Reduced SV2A and GABA_Areceptor levels in the brains of type 2 diabetic rats revealed by [¹⁸F]SDM-8 and [¹⁸F]flumazenil PET

Abstract Purpose Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer’s disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2A (SV2A), γ;-aminobutyric acid type A (GABA A ) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. Methods Positron emission tomography (PET) using [ 18 F]SDM-8 (SV2A), [ 18 F]flumazenil (GABA A receptor), [ 18 F]florbetapir (amyloid-β), [ 18 F]PM-PBB3 (tau), and [ 18 F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and Sprague□Dawley (SD) rats. Proteomic profiling and pathway analysis of the hippocampus of ZDF and SD rats were performed. Results Reduced cortical [ 18 F]SDM-8 and cortical and hippocampal [ 18 F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. [ 18 F]florbetapir and [ 18 F]PM-PBB3 uptake were comparable in the brains of 12-month-old ZDF rats and SD rats. Conclusion The findings provide in vivo evidence for regional reductions in SV2A and GABA A receptor levels in the brains of aged T2DM ZDF rats.