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Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there rema...

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Autores principales: Cavaliere, Alessandra, Probst, Katrin C., Paisey, Stephen J., Marshall, Christopher, Dheere, Abdul K. H., Aigbirhio, Franklin, McGuigan, Christopher, Westwell, Andrew D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037993/
https://www.ncbi.nlm.nih.gov/pubmed/32041321
http://dx.doi.org/10.3390/molecules25030704
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author Cavaliere, Alessandra
Probst, Katrin C.
Paisey, Stephen J.
Marshall, Christopher
Dheere, Abdul K. H.
Aigbirhio, Franklin
McGuigan, Christopher
Westwell, Andrew D.
author_facet Cavaliere, Alessandra
Probst, Katrin C.
Paisey, Stephen J.
Marshall, Christopher
Dheere, Abdul K. H.
Aigbirhio, Franklin
McGuigan, Christopher
Westwell, Andrew D.
author_sort Cavaliere, Alessandra
collection PubMed
description Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [(18)F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [(18)F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[(18)F]FLT ProTide was obtained via a late stage [(18)F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[(18)F]FIAU ProTide was obtained via an early stage [(18)F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).
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spelling pubmed-70379932020-03-10 Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides) Cavaliere, Alessandra Probst, Katrin C. Paisey, Stephen J. Marshall, Christopher Dheere, Abdul K. H. Aigbirhio, Franklin McGuigan, Christopher Westwell, Andrew D. Molecules Article Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [(18)F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [(18)F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[(18)F]FLT ProTide was obtained via a late stage [(18)F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[(18)F]FIAU ProTide was obtained via an early stage [(18)F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min). MDPI 2020-02-06 /pmc/articles/PMC7037993/ /pubmed/32041321 http://dx.doi.org/10.3390/molecules25030704 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cavaliere, Alessandra
Probst, Katrin C.
Paisey, Stephen J.
Marshall, Christopher
Dheere, Abdul K. H.
Aigbirhio, Franklin
McGuigan, Christopher
Westwell, Andrew D.
Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)
title Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)
title_full Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)
title_fullStr Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)
title_full_unstemmed Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)
title_short Radiosynthesis of [(18)F]-Labelled Pro-Nucleotides (ProTides)
title_sort radiosynthesis of [(18)f]-labelled pro-nucleotides (protides)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037993/
https://www.ncbi.nlm.nih.gov/pubmed/32041321
http://dx.doi.org/10.3390/molecules25030704
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