Understanding the mnemonic functions of the brain has been extensively facilitated by the development of functional neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). The present thesis aims at investigating the neural mechanisms underlying memory for personally experienced events (episodic memory), using PET. In paper I, similarities between encoding and retrieval of enacted (motor) information were explored. We observed increased retrieval activation in right premotor areas in the brain when sentences encoded by motor enactment and sentences encoded by maintenance rehearsal were contrasted. In paper II, overlap between encoding and retrieval was explicitly tested for three types of event information: spatial, item, and temporal. Using conjunction analyses, we found that encoding and retrieval of spatial information was associated with increased brain activity in bilateral inferior parietal regions. Encoding and retrieval of item information were related to increased activation in right inferior temporal cortex, and encoding and retrieval of temporal information were associated with increased activation in left inferior temporal and left inferior frontal cortex. In paper III, brain activity associated with retrieval success was examined. Conditions included three levels of retrieval success (high, medium, and low level), for two types of information (pictures and sentences). The results showed a pattern of activation that distinguished between brain regions involved in processing of sentences vs. processing of pictures. A second pattern that distinguished between brain regions involved in encoding vs. retrieval processes, irrespectively of material (sentences and pictures) and retrieval success, was also found. The manipulation of retrieval success was associated with systematic changes in the correlation between material specific regions and other areas of the brain. In study IV, changes in activation related to successful retrieval of pictures were investigated. More specifically, we expected to find decreases in infero-temporal (IT) regions of the brain that were associated with successful recognition memory. As expected, we found a region in left IT cortex that showed decreased activation related to memory for event information. This decrease in activation could be dissociated from responses related to novelty detection, and perceptual priming. The results from study I and II are discussed in relation to findings and theories regarding similarities between encoding and retrieval processes, and reactivation of modality-specific brain areas important for memory storage. The results from studies III and IV are discussed in relation to differences between encoding and retrieval processes, e.g. asymmetric frontal activation and sub-processes of episodic memory, such as retrieval mode, retrieval success, and novelty detection. Taken together, the studies show that different episodic memory processes are correlated with distinct brain areas, hence supporting the view that remembering is based on multiple component processes. / digitalisering@umu.se

No description available.

La neuroinflammation joue un rôle important dans de nombreuses maladies neurodégénératives telles que la maladie d’Alzheimer, Parkinson, ou encore la sclérose en plaques. De récents développements en imagerie moléculaire permettent aujourd’hui un meilleur diagnostique et un meilleur suivi thérapeutique de ces maladies. Parmi les techniques d’imagerie dont nous disposons actuellement, la Tomographie par Emission de Positions (TEP) et Tomographie par Emission Mono Photonique (TEMP) jouent un rôle important de par leur haute sensibilité et leurs aspects quantitatifs. L’objectif de ma thèse est de développer de nouveaux ligands et radioligands dédiés à l’imagerie de cibles spécifiques impliquées dans les processus de neuroinflammation. Pour ce faire, la TEP et ses émetteurs de positons à vie brève associés (notamment le fluor-18 ; T1/2 : 109.8 min) constituent un outil de choix. Le projet est divisé en deux sections principales. La première est dédiée au développement de ligands ciblant la protéine de Translocation 18 kDa (TSPO). Cette protéine est aujourd’hui reconnue comme un biomarqueur précoce des processus neuroinflammatoires, et de nombreux ligands ont déjà été synthétisés pour cette cible. Le plus anciens d’entre eux est le PK11195 appartenant à la famille des isoquinoléines, qui a été marqué au carbone-11 à la fin des années 80. Plus récemment, d’autres familles de composés ont vu le jour, et notamment la familles des pyrazolopyrimidines avec le [11C]DPA-713, ainsi que celle des pyridazinoindoles avec le [11C]SSR180575. A travers cette première partie de ma thèse, l’objectif est de synthétiser et de caractériser in vitro de nouveaux ligands dérivés des deux composés leaders de ces deux familles. Les précurseurs de marquage correspondant ont également été synthétisés pour les composés les plus prometteurs, permettant ainsi un radiomarquage au fluor-18. Certains résultats ont par ailleurs été présentés lors d’un congrès international (21st International Symposium on Radiopharmaceutical Sciences (Columbia, MO, USA – Mai 26-31, 2015)). La seconde partie de ma thèse est dédiée au développement de ligands pour des cibles alternatives à la TSPO, qui sont les récepteurs cannabinoïdes de type 2 (CB2R), et les récepteurs purinergiques P2Y12 et P2Y14. Ces nouvelles cibles, récemment émergées présentent un fort potentiel pour de nouvelles opportunités en imagerie. Une nouvelle série de sept composés a par ailleurs déjà été synthétisée en ce qui concerne le CB2R. Les précurseurs des molécules les plus prometteuses ont également été préparés. La synthèse des ligands dédiés aux récepteurs purinergiques a été initiée, et un premier couple référence /précurseur a été obtenu. / Neuroinflammation plays an important role in many neurodegenerative diseases (Alzheimer, Parkinson, Multiple sclerosis …) and recent developments in molecular imaging provide today new insights into the diagnostic and the treatement managment of these diseases. Among the existing imaging techniques, the highly sensitive and quantitative nuclear modalities SPECT (single photon emission computed tomography) but especially PET (positron emission tomography) play key roles. My PhD program is devoted to the design and synthesis of novel radioligands, all dedicated to the imaging of specific targets and processes linked to neuroinflammation. For this, PET and the short-lived positron-emitter fluorine-18 (T1/2: 109.8 min) remain the main focuses. The project has been divided into two sections, the first one concentrates on the development of novel ligands targeting the Translocator Protein 18 kDa (TSPO). Indeed, this target is today recognized as an early biomarker of neuroinflammatory processes and PK11195, an isoquinoline carboxamide labelled with carbon-11, was, in the late 80’s, the first reported PET-radioligand. More recently, new compounds, all belonging to different chemical classes, have emerged and notably the pyrazolopyrimidine acetamide [11C]DPA-713 and the pyridazinoindole acetamide [11C]SSR180575. Within the first section of my PhD, novel derivatives of both DPA-713 and SSR180575 have been synthesized and in vitro characterized. Dedicated precursors for labelling were also developed for the most promising candidates, and radiolabelling has been performed. Some results have been presented at the 21st International Symposium on Radiopharmaceutical Sciences (Columbia, MO, USA – May 26-31, 2015).The second part of my PhD, deals with the development of ligands for alternative targets to the TSPO, like the type-2 cannabinoid receptor (CB2R) and the purinergic P2Y14 / P2Y12 receptors, the latter emerging today as a hot topic for imaging opportunities. Up to now, a series of seven compounds targeting the CB2R has been successfully synthetized and in vitro characterized. Dedicated precursors of the most promising compounds have also been prepared and labelling will be shortly performed. The synthesis of ligands targeting the purinergic receptors has also been initiated and a first couple of reference / precursor has been obtained for the P2Y12R.

Positron emission tomography (PET) visualizes increased cellular [18F]fluorodeoxyglucose ([18F]FDG) uptake. Pulmonary hypertension (PH) is conceived of a proliferative disease of the lung vessels. Increased glucose uptake can be quantified as pulmonary [18F]FDG uptake via PET imaging. Because the angioproliferative mechanisms in PH are still in need of further description, the aim of the present study was to investigate whether [18F]FDG PET/CT imaging can elucidate these pathophysiologic mechanisms in different etiologies of PH. Patients (n = 109) with end-stage pulmonary disease being evaluated for lung transplant were included in this observational study. Mean standardized uptake value (SUVmean) of predefined regions of interest in lung parenchyma (LP), left (LV), and right ventricle (RV) of the heart, and SUVmax in pulmonary artery (PA) were determined and normalized to liver uptake. These SUV ratios (SUVRs) were compared with results from right heart catheterization (mean pulmonary artery pressure [mPAP], pulmonary vascular resistance [PVR]), and serum N-terminal pro-brain natriuretic peptide. Group comparisons were performed and Pearson correlation coefficients (r) were calculated. The [18F]FDG uptake ratios in LP, RV, RV/LV, and PA, but not in LV, were found to be significantly higher in both patients with mPAP ≥25 mm Hg (P = 0.013, P = 0.006, P = 0.049, P = 0.002, P = 0.68, respectively) and with PVR ≥480 dyn·s/cm5 (P < 0.001, P = 0.045, P < 0.001, P < 0.001, P = 0.26, respectively). The [18F]FDG uptake in these regions positively correlated also with mPAP, PVR, and N-terminal pro-brain natriuretic peptide. The SUVR of PA positively correlated with the SUVR of LP and RV (r=0.55, r=0.42, respectively). Pulmonary and cardiac [18F]FDG uptake in PET imaging positively correlated with the presence and severity of PH in patients with end-stage pulmonary disease. Increased glucose metabolism in the central PAs seems to play a certain role in terms of severity of PH. These results suggest that [18F]FDG-PET imaging can help understand the pathophysiology of PH as a proliferative pulmonary disease.

Ion beam therapy (IBT) is a promising treatment option in radiotherapy. The characteristic physical and biological properties of light ion beams allow for the delivery of highly tumour conformal dose distributions. Related to the sparing of surrounding healthy tissue and nearby organs at risk, it is feasible to escalate the dose in the tumour volume to reach higher tumour control and survival rates. Remarkable clinical outcome was achieved with IBT for radio-resistant, deep-seated, static and well fixated tumour entities. Presumably, more patients could benefit from the advantages of IBT if it would be available for more frequent tumour sites. Those located in the thorax and upper abdominal region are commonly subjected to intra-fractional, respiration related motion. Different motion compensated dose delivery techniques have been developed for active field shaping with scanned pencil beams and are at least available under experimental conditions at the GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany. High standards for quality assurance are required in IBT to ensure a safe and precise dose application. Both underdosage in the tumour and overdosage in the normal tissue might endanger the treatment success. Since minor unexpected anatomical changes e.g. related to patient mispositioning, tumour shrinkage or tissue swelling could already lead to remarkable deviations between planned and delivered dose distribution, a valuable dose monitoring system is desired for IBT. So far, positron emission tomography (PET) is the only in vivo, in situ and non-invasive qualitative dose monitoring method applied under clinical conditions. It makes use of the tissue autoactivation by nuclear fragmentation reactions occurring along the beam path. Among others, +-emitting nuclides are generated and decay according to their half-life under the emission of a positron. The subsequent positron-electron annihilation creates two 511 keV photons which are emitted in opposite direction and can be detected as coincidence event by a dedicated PET scanner. The induced three-dimensional (3D) +- activity distribution in the patient can be reconstructed from the measured coincidences. Conclusions about the delivered dose distribution can be drawn indirectly from a comparison between two +-activity distributions: the measured one and an expected one generated by a Monte-Carlo simulation. This workflow has been proven to be valuable for the dose monitoring in IBT when it was applied for about 440 patients, mainly suffering from deep-seated head and neck tumours that have been treated with 12C ions at GSI. In the presence of intra-fractional target motion, the conventional 3D PET data processing will result in an inaccurate representation of the +-activity distribution in the patient. Fourdimensional, time-resolved (4D) reconstruction algorithms adapted to the special geometry of in-beam PET scanners allow to compensate for the motion related blurring artefacts. Within this thesis, a 4D maximum likelihood expectation maximization (MLEM) reconstruction algorithm has been implemented for the double-head scanner Bastei installed at GSI. The proper functionality of the algorithm and its superior performance in terms of suppressing motion related blurring artefacts compared to an already applied co-registration approach has been demonstrated by a comparative simulation study and by dedicated measurements with moving radioactive sources and irradiated targets. Dedicated phantoms mainly made up of polymethyl methacrylate (PMMA) and a motion table for regular one-dimensional (1D) motion patterns have been designed and manufactured for the experiments. Furthermore, the general applicability of the 4D MLEM algorithm for more complex motion patterns has been demonstrated by the successful reduction of motion artefacts from a measurement with rotating (two-dimensional moving) radioactive sources. For 1D cos2 and cos4 motion, it has been clearly illustrated by systematic point source measurements that the motion influence can be better compensated with the same number of motion phases if amplitudesorted instead of time-sorted phases are utilized. In any case, with an appropriate parameter selection to obtain a mean residual motion per phase of about half of the size of a PET crystal size, acceptable results have been achieved. Additionally, it has been validated that the 4D MLEM algorithm allows to reliably access the relevant parameters (particle range and lateral field position and gradients) for a dose verification in intra-fractionally moving targets even from the intrinsically low counting statistics of IBT-PET data. To evaluate the measured +-activity distribution, it should be compared to a simulated one that is expected from the moving target irradiation. Thus, a 4D version of the simulation software is required. It has to emulate the generation of +-emitters under consideration of the intra-fractional motion, their decay at motion state dependent coordinates and to create listmode data streams from the simulated coincidences. Such a revised and extended version that has been compiled for the special geometry of the Bastei PET scanner is presented within this thesis. The therapy control system provides information about the exact progress of the motion compensated dose delivery. This information and the intra-fractional target motion needs to be taken into account for simulating realistic +-activity distributions. A dedicated preclinical phantom simulation study has been performed to demonstrate the correct functionality of the 4D simulation program and the necessity of the additional, motionrelated input parameters. Different to the data evaluation for static targets, additional effort is required to avoid a potential misleading interpretation of the 4D measured and simulated +-activity distributions in the presence of deficient motion mitigation or data processing. It is presented that in the presence of treatment errors the results from the simulation might be in accordance to the measurement although the planned and delivered dose distribution are different. In contrast to that, deviations may occur between both distributions which are not related to anatomical changes but to deficient 4D data processing. Recommendations are given in this thesis to optimize the 4D IBT-PET workflow and to prevent the observer from a mis-interpretation of the dose monitoring data. In summary, the thesis contributes on a large scale to a potential future application of the IBT-PET monitoring for intra-fractionally moving target volumes by providing the required reconstruction and simulation algorithms. Systematic examinations with more realistic, multi-directional and irregular motion patterns are required for further improvements. For a final rating of the expectable benefit from a 4D IBT-PET dose monitoring, future investigations should include real treatment plans, breathing curves and 4D patient CT images.

Die Strahlentherapie ist einer der drei Partner im interdisziplinären Feld der Onkologie. In Europa, Asien und den USA besteht zunehmend die Möglichkeit einer Therapie mit Strahlen aus geladenen Ionen anstelle von Photonen. Eine Anlage in Dresden befindet sich in der Kommissionierungsphase. Die Ionenstrahltherapie bietet den Vorteil einer sehr konformalen Behandlung des Tumorvolumens durch die endliche Reichweite der Strahlen und ein ausgeprägtes Dosismaximum kurz vor dem Ende des Strahlpfades. Da eine Therapie in der Regel über bis zu 30 Sitzungen an verschiedenen Tagen durchgeführt wird und der Strahlweg stark von dem durchdrungenen Gewebe beeinflusst wird, sind Verfahren für eine in vivo Verifikation der Strahlapplikation wünschenswert. Eine dieser Methoden ist die Partikeltherapie–Positronen-Emissions-Tomografie (PT-PET). Sie beruht auf der Messung der vom Therapiestrahl erzeugten β+-Aktivitätsverteilung. Da eine direkte Berechnung der Dosis aus der Aktivität in lebendem Gewebe nicht möglich ist, wird die gemessene Aktivitätsverteilung mit einer berechneten Vorhersage verglichen und anschließend entschieden, ob die nächste Therapiesitzung wie geplant erfolgen kann oder Anpassungen notwendig sind. Die vorliegende Arbeit beschäftigt sich mit drei Themen aus dem Bereich der Datenverarbeitung für die PT-PET. Im ersten Teil wird ein Algorithmus zur Bestimmung von Reichweitendifferenzen aus zwei β+- Aktivitätsverteilungen adaptiert und evaluiert. Dies geschieht zunächst anhand einer Simulationsstudie mit realen Patientendaten. Ein Ansatz für eine automatisierte Analyse der Daten lieferte keine zufriedenstellenden Ergebnisse. Daher wird ein Software-Prototyp für eine semiautomatische, assistierte Datenanalyse entwickelt. Die Evaluierung erfolgt durch Experimente mit Phantomen am 12C-Strahl. Die erzeugte Aktivitätsverteilung wird von physiologischen Prozessen im Organismus beeinflusst. Dies führt zu einer Entfernung von Emittern vom Ort ihrer Erzeugung und damit zu einer Verringerung der diagnostischen Wertigkeit der erfassten Verteilung. Zur Quantifizierung dieses als Washout bezeichneten Effektes existiert ein am Tierexperiment gewonnenes Modell. Dieses Modell wird im zweiten Teil der Arbeit auf reale Patientendaten angewendet. Es konnte gezeigt werden, dass das Modell grundsätzlich anwendbar ist und für die betrachtete Tumorlokalisation Schädelbasis ein Washout mit einer Halbwertszeit von (155,7±4,6) s existiert. Die Berechnung der Vorhersage der β+-Aktivitätsverteilung kann durch übliche Monte-Carlo-Verfahren erfolgen. Dabei werden die Wechselwirkungsquerschnitte zahlreicher Reaktionskanäle benötigt. Als alternatives Verfahren wurde die Verwendung gemessener Ausbeuten (Yields) radioaktiver Nuklide in verschiedenen Referenzmaterialien vorgeschlagen. Auf Basis einer vorhandenen Datenbank dieser Yields und einer existierenden Condensed-History-Monte-Carlo-Simulation wird ein Programm zur Berechnung von Aktivitätsverteilungen auf Yieldbasis entwickelt. Mit der Methode kann die β+-Aktivitätsverteilung in Phantomen und Patienten zufriedenstellend vorhergesagt werden. Die entwickelten Verfahren sollen einen Einsatz der PT-PET im klinischen Umfeld erleichtern und damit einen breiten Einsatz ermöglichen, um das volle Potential der Ionenstrahltherapie nutzbar zu machen.

Bakgrund: Uträkning av vänsterkammarens (VK) volymer (Enddiastolisk volym, EDV; Endsystolisk volym, ESV; Slagvolym, SV) och ejektionsfraktion (EF) går att göra med elektrokardiografi (EKG)-styrd gating vid positronemissionstomografi (PET) med spårämnet 15O-vatten. Metoden behöver utredas noggrannare och optimeras för att kunna introduceras i klinisk rutinverksamhet. Syfte: Syftet med denna studie var att undersöka bildanalys av PET-rekonstruktioner med olika spatial och temporal upplösning i samband med 15O-vatten-PET utförd med EKG-gating, samt jämföra analysutfallen av VK-volymer och EF mot CMR och sinsemellan, för att utreda möjligheten att optimera metoden. Metod: Totalt 25 patienter som genomgått en 15O-vatten-PET, varav n=11 hade undersökts med CMR samma dag, inkluderades. Olika gating-rekonstruktioner med varierande upplösning utfördes retrospektivt och analyserades automatiskt samt manuellt. Analysutfallen för VK-volymer och EF för PET och CM jämfördes statistiskt. Resultat: I studien fanns en stark till mycket stark korrelation mellan PET och CMR för EDV, stark korrelation för ESV, medel till stark korrelation för SV och svag till medel korrelation för EF. Rekonstruktion med 12 gating-bins och 256x256 matrisstorlek hade starkast korrelation för SV och EF. Samtliga PET-rekonstruktioner korrelerade starkt-till mycket starkt med varandra för VK-volymer och EF. Bland-Altman-analyser visade på en god repeterbarhet, framförallt vid manuell analys, för beräkning av EF med 15O-vatten-PET. Slutsats: VK-volymer och EF kan beräknas med 15O-vatten-PET med en repeterbarhet liknande den för andra, mer använda modaliteter. Att använda en högre upplösning än vad som tidigare testats gav högre värden för EF, och starkare korrelation i jämförelse mot CMR. / Background: Calculation of left ventricle (LV)-volumes (End Diastolic Volume, EDV; End Systolic Volume, ESV; Stroke Volume, SV) and ejection fraction (EF) is possible with electrocardiography (ECG)-gated Positron Emission Tomography (PET) using 15O-water, but the method needs to be further investigated and optimized before clinical routine implementation. Purpose: The purpose of this study was to investigate how altered image resolution affects the analysis and values of LV-volumes and ejection fraction on 15O-water-PET and compare the results against Cardiac Magnetic Resonance imaging (CMR) to enable optimization of the PET-method.  Method: In total, 25 patients who previously underwent a 15O-water-PET, where n=11 also performed CMR on the same day were included in the study. Different gating-reconstructions with varying resolution were performed retrospectively and underwent analysis, both automatically and manually.  Results: Correlation analysis found a strong to very strong correlation comparing PET against CMR for EDV, a strong correlation for ESV, a moderate to strong correlation for SV and a weak to moderate correlation for EF. The reconstruction containing 12 gating-bins and a 256x256 matrix size showed the strongest correlation for SV and EF. All PET-reconstructions correlated strong to very strong against each other for all LV-volumes and EF. Bland-Altman-plots showed good repeatability, especially for manual analysis, when calculating EF on 15O-water-PET.  Conclusion: LV-volumes and EF can be calculated on 15O-water-PET, with repeatability close to that of other modalities. Using an increased resolution than previously tested resulted in higher EF and stronger correlation in comparison with CMR.

Le projet CaLIPSO (Calorimètre Liquide Ionisation Position Scintillation Organométallique) a pour ambition de mettre au point un détecteur de γ 511 keV très efficace et très rapide pour la tomographie par émission de positons. Pour cela nous utilisons comme milieu de détection un nouveau liquide, le TMBi (TriMéthylBismuth). Dans le TMBi, l’interaction de photons γ produit des photons optiques et des paires électrons-ions. Le but de cette thèse est de mesurer les paramètres d’ionisation du TMBi et de construire, un détecteur de charge instrumentant efficacement ce liquide, et son électronique associée. Afin de pouvoir détecter les électrons libres créés par l’ionisation du liquide, celui-ci doit être ultrapur, c’est-à-dire débarrassé de tout composé électronégatif qui pourraient capturer les électrons et diminuer le signal. Ceci a été travaillé à l’aide de tamis moléculaires. Les signaux à détecter sont très faibles (fA, fC). Ainsi, l’environnement de l’expérience et le détecteur ont été développés pour des mesures très bas bruit (niveaux de bruit mesurés inférieurs à 10 fA et 200 électrons). Nous avons travaillé à mesurer le rendement d’ionisation (ou Gfi) qui quantifie le rendement de production de charge dans le liquide, la mobilité des électrons dans le TMBi et la résolution en énergie du détecteur. Ce sont les principaux paramètres permettant de valider l’utilisation de TMBi pour l’imagerie TEP. Les futurs développements comprennent la mise en œuvre d’un détecteur densément pixellisé et l’optimisation de la résolution en énergie. / The CALIPSO project (Calorimètre Liquide Ionisation Position Scintillation Organométallique) aims to develop a very efficient and very fast 511 keV γ detector for positron emission tomography. For this we use an organometallic liquid for the detection medium, the TMBi (TriMéthylBismuth). In TMBi, the interaction of a γ photon produces optical photons and electron-ion pairs.The aim of this thesis is to measure the ionization parameters of the liquid TMBi and build an efficient charge detector and its associated electronics.In order to detect the free electrons created by the ionization in the liquid, this liquid must be highly pure (which means free of any electronegative compound which could capture electrons and reduce the signal). This has been worked on using molecular sieves.The signals to be detected are very weak (fA, fC). Thus, the test setup and detector were developed for very low noise measurements (measured noise levels below 10 fA and 200 electrons).We measured the ionization yield (or Gfi) which quantifies the charge production yield in the liquid, the electrons mobility in the TMBi and the energy resolution of the detector. These are the main parameters to validate the use of TMBi for PET imaging.Future developments include the implementation of a pixelated detector and optimization of the detector energy resolution.

Les travaux de thèse ont porté sur le développement de deux plateformes de radiomarquage polyvalentes pour faciliter l’incorporation du fluor-18, un isotope de choix pour l’imagerie TEP (Tomographie par Emission de Positons). La première plateforme comporte une structure sultone conduisant à un [18F]fluorosulfonate par ouverture du cycle avec le [18F]fluorure. Celle-ci a été valorisée par le couplage avec des ligands 2-nitroimidazoliques pour former un agent d’imagerie TEP spécifique de l’hypoxie. Une série de dérivés caractérisés par des propriétés d’hydrophilie différentes a été synthétisée afin de comparer leur efficacité en imagerie. Parmi ces dérivés, le [18F]FLUSONIM a révélé dans différents modèles précliniques tumoraux (rhabdomyosarcome, tumeurs cérébrales et mélanome) des ratios tumeur sur bruit de fond inégalés jusqu’à présent, et ce à des temps très précoces post-injection. La deuxième plateforme est de nature boratrane. Celle-ci est capable de réagir avec le [18F]fluorure en milieu physiologique pour former un [18F]monofluoroborate zwitterionique facile à séparer du précurseur boratrane. / This work focused on the development of versatile platforms for fluorine-18 labelling. The first platform contained a sultone moiety which was converted to [18F]fluorosulfonate by ring opening with [18F]fluoride. The sultone was coupled to 2-nitroimidazolyl ligands to obtain radiotracers for hypoxia PET imaging. A series of compounds were synthesized in order to compare their performance in PET imaging. Among them, [18F]FLUSONIM displayed high tumor/background ratios after a short delay post-injection on different animal models (rabdomyosarcoma, glioblastoma and melanoma). The second platform was based on a boratrane structure, that was able to captur [18F]fluoride in aqueous medium to form zwiterionic [18F]monofluoroborate.

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18218号 / 薬博第808号 / 新制||薬||238(附属図書館) / 31076 / 京都大学大学院薬学研究科医療薬科学専攻 / (主査)教授 佐治 英郎, 教授 橋田 充, 教授 髙倉 喜信 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM