Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5

Abstract

Tumor hypoxia is an important prognostic indicator for cancer therapy outcome. EF5 [2-(2-nitro-1[ H]-imidazol-1-yl)- N-(2,2,3,3,3-pentafluoropropyl)-acetamide] has been employed to measure tumor hypoxia in animals and humans using immunohistochemical methods. EF5 is a lipophilic molecule designed to have a very uniform biodistribution, a feature of obvious benefit for use in PET imaging. The present study represents the first demonstration of noninvasive PET imaging of rat tumors using fluorine-18 labeled EF5. Because of the small tumor size, partial volume effects may result in underestimation of concentration of the compound. Therefore, validation of the PET data was performed by gamma counting of the imaged tissue. The tumor models studied were the Morris 7777 (Q7) hepatoma (n=5) and the 9L glioma (n=2) grown subcutaneously in rats. Our previous studies have demonstrated that early passage 9L tumors are not severely hypoxic and that Q7 tumors are characterized by heterogeneous regions of tumor hypoxia (i.e., Q7 tumors are usually more hypoxic than early passage 9L tumors). The seven rats were imaged in the HEAD Penn-PET scanner at various time points after administration of 50-100 micro Ci (18)F-EF5 in 30 mg/kg carrier nonradioactive EF5. The carrier was used to ensure drug biodistribution comparable to prior studies using immunohistochemical methods. (18)F-EF5 was excreted primarily via the urinary system. Images obtained 10 min following drug administration demonstrated that the EF5 distributed evenly to all organ systems, including brain. Later images showed increased uptake in most Q7 tumors compared with muscle. Liver uptake remained relatively constant over the same time periods. Tumor to muscle ratios ranged from 0.82 to 1.73 (based on PET images at 120 min post injection) and 1.47 to 2.95 (based on gamma counts at approximately 180 min post injection). Tumors were easily visible by 60 min post injection when the final tumor to muscle ratios (based on gamma counts) were greater than 2. Neither of the 9L tumors nor the smallest Q7 tumor met this criterion, and these tumors were not seen on the PET images. These preliminary results suggest that (18)F-EF5 is a promising agent for noninvasive assessment of tumor hypoxia. Plans are underway to initiate a research project to determine the safety and preliminary evidence for the efficacy of this preparation in patients with brain tumors.

Patterns and Levels of Hypoxia in Head and Neck Squamous Cell Carcinomas and Their Relationship to Patient Outcome

“…Two clinically relevant "invasive" methods are needle electrodes techniques and 2-nitroimidazole binding studies, but the former can seldom be used in primary tumors of the head and neck. For the latter, the 2-nitroimidazole adduct formation in hypoxic cells can be assayed using immunohistochemistry (IHC), flow cytometry (FCM) and/or PET imaging (for example [13][14][15][16][17] ).…”

18F-EF5: A New PET Tracer for Imaging Hypoxia in Head and Neck Cancer

“…18 F-fluoromisonidazole ( 18 F-FMISO) (13), 18 F-fluoroerythronitroimidazole (14), 18 F-fluoroazomycin arabinoside (15), and 18 F-fluoroetanidazole have been used with varying success as PET probes for hypoxia imaging, but only 18 F-FMISO is available in more than a few of the centers worldwide. However, a new group of etanidazole-based compounds, >2-(2-nitroimidazol-1 H-y)-N-(3-flouropropyl)acetamide (EF1) (16), 2-(2-nitroimidazol-1 H-y)-N-(3,3,3-tryflouropropyl)acetamide (EF3), and EF5 (17)(18)(19), has been developed both as biopsy-based (20) and as PET-based agents, and 18 F-EF5 has been synthesized by Dolbier et al (17) as well as at our center.…”

Hypoxia Imaging with 18F-FMISO PET for Brain Tumors

“…Despite evidence, it is still not substantiated whether Cu-ATSM represents hypoxia. Further, 18 F-EF5, 2-(2-nitro-1[H]-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide, was first tested in an animal study by Ziemer [55]. Evens et al found that EF5 uptake correlated with a poor prognosis in glioma patients [18].…”