Synthesis and Preclinical Evaluation of [Methylpiperazine-(11)C]brigatinib as a PET Tracer Targeting Both Mutated Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase

[Image: see text] 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, N-desmethyl brigatinib was successfully synthesized as a precursor in five steps. Radiolabeling with [(11)C]methyl iodide produced [methylpiperazine-(11)C]brigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/μmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min. [Methylpiperazine-(11)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 [methylpiperazine-(11)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.