Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with ⁶⁸Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with ⁶⁸Ga in 95 ± 2% yield, as evidenced by HPLC characterization. The log P value of ⁶⁸Ga-NOTA-Erlotinib was – (0.6 ± 0.1). The ⁶⁸Ga-NOTA-Erlotinib conjugate was characterized using its ^natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, ⁶⁸Ga-NOTA-Erlotinib exhibited an uptake of 9.8 ± 0.4% in A431 cells which was inhibited by 55.1 ± 0.2% on addition of cold Erlotinib (10 µg) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, ⁶⁸Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5 ± 0.1% ID/g at 30 min p.i.; 0.7 ± 0.2% ID/g at 1 h p.i.). Hepatobiliary clearance of the radioconjugate was observed. The ⁶⁸Ga-NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of ⁶⁸Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a ⁶⁸Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of ⁶⁸Ga labeled TKI for imaging of EGFR over-expressing tumors.

使用放射性标记的酪氨酸激酶抑制剂（TKI）的分子成像是检测和分期EGFR阳性癌症的有前途的策略。已开发出一种这样的TKI的新型类似物埃洛替尼，用于通过将母体埃洛替尼分子与双功能螯合剂p -SCN-Bn-NOTA偶联以使其向⁶⁸ Ga放射标记的作用，来进行PET成像。和ESI-MS技术。HPLC鉴定证明，共轭物以⁶⁸ Ga放射标记，产率为95±2％。⁶⁸ Ga-NOTA-埃罗替尼的log P值为–（0.6±0.1）。在⁶⁸利用其Ga的NOTA-厄洛替尼结合物，其特征在于^NATGa-NOTA-厄洛替尼替代品。细胞活力研究表明，NOTA-埃洛替尼偶联物保留了亲本埃洛替尼分子的生物学功效。此外，⁶⁸ Ga-NOTA-埃罗替尼在A431细胞中的摄取为9.8±0.4％，加入冷的埃洛替尼（10 µg）后被55.1±0.2％抑制，从而证实了放射性缀合物对EGFR表达细胞的特异性。在荷瘤SCID小鼠中进行的生物分布研究中，⁶⁸ Ga-NOTA-埃罗替尼偶联物显示中等程度的肿瘤蓄积（在pi 30分钟时为1.5±0.1％ID / g；在pi 1 h时为0.7±0.2％ID / g）。观察到放射性结合物的肝胆清除率。的⁶⁸ Ga的NOTA-厄洛替尼结合物被发现具有高的体内代谢物分析研究确定的稳定性，使用的是注射了该制剂的瑞士小鼠的尿液样品。⁶⁸ Ga-NOTA-埃罗替尼的整体性能是有希望的，值得进一步探索。据我们所知，这是关于用于EGFR的PET成像的⁶⁸ Ga标记的厄洛替尼设计的第一份报告，并为成功开发用于EGFR过度表达的肿瘤的成像的⁶⁸ Ga标记的TKI开辟了道路。