Purpose <p>[¹⁸F]DPA-714 is a valuable tracer for studying (neuro)inflammation, with well-characterized tracer kinetics and an established imaging window. However, its clinical utility is restricted by the TSPO polymorphism (rs6971), which influences binding affinity in humans. The newly developed tracer [¹⁸F]DPA-814 overcomes this limitation and has shown promising results in a preclinical rat model. To further assess its clinical potential, we compared [¹⁸F]DPA-814 to [¹⁸F]DPA-714 for inflammation imaging in SARS-CoV-2-infected macaques in a longitudinal setting.</p> Procedures <p>Dynamic positron emission tomography (PET) imaging was conducted in four healthy macaques to identify the optimal imaging window for [¹⁸F]DPA-814. Four additional macaques were infected with SARS-CoV-2 and monitored for 12 months using whole-body PET-computed tomography (CT) with both tracers. Baseline scans were compared to PET-CTs obtained at 4, 9 and 16 days and at 6 and 12 months post-infection, covering the head, thorax and abdomen. Tracer uptake was assessed in several organs.</p> Results <p>At baseline, [¹⁸F]DPA-814 showed higher lung uptake with minimal washout compared to [¹⁸F]DPA-714. Although lung lesions developed after infection, [¹⁸F]DPA-814 did not demonstrate lesion-specific uptake, unlike [¹⁸F]DPA-714. In the brain, the tracers also displayed divergent uptake patterns despite comparable TSPO levels across animals and regions.</p> Conclusions <p>[¹⁸F]DPA-814 exhibits a distinct whole-body distribution, particularly in the lungs and brain, in both naïve and SARS-CoV-2-infected macaques compared with [¹⁸F]DPA-714, likely reflecting differences in tracer kinetics. Based on these data, [¹⁸F]DPA-814 may not fully replace [¹⁸F]DPA-714 for lung and brain imaging, and further studies are required to evaluate its suitability in other anatomical regions.</p>