MICA: Training and Novel Probes Programme in PET Neurochemistry - PET Call

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

Abstract

Some radioactive molecules emit gamma radiation that can be detected outside the body and so when injected into humans and animals, in safe low levels, can be used to generate images, using sophisticated scanners, of the brain for biomedical research and clinical diagnosis. However, the molecules have to be designed to target the sites of the brain to be investigated, which is done by attaching a biological compound to the radioactive molecule to create products called radiopharmaceuticals. Due to the severe lack of scientists in the UK who have the specialised skills to design and prepare these radiopharmaceuticals we plan to recruit and train a scientist to join our multidisplicinary team. To achieve this we have created a bespoke training programme which will involve learning from researchers in academia and industry, who are either developing and/or using this imaging technology. As part of this training the scientist will help design new radiopharmaceuticals that would then be used in our on-going research programmes to understand the biological mechanisms of some major diseases and disorders of the brain, and thereby identify some possible treatments. For this specific programme we would be undertaking research projects on traumatic brain injury, depression, schizophrenia, obsessive compulsive disorder and drug addiction.

Technical Summary

Technical Summary
To address one of the major restrictions in the use of the molecular imaging technique of positron emission tomography (PET) for neuroscience research at Cambridge, the lack of trained PET chemist to design and prepare the required brain imaging probes, proposed is an integrated programme of training and research. In partnership with PET centres, academic and industrial, in the UK and US we have constructed a training programme designed to train a post-doctoral scientist with a PhD background in chemistry to "group leader" capability within four years. Integrated with this training, is, i) the implementation a radioligand for mGluR5 receptors which will applied in our preclinical programme to understand the role of these receptors in neuropsychiatric disorders such as depression, obsessive compulsive disorder (OCD), drug addiction and schizophrenia, and ii) in collaboration with GE Healthcare to implement a NMDA radioligand to be applied in clinical studies on traumatic brain injury. In the later stages of the programme the trainee will focus on development of novel imaging probes for imaging the tropomyosin-related kinase receptor B for future application in neuropsychiatric research.

Planned Impact

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

Health and Well being: The overarching aim of our programmes of research is to improve health and well-being of the UK population that are affected by the various disease and disorders that are outlined in this proposal. These include traumatic brain injury (TBI), schizophrenia, obsessive-compulsive disorder (OCD), anxiety, depression and autism. A range of neurological disorders that can result in death, severe and permanent disability, neurocognitive and neuropsychiatric deficits. Our objectives are to understand the mechanisms and pathophysiology of these disorders and thereby develop effective treatments and therapies. Therefore, the immediate 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 immediate aim to train much need staff to extend the use of a powerful technology that will greatly enhance and facilitate these on-going programmes of research. Due to the close relationship between the University of Cambridge and Addenbrooke's hospital enabled by being a Comprehensive Biomedical Centre, and collectively with the Cambridgeshire Mental Health Trust and the Cambridgeshire Primary Care Trust been awarded Academic Health Sciences Centre status the research outcomes of the project can be immediately applied to inform clinical decisions on these patients. Therefore our research project will be of benefit 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 radiotracers we plan to develop, in particular fluorine-18 radioligands, which are appropriate for clinical imaging services. These novel radiotracers will be of 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 radioligand would be of commercial interest to the radiopharmaceutical companies e.g. GE healthcare and Siemens 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 our novel radiotracers to the financial benefit of both the university and the radiopharmaceuticals company, through partnership.

The UK pharmaceutical industry could also benefit from the outcome of these projects in several forms. With the specific difficulty of developing drugs for neurological disorders, increased understanding of these pathologies will help to develop more effective drugs, while the availability of validated PET radioligands would be a powerful tool for clinical trials on novel drugs, e.g. to determine receptor occupancy and additional pharmacokinetic and pharmacodynamic data.

Publications

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Bevan Jones WR (2016) [F]AV-1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation. in Annals of clinical and translational neurology

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Bevan-Jones R (2018) [ 18 F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion in Annals of Clinical and Translational Neurology

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Bevan-Jones W. (2016) [18F]AV1451 PET imaging in semantic dementia in JOURNAL OF NEUROCHEMISTRY

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Bevan-Jones W. (2016) [18F]AV1451 PET in frontotemporal dementia from a MAPT mutation in JOURNAL OF NEUROCHEMISTRY

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Bevan-Jones WR (2019) In vivo evidence for pre-symptomatic neuroinflammation in a MAPT mutation carrier. in Annals of clinical and translational neurology

 
Description Dementia Platform UK Executive Team
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Support the mission of Dementias Platform UK (DPUK) to accelerate the development of treatments for dementia - in particular in the application of imaging for experimental medicine . Therefore toward increasing survival and quality of life for patients with dementia
URL https://www.dementiasplatform.uk/
 
Description Developing scientific career as a BME staff
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MRC Stragetic Review of PET imaging in UK
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description A New Method to Develop PET Ligands for Protein Aggregates in Neurodegenerative Disorders Using Soluble Brain-Derived Aggregates
Amount £783,024 (GBP)
Funding ID EP/T01427X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2020 
End 02/2023
 
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 Imaging NMDA receptor activation following head injury using positron emission tomography
Amount £52,856 (GBP)
Organisation National Institute of Academic Anaesthesia 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 04/2016
 
Description MICA: Detecting ictogenicity and epileptogenesis
Amount £1,635,366 (GBP)
Funding ID MR/L013215/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2014 
End 08/2019
 
Description MRC Confidence in Concept
Amount £62,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 10/2018
 
Description MRC Proximity to Industry
Amount £28,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 09/2018
 
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
 
Description NIHR MEDTECH and IN VITRO DIAGNOSTIC CO-OPERATIVES
Amount £1,250,000 (GIP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2018 
End 12/2022
 
Description PET Markers of Oligomeric Misfolded Proteins in Neurodegenerative Disorders
Amount £1,302,276 (GBP)
Funding ID EP/P008224/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2019
 
Description Project grant
Amount £93,105 (GBP)
Organisation Progressive Supranuclear Palsy Association (PSPA) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2015 
End 04/2016
 
Title A novel PET radiotracers for imaging neuroinfammation 
Description A novel PET radiotracer for imaging TSPO expression on activated microglia related to neuroinflammation with lon sensitivity to a human polymorphism 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact No as yet 
 
Title tau compounds 
Description novel chemical compounds that bind to tau tangles for potential use as PET probes 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact enabled further grant funding 
 
Description Application of NMDA PET in schizophrenia 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Production and supply of the[18F]GE179 and development of metabolite analysis
Collaborator Contribution PET scanning
Impact multi-disciplinary : PET chemistry , clinical imaging , psychiatry
Start Year 2016
 
Description Characterising binding of tau PET radiotracers in transgenic rat models of dementia 
Organisation AXON Neuroscience SE
Country Slovakia 
Sector Private 
PI Contribution Undertaking the characterisation in vitro and in vivo of tau PET radiotracer on transgenic rat model
Collaborator Contribution supplied the tau rat model and training of staff in generating model
Impact as yet none to state
Start Year 2017
 
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 Developement of NMDA Radiotracer GE179 
Organisation General Electric
Country United States 
Sector Private 
PI Contribution We are developing and producing the novel radiotracer GE179
Collaborator Contribution They are funding productions, supply consumables, regulatory information and expertise
Impact As yet none. It has just started
Start Year 2014
 
Description Development and Application of Tau PET probes 
Organisation Eli Lilly & Company Ltd
Department Avid Radiopharmaceuticals
Country United States 
Sector Private 
PI Contribution Characterisation of novel PET tau radiotracers
Collaborator Contribution supply of novel chemicals and confidential information
Impact on-going
Start Year 2013
 
Description Development of novel PET markers of neuroinflammation 
Organisation GE Healthcare Life Sciences
Country United Kingdom 
Sector Private 
PI Contribution synthesis of compound, radiosynthesis of PET radiotracers, characterisation of radiotracers
Collaborator Contribution supplied kits for the manufacture of a comparison radiotracers, expertise in the area
Impact we have a potentila radioracer for fiuture developmemt. From this obtained MRC Confidence in Concept grant
Start Year 2016
 
Description Development of novel PET markers of neuroinflammation 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution Synthesis of novel compound and precursors. PET chemistry
Collaborator Contribution Hosting and funding the PET chemistry . Expertise in neuroinflammation
Impact multidisciplinary : organic chemistry , radiochemistry , neuroscience , pharmacology, publication
Start Year 2015
 
Description Development of novel PET markers of neuroinflammation (UofMich) 
Organisation University of Michigan
Department University of Michigan Medical School
Country United States 
Sector Academic/University 
PI Contribution Development and synthesis of novel TSPO radiotracer and funding
Collaborator Contribution Further radiochemistry development and additional preclinical imaging characterisation of the novel radiotracer
Impact We have now obtained the in vivo pharmokinetics of the this new neuroinflamamtion radiotracer . Thsi has provided solid data toward further funding to enable human PET studies
Start Year 2017
 
Description Manufacture of GMP [18F]AV1451 for clinical trial PET studies 
Organisation Eli Lilly & Company Ltd
Department Avid Radiopharmaceuticals
Country United States 
Sector Private 
PI Contribution Manufacture of GMP [18F]AV1451
Collaborator Contribution Supply radiosynthesis and analytical equipment . Supply of precursor material
Impact Production of the tau PET radiotracer to support clinical research and drug trials in dementia
Start Year 2017
 
Title Development of Novel NMDA PET marker 
Description Human studies have started in the application of this radiotracer in acute head injury patients 
Type Diagnostic Tool - Imaging
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact N/A 
 
Title Development of a novel TSPO PET marker for imaging neuroinflamation 
Description We synthesised a novel PET marker for imaging neuroinflammation by TSPO that is not affected by the human genetic polymorphism to binding 
Type Diagnostic Tool - Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status On hold
Impact From our pilot data we have obtained a MRC confidence in concept grant for further development 
 
Title Novel PET tau probes V2 
Description Application for imaging tau pathology in dementia 
Type Diagnostic Tool - Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact These radiotracers can also be used in transgenic mice models of dementia , therefor good for translation and small animal imaging of mice hence help 3R. 
 
Description ARUK Cycle2Corfu event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Meet and thank ARUK supporter that raised funds for the charity . Explain the what there funds will be used for
Year(s) Of Engagement Activity 2019
 
Description BRU Training Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Training in student and postdoc member of the NIHR TRCD
Year(s) Of Engagement Activity 2015
 
Description Physics at Work 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk of techniques used in department following by questions

N/A
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014