Metabolic stability of 6,7-dialkoxy-4-(2-, 3- and 4-[18F]fluoroanilino)quinazolines, potential EGFR imaging probes

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 [18F]fluoride with 1,2- and 1,4-dinitrobenzenes, and 3-nitro-N,N,N-trimethylanilinium triflate in 5 min. Decay-corrected radiochemical yields of [18F]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 [18F]fluoroanilines was achieved with greater than 80% conversion in 5 min. Coupling of [18F]fluoroaniline-hydrochlorides to 6,7-dimethoxy-4-chloro-quinazoline gave the corresponding 6,7-dimethoxy-4-(2-, 3- and 4-[18F]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-[18F]fluoroanilino)quinazolines in 19 ± 6%, 9 ± 3% and 36 ± 6% radiochemical yield, respectively, in 90 minutes to end of synthesis from [18F]fluoride. Biodistribution of 2- and 4-[18F]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 3 h post injection of the radiotracers) was observed. High bone uptake (5 – 15% ID/g) was noted with the 4-[18F]fluoroanilino-quinazolines, 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-[18F]fluoroaniline derivatives were significantly more stable, up to 2 h, corroborating the in vivo biodistribution studies. Para-substituted [18F]fluoroanilines, a common structural motif in radiopharmaceuticals, are highly susceptible to metabolic degradation.

Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX–Targeted PET Imaging

“…Small molecules (e.g., 18 F-fluoromisonidazole, 18 F-fluorothymidine, and a host of others) have been used to probe enzymatic activity that may be associated within a given cell type. Nevertheless, the application of small-molecule inhibitors as PET tracers can be challenged by several effects such as nonspecific uptake in cells, poor clearance from blood (1), and rapid metabolic defluorination with accompanying bone uptake (2,3). In addition, 18 F labeling in high yield and at high specific activity often presents a significant challenge in the development of new PET tracers (4).…”

Modern methodologies and tools for human hazard assessment of chemicals

“…This is mainly due to the potential damage caused by cytotoxic substances produced by the cells in and the variations in the expression levels of phase I and phase II enzymes in cultures (Chen et al, 2011;Vasdev et al, 2011;Abass et al, 2013). It is recognised that for interspecies comparison, hepatocytes in suspensions are more reliable than hepatocytes in culture.…”

Synthesis and evaluation of novel 18F‐labeled quinazoline derivatives with low lipophilicity for tumor PET imaging

“…10 Among positron nuclides, fluoride-18 has been favored as a medical PET nuclide for its convenient half-life (109.8 min) and emission energy (635 keV). To date, the most successful and commonly used 18 17 Because of the high affinity of quinazoline derivatives to overexpressed EGFR in tumor cell lines, researchers have attempted to design radioisotope-labeled quinazoline derivatives as radiotracers to target EGFR for the diagnosis of tumor diseases. To date, the most successful and commonly used 18 17 Because of the high affinity of quinazoline derivatives to overexpressed EGFR in tumor cell lines, researchers have attempted to design radioisotope-labeled quinazoline derivatives as radiotracers to target EGFR for the diagnosis of tumor diseases.…”