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

Abstract

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-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 DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for 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)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 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 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.

Quantification of Dopamine Transporter in Human Brain Using PET with 18F-FE-PE2I

“…Recently, a new ligand, N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methylphenyl)nortropane (PE2I), with a high affinity for DAT (inhibition constant, 17 nM) and good selectivity, was developed (14,15). In human PET studies, 11 C-PE2I showed a high specific-to-nonspecific ratio (15)(16)(17)(18).…”

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

“…Clorgyline, fumitremorgin C, loperamide, p-MPPF (4-(29-methoxyphenyl)-1- (16), and PE2I ((E)-N-(3-iodoprop-2-enyl)-2b-carbomethoxy-3b-(49-methylphenyl) nortropane) (17) were synthesized in-house according to published methods.…”

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

“…3 H or 125 I) fig. 2), which in vitro has similar affinity to dopamine transporter (K i Ω 17 nM) as b-CIT whereas affinity (K i ) to serotonin and nor-MiniReview adrenalin transporters is 500 and Ͼ1000 nM, respectively (Emond et al 1997). [ 125 I]PE2I binding to human post mortem brain ( fig.…”