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Visualisation de l'amyline avec des sondes métalliques pour une imagerie du diabète

Abstract : Diabetes is a major cause of death in the world ; 422 million people are affected of which 90% are diagnosed with type II diabetes (T2DM). This disease is characterized by the formation of toxic aggregates of the amyloid peptide named amylin. During the last decade, several imaging probes have been developed for the detection of amyloid peptides, mostly Aβ aggregates (Aβ₁₋₄₀ et Aβ₁₋₄₂), in the context of Alzheimer’s disease. These probes have been mainly developed for PET and SPECT detection. Only few probes have been developed for MRI detection of amyloid plaques.This work focuses on development and characterization of novel metal-based imaging probes for the visualization of amylin and amyloid peptide Aβ₁₋₄₀ in the pancreas in order to understand the mechanisms behind T2DM. The probes contain one or two amyloid-targeting units (derivatives of PiB = Pittsburgh compound B), a macrocyclic metal chelate as imaging reporter and a spacer between the two. We have optimized the affinity of our probes for amyloid peptides aggregates (amylin and Aβ₁₋₄₀) mainly by modulating the length of the spacer, but also by varying the number of targeting units. We have characterized their lipophilicity, highlighted the different states of aggregation of the probes in these studies and, the importance of this parameter when determining their affinity for amyloid peptides. Finally, we studied the influence of our probes in the aggregation process of amyloid peptides. We remarkably increased the affinity by extending the linker and noted a certain selectivity towards amylin with two targeting units.The in vivo biodistribution in control mice gave encouraging and promising results.
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Submitted on : Friday, October 15, 2021 - 8:43:10 AM
Last modification on : Saturday, March 26, 2022 - 11:49:07 AM
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Saida Majdoub. Visualisation de l'amyline avec des sondes métalliques pour une imagerie du diabète. Chimie analytique. Université d'Orléans, 2020. Français. ⟨NNT : 2020ORLE3114⟩. ⟨tel-03379537⟩

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