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...
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Published in: | Nuclear medicine and biology 2006, Vol.33 (1), p.125-133 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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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. |
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ISSN: | 0969-8051 1872-9614 |
DOI: | 10.1016/j.nucmedbio.2005.08.006 |