  Range verification of clinical protontherapy systems via positron-emission
tomography (PET) still suffers from insufficient signal from low-energy protons
around the Bragg peak and biological washout of PET emitters. Here we
investigate the possibilities of O-18-enriched water (18-W), a potential
contrast agent that could be incorporated in live tissues by replacing regular
water, leading to the production of the F-18 PET emitters in the last
millimeters of the proton path. We hypothesize that 18-W could also mitigate
the problem of washout, as PET (F-18) isotopes created inside live cells would
remain trapped in the form of fluoride anions.
  To test our hypothesis, we designed an experiment to prove that 18-W can
incorporate enough O-18 into a living organism to produce a detectable signal
from F-18 after proton irradiation, and to determine the amount of activity
that remains trapped inside the cells. The experiment was performed on a
chicken embryo chorioallantoic membrane tumor model of head and neck cancer.
Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV
protons, equivalent to clinical protons at the end of particle range. The
activity produced after irradiation was detected and quantified in a
small-animal PET-CT scanner. The specific F-18 activity was detected in the
tumor area of the alive chicken embryo up to 9 h after irradiation. Dynamic PET
studies evidenced a minimal effect of biological washout, with 68% retained
specific 18F activity at 8 hours after irradiation.
  Therefore, an infusion of 18-W can incorporate O-18 in animal tissues by
replacing regular water inside cells, producing a PET signal when irradiated
with low-energy protons that could be used for range verification in
protontherapy. F-18 produced inside cells suffers from minimal biological
washout, allowing for a sharper localization with longer PET acquisitions.
