| Abstract
| - Two novel series of iodinated N-substituted analogs of2β-carbomethoxy-3β-(4‘-iodophenyl)tropane (β-CIT) andN-(3-iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstitutedphenyl)nortropane were synthesized. They were evaluated for theirinhibitory properties on dopamine(DAT), serotonin (5-HTT), and norepinephrine(NET) transporters in rat brain homogenatesusing [3H]GBR-12935,[3H]paroxetine, and[3H]nisoxetine as specific ligands. All newN-substituted analogs of β-CIT exhibited higher DATselectivity over both 5-HTT and NETthanβ-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 affinitiesthan β-CIT(respectively 14, 15, 30, and 30 nM vs 27 nM). Compound3d was found to be the most selectiveDAT agent of this series (5-HTT/DAT= 32.0 vs 0.1 for β-CIT). TheN-(3-iodoprop-(2E)-enyl)chain linked to the tropane nitrogen was therefore maintained on thetropane structure, andphenyl substitution was carried out in order to improve DATaffinity. Ki values ofN-(3-iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstitutedphenyl)nortropanes revealed that phenyl,4‘-isopropyl, and 4‘-n-propyl derivatives weakly inhibitedspecific binding to DAT, whereasphenyl substitution with 4‘-methyl (3c), 3‘,4‘-dichloro(3b), and 4‘-iodo (3d) yieldedhigh-DATreuptake agents with increased DAT selectivity compared toβ-CIT. These results demonstratethat the combination of a nitrogen and a phenyl substitution yieldscompounds with high affinityand selectivity for the dopamine transporter which are usable as SPECTmarkers for DAneurons.
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