Development of a potential PET probe for HDAC6 imaging in Alzheimer?s disease

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we per-formed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [18F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high spec-ificity to HDAC6. PET studies of [18F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippo -campus. The translatability of this radiotracer for AD in a potential human use was supported by addi-tional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD -related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo his-topathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly suscep-tible to AD through an association with amyloid pathology. 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).