The serotonergic system has shown to be altered during epileptogenesis and in chronic epilepsy, making selective serotonin reuptake inhibitors interesting candidates for antiepileptogenic therapy. In this study, we aimed to evaluate disease-modifying effects of fluoxetine during experimental epileptogenesis. Status epilepticus (SE) was induced by lithium-pilocarpine, and female rats were treated either with vehicle or fluoxetine over 15 days. Animals were subjected to 18F-FDG (7 days post-SE), 18F-GE180 (15 days post-SE) and 18F-flumazenil positron emission tomography (PET, 21 days post-SE). Uptake (18F-FDG), volume of distribution (18F-GE180) and binding potential (18F-flumazenil) were calculated. In addition, hyperexcitability testing and video-EEG monitoring were performed. Fluoxetine treatment did not alter brain glucose metabolism. 18F-GE180 PET indicated lower neuroinflammation in the hippocampus of treated animals (-22.6%, p = 0.042), but no differences were found in GABAA receptor density. Video-EEG monitoring did not reveal a treatment effect on seizure frequency. However, independently of the treatment, hippocampal FDG uptake 7 days after SE correlated with seizure frequency during the chronic phase (r = -0.58; p = 0.015). Fluoxetine treatment exerted anti-inflammatory effects in rats during epileptogenesis. However, this effect did not alter disease outcome. Importantly, FDG-PET in early epileptogenesis showed biomarker potential as higher glucose metabolism correlated to lower seizure frequency in the chronic phase.