Introduction: Neuroinflammation is associated with several neurological disorders, including Alzheimer's disease (AD). The translocator protein 18 kDa (TSPO), due to its overexpression during microglial activation and relatively low levels in the brain under normal neurophysiological conditions, is commonly used as an in vivo biomarker for neuroinflammation. Reported here is the preclinical evaluation of [F-18]F-DPA, a promising new TSPO-specific radioligand, as a tool for the detection of activated microglia at different ages in the APP/PS1-21 mouse model of AD and a blocking study to determine the specificity of the tracer.Methods: [F-18]F-DPA was synthesised by the previously reported electrophilic F-18-fluorination methodology. In vivo PET and ex vivo brain autoradiography were used to observe the tracer distribution in the brains of APP/PS1-21 and wildtype mice at different ages (4.5-24 months). The biodistribution and degree of metabolism of [F-18]F-DPA were analysed and the specificity of [F-18]F-DPA for its target was determined by pre-treatment with PK11195.Results: The in vivo PET imaging and ex vivo brain autoradiography data showed that [F-18]F-DPA uptake in the brains of the transgenic animals increased with age, however, there was a drop in the tracer uptake at 19 mo. Despite the slight increase in [F-18]F-DPA uptake with age in healthy animal brains, significant differences between wildtype and transgenic animals were seen in vivo at 9 months and ex vivo already at 4.5 months. The specificity study demonstrated that PK11195 can be used to significantly block [F-18]F-DPA uptake in all the brain regions studied.Conclusions: In vivo time activity curves plateaued at approximately 20-40 min suggesting that this is the optimal imaging time. Significant differences in vivo are seen at 9 and 12 mo. Due to the higher resolution, ex vivo autoradiography with [F-18]F-DPA can be used to visualise activated microglia at an early stage of AD pathology. (C) 2018 The Authors. Published by Elsevier Inc.