Enantioselective synthesis of S-(+)-2β-carboalkoxy-3α-[bis(4-fluorophenyl)methoxy]tropanes as novel probes for the dopamine transporter

Synthesis of a series of pure S-(+)-2β-carboalkoxy-3α-[bis(4-fluorophenyl)methoxy]tropanes (>99% ee) was achieved by employing a chiral amine-induced asymmetric reaction of tropinone with methyl cyanoformate as the key step. In this series, all of the S-(+)-enantiomers were 2-fold more potent than their racemic mixtures and all displayed high-affinity binding for DAT (Ki=13–40 nM). These data support previous findings of significant divergence in structural requirements for high-affinity DAT binding among tropane-based inhibitors. Furthermore, the 2-substituent in the 3α-[bis(4-fluorophenyl)methoxy]tropane series is well tolerated at the DAT but not at SERT (Ki=690–2040 nM), or muscarinic M1 receptors (Ki=133–4380 nM) resulting in highly selective DAT ligands that may provide new leads toward a cocaine-abuse therapeutic.