title: New 2alpha-tropane amides as potential PET ligands for the dopamine transporter.
abstract: Positron emission tomography (PET) imaging of dopamine transporter (DAT) density in the brain is a potentially valuable tool for studying the etiopathology of degenerative brain disorders. The present study evaluated five new potential competitive inhibitors of DAT as ligands for PET. The evaluation of the new compounds measured their ability to compete with the binding of the reference ligand 2beta-carbomethoxy-3beta-(4-[(131)I]iodophenyl)tropane [(131)I]beta-CIT to striatal and cortical membranes from rat and pig brain. Four of the new compounds structurally related to cocaine were synthesized in their 2alpha,3beta configuration; the most potent one, 3beta-(4-iodo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2alpha-carboxylic acid (2-fluoro-ethyl)-amide, was synthesized also in the 2beta,3beta configuration. For comparative studies in rat brain and new evaluation in pig brain homogenate, the established compounds beta-CIT, FP-CIT, PE2I and FETT were also synthesized and evaluated. Contrary to expectation, the 2alpha,3beta and 2beta,3beta isomers of 3-(4-iodo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid (2-fluoro-ethyl)-amide showed the same affinity constant for rat striatum (K(i)=200 nM+/-34), but in pig striatum and rat and pig cortex the 2alpha,3beta form even had a higher affinity than the 2beta,3beta form.
authors.affiliation: Institut für Nuklearchemie, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. b.drewes@fz-juelich.de
authors.forename: Birte
authors.initials: B
authors.lastname: Drewes
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sihver
authors.forename: Sabine
authors.initials: S
authors.lastname: Willbold
authors.forename: Ray A
authors.initials: RA
authors.lastname: Olsson
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Coenen
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005240:Feasibility Studies; D066298:In Vitro Techniques; D008024:Ligands; D008657:Metabolic Clearance Rate; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014018:Tissue Distribution; D014326:Tropanes / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D019275:Radiopharmaceuticals; D014326:Tropanes