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Published on: September 21, 2021
Metabolic stability of 6,7-dialkoxy-4-(2-, 3- and 4-[18F]fluoroanilino)quinazolines, potential EGFR imaging probes
Neil Vasdev1, Peter N Dorff, James P O'Neil
1Department of Radiotracer Development and Imaging Technology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Abstract:
Epidermal growth factor receptors (EGFR), upregulated in many tumor types, have been a target for therapeutic development and molecular imaging. The objective of this study was to evaluate the distribution and metabolic characteristics of fluorine-18 labeled anilinoquinazolines as potential imaging agents for EGFR tyrosine kinase expression. Fluorine-18 labeled fluoronitrobenzenes were prepared by reaction of potassium cryptand [(18)F]fluoride with 1,2- and 1,4-dinitrobenzenes, and 3-nitro-N,N,N-trimethylanilinium triflate in 5min. Decay-corrected radiochemical yields of [(18)F]fluoride incorporation into the nitro-aromatic compounds were 81±2%, 44±4% and 77±5% (n=3-5) for the 2-, 3- and 4-fluoro isomers, respectively. Sodium borohydride reduction to the corresponding [(18)F]fluoroanilines was achieved with greater than 80% conversion in 5min. Coupling of [(18)F]fluoroaniline-hydrochlorides to 6,7-dimethoxy-4-chloro-quinazoline gave the corresponding 6,7-dimethoxy-4-(2-, 3- and 4-[(18)F]fluoroanilino)quinazolines in 31±5%, 17±2% and 55±2% radiochemical yield, respectively, while coupling to the 6,7-diethoxy-4-chloro-quinazoline produced 6,7-diethoxy-4-(2-, 3- and 4-[(18)F]fluoroanilino)quinazolines in 19±6%, 9±3% and 36±6% radiochemical yield, respectively, in 90min to end of synthesis from [(18)F]fluoride. Biodistribution of 2- and 4-[(18)F]fluoroanilinoquinazolines was conducted in tumor-bearing mice (MDA-MB-435 and MDA-MB-468 xenografts). Low tumor uptake (<1% injected dose per gram (ID/g) of tissue up to 3h postinjection of the radiotracers) was observed. High bone uptake (5-15% ID/g) was noted with the 4-[(18)F]fluoroanilinoquinazolines. The metabolic stabilities of radiolabeled quinazolines were further evaluated by incubation with human female cryopreserved isolated hepatocytes. Rapid degeneration of the 4-fluoro-substituted compounds to baseline polar metabolites was observed by radio-TLC, whereas, the 2- and 3-[(18)F]fluoroaniline derivatives were significantly more stable, up to 2h, corroborating the in vivo biodistribution studies. para-Substituted [(18)F]fluoroanilines, a common structural motif in radiopharmaceuticals, are highly susceptible to metabolic degradation.
Insights
This study investigated fluorine-18 labeled anilinoquinazolines for imaging epidermal growth factor receptor (EGFR) tyrosine kinase expression. The para-substituted compounds showed poor tumor uptake and rapid metabolic degradation, limiting their potential as imaging agents.
Area of Science:
- Radiochemistry
- Molecular Imaging
- Oncology
Background:
- Epidermal growth factor receptors (EGFR) are upregulated in many cancers, making them a target for therapies and molecular imaging.
- Anilinoquinazolines are a class of compounds explored for their potential in targeting EGFR.
Purpose of the Study:
- To evaluate fluorine-18 labeled anilinoquinazolines as potential imaging agents for EGFR tyrosine kinase expression.
- To assess the biodistribution and metabolic stability of these novel radiotracers.
Main Methods:
- Synthesis of fluorine-18 labeled anilinoquinazolines via nucleophilic substitution and coupling reactions.
- Radiochemical yield determination for various isomers.
- Biodistribution studies in tumor-bearing mice (MDA-MB-435 and MDA-MB-468 xenografts).
- Metabolic stability assessment using human hepatocytes and radio-TLC.
Main Results:
- High radiochemical yields were achieved for fluorine-18 incorporation into nitroaromatic precursors.
- 2- and 3-[(18)F]fluoroanilinoquinazolines exhibited better metabolic stability compared to the 4-fluoro isomer.
- Low tumor uptake (<1% ID/g) and high bone uptake (5-15% ID/g) were observed for 4-[(18)F]fluoroanilinoquinazolines.
- Rapid in vitro metabolic degradation of para-substituted fluoroanilines was confirmed.
Conclusions:
- The para-substituted [(18)F]fluoroanilinoquinazolines demonstrated poor tumor targeting and rapid metabolic instability.
- The 2- and 3-fluoro isomers showed improved metabolic stability but require further investigation for efficacy.
- Para-substituted fluoroanilines may not be suitable structural motifs for developing effective EGFR-targeting radiopharmaceuticals.
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