PET Markers of Oligomeric Misfolded Proteins in Neurodegenerative Disorders

Lead Research Organisation: University of Cambridge
Department Name: Wolfson Brain Imaging Centre

Abstract

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 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 discover and develop these new chemical probes, will apply chemical screening methods, medicinal chemistry, radiochemistry and biological assessments. The chemical probes with appropriate properties arising from this project we would then take forward with additional funding for human imaging studies.

Planned Impact

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 target aim to introduce 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 immediately translated to inform 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.
Related to clinical care, diagnostic services will benefit from the development and validation of the novel PET probes we plan to develop, in particular any fluorine-18 probes, which are appropriate for clinical imaging services. These novel 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.

Publications

10 25 50
 
Description We have synthesised a novel range of compounds that have good binding affinity to synuclein fibrils . These compounds have shown that good binding affinity can be achieved by designing different linkers lengths between two of more chemotypes.
We have also developed a compound that has been shown to have good selectivity to tau oligomeric species . This would be the first time this has been achieved.
we have shown for the first time the binding of tau PET compound to pathology in rat model.
Exploitation Route assessing tau pathology in human brain tissue
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Developing scientific career as a BME staff
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description A preclinical PET-CT scanner for advancing dementia research
Amount £150,000 (GBP)
Funding ID ARUK-EG2018B-001 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 10/2019
 
Description Molecular Imaging Chemistry Laboratory (MICL) - A Innovation and Translation Hub for PET Probes
Amount £75,000 (GBP)
Funding ID n/A 
Organisation Cambridge Clinical School 
Sector Academic/University
Country United Kingdom
Start 10/2019 
End 09/2020
 
Title novel in vitro marker of oligomeric pathology 
Description A new fluorescent compound which has shown to bind with good selectivity to oligomeric aggregated protein 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? No  
Impact This basis and lead compound for developing a novel PET radiotracer for imagining oligomer in vivo 
 
Description Characterising binding of tau PET radiotracers in transgenic rat models of dementia 
Organisation AXON Neuroscience SE
Country Slovakia 
Sector Private 
PI Contribution Radiosynthesis of radiotracers, in vitro assessment , in vivo imaging and data analysis
Collaborator Contribution AXON Neuroscience will supply transgenic rat models - brain tissue and live animals
Impact obtained a MRC Proximity to Industry grant ,
Start Year 2017
 
Description Collaboration with AR-UK Drug Discovery Insititute on developing PET marker for oligomers 
Organisation Alzheimer's Research UK
Department Alzheimers Research UK, Cambridge
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution As outlined in the EPSRC project proposal
Collaborator Contribution Bringing there expertise in dug discovery and development to the project and when appropriate undertake some biophysical characterisation of lead compound
Impact N/A
Start Year 2017