Histone deacetylase 6 (HDAC6) function
and dysregulation have been
implicated in the etiology of certain cancers and more recently in
central nervous system (CNS) disorders including Rett syndrome, Alzheimer’s
and Parkinson’s diseases, and major depressive disorder. HDAC6-selective
inhibitors have therapeutic potential, but in the CNS drug space the
development of highly brain penetrant HDAC inhibitors has been a persistent
challenge. Moreover, no tool exists to directly characterize HDAC6
and its related biology in the living human brain. Here, we report
a highly brain penetrant HDAC6 inhibitor, Bavarostat, that exhibits
excellent HDAC6 selectivity (>80-fold over all other Zn-containing
HDAC paralogues), modulates tubulin acetylation selectively over histone
acetylation, and has excellent brain penetrance. We further demonstrate
that Bavarostat can be radiolabeled with 18F by deoxyfluorination
through in situ formation of a ruthenium π-complex
of the corresponding phenol precursor: the only method currently suitable
for synthesis of [18F]Bavarostat. Finally, by using [18F]Bavarostat in a series of rodent and nonhuman primate imaging
experiments, we demonstrate its utility for mapping HDAC6 in the living
brain, which sets the stage for first-in-human neurochemical imaging
of this important target.
The deficiency of robust and practical
methods for 18F-radiofluorination is a bottleneck for positron
emission tomography
(PET) tracer development. Here, we report the first transition-metal-assisted 18F-deoxyfluorination of phenols. The transformation benefits
from readily available phenols as starting materials, tolerance of
moisture and ambient atmosphere, large substrate scope, and translatability
to generate doses appropriate for PET imaging.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.