Isotopic Radiolabeling of Crizotinib with Fluorine-18 for In Vivo Pet Imaging

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 12; p. 1568
• Main Authors: Sardana, Malvika, Breuil, Louise, Goutal, Sébastien, Goislard, Maud, Kondrashov, Mikhail, Marchal, Etienne, Besson, Florent L., Dugave, Christophe, Wrigley, Gail, Jonson, Anna C., Kuhnast, Bertrand, Schou, Magnus, Tournier, Nicolas, Elmore, Charles S., Caillé, Fabien
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2022; MDPI
• Subjects: Cancer; Chemical properties; Chromatography; Crizotinib; Diagnosis; Drug dosages; Drug therapy; Fluorine; fluorine-18; Iodine; Kinases; Lung cancer, Non-small cell; Medical prognosis; Metastasis; PET imaging; radiolabeling; Structure; United Kingdom; crizotinib; fluorine-18; radiolabeling; PET imaging
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15121568

Crizotinib is a tyrosine kinase inhibitor approved for the treatment of non-small-cell lung cancer, but it is inefficient on brain metastases. Crizotinib is a substrate of the P-glycoprotein, and non-invasive nuclear imaging can be used to assess the brain penetration of crizotinib. Positron emission tomography (PET) imaging using fluorine-18-labeled crizotinib would be a powerful tool for investigating new strategies to enhance the brain distribution of crizotinib. We have synthesized a spirocyclic hypervalent iodine precursor for the isotopic labeling of crizotinib in a 2.4% yield. Because crizotinib is an enantiomerically pure drug, a chiral separation was performed to afford the (R)-precursor. A two-step radiolabeling process was optimized and automated using the racemic precursor to afford [18F](R,S)-crizotinib in 15 ± 2 radiochemical yield and 103 ± 18 GBq/µmol molar activity. The same radiolabeling process was applied to the (R)-precursor to afford [18F](R)-crizotinib with comparable results. As a proof-of-concept, PET was realized in a single non-human primate to demonstrate the feasibility of [18F](R)-crizotinib in in vivo imaging. Whole-body PET highlighted the elimination routes of crizotinib with negligible penetration in the brain (SUVmean = 0.1). This proof-of-concept paves the way for further studies using [18F](R)-crizotinib to enhance its brain penetration depending on the P-glycoprotein function.