Cambridge PET Neurochemist Training Programme

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 Alzheimer?s disease, depression, schizophrenia, obsessive compulsive disorder and drug addiction.

Technical Summary

To address one of the major restrictions on the use of the molecular imaging technique of positron emission tomography (PET) for neuroscience research at Cambridge, the lack of trained PET chemists 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 US and Europe 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 yours. Integrated with this training, is the development of probes for the 5-HT2a receptors and beta-amyloid plaques and in the second phase of the programme collaboration with Siemens in the development of novel imaging probes for neurofibrillary tangles, one of the main neuropathological features of Alzheimer s disease (AD) and other dementias.
The tracers will then be applied to PET imaging projects in the area of neuropsychiatric and neurodegenerative disorders, with a focus on 1) preclinical studies that have significant translational aspects and 2) human research projects targeted toward understanding the mechanisms of neurological diseases and thereby identifying potential therapeutics. The proposed projects include; i) studies on impulsivity based on imaging 5-HT2a receptors on rats with this behavioural trait; ii) imaging serotonergic modulation in marmosets to investigate mechanistic components common to various neuropsychiatric disorders such of schizophrenia, depression and obsessive compulsive disorder; iii) the role of 5-HT2a in frontotemporal dementia and iv) evaluation of the novel beta-amyloid tracer in AD and MCI patients and normal control subjects, coupled with autoradiographic experiments on brain tissue.

Publications

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Baron JC (2014) Diagnostic utility of amyloid PET in cerebral amyloid angiopathy-related symptomatic intracerebral hemorrhage. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Buell AK (2011) Probing small molecule binding to amyloid fibrils. in Physical chemistry chemical physics : PCCP

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Clarke HF (2014) Orbitofrontal dopamine depletion upregulates caudate dopamine and alters behavior via changes in reinforcement sensitivity. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Lledos M (2018) Synthesis, Radiolabelling and In Vitro Imaging of Multifunctional Nanoceramics. in ChemNanoMat : chemistry of nanomaterials for energy, biology and more

 
Description MRC MHRA PET Expert Panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Help and advising the UK PET community on the UK regulatory framework relating to medicines. Facilitate discussions between the PET community and the UK MHRA
URL http://www.mrc.ac.uk/research/facilities/mhra-mrc-pet-panel/
 
Description MRC PET Strategic Meeting
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Increased level of PET neuroscience chemists in the UK
 
Description Development of a radioligand binding assay for
Amount £30,000 (GBP)
Funding ID ARUK-PPG2011B-28 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 03/2013
 
Description NIHR Biomedical Research Unit in Dementia
Amount £725,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Cambridge Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description NIHR, Biomedical Research Unit in Dementia Capital Funding
Amount £1,537,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2012 
End 02/2012
 
Description Strategic grant
Amount £1,016,891 (GBP)
Funding ID MR/k02308X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2013 
End 10/2017
 
Description Wellcome Trust Multi-user equipment grant
Amount £200,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 07/2018
 
Title A novel PET probe for imaging Opioid Receptors 
Description The first fluorine-18 labelled positron emission tomography agonist radioligand for imaging opioid receptors 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Application for study opioid receptors in models of addictions 
 
Title PET radiotracer for GSK-3 
Description Novel radiotracer for imaging the enzyme GSK-3 in vivo 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Further characterisation of the radiotracer for application and then a joint publication 
URL http://www.ncbi.nlm.nih.gov/pubmed/26005531
 
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 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 Radiochemical methods 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution Member of the research group , spent 5 months as a visiting scientist as part of project collaboration
Collaborator Contribution Hosted the visiting postdoc with full and free access to their research facilities and training in advanced PET radiochemistry . Also intellectual input into the project
Impact publication: Riss PJ, Lu S, Telu S, Aigbirhio FI, Pike VW. Cu(I)-catalyzed (11)C carboxylation of boronic acid esters: a rapid and convenient entry to (11)C-labeled carboxylic acids, esters, and amides. Angew Chem Int Ed Engl 2012; 51:2698-2702
Start Year 2011
 
Description Development of PET probes for imaging tau tangles 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution development of PET probes
Collaborator Contribution Experince in animal models of dementia and transgenic mice tissue
Impact result in award of grants. Details outlined further
Start Year 2010
 
Title Novel PET Probe for imaging tau tangles 
Description Novel compounds with high binding affinity to tau fibrils have been labelled with PET radioisotopes and have been shown to have good brain entry in animal models 
Type Diagnostic Tool - Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact This still under development 
 
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