O consumo de tabaco é uma das principais causas de doenças e morte prematuras no mundo; é a segunda droga mais consumida entre os adolescentes brasileiros, sendo considerado uma importante porta de entrada para o uso de drogas ilícitas. O Brasil é o segundo produtor mundial de tabaco e desde de 1993 destaca-se como o maior exportador. Os radionuclídeos naturais das séries do 232Th e 238U são encontrados no tabaco em baixas concentrações absorvidos diretamente do solo ou por deposição foliar. No ato de fumar ocorre a transferência desses radionuclídeos através da queima do tabaco para os tecidos e órgãos humanos podendo gerar lesões cancerígenas, sendo o mais relevante o câncer de pulmão. Existem poucos dados sobre a caracterização radiológica e elementar dos derivados do tabaco brasileiros, o que torna relevante o presente estudo que teve como objetivos a determinação da radioatividade natural e da concentração de elementos maiores e traços em derivados de tabaco produzidos e comercializados no Brasil. As técnicas analíticas empregadas foram alfa e beta total após separação radioquímica para os radionuclídeos 226Ra, 228Ra e 210Pb com determinação em detector proporcional de fluxo gasoso e baixa radiação de fundo, espectrometria alfa após separação radioquímica para o radionuclídeo 210Po, análise por ativação com nêutrons instrumental (INAA) e fluorescência por dispersão de raios X (EDXRF) para determinação de 238U, 232Th, elementos maiores e traços. Foram analisados produtos derivados da Nicotina tabacum L. de diferentes marcas adquiridas em tabacarias: cigarro não aromatizados, cigarro aromatizado, charuto, rapé, cigarro de palha e fumo de corda. Pela técnica de INAA foi possível determinar a concentração de 19 elementos e pela técnica de EDXRF de 31 elementos o que possibilitou uma ampla caracterização multielementar e as técnicas analíticas empregadas se mostraram complementares. Os elementos que apresentaram maiores valores de concentração foram o Ca e o K entre todas as amostras amostragem e entre todos os radionuclídeos naturais determinados o 228Ra apresentou maiores valores de concentração de atividade. A partir da concentração de atividade determinada foram calculadas a dose anual estimada e a dose anual efetiva para os radionuclídeos 210Pb e 210Po, levando-se em consideração um consumo anual de 3,65 kg de tabaco por ano. A dose anual efetiva variou de 69,5 μSv ano-1 à 121 μSv ano-1. Os produtos que apresentaram maiores valores de concentração e consequentemente maiores valores de dose anual efetiva, para a maioria dos radionuclídeos analisados, foram os cigarros de palha e fumos de corda. / Tobacco use is one of the leading causes of premature illness and death in the world; is the second most consumed drug among Brazilian adolescents, being considered an important gateway to the use of illicit drugs. Brazil is the second largest tobacco producer in the world and since 1993 it has been the largest exporter. The natural radionuclides from the 232Th and 238U series are found in tobacco at low concentrations absorbed directly from the soil or by foliar deposition. In the act of smoking occurs the transference of these radionuclides through the burning of the tobacco to the human tissues and organs and they can generate carcinogenic lesions, being the lung cancer the most relevant. There are few data on the elemental and radiological characterization of Brazilian tobacco products, which makes relevant the present study that had as objectives the determination of the natural radioactivity and the concentration of major and trace elements in tobacco products produced and marketed in Brazil. The analytical techniques employed were gross alpha and beta, after radiochemical separation for the radionuclides 226Ra, 228Ra and 210Pb with determination in a gaseous flow proportional detector of low background radiation, alpha spectrometry after radiochemical separation for the radionuclide 210Po, instrumental neutron activation analysis (INAA) and X-ray scattering fluorescence (EDXRF) for determination of 238U, 232Th, major and trace elements. Nicotine tabacum L. products from different brands acquired in cigar stores were analyzed: non-flavored cigarettes, flavored cigarettes, cigar, snuff, straw cigarettes and rope smoke. Using the INAA technique, it was possible to determine the concentration of 19 elements and with the EDXRF technique 31 elements, which enabled a wide multielementar characterization; the analytical techniques employed were complementary. The elements that presented the highest concentration values were Ca and K among all the samples and among all the natural radionuclides determined the 228Ra presented higher values of activity concentration. The estimated annual dose and annual effective dose for the 210Pb and 210Po radionuclides were calculated from the determined activity concentration, taking into account an annual consumption of 3.65 kg of tobacco per year. The effective annual dose ranged from 69.5 μSv y-1 to 121 μSv y-1. The products with the highest concentration values and hence the highest annual effective dose for the majority of the radionuclides analyzed were straw cigarettes and rope smoke.

In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene. In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

Submitted by Claudinei Pracidelli (cpracide@ipen.br) on 2015-12-10T17:38:32Z No. of bitstreams: 0 / Made available in DSpace on 2015-12-10T17:38:32Z (GMT). No. of bitstreams: 0 / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

Submitted by Claudinei Pracidelli (cpracide@ipen.br) on 2015-12-10T17:38:32Z No. of bitstreams: 0 / Made available in DSpace on 2015-12-10T17:38:32Z (GMT). No. of bitstreams: 0 / Neste trabalho foi desenvolvida uma nova metodologia de produção de iodo-125, que resultou na primeira produção deste radionuclídeo no Brasil. Cápsulas de alumínio foram projetadas, fabricadas e avaliadas para que suportassem condições de pressão, temperatura e fluxo de nêutrons no reator nuclear IEA-R1 do IPEN sem a ocorrência de liberação de material radioativo. Foram projetados, desenvolvidos e fabricados sistemas de carregamento, descarregamento e recuperação dos gases para a manipulação do gás xenônio e do iodo. Foi desenvolvido um novo método de lavagem da cápsula, para dissolução do iodo-125 adsorvido nas paredes, por meio de imersão em banho ultrassônico. Foram irradiadas três cápsulas no reator nuclear IEA-R1, por um período de aproximadamente 60 h contínuas, a um fluxo de nêutrons de 5,5 x 1013 n cm-2 s-1. Foi produzido um total de 13,53 GBq (365,73 mCi) de iodo-125, e o único contaminante encontrado foi o radionuclídeo iodo-126. Na análise radioquímica, pelo método de cromatografia em papel ascendente, o iodo-125 em solução de NaOH apresentou percentual de iodeto acima de 98%, superior à exigência da farmacopeia americana para soluções de iodo radioativo que é de 95%. Para a análise radionuclídica foi desenvolvida uma fonte planar, a base de resina epoxídica, para a contagem do iodo-125 em detector de germânio de alta pureza. A correlação entre o iodo-125 e o iodo-126 produzido apresentou valores entre 0,5 e 0,7% após um período de decaimento de 10 d, grau de pureza suficiente para a utilização em técnicas de radioimunoensaio. / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

Ce travail de thèse réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne porte dans un premier temps sur la synthèse d’agents chélatants bifonctionnels adaptés à la chélation de radiométaux trivalents, notamment l’indium-111. La plus grande partie de ce travail a ensuite consisté à réaliser le greffage d’un agent chélatant bifonctionnel dérivé du DOTA sur différents anticorps ou fragments d’anticorps monoclonaux : le trastuzumab (anti HER2, traitement de cancers du sein), le cétuximab (anti EGFR, traitement de nombreux cancers, dont le cancer colorectal) et l’abciximab (antiagrégant plaquettaire). Une attention particulière a été apportée à la caractérisation des différents immunoconjugués. La dernière étape de ce travail de thèse porte sur le radiomarquage à l’indium-111 de deux immunoconjugués préparés : le trastuzumab et le cétuximab. Ces étapes de radiomarquage nous ont permis de déterminer la fraction immunoréactive et l’affinité de chaque radiotraceur. Nous avons ainsi pu étudier la biodistribution in vivo de ces radiotraceurs chez la souris par imagerie SPECT-CT. Nous avons également développé une méthode de greffage originale pour le marquage d’un fragment d’anticorps de type Fab, l’abciximab, dans le but de suivre la biodistribution de cet antiagrégant plaquettaire. Enfin, nous avons également validé le concept d’imagerie multimodale à travers le greffage et le radiomarquage d’un agent bimodal pour l’imagerie optique et la SPECT sur des lipopolysaccharides bactériens. Les travaux réalisés nous ont permis d’acquérir un savoir faire en matière de greffage d’anticorps et de radiomarquage. Les résultats obtenus permettent d’envisager le greffage d’autres anticorps ou biomolécules, ainsi que l’utilisation d’autres radionucléides pour l’imagerie PET ou la radioimmunothérapie / This work conducted at the “Institut de Chimie Moléculaire de l’Université de Bourgogne” carries at first on the synthesis of bifunctional chelating agents suitable for the chelation of trivalent radiometals, including indium-111. The greater part of this work was then dedicated to the grafting of a DOTA derivative bifunctional chelating agent on different antibodies or fragments of monoclonal antibodies: trastuzumab (anti-HER2 treatment of breast cancer), cetuximab (anti EGFR, treatment of many cancers, including colorectal cancer) and abciximab (antiplatelet). Particular attention was paid to the characterization of various immunoconjugates. The critical step of this thesis consisted in the indium-111 radiolabeling of two previously prepared immunoconjugates: trastuzumab and cetuximab. These steps of radiolabelling allowed us to determine the immunoreactive fraction and affinity of each radiotracer. Thus, we were able to study the in vivo biodistribution of the radiotracers in tumour-bearing mice by SPECT-CT. We also developed an original method for the labeling of a Fab antibody fragment in order to monitor the biodistribution of the antiplatelet agent (abciximab). Finally, we also validated the concept of multimodal imaging through grafting and radiolabeling of a bimodal agent for optical and SPECT imaging on bacterial lipopolysaccharide. Thank’s to this work, we gained an expertise in antibodies radiolabeling. The results obtained allow to consider the labeling of antibodies or other biomolecules, and the use of other radionuclides for PET imaging and radioimmunotherapy

Liver cancer accounts for nearly 10% of all cancers in the US. Intrahepatic Arterial Radiomicrosphere Therapy (RMT), also known as Selective Internal Radiation Treatment (SIRT), is one of the evolving treatment modalities. Successful patient clinical outcomes require suitable treatment planning followed by delivery of the microspheres for therapy. The production and in vitro evaluation of various polymers (PGCD, CHS and CHSg) microspheres for a RMT and RMT planning are described. Microparticles with a 30±10 µm size distribution were prepared by emulsion method. The in vitro half-life of the particles was determined in PBS buffer and porcine plasma and their potential application (treatment or treatment planning) established. Further, the fast degrading microspheres (≤ 48 hours in vitro half-life) were labeled with 68Ga and/or 99mTc as they are suitable for the imaging component of treatment planning, which is the primary emphasis of this dissertation. Labeling kinetics demonstrated that 68Ga-PGCD, 68Ga-CHSg and 68Ga-NOTA-CHSg can be labeled with more than 95% yield in 15 minutes; 99mTc-PGCD and 99mTc-CHSg can also be labeled with high yield within 15-30 minutes. In vitro stability after four hours was more than 90% in saline and PBS buffer for all of them. Experiments in reconstituted hemoglobin lysate were also performed. Two successful imaging (RMT planning) agents were found: 99mTc-CHSg and 68Ga-NOTA-CHSg. For the 99mTc-PGCD a successful perfusion image was obtained after 10 minutes, however the in vivo degradation was very fast (half-life), releasing the 99mTc from the lungs. Slow degrading CHS microparticles (> 21 days half-life) were modified with p-SCN-b-DOTA and labeled with 90Y for production of 90Y-DOTA-CHS. Radiochemical purity was evaluated in vitro and in vivo showing more than 90% stability after 72 and 24 hours respectively. All agents were compared to their respective gold standards (99mTc-MAA for 68Ga-NOTA-CHSg and 99mTc-CHSg; 90Y-SirTEX for 90Y-DOTA-CHS) showing superior in vivo stability. RMT and RMT planning agents (Therapy, PET and SPECT imaging) were designed and successfully evaluated in vitro and in vivo.

L’atome de fluor est omniprésent dans plusieurs domaines grâce à sa capacité à moduler les propriétés biologiques et physicochimiques d’une molécule. De ce fait, la demande en molécules originales ne cesse de croître. Dans ce contexte, la synthèse de nouveaux réactifs fluorés et le développement de nouvelles méthodologies de synthèse pour introduire ces motifs fluorés suscite un fort intérêt. La première partie de cette thèse a été consacrée à l’élaboration d’un réactif inédit, source de CHFMe, et l’étude de sa réactivité. Cela a permis d’accéder à des composés substitués par un groupement OCHFMe, une classe de dérivés sous-explorée et pourtant prometteuse en chimie médicinale (Chapitre 2). Le chapitre 3 a été dédié au groupement CF₂PO(OEt)₂, un motif d’intérêt grâce à son bioisostérisme avec le groupement phosphate. L’étude d’une voie d’accès directe aux molécules aliphatiques comportant le groupement CF₂PO(OEt)₂ a été étudiée. Enfin, en collaboration avec l’UCL, l’étude de nouveaux groupements fluorés radiomarqués a été réalisée. En effet, le chapitre 4 a porté sur le développement d’une méthodologie permettant de synthétiser des molécules comportant un motif SCF₂¹⁸F, combinant ainsi les propriétés du motif émergent SCF₃ à celles du fluor 18. / The fluorine atom is ubiquitous in several fields thanks to its unique feature to modulate the biological and physical properties of a molecule. Thus, the demand for original fluorinated molecules is steadily increasing. In this context, a special attention has been paid to the synthesis of new fluorinated reagents as well as the development of new methodologies to introduce fluorinated motifs. The first part of this PhD thesis focused on the design of an unprecedented CHFMe-containing reagent and the study of its reactivity. A new access to OCHFMe-containing molecules was possible, an underexplored class of compounds despite their potential in medicinal chemistry (Chapter 2). The chapter 3 was dedicated to the CF₂PO(OEt)₂ moiety, which is of high importance due to its bioisosterism with the phosphonate group. A direct pathway toward the synthesis of aliphatic CF₂PO(OEt)₂-containing molecules was investigated. Finally, in collaboration with the Université Catholique de Louvain, the design of new radiolabeled fluorinated groups was studied. Indeed, the chapter 4 was devoted to the development of a methodology to access SCF₂¹⁸F-containing molecules, combining hence the properties of the emerging moiety SCF₃ with the ones of the ¹⁸F atom.

Die Langzeitsicherheitsanalyse für ein Endlager für nukleare Abfälle bedarf einer eingehenden Beschreibung der Mobilität von Radionukliden im Nah- und Fernfeld des Endlagers. Da extrem lange Zeiträume von bis zu einer Million Jahren abgebildet werden müssen, muss diese Beschreibung auf einem molekularen Prozessverständnis beruhen. Nur dann ist eine unbegrenzte zeitliche Extrapolation zulässig. Die wichtigsten Rückhalteprozesse finden an der Wasser/Mineralgrenzfläche statt, wobei in einem realen Endlager sehr viele primäre und sekundäre Mineralphasen vorhanden sind, mit denen die Radionuklide wechselwirken können. Zudem stehen eine Vielzahl verschiedener Reaktionsmechanismen zur Verfügung – innersphärische oder außersphärische Sorption, struktureller Einbau, Oberflächenfällung etc. – die sich hinsichtlich ihrer Rückhaltefähigkeit deutlich unterscheiden. Somit muss auf hochsensitive Methoden zurückgegriffen werden, die in der Lage sind, selektiv Informationen über die relevanten Radionuklide innerhalb der Grenzschicht zu liefern. Die in dieser Arbeit hauptsächlich verwendeten Methoden, die zeitaufgelöste Laser-induzierte Fluoreszenzspektroskopie (TRLFS), und die Oberflächenröntgenbeugungsmethoden crystal truncation rod (CTR) Messung und resonant anomalous X-ray reflectivity (RAXR), haben sich als effiziente Werkzeuge zur Ermittlung struktureller und Speziationsdaten erwiesen. So konnte im Rahmen dieser Arbeit die Wechselwirkung der Radionuklide U, Pu, Am und Cm mit verschiedenen Mineralphasen aufgeklärt, sowie die Abhängigkeit dieser Reaktionen von der Lösungszusammensetzung beschrieben werden.:1 Einleitung 9 1.1 Zeitaufgelöste laser-induzierte Fluoreszenzspektroskopie 12 1.2 Oberflächenröntgenbeugung 18 2 Spektroskopische Charakterisierung von Einbauprozessen 21 2.1 Biswas S, Steudtner R, Schmidt M, McKenna C, Vintró LL 25 Twamley B, et al. An investigation of the interactions of Eu3+ and Am3+ with uranyl minerals: implications for the storage of spent nuclear fuel. Dalton Transactions. 2016; 45(15):6383-93. 2.2 Schmidt M, Heck S, Bosbach D, Ganschow S, Walther 36 C, Stumpf T. Characterization of powellite-based solid solutions by site-selective time resolved laser fluorescence spectroscopy. Dalton Transactions. 2013;42(23):8387 - 93. 2.3 Hellebrandt SE, Hofmann S, Jordan N, Barkleit A, Schmidt M. 43 Incorporation of Eu(III) into Calcite under recrystallization conditions. Scientific Reports. 2016;6:33137. 2.4 Johnstone EV, Hofmann S, Cherkouk A, Schmidt M. 53 Study of the Interaction of Eu3+ with Microbiologically Induced Calcium Carbonate Precipitates using TRLFS. Environmental Science & Technology. 2016;50(22):12411-20. 3 Oberflächeninduzierte Kondensationsreaktionen 63 3.1 Lee SS, Schmidt M, Fister TT, Nagy KL, Sturchio NC, Fenter P. 65 Structural Characterization of Aluminum (Oxy)hydroxide Films at the Muscovite (001)–Water Interface. Langmuir. 2016; 32(2):477-86. 3.2 Hellebrandt S, Lee SS, Knope KE, Lussier AJ, Stubbs JE, Eng 75 PJ, et al. Cooperative effects of adsorption, reduction, and polymerization observed for hexavalent actinides on the muscovitebasal plane. Langmuir. 2016; 32(41):10473-82.6 3.3 Schmidt M, Lee SS, Wilson RE, Knope KE, Bellucci F, Eng 85 PJ, et al. Surface-Mediated Formation of Pu(IV) Nanoparticles at the Muscovite-Electrolyte Interface. Environmental Science & Technology. 2013;47(24):14178-84. 4 Elektrolyteffekte auf Oberflächenprozesse 92 4.1 Lee SS, Schmidt M, Laanait N, Sturchio NC, Fenter P. 94 Investigation of Structure, Adsorption Free Energy, and Overcharging Behavior of Trivalent Yttrium Adsorbed at the Muscovite (001)–Water Interface. The Journal of Physical Chemistry C. 2013;117(45):23738-49. 4.2 Schmidt M, Hellebrandt S, Knope KE, Lee SS, Stubbs JE, 106 Eng PJ, et al. Effects of the Background Electrolyte on Th(IV) Sorption to Muscovite Mica. Geochimica et Cosmochimica Acta. 2015;165:280-93. 4.3 Hofmann S, Voïtchovsky K, Schmidt M, Stumpf T. Trace 120 concentration – Huge impact: Nitrate in the calcite/Eu(III) system. Geochimica et Cosmochimica Acta. 2014;125:528-38. 4.4 Hofmann S, Voïtchovsky K, Spijker P, Schmidt M, Stumpf 131 T. Visualising the molecular alteration of the calcite (104)–water interface by sodium nitrate. Scientific Reports. 2016; 6:21576. 5 Schlussfolgerungen 142 Literatur 146 / The safety assessment of a nuclear waste disposal site requires the accurate description of the radionuclides’ mobility in the near and far field of the site. This description must rely on molecular level understanding of the occurring processes to allow extrapolation for time frames of up to one million years. The most important retention mechanisms take place at the water/mineral interface. A disposal site will contain a large number of mineral phases, both as primary and secondary minerals. Moreover, a large number of potential reaction pathways is conceivable, and must be investigated: inner and outer sphere sorption, structural incorporation, surface precipitation, etc. As these mechanisms will differ significantly in their retention potential, it is crucial to be able to differentiate between them. Hence, the need arises for analytical techniques capable of providing selective information about radionuclides at the water/mineral interface. This work employs time-resolved laser-induced fluorescence spectroscopy (TRLFS), as well as the surface X-ray diffraction techniques crystal truncation rod (CTR) measurements and resonant anomalous X-ray reflectivity (RAXR) as efficient tools to obtain both structural and speciation data from these systems. Following this approach, the interaction of the radionuclides U, Pu, Am, and Cm with various mineral phases could be elucidated, while also characterizing the dependence of these reactions on the composition of the aqueous solution.:1 Einleitung 9 1.1 Zeitaufgelöste laser-induzierte Fluoreszenzspektroskopie 12 1.2 Oberflächenröntgenbeugung 18 2 Spektroskopische Charakterisierung von Einbauprozessen 21 2.1 Biswas S, Steudtner R, Schmidt M, McKenna C, Vintró LL 25 Twamley B, et al. An investigation of the interactions of Eu3+ and Am3+ with uranyl minerals: implications for the storage of spent nuclear fuel. Dalton Transactions. 2016; 45(15):6383-93. 2.2 Schmidt M, Heck S, Bosbach D, Ganschow S, Walther 36 C, Stumpf T. Characterization of powellite-based solid solutions by site-selective time resolved laser fluorescence spectroscopy. Dalton Transactions. 2013;42(23):8387 - 93. 2.3 Hellebrandt SE, Hofmann S, Jordan N, Barkleit A, Schmidt M. 43 Incorporation of Eu(III) into Calcite under recrystallization conditions. Scientific Reports. 2016;6:33137. 2.4 Johnstone EV, Hofmann S, Cherkouk A, Schmidt M. 53 Study of the Interaction of Eu3+ with Microbiologically Induced Calcium Carbonate Precipitates using TRLFS. Environmental Science & Technology. 2016;50(22):12411-20. 3 Oberflächeninduzierte Kondensationsreaktionen 63 3.1 Lee SS, Schmidt M, Fister TT, Nagy KL, Sturchio NC, Fenter P. 65 Structural Characterization of Aluminum (Oxy)hydroxide Films at the Muscovite (001)–Water Interface. Langmuir. 2016; 32(2):477-86. 3.2 Hellebrandt S, Lee SS, Knope KE, Lussier AJ, Stubbs JE, Eng 75 PJ, et al. Cooperative effects of adsorption, reduction, and polymerization observed for hexavalent actinides on the muscovitebasal plane. Langmuir. 2016; 32(41):10473-82.6 3.3 Schmidt M, Lee SS, Wilson RE, Knope KE, Bellucci F, Eng 85 PJ, et al. Surface-Mediated Formation of Pu(IV) Nanoparticles at the Muscovite-Electrolyte Interface. Environmental Science & Technology. 2013;47(24):14178-84. 4 Elektrolyteffekte auf Oberflächenprozesse 92 4.1 Lee SS, Schmidt M, Laanait N, Sturchio NC, Fenter P. 94 Investigation of Structure, Adsorption Free Energy, and Overcharging Behavior of Trivalent Yttrium Adsorbed at the Muscovite (001)–Water Interface. The Journal of Physical Chemistry C. 2013;117(45):23738-49. 4.2 Schmidt M, Hellebrandt S, Knope KE, Lee SS, Stubbs JE, 106 Eng PJ, et al. Effects of the Background Electrolyte on Th(IV) Sorption to Muscovite Mica. Geochimica et Cosmochimica Acta. 2015;165:280-93. 4.3 Hofmann S, Voïtchovsky K, Schmidt M, Stumpf T. Trace 120 concentration – Huge impact: Nitrate in the calcite/Eu(III) system. Geochimica et Cosmochimica Acta. 2014;125:528-38. 4.4 Hofmann S, Voïtchovsky K, Spijker P, Schmidt M, Stumpf 131 T. Visualising the molecular alteration of the calcite (104)–water interface by sodium nitrate. Scientific Reports. 2016; 6:21576. 5 Schlussfolgerungen 142 Literatur 146

Les travaux présentés dans ce manuscrit ont pour objectifs la synthèse chimique de nouveaux ligands de la protéine de translocation 18 kDa (TSPO), leur évaluation in vitro et le radiomarquage isotopique des candidats les plus prometteurs par l’émetteur de positons à vie brève fluor-18 (t1/2 : 109,8 minutes). Ce travail a pour finalité le développement de nouvelles sondes moléculaires ou biomarqueurs pour l’imagerie non-invasive et atraumatique par Tomographie par Emission de Positons (TEP) de la neuroinflammation, processus reconnu dans les maladies neurodégénératives telles la maladie d’Alzheimer, de Parkinson, la sclérose en plaque et certaines maladies psychiatriques.Le radioligand de choix pour l’imagerie de la TSPO est actuellement le [18F]DPA-714, une pyrazolo[1,5-a]pyrimidine marquée au fluor-18 récemment développée au laboratoire. Cependant, cette molécule subit in vivo la perte rapide de l’atome de fluor radioactif par rupture du motif fluoroalkoxy comme démontrée lors de l’étude de son métabolisme. Mon projet de thèse a donc visé à concevoir et développer de nouveaux dérivés structurellement proches de DPA-714 (analogues) pour lesquelles la liaison entre le squelette principal et le fluor-18 serait renforcée. C’est dans ce cadre que dix-neuf composés ont été préparés et évalués pour leur affinité pour la TSPO, et que deux candidats prometteurs, DPA-C5yne et CfO-DPA-714, ont été radiomarqués au fluor-18 avec de bons rendements radiochimiques (20-30 %) et de hautes radioactivités spécifiques (50-90 GBq/µmol). Ces radioligands ont également été évalués in vivo par imagerie TEP et présentent, chez l’animal, des performances équivalentes voire légèrement supérieures à [18F]DPA-714. / The work presented in this manuscript aims to describe the synthesis of new ligands of the translocation protein 18 kDa (TSPO), their in vitro evaluation and, for the most promising candidates, their isotopic radiolabelling with the short-lived positron emitter fluorine-18 (t1/2 : 109.8 minutes). The ultimate goal of this work consists in developing new molecular probes, or biomarkers, for imaging neuroinflammation in a non-invasive and atraumatic manor using Positron Emission Tomography (PET). Neuroinflammatory processes have been identified in Alzheimer and Parkinson diseases, MS and various psychiatric pathologies.The radioligand of choice for imaging TSPO is currently [18F]DPA-714, a pyrazolo[1,5-a]pyrimidine radiolabelled with fluorine-18 which has been recently prepared in our laboratories. However, [18F]DPA-714 undergoes a rapid in vivo loss of the radioactive fluorine by cleavage of the fluoroalkoxy chain as demonstrated in metabolic studies. Therefore, my PhD project aimed to design and develop new structurally related analogues of DPA-714 where the linkage between the main backbone and the fluorine-18 would be reinforced. To this extent, nineteen compounds were prepared and their affinity towards the TSPO was evaluated. Two promising candidates, coded DPA-C5yne and CfO-DPA-714, were radiolabelled with fluorine-18 with good radiochemical yields (20-30 %) and high specific radioactivities (50-90 GBq/µmol). These radioligands were also evaluated by PET imaging at the preclinical stage and displayed equivalent or slightly improved results when compared to [18F]DPA-714.

Pour la gestion des déchets nucléaires, il est prévu de construire un dispositif un système barrière composé en partie de conteneur en acier. La corrosion est évaluée pour que le stockage anoxique soit sûr sur le long-terme. Avec des rayonnements, la radiolyse engendre des espèces oxydantes et réductrices pouvant modifier la corrosion. Le premier axe de cette thèse concerne l'irradiation gamma d'échantillons de coupon de fer en eau désaérée et carbonatée. Il est montré que l'irradiation peut augmenter les vitesses de corrosion suivant les paramètres de dose. Les phases identifiées sont peu modifiées avec l'irradiation. La chimie des solutions montre une baisse du pH avec la dose liée au fer. Des espèces organiques sont repérées. Le deuxième axe est l'irradiation d'analogues archéologiques avec une couche de produits de corrosion ancienne. La stabilité des phases vis-à-vis de la radiolyse est vérifiée; seuls les produits néoformés changent. Le troisième axe est une approche par simulation cinétique. Il vérifie la baisse de pH sous irradiation. L'ensemble de ces résultats nous permette de proposer des données nouvelles pour la corrosion anoxique sous irradiation.