Radiosynthesis and initial in vitro evaluation of [ ¹⁸F]F- PEG ₆-IPQA-A novel PET radiotracer for imaging EGFR expression-activity in lung carcinomas

Introduction: Epidermal growth factor receptor (EGFR)-targeted therapies with antibodies and small molecular EGFR kinase inhibitors have shown poor efficacy in unselected populations of patients with advanced non-small cell lung carcinomas (NSCLC). In contrast, patients with overexpression of EGFR and activating mutations in EGFR kinase domain demonstrated improved responses to EGFR kinase inhibitors. Therefore, we have developed a novel radiotracer, [ ¹⁸F]F-PEG ₆-IPQA for PET imaging of EGFR expression-activity in NSCLC, and have described its radiosynthesis and in vitro evaluation in two NSCLC cell lines with wild-type and L858R active mutant EGFR. Methods: A mesylate precursor was synthesized in multiple steps and radiofluorinated using K ¹⁸F/ Kryptofix. The fluorinated intermediate compound was reduced to an amino derivative then treated with acryloyl isobutyl carbonate, followed by purification by HPLC to obtain the desired product. Results: Decay-corrected radiochemical yields of [ ¹⁸F]F-PEG ₆-IPQA were 3.9-17.6%, with an average of 9.0% (n=11). Radiochemical purity was 997% with specific activity of 34 GBq/μmol (mean value, n=10) at the end of synthesis. The accumulation of [ ¹⁸F]F-PEG ₆-IPQA in H3255 cells was ten-fold higher than in H441 cells, despite a two-fold lower level of activated phospho- EGFR expression in H3255 cells compared with H441 cells. The accumulation of [ ¹⁸F]F-PEG ₆- IPQA in both cell lines was significantly decreased in the presence of a small molecular EGFR kinase inhibitor, Iressa, at 100 μM concentration in culture medium. Conclusion: We have synthesized [ ¹⁸F]F-PEG ₆-IPQA and demonstrated its highly selective accumulation in active mutant L858R EGFR-expressing NSCLC cells in vitro. Further in vivo studies are warranted to assess the ability of PET imaging with [ ¹⁸F]F-PEG ₆-IPQA to discriminate the active mutant L858R EGFR-expressing NSCLC that are sensitive to therapy with EGFR kinase inhibitors vs NSCLC that express wild-type EGFR.