PET imaging of human brain gliosis using Imidazoline2 (I2) binding sites: potential biomarker for Alzheimer's disease

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Illnesses that affect the brain such as dementia cost the NHS and the country tens of billions of pounds and are the main cause of disability in old people. In a recent report for the Alzheimer?s Society it was estimated that dementia as a whole costs the country #17.03 billion per year, or an average of #25,472 per person with dementia. Nearly 700,000 people have dementia in the UK, of which 434,000 have Alzheimer?s disease (AD). There are other brain illnesses that are less common and less costly but still very painful to the people that have them and their relatives, such as multiple sclerosis (MS) and brain tumours. One of the things these illnesses have in common is inflammation within the brain. If we were able to measure this inflammation in living humans, it would enable us better to diagnose these illnesses at an early stage when we have the best chance to cure or slow down their development. Being able to measure this inflammation will also enable us to monitor and understand these illnesses better, and any potential treatments. The purpose of this work is to develop a way of measuring this inflammation using Alzheimer?s disease as a model.
The way we intend to do this is to use a very powerful technique for visualising inside humans, called positron emission tomography, or PET. PET relies on specially designed radioactive chemicals that provide a means to visualise what is happening in the brain. Therefore, we plan to develop such a radioactive chemical for a protein called the imidazoline2 binding site. This protein is found in a type of brain cell called glial. These cells are a normal part of the brain. However, in the illnesses such as Alzheimer?s where the brain is damaged and inflammation exists, there are more of these cells, especially in the inflamed areas. We already know that the amount of this protein is increased in the brains of people who have died of Alzheimer?s by studying post-mortem tissue. If we can measure a change in this protein in living patients with Alzheimer?s, it will mean we have a way of measuring this brain inflammation found in this and similar illnesses, early on giving the sufferer the best chance.

Technical Summary

The imidazoline2 binding sites (I2BS) are a novel brain targets for PET tracer development that may offer a measure of gliois as these sites are thought to be located on glial cells and may regulate glial fibrillary acidic protein (GAFP) expression. This has lead to research interest in I2BS and Imidazoline2 ligands in conditions where glial are altered such as dementia and other neurological disorders. Changes in the density of the I2BS have been seen in a range of diseases and disorders in human post-mortem brain. Key among these is that in Alzheimer‘s Disease (AD) there is a ~60% increase in I2BS density, relative to age matched controls and even larger increases are found in glial tumours. The plan of research is to radiolabel a potential I2BS PET ligand developed at the Universities of Bristol and Bath, to confirm this tracers safety and then to evaluate its kinetics, selectivity and methodology in healthy volunteers. When this has been accomplished we will test the in vivo densities of the I2BS in AD patients and compare them to age matched controls to determine its suitability as a biomarker. This will be carried out in collaboration with GSK, CIC, with whom we have a proven research collaboration. If it proves viable we shall then be in a position to evaluate its value compared with other PET tracers for AD such as PIB and explore utility in other disorders such as glial tumours and other neurological conditions where gliois is prominent e.g. multiple sclerosis.

Publications

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Title I2 tracers 
Description new chemicals with greater specificity for the target have been made and eneaiomers developed to improve signal even more 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact a PET tracer for this indication is looking more promising 
 
Description Yale PET centre 
Organisation Yale University
Department Positron Emission Tomography Center Imaging Center Yale
Country United States 
Sector Academic/University 
PI Contribution working together to esitmate the charcteristics of our ligands in NHP (rhesus) PET prior to testing in humans
Collaborator Contribution helping us define the characteristics of our tracer in NHPs
Impact only just started
Start Year 2011
 
Description link with GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution this is a shared project with the PET analaysi team at GSK Uk in the clinical imaging centre
Collaborator Contribution help in data acquisition and analysis
Impact several abstract presentations at intrnational PET meetings
Start Year 2009
 
Title new I2 tracers 
Description new chemical ligands for the I2 receptor 
IP Reference  
Protection Protection not required
Year Protection Granted 2010
Licensed No
Impact collaborations with Yale under discusion
 
Title I2 receptor PET tracer 
Description a selective PET tracer for this receptor could be useful in diagnosis of brain inflammation and monitoring progress eg in conditions like multiple sclerosis 
Type Diagnostic Tool - Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact too early