N-Phthalimidoalkyl derivatives of 2β-carbomethoxy-3β-(4′-iodophenyl)tropane (β-CIT): Brain monoamine transporter affinity

A series of novel N-phthalimidoalkyl analogs of the stable phenyltropane β-CIT were synthesized and evaluated by selective radioligand binding assays for affinity to transporters for dopamine (DA), serotonin (5-HT) and norepinephrine (NE) in corpus striatum tissue from rat forebrain. β-CIT and novel compounds with the phthalimido moiety separated by ≥4 methylene groups from the nitrogen atom of the tropane ring (6–8) showed similarly greater affinity at 5-HT than DA transporters; this affinity was lost with only 2 or 3 carbon atoms (4 and 5). These results are consistent with interference at a critical binding site for the tropane nitrogen on the transporter proteins and indicate that the tropane nitrogen atom can be substituted with large substituted alkyl moieties without loss of affinity or selectivity for amine transporters.