Clinical validation of the novel HDAC6 radiotracer [ 18 F]EKZ-001 in the human brain

Eur J Nucl Med Mol Imaging. 2021 Feb;48(2):596-611. doi: 10.1007/s00259-020-04891-y. Epub 2020 Jul 8.

Abstract

Purpose: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [18F]EKZ-001 ([18F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects.

Methods: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (VT) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. VT differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches.

Results: The effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA VT were in agreement with 2TCM VT, however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional VT values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher VT than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported.

Conclusion: [18F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

Keywords: First-in-human; HDAC6; Neuroimaging; Positron emission tomography; [18F]Bavarostat; [18F]EKZ-001.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / diagnostic imaging*
  • Female
  • Histone Deacetylase 6
  • Humans
  • Male
  • Positron Emission Tomography Computed Tomography*
  • Positron-Emission Tomography
  • Radiopharmaceuticals*
  • Tissue Distribution
  • Tomography, X-Ray Computed
  • Young Adult

Substances

  • Radiopharmaceuticals
  • HDAC6 protein, human
  • Histone Deacetylase 6