Development of an ¹⁸F-labeled 5-aroylindole derivative for histone deacetylase 6 imaging in spinocerebellar ataxia

Histone deacetylase 6 (HDAC6) is an enzyme crucial in epigenetic regulation and protein degradation, with implications in various cancers and neurodegenerative disorders. While HDAC6 is recognized as a promising therapeutic target for Parkinson's and Alzheimer's diseases, its involvement in spinocerebellar ataxias (SCAs) remains underexplored. Currently, there are no direct methods available for characterizing HDAC6 in the brains of living subjects. Positron emission tomography (PET) techniques offer a noninvasive approach to visualize HDAC6, potentially enhancing our understanding of its neuropathological roles. In this study, we present the synthesis and PET imaging of [¹⁸F]3, an ¹⁸F-labeled 5-aroylindole derivative, which exhibits favorable affinity for HDAC6. The synthesis of [¹⁸F]3 was achieved through microwave-assisted radiofluorination of a nitro-precursor, followed by hydroxamic acid formation. PET studies using [¹⁸F]3 in SCA17 transgenic mice revealed significantly increased radioactivity in the brain compared to wild-type mice, particularly evident in the cerebellum and hippocampus. These findings warrant the potential utility of ¹⁸F-labeled 5-aroylindole derivatives as PET radioligands for HDAC6 neuroimaging and advocate for further exploration in structural optimization endeavors.