PET imaging of human brain a2-adrenoceptors and noradrenaline release: biomarkers for brain diseases; Focus depression

Depression is an extremely debilitating disease that has a major impact on the health services and the nation as a whole, which is estimated financially to be around 12billion a year. Depression is caused by imbalances of normal brain chemicals and process. Powerful techniques available today allow the study of brain chemicals and processes in normal and abnormal brains in living people. These techniques relay on the availability of specially designed radioactive chemicals that provide a means to visualise what is happening in the brain. These radioactive chemicals are only available to study a small number of these brain chemicals and processes. Where they are available, they have been responsible for major increases in our understanding and treatment of brain diseases.
Noradrenaline, a signalling chemical found throughout the brain is one of the many chemicals and process that we are currently unable to study using the techniques mentioned. This chemical and the processes it is involved in have been implicated in depression and many other debilitating brain diseases, in studies using animals and post mortem human tissue. The difficulties in using these sources of information are that they rely on assumptions being made in our understanding of how these diseases progress in humans. For example, we are not laboratory animals and while there are many similarities that have enabled great advances in our understanding of disease and their treatment confirmation in humans is very important. The use of post mortem human tissue only tells us what has happened and not how or when.
Therefore, the development of one of these radioactive chemicals to enable the study of noradrenaline and its related processes in the living human brain of normal people and those suffering depression is critical to our proper understanding of this disease. This in turn will allow us to better diagnose depression and lead to a much better prognosis for the sufferer. It would also permit us to refine the treatments that we already have and to develop new and better ones.

Noradrenaline and is a key amine neurotransmitter that has been implicated in the pathologies of a number of diseases from anxiety and depression to Alzheimer?s disease and multi-system atrophy. Data on noradrenaline from post-mortem human tissue shows that noradrenaline turnover, and (alpha)2-adrenoceptor binding are altered in depression. In vivo confirmation depends on the availability of an noradrenergic PET tracer but at present there are no validated tracers for noradrenaline. The use of PET imaging eg with [11C]-raclopride has greatly increased our knowledge of how dopamine, a similar amine neurotransmitter, is involved in brain function, so in this grant we seek to validate such a tracer in collaboration with GSK, with whom we have a proven research collaboration. We have over the last few years worked to develop a number of potential PET ligands which show many of the necessary characteristics for successful in vivo imaging and this grant will allow validation of one as a biomarker for noradrenaline receptors.
The plan of research is to confirm this tracers safety and then to evaluate its kinetics, selectivity and methodology in healthy volunteers and test if the tracer is sensitive to endogenous noradrenaline release by using the amphetamine and alpha-methylparatyrosine challenge paradigms. When this has been accomplished we will use it to test in vivo the status of (alpha)2-adrenoceptors and noradrenaline in depressed patients. Depression is a common disorder that results in significant morbidity and economic costs, especially in the quarter of patients who experience recurrent episodes and/or are resistant to treatments. Brain noradrenergic dysfunction is one of the principal mechanisms underlying depression and being able to characterise it in vivo may lead to better treatment selection in a group of patients with this condition.
The development of this tracer will enable us to better understand and test the role of the (alpha)2-adrenoceptor and noradrenaline in depression other mental disorders and should enable the development of new treatments and diagnostic tools.