The thesis of this study describes a synthesis way to produce an alkyne equipped clickable precursor of 2-deoxy-2-fluoro-D-glucose (FDG) with a beta-configuration. This FDG-derivate is produced with a clickable link in purpose to be used in PET in vivo imaging. The product was synthesized by acetylation protection and further epoxidation on the glucose analog D-Glucal. Glycosylation occurred by electrophilic reaction of propargyl alcohol and configuration of the product was ensured during Lattrell-Dax inversion.

Antes de se iniciar os estudos clínicos de uma nova droga, é necessário realizar uma bateria de testes de segurança, para avaliar o risco humano. Os radiofármacos como qualquer outra nova droga, devem ser testados levando em conta sua especificidade, duração de tratamento e principalmente a toxicidade de ambas as partes, a molécula não marcada e a sua radioatividade em si, além das impurezas provindas da radiólise. Órgãos regulatórios como o Food and Drug Administration-EUA (FDA) e a Agência de Medicina Européia (EMEA), estabelecem guias para a regulamentação de produção e pesquisas de radiofármacos, No Brasil a produção de radiofármacos não era regulamentada até o final de 2009, quando foram estabelecidas pela Agência Nacional de Vigilância Sanitária (ANVISA) as resoluções nº 63, que visa as Boas Práticas de Fabricação de Radiofármacos e a nº 64 que visa o registro do radiofámaco. Para a obtenção do registro de radiofármacos são necessárias a comprovação da qualidade, segurança, eficácia e especificidade do medicamento. Para a segurança dos radiofármacos devem ser apresentados estudos de toxicidade aguda, subaguda e crônica como também a toxicidade reprodutiva, mutagênica e carcinogênica. Hoje o IPEN-CNEN/SP produz um dos radiofámacos mais importantes da medicina nuclear, o 18F-FDG, que é utilizado em muitas aplicações clínicas, em particular no diagnóstico e estadiamento de tumores. O objetivo deste trabalho foi avaliar a toxicidade sistêmica (aguda/subaguda) do radiofármaco 18F- FDG em um sistema teste in vivo, conforme preconiza a RDC nº 64, que servirá de modelo para os protocolos de toxicidade dos radiofármacos produzidos no IPEN. Os ensaios realizados foram: os testes de toxicidade aguda e de toxicidade subaguda, estudos de biodistribuição do 18F-FDG, ensaio cometa e toxicidade reprodutiva. Na toxicidade aguda, ratos sadios foram injetados com 18F- FDG e observados durante 14 dias enquanto na toxicidade subaguda os animais foram observados durante 28 dias. Os resultados não mostraram nenhuma evidência de toxicidade na exposição ao 18F-FDG na toxicidade aguda e na subaguda. A biodistribuição demonstrou resultados semelhantes aos da literatura, onde a bexiga é o órgão que mais recebe radiação. O ensaio cometa mostrou que a radiação do radiofármaco não foi significativa para gerar danos no DNA. Na toxicidade reprodutiva, casais de ratos expostos ao 18F-FDG geraram filhotes completamente normais e saudáveis. Por fim, o 18F-FDG não evidenciou nenhuma toxicidade. / Before starting clinical trials of a new drug, it is necessary to perform a battery of safety tests for assessing human risk. Radiopharmaceuticals like any new drug must be tested taking into account its specificity, duration of treatment and especially the toxicity of both parties, the unlabeled molecule and its radionuclide, apart from impurities emanating from radiolysis. Regulatory agencies like the Food and Drug Administration - USA (FDA) and the European Medicine Agency (EMEA), establish guidelines for the regulation of production and research of radiopharmaceuticals. In Brazil the production of radiopharmaceuticals was not regulated until the end of 2009, when were established by the National Agency for Sanitary Surveillance (ANVISA) resolutions No. 63, which refers to the Good Manufacturing Practices of Radiopharmaceuticals and No. 64 which seeks the registration of record radiopharmaceuticals. To obtain registration of radiopharmaceuticals are necessary to prove the quality, safety, efficacy and specificity of the drug . For the safety of radiopharmaceuticals must be presented studies of acute toxicity, subacute and chronic toxicity as well as reproductive, mutagenic and carcinogenic. Nowadays IPEN-CNEN/SP produces one of the most important radiopharmaceutical of nuclear medicine, the 18F-FDG, which is used in many clinical applications, particularly in the diagnosis and staging of tumors. The objective of this study was to evaluate the systemic toxicity (acute/ subacute) radiopharmaceutical 18F-FDG in an in vivo test system, as recommended by the RDC No. 64, which will serve as a model for protocols toxicity of radiopharmaceuticals produced at IPEN . The following tests were performed: tests of acute and subacute toxicity, biodistribution studies of 18F-FDG, comet assay and reproductive toxicity. In acute toxicity, healthy rats were injected with 18F-FDG and observed for 14 days while in subacute toxicity animals were observed for 28 days. The results showed no evidence of toxicity at exposure 18F-FDG in acute and subacute toxicity. The biodistribution showed similar results to the literature, where the bladder is the organ that receives the most radiation. The comet assay showed that the radiation from the radiopharmaceutical was not significant to generate DNA damage. In reproductive toxicity in coupled rats exposed to 18F-FDG generated completely normal and healthy puppies. Finally, the 18F-FDG did not show any toxicity.

O aumento da demanda no Brasil pelo radiofármaco [18F]FDG para exames de tomografia por emissão de pósitron (PET-CT) e sua meia-vida de 109,7 minutos exigem uma atenção especial para a cadeia produtiva deste radiofármaco. Desde a irradiação da água enriquecida em 18O até a passagem do paciente pelo tomógrafo, numa seqüência de procedimentos que pode durar até cerca de seis horas, todas as etapas da cadeia produtiva devem ter a maior confiabilidade possível, pois qualquer falha em uma das etapas será sentida na extremidade da cadeia produtiva. A falta de indicação de posição da válvula do Sistema de Carga e Descarga do Porta-alvo de 18F- no Centro de Aceleradores Cíclotron levou a perda de produção de 18F-, contaminação da Sala de Irradiação e aumento da dose dos trabalhadores envolvidos na operação e manutenção dos sistemas de irradiação. Este trabalho testou o comportamento de três tipos de sensores de posição (microswitch, reedswitch e sensor de proximidade indutivo) no ambiente da Sala de Irradiação 1.2 do Centro de Aceleradores Cíclotron, que está sujeito a altas taxas de radiação gama e nêutrons devido à produção rotineira de 18F- e 123I, através deste teste foi possível encontrar o sensor de posição mais adequado para trabalhar no porta-alvo de 18F-, e através da reprogramação do controlador lógico programável, foi possível evitar este tipo de falha durante a produção de 18F- no Centro de Aceleradores Cíclotron, e aumentar a confiabilidade na cadeia produtiva do [18F]FDG. / The demand growing in Brazil by the radiopharmaceutical [18F]FDG in positron emission tomography (PET-CT) and the 109,7 minutes half life claim special attention to the productive chain of this radiopharmaceutical. Since the [18O]water irradiation until the tomograph patient scanning, in sequential procedures that may spent about six hours, all the productive chain stages must be as reliable as possible, because any stage failed will be perceived in productive chain extremity. The position indication absence from Load and Unload 18F- Target System valve in Cyclotron Accelerators Center resulted in 18F- production loss, Irradiation Room contamination and the increase workers dose responsible by operation and maintenance of irradiation systems. This study tested the behaviour of three types of position sensors (microswitch, reedswitch and inductive sensor), into Irradiation Room 1.2 environment of the Cyclotron Accelerators Center, where there are high gamma radiation and neutrons rates because the routine 18F- and 123I production, through this test was possible to discover the fitter position sensor to run on 18F- Target, and after rewriting the programmable logic controller software was possible avoid this type of fail at 18F- production time in Cyclotron Accelerators Center, and to grow up the reliability on [18F]FDG productive chain.

O aumento da demanda no Brasil pelo radiofármaco [18F]FDG para exames de tomografia por emissão de pósitron (PET-CT) e sua meia-vida de 109,7 minutos exigem uma atenção especial para a cadeia produtiva deste radiofármaco. Desde a irradiação da água enriquecida em 18O até a passagem do paciente pelo tomógrafo, numa seqüência de procedimentos que pode durar até cerca de seis horas, todas as etapas da cadeia produtiva devem ter a maior confiabilidade possível, pois qualquer falha em uma das etapas será sentida na extremidade da cadeia produtiva. A falta de indicação de posição da válvula do Sistema de Carga e Descarga do Porta-alvo de 18F- no Centro de Aceleradores Cíclotron levou a perda de produção de 18F-, contaminação da Sala de Irradiação e aumento da dose dos trabalhadores envolvidos na operação e manutenção dos sistemas de irradiação. Este trabalho testou o comportamento de três tipos de sensores de posição (microswitch, reedswitch e sensor de proximidade indutivo) no ambiente da Sala de Irradiação 1.2 do Centro de Aceleradores Cíclotron, que está sujeito a altas taxas de radiação gama e nêutrons devido à produção rotineira de 18F- e 123I, através deste teste foi possível encontrar o sensor de posição mais adequado para trabalhar no porta-alvo de 18F-, e através da reprogramação do controlador lógico programável, foi possível evitar este tipo de falha durante a produção de 18F- no Centro de Aceleradores Cíclotron, e aumentar a confiabilidade na cadeia produtiva do [18F]FDG. / The demand growing in Brazil by the radiopharmaceutical [18F]FDG in positron emission tomography (PET-CT) and the 109,7 minutes half life claim special attention to the productive chain of this radiopharmaceutical. Since the [18O]water irradiation until the tomograph patient scanning, in sequential procedures that may spent about six hours, all the productive chain stages must be as reliable as possible, because any stage failed will be perceived in productive chain extremity. The position indication absence from Load and Unload 18F- Target System valve in Cyclotron Accelerators Center resulted in 18F- production loss, Irradiation Room contamination and the increase workers dose responsible by operation and maintenance of irradiation systems. This study tested the behaviour of three types of position sensors (microswitch, reedswitch and inductive sensor), into Irradiation Room 1.2 environment of the Cyclotron Accelerators Center, where there are high gamma radiation and neutrons rates because the routine 18F- and 123I production, through this test was possible to discover the fitter position sensor to run on 18F- Target, and after rewriting the programmable logic controller software was possible avoid this type of fail at 18F- production time in Cyclotron Accelerators Center, and to grow up the reliability on [18F]FDG productive chain.

Antes de se iniciar os estudos clínicos de uma nova droga, é necessário realizar uma bateria de testes de segurança, para avaliar o risco humano. Os radiofármacos como qualquer outra nova droga, devem ser testados levando em conta sua especificidade, duração de tratamento e principalmente a toxicidade de ambas as partes, a molécula não marcada e a sua radioatividade em si, além das impurezas provindas da radiólise. Órgãos regulatórios como o Food and Drug Administration-EUA (FDA) e a Agência de Medicina Européia (EMEA), estabelecem guias para a regulamentação de produção e pesquisas de radiofármacos, No Brasil a produção de radiofármacos não era regulamentada até o final de 2009, quando foram estabelecidas pela Agência Nacional de Vigilância Sanitária (ANVISA) as resoluções nº 63, que visa as Boas Práticas de Fabricação de Radiofármacos e a nº 64 que visa o registro do radiofámaco. Para a obtenção do registro de radiofármacos são necessárias a comprovação da qualidade, segurança, eficácia e especificidade do medicamento. Para a segurança dos radiofármacos devem ser apresentados estudos de toxicidade aguda, subaguda e crônica como também a toxicidade reprodutiva, mutagênica e carcinogênica. Hoje o IPEN-CNEN/SP produz um dos radiofámacos mais importantes da medicina nuclear, o 18F-FDG, que é utilizado em muitas aplicações clínicas, em particular no diagnóstico e estadiamento de tumores. O objetivo deste trabalho foi avaliar a toxicidade sistêmica (aguda/subaguda) do radiofármaco 18F- FDG em um sistema teste in vivo, conforme preconiza a RDC nº 64, que servirá de modelo para os protocolos de toxicidade dos radiofármacos produzidos no IPEN. Os ensaios realizados foram: os testes de toxicidade aguda e de toxicidade subaguda, estudos de biodistribuição do 18F-FDG, ensaio cometa e toxicidade reprodutiva. Na toxicidade aguda, ratos sadios foram injetados com 18F- FDG e observados durante 14 dias enquanto na toxicidade subaguda os animais foram observados durante 28 dias. Os resultados não mostraram nenhuma evidência de toxicidade na exposição ao 18F-FDG na toxicidade aguda e na subaguda. A biodistribuição demonstrou resultados semelhantes aos da literatura, onde a bexiga é o órgão que mais recebe radiação. O ensaio cometa mostrou que a radiação do radiofármaco não foi significativa para gerar danos no DNA. Na toxicidade reprodutiva, casais de ratos expostos ao 18F-FDG geraram filhotes completamente normais e saudáveis. Por fim, o 18F-FDG não evidenciou nenhuma toxicidade. / Before starting clinical trials of a new drug, it is necessary to perform a battery of safety tests for assessing human risk. Radiopharmaceuticals like any new drug must be tested taking into account its specificity, duration of treatment and especially the toxicity of both parties, the unlabeled molecule and its radionuclide, apart from impurities emanating from radiolysis. Regulatory agencies like the Food and Drug Administration - USA (FDA) and the European Medicine Agency (EMEA), establish guidelines for the regulation of production and research of radiopharmaceuticals. In Brazil the production of radiopharmaceuticals was not regulated until the end of 2009, when were established by the National Agency for Sanitary Surveillance (ANVISA) resolutions No. 63, which refers to the Good Manufacturing Practices of Radiopharmaceuticals and No. 64 which seeks the registration of record radiopharmaceuticals. To obtain registration of radiopharmaceuticals are necessary to prove the quality, safety, efficacy and specificity of the drug . For the safety of radiopharmaceuticals must be presented studies of acute toxicity, subacute and chronic toxicity as well as reproductive, mutagenic and carcinogenic. Nowadays IPEN-CNEN/SP produces one of the most important radiopharmaceutical of nuclear medicine, the 18F-FDG, which is used in many clinical applications, particularly in the diagnosis and staging of tumors. The objective of this study was to evaluate the systemic toxicity (acute/ subacute) radiopharmaceutical 18F-FDG in an in vivo test system, as recommended by the RDC No. 64, which will serve as a model for protocols toxicity of radiopharmaceuticals produced at IPEN . The following tests were performed: tests of acute and subacute toxicity, biodistribution studies of 18F-FDG, comet assay and reproductive toxicity. In acute toxicity, healthy rats were injected with 18F-FDG and observed for 14 days while in subacute toxicity animals were observed for 28 days. The results showed no evidence of toxicity at exposure 18F-FDG in acute and subacute toxicity. The biodistribution showed similar results to the literature, where the bladder is the organ that receives the most radiation. The comet assay showed that the radiation from the radiopharmaceutical was not significant to generate DNA damage. In reproductive toxicity in coupled rats exposed to 18F-FDG generated completely normal and healthy puppies. Finally, the 18F-FDG did not show any toxicity.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19962号 / 医博第4152号 / 新制||医||1017(附属図書館) / 33058 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 伊佐 正, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No Brasil e no mundo a medicina nuclear vem ganhando destaque com as técnicas diagnósticas que permitem o estudo metabólico de doenças, alterando significativamente o gerenciamento dos pacientes. Essa tecnologia inovadora vem trazendo expectativas tanto para os setores especializados como para a sociedade. Nesse trabalho foi estudada a utilização do radiofármaco 18F-FDG na região metropolitana de São Paulo e nas áreas adjacentes, bem como a estrutura do mercado atual e das dificuldades a serem superadas com o aumento da demanda do 18F-FDG. A pesquisa contou com uma análise do mercado de radiofármacos internacional e das principais alterações que vem ocorrendo nessa área no Brasil nos últimos anos. Foram realizadas entrevistas com profissionais atuantes na área de medicina nuclear e coleta de dados através de questionário enviado para os centros consumidores do radiofármaco na região coberta pela pesquisa. As entrevistas expressaram as opiniões dos entrevistados sobre as transformações nesse setor e as tendências futuras e os dados coletados no questionário serviram de complementação a utilização do radiofármaco nos equipamentos do tipo Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET) e Positron Emission Tomography / Computer Tomography (PET/CT). O maior uso do 18F-FDG tem sido para o diagnóstico oncológico nos equipamentos do tipo PET e PET/CT. Essa utilização deverá crescer nos próximos anos, podendo se expandir para outras especialidades como neurologia e cardiologia. Apesar de restrita atualmente as cidades de São Paulo e Rio de Janeiro deverá haver uma expansão dessa modalidade diagnóstica nos outros Estados do país que começam a estruturar produção do radioisótopo. A recente alteração na constituição que permite a produção e comercialização de radioisótopos de meia-vida curta também deverá aumentar o interesse da iniciativa privada nesse mercado, que internacionalmente possui projeções otimistas de crescimento. Existe também uma expectativa que a aprovação dos planos de saúde para a cobertura dos exames utilizando 18F-FDG no PET impulsione esse mercado ainda mais, repetindo a experiência internacional. Os recentes investimentos realizados pelo IPEN para aumentar a produção do 18F-FDG deverá garantir a oferta com confiabilidade, para a região Sudeste e Sul do país. / Nuclear Medicine in Brazil and worldwide has developed distinction with diagnosis techniques that allow metabolic research of the disease, changing in a significant fashion the patients outcome. This innovative technology leads expectations from specific fields up to society itself. This research studied the use of 18F-FDG radiopharmaceutical in the metropolitan region of São Paulo and adjacent areas, as well as the recent trade structure and the difficulties that should be overcome with the increase of the 18F-FDG demand. This research counted on the analysis of the international radiopharmaceutical trade and the main changes that have been happening in this area in Brazil during the past few years. Interviews were performed with professionals within the area of nuclear medicine and data has been collected through questionnaire sent to the consuming centers of the radiopharmaceutical in the region covered in this research. The interviews expressed the opinions of the interviewees concerning transformations in this field and future tendencies and the information obtained from the survey was the basis of complementation of the use of radiopharmaceutical on equipments such as Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET) and Positron Emission Tomography / Computer Tomography (PET/CT). The major use of 18F-FDG has been used for oncology diagnosis with equipments such as PET and PEC/CT. This use shall grow in the next years, maybe expanding to other specialties such as neurology and cardiology. Although nowadays restricted to the cities of São Paulo and Rio de Janeiro, there is a possibility of expansion to other diagnosis modalities in other states of the country that are starting to structure the production of the radioisotope. The recent change in the constitution permitting the production and commerce of short half-life radioisotopes also contributes to the increase the interest of private funding of this sector in which internationally holds optimistic projections of increase. There is also the expectancy that approving health care plans coverage of these exams using 18F-FDG with PET to boast more this sector, repeating international experience. Recent investments made by IPEN to increase the production of 18F-FDG shall guarantee the offer of confidentiality for the Southeast and Southern regions of the country.

Les travaux présentés dans le cadre de cette thèse ont porté sur la modélisation mathématique de la réponse d’une tumeur en traitement par la radiothérapie. Le but étant de fournir aux médecins un outil numérique d’aide pour diagnostiquer le cancer. Comme par exemple, suivre l’évolution du volume de la tumeur pendant et après le traitement, réadapter les stratégies thérapeutiques, etc. Dans un premier temps, nous avons proposé un modèle discret stochastique basé sur une approche multiéchelle. Dans ce contexte, nous nous sommes concentrés sur trois différentes échelles de modélisation tumorale : l’échelle microscopique (les cellules dans un voxel), l’échelle mésoscopique (population de cellules dans un voxel) et l’échelle macroscopique (tissu tumoral), avec des interfaces de transition entre ces trois échelles. Au niveau cellulaire, la description est basée sur des probabilités de transfert de phase dans le cycle cellulaire. À l’échelle mésoscopique, nous représentons les populations de cellules selon les différentes étapes d’un cycle cellulaire. Enfin, à l’échelle macroscopique, la description tumorale est basée sur l’utilisation des images médicales PET FDG. Ces trois échelles existent naturellement : les données biologiques sont collectées au niveau macroscopique mais le comportement pathologique de la tumeur est basé sur un cycle cellulaire anormal à l’échelle microscopique. L’introduction d’une échelle mésoscopique a été essentielle pour réduire l’écart entre les deux extrêmes, en termes de transition entre eux. Nous utilisons le modèle multiéchelle discret pour prédire l’évolution temporelle du nombre de cellules tumorales. Par contre, ce modèle n’est pas bien adapté pour prédire l’évolution du volume de la tumeur. Aussi, avons-nous proposé dans un second temps, un deuxième modèle qui est biomécanique et basé sur une équation d’advection réaction. Enfin, les modèles discrets multiéchelle et biomécanique ont été associés pour former un modèle hybride. En effet, le modèle discret est utilisé pour estimer les trajectoires des pressions partielles d’oxygène dans l’environnement tumoral, ces pressions sont ensuite mises en entrée du modèle continu (biomécanique) pour la prédiction de l’évolution du volume tumoral. / The work presented in this thesis focused on the mathematical modeling of tumor response during treatment by radiotherapy. The goal was to provide for doctors a digital tool to help cancer diagnose. For example, monitoring tumor volume during and after treatment, rehabilitating therapeutic strategies, etc. In a first step, we proposed a discrete stochastic model based on a multiscale approach. In this context, we focused on three different scales of tumor modeling :microscopic scale (cells in a voxel), mesoscopic scale (cell population in a voxel) and macroscopic scale (tumor tissue), with transitional interfaces between these three scales. At the cellular level, the description was based on probabilities of phase transfer in the cellular cycle. At the mesoscopic scale, we represented cell populations according to the differents stages of a cell cycle. Finally, on a macroscopic scale, tumor description was based on the use of FDG PET medical images.These three scales naturally exist : the biological data were collected at the macroscopic level but the pathological behavior of the tumor is based on an abnormal cell cycle at the microscopic scale. Introduction of a mesoscopic scale was essential to reduce the gap between the two extremes, in terms of transition between them. We used the discrete multiscale model to predict the temporal evolution of the tumor cells number. On the other hand, this model was not well adapted to predict the tumor volume evolution. Thus, we had proposed a second model which was biomechanical and based on an advection reaction equation. Finally, the discrete multiscale and the biomechanical models had been combined to form a hybrid model. Indeed, the discrete model was used to estimate the oxygen partial pressures trajectories, in the tumor environment. These pressures were then input to the continuous (biomechanical) model for the tumor volume evolution prediction.

La tomographie par émission de positons au 18F-Fluorodésoxyglucose (TEP au 18F-FDG) est une technique d’imagerie permettant de quantifier le métabolisme glycolytique cérébral. L’objectif de nos travaux de thèse était d’essayer de caractériser au mieux les modifications cérébrales liées au vieillissement, y compris la partie possiblement liée à des dysfonctions vasculaires, grâce à une analyse quantitative tridimensionnelle voxel-à-voxel des images de TEP au 18F-FDG. Nos travaux montrent, tout d’abord, qu’il existe un intérêt pratique à utiliser un logiciel de normalisation spatial particulier (BM : Block Matching) pour l’analyse quantitative cérébrale, au moins pour la fabrication de modèles anatomiques (« template ») adaptés à chaque population étudiée. Cet intérêt a été tout d’abord montré pour localiser des foyers épileptiques temporaux, puis pour quantifier l’impact de l’âge sur le métabolisme cérébral (détermination plus précise des aires cérébrales affectées). Avec cette méthode, il est possible d’observer une diminution du métabolisme cérébral tout au long de la vie, en particulier dans certaines aires frontales. Nous avons essayé de déterminer la composante du vieillissement cérébral qui est possiblement liée à une dysfonction vasculaire et qui serait donc susceptible d’être traitée ou prévenue par des thérapeutiques vasculaires appropriées. Dans ce domaine de recherche, nous avons pu montrer que les anomalies micro-vasculaires de la substance blanche, appelées leucoaraïose, étaient associées à une diminution du métabolisme de la substance grise, en particulier au niveau frontal. Cet effet était indépendant de l’effet spécifique de l’âge et du phénomène d’atrophie corticale. Enfin, dans une population de patients âgés et à forte prévalence d’hypertension artérielle, nous avons montré que la pression artérielle était étroitement corrélée au remodelage métabolique cérébral, en particulier lorsque cette pression est mesurée au niveau central et lorsque l’on tient compte de la pression différentielle, avec alors une valeur seuil de 50 mmHg. Le vieillissement cérébral global et l’accélération qui peut être liée à des facteurs vasculaires sont des données qui peuvent être estimées en TEP au 18F-FDG, avec une méthode d’analyse quantitative voxel-à-voxel adaptée. Cette identification pourrait peut-être guider la prescription de traitements vasculaires appropriés et aussi, aider à différencier ces atteintes liées à l’âge ou d’origine vasculaire des autres maladies cérébrales. / 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is a brain-imaging technique allowing brain glycolytic metabolism to be quantified. The aim of this doctoral thesis work was to try to better characterize the aging-related changes in brain metabolism, including the part with a possible vascular origin, thanks to a three-dimensional voxel-based quantitative analysis of 18F-FDG PET images. Our work shows firstly that there is a clear advantage to use a particular spatial normalization software (BM: Block Matching) for the brain quantitative analysis, at least for the providing of templates adapted to each study population. This advantage was shown, initially, for the localization of temporal epileptic foci and thereafter, for quantifying the age-related changes in brain metabolism (enhanced determination of the involved brain areas). With this method, a decrease in brain metabolism could be documented throughout the life especially within certain frontal areas. In addition, we tried to determine the component of cerebral aging, which might be of a vascular origin and thus, susceptible to be treated or prevented by vascular treatments. In this research field, we have shown that microvascular abnormalities, setting within white-matter and called leukoaraiosis, were associated with a decrease in the grey-matter metabolism, in particular within certain frontal areas. This effect was independent of the inherent effect of age and of cortical atrophy. Finally, in a population of older patients with a high prevalence of hypertension, we showed that the blood pressure level was correlated to a brain metabolic remodeling, especially when this pressure was measured at central level and when considering the pulse pressure and a threshold value of 50 mmHg. The global cerebral aging and its acceleration in relation to vascular factors may be assessed by 18F-FDG PET when using an adapted voxel-based quantitative method. This assessment could potentially be useful for the monitoring of vascular treatments and for differentiating the aging- and vascular-related metabolic changes to those corresponding to brain diseases of other origins.