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

BACKGROUND: [(18)F]BF(4)(−), 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...

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Autores principales: Khoshnevisan, Alex, Jauregui-Osoro, Maite, Shaw, Karen, Torres, Julia Baguña, Young, Jennifer D., Ramakrishnan, Nisha K., Jackson, Alex, Smith, Gareth E., Gee, Antony D., Blower, Philip J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840125/
https://www.ncbi.nlm.nih.gov/pubmed/27103614
http://dx.doi.org/10.1186/s13550-016-0188-5
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author Khoshnevisan, Alex
Jauregui-Osoro, Maite
Shaw, Karen
Torres, Julia Baguña
Young, Jennifer D.
Ramakrishnan, Nisha K.
Jackson, Alex
Smith, Gareth E.
Gee, Antony D.
Blower, Philip J.
author_facet Khoshnevisan, Alex
Jauregui-Osoro, Maite
Shaw, Karen
Torres, Julia Baguña
Young, Jennifer D.
Ramakrishnan, Nisha K.
Jackson, Alex
Smith, Gareth E.
Gee, Antony D.
Blower, Philip J.
author_sort Khoshnevisan, Alex
collection PubMed
description BACKGROUND: [(18)F]BF(4)(−), 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]BF(4)(−) with higher SA. METHODS: A new radiosynthesis of [(18)F]BF(4)(−) 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 BF(4)(−) and BF(3). The SA of the product was determined by ion chromatography. The IC(50) of [(19)F]BF(4)(−) as an inhibitor of [(18)F]BF(4)(−) uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [(19)F]BF(4)(−) dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting. RESULTS: An IC(50) 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]BF(4)(−) 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]BF(4)(−) 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]BF(4)(−) 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. TRIAL REGISTRATION: ISRCTN75827286. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-016-0188-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-48401252016-05-16 [(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity Khoshnevisan, Alex Jauregui-Osoro, Maite Shaw, Karen Torres, Julia Baguña Young, Jennifer D. Ramakrishnan, Nisha K. Jackson, Alex Smith, Gareth E. Gee, Antony D. Blower, Philip J. EJNMMI Res Original Research BACKGROUND: [(18)F]BF(4)(−), 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]BF(4)(−) with higher SA. METHODS: A new radiosynthesis of [(18)F]BF(4)(−) 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 BF(4)(−) and BF(3). The SA of the product was determined by ion chromatography. The IC(50) of [(19)F]BF(4)(−) as an inhibitor of [(18)F]BF(4)(−) uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [(19)F]BF(4)(−) dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting. RESULTS: An IC(50) 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]BF(4)(−) 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]BF(4)(−) 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]BF(4)(−) 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. TRIAL REGISTRATION: ISRCTN75827286. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-016-0188-5) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-04-22 /pmc/articles/PMC4840125/ /pubmed/27103614 http://dx.doi.org/10.1186/s13550-016-0188-5 Text en © Khoshnevisan et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Khoshnevisan, Alex
Jauregui-Osoro, Maite
Shaw, Karen
Torres, Julia Baguña
Young, Jennifer D.
Ramakrishnan, Nisha K.
Jackson, Alex
Smith, Gareth E.
Gee, Antony D.
Blower, Philip J.
[(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity
title [(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity
title_full [(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity
title_fullStr [(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity
title_full_unstemmed [(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity
title_short [(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity
title_sort [(18)f]tetrafluoroborate as a pet tracer for the sodium/iodide symporter: the importance of specific activity
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840125/
https://www.ncbi.nlm.nih.gov/pubmed/27103614
http://dx.doi.org/10.1186/s13550-016-0188-5
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