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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-20 DOI:10.1021/acs.jmedchem.5c02216

Tomoteru Yamasaki,Norio Ohyabu,Takeshi Wakabayashi,Ignacio Ibáñez,Kouichi Iwanaga,Satoshi Yamamoto,Masahiko Hattori,Taku Sugita,Michiko Terada,Tomohiro Onishi,Sho Sato,Yohei Kosugi,Akihiro Takano,Paul McQuade,Takamitsu Maru,Naomi Inui,Masayuki Fujinaga,Wakana Mori,Yuji Nagai,Chie Seki,Shoko Uchida,Takafumi Minamimoto,Makoto Higuchi,Makoto Fushimi,Ming-Rong Zhang

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引用次数: 0

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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发现基于吡唑的正电子发射断层扫描剂，可绘制非人类灵长类大脑中组蛋白去乙酰化酶6 （HDAC6）。

组蛋白去乙酰化酶6 （HDAC6）是开发用于治疗神经退行性疾病的药物的关键靶点。在这里，我们确定了16a作为吡唑衍生物HDAC6成像的正电子发射断层扫描（PET）示踪剂的候选物，该示踪剂显示出较强的HDAC6亲和力（Kd = 1.66 nM），并且在野生型小鼠的大脑中积累量高于HDAC6敲除小鼠。用氟-18进行放射性标记后，含有[18F]16a的PET表现出对放射性的异质吸收，这与HDAC6在猴子大脑中的生物分布相对应。这些放射性分布在预先给药ACY-775（一种有效的HDAC6抑制剂）后均匀减少，这表明PET图像中的放射性积聚可能反映了[18F]16a与HDAC6的特异性结合。因此，[18F]16a是一种很有前景的HDAC6显像PET示踪剂，值得进一步临床研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.