title: Radiosynthesis and initial in vitro evaluation of [18F]F-PEG6-IPQA--a novel PET radiotracer for imaging EGFR expression-activity in lung carcinomas.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Pal
authors.forename: Julius A
authors.initials: JA
authors.lastname: Balatoni
authors.forename: Uday
authors.initials: U
authors.lastname: Mukhopadhyay
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Lepera
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Shavrin
authors.forename: Andrei
authors.initials: A
authors.lastname: Volgin
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D066246:ErbB Receptors / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000493:pharmacokinetics*; D055752:Small Cell Lung Carcinoma / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: C557742:4-((3-iodophenyl)amino)-7-(2-(2-(2-(2-(2-(2-(18F)fluoroethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)quinazoline-6-yl-acrylamide; D005462:Fluorine Radioisotopes; D011799:Quinazolines; D066246:ErbB Receptors