Neuroepigenetic mechanisms of chronic low back pain using histone deacetylases PET imaging

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Project Summary / Abstract Histone deacetylase (HDAC) enzymes are chromatin-modifying proteins that have emerged as an important lead in understanding CNS dysfunction. To date, HDAC expression has been measured in a small number of postmortem brain tissue samples from healthy and diseased patients affected by brain disorders including opioid addiction (heroin), schizophrenia, depression, Alzheimer’s disease and provides evidence that altered expression of HDACs in cortex and some subcortical regions (such as the ventral tegmental area), may play a central role in the underpinnings of brain disease. Research in animal models supports that HDAC expression is a critical mediator of neural development/plasticity, aging, cognition, learning and memory. Further, synthetic small molecules targeting HDACs have been shown to normalize HDAC expression levels and alleviate disease-related behaviors in animals. These preclinical evidence underscoring the great need to improve understanding of the relationship between HDAC expressions, brain function and disease pathogenesis in the living human brain. We have recently achieved a major research goal by resolving a PET imaging agent, [11C]Martinostat that selectively binds to a subset of HDAC enzymes. Our imaging studies to date, including more than 40 healthy human volunteers, have identified key features that make [11C]Martinostat a rare and promising CNS HDAC probe including robust brain uptake and high specific binding. We are extremely excited to take a large step forward in understanding neural dysregulation in chronic pain patients by visualizing HDAC in the brains. As a first towards this goal, we propose to investigate the distribution and availability of [11C]Martinostat in chronic low back pain patients with and without taking prescription opioids. When comparing to healthy control group, we can attribute changes in [11C]Martinostat binding related to chronic pain. In addition, our study design allow further investigations on the effects of prescription opioids and sex differences on HDACs availability. Our team at the Martinos Center is one of few in the world that can directly translate basic science advancements to knowledge of the human system. Our preliminary data on [11C]Martinostat in humans age 18-79 years strongly supports the feasibility and success of our proposal for clinical imaging in healthy subjects in adulthood. PET/MR imaging in humans with [11C]Martinostat will deliver answers to fundamental questions about chromatin modifying enzymes in the living human brain in a way that has not been possible until now. Importantly, using [11C]Martinostat to understand the alternation of HDAC expression in chronic pain patients will enable validation of an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism/target engagement in developing novel analgesics.