Positron emission tomography (PET) has great benefits for developing therapeutics and quantifying pathological markers in neuropsychiatric disorders. This study aimed to firstly demonstrate the feasibility of PET imaging for glucagon-like peptide-1 receptor (GLP-1R) in Alzheimer’s disease (AD) and evaluate the GLP-1R expression. Besides, microglial activation, dopamine D2 receptor (D2R) expression, and glucose metabolism in the brain of APP/PS1/tau transgenic model of AD (3×Tg-AD) were also investigated by PET. [F]FBEM-Cys-exendin-4, [F]DPA-714, [F]fallypride, and [F]FDG were prepared and PET imaging acquisitions for 3×Tg-AD mice and wild-type (WT) mice were performed at 15, 30, and 60 min post-injection. Fifteen regions of interest (ROIs) were selected and %ID/g was calculated. The results showed that the uptake of [F]FBEM-Cys-exendin-4 in 10 ROIs of 3×Tg-AD mice at 60 min post-injection was significantly lower than that of WT mice (p < 0.05). Besides, 3×Tg-AD mice showed significantly higher [F]DPA-714 uptake in 7 ROIs and lower [F]fallypride uptake in 4 ROIs compared to WT mice. [F]FDG PET showed no significant differences in any ROIs between the two groups. A positive correlation between the uptake of [F]fallypride and [F]FBEM-Cys-exendin-4 could be found in the whole brain. In summary, these results validated the feasibility of GLP-1R PET in AD and demonstrated the reduced GLP-1R and D2R expression as well as increased microglial activation caused by AD.Copyright © 2020. Published by Elsevier B.V.