Prediction of the Clinical SUV Ratio in Amyloid PET Imaging Using a Biomathematic Modeling Approach Toward the Efficient Development of a Radioligand.

Abstract

Our study aimed to develop a method to mathematically predict the kinetic parameters <i>K</i>₁ (influx rate constant), <i>k</i>₂ (efflux rate constant), and BP_ND (nondisplaceable binding potential) of amyloid PET tracers and obtain SUV ratios (SUVRs) from predicted time-activity curves of target and reference regions. <b>Methods:</b> We investigated 10 clinically applied amyloid PET radioligands: ¹¹C-Pittsburgh compound B, ¹¹C-BF-227, ¹¹C-AZD2184, ¹¹C-SB-13, ¹⁸F-FACT, ¹⁸F-florbetapir, ¹⁸F-florbetaben, ¹⁸F-flutemetamol, ¹⁸F-FDDNP, and ¹⁸F-AZD4694. For each tracer, time-activity curves of both target and reference regions were generated using a simplified 1-tissue-compartment model, with an arterial plasma input function and the predicted kinetic parameters. <i>K</i>₁, <i>k</i>₂, and BP_ND were derived from the lipophilicity (log<i>P</i>), apparent volume, free fraction in plasma, free fraction in tissue, dissociation constant, and density of amyloid β using biomathematic modeling. Density was fixed at 3 nM to represent healthy control conditions and 50 nM to represent severe Alzheimer disease (AD). Predicted SUVRs for the healthy and AD groups were then obtained by dividing the integrated time-activity curve of the target region by that of the reference region. To validate the presented method, the predicted <i>K</i>₁, <i>k</i>₂, BP_ND, and SUVR for the healthy and AD groups were compared with the respective clinically observed values. <b>Results:</b> The correlation between predicted and clinical kinetic parameters had an <i>R</i>² value of 0.73 for <i>K</i>₁ in the healthy group, 0.71 for <i>K</i>₁ in the AD group, 0.81 for <i>k</i>₂ in the healthy group, 0.85 for <i>k</i>₂ in the AD group, and 0.63 for BP_ND in the AD group. The regression relationship between the predicted SUVR (<i>y</i>) and the clinical SUVR (<i>x</i>) for the healthy and the AD groups was <i>y</i> = 2.73<i>x</i> - 2.11 (<i>R</i>² = 0.72). <b>Conclusion:</b> The proposed method showed a good correlation between predicted and clinical SUVR for the 10 clinically applied amyloid tracers.