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Radiohalogenated 4-anilinoquinazoline-based EGFR-TK inhibitors as potential cancer imaging agents
Carina Neto1, Célia Fernandes, Maria Cristina Oliveira
1Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
Introduction:
The overexpression of epidermal growth factor receptor (EGFR) in tumors underlines the recent interest in EGFR as attractive target for the development of new cancer imaging agents. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) based on the anilinoquinazoline scaffold have been explored as potential probes for EGFR imaging. However, up to now, no optimal radiotracer is available. Herein, we report the synthesis and biological evaluation of three novel halogenated 6-substituted 4-anilinoquinazoline based EGFR-TKIs. Radiosynthesis ((125)I and (18)F) of the corresponding analogues was also performed.
Methods:
6a, 6b and 8 were obtained by reaction of 6-amino-4-anilinoquinazoline (5) with 3-/4-iodobenzoyl and 4-fluorobenzoyl chlorides. Inhibition of EGFR autophosphorylation and A431 cellular proliferation were assessed by Western blot and MTT assays. (125)I-anilinoquinazolines [(125)I]6a/b were prepared via destannylation of the corresponding tributylstannyl precursors with [(125)I]NaI. Cellular uptake studies were conducted in A431 cells. Optimization of the radiosynthesis of the (18)F-anilinoquinazoline [(18)F]8 was attempted by nucleophilic substitution of the trimethylammonium- and nitro-6-substituted 4-anilinoquinazoline precursors.
Results:
6a, 6b and 8 were synthesized in high chemical yield. All of them are inhibitors of EGFR autophosphorylation (0.1
Conclusions:
This study suggests that these quinazoline derivatives can act as EGFR-TKI, warranting further modifications in the chemical structure in order to be explored as potential molecular imaging agents for single photon emission computerized tomography and positron emission tomography.
Insights
Researchers developed novel anilinoquinazoline EGFR-TKIs for cancer imaging. While radiolabeled compounds showed high uptake in cancer cells, further structural modifications are needed for optimal imaging agent development.
Area of Science:
- Medicinal Chemistry
- Radiochemistry
- Molecular Imaging
Background:
- Epidermal growth factor receptor (EGFR) overexpression in tumors presents a target for cancer imaging.
- EGFR-tyrosine kinase inhibitors (EGFR-TKIs) based on anilinoquinazoline scaffolds are explored for EGFR imaging.
- A need exists for optimal radiotracers for EGFR-targeted imaging.
Purpose of the Study:
- Synthesize and biologically evaluate novel halogenated 6-substituted 4-anilinoquinazoline EGFR-TKIs.
- Perform radiosynthesis of iodinated and fluorinated analogues for potential imaging applications.
- Assess the potential of these compounds as molecular imaging agents for EGFR-positive tumors.
Main Methods:
- Synthesis of three novel 6-substituted 4-anilinoquinazoline derivatives (6a, 6b, 8).
- Evaluation of EGFR autophosphorylation inhibition and A431 cellular proliferation inhibition.
- Radiosynthesis of [(125)I]6a/b and optimization attempts for [(18)F]8.
- In vitro cellular uptake studies in A431 cells and in vivo biodistribution in mice.
Main Results:
- Compounds 6a, 6b, and 8 were synthesized in high yield and demonstrated EGFR inhibition.
- [(125)I]6a/b showed high radiochemical purity, specific activity, and significant uptake in A431 cells.
- Biodistribution studies revealed rapid blood clearance and hepatobiliary excretion for [(125)I]6a/b.
- Radiosynthesis of [(18)F]8 yielded only 4% in the optimization attempts, limiting further evaluation.
Conclusions:
- The synthesized quinazoline derivatives function as EGFR-TKIs.
- These compounds show promise for further structural modification to develop molecular imaging agents.
- Potential applications include single photon emission computerized tomography (SPECT) and positron emission tomography (PET) imaging.
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