A tyrosine kinase inhibitor-based high-affinity PET radiopharmaceutical targets vascular endothelial growth factor receptor

Feng Li, Sheng Jiang, Youli Zu, Daniel Y. Lee, Zheng Li

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Tyrosine kinase receptors including vascular endothelial growth factor receptor (VEGFR) have gained significant attention as pharmacologic targets. However, clinical evaluation of small-molecule drugs or biologics that target these pathways has so far yielded mixed results in a variety of solid tumors. The reasons for response variability remain unknown, including the temporal and spatial patterns of receptor tyrosine kinase expression. Methods to detect and quantify the presence of such cellular receptors would greatly facilitate drug development and therapy response assessment. We aimed to generate specific imaging agents as potential companion diagnostics that could also be used for targeted radionuclide therapy. Here, we report on the synthesis and initial preclinical performance of 64Cu-labeled probes that were based on the kinase inhibitor already in clinical use, vandetanib (ZD6474), as a VEGFR-selective theranostic radiopharmaceutical. Methods: A monomeric (ZD-G1) and a dimeric (ZD-G2) derivative of ZD6474 were synthesized and conjugated with DOTA for chelation with 64Cu to produce the probes 64Cu-DOTAZD- G1 and 64Cu-DOTA-ZD-G2. The binding affinity and specificity to VEGFR were measured using U-87 MG cells known to overexpress VEGFR. Small-animal PET and biodistribution studies were performed with 64Cu-labeled probes (3-4 MBq) intravenously administered in U-87 MG tumor-bearing mice with or without coinjection of unlabeled ZD-G2 for up to 24 h after injection. Results: Receptor-binding assays yielded a mean equilibrium dissociation constant of 44.7 and 0.45 nM for monomeric and dimeric forms, respectively, indicating a synergistic effect in VEGFR affinity by multivalency. Small-animal PET/CT imaging showed rapid tumor accumulation of 64Cu-DOTA-ZD-G2, with excellent tumor-to-normal tissue contrast by 24 h. Coinjection of the 64Cu-DOTA-ZD-G2 with 50 nmol (60 μg) of nonradioactive ZD-G2 effectively blocked tumor uptake. Conclusion: A 64Cu-labeled probe derived from an approved oncologic drug selective for VEGFR demonstrates excellent tumor targeting, particularly for the dimeric form. The multivalent probe yielded a 100-fold improvement in receptor affinity while maintaining pharmacokinetic and biodistribution properties well suited for PET imaging in our preclinical model. These results indicate that a clinically relevant theranostic platform can be rapidly developed from known small molecules that target key cellular receptors. COPYRIGHT

Original languageEnglish (US)
Pages (from-to)1525-1531
Number of pages7
JournalJournal of Nuclear Medicine
Issue number9
StatePublished - Sep 1 2014


  • Cu
  • Theranostic
  • Tumor angiogenesis
  • Vascular endothelial growth factor receptor (VEGFR)


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