Dynamic PET-MR imaging with 20-[18F]fluoroarachidonic acid for monitoring brain uptake kinetics in ApoE-amyloid beta double replacement mice

Introduction: The apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for Alzheimer’s disease (AD). The dysregulation of arachidonic acid (AA) metabolism in the brains of APOE4 carriers, a precursor to proinflammatory mediators, further intensifies the pathogenic impact of amyloid plaques in the AD-afflicted brain. Previous studies have investigated the kinetics of AA uptake in rodent brains through autoradiography with [1-¹⁴C]AA and in humans through [1-¹¹C]AA PET. In this study, we utilized 20-[¹⁸F]fluoroarachidonic acid (20-[¹⁸F]FAA), a more easily accessible and longer-lived radiotracer compared to [1-¹¹C]AA, to evaluate brain uptake kinetics of AA in human ApoE-amyloid beta double replacement (ApoE-Ab) mouse models.

Methods: PET-MR images were obtained on a 7T MRI scanner with an integrated PET scanner (MR solutions, Guildford, UK) through 30-minute dynamic scans following the bolus injection of 20-[¹⁸F]FAA via the tail veins of two distinct groups of mice (n = 7/group): ApoE3-Ab and ApoE4-Ab. From the dynamic PET images, the tracer concentrations were extracted in both the brain and the right ventricle of the heart over time. The brain incorporation coefficient (K*) of 20-[¹⁸F]FAA was then estimated using either the Patlak model or the irreversible two-tissue compartmental model (Irr2TCM).

Results: Following dynamic PET-MR imaging, the K* values were successfully calculated through kinetic modeling using an image-derived input function. Employing the Patlak method, the estimated K* values were 5.73 ± 0.44 µL mL^-1 min^-1 for ApoE3-Ab mice and 6.27 ± 0.24 µL mL^-1 min^-1 for ApoE4-Ab mice. Using the Irr2TCM method, the K* values were determined to be 3.76 ± 0.73 µL mL^-1 min^-1 for ApoE3-Ab mice and 5.24 ± 0.62 µL mL^-1 min^-1 for ApoE4-Ab mice.

Conclusions: We established an imaging protocol to monitor the brain incorporation coefficient of 20-[¹⁸F]FAA in ApoE-amyloid beta double replacement mice using dynamic PET-MR. The successful development of 20-[¹⁸F]FAA dynamic PET-MR provides a new tool for investigating the dysregulation of inflammatory pathways in the brain, offering valuable insights into longitudinal studies of AD pathogenesis and treatment.

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