Synthesis and Fundamental Evaluation of Radioiodinated Rociletinib (CO-1686) as a Probe to Lung Cancer with L858R/T790M Mutations of Epidermal Growth Factor Receptor (EGFR)

Molecules

Kazuhiro Shiba¹  Izumi Sawazaki²  Muammar Fawwaz²  Seigo Kinuya²  Kazuma Ogawa²  Kenji Mishiro³  Ryuichi Nishii⁴ 

[1] Advanced Science Research Center, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan;Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan;Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan;National Institute of Radiological Sciences (NIRST), QST, Inage-ku, Chiba 263-8555, Japan;

关键词: imaging;    EGFR;    prediction of therapeutic effects;    mutation status;    radiopharmaceutical;    tyrosine kinase inhibitor;   

DOI  :  10.3390/molecules25122914

来源: DOAJ

【 摘 要 】

Rociletinib (CO-1686), a 2,4-diaminopyrimidine derivative, is a highly potent tyrosine kinase inhibitor (TKI) that acts on epidermal growth factor receptor (EGFR) with L858R/T790M mutations. We supposed radioiodinated CO-1686 would function as a useful tool for monitoring EGFR L858R/T790M mutations. To aid in patient selection before therapy with EGFR-TKIs, this study aimed to develop a ¹²⁵I-labeled derivative of CO-1686, N-{3-[(2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-4-yl] amino}-5-([¹²⁵I]iodophenyl)acrylamide ([¹²⁵I]ICO1686) and evaluate its selectivity toward EGFR L858R/T790M. Radiosynthesis was performed by iododestannylation of the corresponding tributylstannyl precursor with [¹²⁵I]NaI and N-chlorosuccinimide. The selectivity of the tracer for detecting EGFR L858R/T790M was evaluated using three relevant non-small cell lung cancer (NSCLC) cell lines—H1975, H3255 and H441 overexpressing the dual mutation EGFR L858R/T790M, active mutant EGFR L858R and wild-type EGFR, respectively. The nonradioactive ICO1686 and the precursor compound were successfully synthesized. A novel radiolabeled probe, [¹²⁵I]ICO1686, was prepared with high radiochemical yield (77%) and purity (> 99%). ICO1686 exhibited high cytotoxicity toward H1975 (IC₅₀ 0.20 ± 0.05 μM) and H3255 (IC₅₀ 0.50 ± 0.21 μM), which is comparable to that of CO-1686. In contrast, the cytotoxicity of ICO1686 toward H441 was 10-fold lower than that toward H1975. In the cell uptake study, the radioactivity uptake of [¹²⁵I]ICO1686 in H1975 was 101.52% dose/mg, whereas the uptakes in H3255 and H441 were 33.52 and 8.95% dose/mg, respectively. The uptake of [¹²⁵I]ICO1686 in H1975 was greatly reduced to 45.61% dose/mg protein by treatment with excess CO-1686. In vivo biodistribution study of the radiotracer found that its accumulation in H1975 tumor (1.77 ± 0.43% ID/g) was comparable to that in H3255 tumor (1.63 ± 0.23% ID/g) and the accumulation in H1975 tumor was not reduced by pretreatment with an excess dose of CO-1686. Although this radiotracer exhibited highly specific in vitro uptake in target cancer cells, structural modification is required to improve in vivo biodistribution.

【 授权许可】

Unknown