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

Vegard Torp Lien, Jo Klaveness, Dag Erlend Olberg

J Labelled Comp Radiopharm. 2018 Jan;61(1):11-17.

PMID: 28921623

Abstract:

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 [18 F]cabozantinib directly. Hydrolysis was implemented before preparative purification due to challenges with on-column hydrolysis of the precursor 4, and [18 F]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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS793389	(4-methoxycarbonylmethylphenyl)boronic acid pinacol ester			Price
LS793476	1-cyclohepten-1yl boronic acid pinacol ester			Price