Radiosynthesis and Initial In Vitro Evaluation of [18F]F-PEG6-IPQA—A Novel PET Radiotracer for Imaging EGFR Expression-Activity in Lung Carcinomas

• Published in: Molecular imaging and biology Vol. 13; no. 5; pp. 853 - 861
• 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-Verlag 01-10-2011
• Subjects: Cell Line, Tumor; Chromatography, High Pressure Liquid; ErbB Receptors - metabolism; Fluorine Radioisotopes - pharmacokinetics; Humans; Imaging; In Vitro Techniques; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - metabolism; Medicine; Medicine & Public Health; Positron-Emission Tomography; Quinazolines - pharmacokinetics; Radiology; Research Article; Small Cell Lung Carcinoma - diagnostic imaging; Small Cell Lung Carcinoma - metabolism; F]F-PEG; IPQA; Radiochemistry; Non-small cell lung carcinoma; [; Positron emission tomography; Epidermal growth factor receptor
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-010-0408-8

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.