Biodistribution and dosimetry of (18)F-EF5 in cancer patients with preliminary comparison of (18)F-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 (18)F-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 (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.

Methods: (18)F-EF5 was synthesized by electrophilic addition of (18)F(2) 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 (18)F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of (18)F-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.

Fig. 1

Blood SUVs calculated from gamma counts: the three individual values for eight of the ten patients are plotted with a common symbol (+). The dotted line represents the expected change associated with a 13-h plasma half-life (determined in [21]). Individual values from two patients are shown: the solid circles represent the sample containing the earliest time point for blood collection after drug injection (2 min) and the solid triangles indicate data from the patient with highest urinary drug excretion (20%)

Fig. 2

HPLC tracing of three serial blood samples, a standard (visible only on the UV channel, not shown) and urine sample from patient 1. The main urine peak (3,600 s) is actually well off scale (max. 310). Urine metabolites are observed in the range 3,200–3,400 s. The main peaks (650, 1,400, 2,150 and 3,600 s) coincide precisely with the retention of authentic EF5, determined by spiking individual samples with authentic EF5 (data not shown)

Fig. 3

Individual organ SUVs plotted versus time for patients imaged in head to toe orientation (patients 4 and 8). Symbols correspond to brain (closed squares), muscle (open circles), heart (closed triangles), liver (open diamonds), and bladder (+)

Fig. 4

Whole-body PET images for patient 1 at average times of 45 and 165 min. The brain lesion's SUVs increase with time. Excretion is predominantly via kidney/bladder with a smaller component via gallbladder/bowel

Fig. 5

Gadolinium-enhanced MRI image of tumor from patient 1 (upper left) and color-coded PET image (longest time, lower left) from patient 1. The rostral portion of the tumor (red arrow) has little ¹⁸F-EF5 uptake and tissue obtained from this region has no EF5 binding, determined by IHC (upper right). Conversely, the caudal portion of the tumor (green arrow) has high ¹⁸F-EF5 uptake and tissue obtained from this region has high EF5 binding, determined by IHC (lower right)