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 / Mechanical Engineering / Doctoral / Doctor of Philosophy

There has been great interest in recent times in the use of elastography for the characterization of human tissue. Digital Image Elasto-Tomography is a novel breast cancer pre-screening technique under development at the University of Canterbury, which aims to identify and locate stiff areas within the breast that require further investigation using images of the surface motion alone. A calibrated array of five digital cameras is used to capture surface motion of the breast under harmonic actuation. The forward problem, that is the resulting motion for a given mechanical property distribution, is calculated using the Finite Element Method. The inverse problem is to find the mechanical properties which reproduce the measured surface motion through numerical simulation. A reconstruction algorithm is developed using a shape based description to reduce the number of parameters in the inverse problem. A parallel Genetic Algorithm is developed for parameter optimization. A geometric method termed Fitness Function Analysis is shown to improve the inclusion location optimization problem. The ensemble of solutions generated using the Genetic Algorithm is used to produce an optimal and a credible region for inclusion location. Successful single frequency phantom reconstructions are presented. An effective way of combining information from multi-frequency phantom data by examining the characteristics of the measured surface motion using data quality metrics is developed and used to produce improved reconstructions. Results from numerical simulation datasets and a two inclusion phantom used to test the optimization of multiple and ellipsoidal inclusions indicate that although two inclusions can be successfully reconstructed, the single inclusions assumption may suffice even in irregular, heterogeneous cases. This assumption was used to successfully locate the stiffest inclusion in a phantom containing multiple inclusions of differing stiffness based on three multi-frequency datasets. The methods developed in phantoms are applied to three in vivo cases for both single and multi-frequency data with limited success. This thesis builds on previous work undertaken at the University of Canterbury. The original contributions in this work are as follows. A new reconstruction algorithm combining a genetic algorithm with fitness function analysis is developed. The most realistic tissue mimicking phantoms to date are used. An ellipsoidal shape-based description is presented, and applied to the first multi-inclusion reconstructions in DIET. This work presents the first reconstruction using meshes created directly from data using a meshing algorithm developed by Jonas Biehler. A multi-frequency cost function is developed to produce the first multi-frequency and in vivo reconstructions using DIET data.

No description available.

No description available.

An adaptive pre-clinical x-ray computed tomography system, named "FaCT" was designed, built, and tested at the University of Arizona's Center for Gamma-Ray Imaging (CGRI). The FaCT system possesses the unique ability to change its magnification and dynamically mask the x-ray beam profile. Using these two abilities, the FaCT system can adapt its configuration to the object being imaged, and the task being performed, while achieving a reduction in the radiation dose applied for imaging.Development of the system included the design of all mechanical components, motion systems, and safety systems. It also included system integration of all electronics, motors, and communication channels. Control software was developed for the system and several high-performance reconstruction algorithms were implemented on graphics processing units for reconstructing tomographic data sets acquired by the system. A new geometrical calibration method was developed for calibrating the system that makes use of the full image data gathered by the system and does not rely on markers.An adaptive imaging procedure consisting of a preliminary scout scan, human guidance, and a diagnostic quality scan was developed for imaging small volumes of interest in the interior of an object at substantially reduced dose. The adaptive imaging procedure makes use of FaCT's adjustable magnification, beam-masking capability, and high-performance reconstruction software to achieve high-quality reconstruction of a volume of interest with less dose than would be required by a traditional x-ray computed tomography system without adaptive capabilities.To address ongoing research into mathematical rules for adapting an imaging system, such as FaCT, to better perform a given estimation task, a method of quantifying a system's ability to estimate a parameter of interest in the presence of nuisance parameters based on the Fisher Information was proposed. The method requires a statistical model of object variability. Possible strategies for increasing the performance of an estimation task, given an adaptive system, were suggested.

Imaging in nuclear medicine involves the injection of a radioactive tracer into the body and subsequent detection of the radiation emanating from an organ of interest. Single-photon emission computed tomography (SPECT) is the branch of nuclear medicine that yields three-dimensional maps of the distribution of a tracer, most commonly as a series of two-dimensional slices. One major drawback to transaxial tomographic imaging in SPECT today is the rotation required of a gamma camera to collect the tomographic data set. Transaxial SPECT usually involves a large, single-crystal scintillation camera and an aperture (collimator) that together only satisfy a small portion of the spatial sampling requirements simultaneously. It would be very desirable to have a stationary data-collection apparatus that allows all spatial sampling in the data set to occur simultaneously. Aperture or detector motion (or both) is merely an inconvenience in most imaging situations where the patient is stationary. However, aperture or detector motion (or both) enormously complicate the prospect of tomograhically recording dynamic events, such as the beating heart, with radioactive pharmaceuticals. By substituting a set of small modular detectors for the large single-crystal detector, we can arrange the usable detector area in such a way as to collect all spatial samples simultaneously. The modular detectors allow for the possibility of using other types of stationary apertures. We demonstrate the capabilities of one such aperture, the pinhole array. The pinhole array is one of many kinds of collimators known as coded apertures. Coded apertures differ from conventional apertures in nuclear medicine in that they allow for overlapping projections of the object on the detector. Although overlapping projections is not a requirement when using pinhole arrays, there are potential benefits in terms of collection efficiency. There are also potential drawbacks in terms of the position uncertainty of emissions in the reconstruction object. The long-term goal of the research presented is dynamic SPECT imaging of the heart. The basic concepts and tasks involved in transaxial SPECT imaging with pinhole arrays are presented along with arguments for the combination of modular gamma cameras and pinhole arrays. We demonstrate by emulation two methods of tomographically imaging a stationary single object slice and present results for these two systems on object space grids of 10cm x 10cm and 20cm x 20cm.

The Pampean flat slab subduction in west-central Argentina (latitude 30-33S) and the steeply dipping Northern Costa Rica subduction zone (latitude 9-11N) show significant along-trench variations in both the subducting and overriding plates. This dissertation contains the results of three seismological studies using broadband instruments conducted in these subduction zones, with the aim of understanding the structure of the lithosphere and the correlation between the variability observed in the downgoing and the overriding plates. In the Costa Rica region, by analyzing teleseismic receiver functions we investigate the variability in the hydration state of the subducting Cocos Plate and the nature of three distinct crustal terranes within the overriding Caribbean Plate: the Nicoya and Chorotega terranes that display an oceanic character, and the Mesquito Terrane, which is more compatible with continental crust.In the Pampean region of Argentina, we apply a regional-scale double-difference tomography algorithm to earthquake data recorded by the SIEMBRA (2007-2009) and ESP (2008-2010) broadband seismic networks to obtain high-resolution images of the South America lithosphere. We find that most of the upper mantle has seismic properties consistent with a depleted lherzolite or harzburgite, with two anomalous regions above the flat slab: a higher Vp/Vs ratio anomaly consistent with up to 10% hydration of mantle peridotite and a localized lower Vp/Vs ratio anomaly consistent with orthopyroxene enrichment. In addition, we study the geometry and brittle deformation of the subducting Nazca Plate by determining high-quality earthquake locations, slab contours, and focal mechanisms. Our results suggest that the subduction of the incoming Juan Fernandez Ridge controls the slab geometry and that ridge buoyancy and slab pull are key factors in the deformation of the slab. The spatial distribution of the slab seismicity suggests variability in the hydration state of the subducting Nazca Plate and/or in strain due to slab bending. These observations support the hypothesis that the along-trench variability in bathymetric features and hydration state of the incoming plate has profound effects in the subducting slab geometry and the upper plate structure in both flat and steeply dipping subduction zones.