Visualization of synaptic vesicle protein 2A in a rodent model of familial Alzheimer’s disease with a metabolically stable PET probe

AbstractBackgroundSynaptic loss is one of the hallmarks of Alzheimer’s disease (AD) and region‐specific changes in synaptic density is associated with a variety of neuropsychiatric diseases. Here, we investigated the expression levels of synaptic vesicle glycoprotein 2A (SV2A) in APP/PS1 and age‐matched wild‐type (WT) mice using [18F]SDM16, a novel, metabolically stable SV2A PET imaging probe.MethodsThe SV2A tracer [18F]SDM‐16 was synthesized according to previously published procedure [1]. PET scans with [18F]SDM‐16 were performed on a Focus‐220 scanner in APP/PS1 transgenic mice and WT controls. Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images from 0‐90 min post‐injection (p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model (SRTM), with brain stem as the reference region. Averaged SUV ratios (SUVRs) from 60‐90 min were calculated by using brain stem as reference region. Spatially normalized SUVR(BS) were assessed on a voxel‐by‐voxel basis in Matlab R2018 with Statistical Parametric Mapping.ResultsThe mouse brain PET images showed ubiquitous uptake of [18F]SDM‐16. Regional TACs showed high brain uptake in the selected brain regions of mice (SUV up to 2.38), with a steady increase after tracer injection, before plateauing at 60‐90 min p.i. (Fig. 1a). DVR results correlated well with SUVR(BS) from 60‐90 min (R2 = 0.94, p < 0.0001). Compared with age‐matched WT controls, the averaged SUVR(BS) in the whole brain and hippocampus of APP/PS1 mice showed statistically significant lower values by 5.4% (p = 0.01) and 11% (p = 0.001), respectively (Fig. 1b). These results are consistent with those from previous reports using [11C]UCB‐J (4.0% decrease in hippocampus) and [18F]SynVesT‐1 (7.5% decrease in hippocampus) [2, 3]. Voxel‐based parametric analysis also showed a global decrease in tracer uptake in the APP/PS1 mice, with the most significant decrease in the hippocampus, which is consistent with the results from ROI‐based analysis.ConclusionsWe demonstrated that the radioligand [18F]SDM‐16 had high uptake in mouse brain, and APP/PS1 mice showed lower tracer uptake than WT mice, supporting the use of [18F]SDM‐16 in preclinical AD drug discovery and development.