INVASIION

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. Inflammation is widely recognized to play an important role in many neurological disorders. Next to the response of microglia, the resident immune cells in the central nervous system (CNS), infiltration of monocytes from the blood occurs, but the exact role of monocyte infiltration and the interplay between microglia and monocytes in vivo is still largely unknown. Clinical trials with chemokine receptor type 2 (CCR2) antagonists, aiming to reduce recruitment of monocytes and thereby reducing neuroinflammation, do not show clinical efficacy. Together, this emphasizes the need to unravel the role of infiltrating monocytes in human disease in vivo. Positron emission tomography (PET) is an imaging technique well suited to serve this purpose. I propose to develop new PET tracers targeting CCR2 as a tool to visualize infiltration of monocytes in the CNS in vivo to help elucidate their role in disease. Newly developed tracers will be evaluated in vitro, ex vivo and in vivo in an animal model of MS. A successful PET tracer will contribute to a better understanding of monocyte infiltration in disease in vivo and could ultimately serve as an important tool to guide drug development and evaluate novel disease-modifying therapies and therapies inhibiting monocyte infiltration. On a personal level, the proposed project will have a significant impact on my career, as new skills in neuroimaging, computer-aided drug design and in vitro target validation techniques will complement my previous expertise in organic chemistry, radiochemistry and PET tracer development.