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Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers
Kristin Ebert1, Jens Wiemer1, Julio Caballero2
1Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany.
Abstract:
Due to their essential role in the pathogenesis of cancer, members of the Eph (erythropoietin-producing hepatoma cell line-A2) receptor tyrosine kinase family represent promising candidates for molecular imaging. Thus, the development and preparation of novel radiotracers for the noninvasive imaging of the EphB4 receptor via positron emission tomography (PET) is described. First in silico investigations with the indazolylpyrimidine lead compound which is known to be highly affine to EphB4 were executed to identify favorable labeling positions for an introduction of fluorine-18 to retain the affinity. Based on this, reference compounds as well as precursors were developed and labeled with carbon-11 and fluorine-18, respectively. For this purpose, a protecting group strategy essentially had to be generated to prevent unwanted methylation and to enable the introduction of fluorine-18. Further, a convenient radiolabeling strategy using [(11)C]methyl iodide was established which afforded the isotopically labeled radiotracer in 30-35% RCY (d.c.) which is identical with the original inhibitor molecule. A spiro ammonium precursor was prepared for radiolabeling with fluorine-18. Unfortunately, the labeling did not lead to the desired (18)F-radiotracer under the chosen conditions.
Insights
Researchers developed novel radiotracers for imaging the EphB4 receptor, crucial in cancer. Carbon-11 labeled tracers were successfully synthesized, but fluorine-18 labeling of EphB4 receptors faced challenges.
Area of Science:
- Molecular Imaging
- Radiochemistry
- Oncology
Background:
- Eph receptor tyrosine kinases, including EphB4, play a key role in cancer development.
- Targeting EphB4 is a promising strategy for cancer molecular imaging.
- Noninvasive imaging of EphB4 could aid in cancer diagnosis and treatment monitoring.
Purpose of the Study:
- To develop and prepare novel radiotracers for noninvasive positron emission tomography (PET) imaging of the EphB4 receptor.
- To identify optimal labeling positions for introducing fluorine-18 into EphB4-targeting compounds while maintaining high affinity.
- To establish efficient radiolabeling strategies for both carbon-11 and fluorine-18 isotopes.
Main Methods:
- In silico investigations of an indazolylpyrimidine lead compound for EphB4 affinity.
- Synthesis of reference compounds and precursors for radiolabeling.
- Development of a protecting group strategy for radiolabeling.
- Radiolabeling with carbon-11 using [(11)C]methyl iodide.
- Preparation of a spiro ammonium precursor for fluorine-18 labeling.
Main Results:
- In silico studies guided the selection of labeling positions for fluorine-18 introduction.
- A successful radiolabeling strategy using [(11)C]methyl iodide yielded the desired radiotracer with 30-35% radiochemical yield (decay-corrected).
- Radiolabeling attempts with a spiro ammonium precursor for fluorine-18 did not yield the target radiotracer under the tested conditions.
Conclusions:
- Novel carbon-11 labeled radiotracers targeting EphB4 were successfully synthesized for PET imaging.
- Further optimization is required for the development of fluorine-18 labeled EphB4 radiotracers.
- The developed radiotracers hold potential for advancing molecular imaging in EphB4-related cancers.
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