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Synthesis of Tropane and Nortropane Analogues with Phenyl Substitutions as Serotonin Transporter Ligands

2001; Elsevier BV; Volume: 9; Issue: 7 Linguagem: Inglês

10.1016/s0968-0896(01)00083-9

1464-3391

Patrick Emond, Julie Helfenbein, Sylvie Chalon, Lucette Garreau, Johnny Vercouillie, Y. Frangin, Jean Claude Besnard, Denis Guilloteau,

Forensic Toxicology and Drug Analysis

The effects of structural modifications of 2β-carbomethoxy-3β-phenyl tropane analogues were evaluated on in vitro affinity to the dopamine (DAT) and serotonin (5-HTT) transporters in rat brain tissue. The introduction of a large alkyl group at the 4′-position of the phenyl ring, affording 2β-carbomethoxy-3β-(4′-alkylphenyl) tropane, diminished the affinity for the DAT whereas moderate 5-HTT affinity was obtained. The introduction of an iodine at the 3′-position of the 4′-alkylphenyl, affording 2β-carbomethoxy-3β-(3′-iodo-4′-alkylphenyl) tropane, and N-demethylation, affording 2β-carbomethoxy-3β-(3′-iodo-4′-alkylphenyl) nortropane, improved affinity and specificity for the 5-HTT. It could be assumed from these results that the combination of these three modifications of tropane structure yielded highly selective compounds for the 5-HTT. Of the new compounds synthesized, the most selective cocaine derivative, 2β-carbomethoxy-3β-(3′-iodo-4′-isopropylphenyl) nortropane (8d) labeled with iodine-123 or carbon-11, could be a potential ligand for exploration of the 5-HT transporter by SPET or PET.