iodo- biphenyl-4-yl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (11; K_i = 15.1 ± 2.2 nM) demonstrated high binding affinity for the DAT. Moreover, this compound showed moderate binding affinity for the serotonin transporter (SERT, K_i = 109 ± 14 nM), suggesting the potential utility of [¹²⁵I]11 in both DAT and SERT protein structure studies.