'The output is the same, but the timing is not'.

(keywords: oncology, radiology, nuclear medicine, medical physics, PET, hypoxia, ⁴⁴Sc)

The output from a patient in the positron emission tomography (PET) is the annihilation γ-ray photons emitted according to the following equation:

First, the radioactive isotope, e.g. ¹⁸F, undergoes the β⁺ decay and emits a positron (e⁺). Second, the positron collides with an electron (e⁻) in surrounding molecules. Last, the positron and electron annihilate into 2 γ-ray photons due to the matter-antimatter pair annihilation. This is the conventional picture; however, it should be modified to include the positronium (Ps) as described in the lower part of the equation. Ps is a hydrogen-like atom consisting of a positron and an electron and the atom decays into 2 γ-ray photons within a short time: ca. 2 ns (1/500,000,000 s) on average in vivo. 'The output (2γ) is the same' is a reason why Ps has received little attention in PET; however, ca. 100 billion Ps atoms are spontaneously created and annihilated in the human body per examination.

'But the timing is not' is the reason why the Ps can provide new biological information on hypoxia. The emission of the output (2γ) is delayed as long as the lifetime of Ps, and the lifetime is influenced considerably by the partial pressure of oxygen (pO₂) because the annihilation of Ps is accelerated by O₂ due to the unpaired electrons.

The figure below shows the relation between pO₂ in water and Ps annihilation rate (Γ), which is the inverse of the lifetime. Linearity is observed because the chance for Ps to encounter O₂ for quenching is proportional to pO₂, and the line and its equation in the figure describe how to convert Γ into pO₂. The sensitivity can be estimated from the uncertainties of the equation to be ca. 10 mmHg when 300 million counts are obtained from the field-of-view (FOV) and to be ca. 5 mmHg when 1 billion counts are obtained. According to previous reports, pO₂ in healthy liver tissue cells is ca. 41 mmHg [1] and that in liver tumour cells is ca. 6 mmHg [2]; therefore, Ps has enough sensitivity for discriminating the tumour hypoxia region from the control regions.

Figure: The relation between pO₂/mmHg and Ps annihilation rate (Γ/μs^-1), which is the inverse of the lifetime. The parentheses in the equation indicate the uncertainty (1σ). 

The advantage of this method is the absolute determination of pO₂ independently of the scanner and protocol. As this method is based on the fundamental properties of Ps, i.e. the spin and reactions, the results are also independent of the mechanism of the delivery/accumulation of the radiopharmaceuticals. The technical barriers related to the hardware are expected not high because the required specifications of a new timer for measuring the lifetime of Ps is comparable with that of the time-of-flight (TOF) function installed in current scanners. However, the development of radiopharmaceuticals with an appropriate radioactive isotope having a relatively short half-life, i.e. several hours/days, and a prompt-γ-ray emission, such as ⁴⁴Sc [3], is essential for the clinical use.

References

1. Carreau, A. et al. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J. Cell. Mol. Med. 15, 1239–1253 (2011). (DOI: 10.1111/j.1582-4934.2011.01258.x)
2. Vaupel, P. et al. Detection and characterization of tumour hypoxia using pO₂ histography. Antioxid. Redox Signal. 9, 1221–1225 (2007). (DOI: 10.1089/ars.2007.1628)
3. Müller, C. et al. Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application. Brit. J. Radiol. 91, 20180074 (2018). (DOI: 10.1259/bjr.20180074)
4. Shibuya, K., et al. Oxygen sensing ability of positronium atom for tumour hypoxia imaging. Communications Physics 3, 173 (2020). (DOI: 10.1038/s42005-020-00440-z, OPEN ACCESS)
5. Devor, C. Timing the life of antimatter particles may lead to better cancer treatment. UTokyo Focus (2020). (https://www.u-tokyo.ac.jp/focus/en/press/z0508_00133.html)
6. Stephens, M. Positronium formed during PET scans could detect hypoxic tumours. Physics World (2020). (https://physicsworld.com/a/positronium-formed-during-pet-scans-could-detect-hypoxic-tumours/)

This work [4] was published on 1 October 2020, in Communication Physics, a sister journal of Nature Communications and Communications Biology. You can find general commentaries in the press release from the University of Tokyo by Ms Caitlin Devor [5] and in a magazine from the Institute of Physics (IOP, England), i.e. Physics World, by Mr Marric Stephens [6]. Reading them would assist with the understanding of the original paper [4].