Radiosynthesis and Initial In Vitro Evaluation of [^sup 18^F]F-PEG^sub 6^-IPQA--A Novel PET Radiotracer for Imaging EGFR Expression-Activity in Lung Carcinomas

• Published in: Molecular imaging and biology Vol. 13; no. 5; p. 853
• Main Authors: Pal, Ashutosh, Balatoni, Julius A, Mukhopadhyay, Uday, Ogawa, Kazuma, Gonzalez-lepera, Carlos, Shavrin, Aleksandr, Volgin, Andrei, Tong, William, Alauddin, Mian M, Gelovani, Juri G
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01-10-2011
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-010-0408-8

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, [^sup 18^F]F-PEG^sub 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. A mesylate precursor was synthesized in multiple steps and radiofluorinated using K^sup 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. Decay-corrected radiochemical yields of [^sup 18^F]F-PEG^sub 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 [^sup 18^F]F-PEG^sub 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 [^sup 18^F]F-PEG^sub 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. We have synthesized [^sup 18^F]F-PEG^sub 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 [^sup 18^F]F-PEG^sub 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.[PUBLICATION ABSTRACT]