[¹⁸F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (A_m’s). In certain cases, low A_m can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [¹⁸F]F-DPA resulting in high A_m (990 ± 150 GBq/µmol) and performed in vivo comparison with low A_m (9.0 ± 2.9 GBq/µmol) [¹⁸F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing A_m on specific binding. The differing injected masses affect the washout profile and shape of the time–activity curves. Ratios of standardized uptake values obtained with high and low A_m [¹⁸F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high A_m [¹⁸F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high A_m was used.