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

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.

SUBMITTER: Celen S

PROVIDER: S-EPMC7205522 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Celen Sofie S Rokka Johanna J Gilbert Tonya M TM Koole Michel M Vermeulen Isabeau I Serdons Kim K Schroeder Frederick A FA Wagner Florence F FF Bleeser Tom T Hightower Baileigh G BG Hu Jiyun J Rahal Dania D Beyzavi Hudson H Vanduffel Wim W Van Laere Koen K Kranz Janice E JE Hooker Jacob M JM Bormans Guy G Cawthorne Christopher J CJ

ACS chemical neuroscience 20200319 7

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 r ...[more]

PMID: 32159328

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Project description:PurposeThe α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7 nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [18F]ASEM in humans.MethodsPET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (V T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V T was assessed.ResultsIn the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM V T. [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM V T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V T values ranging from 19.6 ± 2.5 mL/cm3 in cerebellum to 25.9 ± 2.9 mL/cm3 in thalamus. Test-retest variability of V T was 11.7 ± 9.8%.ConclusionsThese results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7 nAChRs in humans.

Dataset Information

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

Publications

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

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Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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