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Complexes métalliques pour utilisation en imagerie médicale : application à la maladie d’Alzheimer

Abstract : Detection of beta-amyloid peptide (Aβ) using medical imaging techniques is used for the diagnosis of Alzheimer’s disease. Copper and lanthanide metallic complexes may be used for that goal, if they were able to enter the brain.We studied the cytotoxicity and the cellular incorporation kinetics of two macrocyclic complexes with picolinate arms, [Eu(do2pa)]+ and [Cu(te1pa)]+. Both complexes are able to cross the plasma membrane, entering K562 and K562/ADR cells. The ratios between their intracellular and extracellular concentrations are 5 and 1.4 respectively. No significant difference was observed between K562 and K562/ADR cells, meaning that these complexes are not substrates of P-gp, a well-known efflux transport protein in the blood-brain barrier. The results obtained and the physicochemical properties of complexes suggest that the complexes studied are appropriate platforms for the synthesis of brain-targeted medical imaging agents. Based on the structure of [Cu(te1pa)]+, an Aβ-targeted metallic complex was developed by attaching an aryl-benzofuran derivative (named ONO) to the picolinate arm of the ligand via a Buchwald-Hartwig reaction. ONO is a marker of amyloid plaques that is able to cross the plasma membrane of K562 and K562/ADR cells. Neither ONO nor [Cu(te1pa-ONO)]+ are toxic to SH-SY5Y cells at concentrations that would be appropriate for clinical use. Finally, we studied a series of N-alkanol-N-cyclohexanol amine aryl esters, synthesized as P-gp inhibitors. All inhibitors have [I]0.5 between 60 nM and 510 nM, showing good P-gp inhibition activity. The P-gp inhibitors are 3 to 27 times more powerful than verapamil, being the trans isomers more effective than their cis counterparts.
Keywords : Cytotoxicity
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Submitted on : Thursday, April 19, 2018 - 5:20:13 PM
Last modification on : Saturday, February 15, 2020 - 1:44:13 AM
Long-term archiving on: : Tuesday, September 18, 2018 - 4:25:15 PM


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  • HAL Id : tel-01771728, version 1



Diego Santo Domingo Porqueras. Complexes métalliques pour utilisation en imagerie médicale : application à la maladie d’Alzheimer. Matériaux. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCD016⟩. ⟨tel-01771728⟩



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