RESUME: Le travail de recherche rapporté dans cette thèse concerne lamélioration de traceurs marqués au fluor-18 utilisés en routine clinique : la 2-[18F]fluoro-L-tyrosine et le 2-désoxy-2-[18F]fluoro-D-glucose. Les résultats relatifs à lacide aminé, de valeur confirmative pour les connaissances publiées antérieurement dans la littérature, consistent en une validation chez le rat qui entérine le potentiel de ce traceur pour létude de la vitesse de synthèse des protéines cérébrales in vivo. Les perspectives futures pour ce traceur sont dès lors lextension de son utilité dans le domaine de loncologie et son utilisation pour létude de phénomènes physiologiques neurologiques. Durant ce travail, des techniques décrites dans la littérature, mais non pratiquées au CRC ont fait lobjet dune implémentation et sont maintenant accessibles (modèle du rat vigile, méthodes de synthèse de polymères à empreinte moléculaire). La partie principale du travail concerne la récupération du [18F]fluorure et son utilisation pour le marquage nucléophile sans étape dévaporation. La synthèse du 2-désoxy-2-[18F]fluoro-D-glucose a servi de réaction témoin pour tester lapplicabilité des méthodes développées dans ce cadre. Deux stratégies différentes, lune utilisant des supports ioniques et des solvants protiques, lautre utilisant des supports non ioniques et des solvants non protiques, ont permis datteindre les buts fixés avec des rendements dincorporation du [18F]fluorure de même ordre de grandeur que ceux obtenus en radiochimie usuelle du fluor-18. La méthode utilisant les supports non ioniques a par ailleurs démontré sa grande généralité vis-à-vis de précurseurs divers, aliphatiques et aromatiques, dans des conditions de marquage diverses, notamment à température modérée. Les perspectives de ces méthodes nouvelles pour la fabrication des traceurs TEP tirent parti de la possibilité de les implanter dans un automate miniaturisé (milli- ou micro-réacteur), à visée synthétique ou analytique. Lefficacité et la simplicité des méthodes de récupération sans évaporation mises au point dans ce travail les destinent à être utilisées aussi bien en développement des traceurs quen synthèse de routine. Elles sont applicables aussi bien à léchelle des automates courants quà celle des futures applications microfluidiques. Par ailleurs, nous sommes persuadés de lintérêt des polymères à empreinte moléculaire dans le créneau des méthodes analytiques. Egalement applicables à des systèmes miniaturisés, ils devraient aider à la réalisation danalyses automatisées des produits finis et à une libération accélérée. Le gain de temps et les moindres pertes de principe actif conduiront alors à une meilleure disponibilité des traceurs TEP et à leur participation accrue aux objectifs de la médecine personnalisée. Nous pensons dès lors avoir ouvert quelques pistes de recherche prometteuses pour la mise en application de ses nouvelles technologies au domaine de la tomographie à émission de positon. / SUMMARY: The results reported in this work concern the improvement of 18-fluorine labelled radiopharmaceuticals used in routine clinical applications: 2-[18F]fluoro-L-tyrosine and 2-deoxy-2-[18F]fluoro-D-glucose. The study of the metabolism of non carrier added 2-[18F]fluoro-L-tyrosine in rats confirms that this tracer is rapidly and extensively incorporated into cerebral proteins and is therefore well suited to the assessment of Protein Synthesis Rate (PSR) in vivo by PET. A correction for the appearance of metabolites is advised for quantitative interpretation of the data. An improvement in the radiosynthesis is necessary to make 2-[18F]fluoro-L-tyrosine widely available for its application in oncology and to envisage the extended use of this tracer for the study of the protein synthesis in other physiological or pathological processes. The second chapter deals with use of molecular imprints in the PET radiochemistry. The molecularly imprinted polymers were synthetized, characterized and tested for the production of specific PET tracers and the plasma analysis of the parent metabolites. The third part of the work consisted in a development of new methods for the [18F]fluoride recovery in order to permit the labelling of different precursors through nucleophilic substitution without the evaporation step classically performed in 18-fluorine radiochemistry. The synthesis of 2-deoxy-2-[18F]fluoro-D-glucose has been used as a tool for the evaluation of the developed methods. Two strategies were considered to concentrate and recover the [18F]fluoride. The first one used ionic solid supports and protic solvents. The second one relied on the use of non ionic solid supports and non protic solvents. Both strategies led us to reach [18F]fluoride incorporation yields as high as in classical radiosyntheses with evaporation. Ionic liquids and tertiary alcohols were also evaluated in order to improve the tolerance of the [18F]fluoride nucleophilic substitution to water. The molecularly imprinted polymers and the new methods for the recovery of [18F]fluoride will now be tested for the implementation of PET tracers radiosynthesis and quality control into microchip devices.

The present thesis deals with different aspects of the chemistry and photo-biology of various ferrocene-conjugated metal complexes, their interaction with double helical DNA, DNA photocleavage and photo-enhanced cytotoxicity in visible light. Phenyl analogues of the active complexes have been synthesized and used for comparison in biological assays. Chapter I provides an introduction to the potential of metal complexes as photochemotherapeutic agents with special reference to organometallic compounds. A brief overview of Photodynamic Therapy (PDT) as a new modality of cancer treatment has been given. Various modes of non-covalent interactions of small molecules with duplex DNA are mentioned. Recent reports on the metal-based photocytotoxic and DNA cleaving agents including photoactivatable organometallic compounds are discussed. The objective of the present investigation is also presented in this chapter. Chapter II presents the synthesis, characterization, structure, DNA binding, DNA photocleavage, photocytotoxicity, mechanism of cell death and cellular localization of ferrocene-conjugated L-methionine reduced Schiff base Cu(II) complexes of phenanthroline bases. To explore the role of the ferrocenyl moiety the phenyl analogues of the ferrocenyl complexes are synthesized and used as controls for comparison purpose. Chapter III deals with the photo-induced DNA cleavage and photo-enhanced cytotoxicity of ferrocene-appended L-tryptophan Cu(II) complexes of heterocyclic bases. The synthesis, characterization, structural comparisons, DNA binding, DNA photocleavage, photocytotoxic activity and cell death mechanism in visible light are discussed in detail. Chapter IV describes the synthesis, characterization and structure of ferrocenylmethyl-L-tyrosine Cu(II) complexes of phenanthroline bases. The complexes are evaluated for DNA binding, DNA photocleavage and photocytotoxic activity in visible light. The cellular localization of the complexes and the mechanism of cell death induced by the complexes are also discussed. Chapter V presents the photocytotoxic effect of ferrocene-conjugated L-amino acid reduced Schiff base Cu(II) complexes of anthracenyl/pyrenyl imidazophenanthroline. The ability of the complexes to bind to double helical DNA and cleave it under photo-illumination conditions is described. Evaluation of the complexes as photochemotherapeutic agents and comparison with currently clinically available drug Photofrin are presented. The mechanism of cancer cell death and cellular localization of the complexes are studied by fluorescence microscopy. Chapter VI describes the synthesis, characterization and photochemotherapeutic efficacy of Cu(II) complexes having ferrocene-appended L-amino acid reduced Schiff base ligands and the naturally occurring polyphenol curcumin. Stabilization of curcumin by complexation to metal for improved photodynamic effect in cancer cells is described with comparison to the parent dye and clinically used drug Photofrin. The mechanism of cell death induced by the copper complexes and their localization in cancer cells are also presented. Finally, the summary of the dissertation and conclusions drawn from the present investigations are presented. The references in the text have been indicated as superscript numbers and compiled at the end of each chapter. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the structurally characterized complexes are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.