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

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 2 beta carbomethoxy-3 beta-(4-[I-131]iodophenyl)tropane [I-131]beta-CIT to striatal and cortical membranes from rat and pig brain. Four of the new compounds structurally related to cocaine were synthesized in their 2 alpha,3 beta configuration; the most potent one, 3 beta(4-iodo-phenyl)-8-methyl-8-aza- bicyclo[3.2.1]octane-2 alpha-carboxylic acid (2-fluoro-ethyl)-amide, was synthesized also in the 2 beta,3 beta configuration. For comparative studies in rat brain and new evaluation in pig brain homogenate, the established compounds beta-CIT, FP-CIT, PE2I and FETT were also synthesized and evaluated. Contrary to expectation, the 2 alpha,3 beta and 2 alpha,3 beta 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 striaturn (K-i=200 nM +/- 34), but in pig striaturn and rat and pig cortex the 2a,3 beta form even had a higher affinity than the 2 alpha,3 beta form. (c) 2007 Elsevier Inc. All rights reserved.