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Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging
Deciphering the drug/virus/host interactions at infected cell reservoirs is a key leading to HIV-1 remission for which positron emission tomography (PET) imaging using radiolabeled antiretroviral (ARV) drugs is a powerful asset. Dolutegravir (DTG) is one of the preferred therapeutic options to treat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143889/ https://www.ncbi.nlm.nih.gov/pubmed/35631413 http://dx.doi.org/10.3390/ph15050587 |
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author | Tisseraud, Marion Goutal, Sébastien Bonasera, Thomas Goislard, Maud Desjardins, Delphine Le Grand, Roger Parry, Chris M. Tournier, Nicolas Kuhnast, Bertrand Caillé, Fabien |
author_facet | Tisseraud, Marion Goutal, Sébastien Bonasera, Thomas Goislard, Maud Desjardins, Delphine Le Grand, Roger Parry, Chris M. Tournier, Nicolas Kuhnast, Bertrand Caillé, Fabien |
author_sort | Tisseraud, Marion |
collection | PubMed |
description | Deciphering the drug/virus/host interactions at infected cell reservoirs is a key leading to HIV-1 remission for which positron emission tomography (PET) imaging using radiolabeled antiretroviral (ARV) drugs is a powerful asset. Dolutegravir (DTG) is one of the preferred therapeutic options to treat HIV and can be isotopically labeled with fluorine-18. [(18)F]DTG was synthesized via a three-step approach of radiofluorination/nitrile reduction/peptide coupling with optimization for each step. Radiofluorination was performed on 2-fluoro-4-nitrobenzonitrile in 90% conversion followed by nitrile reduction using sodium borohydride and aqueous nickel(II) chloride with 72% conversion. Final peptide coupling reaction followed by HPLC purification and formulation afforded ready-to-inject [(18)F]DTG in 5.1 ± 0.8% (n = 10) decay-corrected radiochemical yield within 95 min. The whole process was automatized using a TRACERlab(®) FX NPro module, and quality control performed by analytical HPLC showed that [(18)F]DTG was suitable for in vivo injection with >99% chemical and radiochemical purity and a molar activity of 83 ± 18 GBq/µmol (n = 10). Whole-body distribution of [(18)F]DTG was performed by PET imaging on a healthy macaque and highlighted the elimination routes of the tracer. This study demonstrated the feasibility of in vivo [(18)F]DTG PET imaging and paved the way to explore drug/virus/tissues interactions in animals and humans. |
format | Online Article Text |
id | pubmed-9143889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91438892022-05-29 Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging Tisseraud, Marion Goutal, Sébastien Bonasera, Thomas Goislard, Maud Desjardins, Delphine Le Grand, Roger Parry, Chris M. Tournier, Nicolas Kuhnast, Bertrand Caillé, Fabien Pharmaceuticals (Basel) Article Deciphering the drug/virus/host interactions at infected cell reservoirs is a key leading to HIV-1 remission for which positron emission tomography (PET) imaging using radiolabeled antiretroviral (ARV) drugs is a powerful asset. Dolutegravir (DTG) is one of the preferred therapeutic options to treat HIV and can be isotopically labeled with fluorine-18. [(18)F]DTG was synthesized via a three-step approach of radiofluorination/nitrile reduction/peptide coupling with optimization for each step. Radiofluorination was performed on 2-fluoro-4-nitrobenzonitrile in 90% conversion followed by nitrile reduction using sodium borohydride and aqueous nickel(II) chloride with 72% conversion. Final peptide coupling reaction followed by HPLC purification and formulation afforded ready-to-inject [(18)F]DTG in 5.1 ± 0.8% (n = 10) decay-corrected radiochemical yield within 95 min. The whole process was automatized using a TRACERlab(®) FX NPro module, and quality control performed by analytical HPLC showed that [(18)F]DTG was suitable for in vivo injection with >99% chemical and radiochemical purity and a molar activity of 83 ± 18 GBq/µmol (n = 10). Whole-body distribution of [(18)F]DTG was performed by PET imaging on a healthy macaque and highlighted the elimination routes of the tracer. This study demonstrated the feasibility of in vivo [(18)F]DTG PET imaging and paved the way to explore drug/virus/tissues interactions in animals and humans. MDPI 2022-05-10 /pmc/articles/PMC9143889/ /pubmed/35631413 http://dx.doi.org/10.3390/ph15050587 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tisseraud, Marion Goutal, Sébastien Bonasera, Thomas Goislard, Maud Desjardins, Delphine Le Grand, Roger Parry, Chris M. Tournier, Nicolas Kuhnast, Bertrand Caillé, Fabien Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging |
title | Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging |
title_full | Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging |
title_fullStr | Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging |
title_full_unstemmed | Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging |
title_short | Isotopic Radiolabeling of the Antiretroviral Drug [(18)F]Dolutegravir for Pharmacokinetic PET Imaging |
title_sort | isotopic radiolabeling of the antiretroviral drug [(18)f]dolutegravir for pharmacokinetic pet imaging |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143889/ https://www.ncbi.nlm.nih.gov/pubmed/35631413 http://dx.doi.org/10.3390/ph15050587 |
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