Evaluation of novel tropane analogues in comparison with the binding characteristics of [18F]FP-CIT and [131I]β-CIT

This study evaluated novel potential dopamine transporter (DAT) inhibitors as ligands for positron emission tomography. Five new tropane analogs were synthesized and compared with the known ligand 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) and the recently characterized ligands N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)-nortropane (PE2I) and 2β-carbofluoroethoxy-3β-(4-methylphenyl)tropane (FETT). Evaluation with autoradiography measured the ability to antagonize the binding of [131I]iodine-labeled β-CIT and [18F]fluorine-labeled N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodo-phenyl) nortropane in rat and pig brains. The standards for comparison (PE2I and FETT) competed strongly in all regions investigated (striatum, cortex, superior colliculus and cerebellum). Of the new compounds, 2α-amido-fluoroethyl-3β-(4-iodophenyl)tropane ( 4) and 2β-amido-fluoroethyl-3β-(4-iodophenyl)tropane (4a) competed strongly with [131I]β-CIT in DAT-rich striatum, but also in other brain regions suggesting poor DAT selectivity. Because [131I]β-CIT binds unselectively both to DAT and serotonin transporters, no definite conclusion about the selectivity of the new compounds is possible. However, preclinical studies using the compounds and labeled with fluorine-18 or iodine-131 are encouraged.