Synthesis of tropane and nortropane analogues with phenyl substitutions as serotonin transporter ligands.
The effects of structural modifications of 2 beta-carbomethoxy-3 beta-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 2 beta-carbomethoxy-3 beta-(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 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) tropane, and N-demethylation, affording 2 beta-carbomethoxy-3 beta-(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, 2 beta-carbomethoxy-3 beta-(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.
Emond
P
P
INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Université François Rabelais, 31 Avenue Monge, 37200 Tours, France. emond@univ-tours.fr
Helfenbein
J
J
Chalon
S
S
Garreau
L
L
Vercouillie
J
J
Frangin
Y
Y
Besnard
J C
JC
Guilloteau
D
D
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
D002352:Carrier Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D014326:Tropanes