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Docteur» at the University François Rabela UNIVERSITÉ FRANÇOIS – RABELAIS DE TOURS École Doctorale « Santé - Sciences Biologiques - Chimie du Vivant » and UNIVERSITY OF LJUBLJANA, FACULTY OF PHARMACY «Department of Pharmaceutical Chemistry» A cotutelle thesis submitted in fulfillment of the requirements for the degree of «Docteur» at the University François Rabelais of Tours (France) and Doctor of Pharmacy at the University of Ljubljana (Slovenia) In Pharmaceutical Chemistry Publicly defended on the 1st of March 2013 by Mitja KOVAČ in Ljubljana FLUORATION DE DERIVES DU BENZOVESAMICOL POUR L'OBTENTION DE RADIOLIGANDS POTENTIELS DU TRANSPORTEUR VESICULAIRE DE L'ACETYLCHOLINE Under the co-direction of: Associate Professor Sylvie Mavel (MCU, Tours) and Associate Professor Marko Anderluh (Ljubljana) ----------------- JURY for Oral Defense: Ms MAVEL Sylvie – Associate Professor, University François-Rabelais, Tours, France Mr ANDERLUH Marko – Associate Professor, University of Ljubljana, Slovenia Mr DOLLÉ Frédéric – Service Hospitalier Frédéric Joliot, Institut d'Imagerie BioMédicale - CEA, Orsay, France (Reviewer) Mr EMOND Patrick – Professor, University François-Rabelais, Tours, France Ms GMEINER STOPAR Tanja – Assistant Professor, University of Ljubljana, Slovenia (Reviewer) Mr GOBEC Stanislav – Professor, University of Ljubljana, Slovenia (Chairman) This cotutelle PhD was carried out with the collaboration between the University of Tours (Laboratoire de Biophysique Médicale et Pharmaceutique, Unité INSERM U930 - FRANCE) and the University of Ljubljana (Faculty of Pharmacy, Department of Pharmacutical Chemistry - SLOVENIA). The work was supported by a grant from the Slovene Human Resources Development and Scholarship Fund, by a grant from the University of Ljubljana (Inovativna shema za sofinanciranje doktorskega študija za spodbujanje sodelovanja z gospodarstvom in reševanja aktualnih družbenih izzivov - generacija 2010 Univerza v Ljubljani), and by a Slovenia- French bilateral collaboration project (project n° BI-FR/12-13-PROTEUS-007). AKNOWLEDGEMENTS I would like to extend my most sincere gratitude to my supervisors Dr. Sylvie Mavel and Dr. Marko Anderluh for their continued direction, training, and encouragement. Their guidance has been inspirational and instructive throughout my journey along this path, and I will continue to draw on the wisdom they have imparted as I move forward. Special thanks go to Dr. Johnny Vercouille and his team for their training and supervision in the radiopharmaceutical laboratory CERRP (Centre d'Etude et de Recherche sur les Radiopharmaceutiques). I would like to extend my thanks to Dr. Patrick Emond and Dr. Frédérick Dollé for their valuable advices and reading the thesis. Thanks are given to Dr. Tanja Gmeiner Stopar and Dr. Stanislav Gobec for reading the thesis. Thanks also to Dr. Sylvie Chalon, and Dr. Mohamed Abarbri. Finally, I would like to thank my mother and all the family who have always been loving, supportive, and a guiding light throughout my life. RÉSUMÉ La maladie d’Alzheimer (MA) est une maladie neurodégénérative progressive et l’une des principales démences. Les plaques amyloïdes extracellulaires, les dégénérescences neurofibrillaires intracellulaires, et la dégénérescence synaptique sont des marqueurs neurophysiopathologiques de la MA. Il a été montré que la diminution en transporteur vésiculaire de l’acétylcholine (VAChT) est un paramètre neurologique précoce, précédant les signes cliniques de la maladie, et fortement corrélée avec la démence associée à la maladie. L’utilisation de radiotraceur sélectif et spécifique pouvant être utilisé en tomographie par émission de positrons (TEP) ou par tomographie d'émission monophotonique (TEMP) offre la possibilité d’identifier de subtils changements neurologiques aux stades précoces de la maladie, et ainsi aider au diagnostic différentiel de la MA avec d’autres démences corticales ou sous-corticales. Le (2R,3R)-5-IBVM, dérivé du benzovésamicol, est un ligand de haute affinité et sélectivité du VAChT, et est le seul radiotraceur utilisé en imagerie humaine par TEMP pour le diagnostic de la MA. Or, la TEP présente des avantages par rapport à la TEMP telle qu'une meilleure détection, meilleure résolution de l'image et possibilité de quantification. Sachant que l’analogue fluoré du 5-IBVM devrait présenter une affinité et sélectivité pour le VAChT du même ordre, nous avons donc synthétisé les énantiomères du 5-FBVM et nous avons développé des méthodes d'introduction régiosélective d'ion fluorure en position 5 du benzovésamicol, qui est une position non activée. Pour cela, nous avons choisi comme précurseur, la fonction triazène (Ar-N=N-NR2) en tant que «groupe partant » pour l'obtention d'aryles fluorés. En partant d'études théoriques de fluoro-dediazénation, nous avons synthétisé les énantiomères du 5-FBVM, dans un rendement de 25%, en utilisant le t-butyle de nitrite comme agent de diazotation et l'éthérate de trifluorure de bore en tant qu'agent de fluoration. Des études de modélisation moléculaire (QSAR), faites sur 32 composés de type vésamicol, ont été réalisées en tenant compte de la stéréospécificité du site de fixation du VAChT. L'évaluation in vitro a montré la très bonne affinité pour le VAChT des 2 énantiomères, du même ordre que le 5-IBVM, comme le prédisaient les études QSAR. Le (2S,3S)-5-FBVM présente une meilleure sélectivité vis-à-vis des récepteurs 1 et pourrait être un traceur potentiel pour l'imagerie in vivo des neurones cholinergiques. Actuellement un des facteurs limitants du développement de la technologie TEP est l'introduction d'un ion fluorure sur un système aromatique non activé. Nous nous sommes donc focalisés dans un deuxième temps sur la fluoration d'aryles non activés possédant un triazène. Nous avons recherché un acide n'interférant pas lors d'un potentiel radiomarquage. Nous avons étudié différentes conditions expérimentales (acide, solvant, et agent de fluoration) pour la fluoration du 3,3-diéthyl-1-naphtyltriazène choisi comme modèle d'étude. À partir des résultats obtenus en chimie froide, l'acide polyphosphorique (PPA) dans un solvant chloré est le plus prometteur et de plus innovant dans ce type de réaction. De plus, en se basant sur la chimie de coordination des triazènes avec le trifluorure de bore, nous proposons que la fluoro-detriazénation pourrait être obtenue, avec uniquement de l'éthérate de trifluorure de bore, sans addition d'acide protique, à partir d'une température suffisante. Nous avons confirmé cette hypothèse sur le naphtyltriazène ainsi que sur des phényltriazènes para- substitués en comparant chauffage traditionnel et chauffage par micro-ondes. Nous avons validé notre méthode en fluorant un système plus complexe, à savoir le 5-TBV qui a conduit au 5-FBVM dans un rendement de 72%, sous micro-onde, dans le tétrachlorure de carbone. Des tests préliminaires de radiomarquage du 5-TBV, en utilisant le PPA dans le chloroforme sous micro-onde ont donné des résultats prometteurs. Mots Clés: fluorination, triazène, benzovésamicol, VAChT, TEP ABSTRACT Alzheimer's disease (AD), a progressive neurodegenerative and terminal disorder, is the most common cause of dementia in the elderly. Extracellular amyloid plaques, intracellular neurofibrillary tangles, and degeneration of the synaptic terminals are the most characteristic neuropathophysiological hallmarks of AD. It has been shown that deficiencies in vesicular acetylcholine transporter (VAChT) are among the earliest neuronal changes, preceding clinical symptoms of the disease, and showing a strong correlation with the severity of dementia. Thus, the use of selective and specific radiotracer functional imaging modalities, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), offers non-invasive in vivo identification of subtle neurological changes in the early stages of AD and, therefore, offers value in the differential diagnosis of AD from other cortical and subcortical dementias. Benzovesamicol-related ligand (2R,3R)-5-IBVM has a high affinity and enough selectivity for the VAChT, and is the only SPECT VAChT radiotracer used in human to obtain an early diagnosis of AD. Regarding physico-chemical properties of fluorine-19 and fluorine-18, and PET advantages over SPECT in terms of higher detection efficiency, better spatial resolution and possibility for quantification, it is expected that the fluoro analog of 5-IBVM should be of the same order of affinity and selectivity for the VAChT. Thus, we have prepared pure enantiomers of 5-FBVM and developed method for regioselective introduction of fluorine into the 5-position of non-activated benzovesamicol scaffold. We have chosen as a precursor system triazene function (Ar-N=N-NR2) as a leaving group for arylfluorination. Firstly, we built theoretical model by studying characteristics of fluoro-de-diazoniation process. Accordingly, we have synthesized pure enantiomers of 5-FBVM from amino analog 5-ABV in around 25% yield by using t-butyl nitrite as diazonating agent and boron trifluoride etherate as fluorinating agent. Furthermore, to demonstrate the suitability of a triazene as a leaving group, the fluoro-de-triazenation of the corresponding triazene precursor (5-TBV), using triflic acid to trigger triazene moiety decomposition and boron trifluoride etherate, afforded 5-FBVM in reasonable yield (25%). QSAR studies based on 32 vesamicol derivatives taking into account the stereoselectivity of the VAChT binding site were performed. Both enantiomers exhibited high in vitro VAChT binding affinities
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