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

Abstract

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.

Imaging tumor hypoxia by magnetic resonance methods

“…The pharmacokinetic and toxicity profiles appear to be favorable for use as a hypoxia marker. More recently, a mean retention index of 13.6 in human neoplasms has been reported, compared to the retention index of 4.1 found in plasma samples obtained simultaneously with the spectroscopic measurement, revealing the presence of hypoxia in those tumours (128).…”

Molecular Imaging of the Tumor Microenvironment for Precision Medicine and Theranostics

“…Its accumulation can be used to report on hypoxia in vivo with 19 F MRS (Procissi et al, 2007). Very few first-in-human studies have been performed so far (Lee et al, 2009). The nitroimidazole hypoxia marker SR4554 was tested in 26 patients in various malignancies, with a predominance of gastrointestinal stromal tumors, head and neck cancer, and melanoma.…”

“…Tumors that were at least 3 cm in size and no more than 4 cm depth were investigated to allow acquisition of 19 F MRS data with a surface coil. While the study showed the feasibility of using MRS to study the retention of the probe in some tumors, it also highlighted the low sensitivity of MRS compared to PET (Lee et al, 2009). …”

MRI of Metastasis-Permissive Microenvironments

“…The spatial distribution of the probe can be visualized with 19 F MR spectroscopic images overlaid with anatomic images [58]. Phase I studies of SR-4554, a fluorinated 2-nitroimidazole, demonstrated that 19 F MR spectra can detect retention of the probe in tumors after intravenous injection [59,60]. Hypoxia in tumors can also be detected with 19 F MRS of hexafluorobenzene, a reporter molecule with an oxygen-dependent T 1 relaxation rate [56].…”