Histone deacetylase 6 (HDAC6) function and dysregulation have been implicated in the etiology of certain cancers and more recently in central nervous system (CNS) disorders including Rett syndrome, Alzheimer's and Parkinson's diseases, and major depressive disorder. HDAC6-selective inhibitors have therapeutic potential, but in the CNS drug space the development of highly brain penetrant HDAC inhibitors has been a persistent challenge. Moreover, no tool exists to directly characterize HDAC6 and its related biology in the living human brain. Here, we report a highly brain penetrant HDAC6 inhibitor, Bavarostat, that exhibits excellent HDAC6 selectivity (>80-fold over all other Zn-containing HDAC paralogues), modulates tubulin acetylation selectively over histone acetylation, and has excellent brain penetrance. We further demonstrate that Bavarostat can be radiolabeled with 18F by deoxyfluorination through in situ formation of a ruthenium π-complex of the corresponding phenol precursor: the only method currently suitable for synthesis of [18F]Bavarostat. Finally, by using [18F]Bavarostat in a series of rodent and nonhuman primate imaging experiments, we demonstrate its utility for mapping HDAC6 in the living brain, which sets the stage for first-in-human neurochemical imaging of this important target.

中文翻译：

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通过Ru介导的脱氧氟化作用启用[18F] Bavarostat的HDAC6脑图。

组蛋白脱乙酰基酶6（HDAC6）的功能和失调与某些癌症的病因有关，最近与中枢神经系统（CNS）疾病有关，包括Rett综合征，阿尔茨海默氏病和帕金森氏病以及重度抑郁症。HDAC6选择性抑制剂具有治疗潜力，但是在中枢神经系统药物领域，高脑渗透性HDAC抑制剂的开发一直是一项持续的挑战。此外，还没有工具可以在活人的大脑中直接表征HDAC6及其相关生物学。在这里，我们报告了一种具有高脑渗透性的HDAC6抑制剂Bavarostat，它具有出色的HDAC6选择性（比所有其他含锌的HDAC仿生物高80倍以上），选择性地调节微管蛋白的乙酰化超过组蛋白的乙酰化，并且具有出色的脑渗透性。我们进一步证明，可以通过相应的酚前体的钌π-络合物的原位形成脱氧氟化作用，用18F放射性标记巴伐他汀：这是目前唯一适用于合成[18F]巴伐他汀的方法。最后，通过在一系列啮齿动物和非人类灵长类动物成像实验中使用[18F] Bavarostat，我们证明了其在活脑中定位HDAC6的效用，这为该重要靶标在人类中进行神经化学成像奠定了基础。