1 in 8 women in the UK will develop breast cancer, 20% of whom will have cancer which is her2 positive - meaning that the tumours have a protein receptor on the surface of the cancer cells. The presence of the her2 receptor has been found to make cancers more aggressive, and generally their outcomes are worse than those tumours that are her2 negative. Her2 positive breast cancer can be treated with drugs such as trastuzumab (otherwise known as Herceptin) which is used in the early stages to reduce the risk of relapse, or in the metastatic stage when the cancer has spread to distant organs to try and control the disease. This study aims to develop a new type of scan for imaging patients with her2 positive breast cancer. The test involves a very small amount of a radioactive chemical (called a tracer), which can bind to the her2 receptor. This tracer can be detected in a PET scanner and used to localise the areas that are her2 positive. At present doctors rely on biopsies of tumours to detect her2, the biopsies can be painful and are not always possible from certain areas of the body for example the biopsy might cause bleeding if the tumour is near a blood vessel. In patients with advanced cancer (meaning that the tumour has spread to distant parts of the body) new drugs have been developed which target the her2 receptor. Compared to standard treatments the newer drugs have significantly higher response rates and have been hailed as breakthroughs in the treatment of her2 positive cancer. However the prognosis for this disease remains poor, and the clinical studies show that between 20 and 50% of patients with metastatic her2 positive cancer will not respond to some of these newer agents. Resistance only becomes apparent after several treatments have been given, and is generally found in CT scans which show either new lesions or that the existing tumour lesions have enlarged in size. The newer drugs do have a significant risk of side effects including low platelets (which help the blood to clot in 12%), and heart toxicity (1%). However for individual patients we cannot predict before the start of treatment if their metastatic tumours will respond to treatment, and it is not possible to biopsy every single lesion. This study will be divided into two phases, in the first phase we will assess whether the tracer is taken up more in her2 positive tumours than her2 negative tumours, this will involve detailed PET scans lasting approximately 90 minutes in 16 patients in total, as the tracer (also known as GE-226) has not been used in this specific form before, we will also study safety by monitoring patients carefully before and after the scans, this phase will all be done in one centre in London (Imperial College) which has particular expertise in this type of study, if this phase is successful and there is no significant toxicity we will proceed to the second phase which will involve 25 patients with her2 positive patients who will have a PET scan with GE-226 in one of four centres (whichever is closest), the PET scan will be done at the start of a course of therapy and compared to standard CT scans which are done before treatment and after 3 cycles of treatment (63 days) to measure if the findings from the PET scan can predict which patients will respond to treatment. We will have regulatory approval from all the relevant committees in place (ethics, radiation, MHRA) before the study can start. The outcomes for this project we hope for are to demonstrate that GE-226 has higher uptake in her2 positive disease, that it is safe and well tolerated, and that it can predict response to treatment. If this is successful then larger studies could be done in the future to confirm this, and eventually this could become a routine test in this group of patients which would help oncologists select the best treatments, and also reduce drug costs for the NHS. The study will be led by leading oncologists and imaging scientists from the UK.

The lifetime risk for a single seizure is 1:20, but 1:200 for epilepsy. Epilepsy develops in 20% of individuals after a severe head injury, but this can occur >20 years after the injury. We don't know the exact mechanisms pertinent to the development of epilepsy, or progression after the condition is established (=epileptogenesis). In only about 75% of patients with chronic epilepsy, we are able to localise an epileptogenic lesion, but even then we cannot quantify the capacity of this lesion to generate seizures (=ictogenicity). There are >20 so-called "anti-epileptic drugs" with different mode of actions to suppress seizures, but none prevents or cures epilepsy, and ~30% of patients are drug-refractory. Our objective is to improve understanding of the molecular and cellular mechanisms involved in epileptogenesis and ictogenicity. Better understanding of the underlying mechanisms of epileptogenesis could permit selection of patients with the highest risk for developing epilepsy, and allow staging of the epileptogenic process. A quantitative measure of epileptogenicity would allow monitoring the brain's response to treatment and documenting prevention and cure. Specifically, this will help to: 1. pursue aggressive surgical approaches in those with established epilepsy and localised presence of active epileptogenesis that would indicate good prognosis, if the are of hyperexcitability is surgically amenable 2. diagnose and treat patients at high-risk of developing epilepsy following TBI or CVA and a 1st seizure to prevent further seizures

Imaging is a multidisciplinary research area. Positron emission tomography (PET), a non-invasive molecular imaging technique, relies on the availability of radiolabeled probes for molecular-level diagnostics [early diseases state detection], biological research [fundamental understanding of complex biological processes] and drug discovery [control of diseases]. PET can revolutionise these fields but its impact is limited by the worldwide shortage of skills needed to design and produce the radiotracers. This project supervised by Professor V. Gouverneur (University of Oxford - Chemistry Department), Dr Ian Newington and Dr Rajiv Bhalla (GE Healthcare Medical Diagnostics) will provide the opportunity to acquire these skills. Rapid progress in PET imaging is restricted by the cost, speed, and efficiency of radiosynthetic methods to access radiolabeled probes. 18F is identified as one of the radionuclides of choice due to its half-life of 110 mins, which allows for multistep radiosyntheses and commercial distribution. Currently, radiochemists select the site of 18F-radiolabeling to fit existing radiosynthetic methods, an approach that could be detrimental for rapid progress in PET probe discovery. 18F-Radio-retrosynthetic routes used to date are based on linear sequences of transformations designed with the aim of introducing the 18F-label ideally in the last step or as late as possible. This becomes increasingly difficult to implement when the probe is structurally complex or highly functionalised. Academics, industrialists and clinicians interested in PET-based imaging are in need of a wider range of structurally diverse radiotracers, which are currently not accessible using existing 18F-radiolabelling methods. The central proposition advanced here is that 18F-radiochemistry will benefit from convergent synthetic tactics assembling in one step a 18F-labelled component with two or more reactants simultaneously. Using this new radiochemistry, high value radiotracers will be prepared rapidly for applications in diagnostics or drug development. To validate this new conceptual framework, we selected multicomponent reactions (MCR) because these highly convergent atom- and step-economic procedures can deliver structurally diverse and complex molecules in a single step by reacting more than two substrates simultaneously. This class of reactions is attractive because the 18F-labeled precursor become integrated in the intrinsic structure of the probe and offers the possibility to introduce the 18F-label on different positions of the target probe without the need to redesign the overall radiosynthetic route. This chemistry will be validated with the preparation of targets not accessible by direct nucleophilic fluorination, for example electron rich 18F-aromatic motif. After proof of concept examining the value of 18F-labelled components for so-called 'radio-MCRs', further studies will aim at expanding the range of radio-MCRs suitable for 18F-labeling as well as the pool of radioactive building blocks and at mapping the various possible combinations of non-labeled and labeled components. Since the development of novel MCRs inclusive of asymmetric transformations is such an active area of research, a tantalizing range of opportunities emerges for the synthesis of structurally complex 18F-labeled PET tracers but also to access biomarkers for other imaging modalities. This work will establish that the inclusion of more convergent retro-radiosynthetic approach in the context of 18F-indirect labelling can greatly expand the range of 18F-labeled radiotracers made accessible for PET. This proposal represents a conceptual advance that would enlarge dramatically the scope of 18F-prosthetic group radiochemistry and provide immense benefit to diagnostics and drugs development.

The use of metal complexes in molecular imaging is well established. The availability of technetium-99m from a commercial generator coupled with the properties of this radioisotope (technetium-99m emits 140 keV gamma-ray with 89% abundance) has meant that technetium-99m has become the preferred radioisotope for SPECT imaging. The 6 hour half life is attractive since it allows sufficient time for radiosynthesis and distribution of labelled compounds to imaging centres. The design of chelates and the corresponding metal-complexes plays a significant role in the development of new tracers. The properties of the metal-chelate moiety (e.g. lipophilicity, charge, size) can greatly influence the in vivo characteristics of the final labelled candidate. Another key factor of the design of chelates relates to the radiolabelling conditions utilized - for example, the physiochemical properties of the macromolecule will influence the choice of conditions. For example the pH and temperature can impact on the nature of the macromolecule (aggregation and stability). The labelling conditions (and consequently the design and modification of the chelate) need to be 'tuned' to the properties of the macromolecule. One of the critical properties of the resultant metal-chelate complex is that it is highly stable in vivo. Although, there have been significant developments in the use of chelates in technetium chemistry, recently the requirement to label more complex and larger macromolecules (> 10 kDa) has demonstrated the need to develop alternative chelates. Proposed Programme: (i) Novel chelate synthesis - the IC Chemistry Department and GEHC have considerable experience in this area. The plan is to design chelates which are suited to a broader range of labelling conditions e.g. pH, temperature. Tailored, multifunctional ligands can allow the modification of reactivity and lipophilicity, stablisation of specific oxidation states and investigation of substitution inertness. They can also play an integral role in muting the potential toxicity of a metallodrug to have a positive impact in areas of diagnosis and therapy. To date, ligand coordination to 99mTc has generally utilized N2S2 or N4-donating atoms but within this project, wider and unexplored aspects of Tc coordination chemistry will be investigated in the search for compounds with increased specificity. Chelate motifs to be studied will include P2N2, P4N2, P(=O)2N2, P(=O)4N2, P(=S)2N2 or P(=S)4N2 donor sets, either within a macrocyclic structure or within an open-chained multidentate ligand, such as a functionalised tris(pyrazolyl)borate or similar tripodal species. Another novel facet will involve the incorporation of redox-active groups within the chelate framework i.e. ferrocene, quinolines, dithiolenes, in order to harness and exploit the rich oxidation state chemistry of technetium, focusing on biological and biomedical applications. (ii) Labelling conditions will be developed using Tc-99m. Parameters including reducing agents, pH, temperature, reaction time will be investigated. (iii) Metal-complex stability will be assessed using standard methodology (in vitro & in vivo) and will be compared against existing chelate including bis(amine-oxime), bis-amine-dithiol, tetra-amine and polypyridyl. (iv) Successful chelates will be conjugated onto biomolecules e.g alpha-v-beta-3 inegrin peptide (RGD), Octreotide the somatostatin receptor ligand and other novel macromoles from the GEHC library. Key disease areas for application of these probes will be in oncology, neurology and metabolic disorders. (v) Biological evaluation of the above labelled candidates will be carried out in collaboration with the biology groups. The biological studies will include biodistribution, metabolism and imaging of probe in a suitable animal model. These studies will be carried out at GEHC laboratories.

The LSI DTC provides a comprehensive training programme, and facilitates leading-edge research, in the mathematical, physical, and engineering science techniques that underpin four interlinked application areas at the Life Sciences Interface within the University: biological physics arising from the joint EPSRC/BBSRC IRC in Bionanotechnology based primarily in the Physics Department; medical imaging and signals arising from the joint EPSRC/MRC IRC: From Medical Images and Signals to Useful Clinical Information based primarily in the Engineering Science Department; mathematical genetics and bioinformatics linked to the Oxford Centre for Gene Function and based in the Statistics Department; and Computational Biology arising from the Integrative Biology e-Science Pilot Project and based in the Computing Laboratory. Each of these application areas and associated groups are involved in extensive interdisciplinary collaborations with life sciences and clinical colleagues across the University, and more widely, and each represents a key strategic research direction for both the host depaitinents and the University. Demand for trained researchers in both industry and academia is very strong in all four research areas, and the DTC has very strong industrial input into the programme, including a pilot industry-based D. Phil programme.