OBJECTIVE

To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS).

METHODS

SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed.

RESULTS

Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h.

CONCLUSIONS

SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.