Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tisseraud, Marion, Goutal, Sébastien, Bonasera, Thomas, Goislard, Maud, Desjardins, Delphine, Le Grand, Roger, Parry, Chris M., Tournier, Nicolas, Kuhnast, Bertrand, Caillé, Fabien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784715916454395904
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
work_keys_str_mv AT tisseraudmarion isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT goutalsebastien isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT bonaserathomas isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT goislardmaud isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT desjardinsdelphine isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT legrandroger isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT parrychrism isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT tourniernicolas isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT kuhnastbertrand isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging
AT caillefabien isotopicradiolabelingoftheantiretroviraldrug18fdolutegravirforpharmacokineticpetimaging