C-glycosides fluorés pour le marquage de peptides : Applications en imageries TEP et bimodale TEP/FPIR

The work developed in this thesis is based on saccharidic derivatives especially C-glycosides for which new synthetic methodologies and applications in the field of PET and PET/NIRF imaging have been developed. Some peptides play a major role in therapy and diagnosis of various pathologies and their conjugation with a saccharidic derivative significantly improves their biodistribution. The first part of this work concerns the synthesis of fluorinated (19F) and radiofluorinated (18F) C-glycosides fonctionalized in anomeric position by an arm bearing an azide function. These compounds were coupled by 1,3-dipolar cycloaddition to peptides derived from RGD, allowing the labeling of these peptides by an indirect method namely prosthetic strategy. The radiosynthesis of one radiotracer was fully automated. The in vitro biological evaluation on two types of integrins and in vivo by PET imaging showed the interest of these radiotracers in the field of oncology. The second part is closely linked to these first results. To go further in terms of diagnostic tools, dual (radio)fluorinated probes for bimodal PET/NIRF imaging were developed. This required an elaborated synthetic strategy to introduce a fluorine atom and a cyanine dye, both being PET and NIRF specific imaging probes. The coupling of a biomolecule (RGD peptide) was also performed by "Click" reaction. Regiocontrolled functionalization methods enabled the introduction of these various moieties. The perspective is to evaluate the in vitro biological properties of the synthetized tools and to consider this dual probe for diagnostic and theranostic applications in PET/NIRF imaging.Les travaux développés dans cette thèse s’articulent autour de dérivés saccharidiques de type C-glycosides pour lesquels de nouvelles méthodologies synthétiques ainsi que des applications dans le domaine de l’imagerie TEP et TEP/FPIR ont été développées. Certains peptides possèdent un rôle majeur dans la thérapie et le diagnostic de diverses pathologies et le fait de les conjuguer à un dérivé saccharidique permet d’améliorer significativement leur biodistribution. La première partie de ce travail concerne la synthèse de C-glycosides fluorés (19F) et radiofluorés (18F) fonctionnalisés en position anomérique par un bras portant une fonction azide. Par réaction de cycloaddition 1,3-dipolaire, ces composés ont été couplés à des peptides dérivés de RGD, permettant ainsi le marquage de ces peptides par une méthode indirecte appelée stratégie prosthétique. La radiosynthèse d’un des radiotraceurs a été menée de manière complètement automatisée et l’évaluation biologique in vitro sur deux types d’intégrines et in vivo par imagerie TEP a pu mettre en évidence l’intérêt de ces radiotraceurs dans le domaine de l’oncologie. La seconde partie s’appuie sur ces premiers résultats concernant le développement de groupes prosthétiques saccharidiques pour aller plus loin en termes d’outils de diagnostic. L’objectif a été de mettre au point des sondes duales (radio)fluorées pour l’imagerie bimodale TEP/FPIR. Ceci a nécessité une stratégie synthétique élaborée pour introduire un atome de fluor et un fluorophore de type cyanine, tous deux étant les sondes d’imagerie spécifiques TEP et FPIR. L’accrochage d’une biomolécule (peptide RGD) a pu se faire là encore par réaction "Click". Des méthodes de fonctionnalisation régiosélectives ont permis la mise en place de ces divers éléments. Une perspective à ce travail sera d’évaluer les propriétés biologiques in vitro des outils synthétisés et de considérer cette sonde duale pour des applications diagnostique et théranostique en imagerie TEP/FPIR

Fully automated radiosynthesis of [ 18 F]fluoro- C -glyco-c(RGDfC): exploiting all the abilities of the AllInOne synthesizer

International audienc

Sugar γ-Amino Acids as Building Blocks for the Synthesis of Cyclic Neoglycopeptides.

International audienc

Synthesis and revised stereochemical assignment of C -allyl glucopyranosides and derivatives

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C-glyco“RGD” as αIIbβ3 and αvβ integrin ligands for imaging applications: synthesis, in vitro evaluation and molecular modeling

International audienceThe design of conjugates displaying simultaneously high selectivity and high affinity for different subtypes of integrins is a current challenge. The arginine-glycine-aspartic acid amino acid sequence (RGD) is one of the most efficient short peptides targeting these receptors. We report herein the development of linear and cyclic fluoro-C-glycoside"RGD" conjugates, taking advantage of the robustness and hydrophilicity of C-glycosides. As attested by in vitro evaluation, the design of these C-glyco"RGD" with a flexible three-carbon triazolyl linker allows distinct profiles towards αIIbβ3 and αvβ3 integrins. Molecular-dynamics simulations confirm the suitability of cyclic C-glyco-c(RGDfC) to target αvβ3 integrin. These C-glyco"RGD" could become promising biological tools in particular for Positron Emission Tomography imaging

C-glycosyl compounds: multifunctional scaffolds for the development of dual imaging tools

International audienceClose analogs of O-glycosides, C-glycosyl compounds display chemical and biological stabilities toward enzymatic hydrolysis and are thus used to build bioactive compounds, peptidomimetics and more complex sugars. In this work, C-glycosyl compounds are selected as multifunctional scaffolds for the development of imaging tools. More precisely, we focused here on bimodal molecular imaging, a current trend which combined two complementary modalities: PET (Positron Emission Tomography) and NIRF (Near Infra-Red Fluorescence). Two C-glycosyl scaffolds are thus functionalized in a regiocontrolled manner in order to introduce the key elements at different stages: a fluorescent cyanine derivative for NIRF, a fluorine-18 atom for PET and two c(RGDfK) peptides targeting integrins overexpressed in some malignant tumours. The copper-catalyzed alkyne-azide cycloaddition (CuAAC) was used for the introduction of the fluorophore and for the bioconjugation step with peptides. In vitro and in vivo evaluations by fluorescence imaging and the resection of the tumor demonstrated the potential of the conjugates in glioblastoma cancer diagnosis and image-guided surgery