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Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase
T A Bonasera1, G Ortu, Y Rozen
1Hebrew University, Hadassah University Hospital Campus, Department of Medical Biophysics and Nuclear Medicine, IL-91120, Jerusalem, Israel.
Abstract:
As PET candidate tracers for EGFr-TK, five 4-(anilino)quinazoline derivatives, each fluorinated in the aniline moiety, were prepared. Each was tested in vitro for inhibition of EGFr autophosphorylation in A431 cell line. The leading compounds were then radiolabeled with (18)F and cell binding experiments, biodistribution and PET studies in A431 tumor-bearing mice were performed. Metabolic studies were carried out in a mice control group. From our results, we concluded that while in vitro experiments indicates efficacy of 4-(anilino)quinazoline compounds, kinetic factors and rapid blood clearance make them unsuitable as tracers for nuclear medicine imaging of EGFr-TK.
Insights
Five 4-(anilino)quinazoline derivatives showed in vitro efficacy against epidermal growth factor receptor tyrosine kinase (EGFr-TK). However, kinetic factors and rapid blood clearance render them unsuitable for nuclear medicine imaging.
Area of Science:
- Medicinal Chemistry
- Radiochemistry
- Oncology
Background:
- Epidermal growth factor receptor tyrosine kinase (EGFr-TK) is a key target in cancer therapy.
- Development of targeted radiotracers for EGFr-TK imaging is crucial for personalized medicine.
Purpose of the Study:
- To synthesize and evaluate novel 4-(anilino)quinazoline derivatives as potential positron emission tomography (PET) tracers for EGFr-TK.
- To assess the in vitro and in vivo performance of these compounds for imaging EGFr-TK expression.
Main Methods:
- Synthesis of five fluorinated 4-(anilino)quinazoline derivatives.
- In vitro assessment of EGFr autophosphorylation inhibition in A431 cells.
- Radiolabeling with fluorine-18 ((18)F).
- In vivo studies including cell binding, biodistribution, and PET imaging in A431 tumor-bearing mice.
- Metabolic studies in mice.
Main Results:
- All synthesized compounds demonstrated in vitro inhibition of EGFr autophosphorylation.
- The leading compounds were successfully radiolabeled with (18)F.
- In vivo studies revealed rapid blood clearance and unfavorable pharmacokinetic profiles.
- Metabolic studies indicated potential for rapid degradation.
Conclusions:
- While 4-(anilino)quinazoline derivatives show promise in vitro for targeting EGFr-TK, their rapid blood clearance and kinetic properties limit their utility as PET tracers.
- Further optimization is required to develop suitable radiotracers for nuclear medicine imaging of EGFr-TK.