HDAC6型
正电子发射断层摄影术
Pet成像
放射性配体
结合势
化学
细胞内
神经科学
核医学
组蛋白脱乙酰基酶
医学
生物化学
生物
组蛋白
体外
基因
作者
Sofie Celen,Johanna Rokka,Tonya M. Gilbert,Michel Koole,Isabeau Vermeulen,Kim Serdons,Frederick A. Schroeder,Florence F. Wagner,Tom Bleeser,B. G. Hightower,Jiyun Hu,Dania Rahal,M. Hassan Beyzavi,Wim Vanduffel,Koen Van Laere,Janice E. Kranz,Jacob M. Hooker,Guy Bormans,Christopher Cawthorne
标识
DOI:10.1021/acschemneuro.0c00074
摘要
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, [18F]EKZ-001 ([18F]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. [18F]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [18F]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [18F]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/μmol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [18F]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 [18F]EKZ-001 PET for first-in-human studies.
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