title: Evaluation of (99m)Tc-labeled tropanes with alkyl substituents on the 3beta-phenyl ring as potential dopamine transporter tracers.
abstract: Technetium(V)-oxo-3beta-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl[N-(2-mercaptoethyl), N-(N'-(2-mercaptoethyl)-2-aminoethyl)]-aminomethyl ((99m)Tc-TRODAT-1) and three derivatives with one or two substituents on the 3beta-phenyl ring (4-methylphenyl, 4-ethylphenyl and 2,4-dimethylphenyl) were prepared and evaluated as potential imaging agents for the central nervous dopamine transporter (DAT). Labeling of the ligands with (99m)Tc yielded for each of them a mixture of two radiolabeled species, which were purified and isolated using reversed-phase high-performance liquid chromatography. Employing radio-LC-MS, we found both species to have the same molecular mass suggesting diastereoisomers. After intravenous injection in mice and rats, the compounds were stable in vivo and no important metabolites were found in plasma or urine. Replacement of the 4-chloro atom on the 3beta-phenyl ring by a methyl group causes no loss of affinity for the DAT system. However, substitution of an ethyl group for the 4-chloro atom or introduction of a second methyl group in the 2-position of the phenyl ring results in a serious reduction of the affinity for the DAT transporter. Ex vivo autoradiography on mice brain slices and biodistribution studies in rats showed specific uptake of (99m)Tc-TRODAT-1 and the 4-methylphenyl derivative in striatum and putamen. Although the 4-ethylphenyl and 2,4-dimethylphenyl derivatives show brain uptake in rats and mice, no specific uptake in striatum was found. In addition, differences in biological behavior between the different diastereomers were observed. In conclusion, small changes to (99m)Tc-TRODAT-1 at the phenyl ring in the 3beta position of the tropane moiety significantly change the biological behavior of the studied compounds.
authors.affiliation: Radiopharmacy, U.Z. Gasthuisberg, B-3000 Leuven, Belgium. bert.vanbilloen@uz.kuleuven.ac.be
authors.forename: Hubert P
authors.initials: HP
authors.lastname: Vanbilloen
authors.forename: Davy M
authors.initials: DM
authors.lastname: Kieffer
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Cleynhens
authors.forename: Guy M
authors.initials: GM
authors.lastname: Bormans
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Alfons M
authors.initials: AM
authors.lastname: Verbruggen
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D010636:Phenols / Q000737:chemistry; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution; D014326:Tropanes / Q000493:pharmacokinetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D015609:Organotechnetium Compounds; D010636:Phenols; D019275:Radiopharmaceuticals; D014326:Tropanes; C104196:technetium Tc 99m TRODAT-1