Biological evaluation of a technetium-99m-labeled integrated tropane-BAT and its piperidine congener as potential dopamine transporter imaging agents

Recently, we have reported modification of 99mTc-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 o...

Full description

Saved in:
Bibliographic Details
Published in:Nuclear medicine and biology 2006, Vol.33 (1), p.125-133
Main Authors: Kieffer, Davy M., Vanbilloen, Hubert P., Cleynhens, Bernard J., Terwinghe, Christelle Y., Mortelmans, Luc, Bormans, Guy M., Verbruggen, Alfons M.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Recently, we have reported modification of 99mTc-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 99mTc-labelled integrated TRODAT derivatives ( 99mTc-TropaBAT and 99mTc-norchloro-TropaBAT) and with the synthesis and biological evaluation of a novel 99mTc-labelled piperidine-based derivative ( 99mTc-PipBAT). Biodistribution of all radiolabelled complexes was studied in normal mice. A more detailed ex vivo intracerebral distribution study of the two 99mTc-TropaBAT complexes was additionally performed in normal rats. Autoradiography of brain sections of normal mice (with or without pretreatment with FP-β-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. Both 99mTc-TropaBAT complexes show a slightly higher brain uptake than 99mTc-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-β-CIT. Unexpectedly, no striatal uptake was detected after in vitro incubation of mouse brain sections with the tracer agents. For 99mTc-PipBAT, neither brain uptake nor in vitro striatal uptake was found. Both 99mTc-TropaBAT complexes exhibit similar diffusion into brain as 99mTc-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-β-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.
ISSN:0969-8051
1872-9614
DOI:10.1016/j.nucmedbio.2005.08.006