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

ABSTRACT

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 [11C]methyl iodide produced [methylpiperazine-11C]brigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/µmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min. [Methylpiperazine-11C]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-11C]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.