Synthesis of a [¹⁸F]-labeled ceritinib analogue for positron emission tomography of anaplastic lymphoma kinase, a receptor tyrosine kinase, in lung cancer

Objectives Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, has emerged as a therapeutic target in solid and hematologic tumors. Although several ALK inhibitors have gained approval for therapy, non-invasive indicators of target engagement or predictive biomarkers in vivo are lacking. Therefore, we designed and synthesized a radiolabeled analogue of the ALK inhibitor ceritinib, [¹⁸F]fluoroethyl-ceritinib, ([¹⁸F]-FEC), for use with positron emission tomography (PET).

Methods We used two methods to synthesize [¹⁸F]-FEC. First method: [¹⁸F]fluoroethyl-tosylate was prepared by radiofluorination of ethylene glycol di-tosylate, purified by HPLC and coupled with ceritinib at 120^oC for 20 min. The product was purified by flash chromatography to yield [¹⁸F]-FEC. Alternatively, a precursor compound, chloroethyl-ceritnib, was synthesized in multiple steps and directly fluorinated with K¹⁸F-fluoride/kryptofix 2.2.2., and the product was purified either by HPLC or flash chromatography to yield [¹⁸F]-FEC.

Results The first method produced [¹⁸F]-FEC with an average decay-corrected yield of 24% (n=4), specific activity of 1200 mCi/μmol, and >99% purity; synthesis time was 115 min from the end of bombardment (EOB). The second method produced [¹⁸F]-FEC with an average yield of 7% (n=4), specific activity of 1500 mCi/μmol, and >99% purity; synthesis time was 65 min from the EOB. Of these two methods, we judged Method 1 to be the better choice for producing a pure compound for biological applications in vitro and in vivo.

Conclusions Synthesis of a novel [¹⁸F]ceritinib analogue has been achieved in good yields, with high purity and specific activity. The compound is a potential PET imaging agent for the detection of ALK overexpressing solid tumors, such as lung cancer, and should be tested in vitro in cell culture and in vivo in tumor-bearing mice.