title: Biological evaluation of a technetium-99m-labeled integrated tropane-BAT and its piperidine congener as potential dopamine transporter imaging agents.
abstract: BACKGROUND
  Recently, we have reported modification of (99m)Tc-TRODAT-1 by integrating the N2S2 metal chelating unit and the tropane skeleton. Results of a preliminary biodistribution study in rats were promising with respect to brain uptake. The present report deals with the further biological characterization of the (99m)Tc-labelled integrated TRODAT derivatives ((99m)Tc-TropaBAT and (99m)Tc-norchloro-TropaBAT) and with the synthesis and biological evaluation of a novel (99m)Tc-labelled piperidine-based derivative ((99m)Tc-PipBAT).
  
  
  METHODS
  Biodistribution of all radiolabelled complexes was studied in normal mice. A more detailed ex vivo intracerebral distribution study of the two (99m)Tc-TropaBAT complexes was additionally performed in normal rats. Autoradiography of brain sections of normal mice (with or without pretreatment with FP-beta-CIT or haloperidol) and rats was performed. Affinity for the dopamine transporter (DAT) was also assessed in vitro in the presence or absence of cocaine.
  
  
  RESULTS
  Both (99m)Tc-TropaBAT complexes show a slightly higher brain uptake than (99m)Tc-TRODAT-1, but the striatum/cerebellum activity ratio is less favourable. Nevertheless, significant striatal uptake was detected after ex vivo autoradiography, but this uptake was also observed after pretreatment with FP-beta-CIT. Unexpectedly, no striatal uptake was detected after in vitro incubation of mouse brain sections with the tracer agents. For (99m)Tc-PipBAT, neither brain uptake nor in vitro striatal uptake was found.
  
  
  CONCLUSIONS
  Both (99m)Tc-TropaBAT complexes exhibit similar diffusion into brain as (99m)Tc-TRODAT-1, and ex vivo autoradiography shows significant striatal uptake. However, the inferior striatum/cerebellum activity ratio, the striatal uptake in mice pretreated with FP-beta-CIT or haloperidol, and the lack of striatal uptake during in vitro incubation prove that the DAT is not targeted. Brain uptake disappears when the tropane skeleton is replaced by a piperidine ring, and also in this case no striatal uptake is found in vitro.
authors.affiliation: Laboratory of Radiopharmaceutical Chemistry, University of Leuven, UZ Gasthuisberg, Belgium.
authors.forename: Davy M
authors.initials: DM
authors.lastname: Kieffer
authors.forename: Hubert P
authors.initials: HP
authors.lastname: Vanbilloen
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Cleynhens
authors.forename: Christelle Y
authors.initials: CY
authors.lastname: Terwinghe
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Guy M
authors.initials: GM
authors.lastname: Bormans
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; D005240:Feasibility Studies; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014326:Tropanes / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D015609:Organotechnetium Compounds; D010880:Piperidines; D019275:Radiopharmaceuticals; D014326:Tropanes; C104196:technetium Tc 99m TRODAT-1