Preclinical Evaluation of an 18F-Labeled SW-100 Derivative for PET Imaging of Histone Deacetylase 6 in the Brain
Preclinical Evaluation of an 18F-Labeled SW-100 Derivative for PET Imaging of Histone Deacetylase 6 in the Brain
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18F 标记的 SW-100 衍生物用于大脑中组蛋白脱乙酰酶 6 PET 成像的临床前评估
DOI：
10.1021/acschemneuro.0c00774
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发表时间：
2021
影响因子：
5
通讯作者：
Ishii Kenji
中科院分区：
文献类型：
--
作者：
Tago Tetsuro;Toyohara Jun;Ishii Kenji
组蛋白去乙酰化酶6 （HDAC6）是一种参与蛋白质降解的酶，具有细胞质定位和泛素结合等独特特性。HDAC6已成为治疗神经退行性疾病（如阿尔茨海默病和帕金森病）的一个有趣的治疗靶点。脑内无创HDAC6成像技术可以增强对其病理作用的理解，但开发用于HDAC6正电子发射断层扫描（PET）成像的脑穿透放射配体仍然具有挑战性。在这里，我们报道了基于HDAC6选择性抑制剂SW-100作为脑HDAC6成像放射配体的一种18F标记的四氢喹啉衍生物[18F]2的合成和评价。[18F]2由芳基硼前驱体经铜介导的放射性氟化合成，然后用固相萃取法去除催化剂，然后生成羟肟酸。[18F]2在小鼠大脑中表现出良好的渗透性和适度的稳定性。然而，在小鼠血浆中，[18F]2被迅速代谢为相应的羧酸形式。在小鼠中使用未标记化合物2和HDAC6选择性抑制剂（包括tubastatin A和ACY-775）阻断研究表明，HDAC6抑制剂取代了大脑中80%以上的[18F]2，表明[18F]2具有选择性结合。这些结果表明[18F]2是一种潜在的有用的PET放射配体，用于脑HDAC6成像。
Histone deacetylase 6 (HDAC6), an enzyme involved in protein degradation, exhibits several unique properties, such as cytoplasmic localization and ubiquitin binding. HDAC6 has emerged as an interesting therapeutic target in the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Techniques enabling noninvasive HDAC6 imaging in the brain could enhance understanding of its pathologic role, but development of brain-penetrating radioligands for HDACs imaging by positron emission tomography (PET) remains challenging. Here, we report the synthesis and evaluation of an18F-labeled tetrahydroquinoline derivative, [18F]2, based on the HDAC6 selective inhibitor SW-100 as a brain HDAC6 imaging radioligand. [18F]2was synthesized via copper-mediated radiofluorination from an arylboronic precursor, followed by removal of the catalyst by solid-phase extraction and then hydroxamic acid formation. [18F]2demonstrated good penetration and moderate stability in the mouse brain. In mouse plasma, however, [18F]2was rapidly metabolized to a corresponding carboxylic acid form. Blocking studies in mice with unlabeled compound2and HDAC6 selective inhibitors, including tubastatin A and ACY-775, demonstrated that the HDAC6 inhibitors displaced over 80% of [18F]2taken up in the brain, indicating selective binding of [18F]2. These results suggest that [18F]2is a potentially useful PET radioligand for brain HDAC6 imaging.