Update on F-Fluoroestradiol.

F-16α-Fluoroestradiol (F-FES) is a radiolabeled estrogen analogue positron emission tomography (PET) imaging agent that binds to the estrogen receptor (ER) in the nucleus of ER-expressing cells. Proof-of-concept studies of F-FES demonstrated expected correlation between tumoral F-FES-positivity on PET-imaging and ER+ status assessed on biopsy samples by radioligand binding and immunohistochemistry. After decades of study, F-FES PET/CT gained clinical approval in 2016 in France and 2020 in the United States for use in patients with ER+ metastatic or recurrent breast cancer. ER+ as assessed by F-FES PET/CT has been shown to serve as a biomarker, identifying metastatic breast cancer patients who may respond to endocrine therapy and those who are unlikely to respond. In 2023, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published Appropriate Use Criteria for F-FES PET/CT, identifying four indications in which use of F-FES PET/CT was "appropriate": (1) To assess functional ER status in metastatic lesions unfavorable to biopsy or when biopsy is nondiagnostic, (2) To detect ER status when other imaging tests are equivocal or suspicious, and at (3) initial diagnosis of metastatic disease or (4) progression of metastatic disease, for considering endocrine therapy. This article reviews the foundations of F-FES imaging, including normal distribution, false positives, and false negatives, and describes the most up-to-date clinical uses as well as emerging research in breast cancer and other patient populations.