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Conception de nouveaux agents iodés pour l'imagerie TEMP des récepteurs 5-HT4

Abstract : Alzheimer’s disease is a neurodegenerative disorder affecting almost 50 millions people in the world. Even if the biological mechanisms implied on this pathology are known, no treatments stop or reverse its progression. Serotoninergic receptor 5-HT4R is one of the incriminated target and many ligands have been synthesized in order to develop an efficient treatment but a functionnal study of the brain is impossible. That’s why, development of efficient radiotracers is essential for the in vivo evaluation of new drugs targeting 5-HT4R and also for investigation of the receptor involvement in a variety of neurodegenerative and neuropsychiatric disorders. Starting from previsous studies made in the laboratory, a new generation of ligands, focused on diazaphenanthridine scaffold and with reduced lipophilicity, have been designed. Various hydrophilic functions have been introduced and 25 new ligands have been synthesized and biological assays have been realised. Five of this compounds have been radiolabeled and the in vitro imaging experiments on human slice brain showed the ability of the new « hit » compound to move the radioligand of reference and to label the 5-HT4R.Due to the difficulties encountered to the synthesis of tin precursors for the radiolabeling, a new strategy of radioiodation has been developed based on palladium mediated C-H activation. Using first N-tosylbenzamide as directing group for the proof of concept, the scope of this methodology have been enhanced to about fifteen directing groups. Finally, the C-H radioiodation have been applied to more complex biological molecules.
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Submitted on : Tuesday, February 12, 2019 - 10:38:07 AM
Last modification on : Thursday, November 28, 2019 - 3:06:22 AM
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  • HAL Id : tel-02015357, version 1


Victor Babin. Conception de nouveaux agents iodés pour l'imagerie TEMP des récepteurs 5-HT4. Chimie organique. Normandie Université, 2018. Français. ⟨NNT : 2018NORMC244⟩. ⟨tel-02015357⟩



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