J Nucl Med. 2008; 49 (Supplement 1):290P
Radiopharmaceutical Chemistry: New Chemistry-OncologyNew Chemistry-Oncology Posters |
[18F]Fluoroethylated VEGFR-2 tyrosine kinase inhibitors
Holger Kubas1,
Claudia Bauer1,
Dörte Oltmanns1,
Sabine Zitzmann-Kolbe2,
Walter Mier3,
Uwe Haberkorn3 and
Michael Eisenhut1
1 Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany;
2 PET Research, Bayer Schering Pharma AG, Berlin, Germany;
3 Nuclear Medicine, University Clinics, Heidelberg, Germany
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Objectives: The vascular endothelial growth factor receptor-2 (VEGFR-2) crucially mediates both physiological and pathological angiogenic signaling via strong tyrosine kinase activity. Because of its immense relevance in terms of tumor neovascularization this receptor emerged as promising target for cancer therapy as well as diagnostics. We here present potent anilino-quinazoline-based VEGFR-2 tyrosine kinase inhibitors with 2-fluoroethyl substructure as potential novel tumor imaging agents for positron-emission-tomography (PET).
Methods: Based on the template structure ZM323881 four differently substituted, non-radiolabeled anilino-quinazolines (Z-2, Z-4, CB-77 and HK-26) were synthesized in a multi-step procedure for pharmacological evaluation. The corresponding IC50 values for a series of recombinant tyrosine and other kinases were measured in a screening assay. Radiolabeled HK-26 was prepared by regioselective fluoroethylation of the hydroxy group in 7-position with [18F]2-fluoroethyl tosylate using a protection group technique.
Results: With compounds Z-2 and HK-26 highly active VEGFR-2 tyrosine kinase inhibitors were obtained showing IC50 values in low nanomolar range (2 nM and 1 nM, respectively). Furthermore a sufficient selectivity with respect to other kinases was observed. Radiolabeling by [18F]fluoroethylation of the appropriate precursor succeeded within three steps resulting in pure [18F]HK-26.
Conclusions: Radiofluorinated [18F]HK-26 as highly potent VEGFR-2 tyrosine kinase ligand offers promise for serving as an effective tool for tumor imaging. This is currently evaluated in further studies concerning biodistribution and clinical efficacy.
