CORDIS

The societal burden of brain disorders, such as multiple sclerosis (MS), Alzheimer’s and Parkinson’s disease is enormous and is considered one of the world’s most important health challenges. They affect millions of people worldwide and the annual healthcare costs are high and are increasing with the aging population. There is an immediate need to better understand the underlying molecular mechanisms of these disorders. Particularly, the important role of the brain-specific immune cells called microglia needs to be unravelled. Microglia become activated upon inflammation in the brain and its activation covers a wide spectrum of activation states, ranging from stimulating the inflammation (pro-inflammatory status) to reducing the inflammation (anti-inflammatory status). To fill the current knowledge gaps regarding the role and regulation of the different activation states of microglia, I will use positron emission tomography (PET) imaging. My host institution has recently succeeded in developing a PET tracer for imaging pro-inflammatory microglia. However, there is no complementary tracer existing for selective imaging of the anti-inflammatory status. In the proposed project, I will develop a PET tracer targeting the P2Y12 receptor, a receptor over-expressed on anti-inflammatory microglia. To achieve this, I will use an interdisciplinary approach spanning from computational medicinal chemistry through synthetic organic chemistry and radiochemistry to in vitro and eventually in vivo evaluation studies in an animal model for MS. A successful PET tracer will find widespread application in the research regarding brain disorders and ultimately guide drug development and treatment opportunities. On a personal level, the proposed project will have a substantial impact on my career, as new skills in neuroimaging, computer-aided drug design and in vitro evaluation techniques will complement my previous expertise in organic chemistry, radiochemistry and PET tracer development.