2-(2-nitro-1h-imidazol-1-yl)-n-(2-2-3-3-3-pentafluoropropyl)acetamide and Glioblastoma

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.. (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).. 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.. 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.

Topics: Biological Transport; Brain Neoplasms; Cell Hypoxia; Etanidazole; Female; Fluorine Radioisotopes; Glioblastoma; Humans; Hydrocarbons, Fluorinated; Immunohistochemistry; Male; Middle Aged; Positron-Emission Tomography; Radiometry; Tissue Distribution; Whole Body Imaging

Tissue hypoxia results from the interaction of cellular respiration, vascular oxygen carrying capacity, and vessel distribution. We studied the relationship between tumor vasculature and regions of low pO(2) using quantitative analysis of binding of the 2-nitroimidazole EF5 given to patients intravenously (21 mg/kg) approximately 24 h preceding surgery. We describe new computer algorithms for determining EF5 binding as a function of radial distance from individual blood vessels and converting this value to tissue pO(2). Tissues from six human brain tumors were assessed. In a hemangiopericytoma, a WHO Grade 2 and WHO Grade 3 glial brain tumor, all tissue pO(2) values calculated by EF5 binding were >20 mmHg (described as "physiologically oxygenated"). In these three tumors, EF5 binding gradients (measured as a function of distance from each observed vessel) were low, with small positive and negative values averaging close to zero. Much lower tissue oxygen levels were found, including near some vessels, in glioblastomas. Gradients of EF5 binding away from vessels were larger in glioblastomas than in the low-grade tumors, but positive and negative values again averaged to near zero. Based on these preliminary data, we hypothesize a new paradigm for tumor blood flow in human brain tumors whereby in-flowing and out-flowing blood patterns may have contrasting effects on average tissue EF5 (and by inference, oxygen) gradients. Our studies also imply that neither distance to the nearest blood vessel nor distance from each observed blood vessel provide reliable estimates of tissue pO(2).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Animals; Brain Neoplasms; Etanidazole; Glioblastoma; Humans; Hydrocarbons, Fluorinated; Hypoxia; Mice; Middle Aged; Oxygen