Neurodegenerative and neurological diseases, such as multiple sclerosis (MS), Alzheimer’s (AD) and Parkinson’s disease (PD) affect millions of people worldwide. MS is the most common neurological disorder among young adults and the number of affected people continues to grow. To date, already 700.000 people in Europe are affected. In order to guide drug development, a better understanding of the underlying mechanism is of utmost importance. However, diseases in the central nervous system (CNS) are complex pathologies, in which several factors and mechanisms are involved and contribute to the development and progression. A common hallmark for most of these diseases is neuroinflammation – an inflammatory response within the CNS caused by a disturbance in the brain from e.g. tissue damage or the formation of protein aggregates. As a result, microglia, the brain-specific immune cells become activated. The activation process of microglia is highly dynamic, covering a broad spectrum of activation phenotypes with pro-inflammatory neurotoxic microglia on one end and anti-inflammatory neuroprotective microglia on the other end of the activation spectrum. The exact role of the different phenotypes in neuroinflammation is still not fully clarified. The activation state is dependent on several factors and most likely it changes during disease progression. To better understand the role of activated microglia in the living brain, a molecular imaging technique is required. Positron Emission Tomography (PET) is such a technique. It makes use of radiolabeled molecules at tracer levels, so-called PET tracers, which target a specific protein that is representative for the biochemical process being studied. To date, the most often applied target to image activated microglia is the 18 kDa translocator protein (TSPO), a mitochondrial protein, overexpressed on activated microglia. Even though TSPO enables the detection of activated microglia, it cannot be used to discriminate between the pro-inflammatory and anti-inflammatory phenotype. In addition, a number of other drawbacks with PET tracers targeting TSPO have been reported, such as low brain uptake, high non-specific binding and a high level of variability of binding between patients due to polymorphism in the TSPO binding domain. Therefore, there is an immediate need to explore alternative targets, beyond TSPO, for selective PET imaging of a specific phenotype of activated microglia. PET tracers that can be used for imaging of either pro- or anti-inflammatory microglia, would allow for monitoring and measuring the dynamical changes in microglia activity in the onset and progression of neuroinflammatory diseases. This, in turn, can guide drug development and the identification of new treatment opportunities in such diseases.
The overall objective of MIM was to develop a novel BBB-penetrant PET tracer targeting the P2Y12R for imaging of anti-inflammatory microglia. In combination with the previously developed PET tracer for pro-inflammatory microglia, developed by the host institution, these PET tracers will allow for imaging of the dynamical changes of activated microglia.
