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

• Main Authors: Marion Tisseraud (Author), Sébastien Goutal (Author), Thomas Bonasera (Author), Maud Goislard (Author), Delphine Desjardins (Author), Roger Le Grand (Author), Chris M. Parry (Author), Nicolas Tournier (Author), Bertrand Kuhnast (Author), Fabien Caillé (Author)
• Format: Book
• Published: MDPI AG, 2022-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15050587; 1424-8247
• Keywords: fluorine-18; radiolabeling; dolutegravir; PET imaging; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 5, p 587 (2022)

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% (<i>n</i> = 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 (<i>n</i> = 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.