Abstract
Purpose
The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of 18F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of 18F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.
Methods
18F-EF5 was synthesized by electrophilic addition of 18F2 gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus. Three whole-body images were collected for each of ten patients using an Allegro (Philips) scanner. Gamma counts were determined in blood, drawn during each image, and urine, pooled as a single sample. PET images were analyzed to determine radiotracer uptake in several tissues and the resulting radiation dose calculated using OLINDA software and standard phantom. For three patients, 21 mg/kg unlabeled EF5 was administered after the PET scans, and tissue samples obtained the next day at surgery to determine EF5 binding using immunohistochemistry techniques (IHC).
Results
EF5 distributes evenly throughout soft tissue within minutes of injection. Its concentration in blood over the typical time frame of the study (∼3.5 h) was nearly constant, consistent with a previously determined EF5 plasma half-life of ∼13 h. Elimination was primarily via urine and bile. Radiation exposure from labeled EF5 is similar to other 18F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of 18F-EF5 was confirmed by IHC.
Conclusion
These results confirm predictions of biodistribution and safety based on EF5’s characteristics (high biological stability, high lipophilicity). EF5 is a novel hypoxia marker with unique pharmacological characteristics allowing both noninvasive and invasive measurements.
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Notes
EF5’s partition coefficient was originally determined to be 4 by outside contractors and this value was reported in an initial pharmacology paper [21]. The correct value is 5.7 (at room temperature) and ∼6.25 at 37°.
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Acknowledgement
This work was supported by grants from the NIH/NCI RO1-75284, RO1-87645
Conflicts of interest
EF5 and its labeled counterpart (18F-EF5) are patented (CJK and AVK and others not part of this manuscript, co-inventors) with patents owned by several universities. These patents have been licensed to Varian Biosynergy but this work was entirely supported by grants as indicated in the acknowledgement.
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Koch, C.J., Scheuermann, J.S., Divgi, C. et al. Biodistribution and dosimetry of 18F-EF5 in cancer patients with preliminary comparison of 18F-EF5 uptake versus EF5 binding in human glioblastoma. Eur J Nucl Med Mol Imaging 37, 2048–2059 (2010). https://doi.org/10.1007/s00259-010-1517-y
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DOI: https://doi.org/10.1007/s00259-010-1517-y