Isotopic Radiolabeling of the Antiretroviral Drug [ 18 F]Dolutegravir for Pharmacokinetic PET Imaging.
Marion TisseraudSébastien GoutalThomas BonaseraMaud GoislardDelphine DesjardinsRoger Le GrandChris M ParryNicolas TournierBertrand KuhnastFabien CailléPublished in: Pharmaceuticals (Basel, Switzerland) (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. [ 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.
Keyphrases
- pet imaging
- positron emission tomography
- antiretroviral therapy
- hiv infected
- hiv positive
- human immunodeficiency virus
- hiv infected patients
- hiv aids
- computed tomography
- quality control
- ms ms
- men who have sex with men
- simultaneous determination
- hiv testing
- hepatitis c virus
- pet ct
- south africa
- high performance liquid chromatography
- room temperature
- drug delivery
- emergency department
- stem cells
- mass spectrometry
- solid phase extraction
- liquid chromatography
- single cell
- ionic liquid
- rheumatoid arthritis
- gene expression
- high resolution
- bone marrow
- ulcerative colitis
- systemic lupus erythematosus
- oxide nanoparticles