Abstract
1048
Objectives: Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, has emerged as a therapeutic target in various cancers, especially non-small cell lung cancer. Although several ALK inhibitors have gained regulatory approval, clinical evidence indicates that long term benefit is often limited by the acquisition of resistance deriving from secondary point mutations in the target. Importantly, some members of this class of compounds are unable to cross the blood-brain barrier, preventing efficacy in brain metastases. Herein, we report the fluoroethyl analogues of Crizotinib, Alectinib and Ceritinib as potential drug candidates with improved brain penetration.
Methods: The fluoroethyl analogues of Crizotinib, Alectinib and Ceritinib were synthesized using fluoroethyl tosylate coupled with Crizotinib, Alectinib, Ceritinib, respectively. In cellulo cytotoxicity screening was performed in ALK-positive lung cancer H2228 cells and ALK-negative lung cancer H441 cells. The F-18-fluoroethyl analogues of Crizotinib (18F-FECrizotinib), Ceritinib (18F-FECeritinib) were synthesized using [18F]fluoroethyl tosylate coupled with Crizotinib, Ceritinib, respectively. [18F]-FEAlectinib was synthesized from mesylate or tosylate precursors by direct fluorination with 18F-fluoride. To study the fluoroethyl ALK inhibitors pharmacokinetics in vivo, positron emission tomography (PET) imaging was performed using the respective F-18 radiolabeled analogues in healthy nude mice.
Results: Cytotoxicity of fluoroethyl analogues in ALK-positive H2228 cells showed up to nanomolar potency, with no significant change compared to parent compounds. The F-18-fluoroethyl analogues of ALK inhibitors were obtained with good yields, high purity and high specific activity. PET imaging in healthy mice showed significant early brain uptake (%ID/cc) for the series as a whole (18F-FECrizotinib: 6.6±2.6; 18F-FEAlectinib: 8.1±2.6; 18F-FECeritinib: 6.6±1.8, at 5 minutes post injection) suggesting penetration of the blood brain barrier. Conclusion: These novel fluoroethyl ALK inhibitor analogues show promise for enhanced blood brain barrier penetration and therapeutic potential in the central nervous system (CNS).