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

Histone deacetylase 6 (HDAC6) is a lysine deacetylase that modulates protein function and turnover, and is critically implicated in the pathogenesis of neurodegenerative disorders. [ 18 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 [ 18 F]FSW-100 by comprehensively assessing its safety profile, biodistribution, radiation dosimetry, and brain kinetics. 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 ( V T ). Safety was monitored throughout both cohorts. 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. V T was highest in cerebellar gray matter (42.6 ± 9.7 mL/cm 3 ) and lowest in white matter (12.2 ± 3.6 mL/cm 3 ). V T values from 2-TCM strongly correlated with those from LGA. The mean V T 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 V T values were normalized to white matter. [ 18 F]FSW-100 PET demonstrated an acceptable safety profile. V T estimation via 2-TCM appears suitable for quantitative assessment of HDAC6 in the brain. Japan Registry of Clinical Trials (jRCT), jRCTs031240173. Registered 19 June 2024, https://jrct.mhlw.go.jp/latest-detail/jRCTs031240173 .