Introduction:18F-GE180 is a third-generation positron emission tomography (PET) tracer to quantify the translocator protein TSPO, a biomarker for inflammation. The aim of this study was to compare head-to-head 18F-GE180 to the well-established translocator protein (TSPO) tracer 11C-PBR28, by scanning with either tracer during the same day in the same subjects. Materials and Methods: Five subjects underwent a 90-minute PET scan with 11C-PBR28 in the morning and 18F-GE180 in the afternoon. A metabolite-corrected arterial input function was obtained in each subject for both tracers, and the brain uptake was quantified with a two-tissue compartmental model. Results: The rate of metabolism of 18F-GE180 in arterial blood was slower than that of 11C-PBR28 (the percentages of unmetabolized parent in plasma at 90 minutes were 74.9 ± 4.15% and 11.2 ± 1.90%, respectively). The plasma free fraction was similar for both tracers: 3.5% ± 1.1 for 18F-GE180 and 4.1% ± 1.1 for 11C-PBR28. The average total volume of distribution (VT) of 18F-GE180 was about 20 times smaller than that of 11C-PBR28 (0.15 ± 0.03 mL/cm3 for 18F-GE180 and 3.27 ± 0.66 mL/cm3 for 11C-PBR28). 18F-GE180 was characterized by a poor transfer from the vascular compartment to the brain (K1 was about ten times smaller than that of 11C-PBR28). Moreover, kinetic modeling was more difficult with 18F-GE180, as its VT values were identified with a lower precision than those of 11C-PBR28 and outlying values were more frequent. Conclusion: The VT of 18F-GE180 is about 20 times smaller than that of 11C-PBR28, due to a low penetration in the brain from the vascular compartment. In addition, kinetic modeling of 18F-GE180 is more challenging than with 11C-PBR28. Therefore, compared to 11C-PBR28, 18F-GE180 has unfavorable characteristics for TSPO imaging of the brain.