SYNTHESIS AND LIGAND-BINDING OF NORTROPANE DERIVATIVES - N-SUBSTITUTED BETA-CARBOMETHOXY-3-BETA-(4'-IODOPHENYL)NORTROPANE AND L)-2-BETA-CARBOMETHOXY-3-BETA-(3',4'-DISUBSTITUTED PHENYL)NORTROPANE - NEW HIGH-AFFINITY AND SELECTIVE COMPOUNDS FOR THE DOPAMINE TRANSPORTER

Two novel series of iodinated N-substituted analogs of 2 beta-carbomet hoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-e nyl)-2 beta-carbomethoxy-3 beta-(3',4'-disubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HTT), and norepinephrine (NET) tran sporters in rat brain homogenates using [H-3]GBR-12935, [H-3]paroxetin e, and [H-3]nisoxetine as specific ligands. All new N-substituted anal ogs of beta-CIT exhibited higher DA(T) selectivity over both 5-HTT and NET than beta-CIT. Moreover compounds with the N-substituents propyny l (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respect ively 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/DA(T) = 32.0 vs 0.1 fo r beta-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 DA(T) affinity. K-i values of N-(3-iodoprop-(2E)-enyl)-2 beta-carbomethoxy-3 beta-(3',4'-d isubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, an d 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA( T) selectivity compared to beta-CIT. These results demonstrate that th e 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.