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Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer’s disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([18F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [18F]FSW-100.

Methods

Process validation of [18F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [18F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans.

Results

Three consecutive validation runs of the automated radiosynthesis gave [18F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [18F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [18F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific.

Conclusion

These results support the clinical utility of [18F]FSW-100 for in vivo imaging of HDAC6 in the brain.

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Data availability

The data obtained in the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Mr. Kosuke Nishino and Mr. Masanari Sakai (SHI Accelerator Service Ltd, Tokyo, Japan) for technical support with the cyclotron operation and radiosynthesis.

Funding

This work was supported by Grants-in-Aid for Young Scientists (No. 20K16778) and Scientific Research (C) (No. 22K07682) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Research Team for Neuroimaging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

    Tetsuro Tago, Muneyuki Sakata, Kenji Ishii & Jun Toyohara

  2. Central Research Laboratory, Hamamatsu Photonics, Hamamatsu, Japan

    Masakatsu Kanazawa & Shigeyuki Yamamoto

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  1. Tetsuro Tago
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Contributions

T.T., J.T., and K.I. designed the study. T.T. performed the radiosynthesis studies. T.T. and M.S. performed the dosimetry study. T.T., M.S., M.K., S.Y., and J.T. contributed to the NHP PET study. T.T. and J.T. wrote the manuscript. K.I. commented on the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jun Toyohara.

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Ethics approval

Studies using rodents were approved by the Animal Care and Use Committee of TMIG (Approval Nos. 21023, 22011, and 22012) and Bozo Research Center (Approval Nos. G220322, G220323). Studies using monkeys were carried out in accordance with the recommendations of the US NIH and approved by the Ethics Committee of the Central Research Laboratory, Hamamatsu Photonics (Approval No. HPK-2022–09) and the Animal Care and Use Committee of TMIG (Approval No. 22009).

Competing interests

M.K. and S.Y. are employed by Hamamatsu Photonics. The other authors declare no competing financial interest.

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Tago, T., Sakata, M., Kanazawa, M. et al. Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06666-1

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