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.

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.

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.

Introduction. Fused Positron Emission Tomography and Computed Tomography (PET/CT) is an emerging investigative tool in cardiovascular disease that provides an imaging-based quantification of pathophysiological processes of interest. The purpose of this thesis was to study the application of PET to identify fundamental pathophysiological processes driving 3 forms of cardiovascular disease: aortic stenosis, myocardial infarction, and atherosclerosis. Methods. Aortic Stenosis. Patients with a spectrum of calcific aortic valve disease (n=121) who underwent PET-CT imaging for the identification of valvular calcification (18Ffluoride) and inflammation (18F-fluorodeoxyglucose, 18F-FDG) underwent serial imaging and clinical follow-up over 2 years. Baseline imaging findings were compared with echocardiographic and CT markers of disease progression and clinical outcome. Myocardial Infarction. Patients underwent PET-CT imaging with 18F-fluciclatide (a novel αvβ3-selective radiotracer highlighting active angiogenesis, inflammation and fibrosis) after ST-segment elevation MI (n=21), alongside stable patients with chronic total occlusion (CTO) of a major coronary vessel (n=7), and healthy volunteers (n=9). Myocardial radiotracer uptake was compared with clinical and cardiac magnetic resonance imaging (CMR) markers of infarction and remodeling. Atherosclerosis. Patients with a spectrum of atherosclerotic disease categorized as stable or unstable (recent MI) underwent PET/CT imaging with 18F-fluciclatide (n=46). Thoracic aortic 18F-fluciclatide uptake was compared with aortic atherosclerotic burden quantified by CT plaque thickness, plaque volume and calcium scoring. Histological validation. Tissue from the aortic valve, myocardium and carotid arteries of study subjects was acquired and examined ex vivo using histology and autoradiography. Results. Aortic Stenosis. Baseline valvular 18F-fluoride uptake correlated strongly with the rate of progression in AVC (r=0.80, p < 0.001) and with haemodynamic progression (mean aortic valve gradient r=0.32, p=0.001). It emerged as independently associated with clinical outcome after age and sex-adjustment (HR 1.55 [1.33-1.81], p < 0.001). 18F-FDG demonstrated moderate correlations with disease progression as assessed by CT (r=0.43, p=0.001) and echocardiography (18F-FDG r=0.30, p=0.001), and was associated with clinical outcomes independent of age and sex (HR 1.35 [1.16-1.58], p < 0.001). Valvular 18F-fluoride uptake correlated with immunohistochemical markers of calcification activity. There was no correlation between 18F-FDG uptake and inflammation. Myocardial Infarction. 18F-Fluciclatide binding was demonstrated in ex vivo peri-infarct myocardium and uptake was increased in vivo at sites of acute infarction compared to remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17 respectively, p < 0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p < 0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with myocardial activity similar to healthy volunteers (TBRmean 0.71±0.06 vs. 0.70±0.03,p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index ≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p < 0.001), was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Atherosclerosis. 18F-Fluciclatide vascular binding ex vivo co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide uptake in vivo correlated with measures of aortic atherosclerotic burden: plaque thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and the CT aortic calcium score (r=0.37, p=0.01). Patients with recent MI had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.33 vs 1.21, p=0.01). Conclusions. In a range of cardiovascular diseases, PET-CT can provide insights into key pathophysiological processes, guide patient risk stratification and prognosis, and identify important biomarkers of disease activity that can be used for the development of future therapeutic interventions.

Computed tomography imaging has revolutionised modern medicine and we can now study the body in greater detail than ever before. Cardiac computed tomography has the potential to provide information not just on coronary anatomy, but also on myocardial function, perfusion and viability. This thesis addresses the optimisation and validation of computed tomography imaging of the heart using a wide volume 320-multidetector scanner. Computed tomography coronary angiography now has diagnostic accuracy comparable to invasive coronary angiography. However, radiation dose remains an important concern. It is therefore important to minimise computed tomography radiation dose while maintaining image quality. I was able to demonstrate that iterative reconstruction and patient tailored imaging techniques led to a 39% reduction in radiation dose in computed tomography coronary angiography, while maintaining subjective and objective assessments of image quality. In addition, I demonstrated that diagnostic images can be obtained in 99% of unselected patients presenting with suspected coronary artery disease when using single heart-beat 320- multidetector computed tomography coronary angiography. Computed tomography myocardial perfusion imaging can provide additional and complementary information as compared to computed tomography coronary angiography that can aid diagnosis and management. I established both quantitative and qualitative assessment of computed tomography myocardial perfusion imaging and validated it against both a clinical “gold-standard”, fractional flow reserve during invasive coronary angiography, and a physiological “gold-standard”, positron emission tomography with oxygen-15 labelled water. Finally, I was able to show that techniques to reduce radiation dose can also be applied to computed tomography myocardial perfusion imaging, leading to a 60% reduction in radiation dose, while maintaining image quality. In my thesis, I have established that comprehensive cardiac angiographic and perfusion imaging can be performed with wide volume computed tomography in a broad generalizable population of patients with relatively low radiation exposure. These techniques provide both structural and functional assessments from a single imaging modality that are valid and readily applicable to the clinic in the assessment and management of patients with suspected coronary artery disease.

Positron Emission Tomography (PET) has great value in research and clinical applications from oncology to neurodegenerative disorders. However, there is a barrier in translating biological knowledge into new PET applications due in part to the lack of efficient, widely applicable methods for labelling compounds with PET radioisotopes. Herein, a generic approach to radiolabelling is presented which is direct, broadly applicable and potentially adaptable to either of the two most commonly used PET radioisotopes, 11C and 18F. This approach employs the advantages of solid phase synthesis to achieve selective release of only the desired radiolabelled product from a solid support in a single step, simplifying purification and hence improving synthetic efficiency. Polystyrene resin was functionalised with a 1,2-diol group; this allowed the covalent attachment of compounds bearing boronic acid groups via formation of a boronate ester linkage. A Suzuki-Miyaura reaction with methyl iodide was used to cleave a model compound from the resin in 61% conversion after five minutes. This reaction was adapted to develop a fully automated radiosynthesis with [11C]- methyl iodide which generated a radiolabelled model compound in 2 – 7% non-decay-corrected radiochemical yield. This provided proof of concept for the simultaneous cleavage of compounds from the resin and radiolabelling with 11C. A boronic acid precursor of the known radiotracer [11C]-M-MTEB was attached to the resin and successfully radiolabelled with 11C in 2.4% non-decay-corrected radiochemical yield and 96 – 100% radiochemical purity under the same conditions. Furthermore, the potential adaptability of this solid phase approach to 18F radiolabelling was demonstrated by treatment of the resin-bound small molecules and peptides with potassium bifluoride, which released the compounds rapidly as trifluoroborate salts.

A characteristic feature of Chronic Obstructive Pulmonary Disease (COPD) is an abnormal inflammatory response in the lungs to inhaled particles or gases. The ability to assess and monitor this response in the lungs of COPD patients is important for understanding the pathogenic mechanisms, but also provides a measure of the activity of the disease. Disease activity is more likely to relate to lung inflammation rather than the degree of airflow limitation as measured by the FEV1. Preliminary studies have shown the 18F fluorodeoxyglucose positron emission tomography (18F FDG-PET) signal, as a measure of lung inflammation, is quantifiable in the lungs and is increased in COPD patients compared to controls. However, the methodology requires standardisation and any further enhancement of the methodology would improve its application to assess inflammation in the lungs. I investigated various methods of assessing FDG uptake in the lungs and assessed the reproducibility of these methods, and particularly evaluated whether the data was reproducible or not in the COPD patients (smokers and ex-smokers). This data was then compared with a group of healthy controls to assess the role of dynamic 18F FDG-PET scanning as a surrogate marker of lung inflammation. My data showed a good reproducibility of all methods of assessing FDG lung uptake. However, using conventional Patlak analysis, the uptake was not statistically different between COPD and the control group. Encouraging results in favour of COPD patients were nonetheless shown using compartmental methods of assessing the FDG lung uptake, suggesting the need to correct for the effect of air and blood (tissue fraction effect) when assessing this in a highly vascular organ like the lungs. A prospective study analysis involving a bigger cohort of COPD patients would be desirable to investigate this further.

Neste trabalho foi feito um estudo do perfil tomográfico da emissão da linha do átomo de hidrogênio, H-alfa (?=656,28 nm) no plasma do TCABR, um tokamak de porte médio em operação no Laboratório de Física de Plasmas do Instituto de Física da Universidade de São Paulo. Nosso trabalho centrou-se no estudo dos efeitos da introdução de um eletrodo polarizado na borda do plasma no tokamak TCABR. O eletrodo pode ser introduzido até 1,5 cm para dentro da coluna do plasma, sem causar disrupturas para polarização positiva de 0 até +350V, e situado no plano equatorial do tokamak. Perfis tomográficos de H-alfa com e sem polarização foram medidos. A comparação dos perfis mostra um aumento da densidade de linha na posição central, quando a emissividade H-alfa diminui. A análise dos perfis tomográficos de H-alfa, tempo de confinamento das partículas e também do estudo de reciclagem das partículas neutras, indica que o plasma entra no regime de alto confinamento (modo-H). Cálculos de turbulência e de transporte na borda do plasma (SOL), feitos medindo o potencial flutuante e a corrente de saturação de íons, mostram uma diminuição forte no espectro de potência e de transporte. Também foram feitos estudos do novo regime de descargas com elétrons fugitivos (\"runaway electron\"), descoberto no tokamak TCABR. As características distintivas deste regime são um plasma de baixa temperatura fracamente ionizado, destacado do limitador devido a processos de recombinação, e instabilidade de relaxação com fortes picos de emissão H-alfa correlacionados com instabilidade dente de serra da densidade eletrônica de linha. No presente trabalho fazemos a descrição das condições experimentais para a geração destas descargas. A produção dos elétrons fugitivos é analisada; mostrando que a geração de elétrons fugitivos somente pode ser explicada pelo mecanismo de avalanche. A confirmação de baixa temperatura do plasma é obtida de uma análise do perfil tomográfico da emissão H-alfa. Esta emissão não pode ser explicada por excitação de elétrons no plasma. A recombinação, de outro lado, dá uma explicação plausível para a dependência temporal da emissão, em particular para alta densidade de partículas neutras. / A study of the tomography profile of the emission of the line of Hydrogen, atomic H-alpha line (?=656.28 nm), was carried out in TCABR, a medium-size tokamak in operation at the Laboratory of Plasma Physics of the Institute of Physics of the University of São Paulo. Our work focuses on the study of the effects of due to the introduction of a biased electrode in the plasma edge of the TCABR tokamak. The electrode could be introduced up to 1.5 cm inside the plasma, without plasma disruptions for positive voltages from 0 to +350V, and was located on the equatorial plane of the plasma column. Tomography profiles of H-alpha with and without bias were measured. Comparison of the profiles shows an increase of the central line-averaged density, while the emissivity of the line H-alpha decreases. The analysis of the tomography profiles of H-alpha, time of confinement of particles and also the study of recycling of the neutral particles, indicate that the confined plasma enters the H-mode regime. Calculations of turbulence and transport at the Scrape-Off-Layer, using measured floating potentials and ion saturation currents, show a strong decrease in the power spectra and transport. The H-alpha tomography was also employed to study the new regime of runaway discharges that has been discovered in the TCABR tokamak. The distinctive features of this regime are weakly ionized low-temperature plasma detached from the limiter due to the recombination process, and a relaxation instability with strong spikes of H-alpha emission correlated with sawtooth relaxation of the line density. In the present thesis we report experimental data on conditions for generation of these discharges. The runaway electron production is analyzed; show that generation of runaway electrons can only be explained by the runaway avalanche mechanism. The confirmation of low plasma temperature is a obtained from an analysis of the tomography profile of H-alpha emission. This emission cannot be explained by excitation by plasma electrons. Recombination, on the other hand, gives a rather plausible explanation for the time dependency of the emission, in particular at high neutral densities.

Reconstructed tomographic image resolution of small animal PET imaging systems is improving with advances in radiation detector development. However the trend towards higher resolution systems has come with an increase in price and system complexity. Recent developments in the area of solid-state photomultiplication devices like silicon photomultiplier arrays (SPMA) are creating opportunities for new high performance tools for PET scanner design. Imaging of excised small animal organs and tissues has been used as part of post-mortem studies in order to gain detailed, high-resolution anatomical information on sacrificed animals. However, this kind of ex-vivo specimen imaging has largely been limited to ultra-high resolution μCT. The inherent limitations to PET resolution have, to date, excluded PET imaging from these ex-vivo imaging studies. In this work, we leverage the diminishing physical size of current generation SPMA designs to create a very small, simple, and high-resolution prototype detector system targeting ex-vivo tomographic imaging of small animal organs and tissues. We investigate sensitivity, spatial resolution, and the reconstructed image quality of a prototype small animal PET scanner designed specifically for imaging of excised murine tissue and organs. We aim to demonstrate that a cost-effective silicon photomultiplier (SiPM) array based design with thin crystals (2 mm) to minimize depth of interaction errors might be able to achieve sub-millimeter resolution. We hypothesize that the substantial decrease in sensitivity associated with the thin crystals can be compensated for with increased solid angle detection, longer acquisitions, higher activity and wider acceptance energy windows (due to minimal scatter from excised organs). The constructed system has a functional field of view (FoV) of 40 mm diameter, which is adequate for most small animal specimen studies. We perform both analytical (3D-FBP) and iterative (ML-EM) methods in order to reconstruct tomographic images. Results demonstrate good agreement between the simulation and the prototype. Our detector system with pixelated crystals is able to separate small objects as close as 1.25 mm apart, whereas spatial resolution converges to the theoretical limit of 1.6 mm (half the size of the smallest detecting element), which is to comparable to the spatial resolution of the existing commercial small animal PET systems. Better system spatial resolution is achievable with new generation SiPM detector boards with 1 mm x 1 mm cell dimensions. We demonstrate through Monte Carlo simulations that it is possible to achieve sub-millimeter spatial image resolution (0.7 mm for our scanner) in complex objects using monolithic crystals and exploiting the light-sharing mechanism among the neighboring detector cells. Results also suggest that scanner (or object) rotation minimizes artifacts arising from poor angular sampling, which is even more significant in smaller PET designs as the gaps between the sensitive regions of the detector have a more exaggerated effect on the overall reconstructed image quality when the design is more compact. Sensitivity of the system, on the other hand, can be doubled by adding two additional detector heads resulting in a, fully closed, 4π geometry.