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

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.

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

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.

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.

At the Gesellschaft für Schwerionenforschung in Darmstadt a therapy unit for heavy ion cancer treatment has been established in collaboration with the Deutsches Krebsforschungszentrum Heidelberg, the Radiologische Universitätsklinik Heidelberg and the Forschungszentrum Rossendorf. For quality assurance the dual-head positron camera BASTEI (Beta Activity meaSurements at the Therapy with Energetic Ions) has been integrated into this facility. It measures ß+-activity distributions generated via nuclear fragmentation reactions within the target volume. BASTEI has about 4 million coincidence channels. The emission data are acquired in a 3D regime and stored in a list mode data format. Typically counting statstics is two to three orders of magnitude lower than those of typical PET-scans in nuclear medicine. Two iterative 3D reconstruction algorithms based on ISRA (Image Space Reconstruction Algorithm) and MLEM (Maximum Likelihood Expectation Maximization), respectively, have been adapted to this imaging geometry. The major advantage of the developed approaches are run-time Monte-Carlo simulations which are used to calculate the transition matrix. The influences of detector sensitivity variations, randoms, activity from outside of the field of view and attenuation are corrected for the individual coincidence channels. Performance studies show, that the implementation based on MLEM is the algorithm of merit. Since 1997 it has been applied sucessfully to patient data. The localization of distal and lateral gradients of the ß+-activity distribution is guaranteed in the longitudinal sections. Out of the longitudinal sections the lateral gradients of the ß+-activity distribution should be interpreted using a priori knowledge.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20262号 / 医博第4221号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 松原 和夫, 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

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine. Johannesburg, October 2017. / Background: Positron Emission Tomography (PET) is an imaging modality that guides the revascularization management of patients with left ventricular systolic dysfunction secondary to coronary artery disease. Segments of the myocardium demonstrating reduced perfusion and increased or preserved 18FFluorodeoxyglucose (18F-FDG) uptake are considered to be viable and thus suitable for revascularization. The aim of our study was to determine the prevalence of myocardial viability as determined by FDG-PET in our local cohort and to compare our prevalence of myocardial viability to data published elsewhere. Methods: We retrospectively reviewed 240 consecutive 99mTc-sestamibi myocardial perfusion Gated Single Photon Emission Tomography (SPECT) and 18FFDG PET reports of patients referred for evaluation of myocardial viability between January 2009 and June 2015. Results: 236 patients met the inclusion criteria. There were 194 (82.2%) males. The mean age was 59.1 (SD 11.0) years. A total of 4012 segments of the left ventricle were analyzed on the gated SPECT and reduced perfusion was noted in 1862 (46.4%) segments. Perfusion-metabolism mismatch (viable myocardium) was observed in 586 (31.5%) out of 1862 perfusion defects. The prevalence of myocardial viability in the study population was 61.4%. On the multivariate logistic regression model, aspirin intake [OR:0.37; CI:0.16-0.83; p=0.016] and hypertension [OR:0.26; CI:0.12-0.58; p=0.001] were associated with the presence of viable myocardium. Smoking was associated with the likelihood of having non-viable myocardium [OR:2.31; CI:1.01-5.29; p=0.048] Conclusion: The prevalence of myocardial viability as detected by 18F FDG PET in our local cohort is similar to prevalence rates reported in the developed world. / LG2018

A well-established method for treating lung cancer is curative-intent radiation therapy (RT). The most significant challenge for RT is to accurately target the lesion volume while avoiding the irradiation of surrounding healthy tissue. Currently at the Juravinski Cancer Centre (JCC), treatment plans for lung cancer patients are completed using fluorodeoxyglucose positron emission tomography (FDG-PET) and four-dimensional computed tomography (4DCT) images. There is no clear protocol, however, to compensate for respiratory motion in PET images and it is not known how lesion volumes generated from PET reflect the true volume. This project evaluated methods to optimize the use of PET images in the radiation treatment planning workflow and quantify the effects of respiratory motion. First, a 4D XCAT digital phantom was used to quantify respiratory motion and its effects on lesion displacement. A CTN physical phantom and 3D-printed irregularly shaped lesion were imaged to determine the accuracy of the PET EDGE automated segmentation algorithm (ASA). Lastly, rigid and deformable image registration techniques were used to propagate the diagnostic PET scan of the irregular lesion to the 4D planning CT. PET EDGE was used to generate target volumes which were then compared to internal target volumes (ITVs) generated from manual contouring of the 4DCT image alone. We found that lesion displacement due to respiratory motion can be adequately modeled using a moving platform set to oscillate 1 cm and 2 cm for normal and deep breathing, respectively. Optimal target delineation was found when diagnostic PET was propagated to the planning CT using rigid image registration for lesions that experienced 1 cm of oscillatory motion during imaging. In contrast, PET EDGE would overestimate volumes in static cases and underestimate volumes in instances of 2 cm dynamic motion meant to simulate deep breathing. / Thesis / Master of Science (MSc)

No description available.