ABSTRACT. Alzheimer’s diseases (AD) is a devastating brain neurodegenerative disease with no cure currently available. AD is associated with progressive dementia and cognitive decline, which highlight the glaring need for new biomarker-based tools to accurately detect early AD and select patients for targeted therapies. The discovery of epigenetic mechanisms and their substantial contribution to cognitive decline in AD inspired extensive research in an attempt to delineate the role of Histone Deacetylases (HDACs) in memory function. As such, HDAC blockade with panHDAC inhibitors have been perused to alleviate the memory decline in the AD brain. However, two recent and independent human imaging studies reported that class-I HDAC levels decrease as AD advances, which emphasizes the need for specific targeting of HDACs in the AD brain. The class-IIa HDAC members HDAC4 and HDAC5 play a key role in neuronal synaptic plasticity and memory formation. A quantitative study by Anderson KW, et al. found a 47% increase in the class-IIa HDAC5 expression in the AD human frontal cortex, while class-I HDACs were downregulated in AD (HDAC1,2 decreased 32%), which is consistent with recent clinical data obtained with 11C-Martinostate. These findings establish strong evidence for our approach to quantitate changes in class-IIa HDAC expression in the human AD brain and validate class-IIa HDACs as a therapeutic target in AD; this will have a significant positive impact for AD patients. Therefore, we aim to develop and validate radiotracers for positron emission tomography (PET) to non-invasively and quantitatively map the expression and localization of class-IIa HDACs in the brain in its entirety, thus providing a contrast view of the whole healthy brain versus the AD brain. Our preliminary results support the suitability and feasibility of the proposed studies, with one tracer (18F-26) demonstrating the characteristics of a useful CNS PET tracer. 18F-26 displays excellent pharmacokinetic and imaging characteristics, since brain uptake is high in gray matter regions, leading to high-quality PET images; tissue kinetics are appropriate for an 18F tracer, and specific binding for class-IIa HDAC is demonstrated by self-blockade and with SAHA (panHDAC inhibitor). Therefore, we propose these three specific aims: (1) to synthesize and screen a focused library of 30 candidate inhibitors, (2) to radiolabel the selected tracer candidates (N=6) from aim1 using our novel radiosynthetic route and other established radiochemical methods, and (3) to validate the best three radiotracers for in vivo PET/CT imaging of class-IIa HDAC expression in the brain of healthy rats. We will perform quantitative in vitro autoradiography with our lead tracer to measure class-IIa HDAC expression in postmortem brain sections from patients who died with AD and compare those samples with sections obtained from healthy controls (sans AD). Early detection of AD by class-IIa HDAC PET imaging will allow early intervention to slow or halt disease progression with class-IIa HDAC inhibitors. Further, class-IIa HDAC PET imaging is of great relevance to other diseases, such as Huntington’s disease, ischemic stroke, traumatic brain injuries, and cancer.