In this study, procedures were developed to produce ultra-clean, ultra-thin target foils and to remove x-ray interference from electron bremsstrahlung and low energy K-shell x-rays from contaminant elements.

Les composés organofluorés constituent une grande partie de produits pharmaceutiques, ainsi que pesticides, herbicides et matériaux fabriqués actuellement. Développement des méthodes sélectives de la synthèse des composés organofluorés est donc d'intérêt principal pour la chimie. Dans cette thèse, nous décrivons la nouvelle méthode de synthèse des cyclopropanes monofluorés basé sur la cyclisation initiée par la réaction de Michaël (MIRC). Notre méthode permet d'obtenir les cyclopropanes monofluorés polysubstitués à partir de dibromofluorocetate d'éthyle et différents accpteurs de Michaël. Nous avons aussi réalisé la cyclopropanation asymétrique en utilisant le nouveau réactif fluoré chiral à base d'oxazolidinone. Dans la partie finale de cette thèse nous décrivons la synthèse de l'analogue fluoré de L-FAP4, l'agoniste puissant des récepteurs métabotropiques de glutamate groupe II(mGluR II), afin d'augmenter l'activité biologique et la biodisponibilité de ce composé. / Organofluorine compounds constitute a large part of all the drugs, crop protection agents and advanced materials produced nowadays. Therefore, there is a great interest in developing the new methods of synthesis of organofluorine compounds. In this thesis we report a novel method of synthesis of monofluorinated cyclopropanes based on the Michael-initiating ring closure (MIRC) reaction. Our method allows obtaining polysubstituted monofluorinated cyclopropanes from ethyl dibromofluoroacetate and various Michael acceptors. We have also implemented the asymetric version of cyclopropanation using a novel oxazolodinone-derived chiral fluorinated reagent. In the final part of this thesis we report the synthesis of a fluorinated analog of L-FAP4, a potent agonist of group II metabotropic glutamate receptors (mGluR II). Incorporation of a fluorine atom is expected to increase the biological activity and bioavailabiblity of this compound.

La Tomographie par Emission de Positons (TEP) est une modalité d’imagerie médicale en pleine expansion depuis une quinzaine d’années. En oncologie, la TEP au 18F-fluorodésoxyglucose (FDG) est devenue un outil essentiel pour la prise en charge des patients souffrant de cancer. Cependant il ne permet pas la détection et le suivi de tous les cancers, de nombreux radiotraceurs sont donc développés, plus ciblés et plus spécifiques que les analogues des substrats métaboliques. Durant ce travail de doctorat, la première étude TEP a été réalisée avec du 68Ga-DOTATOC dans un modèle préclinique de neuroblastome (NB) humain. Cette tumeur, qui présente des analogies avec les tumeurs neuroendocrines, exprime fréquemment des récepteurs de type 2 de la somatostatine (SSTR2). Nous avons comparé, le FDG au 68Ga-DOTATOC dans 3 modèles murins de différents NB humains, exprimant les SSTR2 avec une densité différente. La deuxième étude a comparé et évalué le FDG et un 68Ga-RGD, ligand des intégrines, sur des modèles murins de glioblastome (GB) humain surexpriment l’intégrine αvβ3. L’évaluation s’est faite dans le suivi de 4 groupes d’animaux traités ou non avec un anti-angiogénique et/ou une chimiothérapie. La troisième étude a comparé et évalué le 68Ga-RGD et le 18F-RGD-K5 dans un modèle murin, associant GB humain et carcinome pulmonaire humain, lors du suivi d’un traitement anti-angiogénique. Le 68Ga-DOTATOC et le FDG ont tous deux permis de visualiser les 3 différents modèles de NB. La fixation du FDG s’est avérée corrélée à celle du 68Ga-DOTATOC et, ex vivo, à l’expression des SSTR2 et du Ki-67. Le 68Ga-RGD, contrairement au FDG, a permis de discriminer les groupes répondeurs après 6 jours de traitement. Bien que les résultats soient concordants entre le 68Ga-RGD et le 18F-RGD-K5, celui-ci a permis une meilleure visualisation et un meilleur suivi sous traitement des GB. / Positron Emission Tomography (PET), a modality of functional medical imaging, has been developing for about 15 years. In oncology, 18F-fluorodeoxyglucose (FDG) PET has become a main tool for cancer diagnosis. However, FDG cannot detect and monitor all types of cancer. Thus research is continuing, exploring new applications for other documented tracers and developing more specific and targeted tracers than analogues of metabolic substrates. The first study of this doctorate was done with 68Ga-DOTATOC PET in preclinical model of neuroblastoma (NB), which share some biologic properties with neuroendocrine tumours, frequently expressing somatostatin receptors subtype 2 (SSTR2). Our aim was to compare FDG and 68Ga-DOTATOC PET in 3 different mouse models of human NB that express SSTR2 at different levels. The second study compared FDG and 68Ga-RGD, a ligand of integrins, in a mouse model of human glioblastoma (GB) that overexpresses αvβ3 integrin. Both tracers have been evaluated in monitoring 4 groups of animals untreated or treated with an anti-angiogenic agent and/or chemotherapy. The third study compared the 18F-RGD-K5 and 68Ga-RGD in a mouse model bearing human GB and pulmonary carcinoma, which has a low expression of αvβ3 integrin. The potential of those tracers for monitoring an anti-angiogenic treatment was subsequently studied. Both 68Ga-DOTATOC and FDG allowed visualizing the different models of NB. There was a correlation between tumour uptake of FDG and of 68Ga-DOTATOC and, ex vivo, with SSTR2 and Ki-67. 68Ga-RGD, unlike FDG, discriminated responders after 6 days of treatment. Results with 18F-RGD-K5 and 68Ga-RGD were concordant, but 18F-RGD-K5 was more efficient than 68Ga-RGD for visualization and treatment monitoring GB.

Les transporteurs d’acides aminés sont très souvent surexprimés au niveau des cellules tumorales et représentent une cible moléculaire privilégiée pour l’imagerie TEP (Tomographie par Emission de Positons) des cancers. Dans le but d’accéder à des radiotraceurs spécifiques de ces transporteurs, les travaux de thèse ont consisté à mettre au point - dans une première partie, une nouvelle méthode de marquage au fluor-18 d’acides aminés fluorés basée sur la déoxyradiofluoration de précurseurs hydroxyaminoesters, via un intermédiaire aziridinium, - et dans une seconde partie, le marquage au carbone-11 de la sulfasalazine, un inhibiteur sélectif des transporteurs Xc-. La réaction de déoxyradiofluoration des hydroxyaminoesters de structure sérine, méthylsérine ou hydroxyphénylalanine, facilement accessibles et stables, a permis d’obtenir à température ambiante les [18F]fluoroaminoesters correspondants avec efficacité et reproductibilité. La régiosélectivité de la réaction a été trouvée dépendante des substituants du cycle aziridinium et de la fonction amine. La radiosynthèse de la [11C]-sulfasalazine a été réalisée avec succès par couplage d’un sel de diazonium approprié avec l’acide [11C]salicylique obtenu par réaction de [11C]carboxylation d’un précurseur bismagnésien issu du iodophénol. L’automatisation de cette radiosynthèse est en cours d’optimisation afin de produire la [11C]sulfasalazine en quantité suffisante pour réaliser les études in vivo. / Aminoacid transporters are often overexpressed in tumour cells and they represent molecular targets of choice for cancer imaging by Positron Emission Tomography (PET). In order to access to specific radiotracers of these transporters, the thesis project aimed at developing – in a first part, a new 18F-radiolabeling method of fluoroaminoacids based on deoxyradiofluorination of hydroxyaminoester precursors via an aziridinium intermediate – and in a second part, the radiolabelling with carbon-11 of sulfasalazine, an selective inhibiter of Xc- transporters. Deoxyradiofluorination reaction of stable and easily accessible hydroxyaminoesters possessing a serine, methylserine or hydroxyphenylalanine moiety, led to [18F]fluoroaminoesters at room temperature in high and reproducible radiochemical yields. Regioselectivity was function of the substituents on aziridinium ring and amine function. The radiosynthesis of [11C]sulfasalazine has been successfully achieved by coupling reaction of an appropriate diazonium salt with [11C]salicylic acid, obtained by [11C]carboxylation of a bismagnesium precursor from iodophenol. The automation of the radiosynthesis is in progress to produce [11C]sulfasalazine for in vivo studies.

Le motif fluoropyridine est très fréquent dans les molécules d’intérêt thérapeutique et diagnostique pour l’imagerie par tomographie par émission de positons. Bien que les 3/5-[18F]fluoropyridines soient a priori plus stables in vivo que leurs analogues radiofluorés en position 2, 4 ou 6, leur radiosynthèse par voie nucléophile à partir du [18F]fluorure reste difficile et peu documentée. Dans ce contexte, les travaux ont porté sur l’étude du radiomarquage au fluor-18 de 3/5-fluoropyridines par radiofluoration de précurseurs iodoniums. Dans une première partie, la préparation d’une vingtaine de sels de iodonium possédant une structure pyridine ou pyridinium différemment substituée, a été mise au point. Une seconde partie a été dédiée à l’optimisation de la réaction de radiofluoration des sels de iodoniums. Cette étude a conduit à la mise en évidence du rôle important du TEMPO et de la base K2CO3 dans cette réaction. Enfin, la dernière partie a été consacrée à la radiosynthèse de 3/5-[18F]fluoropyridines portant des groupements carboxamides ou aminés par une approche multi-étape. L’ensemble des résultats ont montré que la radiofluoration de triflates de iodonium en présence de TEMPO était une méthode efficace, générale et robuste de radiosynthèse de 3/5-[18F]fluoropyridines. Cette méthode a été transposée avec succès sur deux automates de synthèse. / The fluoropyridinyl moieties have become of increasing importance in the development of drug candidates as well as of radiotracers for positron emission tomography (PET) imaging after radiolabeling with fluorine-18. Although 3/5-[18F]fluoropyridines are more stable in vivo than their 2,4 or 6 radiofluorinated analogues, their radiosynthesis by nucleophilic pathway from cyclotron produced [18F]fluoride remains difficult and poorly documented. In this context, the work focused on the development of a robust and general route to 3/5-[18F]fluoropyridines based on the radiofluorination of iodonium precursors. In a first part, the preparation of about twenty iodonium salts containing a pyridine or pyridinium scaffold, has been developed. A second part was devoted to the optimization of the radiofluorination reaction of iodonium salts. This study highlighted the important role of TEMPO and K2CO3 in this reaction. Finally, the last part was dedicated to the radiosynthesis of 3/5-[18F]fluoropyridines bearing carboxamide or amine groups according to a multistep approach. All the results showed that radiofluorination of iodonium triflates in the presence of TEMPO was an efficient, general and robust method for the radiosynthesis of 3/5-[18F]fluoropyridines. This method was also successfully transposed on two automated systems.

<p><strong>Apstrakt je obrađen tehnologijama za optičko prepoznavanje teksta (OCR).</strong></p><p>Mehanizam nastanka mulita zavisi od načina doziranja polaznih oblika reaktanata kao &scaron;to su alumina i silika. Dobijanje mulita sol-gel postupkom je u velikoj meri pobolj&scaron;ano u odnosu na klasično procesiranje zbog mogućnosti homogenog me&scaron;anja AI₂O₃ i SiO₂ komponenti i kontrole dodataka. Sol-gel metod omogućuje pripremu vrlo homogenih i reaktivnih gelova koji mogu da sinteruju na nižim temperaturama pri čemu se može postići vrlo fina mikrostruktura. U ovom radu koji se odnosio na procesiranje mulita sol-gel postupkom, hipoteza je bila da se na samom početku procesiranja aluminijumovi joni iz alkoholnog rastvora Al-soli uključuju u polimernu gel strukturu koju formira silika. Svrha ovog rada, je proučavanje uticaja procesnih promenjivih, dodatka fluornog jona i &ldquo;seedinga&rdquo; na temperaturu nastanka sol-gel mulita pri čemu se očekuje &scaron;to je moguće niža tempertura nastanka mulita (niža od 980⁰C). Polimerni sol je dobijen u prvom slučaju me&scaron;anjem TEOS-a i aluminijum nitrata nanohidrata koji je prethodno rastvoren u etil alkoholu. U drugom slučaju, u polimerni sol je dodavan fluorni jon u koncentraciji 2 do 5 % mas. u odnosu na očekivani prinos mulita i u trećem slučaju je dodavana različita količina mulitnih klica (2-4 % mas.). Eksperimantalno je potvrđeno da procesne promenljive; pH, temperatura geliranja i R odnos imaju, veliki uticaj na brzinu geliranja i na nastanak mulita. U slučaju dodavanja fluornog jona, potvrdena je hipoteza da fluorni jona na različite načine utiče na mehanizam nastanka mulita, pri čemu u prvom slučaju prisustvo fluornog jona obezbeduje mesta u oblastima razdvajanja granica faza nakon geliranja koja utiču na proces nukleacije. Ova mesta slično procesu kristalizacije stakla, omogućuju lak&scaron;u nukleaciju mulita prilikom njegove transformacije iz gela. Mesta na granici razdvanja faza postaju mesta na kojima se uspostavlja proces heterogene nukleacije &scaron;to je jedan od mogućih načina za snižavanje temperature nastanka mulita. Pored ovoga, dodavanje fluornog jona je doprinelo promeni mulitnih gel struktura, pri čemu je promena brzine hidrolize silike imala za posledicu promenu sadržaja vezane vode u toku geliranja &scaron;to se takođe značajno odražavalo na temperaturu nastanka mulita. Eksperimentalni rezultati termički obradenih gelova su pokazali, da dodavanje lluornog jona u polimerni mulitni sol stvara uslove za snižavanje temperature obrazovanja mulita sve do 890⁰C. U ovom radu je takođe pokazano da mulitne čestice, kao nukleanti pri &ldquo;seeding&quot; procesiranju, doprinose nastanku mulitnog gela koji nakon termičke obrade na 1000⁰C pokazuje veoma finu mikrostrukturu.</p> / <p><strong>Abstract was processed by technology for Optical character recognition (OCR).</strong></p><p>The mechanism of mullite formation depends upon the method of combining the alumina and silica containing reactants. Mullite can be obtained through the sol-gel process and can be greatly improved by the control of some reaction conditions particulaiiy by homogeneous mixing of Al2O3 and SiO2, and controlling of the additions. Sol-gel method allow preparation of very homogenous and reactive gels which can be sintering at low temperature and consequently submicronic microstructure can be reached. In this study of the mullite formation by sol-gel method, the hypothesis was that aluminium ions from alcoholic solulion of its salts incorporate to polymeric silica gel structure. The aim of this work was the investigation of the effect processing variables, fluorine addition and &ldquo;seeding&rdquo;on the temperature of sol-gel mullite formation and to obtain as lower temperature of mullite formation as possible (smaller than 980&deg;C). Polymeric sols, were prepared by the mixing of TEOS and aluminum nitrate nanohydrate dissolved in absolute ethyl alcohol and by adding fluorine ions in the second case from 2 wt.% to 5 wt.% and by different content of mullite seeded (2- 4 wt. %). Experimentally is determined that the processing variables as pH, gelling temperature and R ratio have high influence on the gelling rate and mullite formation. The hypothesis in the case of fluorine addition was that addition of fluorine ions could have different effects on the mechanism of mullite formation; the first it makes the sites at boundary of phase separation regions after gelling which influence at the process of the nucleation. These sites will act as a place for easy mullite nucleation, similar to process of the glass crystallization. The boundaries of the phase separation are the sites for heterogeneous nucleation which is one of the condition for lowering the temperature of mullite formation. Besides, fluorine addition could change the mullite gel structure (by changing the rate of hydrolyses of silica and it could change the content of bonded water during gelling), which should be very important for the temperature of mullite formation, too. The experimental results of heat treated gels showed that the addition of fluorine ion does decrease the temperature of mullite formation (in respect to classical sol-gel mullite processing) up to 8900C. As a nucleant in this study the mullite powder by &ldquo;seeding&rdquo; process contribute to muillite gel formation that after heat treatment up to 10000C showed very fine microstructure.</p>

Les travaux de thèse ont porté sur le développement de deux plateformes de radiomarquage polyvalentes pour faciliter l’incorporation du fluor-18, un isotope de choix pour l’imagerie TEP (Tomographie par Emission de Positons). La première plateforme comporte une structure sultone conduisant à un [18F]fluorosulfonate par ouverture du cycle avec le [18F]fluorure. Celle-ci a été valorisée par le couplage avec des ligands 2-nitroimidazoliques pour former un agent d’imagerie TEP spécifique de l’hypoxie. Une série de dérivés caractérisés par des propriétés d’hydrophilie différentes a été synthétisée afin de comparer leur efficacité en imagerie. Parmi ces dérivés, le [18F]FLUSONIM a révélé dans différents modèles précliniques tumoraux (rhabdomyosarcome, tumeurs cérébrales et mélanome) des ratios tumeur sur bruit de fond inégalés jusqu’à présent, et ce à des temps très précoces post-injection. La deuxième plateforme est de nature boratrane. Celle-ci est capable de réagir avec le [18F]fluorure en milieu physiologique pour former un [18F]monofluoroborate zwitterionique facile à séparer du précurseur boratrane. / This work focused on the development of versatile platforms for fluorine-18 labelling. The first platform contained a sultone moiety which was converted to [18F]fluorosulfonate by ring opening with [18F]fluoride. The sultone was coupled to 2-nitroimidazolyl ligands to obtain radiotracers for hypoxia PET imaging. A series of compounds were synthesized in order to compare their performance in PET imaging. Among them, [18F]FLUSONIM displayed high tumor/background ratios after a short delay post-injection on different animal models (rabdomyosarcoma, glioblastoma and melanoma). The second platform was based on a boratrane structure, that was able to captur [18F]fluoride in aqueous medium to form zwiterionic [18F]monofluoroborate.

Due to the successful commercialization of lithium-ion batteries (LIBs), there is a growing interest in developing new battery materials with beneficial electrochemical properties. However, the uneven distribution of lithium resources and the low abundance of lithium in the earth crust are the main obstacles for further development and large-scale production of LIBs. Sodium-ion batteries (SIBs), an alternative that can partly meet the energy storage challenges, are getting attentions of researchers due to the wide availability and lower cost of sodium resources. Nevertheless, the conventional liquid electrolytes of either LIBs or SIBs composed of fluorinated salts dissolved in volatile organic solvents, posing serious safety issues due to the instability of the salts and flammability of the solvents. There is an urge to develop new fluorine-free electrolytes with improved physicochemical and electrochemical properties. In this context, the conventional fluorinated salts should be replaced with fluorine-free salts and the flammable solvents should be substituted with non-flammable solvents. There are a number of strategies to develop high-performant electrolytes including ambient-temperature ionic liquids (ILs), organic ionic plastic crystals (OIPCs) and highly concentrated electrolytes (HCEs) utilizing new salts and solvents. In this thesis, novel phosphorus-based ionic materials and electrolytes are introduced and their properties are thoroughly investigated. In the first part (Paper I), fluorine-free NaDEEP salt and TEOP solvent are employed to make “solvent-in-salt” (SIS) sodium electrolytes, also known as HCEs. Unexpectedly, the addition of TEOP solvent lead to an increase in the oxidation stability of the SIS electrolytes. In addition, an unusual ionic conductivity behavior is found – the ionic conductivities of Na electrolytes increase with increasing salt concentration. The “salt-rich” and “solvent-rich” phases formed within the electrolytes are investigated using multinuclear liquid-state NMR spectroscopy and NMR diffusometry. In the second part (Paper II), a series of orthoborate-based ionic materials, specifically OIPCs, containing phosphonium/ammonium cations are prepared to compare with the popular fluorine-free, bis(oxalato)borate (BOB) salts. The tetrabutyl phosphonium bis(glycolato)borate ([P4444][BGB]) OIPC displays much higher decomposition temperature than the structural analogous [P4444][BOB] IL. The crystal structures of LiBGB and NaBGB salts are resolved using single-crystal X-ray diffraction analysis. Unlike LiBOB, the BGB-based salts revealed excellent moisture stability over an extended time of up to 8-weeks air exposure. Multinuclear solid-state NMR spectroscopy indicates weaker cation-anion interactions in phosphonium-based salts than the ammonium-based ones. Finally, in the third part (Paper III), two-component and three-component eutectic electrolytes, composed of pyrrolidinium saccharin (PySc), lithium saccharin (LiSc) and/or [P4444][BGB] salt. The resulting mixtures showed significantly lower melting temperatures than the neat salts. The physicochemical and thermal properties of these salts are thoroughly investigated and discussed.

No description available.

No description available.