Alzheimer's Disease (AD) is the most common cause of dementia in elderly people. Although the exact pathogenesis of AD remains unclear, accumulation of β- amyloid (Aβ) plaques seems to be among the causative events. In view of this, Aβ- PET imaging is considered to be a powerful non-invasive diagnostic tool that could also contribute to the development of therapies by monitoring responses. However, Aβ-PET ligands approved so far can only detect heavy plaque load and cannot replace post-mortem examination of brain tissue. The aim of this multidisciplinary study was to develop structurally novel PET tracers for AD. We focused on barbiturates for two main reasons: (i) barbiturates have an excellent ability to cross the blood-brain-barrier, (ii) they are chelators of cations involved in AD. A group of seven “cold” fluorinated barbiturates, along with the corresponding precursors for the “hot” radiosyntheses, was designed and synthesised. All the experimental logP values fell into the optimum range for brain uptake. Barbiturate 1a (Figure I) was selected for further investigations. Upon assessment of its affinity and specificity for Aβ, the radiosynthesis of [18F]1a was optimised. The imaging potential of this tracer was investigated in vivo in pre-clinical mouse models of AD. Brain PET/CT scans with [18F]1a showed reproducible brain uptake and clearance in three different mouse genotypes (WT, APP/PS1 and PLB2-Tau). The significantly higher uptake observed in APP/PS1 mice provided evidence for (i) the in vivo targeting of Aβ- plaques and (ii) the specificity of the tracer towards Aβ pathology. Finally, we designed a second-generation of barbiturates incorporating stilbene groups as dual metal/Ab targeting tracers and we developed a partial synthesis. With this study we paved the way for a larger scale research endeavour that may ultimately result in the rational design of an optimised lead tracer with the potential to ultimately translate into clinical use.

A novel class of potential positron emission tomography (PET) radiotracers for imaging aminopeptidase N (also known as APN or CD13) and cannabinoid type 1 (CB1) receptors were designed and synthesised with an efficient chemical strategy. Both targets have remarkable diagnostic and therapeutic potential, in fact the CD13 receptors are over-expressed during tumour angiogenesis and the CB1 receptors are highly expressed in the brain playing important functions in several pathophysiological processes. The target compounds were obtained by means of oxime-bio-conjugation between fluoro-deoxy-carbohydrates, used as prosthetic groups, and hydroxylamine-functionalised cyclic NGR (asparagine-glycine-arginine) motif sequences for CD13 receptor and rimonabant-type pyrazoles for the CB1 receptor. In particular, aminooxy-cyclic NGR peptides were conjugated with the novel prosthetic group 5-FDR (5-fluoro-5-deoxy-D-ribose) and the aminooxy- pyrazole-type cannabinoid molecules were conjugated with both 5-FDR and with FDG (2-fluoro-2-deoxy-D-glucose). 5-FDR proved to be superior to FDG, as the bioconjugation reaction occurred in milder conditions (room temperature vs 100 °C) and at faster rate. Furthermore, we observed that the rate of the oxime bond formation depends on the solubility of the aminooxy-functionalized core used. In fact, the bioconjugation with hydrophilic cyclic aminooxy-NGR peptides was faster than in the case of lipophilic aminooxy-pyrazoles (10 min vs 20-30 min). The receptor affinity is decreased in the case of the CB1 receptors after conjugation with the fluoro-carbohydrates. This is not observed with the conjugated NGR peptides, which maintain similar affinity for the CD13 receptor compared with the unconjugated NGR. In conclusion, we have developed an efficient strategy for the synthesis of a novel class of CD13 ligands, which may be also produced in radiofluorinated form, and explored a novel bioconjugation strategy for CB1 receptor ligands. Both may have important applications in the development of PET tracers.

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published_or_final_version / Civil Engineering / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Master / Master of Philosophy

published_or_final_version / abstract / Physics / Master / Master of Philosophy

The automotive industry is required to meet improved fuel efficiency standards and stricter emission controls. Aluminum tube hydroforming is particularly well suited in meeting the goals of lighter, more fuel-efficient and less polluting cars. Its wider use in industry is hindered however by the reduced ductility and more complex constitutive behavior of aluminum in comparison to the steels that it is meant to replace. This study aims to address these issues by improving the understanding of the limitations of the process as applied to aluminum alloys. A series of hydroforming experiments were conducted in a custom testing facility, designed and constructed for the purposes of this project. At the same time, several levels of modeling of the process, of increasing complexity, were developed. A comparison of these models to the experiments revealed a serious deficiency in predicting burst, which was found experimentally to be one of the main limiting factors of the process. This discrepancy between theory and experiment was linked to the adoption of the von Mises yield function for the material at hand. This prompted a separate study, combining experiments and analysis, to calibrate alternative, non-quadratic anisotropic yield functions and assess their performance in predicting burst. The experiments involved testing tubes under combined internal pressure and axial load to failure using various proportional and non-proportional loading paths (free inflation). A number of state of the art yield functions were then implemented in numerical models of these experiments and calibrated to reproduce the induced strain paths and failure strains. The constitutive models were subsequently employed in the finite element models of the hydroforming experiments. The results demonstrate that localized wall thinning in the presence of contact, as it occurs in hydroforming as well as other sheet metal forming problems, is a fully 3D process requiring appropriate modeling with solid elements. This success also required the use of non-quadratic yield functions in the constitutive modeling, although the anisotropy present did not play as profound a role as it did in the simulation of the free inflation experiments. In addition, corresponding shell element calculations were deficient in capturing this type of localization that precipitates failure, irrespective of the sophistication of the constitutive model adopted. This finding contradicts current practice in modeling of sheet metal forming, where the thin-walled assumption is customarily adopted. / text

The accurate determination of wear metals in lubricating fluids is of great potential value in the proper maintainence of all types of machinery. Savings of both time and money have been reported in the military and civilian sectors following the implementation of routine wear metal screening in lubricating oils. Current methods are known to discriminate against metals present in the form of particulates. The first part of this dissertation focusses on the direct determination of wear metals in lubricating oils by atomic emission spectroscopy utilizing an inverted inductively coupled plasma as a source. Data are presented which show the effects of power and viewing position on the signal intensity of a variety of sized iron particulate samples in lubricating oil. The second part of this dissertation describes the characterization of a relatively new spectroscopic source--the dual inductively coupled plasma (DICP). The DICP increases the residence time of the analyte in the source by extending the physical length of the plasma discharge and providing two energy deposition regions. Emission intensity, electron density, ion-to-atom intensity ratios, and calculated temperatures are used to compare the DICP with standard inductively coupled plasmas recorded in the literature.

No description available.

No description available.