Résumé : La tomographie d’émission par positrons (TEP) permet une imagerie fonctionnelle et moléculaire qui peut bénéficier de l’utilisation conjointe de la tomodensitométrie (TDM), d’abord pour fournir un support anatomique aux images TEP, mais aussi pour permettre une correction plus précise des images TEP. Les appareils existants sont composés de deux scanners juxtaposés nécessitant un déplacement du sujet entre les deux acquisitions, ce qui peut causer des artéfacts de mouvement dans l’image fusionnée TEP/TDM. De plus, le mode de fonctionnement des scanners TDM, basé sur l’intégration du flux de rayons X, délivre une dose de radiations relativement élevée qui peut interférer avec la réalisation d’études/protocoles d’imagerie longitudinales. La réalisation d’un appareil TEP/TDM partageant le même système de détection basé sur le détecteur LabPET II pourrait remédier à ces problèmes. Dans un premier temps, le module de détection LabPET II a été caractérisé pour la TEP et la TDM. Les premières études d’imagerie TDM avec ce détecteur ont aussi été conduites avec un simulateur. Ce travail a permis de déceler un phénomène de diaphonie optique au sein du module de détection. La recherche d’une solution à ce problème a motivé l’évaluation de nouveaux types de réflecteurs métallisés, donc plus opaques, pour en limiter les effets. Le signal relativement faible détecté en TDM a par la suite mené à explorer des scintillateurs alternatifs présentant un rendement lumineux supérieur. L’un de ces scintillateurs permettra d’améliorer sensiblement les performances du scanner LabPET I et pourrait être retenu pour la génération future de scanners LabPET II. || Abstract : Positron emission tomography (PET) provides functional and molecular imaging capabilities that can benefit from joint use with computed tomography (CT), first to provide anatomical support to PET images, but also to allow a more precise correction of PET images. Existing devices are composed of two back-to-back scanners which require displacing the subject between the two acquisitions, possibly causing motion artifacts in the fused PET/CT images. Moreover, the operation mode of CT scanners based on the X-ray signal integration delivers a relatively high radiation dose that can interfere with longitudinal imaging studies/protocols. The realization of a PET/CT scanner sharing the same detection system for both 511 keV and X-ray photons and based on the LabPET II could remedy these problems. As a first step, a characterization of the detection module LabPET II was performed in PET and CT mode. The first CT imaging studies with this detector were also conducted with a simulator. This work allowed identifying an optical crosstalk phenomenon in the detection module. The search for a solution to this problem has motivated the evaluation of new types of metallized, more opaque, reflectors to limit crosstalk effects. The relatively low signal detected in CT led us to explore alternative scintillators having a higher light output. One of these scintillators will significantly improve the performance of the LabPET I scanner and could be used for the next generation of LabPET II scanners.

Résumé : Les performances de détecteurs à scintillation, composés d’un cristal scintillateur couplé à un photodétecteur, dépendent de façon critique de l’efficacité de la collecte et de l’extraction des photons de scintillation du cristal vers le capteur. Dans les systèmes d’imagerie hautement pixellisés (e.g. TEP, TDM), les scintillateurs doivent être arrangés en matrices compactes avec des facteurs de forme défavorables pour le transport des photons, au détriment des performances du détecteur. Le but du projet est d’optimiser les performances de ces détecteurs pixels par l'identification des sources de pertes de lumière liées aux caractéristiques spectrales, spatiales et angulaires des photons de scintillation incidents sur les faces des scintillateurs. De telles informations acquises par simulation Monte Carlo permettent une pondération adéquate pour l'évaluation de gains atteignables par des méthodes de structuration du scintillateur visant à une extraction de lumière améliorée vers le photodétecteur. Un plan factoriel a permis d'évaluer la magnitude de paramètres affectant la collecte de lumière, notamment l'absorption des matériaux adhésifs assurant l'intégrité matricielle des cristaux ainsi que la performance optique de réflecteurs, tous deux ayant un impact considérable sur le rendement lumineux. D'ailleurs, un réflecteur abondamment utilisé en raison de ses performances optiques exceptionnelles a été caractérisé dans des conditions davantage réalistes par rapport à une immersion dans l'air, où sa réflectivité est toujours rapportée. Une importante perte de réflectivité lorsqu'il est inséré au sein de matrices de scintillateurs a été mise en évidence par simulations puis confirmée expérimentalement. Ceci explique donc les hauts taux de diaphonie observés en plus d'ouvrir la voie à des méthodes d'assemblage en matrices limitant ou tirant profit, selon les applications, de cette transparence insoupçonnée. / Abstract : The performance of scintillation detectors, made up of a scintillating crystal coupled to a photodetector, critically depends on the collection and extraction efficiency of scintillation photons from the crystal by the sensor. In highly pixelated imaging systems (e.g. PET, CT), scintillators must be arranged in compact arrays with form factors detrimental to light transport, deteriorating the detector performance. The goal of the study was to optimize the pixelated detectors performance by identifying the light loss sources related to the spectral, spatial and angular characteristics of the scintillation photons impinging on scintillators faces. Such information acquired by Monte Carlo simulations enables adequate weighting for the evaluation of achievable gains through structuring of the scintillators for enhanced light extraction to the photodetector. The magnitude of parameters affecting the light collection in arrays, such as adhesive materials absorption and reflector opacity that both have high impact on light output, was evaluated through a factorial design. A frequently used reflector because of its outstanding optical performance was characterized in more realistic conditions compared to air immersion in which its reflectivity is always reported. An important reflectivity quenching of the reflector in optically bonded scintillator arrays was discovered by simulation and confirmed experimentally. This explains the high light crosstalk measured in pixelated arrays as well as paving the way to assembling methods limiting or taking advantage, depending on the application, of this unsuspected transparency.

No description available.

Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

La maladie veineuse thrombombolique (MVTE), associant thrombose veineuse profonde et embolie pulmonaire, peut être le premier signe d’un cancer jusque-là méconnu. Des études anciennes ont rapporté que 6 à 15% des patients étaient diagnostiqués d’un cancer occulte dans l’année suivant l’épisode de MVTE. L'identification précoce d’un cancer occulte au moment du diagnostic de la MVTE non provoquée est fondamentale car la présence d’un cancer va conditionner la prise en charge du patient, que ce soit au niveau de la thrombose ou du cancer. Actuellement, les recommandations préconisent un dépistage limité du cancer en cas de MVTE non-provoquée, basé sur un examen clinique complet (interrogatoire, examen physique), un bilan biologique de base, une radiographie thoracique ainsi que tous les examens communément admis pour le dépistage du cancer en fonction de l’âge et du sexe du patient (PSA chez les hommes, mammographie et examen gynécologique chez les femmes). La tomographie par émission de positon (TEP) au 18F-fluorodéoxyglucose (FDG) est une technique d’imagerie en pleine expansion depuis les années 2000. Elle est largement utilisée en routine clinique pour la détection des foyers tumoraux, leur bilan d’extension, l’évaluation des traitements ainsi que le bilan de possibles récidives. En revanche, aucune étude n’a aujourd’hui évalué l’intérêt de cette technique dans le dépistage du cancer chez les patients présentant une MVTE non provoquée. Afin de répondre à cette problématique, l’objectif de cette thèse a été spécifiquement d’étudier l’intérêt de la TEP au FDG pour la détection des néoplasies dans le bilan étiologique d’une MVTE non provoquée au travers des résultats de l'étude MVTEP, étude multicentrique randomisée comprenant une stratégie de dépistage limitée associée à une TEP au FDG à une stratégie limitée seule. / Venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism, can occur as the first manifestation of an underlying occult malignancy. Previous studies reported that the incidence of undiagnosed cancer is 6% to 15% in the year following an unprovoked VTE épisode, i.e. VTE not provoked by a major risk factor.In patients with unprovoked VTE, extensive screening for cancer has been proposed in order to diagnose occult malignancy as early as possible in the hope of improving the prognosis. Current guidelines for occult cancer screening in patients with unprovoked VTE recommend limited cancer screening, including of a thorough medical history and physical examination, basic laboratory investigations, chest X-ray, as well as age-specific and gender-specific cancer screening (colon, breast, and prostate) according to national guidelines.18F-Fluorodesoxyglucose Positron Emission Tomography combined with Computed Tomography (FDG PET/CT) is routinely used for the diagnosis and staging of various malignancies. The use of FDG PET/CT might overcome the limitations of previous extensive screening strategies as it involves whole-body imaging using a single, non-invasive test. To date, there has been no formal assessment of the additional value of FDG PET/CT for occult malignancy screening in patients with unprovoked venous thromboembolism.To address this issue, we conducted a multicenter randomised controlled trial comparing a limited screening strategy to a strategy combining limited screening and FDG PET/CT in patients with unprovoked venous thromboembolism, and then assessed the additional value of FDG PET/CT in addition to a limited strategy.

INTRODUÇÃO: Obesidade e doença de Alzheimer afetam um número cada vez maior de pessoas no mundo. Nos últimos anos, surgiram várias evidências de que essas duas doenças estão interligadas, sendo obesidade um fator de risco para a ocorrência de demência. A doença de Alzheimer é de mau prognóstico e de difícil tratamento e estão envolvidos na sua patogênese fatores genéticos e ambientais. A obesidade é encarada como um fator ambiental modificável e, talvez, capaz de mudar a história natural da doença se precocemente controlada. A cirurgia bariátrica é o tratamento mais eficaz para obesidade severa; no entanto, não se sabe claramente o efeito da cirurgia bariátrica sobre o metabolismo cerebral e a função cognitiva. OBJETIVOS: Avaliar prospectivamente o impacto da perda de peso induzida pela cirurgia bariátrica sobre metabolismo cerebral e função cognitiva de obesos; correlacionar metabolismo cerebral e função cognitiva antes e após a cirurgia bariátrica com marcadores metabólicos e inflamatórios. MÉTODOS: 17 mulheres obesas realizaram tomografia computadorizada com emissão de pósitrons com flúor-desoxi-glicose (PET-FDG) para avaliação do metabolismo cerebral de repouso (metabolismo glicolítico regional), testes neuropsicológicos para avaliação da função cognitiva e dosagens de marcadores metabólicos e inflamatórios antes e após a cirurgia bariátrica e, foram comparadas com 16 mulheres de peso normal, eutróficas, pareadas em idade e escolaridade. Foram excluídas da seleção pacientes portadoras de diabetes, usuárias de medicação psicotrópica nos três meses que antecederam as avaliações, portadoras de doença psiquiátrica grave atual ou prévia e mulheres com história de pais acometidos por demência antes dos 70 anos de idade. Nas mulheres obesas as avaliações do metabolismo cerebral, da função cognitiva e das dosagens laboratoriais foram realizadas antes e aproximadamente seis meses após a cirurgia bariátrica, enquanto nas mulheres eutróficas foram realizadas apenas uma vez. Os dados de imagem foram processados através do programa Statistical Parametric Mapping (SPM versão 8) e os demais através do Statistical Analysis System (SAS versão 9.3). Os dados encontrados nas obesas antes da cirurgia foram comparados aos obtidos após a perda de peso e, ambos foram comparados aos dados obtidos nas mulheres eutróficas. RESULTADOS: Mulheres com idade média de 40,5±9,1 anos e índice de massa corporal (IMC) médio de 50.1±4,7 kg/m2 quando comparadas a mulheres de mesma faixa etária com IMC médio de 22.3±2,1 kg/m2 apresentaram aumento do metabolismo cerebral em algumas áreas, principalmente do giro cingulado posterior, com valor de p corrigido para comparações múltiplas de 0,004. No entanto, não encontramos diferença no desempenho dos testes neuropsicológicos entre os grupos. Após a perda de peso, o metabolismo cerebral das mulheres obesas ficou semelhante ao das mulheres eutróficas e houve melhora no desempenho de teste que avalia função executiva (Trail Making Test). CONCLUSÃO: Estudos mostram que o giro cingulado posterior é uma das primeiras áreas acometidas pela doença de Alzheimer e que o aumento do metabolismo cerebral regional pode ser deletério. Esta condição encontrada em obesas, parece ser revertida após a perda de peso induzida por cirurgia bariátrica, acompanhando melhora da função executiva e de marcadores metabólicos e inflamatórios / INTRODUCTION: Obesity and Alzheimer\'s disease affect a growing number of people in the world. In recent years, evidence has arisen suggesting that these two illnesses are linked, with obesity being a risk factor for the occurrence of dementia. Alzheimer\'s disease has an unfavorable prognosis, is hard to treat and genetic and environmental factors are involved in the pathogenesis. Obesity is regarded as a modifiable environmental factor and maybe capable of changing the natural prognosis of the disease if controlled at an early stage. Bariatric surgery is the most effective treatment for severe obesity, however the effect of bariatric surgery on cerebral metabolism and cognitive function is not clearly known. OBJECTIVES: Prospectively assess the impact of weight loss caused by bariatric surgery on the cerebral metabolism and cognitive function of the obese. Correlate the cerebral metabolism and cognitive function before and after bariatric surgery with metabolic and inflammatory markers. METHODS: 17 obese women performed computerized positron emission tomography with fluoro-deoxy-glucose (FDG-PET) for the assessment of resting cerebral metabolism (regional glycolytic metabolism), neuropsychological tests to assess cognitive function and doses of metabolic and inflammatory markers before and after bariatric surgery and compared with 16 women of normal weight, eutrophic, paired by age and level of education. Patients with diabetes, those who had used psychotropic medication within three months prior to the assessments, people with current or previous history of severe psychiatric illness and women with a family history of dementia before 70 years of age. The assessments of cerebral metabolism, cognitive function and laboratory doses were conducted before and approximately 6 months after bariatric surgery in the obese women, whereas the women of normal weight were only assessed once. The imaging data was processed using the Statistic Parametric Mapping (SPM version 8) program and the others through the Statistical Analysis System (SAS version 9.3). The data found in the obese women prior to surgery were compared with those after the weight loss, and both were compared to the data taken from the eutrophic women. RESULTS: Women with a mean age of 40.5±9.1 years and mean body mass index (BMI) of 50.1±4.7 kg/m2 when compared to women of the same age group with mean BMI of 22.3±2.1 kg/m2 presented increased cerebral metabolism in some areas, in particular of the posterior cingulate gyrus, with a corrected p value for multiple comparisons of 0.004. However, differences were not found between the groups for the performance of the neuropsychological tests. After weight loss, the cerebral metabolism of the obese women was similar to the eutrophic women and they performed better in the tests to assess executive function (Trail Making Test). CONCLUSION: Studies show that the posterior cingulate gyrus is one of the first areas affected by Alzheimer\'s disease and that having increased regional cerebral metabolism may be deleterious. This condition found in the obese, appears to be reversed after weight loss induced by bariatric surgery, followed by improved executive function and metabolic and inflammatory markers

No Brasil, a difusão de conceitos da física nuclear na área médica ganhou destaque ao longo da última década com o uso do FDG-18F, substância análoga à glicose marcada radioativamente para atuar em procedimentos de diagnóstico e tratamento em oncologia, neurologia e cardiologia. Das três especialidades é no uso oncológico que estão suas aplicações de maior relevância como a detecção precoce de metástase e outras formas de monitoramento tumoral que resultam em maiores chances de sobrevida ao paciente. Estas possibilidades passaram a fazer parte da realidade nacional com a incorporação da tecnologia híbrida de PET-CT, equipamento gerador de imagens anatômicas e metabólicas para mapeamento preciso de lesões por meio da concentração de FDG-18F. O uso médico deste composto ganhou tamanha repercussão que a necessidade de expandir a oferta de FDG-18F para além dos bolsões geográficos contemplados pela produção pública culminou na aprovação de emenda constitucional que abriu o mercado de radiofármacos no país. O presente estudo aborda a formação da cadeia produtiva de radiofármacos irradiados em cíclotron a partir da quebra do monopólio de produção e comercialização de radioisótopos de meia-vida curta, em 2006, para demonstrar que, ao consolidar a cadeia produtiva de FDG-18F, instituições e atores sociais nela envolvidos constituíram um subsistema nacional de inovação em saúde / In Brazil, nuclear physics concepts become prominent in healthcare throughout the last decade with FDG-18F use, a glucose similar substance radioactively marked to be used in diagnosis and treatment procedures in oncology, neurology and cardiology, but it´s in oncology treatments that we can find the biggest relevance application with the early cancer metastasis detection and many other cancerous tumor monitoring forms that may be revert in patient life time gain. PET-CT hybrid technology incorporation made these possibilities become part of national reality. The equipment is able to produce integrated anatomical and metabolic images that shows tiny tissue damages tracking FDG-18F concentration. This medical composition become renowned enough to claim loud for geographic offer expansion until it raised a new law allowing private initiative taking part in radiopharmaceuticals production market. This research intent to describe the cyclotron radiopharmaceuticals irradiated supply chain building up process since productive and commercial public monopoly broke up in 2006, so then it will be able to prove that a new innovative healthcare subsystem has resulted by the social actors and institutions efforts to establish FDG-18F supply chain

L’obésité et le surpoids ont été décrits comme une pandémie. L’obésité et le vieillissement vont conduire à des complications cardiovasculaires. De plus, l’obésité favoriserait un vieillissement cardiaque prématuré chez les adultes jeunes. L’hypothèse de ce travail est qu’un régime riche en graisses, démarré avant l’âge adulte, poursuivi sur une longue durée, pourrait entraîner un vieillissement « accéléré » cardiovasculaire et métabolique. Nous avons démontré, dans un modèle murin vieillissant, qu’un régime riche en graisses conduit à des troubles métaboliques ainsi qu’à une augmentation de la masse grasse et à une détérioration du métabolisme au niveau du tissu adipeux blanc. Ces troubles sont associés à des altérations au niveau cardiaque, malgré l’absence de modifications de la pression artérielle et de la fréquence cardiaque. Le vieillissement, chez les souris obèses, va conduire à un remodelage du ventricule gauche accompagné par une dysfonction systolique. Au niveau tissulaire cardiaque, le vieillissement et le régime précoce conduisent à l’augmentation de l’expression de gènes de fibrose confirmant ainsi le phénotype hypertrophique. Le vieillissement associé à un régime riche en graisses précoce conduit également à une up-régulation de GDF11. GDF11 peut alors être considéré comme un marqueur de vieillissement cardiaque accéléré. Ces résultats peuvent suggérer des voies thérapeutiques ou préventives, où l’inhibition de GDF11 améliorerait le pronostic et la survie cardiovasculaire des sujets obèses. L’étude de ce modèle nous a ainsi permis de mettre en évidence qu’un régime riche en graisses conduit à un vieillissement accéléré au niveau cardiaque / Obesity and being overweight have been described as a global pandemic. Both obesity and aging will lead to cardiovascular complications. In addition, it has been highlighted that obesity promotes premature cardiac aging in young adults. The hypothesis of this work is that a high fat diet begun before adulthood, pursued over a long period of time, could lead to “accelerated” cardiovascular and metabolic aging. We have demonstrated, in an aging mouse model, that an early high fat diet leads to metabolic disorders and to an increase in fat mass and a deterioration in metabolism of white adipose tissue. These disorders are associated with alterations in cardiac morphology and function, despite an absence of changes in blood pressure and heart rate. Ageing, in obese mice, leads to ventricular remodeling accompanied by systolic dysfunction. In cardiac tissue, aging and early diet lead to an increased expression of fibrosis genes confirming the hypertrophic phenotype. Aging associated with an early high fat diet led also to an up-regulation of GDF11. GDF11 may then be considered as a marker of accelerated cardiac aging. These results may suggest therapeutic or preventive pathways, where inhibition of GDF11 improves prognosis and survival in obese subjects with cardiovascular disease. The study of this model has allowed us to demonstrate that a high fat diet leads to accelerated aging at the level of the heart

La tomographie par émission de positons (TEP) est une méthode d’imagerie fonctionnelle, utilisée en particulier lors du développement de nouveaux médicaments et pour imager les tumeurs. En TEP, l’estimation de la concentration plasmatique artérielle d’activité du traceur non métabolisé (nommée « fonction d’entrée ») est nécessaire pour l’extraction des paramètres pharmacocinétiques. Ceux-ci permettent de quantifier le comportement du traceur dans les tissus, ou plus précisément le traitement du traceur par les tissus. Cette thèse constitue une contribution à l’étude de la fonction d’entrée, par l’élaboration d’une méthode d’estimation de la fonction d’entrée peu invasive à partir des images TEP et de prélèvements veineux. L’exemple du traceur FDG (analogue du glucose) dans le cerveau humain a été choisi. La méthode proposée repose sur la modélisation compartimentale de l’organisme : elle déconvolue le modèle à trois compartiments utilisé pour le FDG. L’originalité de la méthode repose sur trois points : l’utilisation d’un grand nombre de régions d’intérêt ; l’utilisation d’un grand nombre de jeux de trois régions d’intérêt différentes; une estimation itérative. Pour la validation de la méthode, un soin particulier a été porté à la simulation d’images TEP (simulation d’acquisition, reconstruction, corrections) de plus en plus réalistes, depuis une image simple simulée avec un simulateur analytique jusqu’à une image la plus proche possible de la réalité, simulée avec simulateur Monte-Carlo. Une chaîne de pré-traitement (segmentation des IRM associés, recalage entre images TEP et IRM et correction de l’effet de volume partiel par une variante de la méthode de Rousset) a ensuite été appliquée à ces images afin d’extraire les cinétiques des régions d’intérêt, données d’entrée de la méthode d’estimation de la fonction d’entrée. L’évaluation de la méthode sur différentes données, simulées et réelles, est présentée, ainsi que l’étude de la sensibilité de la méthode à différents facteurs tels que les erreurs de segmentation, de recalage, de mesure de l’activité des prélèvements sanguins. / Positron Emission Tomography (PET) is a method of functional imaging, used in particular for drug development and tumor imaging. In PET, the estimation of the arterial plasmatic activity concentration of the non-metabolized compound (the "input function") is necessary for the extraction of the pharmacokinetic parameters. These parameters enable the quantification of the compound dynamics in the tissues. This PhD thesis contributes to the study of the input function by the development of a minimally invasive method to estimate the input function. This method uses the PET image and a few blood samples. In this work, the example of the FDG tracer is chosen. The proposed method relies on compartmental modeling: it deconvoluates the three-compartment-model. The originality of the method consists in using a large number of regions of interest (ROIs), a large number of sets of three ROIs, and an iterative process. To validate the method, simulations of PET images of increasing complexity have been performed, from a simple image simulated with an analytic simulator to a complex image simulated with a Monte-Carlo simulator. After simulation of the acquisition, reconstruction and corrections, the images were segmented (through segmentation of an IRM image and registration between PET and IRM images) and corrected for partial volume effect by a variant of Rousset’s method, to obtain the kinetics in the ROIs, which are the input data of the estimation method. The evaluation of the method on simulated and real data is presented, as well as a study of the method robustness to different error sources, for example in the segmentation, in the registration or in the activity of the used blood samples.

Le système sérotoninergique, impliqué dans plusieurs pathologies du système nerveux central, peut être exploré in vivo par l’imagerie TEP (tomographie par émission de positons). La recherche et la validation préclinique de radiotraceurs ciblant spécifiquement les récepteurs sérotoninergiques est donc cruciale. Au cours de ce travail, nous nous sommes intéressés à deux récepteurs sérotoninergiques pour lesquels nous avons développé des outils moléculaires pour leur imagerie fonctionnelle: (i) les récepteurs 5-HT1A et (ii) les récepteurs 5-HT7. (i) Les récepteurs 5-HT1A sont parmi les récepteurs à sérotonine les mieux décrits à l’heure actuelle. Cependant, si des radiotraceurs TEP sont déjà disponibles, ceux-ci sont des antagonistes qui se fixent indifféremment aux récepteurs 5-HT1A, couplés aux protéines G et fonctionnels, et aux récepteurs 5-HT1A, découplés et non fonctionnels. Nous avons donc proposé une stratégie originale de développement d’un agoniste 5- HT1A radiomarqué au fluor afin d’accéder à une imagerie des récepteurs fonctionnels. Deux molécules, le F15599 et le F13714, initialement développées pour leurs propriétés antidépressives par un partenaire industriel, ont été radiomarquées au fluor 18 puis ont été évaluées in vitro, ex vivo et in vivo chez le rat et le chat. Nos résultats montrent que le [18F]F13714 permet de visualiser de manière inédite les récepteurs 5- HT1A couplés aux protéines G. (ii) Le deuxième axe de cette thèse concerne les récepteurs 5-HT7, de découverte récente et proposés comme cible thérapeutique antidépressive. A l’inverse des récepteurs 5-HT1A, les récepteurs 5-HT7 ne disposent pas encore de radiotraceur TEP. Notre approche a consisté à sélectionner, à partir du pharmacophore du récepteur, quatre structures d’antagonistes 5-HT7, synthétisées par un laboratoire partenaire de chimie : le 2FP3, le 4FP3, le 2FPMP et le 4FPMP. Nos études radiopharmacologiques in vitro, ex vivo et in vivo nous ont conduit à retenir un radiotraceur, le [18F]2FP3. À l’issue de ce travail de thèse CIFRE, nous pouvons donc proposer deux radiotraceurs TEP originaux, ouvrant des perspectives inédites d’imagerie moléculaires de la neurotransmission 5-HT1A et 5-HT7 et dont nous envisageons la poursuite du développement comme radiopharmaceutiques cliniques / The serotonergic system, implicated in several diseases of central nervous system, can be explored in vivo by PET imaging (positron emission tomography). The research and the preclinical validation of radiotracers that specifically target serotonin are crucial. In this work, we focused on two serotonin receptors for which we have developed molecular tools for functional imaging: (i) the 5-HT1A and (ii) the 5-HT7. (i) 5-HT1A receptors are among the serotonin receptors the best described at present. However, if PET radiotracers are already available, they are antagonists and bind either to 5-HT1A receptors, G protein-coupled and functional, and to 5-HT1A receptors decoupled and non-functional. We therefore proposed an original strategy to develop a 5-HT1A agonist labeled with fluorine to access imagery of functional receptors. Two molecules, the F15599 and F13714, initially developed for their antidepressant properties by an industrial partner, were radiolabeled with fluorine-18 and were evaluated in vitro, ex vivo and in vivo in rats and cats. Our results show that the [18F] F13714 may view in a new way the 5-HT1A G protein-coupled (ii) The second focus of this thesis for the 5-HT7, recently discovered and proposed as a therapeutic target antidepressant. Unlike the 5-HT1A, 5-HT7 receptors do not yet have PET radiotracer. Our approach was to select, from the pharmacophore of the receptor, four structures of 5-HT7 antagonists, synthesized by a lab partner in chemistry: the 2FP3, the 4FP3, the 2FPMP and 4FPMP. Our radiopharmacology in vitro, ex vivo and in vivo led us to retain a radiotracer, the [18F] 2FP3. At the conclusion of this thesis CIFRE, we can propose two originals PET radiotracers , opening new perspectives for molecular imaging of neurotransmission of 5-HT1A and 5-HT7 receptors and which we plan further development as clinical radiopharmaceuticals