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Preclinical Evaluation of an 18F-Labeled SW-100 Derivative for PET Imaging of Histone Deacetylase 6 in the Brain

Histone deacetylase 6 (HDAC6), an enzyme involved in protein degradation, exhibits several unique properties, such as cytoplasmic localization and ubiquitin binding. HDAC6 has emerged as an interesting therapeutic target in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Techniques enabling noninvasive HDAC6 imaging in the brain could enhance understanding of its pathologic role, but development of brain-penetrating radioligands for HDACs imaging by positron emission tomography (PET) remains challenging. Here, we report the synthesis and evaluation of an 18F-labeled tetrahydroquinoline derivative, [18F]2, based on the HDAC6 selective inhibitor SW-100 as a brain HDAC6 imaging radioligand. [18F]2 was synthesized via copper-mediated radiofluorination from an arylboronic precursor, followed by removal of the catalyst by solid-phase extraction and then hydroxamic acid formation. [18F]2 demonstrated good penetration and moderate stability in the mouse brain. In mouse plasma, however, [18F]2 was rapidly metabolized to a corresponding carboxylic acid form. Blocking studies in mice with unlabeled compound 2 and HDAC6 selective inhibitors, including tubastatin A and ACY-775, demonstrated that the HDAC6 inhibitors displaced over 80% of [18F]2 taken up in the brain, indicating selective binding of [18F]2. These results suggest that [18F]2 is a potentially useful PET radioligand for brain HDAC6 imaging.

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Cat.No. Product Name Information
S0864 ACY-775 ACY-775 is a potent and selective histone deacetylase 6 (HDAC6) inhibitor with IC50 of 7.5  nM.

Related Targets

HDAC