Determination of tumour hypoxia with [18F]EF3 in patients with head and neck tumours: a phase I study to assess the tracer pharmacokinetics, biodistribution and metabolism.

PURPOSE: The aim of this study was to assess the pharmacokinetics, biodistribution and metabolism of [(18)F]EF3, a labelled 2-nitroimidazole hypoxia marker, in ten patients with head and neck cancer. METHODS: [(18)F]EF3 was administered intravenously (group 1, n=5, mean dose+/-SD: 324+/-108 MBq; group 2, n=5, mean dose+/-SD: 1,134+/-138 MBq) to patients (nine male, one female). Blood and urine samples and whole-body PET scans were obtained from 20 s to 4-6 h. Radioactivity was determined in several regions of interest. RESULTS: No serious adverse event was reported. [(18)F]EF3 concentration in blood exhibited a bi-exponential decline. [(18)F]EF3 was mainly eliminated in the urine. By 7 h 40 min after injection, 53+/-14% of the injected dose was collected in the urine. There was no significant difference between the low- and high-dose groups. A progressive accumulation occurred also in the colon, indicating a hepatobiliary excretion. Except in organs involved in the elimination of [(18)F]EF3, the tumour-to-organ ratio remained close to or below unity in muscle, lungs, heart and brain at various times after injection. In one patient, tumour hypoxia was observed with a tumour-to-blood ratio ranging from 1.4 to 1.9. Last, [(18)F]EF3 remained very stable after injection, with percentage of native tracer above 87% in the serum and 84% in the urine. CONCLUSION: Administration of [(18)F]EF3 in head and neck cancer patients is feasible and safe. Uptake and retention in tumour was observed, indicating the presence of hypoxia.

Detection of tumour hypoxia: comparison between EF5 adducts and [18F]EF3 uptake on an individual mouse tumour basis.

In the framework of the preclinical validation of the hypoxic tracer [(18)F]EF3, a comparison was performed between uptake of [(18)F]EF3 and EF5 adducts detected by immunofluorescence in MCa-4, FSA, FSAII, Sa-NH and NFSA tumour-bearing mice. Mice were allowed to breath carbogen (5% CO(2), 95% O(2)), 21% oxygen or 10% oxygen. A significant correlation (r (2)=0.57; p<0.01) was found between the [(18)F]EF3 tumour-to-muscle ratio and the fluorescence intensity of EF5.

Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3-[(18)F]trifluoropropyl)acetamide, [(18)F]EF3.

The 2-nitroimidazole derivative 2-(2-nitroimidazol-1-yl)- N-(3,3,3-trifluoropropyl)acetamide (EF3) is a marker which forms adducts into hypoxic cells. Radiosynthesis of [(18)F]EF3 was recently performed by our group. Our aim was to study the pharmacokinetics, biodistribution, metabolism and specificity for hypoxia of [(18)F]EF3. MCa-4, SCC VII, NFSA, FSA, FSA II or Sa-NH tumour-bearing C3H mice were injected intravenously with [(18)F]EF3 and allowed to breathe air, 10% O(2) or carbogen until sacrifice 5-770 min after injection. Radioactivity was measured ex vivo in various organs, including urine and faeces. Selected organs were additionally processed to measure tracer metabolites with high-performance liquid chromatography. The half-life in blood was 73.9 min. [(18)F]EF3 was eliminated mainly via the kidneys, with 75% of the injected activity found in the urine by 12 h 50 min. The biodistribution was fast and homogeneous except in the brain and the bone, where it was significantly lower, and in the liver and the kidney, where it was significantly higher. In most organs, the exceptions being the gastrointestinal and urinary tract, tissue-to-blood ratios were below or close to unity. In tumours, a relative accumulation of the tracer was observed with time, which, at 220 min after injection, depended on tumour strain and oxygenation conditions, i.e. 10% O(2) significantly increased the tumour-to-muscle ratio whereas carbogen decreased it. [(18)F]EF3 was rapidly metabolised in the kidney and the liver. [(18)F]EF3 is a promising tracer for detection of tumour hypoxia. A phase I study in head and neck cancer patients is in progress at our institution.