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 subjects and diseased patients affected by brain disorders including schizophrenia, depression, and Alzheimer?s disease (AD). These studies provided evidence that altered expression of HDACs in the frontal cortex and hippocampus may play a central role in the etiology of brain disorders. Research in preclinical animal models supported that HDAC expression is a critical mediator of neural development, aging, mood regulation, learning, and memory. Further, synthetic small molecules targeting HDACs alleviated deficits in neural plasticity and disease-related behaviors in animal models, underscoring the great need to understand the relationship between HDAC expression, brain function, and disease pathogenesis. We have recently achieved a major research goal by developing a positron emission tomography (PET) radiotracer, [11C]Martinostat, which selectively binds to a subset of HDAC enzymes. Our imaging studies to date, including in 25 healthy human volunteers, identified key features that make [11C]Martinostat an excellent CNS research tool including robust brain uptake and high specific binding. [11C]Martinostat imaging is poised for application in CNS disorder populations. Using a set of > 700 postmortem samples from the dorsolateral prefrontal cortex, our emerging biochemical data strongly supports HDAC expression is decreased in schizophrenic samples as compared to controls, an effect distinct from bipolar disorder and major depressive disorder sample populations. We are extremely excited to take a large step forward in understanding neural dysregulation in schizophrenia by visualizing HDAC expression in the healthy and dysfunctional human brain. Our lab at the MGH Martinos Center for Biomedical Imaging is one of few in the world that can directly translate basic science advancements to humans. Together with our multidisciplinary teams and strong collaborations, we are seeking the support through the R21 mechanism for this high-risk, high-reward study to characterize the density and distribution of HDACs throughout the brain of healthy subjects as compared to patients with schizophrenia. Our recently published data on human [11C]Martinostat imaging in healthy subjects age 18-35 years old strongly supports the success of our proposal for imaging schizophrenic patients and healthy controls to quantify HDAC density and distribution (Aim 1) as well as to assess correlations with neural connectivity via magnetic resonance (MR) and cognitive function via standardized testing instruments. MR-PET 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 HDAC expression in schizophrenia, a powerful example of neural dysregulation, will enable validation of an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism/target engagement in novel therapeutic trials.