[^sup 18^F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity

Abstract

Background

[^sup 18^F]BF^sub 4^ ^sup -^, the first ^sup 18^F-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/[mu]mol) 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 [^sup 18^F]BF^sub 4^ ^sup -^ with higher SA.

Methods

A new radiosynthesis of [^sup 18^F]BF^sub 4^ ^sup -^ was developed, involving reaction of [^sup 18^F]F^sup -^ with boron trifluoride diethyl etherate under anhydrous conditions, guided by ^sup 11^B and ^sup 19^F NMR studies of equilibria involving BF^sub 4^ ^sup -^ and BF^sub 3^. The SA of the product was determined by ion chromatography. The IC^sub 50^ of [^sup 19^F]BF^sub 4^ ^sup -^ as an inhibitor of [^sup 18^F]BF^sub 4^ ^sup -^ uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [^sup 19^F]BF^sub 4^ ^sup -^ dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting.

Results

An IC^sub 50^ of 4.8 [mu][Mu] 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 [^sup 19^F]BF^sub 4^ ^sup -^ doses above ca. 10 [mu]g/kg. The new radiosynthesis gave high radiochemical purity (>99 %) and moderate yield (15 %) and improved SA (>5 GBq/[mu]mol) from a starting activity of only 1.5 GBq.

Conclusions

[^sup 18^F]BF^sub 4^ ^sup -^ produced at previously reported levels of SA (1 GBq/[mu]mol) 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 [^sup 18^F]BF^sub 4^ ^sup -^ at higher SA with sufficient yield and without need for unusually high starting activity of [^sup 18^F]fluoride, removing the risk of NIS saturation in vivo even in mice.

Trial registration

ISRCTN75827286.