Abstract
1628
Purpose: Dysregulated microglia-dependent synaptic pruning through the complement cascade and associated neuroinflammation processes have been linked with a wide range of neurodevelopment and neurodegenerative diseases such as schizophrenia, Alzheimer and Huntington disorders. For over 20 years, in vivo measurements with PET (Positron Emission Tomography) ligands targeting the 18kDa translocator protein (TSPO), [11C]-PK11195 and [11C]-PBR28, have been widely used to describe a general state of neuroinflammation associated with damage to the brain and neurodegenerative diseases, including HD. While these radiotracers have been effective in identifying a notable neuroinflammatory brain signature, their target is not unique to one cell type in the brain, limiting any specific insight into the molecular mechanisms responsible for disease. Here we investigate the possibility of using COX-2, the rate-limiting enzyme in the biosynthesis of prostaglandins during the inflammation process, as a clinical marker of neuroinflammation, pathophysiological onset and progression of Huntington’s disease through the development of a brain-penetrant COX-2 specific PET radiotracer. We show that COX-2 protein levels are highly up-regulated in Huntington’s disease (HD) human post-mortem brain tissue, and 2 mouse models of HD (ZQ175 and ΔN17). This up-regulation is microglia specific and could constitute a better clinical marker of microglia-dependent neuroinflammation. We then present the development of a highly selective COX-2 ligand (BRD3096) based on the multi-parametric optimization of properties paramount to brain PET tracers; 1) high brain penetration, 2) high binding affinity, 3) fast binding kinetics (on-rate), and 4) low non-specific binding (NSB).