Radiosynthesis and Initial In Vitro Evaluation of [ 18 F]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, [ 18 F]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 18 F/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 [ 18 F]F-PEG 6 -IPQA were 3.9–17.6%, with an average of 9.0% ( n = 11). Radiochemical purity was >97% with specific activity of 34 GBq/μmol (mean value, n = 10) at the end of synthesis. The accumulation of [ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]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.