Phase I Randomized Trial of 17 O-Labeled Water: Safety and Feasibility Study of Indirect Proton MRI for the Evaluation of Cerebral Water Dynamics

Abstract

Background: ¹⁷ O-labeled water (PSO17) is a contrast agent developed to measure brain water dynamics and cerebral blood flow.

Purpose: To evaluate the safety and feasibility of PSO17.

Study type: Prospective study.

Subjects: A total of 12 male healthy volunteers (23.1 ± 1.9 years) were assigned to three groups of four subjects: placebo (normal saline), PSO17 10%, and PSO17 20%.

Field strength/sequence: Dynamic 3D fluid attenuated inversion recovery (FLAIR, fast spin echo with variable refocusing flip angle) scans of the brain were performed with 3-T MRI.

Assessment: Contrast agents were injected 5 minutes after the start of a 10-minute scan. Any symptoms, vital signs, and blood and urine tests were evaluated at five timepoints from preinjection to 4 days after. Blood samples for pharmacokinetic analysis, including half-life (T1/2), maximum fraction (C_max ), time-to-maximum fraction (T_max ), and area under the curve (AUC), were collected at 13 timepoints from preinjection to 168 hours after. Regions of interest were set in the cerebral cortex (CC), basal ganglia/thalamus (BG/TM), and white matter (WM), and ¹⁷ O concentrations were calculated from signal changes and evaluated using C_max .

Statistical tests: All items were compared among the three groups using Tukey-Kramer's honestly significant difference test. Statistical significance was defined as P < 0.5.

Results: No safety issues were noted with the intravenous administration of PSO17. The T1/2 was approximately 160 hours, and the AUCs were 1.77 ± 0.10 and 3.75 ± 0.36 in the PSO17 10% and 20% groups, respectively. ¹⁷ O fractions calculated from MRI signals were higher in the PSO17 20% group than in the 10% and placebo groups. Significant differences were noted between all pairs of groups in the CC and BG/TM, and between PSO17 20% and both placebo and 10% groups in the WM.

Data conclusion: PSO17 might be considered safe as a contrast medium. Dynamic 3D-FLAIR might detect dose-dependent signal changes and estimate ¹⁷ O.

Evidence level: 1 TECHNICAL EFFICACY: Stage 1.

Keywords: 17O-labeled water; cerebral water dynamics; contrast media.