Abstract
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Introduction: Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for treatment in non-small cell lung carcinoma (NSCLC). Although they have a great clinical effect, patients carrying the dual mutation EGFRL858R/T790M only respond to third-generation EGFR-TKIs. Thus, detecting the mutation status of EGFR is essential before therapy to ensure effectiveness and efficiency. CO-1686 is one of the third-generation EGFR-TKIs, which are selective toward EGFRL858R/T790M and so radiolabeled CO-1686 is expected to work in monitoring EGFRL858R/T790M mutation. In this study, we aim to provide a novel radiolabeled probe, N-{3-[(2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-4-yl] amino}-5-([125I]iodophenyl)acrylamide ([125I]ICO1686) to determine the EGFRL858R/T790M mutation for selection of sensitive patients to the therapy by imaging.
Methods: The precursor was synthesized by tributylstannylation of cold ICO1686. [125I]ICO1686 was prepared by iododestannylation of a corresponding tributylstannyl precursor with [125I]NaI and NCS. We evaluated the plasma stability and biological potency of [125I]ICO1686 as molecular probes for detecting EGFRL858R/T790M using three human NSCLC cell lines: H1975 (dual mutation EGFRL858R/T790M), H3255 (EGFRL858R active mutant), and H441 (wild-type EGFR).Results: A reliable [125I]ICO1686 radiosynthesis was established with high radiochemical yield (77%) and purity (>99%). In vitro radioactivity accumulation in H1975 was three and ten-fold higher than those in H3255 and H441, respectively. The cell uptake of [125I]ICO1686 into H1975 was significantly blocked with nonradioactive CO-1686, which indicates that the binding site of [125I]ICO1686 is identical with that of CO-1686. The tracer revealed high stability in plasma with >90% at 60 min. In vivo biodistribution study, the accumulation of the tracer in H1975 tumor (1.8 %ID/g) tended to be higher compared to that in H3255 tumor (1.6 %ID/g) at 60 min postinjection. However, the tumor-to-background ratio needs to optimize.Conclusion: This radiotracer holds great potential and can serve as a pioneer to discover new potential radiotracers for EGFRL858R/T790M mutation.