Discovery of Pyrazole-Based Positron Emission Tomography Agent that Maps Histone Deacetylase 6 (HDAC6) in the Nonhuman Primate Brain
Histone deacetylase 6 (HDAC6) is a crucial target for the development of pharmaceuticals used in the treatment of neurodegenerative disorders. Here, we identified <b>16a</b> as a candidate of positron emission tomography (PET) tracer for HDAC6 imaging from pyrazole derivatives, which showed strong HDAC6 affinity (<i>K</i><sub>d</sub> = 1.66 nM) and higher accumulation in the brain of wild-type mice than in HDAC6 knockout mice. Following radiolabeling with fluorine-18, PET with [<sup>18</sup>F]<b>16a</b> exhibited heterogeneous uptake of radioactivity, corresponding to the biological distribution of HDAC6 in the monkey brain. These radioactive distributions were homogeneously diminished by the preadministration of ACY-775, a potent inhibitor of HDAC6, suggesting that radioactive accumulation in PET images could reflect the specific binding of [<sup>18</sup>F]<b>16a</b> with HDAC6. Thus, [<sup>18</sup>F]<b>16a</b> is a promising PET tracer for HDAC6 imaging that motivates future clinical research.
Authors
- Tomoteru Yamasaki (ORCID: https://orcid.org/0000-0001-7773-3665)
- Paul McQuade (ORCID: https://orcid.org/0000-0003-0282-0208)
- Makoto Higuchi (ORCID: https://orcid.org/0000-0002-3934-5810)
- Ignacio Ibáñez
- Naoki Inui (ORCID: https://orcid.org/0000-0002-4624-7119)
- Takamitsu Maru (ORCID: https://orcid.org/0000-0002-9540-9276)
- Satoshi Yamamoto (ORCID: https://orcid.org/0000-0001-6408-626X)
- Taku Sugita
- Ming‐Rong Zhang (ORCID: https://orcid.org/0000-0002-3001-9605)
- Norio Ohyabu
- Tomohiro Onishi (ORCID: https://orcid.org/0000-0003-0633-9323)
- Takafumi Minamimoto (ORCID: https://orcid.org/0000-0003-4305-0174)
- Wakana Mori
- Sho Sato (ORCID: https://orcid.org/0000-0001-8599-5374)
- Chie Seki (ORCID: https://orcid.org/0000-0002-3222-7125)
- Makoto Fushimi
- Akihiro Takano
- Masayuki Fujinaga (ORCID: https://orcid.org/0000-0002-0418-229X)
- Yuji Nagai (ORCID: https://orcid.org/0000-0001-7005-0749)
- Kazunori Iwanaga
- Yohei Kosugi (ORCID: https://orcid.org/0000-0001-9318-4723)
- Takeshi Wakabayashi
- Michiko Terada
- Masahiko Hattori
- Shoko Uchida
Institutions
- National Institutes for Quantum Science and Technology (JP)
- Takeda (United States) (US)
- Takeda (Japan) (JP)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02216
- Citations
- 1
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81