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Thèse + Premiere Page N° d'ordre : 3900 THÈSE présentée à L'UNIVERSITÉ BORDEAUX I ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES par Damien JAMES POUR OBTENIR LE GRADE DE DOCTEUR SPÉCIALITÉ : CHIMIE ORGANIQUE ********************* DEVELOPPEMENT D’OUTILS ORGANOMETALLIQUES EN VUE DU TRANSFERT DE METHYLE, APPLICATION A LA SYNTHESE DE RADIOTRACEURS POUR LA TEP ********************* Soutenue le : 30 novembre 2009 Après avis de : M. F. DENAT Professeur, Université de Bourgogne Rapporteur Mme. I. GILLAIZEAU Maître de Conférences, Université d’Orléans Rapporteur Devant la commission d'examen formée de : Mme. M. ALLARD Professeur, Université de Bordeaux 2 Examinateur M. F. DENAT Professeur, Université de Bourgogne Rapporteur Mme. I. GILLAIZEAU Maître de Conférences, Université d’Orléans Rapporteur M. J.M. ESCUDIER. Chargé de Recherche CNRS, Université de Toulouse 3 Examinateur M. B. BENNETAU Directeur de Recherche CNRS, Université de Bordeaux 1 Examinateur Mme. M. SZLOSEK-PINAUD Maître de conférences, Université de Bordeaux 1 Co-directrice de thèse M. E. FOUQUET Professeur, Université de Bordeaux 1 Directeur de thèse - 2009 - REMERCIEMENTS Tout d’abord, je souhaite remercier les personnes qui ont composé le jury lors de ma soutenance : Pr. Michèle Allard, Pr. Bernard Benetau, Dr. Jean-Marc Escudier et plus particulièrement Dr. Isabelle Gillaizeau et Pr. Franck Denat qui ont bien voulu rapporter mon manuscrit. Je les remercie pour les remarques constructives qui ont permis d’améliorer la qualité de mon manuscrit de thèse. Je remercie également mes directeurs de thèse, le Pr. Eric Fouquet ainsi que le Dr. Magali Slozek-Pinaud pour leur disponibilité et leur confiance tout au long de ces trois années pour mener un projet si intéressant. Magali, nous avons eu des hauts et des bas mais avec du recul je pense que nous avons fait du bon travail ensemble. Je ne saurais continuer ces remerciements sans remercier Jean-Marc Escudier. Je suis vraiment très heureux d’avoir pu collaborer avec toi et je peux dire que sans toi, le projet n’aurait pu se développer de cette manière. Durant mes différents séjours dans ton laboratoire, tu m’as fait partager ton expérience des nucléosides et oligonucléotides qui m’a permis de mieux appréhender les différentes synthèses de thymidines modifiées. J’ai vraiment apprécié tes qualités humaines (surtout ton sens de l’humour), ta disponibilité et ton immense culture générale. Je remercie l’ensemble du service d’analyses du CESAMO et plus particulièrement Jean-Claude Lartigues et Noël Pinaud pour leur disponibilité et leur aide en RMN, Christiane Vitry et Claire Mouche pour la masse. Christiane, merci de t’avoir donné autant de mal pour analyser mes oligonucléotides. Je tiens également à remercier deux personnes : Fabrice et Titi pour leur sympathie et surtout leur sens de l’humour un peu « gras » mais toujours le bienvenu. Mes remerciements vont également aux membres permanents du groupe Synthèse, Yannick Landais, François-Xavier, Fred et Valérie. Valérie, ce fut un réel plaisir d’évaluer ton sens de l’humour en te taquinant pendant ces trois années. Merci également à Jürgen, le râleur invétéré du grand labo et fan de Patrick Sébastien pour sa chanson « le petit bonhomme en mousse ». Je me souviendrai longtemps de notre petite partie de rugby à la campagne. Mis à part ton côté bout en train, toujours prêt à dire ou à faire une blague, je te remercie pour ton aide et ta collaboration. Je ne pourrais oublier Anil, ta générosité, ta gentillesse ainsi que ton savoir m’ont marqué à vie. Je remercie également les techniciens, anciens et nouveaux, du groupe Synthèse : Fifine, Mumu, Marie-Hélène et le nouveau venu Dimitri. Merci à tous les thésards et post-doc du groupe Synthèse pour leur bonne humeur et les bons moments partagés ensemble. Tout d’abord les anciens : Isabelle « Zaza », toujours à l’affût du moindre potin mais aussi toujours là pour me faire rater une distillation de « Stanny », Edouard, le chimiste le plus talentueux que j’ai rencontré et véritable SciFinder ambulant, Géraldine dit Gégé, vive St Lambert du Lattay et la douceur angevine. Puis les actuels : les « radicalistes », Lolo, tu es un personnage à part entière ne change rien, merci, Guy, Emeline ; le « grand labo », Dawood, courage c’est bientôt fini, Sylvestre, ta gentillesse et ton sens de l’humour m’ont vraiment touché, Redouane Beniazou, toujours à marchander, ce qui est normal pour un marocain, j’espère que l’on ne se perdra pas de vue et merci pour ton thé à la menthe, Anthony et Thomas, ce fut bref mais j’ai été ravi de passer quelques mois avec vous, Thomas je te laisse le sujet avec confiance, je sais que tu en feras quelque chose de bien ; la team Fouquet, Eric le Barbu, quelques kilos de brutalité dans un monde de douceur, merci pour ton aide et tes conseils Professeur Tournesol, Sandy, Mlle Ouech-Ouech, merci pour tes petites histoires dans lesquelles tu es dans des situations impossibles et enfin Luma, la douceur incarnée avec tout de même une sacrée pointe d’humour. Je voudrais également remercier « en vrac » les thésards des autres groupes pour leur sympathie à chaque fois que l’on s’est croisé dans les couloirs ou en RMN : Elodie, Claire, Abdou et Daniel. Je tiens à remercier Séverine et Nico ainsi qu’Emilie et Olivier avec qui j’ai eu la chance de tisser des liens d’amitié au cours de soirées bien arrosées et de discussions enflammées. Au cours de cette thèse, une personne spéciale a croisé mon chemin, Mademoiselle Julie DUNET. Je te dois tout ce qui m’est arrivé de merveilleux pendant ces trois années. Tu as été là dans les moments heureux comme dans les moments de découragements où tu as su me redonner confiance. Je te remercie du plus profond du cœur. Je remercie également la famille Dunet d’avoir veiller à ma santé mentale grâce à mes nombreux séjours dans le pays du Lot et Garonne. Enfin je souhaite remercier ma famille qui m’a poussé et a cru en moi tout au long de mon cursus. Cet aboutissement a également été rendu possible grâce à vous. SOMMAIRE ABBREVIATIONS ............................................................................................. 1 INTRODUCTION .............................................................................................. 3 PARTIE A : LA TOMOGRAPHIE PAR EMISSION DE POSITONS ........................... 7 1 Généralités ............................................................................................... 9 1.1 Principe ....................................................................................................................... 9 1.2 Les émetteurs β+ ...................................................................................................... 10 2 TEP et diagnostic ..................................................................................... 12 2.1 Mise en place d’un examen TEP ............................................................................... 12 2.2 Conditions requises pour l’exploitation optimale d’un radiotraceur en TEP pour le diagnostic .............................................................................................................................. 14 2.3 Les radiopharmaceutiques utilisés en routine dans les services de médecine nucléaire pour le diagnostic ................................................................................................. 15 2.3.1 Le 2-deoxy-2-[18 F]-Fluoro-D-glucose ([ 18 F]-FDG) ................................................ 15 2.3.2 La 2’-déoxy-2’-[18 F]-fluorothymidine ([ 18 F]-FLT) ................................................. 16 2.3.3 La 6-[18 F]-Fluoro-L-DOPA ([ 18 F]-FDOPA) .............................................................. 18 2.3.4 Conclusion ........................................................................................................... 21 PARTIE B : CARBONE 11 ET BIOMOLECULES ................................................... 23 1 Méthodes d’introduction du carbone 11 dans des molécules organiques 25 1.1 Les réactions de cyanation ....................................................................................... 26 1.1.1 [11 C]-Cyanation nucléophile ................................................................................ 26 1.1.2 [11 C]-Cyanation pallado-assistée ......................................................................... 27 1.2 Les réactions de [ 11 C]-méthylation ........................................................................... 28 1.2.1 Les [ 11 C]-Méthylations électrophiles .................................................................. 28 11 11 1.2.1.1 CH 3I et CH 3OTf ...................................................................................... 28 1.2.1.1.1 N-alkylation ........................................................................................... 30 1.2.1.1.2 O-Alkylation .......................................................................................... 44 1.2.1.1.3 S-alkylation ............................................................................................ 50 1.2.2 Les [ 11 C]-méthylations nucléophiles ................................................................... 51 1.2.2.1 Le couplage de Suzuki ................................................................................ 52 1.2.2.2 Le couplage avec les organoétains ............................................................ 53 1.2.2.2.1 Le couplage de Stille « classique » ........................................................ 53 1.2.2.2.2 Le Couplage de Stille selon Vedejs.......................................................
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