[18F]Bavarostat

Histone deacetylase 6 (HDAC6) is an enzyme pivotal for gene regulation, influencing cellular pathways through protein deacetylation. HDAC6 is a potential therapeutic target in diseases such as cancer and neurodegenerative disorders. Koole et al. investigated brain binding of [¹⁸F]Bavarostat, an HDAC6 inhibitor, in healthy participants, revealing an absolute test-retest variability (aTRV) of 7.7% (n = 4) for the distribution volume (V_T) with a 1-day interscan interval. This study aims to evaluate test-retest reproducibility with a more extended interscan interval.

Six participants (3 M/3F) underwent a test-retest scan, each lasting for 120 min using a 4-ring Biograph mCT PET/CT scanner. Arterial blood sampling and metabolite analysis were performed to derive the input function. The two scans were 28 ± 12 days apart (14-43 days, n = 6). Regional time-activity curves (TACs) were generated for 15 regions of interest (ROIs). Kinetic analysis of the 120-min TACs was performed using one-tissue and two-tissue compartment models (1TC, 2TC) and multilinear analysis-1 (MA1) to quantify V_T values and compute absolute test-retest variability (aTRV). The effects of scan duration (60 to 120 min) and MA1 t* setting on aTRV and bias were investigated. Careful analysis of the plasma HPLC data was needed since metabolites eluted close in time to the parent. The MA1 model (t* = 40 min) adequately described regional TACs and produced stable kinetic parameters with good agreement to 2TC (MA1 V_T=0.98 × 2TC V_T + 0.48, bias: -0.1%) while 1TC underestimated V_T by 5.1%. Regional V_T values exhibited a relatively uniform pattern, highest in the amygdala and lowest in the centrum semiovale. Individual aTRV values ranged from 2 to 9%. Scan durations between 100 and 120 min provided the most consistent results, with minimal bias and acceptable aTRV across all tested t* values. Although a 90-minute scan with t*=10 or 20-minute balanced scan time and aTRV, optimal parameters varied by brain region. Smaller regions (e.g., amygdala) required longer scans to achieve reliable V_T quantification.

The test-retest variability of [¹⁸F]Bavarostat V_T values demonstrated favorable results for a one-month scan interval, comparable to the reported values.

Fluorine is increasingly being incorporated into pharmaceuticals to modulate their physical properties. Furthermore, 18F can be utilized in positron emission tomography (PET) probes for in vivo imaging. Bavarostat is a selective inhibitor of histone deacetylase 6 (HDAC6), and when derivatized with 18F is used to map out HDAC6 localisation within the brain. As HDAC6 is implicated in Alzheimer’s disease due to its function as a Tau deacetylase, it may serve as an effective biomarker for this disease. The active site cavity of HDAC6 contains two phenylalanine residues that form an aromatic crevice, F583 and F643, that engage in offset π‐π interactions with phenylhydroxymate binding groups. Moreover, the fluoroaromatic ring of Bavarostat orientates such that the C–F group binds in the aromatic crevice instead of being exposed to solvent. Structure activity relationships were determined for a series of fluorophenylhydroxymates to inform the design of fluorinated inhibitors of HDAC6 as well PET probes. Our studies show the aromatic crevice of HDAC6 preferentially binds C–F groups in this series of inhibitors. The inhibitors show differences in zinc binding orientations, likely due to the electronic influence of fluorine on the hydroxymate zinc‐binding group.