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Range verification of clinical protontherapy systems via positron-emissiontomography (PET) still suffers from insufficient signal from low-energy protonsaround the Bragg peak and biological washout of PET emitters. Here weinvestigate the possibilities of O-18-enriched water (18-W), a potentialcontrast agent that could be incorporated in live tissues by replacing regularwater, leading to the production of the F-18 PET emitters in the lastmillimeters of the proton path. We hypothesize that 18-W could also mitigatethe problem of washout, as PET (F-18) isotopes created inside live cells wouldremain trapped in the form of fluoride anions.  To test our hypothesis, we designed an experiment to prove that 18-W canincorporate enough O-18 into a living organism to produce a detectable signalfrom F-18 after proton irradiation, and to determine the amount of activitythat remains trapped inside the cells. The experiment was performed on achicken embryo chorioallantoic membrane tumor model of head and neck cancer.Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeVprotons, equivalent to clinical protons at the end of particle range. Theactivity produced after irradiation was detected and quantified in asmall-animal PET-CT scanner. The specific F-18 activity was detected in thetumor area of the alive chicken embryo up to 9 h after irradiation. Dynamic PETstudies evidenced a minimal effect of biological washout, with 68% retainedspecific 18F activity at 8 hours after irradiation.  Therefore, an infusion of 18-W can incorporate O-18 in animal tissues byreplacing regular water inside cells, producing a PET signal when irradiatedwith low-energy protons that could be used for range verification inprotontherapy. F-18 produced inside cells suffers from minimal biologicalwashout, allowing for a sharper localization with longer PET acquisitions.

Could 18O-enriched water increase signal for PET proton range verification? A study using a chicken embryo model