Abstract Purpose In this study we compared the recently developed TSPO tracer [¹⁸F]F-DPA, with [¹⁸F]DPA-714 and [¹¹C]PBR28 by performing in vivo PET imaging on the same Alzheimer’s disease mouse model APP/PS1-21 (TG) and wild-type (WT) mice with all three radiotracers. Procedures To compare the radiotracer uptake, percentage of injected dose/mL (%ID/mL), standardized uptake value ratios to cerebellum (SUVR_CB), and voxel-wise analyses were performed. Results The peak uptake of [¹⁸F]F-DPA was higher than 4.3% ID/mL, while [¹⁸F]DPA-714 reached just over 3% ID/mL, and [¹¹C]PBR28 was over 4% ID/mL in only one brain region in the WT mice. The peak/60-min uptake ratios of [¹⁸F]F-DPA were significantly higher (p < 0.001) than those of [¹⁸F]DPA-714 and [¹¹C]PBR28. The differences in [¹⁸F]F-DPA SUVR_CB between WT and TG mice were highly significant (p < 0.001) in the three studied time periods after injection. [¹⁸F]DPA-714 uptake was significantly higher in TG mice starting in the 20–40-min timeframe and increased thereafter, whereas [¹¹C]PBR28 uptake became significant at 10–20 min (p < 0.05). The voxel-wise analysis confirmed the differences between the radiotracers. Conclusions [¹⁸F]F-DPA displays higher brain uptake, higher TG-to-WT SUVR_CB ratios, and faster clearance than [¹⁸F]DPA-714 and [¹¹C]PBR28, and could prove useful for detecting low levels of inflammation and allow for shorter dynamic PET scans.