Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in 11C chemistry and the biological target. Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). 15N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19–90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. 15N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide. Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 11C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/µmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a 11C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies.   Section 4 describes the development of a multicomponent method for the synthesis of 3,4-dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.

Synthesis and capture of antihydrogen in controlled laboratory conditions will enable precise studies of neutral antimatter. The work presented deals with some of the physics pertinent to manipulating charged antiparticles in order to create neutral antimatter, and may be applicable to other scenarios of plasma confinement and charged particle interaction. The topics covered include the electrostatic confinement of a reflecting ion beam and the transverse confinement of an ion beam in a purely electrostatic configuration; the charge sign effect on the Coulomb logarithm for a two component (e.g., antihydrogen) plasma in a Penning trap as well as the collisional scattering for binary Coulomb interactions that are cut off at a distance different than the Debye length; and the formation of magnetobound positronium and protonium.

The aim of this work was studying of the coordination properties of TACN macrocyclic derivatives with aminophosphinate pendant arms. Two ligands were prepared, one with two pendant arms NODPam and one with three pendant arms NOTPam. Because of degradation of ligand NODPam during its synthesis, only the ligand NOTPam was studied further. Acid-base properties of ligand and termodynamic stability of aluminium and gallium complexes were studied. Formation and disociation studies were performed with the complexes. Coordination of fluoride ions to aluminium complex was studied using ion selective fluoride electrode. Finally coordination of complex AlFx with ligand NOTPam was studied using 19F and 27Al NMR spectroscopy. Selected experiments were made also with ligand NOTA. Key words: macrocyclic complexes, positron emission tomography, phosphinic acids

La Tomographie par Émission de Positon (TEP) combinée à l'imagerie scanner est intéressante pour la planification de traitement en radiothérapie. Elle réduit la variabilité inter et intra-observateur dans la définition du volume cible et permet de visualiser les hétérogénéités biologiques. Plusieurs algorithmes de segmentation ont été proposés mais aucun ne fait consensus. Pour valider ces algorithmes, les simulations de Monte-Carlo offrent la possibilité de maîtriser la vérité terrain et l'ensemble des paramètres d'acquisition.Nous avons proposé plusieurs méthodologies d'amélioration du réalisme des simulations. Des jeux de données présentant une variabilité anatomique, une hétérogénéité tumorale réaliste et intégrant les mouvements respiratoires ont ainsi été générés.Ces données ont été utilisées dans une première étude sur la segmentation du volume cible. Plusieurs algorithmes ont été comparés dans le cadre de la planification de traitement. L'utilisation de données simulées a permis de relier la précision de la segmentation à la qualité de la couverture de la vérité terrain. Nous avons aussi étudié l'impact de la respiration sur la précision de la segmentation.L'utilisation d'un algorithme de segmentation avancé permettant de définir un sous-volume plus actif pour la prescription d'une dose hétérogène a été proposée. Plusieurs scénarios de prescription ont été comparés en terme de probabilité de contrôle tumorale (TCP) calculée sur la TEP. La variabilité de la TCP liée aux paramètres d'acquisitions a été quantifiée. L'impact du contraste et de la taille du sous-volume fut étudié. Pour finir l'apport d'un ajout de compartiments à de telles prescriptions a été analysé. / There has been an increasing interest for the use Positron Emission Tomography (PET) combined with Computed Tomography for radiotherapy treatment planning. It improves target volume delineation by reducing inter and intra-observer variability and allows visualizing biological heterogeneities. Plethoras of segmentation algorithm have been proposed but there is a lack of consensus regarding which one to use. Monte Carlo simulations are interesting to validate these algorithms since they allow creating datasets with known ground-truth and for which all acquisition parameters are controlled.We proposed several methodologies for improving the realism of simulations. Several datasets incorporating patient specific variability in terms of anatomy and activity distributions, realistic tumor shape and activity modeling and integrating the respiratory motions were created.These data were used in a first study concerning target volume definition. Several algorithms were compared for radiotherapy treatment planning. The accuracy of segmentation was related to the quality of ground-truth volume coverage. We also studied the impact of respiratory motion on segmentation accuracy.We investigated the use of an advanced segmentation method able to define high uptake sub-volumes, for heterogeneous dose prescriptions. Several scenarios of prescriptions were compares in terms of Tumor Control Probability (TCP) computed on PET images. Variability of this TCP due to acquisition parameters was quantified. The impact of contrast and size of sub-volume was studied. Finally we studied the usefulness of the addition of compartments to such heterogeneous prescriptions.

<p>Manganese (Mn) is an essential element and, at high doses, a neurotoxin that many workers are exposed to daily. Increased Mn body burden due to occupational exposures leads to a parkinsonian disorder that features symptoms such as mood disturbances, cognition deficits, and motor dysfunction. To understand exposed workers’ risk, biomarkers of exposure have been developed using blood, hair, bone, and toenails. None of these biomarkers take into account how much Mn is in the brain and instead rely on the assumption that Mn uptake in these materials is proportional and related to the levels in the brain. One way to measure Mn in the brain is through neuroimaging modalities, such as magnetic resonance imaging and positron emission tomography, however there remains a need to establish reliable neuroimaging biomarkers for Mn exposure and its toxicological effects. This thesis addresses this need.</p><p>First, we hypothesized that changes in Mn exposure would be reflected by changes in the MRI relaxation rate R1 and thalamic γ-aminobutyric acid (GABA). As part of a prospective cohort study, 17 welders were recruited and imaged on two separate occasions approximately two years apart. MRI relaxometry was used to assess changes of Mn accumulation in the brain. Additionally, GABA was measured using magnetic resonance spectroscopy (MRS) in the thalamic and striatal regions of the brain. Air Mn exposure ([Mn]air) and cumulative exposure indexes of Mn (Mn-CEI) for the past three months (Mn-CEI3M), past year (Mn-CEI12M), and lifetime (Mn-CEILife) were calculated using personal air sampling and a comprehensive work history, while toenails were collected for analysis of internal Mn body burden. Finally, welders’ motor function was examined using the Unified Parkinson’s Disease Rating Scale (UPDRS). Mn-CEI12M decreased significantly between the first and second scan (Wilcoxon Signed Rank, p = 0.02). ΔMn-CEI3M were correlated with R1 in the substantia nigra (spearman partial correlation, ρ = 0.50, p = 0.036) and thalamic GABA (ρ = 0.66, p = 0.001), but only GABA significantly decreased linearly with Mn-CEI3M (quantile regression, β = 15.22, p = 0.02). Finally, Mn-CEILife influences the change in R1 in the substantia nigra with Δ[Mn]Air, where higher Mn-CEILife lessened the ΔR1 per Δ[Mn]Air (F-test, p = 0.005). While R1 and GABA changed with Mn exposure, UPDRS was unaffected.</p><p>Secondly, we hypothesized that occupational exposure to Mn would lead to disturbances in dopamine release (DA), as measured with PET. Excess exposure to manganese (Mn) can lead to symptoms similar to Parkinson’s disease (PD). While symptoms of PD are due to loss of nigrostriatal dopaminergic neurons, there is no DA neuron loss with Mn toxicity. To assess how DA release may be affected by Mn exposure, 6 subjects (3 welders, 3 controls) were scanned with positron emission tomography and [11C]raclopride (a DA D2/D3 receptor antagonist displaceable by endogenous DA) at baseline and during an amphetamine challenge. There were no apparent differences in amphetamine-induced striatal DA release between groups. However, UPDRS motor scores were positively linearly related to [11C]raclopride binding potential (BPND) in the putamen, whereas Mn-CEILife was negatively related to baseline pre-commissural caudate and ventral striatum BPND. The pilot results suggest that [11C]raclopride PET might delineate the cause of mood and motor dysfunction in subjects exposed to Mn.</p><p>Third, we hypothesized that advanced data analysis techniques, such as machine learning, would increase our power in finding differences between groups of welders and controls based on exposure and biological outcomes. This study used data from previous studies in occupationally exposed welders and controls. Whole brain relaxometry using MRI measuring the relaxation rate R1 was acquired in 52 welders and 37 controls. Because measures of R1 in selected regions of the brain have been previously found to be proportional to Mn, we hypothesized that an advanced model taking into account the whole brain might be more predictive for Mn exposure. Additionally, because R1 is proportional to Mn in the region, we used a biokinetic model to estimate the amount of excess Mn in the brain from occupational exposures. Support vector machines (SVM) with a linear kernel were trained using leave-one-out cross-validation. Results indicated that models had recall and accuracy better than chance targeting air Mn exposure, years welding, age, and thalamic GABA. In comparison to all models, R1 appears to reliably predict thalamic GABA across all thresholds, which was previously shown to change with increased Mn exposure. This suggests that while R1 may be proportional to Mn, some Mn may not be free to contribute to signal, and instead thalamic GABA might better reflect the overall amount of free Mn in the brain. </p><p>Collectively, this thesis is a successful step towards establishing neuroimaging biomarkers of effect from occupational Mn exposure. The MRI relaxation rate R1, with adequate modeling, could eventually be used to measure total Mn brain burden while thalamic GABA might represent a better metric for measuring the neurochemical effects from recent exposures. However, future research should incorporate more endpoints, such as motor tests, mood assessments, and behavior assessments. </p><div><br></div><p><br></p>

In this dissertation, we discuss the development of new phase transfer agents, which are capable of rapid fluorination of silicon. These are 18-C-6 derivatives containing a hydroxyl group in the side arm (podand), also known as C-pivot lariats. The syntheses of these lariats including several that have not been previously reported and their efficient purification are described. The synthesis route leads to a robust and generalized approach to obtain these lariats on the gram scale. These agents were initially designed for applications in positron emission tomography (PET). In this medical imaging modality, tracer agents containing silicon have found promising utility as fluoride receptors for more rapid radiolabeling. Phase transfer agents are generally required for 18F-labeling due to the low solubility in organic reaction media and reactivity of cyclotron-generated [18F]potassium fluoride. We envisioned that 18-C-6 derivatives may serve as both phase transfer agents as well as nucleophilic catalysts (CENCs). In this conception, CENCs were rapidly pre-complexed with KF followed by silicon fluorination, which takes advantage of a previously established silicon dianion mechanism. In collaboration with researchers at the NIH, we studied the effect of various linkers connecting the metal chelating unit to the nucleophilic hydroxyl group on the radiofluorination of silicon under mild condition. A hydrolysis resistant aryl silicon fragment has also been developed that contains various functional groups for convenient attachment to the potential PET radiotracer agents. In a second project, we demonstrate the unique reactivity of γ-silyl allenyl esters. Taking advantage of the silyl group as a fluoride acceptor, these allenoates readily underwent addition to a variety of carbon electrophiles, including aryl fluorides, to afford all-carbon quaternary centers bearing an ethynyl group. Surprisingly, in the presence of aldehydes, exclusive bis-substitution occurs at the γ-position to afford the dicarbinol. Details relating to reaction optimization and substrate scope for both the reactions are presented. Dicarbinol allenes were subsequently converted to highly substituted δ-lactones, a novel 6-hydro-2-pyrone as single diastereomers. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

This thesis combines phenomenological and neuroscientific research to elucidate the effects of psychedelic agents on the human brain, mind and psychological well-being. Psychoactive plants have been used for thousands of years for ceremonial and ritual purposes. Psychedelics are psychoactive substances that affect cognitive processes and alter perception, thoughts, and mood. Illegalization of psychedelics in the 1960s rendered them impossible to study empirically but in the last couple of decades, relaxed legal restrictions regarding research purposes, renewed interest in the effects of psychedelic drugs and new brain imaging techniques have started to reveal the possibilities of these mind-altering substances. Psychedelics mainly affect the serotonin receptor 5-HT2A which in turn affect the functioning of largescale cortical areas by changing cerebral blood flow, alpha oscillations, and functional connectivity. These cortical changes not only induce immediate alterations in perception and cognition but have been shown to have positive effects in therapeutic interventions for depression, anxiety, and addiction, and also positively affect well-being in general. Although the pharmacology and neurobiology of psychedelics are still poorly understood, the potential benefits justify empirical research on psychedelics in humans.

As tiossemicarbazonas têm despertado grande interesse farmacológico por causa de suas propriedades biológicas, tais como a atividade citotóxica contra várias linhagens de tumores humanos. A maioria destes compostos sintetizados é baseada na piridina, por causa da sua semelhança a metabólitos piridoxal que estão presentes na co-enzima B6. Os objetivos deste estudo foram a caracterização do efeito antitumoral de tiossemicarbazonas derivadas de N(4)-metil-toluil-2-acetilpiridina e 2- piridinoformamida e o desenvolvimento de um radiofármaco baseado num complexo metálico de tiossemicarbazona para aplicação na tomografia por emissão de pósitron (PET). Na primeira fase deste trabalho foram sintetizadas vinte e uma tiossemicarbazonas, derivadas de N(4)-metil-toluil-2-acetilpiridina e 2-piridinoformamida, bem como seus complexos metálicos (Sn, Ga e Cu), para se avaliar seus potenciais citotóxicos e antiproliferativos in vitro sobre células de tumores cerebrais e mamários. Nossos resultados mostraram que todas tiossemicarbazonas testadas apresentaram potente efeito citotóxico e antiproliferativo contra linhagens de células de glioblastoma multiforme e carcinoma de mama, com valores de IC50 (concentração do composto que produziu 50% de morte celular) na ordem de nanomolar. Além disso, foram observadas alterações morfológicas como arredondamento celular, redução do volume citoplasmático e condensação da cromatina, característicos do mecanismo apoptótico. O cloreto de cobre foi usado como controle e apresentou o valor da IC50 na ordem de milimolar, indicando que a complexação do cobre com tiossemicarbazona foi capaz de aumentar mais de 1 milhão de vezes a potência antitumoral deste metal. Na segunda etapa deste trabalho, devido a potente atividade antitumoral das tiossemicarbazonas derivadas de N(4)-metil-toluil-2-acetilpiridina e das excelentes propriedades do 64Cu (T1/2= 12,7 h, decaimento por &#946;+, &#946;- e EC) foi desenvolvido um novo agente de imagem (radiofármaco) para detecção de tumores através da PET. Os radiofármacos foram produzidos no reator nuclear TRIGA-IPR-R1 do CDTN, via reação de captura neutrônica 63Cu(n, y)64Cu, do complexo de cobre N(4)-orto-toluil-2- acetilpiridina tiossemicarbazona (Culac). A maior atividade específica induzida foi 5,55 MBq/mg. Depois de irradiadas, as amostras de 64Culac foram analisadas por espectroscopia de absorção no infravermelho (IV) para se avaliar a integridade estrutural química. Todos os compostos irradiados mantiveram sua estrutura química íntegra. Em seguida, foi avaliada a manutenção da atividade antitumoral in vitro do 64Culac, pelo ensaio do MTT, nas linhagens de células RT2 (p53 selvagem), T98 (p53 mutante), MCF-7 (p53 selvagem), CAE (p53 selvagem). Os resultados mostraram a manutenção da potente atividade antitumoral do 64Culac em todas as células tratadas e apresentou valores da IC50 da ordem de nanomolar. Os estudos de biodistribuição do 64Culac, realizados por injeções via endovenosa caudal, em camundongos implantados nos coxins plantares com tumor de Ehrlich mostraram captação significativa na pata com tumor (razão tumor/músculo esquelético de 6,55) em relação ao controle no tempo de 240 minutos após administração deste composto. Estudos histopatológicos revelaram leve hepatotoxicidade após 144 horas (6 dias) da administração endovenosa de 136 &#956;g/kg do Culac. Contudo, nesta dose não foi observada letalidade, nem alterações comportamentais, locomotoras ou nutricionais nos animais. Os nossos resultados demonstraram que o complexo de cobre-64 N(4)-orto-toluil-2- acetilpiridina tiossemicarbazona (64Culac) é um promissor radiofármaco para detecção de tumores sólidos pela tomografia por emissão de pósitrons (PET). / Thiosemicarbazones have attracted great pharmacological interest because of their biological properties, such as cytotoxic activity against multiple strains of human tumors. The most studied compounds are pyridine-based because of their resemblance to pyridoxal metabolites that attach to co-enzyme B6-dependant enzymes. This work aimed the characterization of the antitumoral effect of N(4)-methyl-tolyl-2-acetilpiridine and 2- pyridinoformamidederived thiosemicarbazones and the development of a radiopharmaceutical based on a thiosemicarbazone metal complex for positron emission tomography. In the first phase of this study were synthesized twenty-one thiosemicarbazones, derived from N(4)methyl-2 acetylpyridine and 2-pyridineformamide, as well as their metal complexes (Sn, Ga and Cu). Their cytotoxic potential were evaluated against brain and breast tumor cells in vitro. Our results showed all of them presented powerful cytotoxic and antiproliferative activities against glioblastoma multiforme and breast adenocarcinoma at very low concentrations (nanomolar range). Morphological alterations characteristic of apoptosis, such as cell shrinkage, chromatin condensation were observed. Copper chloride was used as control and has presented IC50 at milimolar range suggesting that copper complexation with thiosemicarbazone significantly increases (more than 1 million) the antitumoral effect of this metal. Due to the potent antitumoral activity of N(4)-methyl-tolyl-2-acetilpiridine derived thiosemicarbazones and the excellent properties of 64Cu (T1/2 = 12.7 hours, &#946;+, &#946;-, and EC decay), at the second part for this work it was developed a new imaging agent (radiopharmaceutical) for tumor detection by positron emission tomography (PET). The radiopharmaceuticals were produced in the nuclear reactor TRIGA-IPR-R1 from CDTN, via neutron capture reaction 63Cu (n,&#947;) 64Cu, of the copper complex N(4)-ortho-toluyl-2- acetylpyridine thiosemicarbazone (Culac). The induced specific activity was found to be 5.55 MBq /mg. After irradiation 64Culac samples were analyzed by the absorption of infrared spectroscopy (IR) to assess the structural integrity. The irradiated compound kept its structural integrity. The maintenance of 64Culac biological activity was also evaluated by MTT assay on RT2 (wild p53), T98 (mutant p53), MCF-7 (wild p53) and CAE cells (wild p53). The results showed that 64Culac kept its potent antitumural activity against all treated cells presenting IC50 values at nanomolar range. 64Culac biodistribution studies after intravenous injection in mice bearing Erlich tumor implanted in the paw, showed significant uptake in the tumor paw (tumor/skeletal muscle ratio= 6.55), 240 minutes after administration. Histopathological studies have shown mild hepatotoxicity 144 hours (6 days) after intravenous administration of 308 mg/kg of Culac. However, no lethality, behavioural, or feeding changes were observed at this dose. Our results demonstrate that the complex of copper-64 N(4)-ortho-toluyl-2- acetylpyridine thiosemicarbazone (64Culac) is a promising radiopharmaceutical for detection of solid tumors by positron emission tomography (PET).

A Tomografia por Emissão de Pósitrons (PET - Positron Emission Tomography) é uma modalidade de imagens para o diagnóstico em Medicina Nuclear. São utilizados radiofármacos emissores de pósitrons que possibilitam obter imagens que representam o processo bioquímico dessas substâncias no órgão ou tecido de interesse in vivo. São detectados, em coincidência, os fótons provenientes da aniquilação pósitron/elétron, que ocorre dentro do corpo do paciente. Esta informação é posteriormente utilizada para a reconstrução do objeto em estudo. Atualmente, existem dois tipos de equipamentos capazes de realizar estudos tomográficos por emissão de pósitrons: o dedicado e a câmara PET/SPCET. Este trabalho abordou este último tipo, que permite também a realização de exames habituais de Medicina Nuclear, que usam emissores de fótons. Existem dificuldades inerentes ao método de aquisição destas imagens que afetam a quantificação de índices ou atividade. Elas estão relacionadas ao fato de a emissão de radiação obedecer a uma distribuição de Poisson, às interações físicas da radiação com o corpo do paciente e com o detector, ao ruído devido à natureza estatística destas interações e de todo o processo de detecção, assim como à metodologia de aquisição dos exames (preparo e posicionamento do paciente, taxa de contagens etc.). Correções são propostas na literatura que não são totalmente implementadas pelos fabricantes: de espalhamento, de atenuação, de eventos aleatórios, do tempo morto, de decaimento, da resolução espacial e de outras características do equipamento. O objetivo deste trabalho foi o de realizar um estudo dos métodos aplicados por dois fabricantes, assim como algumas influências das características técnicas das câmaras PET/SPECT na obtenção do índice de SUV (Standardized Uptake Value). Para isso, dados de simuladores físicos, dispostos em várias montagens, foram obtidos com uma câmara no modo 3D e outra no modo 20. Constatou-se também que a forma das fontes usadas para calibração influencia no resultado final e impõe novos desafios para a quantificação em uma situação clínica. Por fim, no momento da quantificação, a região de interesse deve ser escolhida de acordo com aquela usada para a determinação dos coeficientes de correção e calibração. Verificou-se que é viável realizar quantificações com câmaras PET/SPECT, inclusive o índice SUV. Para tanto, além das correções citadas anteriormente, é imprescindível ter o equipamento bem ajustado, assim como a obtenção de coeficientes para normalização da sensibilidade e correção do efeito de volume parcial. / Positron Emission Tomography (PET) is a Nuclear Medicine imaging modality for diagnostic purposes. Pharmaceuticals labeled with positron emitters are used and images which represent the in vivo biochemical process within tissues can be obtained. The positron/electron annihilation photons are detected in coincidence and this information is used for object reconstruction. Presently, there are two types of systems available for this imaging modality: the dedicated systems and those based on gamma camera technology. In this work, we utilized PET/SPECT systems, which also allows for the traditional Nuclear Medicine studies based on single photon emitters. There are inherent difficulties which affect quantification of activity and other indices. They are related to the Poisson nature of radioactivity, to radiation interactions with patient body and detector, noise due to statistical nature of these interactions and to all the detection processes, as well as the patient acquisition protocols. Corrections are described in the literature and not all of them are implemented by the manufacturers: scatter, attenuation, randoms, decay, dead time, spatial resolution, and others related to the properties of each equipment. The goal of this work was to assess these methods adopted by two manufacturers, as well as the influence of some technical characteristics of PET/SPECT systems on the estimation of SUV. Data from a set of phantoms were collected in 3D mode by one camera and 20, by the other. We concluded that quantification is viable in PET/SPECT systems, including the estimation of SUVs. This is only possible if, apart from the above mentioned corrections, the camera is well tuned and coefficients for sensitivity normalization and partial volume corrections are applied. We also verified that the shapes of the sources used for obtaining these factors play a role on the final results and should be dealt with carefully in clinical quantification. Finally, the choice of the region of interest is critical and it should be the same used to calculate the correction factors.