Development of class-IIa HDAC targeting PET probes for molecular imaging of disorders of the CNS

Summary The aim of this application is to validate a novel class-IIa histone deacetylase (class-IIa HDAC) positron emission tomography (PET) imaging probe, to obtain IRB approval and an exploratory IND for translational research in Alzheimer's disease (AD) and other diseases, in order to test this radiopharmaceutical to human volunteers. Despite decades of intensive research and a large financial investment in clinical trials, AD is a fast-growing public health problem. The development of novel diagnostic tools to guide the development of an efficacious pharmacological treatment of AD is still an unmet and urgent need. Therefore, we plan to validate a novel class- IIa HDACs PET probe to bridge the gap that exists between postmortem studies and the need for real time non- invasive and longitudinal quantification of class-IIa HDAC expression in human AD. If successful, our novel probe may provide information on AD progression and early detection of AD. The success of our imaging studies may delineate a novel role for class-IIa HDAC in the pathophysiology and progression of AD and may identify class- IIa HDAC as druggable target for AD, which potentially will incentivize the development and deployment of class- IIa HDAC targeting drugs. We propose three specific aims to facilitate the clinical translation of a novel class-IIa HDAC targeting radioligand named [18F]NT311D. In aim1, we plan to optimize and automate the radiosynthesis of [18F]NT311D and to perform PET imaging in rats. In aim2 we plan to validate class-IIa HDACs in AD human tissues using in vitro autoradiography and immunohistochemistry (IHC) and in aim3, we plan to perform PET imaging, biodistribution, metabolism, kinetic modeling, and radiation dosimetry with [18F]NT311D in pigs. We will also perform the studies needed for translation to humans. With completion of this proposal, we will seek IRB approval and file an IND application with the FDA for first in human studies for PET imaging of AD and other diseases.