A phase I study of the nitroimidazole hypoxia marker SR4554 using (19)F magnetic resonance spectroscopy

BACKGROUND: SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with (19)F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m(−2) was established as MTD. Preliminary MRS studies demonstrated some evidence of (19)F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the (19)F MRS signal. METHODS: Patients had tumours ⩾3 cm in diameter and ⩽4 cm deep. Measurements were performed using (1)H/(19)F surface coils and localised (19)F MRS acquisition. SR4554 was administered at 1400 mg m(−2), with subsequent increase to 2600 mg m(−2) using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. (19)Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)*100. RESULTS: A total of 26 patients enrolled at: 1400 (n=16), 1800 (n=1), 2200 (n=1) and 2600 mg m(−2) (n=8). SR4554 was well tolerated and toxicities were all ⩽grade 1; mean plasma elimination half-life was 3.7±0.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised (19)F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6–43.7) compared with 4.1 (range 0.6–7.3) for plasma samples taken at the same times (P=0.001) suggesting (19)F retention in tumour and, therefore, the presence of hypoxia. CONCLUSION: We have demonstrated the feasibility of using (19)F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of (19)F retention in tumour, supporting further development of this technique for detection of tumour hypoxia.