Abstract Background [18F]BF4 −, the first 18F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [18F]BF4 − with higher SA. Methods A new radiosynthesis of [18F]BF4 − was developed, involving reaction of [18F]F− with boron trifluoride diethyl etherate under anhydrous conditions, guided by 11B and 19F NMR studies of equilibria involving BF4 − and BF3. The SA of the product was determined by ion chromatography. The IC50 of [19F]BF4 − as an inhibitor of [18F]BF4 − uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [19F]BF4 − dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting. Results An IC50 of 4.8 μΜ was found in vitro indicating a significant risk of in vivo NIS saturation at SA achieved by the isotopic exchange labelling method. In vivo thyroid and salivary gland uptake decreased significantly with [19F]BF4 − doses above ca. 10 μg/kg. The new radiosynthesis gave high radiochemical purity (>99 %) and moderate yield (15 %) and improved SA (>5 GBq/μmol) from a starting activity of only 1.5 GBq. Conclusions [18F]BF4 − produced at previously reported levels of SA (1 GBq/μmol) can lead to reduced uptake in NIS-expressing tissues in mice. This is much less likely in humans. The synthetic approach described provides an alternative for production of [18F]BF4 − at higher SA with sufficient yield and without need for unusually high starting activity of [18F]fluoride, removing the risk of NIS saturation in vivo even in mice. Trial registration ISRCTN75827286 .