Evaluation of [18F]gefitinib as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in malignant tumors
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Gefitinib, an inhibitor of the epidermal growth factor receptor–tyrosine kinase (EGFR-TK), has shown potent effects in a subset of patients carrying specific EGFR-TK mutations in advanced non-small-cell lung cancer. In this study, we asked whether PET with [18F]gefitinib may be used to study noninvasively the pharmacokinetics of gefitinib in vivo and to image the EGFR status of cancer cells.
Materials and methods
Synthesis of [18F]gefitinib has been previously described. The biodistribution and metabolic stability of [18F]gefitinib was assessed in mice and vervet monkeys for up to 2 h post injection by both micropositron emission tomography (PET)/computed tomography (CT) scans and postmortem ex vivo tissue harvesting. Uptake levels of radiolabeled gefitinib in EGFR-expressing human cancer cell lines with various levels of EGFR expression or mutation status were evaluated both in vivo and in vitro.
MicroPET/CT scans in two species demonstrated a rapid and predominantly hepatobiliary clearance of [18F]gefitinib in vivo. However, uptake levels of radiolabeled gefitinib, both in vivo and in vitro, did not correlate with EGFR expression levels or functional status. This unexpected observation was due to high nonspecific, nonsaturable cellular uptake of gefitinib.
The biodistribution of the drug analogue [18F]gefitinib suggests that it may be used to assess noninvasively the pharmacokinetics of gefitinib in patients by PET imaging. This is of clinical relevance, as insufficient intratumoral drug concentrations are considered to be a factor for resistance to gefitinib therapy. However, the highly nonspecific cellular binding of [18F]gefitinib may preclude the use of this imaging probe for noninvasive assessment of EGFR receptor status in patients.
KeywordsPositron emission tomography Gefitinib Epidermal growth factor receptor Non-small-cell lung cancer
We thank Dr. Waldemar Ladno, Judy Edwards, Victor Dominguez, and Dr. David Stout for excellent animal imaging technical assistance and Dr. Nagichettiar Satyamurthy and the UCLA Cyclotron staff for providing the radiolabeled compounds. We thank Dr. Jorge Barrio for allowing us to use the Automatic TLC-Linear Analyzer and Arash Safaei for help with the metabolite and monkey studies. We thank Drs. Henry Huang and Christine Wu for critical reading of the manuscript. This study was funded by the UCLA Institute of Molecular Medicine (DE-FC03-87E60615) and UCLA Lung SPORE (NIH P50 CA9038). All experiments reported in this study were conducted in compliance to laws of the state in which they were performed, inclusive of ethics approval.
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