ArticleBioorganic & medicinal chemistry2011
Metabolic stability of 6,7-dialkoxy-4-(2-, 3- and 4-[18F]fluoroanilino)quinazolines, potential EGFR imaging probes.
Article in Bioorganic & medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed.
- Molecular Imaging of In Vivo Zinc Distribution Using Nuclear and Magnetic Resonance Imaging.Chemical & biomedical imaging · 2026Review
- Controlled Release of Pyrimidine Compound Using Polymeric Coated ZIF-8 Metal-Organic Framework as Glucagon-Like Peptide-1 Receptor Agonist Carrier.Molecules (Basel, Switzerland) · 2020Article
- Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors.Bioorganic & medicinal chemistry letters · 2018Article
- Recent Advances in the Development and Application of Radiolabeled Kinase Inhibitors for PET Imaging.Molecules (Basel, Switzerland) · 2015Review
- Article
- Fluorine bonding enhances the energetics of protein-lipid binding in the gas phase.Journal of the American Society for Mass Spectrometry · 2014Article
- Quantitative analysis of [11C]-erlotinib PET demonstrates specific binding for activating mutations of the EGFR kinase domain.Neoplasia (New York, N.Y.) · 2013Article
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6 authors.
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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.
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