Translation of HDAC6 PET Imaging Using [18F]EKZ-001-cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates
Translation of HDAC6 PET Imaging Using [18F]EKZ-001-cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates
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DOI：
10.1021/acschemneuro.0c00074
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发表时间：
2020-04-01
影响因子：
5
通讯作者：
Cawthorne, Christopher J.
中科院分区：
文献类型：
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作者：
Celen, Sofie;Rokka, Johanna;Cawthorne, Christopher J.
组蛋白去乙酰化酶6（HDAC 6）是一种多功能的细胞质酶，参与多种细胞过程，如细胞内运输和蛋白质质量控制。HDAC 6的抑制可以减轻某些疾病，特别是神经退行性疾病，包括阿尔茨海默病和肌萎缩性侧索硬化症的细胞和啮齿动物模型中的缺陷。然而，虽然HDAC 6代表了一个潜在的强大的治疗靶点，但有效的脑渗透HDAC 6抑制剂的开发仍然具有挑战性。最近，开发了[F-18]EKZ-001（[F-18] Bavarostat），一种对HDAC 6具有高亲和力和选择性的脑穿透正电子发射断层扫描（PET）放射性配体，并对其结合HDAC 6的能力进行了临床前评价。在这里，我们描述了高效和稳健的全自动化的符合现行良好生产规范（cGMP）的生产方法。使用全动力学建模在非人灵长类动物（NHP）中验证了[F-18]EKZ-001定量方法，并应用[F-18]EKZ-001 PET比较两种HDAC 6抑制剂EKZ-317和ACY-775之间的剂量占用关系。[F-18]EKZ-001是cGMP，平均衰变校正放射化学产率为14%，平均摩尔活性为204 GBq/μ mol。我们证明了双组织房室模型和Logan图形分析适用于NHP脑中的[F-18]EKZ-001 PET定量。阻断研究表明，新化合物EKZ-317比ACY-775实现了更高的靶标占有率。这项工作支持翻译[F-18]EKZ-001 PET用于首次人体研究。
Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic enzyme involved in diverse cellular processes such as intracellular transport and protein quality control. Inhibition of HDAC6 can alleviate defects in cell and rodent models of certain diseases, particularly neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Recently, [F-18]EKZ-001 ([F-18] Bavarostat), a brain-penetrant positron emission tomography (PET) radioligand with high affinity and selectivity toward HDAC6, was developed and evaluated preclinically for its ability to bind HDAC6. Herein, we describe the efficient and robust fully automated current Good Manufacturing Practices (cGMP) compliant production method. [F-18]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [F-18]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [F-18]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/mu mol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [F-18]EKZ-001 PET quantification in NHP brain. Blocking studies show that the novel compound EKZ-317 achieves higher target occupancy than ACY-775. This work supports the translation of [F-18]EKZ-001 PET for first-in-human studies.