MICA: [11C]BU99008 - A novel Positron Emission Tomography ligand for the Imidazoline2 Binding Site, First in human and initial patient group

Illnesses that affect the brain such as dementias and depression cost the NHS and the country tens of billions of pounds each year and are a major cause of disability. There are other brain illnesses that are less common and less costly but are 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 in an early stage of dementia called Mild Cognitive Impairment, or MCI. MCI is an early stage of different types of dementia such as Alzheimer's Disease.

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 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 these diseases such as Alzheimer's Disease. If we can measure a change in this protein in living patients 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 of treatment.

The Imidazoline2 binding sites (I2BS) are located on astrocytes and seem to be involved in the regulation of glial fibrillary acidic protein (GFAP). In addition the densities of the I2BS are altered in a range of psychiatric and neurological disorders (e.g. depression, glial tumours, Alzheimer's and Parkinson's Disease). A positron emission tomography (PET) ligand for these sites would be invaluable in studying these binding sites and disorders in vivo, in humans. Due to the association of I2BS with GFAP such a PET ligand could also be an in vivo marker for astrocytes and their role in these and other psychiatric and neurological disorders. We have developed and evaluated, such a PET ligand, [11C]BU99008, in a range of pre-clinical species. The results of these investigations have indicated that this is an excellent ligand for the I2BS showing high specificity and selectivity for these sites in vitro and in vivo. The next step is to evaluate this ligand in humans. This project aims to do this. The ligand will be initially evaluated in healthy subjects and its pharmacological specificity, selectivity and practicality as a PET ligand in humans, will be determined. On successful completion of these investigations we will then study [11C]BU99008 in a patient population. We plan to use people diagnosed with mild cognitive impairment (MCI) as a group potentially suffering from the early stages of dementia as an initial study group. We will compare the signal obtained in this group with that of the healthy subjects. As the I2BS is correlated with age, care will be taken to ensure that the healthy subjects and the MCI patients are as closely matched for age as possible.

If successful, [11C]BU99008 would represent the first clinically available PET ligand for imaging the I2BS, with the additional benefit of providing an in vivo marker for elucidating the role of astrocytes in these conditions. Clinical evaluation of this I2BS PET radioligand will be of benefit to end users as it will represent the first clinical in vivo imaging agent of its kind to allow identification of such markers in CNS disorders. The availability of this ligand to the wider scientific research community will greatly increase our knowledge of the I2BS and astrocytes in normal and pathological brain. In the longer term this increased knowledge has the potential for the development of new treatments and diagnostic and/or prognostic marker(s).