HDAC6 Brain Mapping with [¹⁸F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Histone deacetylase 6 (HDAC6) dysregulation is linked to cancers and central nervous system (CNS) disorders like Alzheimer's and Parkinson's.
• Developing brain-penetrant HDAC inhibitors for CNS applications remains a significant challenge.
• There is a lack of tools to directly study HDAC6 biology in the living human brain.

Purpose of the Study:

• To develop a highly brain-penetrant and selective HDAC6 inhibitor.
• To create a tool for visualizing and characterizing HDAC6 in the living brain.
• To enable first-in-human neurochemical imaging of HDAC6.

Main Methods:

• Synthesis and characterization of Bavarostat, a novel HDAC6 inhibitor.
• Radiolabeling of Bavarostat with fluorine-18 ([18F]) using a ruthenium π-complex method.
• In vivo imaging studies in rodent and nonhuman primate models using [18F]Bavarostat.

Main Results:

• Bavarostat demonstrated high selectivity for HDAC6 (>80-fold) and modulated tubulin acetylation over histone acetylation.
• The compound exhibited excellent brain penetrance.
• [18F]Bavarostat successfully mapped HDAC6 distribution in the living brains of animal models.

Conclusions:

• Bavarostat is a promising, brain-penetrant, and selective HDAC6 inhibitor.
• The development of [18F]Bavarostat provides the first tool for direct neurochemical imaging of HDAC6.
• This work paves the way for human studies of HDAC6 in neurological disorders.