[18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) PET imaging repurposed for quantitative estimation of blood-brain barrier permeability in a rat model of Alzheimer's disease

Abstract

Numerous studies suggest that blood-brain barrier (BBB) dysfunction may contribute to the progression of Alzheimer's disease (AD). Clinically available neuroimaging methods are needed for quantitative "scoring" of BBB permeability in AD patients. [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS), which can be easily obtained from simple chemical reduction of commercial [18F]2-fluoro-2-deoxy-glucose ([18F]FDG), was investigated as a small-molecule marker of BBB permeability, in a pre-clinical model of AD using in vivo PET imaging. Chemical reduction of [18F]FDG to [18F]FDS was obtained with a 100% conversion yield. Dynamic PET acquisitions were performed in the APP/PS1 rat model of AD (TgF344-AD, n=3) compared with age-matched littermates (WT, n=4). The brain uptake of [18F]FDS was determined in selected brain regions, delineated from a coregistered rat brain template. The brain uptake of [18F]FDS in the brain regions of AD rats versus WT rats was compared using a 2-way ANOVA. The uptake of [18F]FDS was significantly higher in the whole brain of AD rats, as compared with WT rats (P<0.001), suggesting increased BBB permeability. Enhanced brain uptake of [18F]FDS in AD rats was significantly different across brain regions (P<0.001). Minimum difference was observed in the amygdala (+89.0±7.6%, P<0.001) and maximum difference was observed in the midbrain (+177.8±29.2%, P<0.001). [18F]FDS, initially proposed as radio-pharmaceutical to estimate renal filtration using PET imaging, can be repurposed for non-invasive and quantitative determination of BBB permeability in vivo. Making the best with the quantitative properties of PET imaging, it was possible to estimate the extent of enhanced BBB permeability in a rat model of AD.