[(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity.
BACKGROUND
[(18)F]BF4 (-), the first (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/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 [(18)F]BF4 (-) with higher SA.


METHODS
A new radiosynthesis of [(18)F]BF4 (-) was developed, involving reaction of [(18)F]F(-) with boron trifluoride diethyl etherate under anhydrous conditions, guided by (11)B and (19)F NMR studies of equilibria involving BF4 (-) and BF3. The SA of the product was determined by ion chromatography. The IC50 of [(19)F]BF4 (-) as an inhibitor of [(18)F]BF4 (-) uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [(19)F]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 [(19)F]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
[(18)F]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 [(18)F]BF4 (-) at higher SA with sufficient yield and without need for unusually high starting activity of [(18)F]fluoride, removing the risk of NIS saturation in vivo even in mice.


BACKGROUND
ISRCTN75827286 .
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Alex
A
Khoshnevisan
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Maite
M
Jauregui-Osoro
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Karen
K
Shaw
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Julia Baguña
JB
Torres
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Jennifer D
JD
Young
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Nisha K
NK
Ramakrishnan
The Grove Centre, GE Healthcare, White Lion Road, Amersham, UK.
Alex
A
Jackson
The Grove Centre, GE Healthcare, White Lion Road, Amersham, UK.
Gareth E
GE
Smith
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK.
Antony D
AD
Gee
Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, London, SE1 7EH, UK. philip.blower@kcl.ac.uk.
Philip J
PJ
Blower
Fluorine-18; PET; Sodium/iodide symporter; Specific activity; Tetrafluoroborate; Thyroid