Synthesis and evaluation of 2-amino-dihydrotetrabenzine derivatives as probes for imaging vesicular monoamine transporter-2.

A novel series of analogs of 2-amino-dihydrotetrabenazine derivatives, 4-6, targeting the vesicular monoamine transporter have been prepared. In vitro binding was carried out in tissue homogenates prepared from rat striatal tissue homogenates with both [(125)I]-iodovinyl-TBZ and [(3)H]DTBZ. There was a good correlation (r(2)=0.925) between the affinities of the different compounds for [(125)I]-iodovinyl-TBZ and [(3)H]-DTBZ binding. Compound 5 exhibited a better affinity for the vesicular monoamine transporter (K(i)=8.68+/-1.26 nM and 7.01+/-0.07 nM, respectively), which may be a good lead compound for further structural modification to develop useful probes for VMAT2.