Synthesis and Ligand Binding of Nortropane Derivatives: N-Substituted 2β-Carbomethoxy-3β-(4‘-iodophenyl)nortropane and N-(3-Iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstituted phenyl)nortropane. New High-Affinity and Selective Compounds for the Dopamine Transporter

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Abstract
Two novel series of iodinated N-substituted analogs of 2β-carbomethoxy-3β-(4‘-iodophenyl)tropane (β-CIT) and N-(3-iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DAT), serotonin (5-HTT), and norepinephrine (NET) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of β-CIT exhibited higher DAT selectivity over both 5-HTT and NET than β-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DAT affinities than β-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DAT agent of this series (5-HTT/DAT = 32.0 vs 0.1 for β-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DAT affinity. Ki values of N-(3-iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstituted phenyl)nortropanes revealed that phenyl, 4‘-isopropyl, and 4‘-n-propyl derivatives weakly inhibited specific binding to DAT, whereas phenyl substitution with 4‘-methyl (3c), 3‘,4‘-dichloro (3b), and 4‘-iodo (3d) yielded high-DAT reuptake agents with increased DAT selectivity compared to β-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

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