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Background <p>Histone deacetylase 6 (HDAC6) is a lysine deacetylase that modulates protein function and turnover, and is critically implicated in the pathogenesis of neurodegenerative disorders. [<sup>18</sup>F]FSW-100 is a promising radioligand designed to enable visualization of HDAC6 in the brain. In this first-in-human PET study, we evaluated the clinical applicability of [<sup>18</sup>F]FSW-100 by comprehensively assessing its safety profile, biodistribution, radiation dosimetry, and brain kinetics.</p> Methods <p>In cohort A, whole-body PET was performed in three healthy men to evaluate radiation dosimetry, with serial imaging conducted from 1&#xa0;min to 2&#xa0;h after injection followed by additional scans at 4&#xa0;h and 6&#xa0;h. Absorbed doses in individual organs and the effective dose were estimated. In cohort B, five healthy men underwent 120-min dynamic brain PET with arterial blood sampling for radioactivity measurement and metabolite analysis. To determine optimal kinetic modeling, one- and two-tissue compartment models (1-TCM and 2-TCM), along with Logan graphical analysis (LGA), were applied to estimate distribution volume (<i>V</i><sub>T</sub>). Safety was monitored throughout both cohorts.</p> Results <p>The scan protocol was well tolerated by all subjects. In cohort A, effective dose was estimated at 18.9 ± 1.7 µSv/MBq, with the highest absorbed dose observed in the gallbladder wall (379 ± 136 µGy/MBq). Accordingly, as a precaution to minimize gallbladder dose, cohort B received a lower administered radioactivity. In brain PET analysis, 2-TCM better described radioligand kinetics than 1-TCM. <i>V</i><sub>T</sub> was highest in cerebellar gray matter (42.6 ± 9.7 mL/cm<sup>3</sup>) and lowest in white matter (12.2 ± 3.6 mL/cm<sup>3</sup>). <i>V</i><sub>T</sub> values from 2-TCM strongly correlated with those from LGA. The mean <i>V</i><sub>T</sub> coefficient of variation across regions was 26 ± 3%, decreasing to 19 ± 3% when the input function was derived from averaged unchanged fractions, and further to 9 ± 2% when <i>V</i><sub>T</sub> values were normalized to white matter.</p> Conclusions <p>[<sup>18</sup>F]FSW-100 PET demonstrated an acceptable safety profile. <i>V</i><sub>T</sub> estimation via 2-TCM appears suitable for quantitative assessment of HDAC6 in the brain.</p> Trial registration <p>Japan Registry of Clinical Trials (jRCT), jRCTs031240173. Registered 19 June 2024, <a href="https://jrct.mhlw.go.jp/latest-detail/jRCTs031240173">https://jrct.mhlw.go.jp/latest-detail/jRCTs031240173</a>.</p>

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First-in-human PET study of [18F]FSW-100 for imaging histone deacetylase 6 in the brain: safety, biodistribution, radiation dosimetry, and brain kinetic analyses

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  • 发表日期：

    2026年6月15日

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  • Tetsuro Tago,
  • Muneyuki Sakata,
  • Yuto Kamitaka,
  • Masashi Kameyama,
  • Kenji Ishii,
  • Jun Toyohara

摘要

Background

Histone deacetylase 6 (HDAC6) is a lysine deacetylase that modulates protein function and turnover, and is critically implicated in the pathogenesis of neurodegenerative disorders. [18F]FSW-100 is a promising radioligand designed to enable visualization of HDAC6 in the brain. In this first-in-human PET study, we evaluated the clinical applicability of [18F]FSW-100 by comprehensively assessing its safety profile, biodistribution, radiation dosimetry, and brain kinetics.

Methods

In cohort A, whole-body PET was performed in three healthy men to evaluate radiation dosimetry, with serial imaging conducted from 1 min to 2 h after injection followed by additional scans at 4 h and 6 h. Absorbed doses in individual organs and the effective dose were estimated. In cohort B, five healthy men underwent 120-min dynamic brain PET with arterial blood sampling for radioactivity measurement and metabolite analysis. To determine optimal kinetic modeling, one- and two-tissue compartment models (1-TCM and 2-TCM), along with Logan graphical analysis (LGA), were applied to estimate distribution volume (VT). Safety was monitored throughout both cohorts.

Results

The scan protocol was well tolerated by all subjects. In cohort A, effective dose was estimated at 18.9 ± 1.7 µSv/MBq, with the highest absorbed dose observed in the gallbladder wall (379 ± 136 µGy/MBq). Accordingly, as a precaution to minimize gallbladder dose, cohort B received a lower administered radioactivity. In brain PET analysis, 2-TCM better described radioligand kinetics than 1-TCM. VT was highest in cerebellar gray matter (42.6 ± 9.7 mL/cm3) and lowest in white matter (12.2 ± 3.6 mL/cm3). VT values from 2-TCM strongly correlated with those from LGA. The mean VT coefficient of variation across regions was 26 ± 3%, decreasing to 19 ± 3% when the input function was derived from averaged unchanged fractions, and further to 9 ± 2% when VT values were normalized to white matter.

Conclusions

[18F]FSW-100 PET demonstrated an acceptable safety profile. VT estimation via 2-TCM appears suitable for quantitative assessment of HDAC6 in the brain.

Trial registration

Japan Registry of Clinical Trials (jRCT), jRCTs031240173. Registered 19 June 2024, https://jrct.mhlw.go.jp/latest-detail/jRCTs031240173.