Discovery of Pyrazole-Based Positron Emission Tomography Agent that Maps Histone Deacetylase 6 (HDAC6) in the Nonhuman Primate Brain

  • J Med Chem. 2025 Nov 13;68(21):23375-23388. doi: 10.1021/acs.jmedchem.5c02216.
Tomoteru Yamasaki  1 ,  Norio Ohyabu  2 ,  Takeshi Wakabayashi  2 ,  Ignacio Ibáñez  2 ,  Kouichi Iwanaga  2 ,  Satoshi Yamamoto  2 ,  Masahiko Hattori  2 ,  Taku Sugita  2 ,  Michiko Terada  2 ,  Tomohiro Onishi  2 ,  Sho Sato  2 ,  Yohei Kosugi  2 ,  Akihiro Takano  3 ,  Paul McQuade  4 ,  Takamitsu Maru  5 ,  Naomi Inui  5 ,  Masayuki Fujinaga  1 ,  Wakana Mori  1 ,  Yuji Nagai  1 ,  Chie Seki  1 ,  Shoko Uchida  1 ,  Takafumi Minamimoto  1 ,  Makoto Higuchi  1 ,  Makoto Fushimi  2 ,  Ming-Rong Zhang  1
Affiliations
  • 1. National Institute for Quantum Science and Technology, Inage-ku, Chiba 263-8555, Japan.
  • 2. Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
  • 3. Takeda Pharmaceutical Company Limited, Chuo-ku, Osaka 540-8645, Japan.
  • 4. Takeda Development Center Americas, Inc., Cambridge, Massachusetts 02142, United States.
  • 5. Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa 251-0012, Japan.
PMID: 41116332 DOI: 10.1021/acs.jmedchem.5c02216
Abstract

Histone deacetylase 6 (HDAC6) is a crucial target for the development of pharmaceuticals used in the treatment of neurodegenerative disorders. Here, we identified 16a as a candidate of positron emission tomography (PET) tracer for HDAC6 imaging from pyrazole derivatives, which showed strong HDAC6 affinity (Kd = 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 [18F]16a 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 [18F]16a with HDAC6. Thus, [18F]16a is a promising PET tracer for HDAC6 imaging that motivates future clinical research.

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