New 2α-tropane amides as potential PET ligands for the dopamine transporter

Abstract 

Positron emission tomography (PET) imaging of dopamine transporter (DAT) density in the brain is a potentially valuable tool for studying the etiopathology of degenerative brain disorders. The present study evaluated five new potential competitive inhibitors of DAT as ligands for PET. The evaluation of the new compounds measured their ability to compete with the binding of the reference ligand 2β-carbomethoxy-3β-(4-[¹³¹I]iodophenyl)tropane [¹³¹I]β-CIT to striatal and cortical membranes from rat and pig brain. Four of the new compounds structurally related to cocaine were synthesized in their 2α,3β configuration; the most potent one, 3β-(4-iodo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2α-carboxylic acid (2-fluoro-ethyl)-amide, was synthesized also in the 2β,3β configuration. For comparative studies in rat brain and new evaluation in pig brain homogenate, the established compounds β-CIT, FP-CIT, PE2I and FETT were also synthesized and evaluated. Contrary to expectation, the 2α,3β and 2β,3β isomers of 3-(4-iodo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid (2-fluoro-ethyl)-amide showed the same affinity constant for rat striatum (K_i=200 nM±34), but in pig striatum and rat and pig cortex the 2α,3β form even had a higher affinity than the 2β,3β form.

Keywords: DAT ligands, PET, Cocaine derivatives, 2α,3β Tropanes