Isotopic Radiolabeling of the Antiretroviral Drug [18F]Dolutegravir for Pharmacokinetic PET Imaging

Pharmaceuticals

Thomas Bonasera¹  Roger Le Grand²  Delphine Desjardins²  Maud Goislard³  Bertrand Kuhnast³  Fabien Caillé³  Sébastien Goutal³  Nicolas Tournier³  Marion Tisseraud³  Chris M. Parry⁴ 

[1] GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK;Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Viral Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses, 92032 Paris, France;Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay (BioMaps), 91401 Orsay, France;ViiV Healthcare, 980 Great West Road, London TW8 9GS, UK;

关键词: fluorine-18;    radiolabeling;    dolutegravir;    PET imaging;   

DOI  :  10.3390/ph15050587

来源: DOAJ

【 摘 要 】

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. [¹⁸F]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 [¹⁸F]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 [¹⁸F]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 [¹⁸F]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 [¹⁸F]DTG PET imaging and paved the way to explore drug/virus/tissues interactions in animals and humans.

【 授权许可】

Unknown