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

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

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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