Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Chemistry, Medicinal, Neurosciences, Pharmacology & Pharmacy, Neurosciences & Neurology, Histone deacetylase 6, Central nervous system, Positron emission tomography, [F-18]EKZ-001, [F-18]Bavarostat, Current Good Manufacturing Practice, GLUCOCORTICOID-RECEPTOR, ACETYLATION, INHIBITION, DISEASE, [18F]Bavarostat, [18F]EKZ-001, Alzheimer Disease, Animals, Brain, Cyclic GMP, Fluorine Radioisotopes, Histone Deacetylase 6, Hydroxamic Acids, Macaca mulatta, Positron-Emission Tomography, Pyrimidines, Radiochemistry, Radiopharmaceuticals, C14/17/109#54271217, 0304 Medicinal and Biomolecular Chemistry, 3101 Biochemistry and cell biology, 3401 Analytical chemistry, 3404 Medicinal and biomolecular chemistry

Abstract:

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.