Department of Radiology & Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
Biomarkers & Imaging, Cancer Center Amsterdam, Amsterdam, The Netherlands.
J Med Chem. 2023 Sep 14;66(17):12130-12140. doi: 10.1021/acs.jmedchem.3c00722. Epub 2023 Aug 30.
Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4-ALK, has shown a potential to inhibit mutated epidermal growth factor receptor (EGFR). In this study, -desmethyl brigatinib was successfully synthesized as a precursor in five steps. Radiolabeling with [C]methyl iodide produced [-C]brigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/μmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min. [-C]brigatinib was evaluated in non-small cell lung cancer xenografted female nu/nu mice. An hour post-injection (p.i.), 87% of the total radioactivity in plasma originated from intact [-C]brigatinib. Significant differences in tumor uptake were observed between the endogenously EML4-ALK mutated H2228 and the control xenograft A549. The tumor-to-blood ratio in H2228 xenografts could be reduced by pretreatment with ALK inhibitor crizotinib. Tracer uptake in EGFR Del19 mutated HCC827 and EML4-ALK fusion A549 was not significantly different from uptake in A549 xenografts.
布加替尼，一种针对基因重排间变性淋巴瘤激酶（ALK）的酪氨酸激酶抑制剂（TKI），如 EML4-ALK，具有抑制突变型表皮生长因子受体（EGFR）的潜力。在这项研究中，-去甲布加替尼成功地通过五步合成作为前体。用 [C]甲基碘进行放射性标记，在 49 ± 4 分钟内以 10 ± 2%的放射性化学产率、91 ± 17 GBq/μmol 摩尔活性和≥95%的放射性化学纯度产生 [-C]布加替尼。[-C]布加替尼在非小细胞肺癌异种移植的雌性 nu/nu 小鼠中进行了评估。注射后 1 小时（p.i.），血浆中总放射性的 87%来自完整的 [-C]布加替尼。在 H2228 和对照异种移植 A549 中，内源 EML4-ALK 突变的 H2228 和对照异种移植 A549 之间观察到肿瘤摄取的显著差异。用 ALK 抑制剂克唑替尼预处理可降低 H2228 异种移植瘤中的肿瘤-血液比。在 EGFR Del19 突变 HCC827 和 EML4-ALK 融合 A549 中，示踪剂摄取与 A549 异种移植瘤中的摄取没有显著差异。
