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

Michel Koole,Guy Bormans,Kim Serdons,Sofie Celen,Donatienne Van Weehaeghe,Marissa Herbots,Koen Van Laere,Tonya M Gilbert,Janice E Kranz,Jacob M Hooker,Frederick A Schroeder,Christopher Cawthorne,Jan De Hoon

doi:10.1007/s00259-020-04891-y

Abstract

PurposeHistone 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.MethodsBiodistribution 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.ResultsThe 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.

Highlights

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that contains two catalytic domains, a dynein motor binding domain and a ubiquitin-binding zinc finger domain (ZnFUBP)
Regional Logan graphical analysis (LGA) volume of distribution (VT) were in agreement with 2TCM VT, demonstrated a lower absolute test-retest variability (TRV) of 7.7 ± 4.9%
The fraction of injected activity entering the small intestine, determined as the decay-corrected plateau fraction of injected activity encompassed by the intestinal Volumes of interest (VOIs), was 63%, 49%, 67%, and 68%, for each subject, respectively, and used as input for the ICRP 30 GI model (ICRP 1979) to determine the normalized cumulated activities (NCA) for the organs involved in the GI tract

Summary

Introduction

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that contains two catalytic domains, a dynein motor binding domain and a ubiquitin-binding zinc finger domain (ZnFUBP). Modulation of HDAC6 expression levels or enzymatic activity has shown beneficial effects in multiple cell and animal models of disease, including neurodegenerative disorders [13,14,15,16,17,18,19,20,21,22,23], psychiatric disorders [24, 25], peripheral neuropathies [26,27,28,29,30,31,32,33], and cancer [34, 35]. Quantifying the expression and distribution of HDAC6 in humans is of great importance to understand how HDAC6 may relate to disease pathogenesis, progression, and treatment response

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