A New Method to Develop PET Ligands for Protein Aggregates in Neurodegenerative Disorders Using Soluble Brain-Derived Aggregates

A common feature of all dementias e.g. Alzheimer's, Parkinson's and Huntington's diseases are the presence of specific proteins in the brain, which due to having abnormal structures, accumulate into increasingly large assemblies and fibrils. These structures, which are present in many regions of the brain, are considered to be toxic and damage brain cells, leading to the symptoms of dementia. Using the clinical brain imaging technique of Positron Emission Tomography (PET) combined with injecting into patients chemical probes, which selectively bind to these assembles, we can now visualize the presence and distribution of some of these toxic proteins. However, with the present range of these chemical probes we can only image the late stages of these assemblies when most of the brain damage has occurred and so too late for effective drugs therapies. Therefore, our aim is to develop a general method to find the next generation chemical probes that can image the earlier stages and structures of these abnormal proteins when they are considered most toxic and hence cause the most damage to brains cells. This would then create a powerful means for earlier more accurate diagnosis of dementia and a means of evaluating the new types of drugs that are been developed that target these assemblies. To do this we will extract small amounts of soluble toxic aggregates from samples of brain tissue from patients who unfortunately died with a neurodegenerative disease and directly image the binding of labelled probes to these aggregates, using a very sensitive fluorescence method that we have developed that can detect single aggregates. This method will directly test binding to the aggregates in humans and needs only very small amounts of reagents. Once we have probes that bind to the soluble aggregates we can see if other unlabelled potential probes can remove them and hence more rapidly screen for better probes that will work in humans and can be used to detect the aggregates formed at early stages of disease.

The impact of this project and the beneficiaries are in two main areas:

Health and Well being: The overarching aim of our programme of research is to improve health and well-being of the UK population that are affected by neurodegenerative disorders. This disorders include Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy and Dementia with Lewy bodies, a range of disorders that result in increasing neurocognitive and neuropsychiatric deficits, physical disabilities and eventual death. Our novel technology would be of benefit to help understand the mechanisms and pathophysiology of these disorders and thereby develop effective treatments and therapies. Therefore, the final beneficiaries of our research outcomes will be these patients. Indirectly their families, who often carry major burden of care, will benefit and the general population through a reduction in the substantial NHS and social service budgets that arise from these disorders. Savings that would be of benefit to the nation's general economy. The projects outlined in this proposal are consistent with our overall objectives, with the long term target aim to develop a powerful imaging technology that will greatly enhance and facilitate these on-going clinical research programmes of research. Due to the close relationship between the University of Cambridge and Addenbrooke's hospital, enabled by being a Comprehensive Biomedical Centre, including a Biomedical Research Unit for Dementia and major memory clinics the research outcomes of the project can also be readily translated to develop new PET ligands in future work to ultimately be used to make clinical decisions on these patients. Therefore our research project will be of benefit and aid to the clinical staff responsible for the care of these patients in the longer term. Related to clinical care, diagnostic services will benefit from the validation of the current PET probes and the new potential probes that we find from our screening. The development of new radiotracers will be significant additions to the growing field of molecular imaging, which can help in early diagnosis of disease, clinical characterisation and evaluation of subsequent treatment.

Wealth creation and prosperity: The development of a validated PET probe, especially for application in the early detection and characterisation of neurodegenerative diseases would be of commercial interest to the radiopharmaceutical companies e.g. GE Healthcare, PETnet, and Alliance Medical who have established manufacturing sites in the UK to underpin the increasing use of PET diagnostic service in the NHS. We would exploit the commercial potential of these PET probes to the financial benefit of both the university and the radiopharmaceuticals company, through partnership.

The UK pharmaceutical industry would also benefit from the outcome of these projects. Applying the increased understanding of PET imaging to research into these pathologies to develop more effective drugs. This need is now more pressing with the emergence of novel therapeutics (e.g. immunisation therapies) that targets early stages of the disease process for which there is an urgent requirement for in vivo biomarkers for assessing their efficacy. Therefore the availability of these PET probes would be a powerful tool for clinical trials on novel drugs. The relocation of Medimmune and AstraZeneca to the Cambridge Biomedical Campus (CBC) site with their human antibody therapy programmes, means that they could obtain immediate benefit of these new technology.