16α-[18F]-fluoroestradiol ([18F]FES), a steroid-based positron emission tomography (PET) tracer, has emerged as a dependable tracer for the evaluation and management of estrogen receptor-positive (ER+) breast cancer patients. We have developed a fully automatic, one-pot procedure for the synthesis of [18F]FES using the Eckert & Ziegler (E & Z) radiomodular system. After [18F]fluorination, the intermediate was hydrolyzed with 2.0？M HCl twice and neutralized with sodium bicarbonate. After high-performance liquid chromatography (HPLC) purification, the decay-corrected radiochemical yield and purity of [18F]FES were 40 ± 5.0% ( ) and >97%, respectively. The product was stable up to 10？h. Total synthesis time including HPLC purification was 80？min. This new, fully automated rapid synthetic procedure provided high and reproducible yields of [18F]FES. Quality control (QC) tests showed that the [18F]FES produced by this method met all specifications for human injection. 1. Introduction Fluoroestradiol (FES) has high binding affinity for estrogen receptors and has high tissue permeability including the blood-brain barrier [1, 2]. In clinical setting, using [18F]FES as radiopharmaceutical, clear PET images of primary and metastatic breast tumors can be obtained. Prior studies have suggested that [18F]FES can be used as a valuable PET tracer to determine the tissue levels of ER in patients with breast cancer and may emerge as a valuable tool to predict which patients with primary, recurrent, or metastatic breast cancer will respond to hormone therapy [3, 4]. In order to validate this potential use of [18F]FES, a multicenter clinical trial will eventually be essential, and [18F]FES will need to be manufactured at the individual sites. However, routine production of clinical-grade [18F]FES presents many challenging laboratory requirements. Yield and product quality may vary from one site to other. In-vivo target interaction studies of experimental drug in human by PET (using a surrogate tracer) can reduce the substantial uncertainty in early-phase drug development [5]. In our newly established United States Pharmacopeia (USP) laboratory at the Frederick National Laboratory for Cancer Research, we are developing clinical-grade [18F]FES as a surrogate biomarker to support the endoxifen clinical trial (Phase I) in breast cancer patients [6, 7]. Endoxifen is an ER-targeting experimental drug related to another U.S Food and Drug Administration-(FDA-) approved ER+ cancer drug named tamoxifen and is under evaluation for the treatment of ER+ cancers. PET scans using
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