Histone deacetylases and PET

Histone deacetylases (HDACs) catalyse the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. Deacetylation of nonhistone proteins, including nuclear receptors, controls diverse cellular processes. Also some sirtuins deacetylate protein lysine residues.

DNA transcription is influenced by the packaging of DNA into chromatin. The architecture of nucleosome, consisting of 146 bp of DNA and an octamer of histones, is modified by methylation, phosphorylation, and acetylation of histones. Transcriptionally active chromatin is hyperacetylated. Deacetylation by HDACs causes chromatin condensation and blocks the transcriptional proteins from accessing the DNA.

HDACs are also subject to post-transitional modifications by phosphorylation, acetylation, ubiquitylation, and sumoylation, affecting their activity. Histone deacetylase inhibitors (HDIs) have been used as anti-epileptics and anticancer agents, and show promise in epigenetic-based therapies of many diseases. Ketone body β-hydroxybutyrate (β-HB) is an endogenous inhibitor of HDACs.

[11C]Martinostat is selective for class I HDACs (HDAC1, HDAC2, and HDAC3), which are implicated in regulating neuroplasticity and cognitive function, and can be used to assess the density and occupancy of these HDACs in the brain (Wei et al., 2015). For instance, [11C]Martinostat PET has revealed reduced HDAC availability in schizophrenia (Gilbert et al., 2019) and Alzheimer's disease (Pascoal et al., 2022).

[18F]FAHA shows highest substrate affinity to class IIa HDACs (HDAC4, HDAC5, HDAC7, and HDAC9). In the brain cells, [18F]FAHA is metabolized to [18F]fluoroacetate and further anabolised to [18F]citrate, which are trapped in cells; thus [18F]FAHA PET could be used to assess the class IIa HDAC inhibitors (Yeh et al., 2013).

HDAC6

[18F]Bavarostat ([18F]EKZ-001) has high affinity and selectivity toward HDAC6. Reversible two-tissue compartment model and Logan plot can be used to analyse brain data from non-human primates (Strebl et al., 2017; Celen et al., 2020). In human brain, Logan plot produced results with better test-retest performance (Koole et al., 2021). Multilinear analysis method (MA1) produced results comparable to two-tissue compartment model (Naganawa et al., 2025). [18F]Bavarostat has shown reduced HDAC6 availability in the amygdala in PTSD (Bonomi et al., 2025).

[18F]FSW-100 has high specificity toward HDAC6 and good brain penetration in mice and non-human primates, but it is metabolized rapidly in vivo, complicating quantitative analysis (Tago et al., 2021 and 2024).


Literature

Brandl A, Heinzel T, Krämer OH. Histone deacetylases: salesmen and customers in the post-translational modification market. Biol Cell. 2009; 101(4): 193-205. doi: 10.1042/BC20080158.

de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003; 370(Pt 3): 737-749. doi: 10.1042/BJ20021321.

Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014; 6(4): a018713. doi: 10.1101/cshperspect.a018713.

Wey HY, Gilbert TM, Zürcher NR, She A, Bhanot A, Taillon BD, Schroeder FA, Wang C, Haggarty SJ, Hooker JM. Insights into neuroepigenetics through human histone deacetylase PET imaging. Sci Transl Med. 2016; 8(351): 351ra106. doi: 10.1126/scitranslmed.aaf7551.



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Updated at: 2025-08-14
Created at: 2023-08-01
Written by: Vesa Oikonen