Angiogenesis is a fundament al process in the survival, growth and spread of cancers. In recent years several therapies have been developed to interfere with this process. Despite initial optimism these agents have rarely provided durable clinical responses. Methods capable 0f assessing angiogenesis are required to help develop effective anti-angiogenic approaches Radionuclide imaging is one potential method of assessing angiogenesis. VEGF and integrin expression are two key factors in regulation of angiogenesis in tumours and provide potential targets for radionuclide imaging of angiogenesis. This thesis investigates whether targeting of VEGF and integrins can be performed to image angiogenesis and if treatment with antiangiogenic therapy can be detected via such imaging. VEGF imaging was successfully performed by radiolabelling bevacizumab, a monoclonal antibody directed against all isoforms of VEGF, with 111 indium for SPECT imaging. This agent was validate in vitro and in vivo mouse xenograft models, and appears to bind to matrix and cell membrane associated VEGF within tumours. lntegrin imaging was attempted using 99Tc-maraciclatide, another SPECT imaging agent. This is a commercial agent based on the RGD tripeptide sequence and binds primarily to α,β3 and α,β5 integrins. It was assessed in a clinical trial and compared with histological markers of angiogenes' in patients with colorectal, renal and breast tumours. There was an inverse relationship between 99mTc•maraciclatide uptake and β13 vascular density but no correlation with other angiogenic markers. Both tracers were investigated in a preclinical xenograft model with antiangiogenic therapies Rapamycin, an mTOR inhibitor, increased uptake of 111ln-bnDTPA-bevacizumab and decrease uptake of 99"'Tc-maraciclatide. These responses corresponded with an increase in VEGF an decrease in β3 integrin levels in the tumours. Rapamycin therapy was also associated with reduction in blood vessel number and changes in perfusion as demonstrated by DCE•MRI. The effect of bevacizumab therapy on 99Tc•maraciclatide uptake was also investigated. Bevacizumab had no significant effect on either 99mTc-maraciclatide uptake or β3 integrin levels. These preliminary results demonstrate that both radiotracers have potential for imagin, angiogenesis and detecting response to angiogenic therapies. They also highlight the complex nature of the angiogenic process and that further work is necessary to determine the clinical usefulness of these agents.

Positron Emission Tomography has experienced several advances-in the last decade. This thesis assesses the recent developments in PET scanners: New, fast scintillators, higher resolution detectors, fully 3D imaging and increased sensitivity, iterative reconstruction algorithms with implementation of point spread function modelling and time-of- flight. The physical performance characteristics of three multi-ring and one panel based configuration were quantified using phantom experiments. The clinical impact of increased sensitivity was explored. Figures of merit to assess image quality were established and a method to optimise reconstruction algorithms for signal-to-noise was developed and applied. The improvements of implementing point spread function modelling into image reconstruction were investigated and quantified. The implementation of time-of- flight in addition to point-spread-function modelling was explored in substantial detail and compared. Experimental results were obtained and the clinical impact of time-of- flight was assessed. In a final investigation, the panel based PET scanner design was successfully applied in veterinary medicine.

In this thesis we consider the task of dynamic imaging using a gcPET system. Our technique is based on a mathematical method (developed for SPECT), which processes all dynamic projection data simultaneously instead of reconstructing a series of static images individually.  The algorithm was modified to account for the extra data that is obtained with gcPET (compared with SPECT).  The method was tested using simulated projection data for both a SPECT and a gcPET geometry.  These studies showed the ability of the code to reconstruct simulated data with a varying range of half-lives.  For SEPCT data the characteristic parameters of half-life (T_1/2) and initial activity (A₀) were reconstructed with a percentage error of 35.1%, and 40.8% (at 50 iterations) for a 2 minutes half-life, respectively.  The reconstruction of gcPET data showed improvement in half-life and activity compared to SPECT data by 27% and 31%, respectively (at 50 iterations). The method was also extended to enable reconstruction of images in which some regions increased in activity while other regions decreased.  Information of the spatial location of these images was provided in the form of a mask. The method was applied to experimental data.  These data were acquired using a dPET system and re-binned to the gcPET geometry.  The results, obtained from dynamic phantoms, showed that the characteristic behaviour could be recovered and that the code produced satisfactory dynamic images.  The method was also applied to data from a patient with a tumour.  Again, the reconstructed image showed good results compared to the dPET reconstruction.  Time activity curves showed a significant difference between the uptake of tumour and myocardium. Finally, we presented a method to deal with the situation where the activity in certain pixels decreases and then increases during the acquisition.

Traditionally, in Positron emission tomography (PET) scanners, the detection of simultaneous gamma ray emissions resulting from positron annihilations has been achieved using Photo-multiplier tubes (PMTs) optically coupled to dense scintillators. The recent development of the Avalanche photo-diode (APD) offers the possibility of replacing the PMT, however, such a step is not without its problems. The introduction of APD technology into scintillation detector design offers: more compact scanner design; the possibility of a multi-layer scintillation detector, with an inherent reduction in parallax errors; improved spatial, energy and timing resolutions; increased count-rate; and a higher packaging fraction with correspondingly increased scanner sensitivity. A well-designed APD-based scintillation detector can only be realised if all stages of the detection process are fully understood. The work described in this thesis shows that it is possible to model the complex processes of gamma ray interaction, scintillation, and light transport, using Monte Carlo methods; and to model the photo-detector output signal and its processing using both simplified circuit analysis and a standard circuit simulation software. These models were then combined to form a powerful modelling tool for APD-based scintillation detector design; this modelling tool was then used to design a multi-layer scintillation detector, which was built and tested. The performance of the detector closely matched the simulations. The measured performance parameters of the laboratory prototype were: intrinsic spatial resolution 2.0 mm (FWHM at 0.511 MeV), energy resolution 15% (FWHM at 0.511 MeV) and timing resolution of 2.2ns (FWHM), with a reconstructed image resolution of 1.6 mm (FWHM). THE prototype performance figures match any known commercially available Small animal PET scanner at this time.

In this thesis the main aspects of three photon positron annihilation processes and their potential use in medical imaging have been investigated as a positron emission tomography technique. The main objectives are focused on: three-photon positron annihilation measurement and imaging, analytical modelling and Monte Carlo simulation and the evaluation of the detection system requirements. A novel method as proof-of-principle of the three photon positron annihilation imaging concept based on a triple coincidence imaging technique using high energy resolution semiconductor detectors has been introduced. It has been shown that a simple system of three high-energy resolution detectors is able to produce images of three photon positron annihilations events. The full energy photopeak detected of the true 3y events can be easily identified in the spectrum. Although the sensitivity is small due to a very small solid angle (~0.05 str) subtended by the detectors and rather poor detection efficiency, it is a first step towards a scanner capable of a new imaging modality. This method has been investigated using Monte Carlo simulation results and experimental data acquired. Further a new three-photon yield measurement method based on three-photon positron annihilation imaging technique with correction for scattered and random events is proposed. The feasibility of this approach has been verified using experiments and compared to existing methods. Results show that this method is more accurate with better scatter correction due to electronic collimation than others but it has also some limitations. In order to obtain quantitative information from the detection system it is necessary to establish mathematical or analytical models, which describe the system. This was achieved for the triple coincidence condition. The count rate of single and triple detected events was investigated. Results have shown differences due to scatter and random events estimation. The effect of semiconductor detectors properties on three-photon image quality and scanner design was also investigated. It was in addition shown that computer simulations can be effectively used to predict the image quality and background noise for a particular scanner design. Important characteristics which affect scanner performance were evaluated. The effect of detector and scanner size on spatial resolution of three photon images was discussed. It was found that by reducing scanner size spatial resolution was improved for three-photon positron annihilation imaging as for conventional two photon-positron annihilation. Variation of scanner size (scanner diameter) affects the point spread function of the three photon positron annihilation image profile and introduces a combination of errors due to photon energy and detection position. To introduce the three-photon technique in a dedicated PET system, high- energy resolution detectors are needed to improve the quality of the image and reduce the noise due to scattered events arising from Compton scattering which do not correspond to 3y events. Semiconductor detectors, particularly CZT which have good energy resolution, significantly better stopping power and can be used at room temperature are proposed as the detectors of choice for the new detection system. Therefore, images of two photon-positron annihilation can be mapped with those of 3- photon events and new valuable information can be extracted. This information will be valuable to treatments involving external beam radiotherapy and may also be of use in brachytherapy.

A novel experimental set-up was installed at the University of Surrey Ion Beam Centre for the purpose of producing 3D quantitative elemental maps of biological samples by combining simultaneous Proton Induced X-Ray Emission Tomography (PIXE- T), on/off-Axis Scanning Transmission Ion Microscopy-Tomography (STIM-T) and Rutherford Backscatter Spectrometry (RBS). A tomographic sample holder was designed and built and a scattering system developed for On/Off-Axis STIM. 2D PIXE and off-STIM analysis of leukocytes was performed to complement concurrent research and to identify problems with the very recently installed proton microbeam at the Ion Beam Centre. The other major aim was to see if a leukocyte would be a suitable sample for tomographic analysis and to study the damage induced by the beam on biological samples. Instrumental Neutron Activation Analysis (INAA) was performed on hair samples collected from MSc students at the University of Surrey and a database compiled of all elemental analysis of hair performed at the University. This complemented the tomographic analysis performed on a section of a strand of hair. Si, S, Cl, K, Ca, Fe and Zn were mapped using simultaneous PIXE-T, On/Off- Axis STIM-T and RBS.

No description available.

The non-invasive imaging modality positron emission tomography (PET) is used extensively in clinical settings and is increasingly being used by the pharmaceutical industry in drug development. Molecules of biological interest are labelled with positron emitting isotopes e.g. 11C, allowing their biodistribution and kinetics to be followed in vivo. A major factor in the failure of radioligands is the magnitude of unwanted background signal, non-specific binding (NSB) obscuring binding to the desired target. Assumptions have previously been made as to the physiochemical and pharmacological properties of radioligands that can affect NSB. However, little work has been carried out to quantify NSB with regard to determining structure-activity relationships (SARs) in order to optimise efficient radiotracer discovery. Non-specific binding is a poorly understood process but is believed to be related to the non-saturable binding of labelled molecules with tissue membranes. In this work the synthesis of novel radiolabelled molecular libraries has been conducted, their physicochemical properties determined and their non-specific binding measured in vitro using autoradiographical and cell based mass spectrometry assay methods. Structure-activity relationships have been formed between partition coefficient properties, acid dissociation constants, interaction energies and molecular weight in order to determine the effect each of these properties has on non-specific binding. Traditionally lipophilicity, log P, of a radioligand is the main predictor to its non-specific binding properties. However from this work it has been shown that a single physicochemical property cannot be relied on to predict the NSB of a radioligand but multiple properties must be considered.

No description available.

Positron emission tomography (PET) employs short half-life positron emitting isotopes, typically ¹⁸F, for in vivo measurement of physiological processes. Easy access to structurally diverse radiolabelled probes would accelerate the rapid progress of PET imaging but, to date, radiochemistry is still limited by cost and efficiency. Nucleophilic fluorination with ¹⁸F-fluoride is the preferred “non-carrier-added” methodology in the synthesis of ¹⁸F-labelled pharmaceuticals because it leads to radiotracers with a high specific activity, a key feature allowing for investigations to be performed in sub-toxic doses. Chapter 1 serves as an introduction on radiochemistry, especially focussing on current radiosynthetic methods for the synthesis of ¹⁸F-labelled aromatics. Aromatic compounds without electron-withdrawing groups are notoriously difficult to label with ¹⁸F-fluoride. In this thesis, we present two novel methodologies to deliver ¹⁸F-labelled aromatic compounds from nucleophilic 18F-fluoride. Chapter 2 details the experimental efforts towards “Convergent Radiosynthesis” (Scheme 1). We proposed a convergent synthetic tactic that allows for simultaneous reaction between three or more substrates, including an ¹⁸F-labelled building block. This chemistry has been validated by the radiosynthesis of various structural scaffolds which are not responsive to direct nucleophilic fluorination. Chapter 3 presents our research into “Oxidative Nucleophilic ¹⁸F-Fluorination” (Scheme 2). We proposed that electron-rich aromatics, such as phenols, which are not responsive to nucleophilic fluorination may undergo umpolung reactivity under oxidative conditions. This “umpolung strategy” allows for the direct transformation from ¹⁸F-fluoride to 4-[¹⁸F]fluorophenol. Potentially, this established oxidative fluorination strategy could be adapted to the radiosynthesis of radiotracers containing a 4-fluorophenol sub-motif, such as 6-fluoro-meta-tyrosine. An appropriate precursor has been validated for the prospective radiosynthesis of 6-[18F]fluoro-meta-tyrosine.