3 years ago

One-step synthesis of [18F]cabozantinib for use in positron emission tomography imaging of c-Met

One-step synthesis of [18F]cabozantinib for use in positron emission tomography imaging of c-Met
Dag Erlend Olberg, Jo Klaveness, Vegard Torp Lien
Cabozantinib is an FDA-approved kinase inhibitor for the treatment of medullary thyroid cancer and advanced renal cell carcinoma, which exerts its therapeutic effect by inhibiting, among others, the tyrosine kinase c-Met. Noninvasive imaging techniques are becoming increasingly important clinically to ensure drug efficacy, staging, monitoring, and patient stratification. PET isotope labelled tyrosine kinase inhibitors have, for the same reason, potential as PET tracers for imaging of various cancers. On the basis of cabozantinib, we synthesized the novel boronic acid pinacol ester 4 as a labelling precursor, where the boronic ester moiety replaces the fluorine native to this kinase inhibitor. By this, we wanted to explore whether recently developed Cu-mediated fluorination methods are adaptable to more complex substrates and thereby provide easy access to [18F]cabozantinib directly. Hydrolysis was implemented before preparative purification due to challenges with on-column hydrolysis of the precursor 4, and [18F]cabozantinib was obtained in ≥99% radiochemical purity and in 2.8 ± 0.05% (n = 4) isolated decay corrected yield in a synthesis time of 90 minutes. The molar activity of representative batches was determined to be 17 ± 8 GBq/μmol. [18F]cabozantinib was synthesized via a Cu-mediated reaction from a boronic acid pinacol ester precursor in 2.8 ± 0.05% yield and ≥99% radiochemical purity. The aim of the study was to achieve the synthesis of [18F]cabozantinib and at the same time evaluate if this methodology is applicable to more complex substrates. Nonradioactive impurities due to hydrolysis of the precursor 4 prompted us to explore a precolumn hydrolysis strategy which improved the chemical purity of the final product.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/jlcr.3564

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