“Translation of HDAC6 PET imaging using [18F]EKZ-001 – cGMP production and measurement of HDAC6 target occupancy in NHPs” – A Review

The inhibition of histone deacetylase 6 (HDAC6) has been reported to alleviate the effects of neurodegenerative diseases such as Alzheimer’s disease. The brain-penetrant PET radioligand [18F]EKZ-001 has high affinity and selectivity towards HDAC6 and therefore suggests great promise in therapeutic treatment studies and development for neurodegenerative diseases. “Translation of HDAC6 PET imaging using [18F]EKZ-001 – cGMP production and measurement of HDAC6 target occupancy in NHPs” has achieved an effective, fully automated method of producing [18F]EKZ-001 in compliance with current good manufacturing practices (cGMP) to support the translation of [18F]EKZ-001 PET for first-in-human studies. This cGMP compliantly produced radioligand was utilized in PET studies in non-human primates (NHPs), where it was determined that the HDAC6 inhibitor EKZ-317 achieves greater target occupancy than the HDAC6 inhibitor ACY-775. The developments made by this research have had significant impact on the progression of therapeutic treatment studies for neurodegenerative diseases. The success of a cGMP compliant method of [18F]EKZ-001 production has enabled the first-in-human [18F]EKZ-001 PET study, further paving the way to a potential treatment for neurodegenerative diseases. This editorial aims to overview “Translation of HDAC6 PET imaging using [18F]EKZ-001 – cGMP production and measurement of HDAC6 target occupancy in NHPs”, to analyze and highlight the impact and relevance of this research, and propose future considerations for research in this area

Translation of HDAC6 PET Imaging Using [F-18]EKZ-001-cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates

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.status: publishe