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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
51

Development of PET radioligands synthesized from in-target produced [¹¹C] methane

Andersson, Jan, January 2010 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.
52

Novel methods for 18F-radiolabelling

Calderwood, Samuel January 2016 (has links)
The expansion of [<sup>18</sup>F]-radiolabelling methodologies is vital for the advancement of Positron Emission Tomography (PET) as a medical imaging tool. Novel protocols will simplify access to current PET tracers and allow development of original tracers, potentially enhancing the imaging quality or permit imaging of a wider range of clinical problems. A general introduction is presented in <b>Chapter 1</b>, covering PET, application of fluorine-19 in the pharmaceutical industry, the production of fluorine-18 and the current state-of -art for [<sup>18</sup>F]-radiolabelling. The results chapters are divided in to two parts; <b>Part 1</b> (<b>Chapters 2 - 4</b>) concern the synthesis of [18F]fluoroarenes and <b>Part II</b> (<b>Chapters 5</b> and <b>6</b>) discuss diversity oriented radiofluorination techniques, targeting novel [<sup>18</sup>F]motifs. In <b>Part I</b>, Chapter 2 describes the use of hypervalent iodine reagents to meditate an umpolung approach for fluorination and radiofluorination of N-arylsulfonamides and anilides. <b>Chapter 3</b> again utilises hypervalent iodine reagents, but as spirocyclic iodonium(III) ylide precursors, being applied to semi-automated and automated microfluidic conditions. <b>Chapter 4</b> discusses the development of conditions for the production and isolation of radiopharmaceuticals employing Cu(II)-mediated radiofluorination of aryl boronic pinacol esters. In <b>Part II, Chapter 5</b> discusses the applicability of halogen exchange reactions to reach polyfluorinated motfis and <b>Chapter 6</b> focuses on the application of a single diazo precursor to access three polyfluorinated motifs with single-step reactions. Finally, <b>Chapter 7</b> provides experimental data for compounds discussed in this thesis.
53

Atherosclerotic inflammation imaging using somatostatin receptor-2 positron emission tomography

Tarkin, Jason Michael January 2017 (has links)
Systemic inflammatory networks and local signaling cascades trigger culprit pathogenic mechanisms relating clinical cardiovascular disease (CVD) risk factors to atherosclerotic plaque progression and rupture. Imaging vascular inflammation affords a valuable marker of atherosclerotic disease activity to reveal important mechanistic insights for CVD research, to quantify early anti-inflammatory effects of new atherosclerosis drugs, and, ultimately, to help improve CVD risk prediction. While carotid, aortic, and peripheral arterial inflammation can be measured by 18F-fluorodeoxyglucose (FDG) PET-computed tomography (CT), as a glucose analog, high 18F-FDG signal spillover owing to physiological myocardial muscle metabolism prevents reliable coronary interpretation. Lack of cell specificity, and the influence of hypoxia on 18F-FDG uptake within macrophages and other plaque cells, are further limitations that drive the search for an alternative PET tracer for imaging inflammation in atherosclerosis. Up-regulation of the G-protein coupled receptor somatostatin receptor subtype-2 (SST2) occurs on the cell surface of activated macrophages. The central hypothesis tested in this thesis is that vascular SST2 PET imaging using 68Ga-DOTATATE might offer a more accurate marker of macrophage inflammation than 18F-FDG, with superior coronary imaging and therefore better power to discriminate high-risk vs. low-risk atherosclerotic lesions. Comprehensive molecular, histological and clinical evaluation of this experimental CVD imaging biomarker was undertaken, including a prospective clinical study with head-to-head comparison to 18F-FDG in coronary, carotid, and aortic vasculature. In vitro data showed that (i) target SSTR2 gene expression occurred in “pro-inflammatory” M1 macrophages, (ii) specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and (iii) and carotid SSTR2 mRNA was highly correlated with both the pan-macrophage marker CD68 and in vivo 68Ga-DOTATATE PET signals. In clinical imaging, increased 68Ga-DOTATATE inflammatory signals correctly identified culprit vs. non-culprit arteries in patients with acute coronary syndrome and transient ischemic attack/stroke. 68Ga-DOTATATE also demonstrated good diagnostic accuracy for high-risk coronary CT features, and strong correlations with clinical CVD risk factors and 18F-FDG-defined vascular inflammation. While 18F-FDG also differentiated culprit vs. non-culprit carotid and high-risk coronary arteries, myocardial 18F-FDG overspill rendered coronary scans uninterpretable in most patients. In contrast, 68Ga-DOTATATE allowed unimpeded coronary interpretation in all patients. Findings of this thesis provide compelling evidence, from gene, to cell, to plaque, to patient, that SST2 PET imaging using 68Ga-DOTATATE provides a quantifiable marker of macrophage-related atherosclerotic inflammation and disease activity. Further studies are needed to establish whether 68Ga-DOTATATE PET can improve CVD risk prediction when added to current clinical methods, or offer a novel imaging platform to rapidly test the anti-inflammatory capacity of emerging atherosclerosis drugs. Broader translational applications of 68Ga-DOTATATE PET include possible use in diagnosis and therapeutic monitoring of vasculitis, endocarditis, myocarditis, and other manifestations of cardiovascular inflammation.
54

Investigating imaging biomarkers of neuroinflammation and neurodegeneration in rodent models of Alzheimer's disease

Chaney, Aisling January 2016 (has links)
Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in alterations in memory, language, executive function and emotional behaviour. Although it can be characterised by symptoms, by the time they arise significant pathological alterations have already emerged in the central nervous system, namely increased amyloid plaques, neurofibrillary tangles and neuronal loss. Despite known pathological hallmarks the exact aetiology of AD is poorly understood and no current treatments are available. However, there is growing interest in the role of neuroinflammation in AD, with increases observed in the early stages of disease and with disease progression. Moreover, it has been suggested that peripheral inflammation can influence neuroinflammation and worsen neurodegeneration. Using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRS) we can non-invasively measure biomarkers of neuroinflammation and degeneration allowing multi-modal investigation of its role in normal aging and AD. Considering this the objectives of this study were to (i) Use PET and MRS to investigate neuroinflammatory and metabolite alterations in transgenic (TG) models of AD and their wildtype (WT) animals. (ii) Assess rates of cognitive decline in these models using memory based tests. (iii) Investigate relatively new TgF344AD rat as an AD model by characterising younger time-points than previously reported. (iv) Investigate the contribution of peripheral inflammation on AD progression. PET and MRS imaging was carried out longitudinally in the APPswe×PS1de9 mouse. Neuroinflammation was confirmed ex vivo and cognitive ability was assessed by behavioural tests. Results revealed significantly increase hippocampal and thalamic neuoinflammation in old TG mice as assessed by [18F]DPA-714 PET and supported by immunohistochemistry. Reduced neuronal marker N-acetlyaspartate was seen with age and was exacerbated in the TG mice. Accelerated cognitive decline was also seen in TG mice. PET and MRS imaging was carried out at 6 and 12 months in the TgF344AD model, which expresses amyloid and tau pathology as well as neuronal loss. No cognitive decline was observed in TG rats; however increased anxiety behaviour was seen. Increased [18F]DPA-714 PET was observed as an effect of gene in the thalamus at 6 months and the hypothalamus at 12 months. Increases in glutamate were seen with age in the TG rats but not the WTs. Increased inflammation and metabolite alterations were seen with aging. The effect of peripheral urinary tract infection (UTI) on cognition and imaging out was assessed. Imaging was carried out prior to and after re-current UTI. Infection induced cognitive decline in infected TG but not WT rats. Infection had an increasing effect on hypothalamic neuroinflammation in WT rats but a decreasing effect on TG rats, which masked the original gene differences. This thesis is set out in the alternative format with each experimental study represented as a chapter. Results in this thesis implicate neuroinflammation in AD development and progression. In addition, we report systemic infection-CNS interactions accelerating cognitive decline in AD and highlight the importance of understanding the effects of comorbidities in disease.
55

Systemic Biodistribution and Intravitreal Pharmacokinetic Properties of Bevacizumab, Ranibizumab, and Aflibercept in a Nonhuman Primate Model

Christoforidis, John Byron, Briley, Karen, Binzel, Katherine, Bhatia, Prayna, Wei, Lai, Kumar, Krishan, Knopp, Michael Vinzenz 01 November 2017 (has links)
PURPOSE. To determine the intravitreal pharmacokinetic properties and to study the systemic biodistribution characteristics of 1-124-labeled bevacizumab, ranibizumab, and aflibercept with positron emission tomography-computed tomography (PET/CT) imaging in a nonhuman primate model. METHODS. Three groups with four owl monkeys per group underwent intravitreal injection with 1.25 mg/0.05 mL 1-124 bevacizumab, 0.5 mg/0.05 mL 1-124 ranibizumab, or 2.0 mg/0.05 mL 1-124 aflibercept in the right eye of each subject. All subjects were imaged using PET/CT on days 0, 1, 2, 4, 8, 14, 21, 28, and 35. Serum blood draws were performed at hours 1, 2, 4, 8, 12 and days 1, 2, 4, 8, 14, 21, 28, and 35. Radioactivity emission measurements were used to determine the intravitreal half-lives of each agent and to study the differences of radioactivity uptake in nonocular organs. RESULTS. The intravitreal half-lives were 3.60 days for 1-124 bevacizumab, 2.73 days for 1-124 ranibizumab, and 2.44 days for 1-124 aflibercept. Serum levels were highest and most prolonged for bevacizumab as compared to both ranibizumab and aflibercept. All agents were primarily excreted through the renal and mononuclear phagocyte systems. However, bevacizumab was also found in significantly higher levels in the liver, heart, and distal femur bones. CONCLUSIONS. Among the three anti-VEGF agents used in clinical practice, bevacizumab demonstrated the longest intravitreal retention time and aflibercept the shortest. Significantly higher and prolonged levels of bevacizumab were found in the serum as well as in the heart, liver, and distal bones. These differences may be considered by clinicians when formulating treatment algorithms for intravitreal therapies with these agents.
56

Ligandové systémy pro komplexaci zirkonia / Ligand systems for zirconium complexation

Hacaperková, Eliška January 2016 (has links)
The aim of this thesis is to synthesize new kind of macrocyclic ligands for complexation of Zr4+ . Zirconium(IV) complexes have potential as contrast agents in immuno-PET. Three macrocyclic ligands L1, L2 and L3 with dif- ferent pendant arms (HOPO, maltol, hydroxamate) were designed. Despite numerous attempts syntheses of L1 and L2 were unsuccessful. Ligand L3 was synthesized and the protonation constants were determined by poten- tiometric titration. Complexes [Zr4+ (L3)] were studied too. Catechol ligand L4 was prepared and complexes with cations Zn2+ , Ga3+ and Zr4+ were investigated. 1
57

Transfer of learning with an application to the physics of positron emission tomography

Aryal, Bijaya January 1900 (has links)
Doctor of Philosophy / Department of Physics / Dean A. Zollman / A series of teaching activities using physical models was developed to present some portions of physics of Positron Emission Tomography (PET) and investigate students’ understanding and transfer of learning in physics to a medical technology. A teaching interview protocol consistent with a qualitative research methodology was developed and administered to the students enrolled in an algebra-based introductory level physics course. 16 students participated in individual interviews and another 21 students participated in the group sessions. The major objectives of the teaching interviews were to investigate students’ transfer of physics learning from their prior experiences to the provided physical models, from one model to the other and from the models to the PET problems. The study adapted phenomenological research methodology in analyzing students’ use of cognitive resources and cognitive strategies during knowledge construction and reconstruction. A resource based transfer model framed under the cognitive theory of learning and consistent with contemporary views of transfer was used to describe the transfer of physics learning. Results of the study indicated both appropriate and inappropriate use of the students’ prior conceptual resources in novel contexts. Scaffolding and questioning were found to be effective in activating appropriate and suppressing the inappropriate resources. The physical models used as analogies were found useful in transferring physics learning to understand image construction in PET. Positive transfer was possible when the models were introduced in an appropriate sequence. The results of the study indicate the occurrence of three types of non-scaffolded transfer – spontaneous, semi spontaneous and non-spontaneous. The research found connections between sequencing of hints and phrasing of information in activating students’ different conceptual resources. A qualitative investigation based on Vygotsky’s Zone of Proximal Development (ZPD) has been completed in two contexts – one involving an instructor and the other involving peers. Significant expansion of the students’ ZPD occurred through peer interaction. The results indicate that the appropriate sequencing of learning activities and group interactions can promote learning. Additional research in transfer of physics learning from macroscopic phenomena to microscopic phenomena are warranted by the conclusions of this work.
58

Monte-Carlo simulations of positron emission tomography based on liquid xenon detectors

Lu, Philip Fei-Tung 05 1900 (has links)
The prospects for enhanced Positron Emission Tomography imaging using liquid xenon (LXe) gamma ray detectors had been examined. Monte-Carlo simulations using GEANT4 were performed and the results were used to study the expected performance of a small animal PET scanner in comparison with a simulated conventional small animal scanner (LSO Focus 120). A NEMA-like cylinder phantom and an image contrast phantom were simulated with both scanners to compare performance characteristics. A Compton reconstruction algorithm was developed for the LXe scanner, and its performance and limitations studied. / Science, Faculty of / Physics and Astronomy, Department of / Graduate
59

Evaluation of the Altered Pathophysiological Mechanism of the Human Arg302Gln-PRKAG2 Mutation-Induced Metabolic Cardiomyopathy: Studying the Glucose Metabolism Pathway in a Transgenic Mouse Model

Thorn, Stephanie January 2013 (has links)
Characterized by excessive myocardial glycogen deposition, cardiac hypertrophy, frequent cardiac arrhythmias and progressive conduction system disease, the PRKAG2 cardiac syndrome stems from a genetic mutation in the γ2-subunit of AMP-activated protein kinase (AMPK). Although functionally diverse, the main role of AMPK is to modulate cardiac metabolism in response to depleted ATP levels. A comprehensive study of the dysfunctional regulation of AMPK activity involved in the progression of the human PRKAG2 cardiac syndrome is hindered by the limitations of in vitro techniques. Positron emission tomography (PET) imaging with the glucose analogue, FDG, offers a quantitative assessment of myocardial glucose uptake non-invasively. The aim of this thesis was to determine the ability of FDG to detect changes in glucose uptake, storage and metabolism in the heart in relation to AMPK activity and provide insights into the mechanism of PRKAG2 cardiac hypertrophy. To achieve this aim, a transgenic AMPK γ2-subunit Arg302Gln mouse model was evaluated with small animal FDG PET with correlation to biochemical assays of cardiac AMPK activity and the glycogen metabolism pathway. Using the vena cava blood input function, FDG myocardial glucose uptake was reliably assessed in mice for the first time with Patlak modeling. Reduced FDG uptake in the Arg302Gln PRKAG2 mouse model suggested a feedback pathway reducing exogenous glucose uptake due to excessive intracellular glycogen stores. Despite an increase in FDG uptake in the skeletal muscle of the PRKAG2 mutant mice following insulin stimulation, there was no change in cardiac uptake, signifying myocardial insulin resistance. Increased reliance on glucose oxidation by TMZ inhibition of fatty acid oxidation reduced glycogen stores, restored cardiac function and eliminated ventricular preexcitation. The observed reduction in mouse myocardial FDG uptake mirrors the reduction previously observed in the human PRKAG2 patients. The potential now exists to evaluate both progression and therapeutic interventions for the PRKAG2 cardiac syndrome with the transgenic mouse model with translation to the affected patients using FDG cardiac imaging.
60

Translocator protein expression and microglial activation in gliomas

Su, Zhangjie January 2013 (has links)
Background: Gliomas are the most frequent primary brain tumours in adults with two main histological subtypes: astrocytoma and oligodendroglioma. Translocator protein (TSPO) is a pro-inflammatory molecule over-expressed predominantly in activated microglia under pathological conditions. In astrocytoma samples, TSPO has also been found to be up-regulated and correlated with the malignancy of the tumours. [11C]-(R)PK11195 is a selective radioligand for the TSPO widely applied in clinical PET studies. We used [11C]-(R)PK11195 PET to investigate in vivo cerebral TSPO expression and microglial activation in patients with gliomas of different histological subtypes and grades. Methods: 24 glioma patients and 10 healthy volunteers underwent volumetric MRI and dynamic [11C]-(R)PK11195 PET scans. Tissue time-activity curves (TACs) were extracted from tumour regions and normal grey and white matter of the brains. Parametric maps of binding potential (BPND) were generated with the simplified reference tissue model. Co-registered MRI/PET was used to guide tumour biopsies. Tumour tissue was quantitatively assessed for TSPO expression and microglial infiltration by immunohistochemistry. Results: Three types of tumour TAC were observed in gliomas (grey matter-like kinetics, white matter-like kinetics and mixed kinetics), which differed between low-grade astrocytomas and low-grade oligodendrogliomas but were independent of the tumour grade. [11C]-(R)PK11195 BPND also differed between the two subtypes of low-grade gliomas, and low-grade gliomas demonstrated lower BPND than high-grade gliomas. 4 cases of high-grade glioma with minor or no contrast enhancement on MRI showed pronounced [11C]-(R)PK11195 binding. Immunohistochemistry confirmed that expression of TSPO correlated with [11C]-(R)PK11195 BPND of the tumour. It was related mainly to expression by neoplastic cells while the contribution from tumour-infiltrating microglia was minimal. When compared with control subjects, increased [11C]-(R)PK11195 BPND was found in patients’ normal appearing cerebral structures, being more prominent in the tumour-bearing than the tumour-free hemisphere. This extra-tumoral [11C]-(R)PK11195 binding was correlated with the duration of epileptic seizures, the symptom shared by the majority of our patients. Conclusions: Gliomas show differences in [11C]-(R)PK11195 kinetics and binding that are related to histological subtype and grade. Neoplastic cells rather than activated microglia are the main cellular sources expressing TSPO and determine the [11C]-(R)PK11195 binding within the tumours. [11C]-(R)PK11195 PET has the potential to detect malignant transformation of non-enhancing gliomas and facilitate the targeting of more aggressive areas in tumour biopsy. The high extra-tumoral [11C]-(R)PK11195 binding indicates widespread microglial activation in otherwise normal appearing cerebral structures of glioma patients. It is associated with epilepsy and could open up novel therapeutic perspectives for seizure control in this patient population.

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