Biodistribution and dosimetry of 18F-EF5 in cancer patients with preliminary comparison of 18F-EF5 uptake versus EF5 binding in human glioblastoma

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.

First Evaluation of PET-Based Human Biodistribution and Dosimetry of 18F-FAZA, a Tracer for Imaging Tumor Hypoxia

“…We found that the EDE value for 18 F-FAZA (0.015 mSv/MBq) was between the values for 18 F-FETNIM (0.017 mSv/ MBq) and 18 F-FMISO (0.013 mSv/MBq), whereas 18 F-EF5 had an EDE of 0.029 mSv/MBq. The higher doses for 18 F-EF5, both for urinary bladder and EDE, are probably due to the authors' assumption-in the evaluation of doses-that no activity was excreted (25). 18 F-FAZA PET/CT has also been found to be valuable as a prognostic biomarker in oncologic patients (27) and as a guide to tailoring treatment approaches such as hypoxia-directed intensitymodulated radiotherapy (14,28).…”

“…To overcome these disadvantages, other nitroimidazole PET tracers with high avidity for hypoxic tissue have been investigated and developed, including 18 F-FETNIM (23), which is more hydrophilic than 18 F-FMISO and washes out more rapidly from normal oxygenated tissues, theoretically allowing a higher tumor-to-background ratio (8). In addition, another hypoxia tracer, with a more stable but also more complex labeling chemistry, is represented by 18 F-EF5 (8,24,25). This tracer is slightly more lipophilic than the formerly described compounds and has been investigated in various tumors in animal and clinical studies (25).…”

“…In addition, another hypoxia tracer, with a more stable but also more complex labeling chemistry, is represented by 18 F-EF5 (8,24,25). This tracer is slightly more lipophilic than the formerly described compounds and has been investigated in various tumors in animal and clinical studies (25). For these tracers, the optimal tumor-to-muscle cutoff is low (1.5) and the potential advantage over 18 F-FMISO is still negligible (8).…”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…[ 18 F]EF-5 contains five fluorine atoms and is a very lipophilic molecule in comparison with other nitroimidazole derivatives (Koch et al, 2010;Lin et al, 2012). In a research reported by Koch et al (2010), three patients with gliobastoma were assessed by [ 18 F]EF-5 PET. Binding was also measured ex vivo on tumor biopsies by immunohistochemistry using fluorescent anti-EF-5 monoclonal antibody (Koch et al, 2010).…”

New Strategies in Non–Small Cell Lung Cancer: Improving Outcomes in Chemoradiotherapy for Locally Advanced Disease

“…However, other markers of hypoxia have been developed that could have broader applicability in NSCLC. The 2-nitroimidazole 18 F-EF5 has also been used to image glioblastomas, but its use in NSCLC remains to be evaluated (56).…”