Xenon gas MRI

Hyperpolarized ¹²⁹Xe gas magnetic resonance imaging (MRI) is a medical imaging technique used to visualize the anatomy and physiology of body regions that are difficult to image with standard proton MRI. In particular, the lung, which lacks substantial density of protons, is particularly useful to be visualized with ¹²⁹Xe gas MRI. This technique has promise as an early-detection technology for chronic lung diseases and imaging technique for processes and structures reliant on dissolved gases. ¹²⁹Xe is a stable, naturally occurring isotope of xenon with 26.44% isotope abundance. It is one of two Xe isotopes, along with ¹³¹Xe, that has non-zero spin, which allows for magnetic resonance. ¹²⁹Xe is used for MRI because its large electron cloud permits hyperpolarization and a wide range of chemical shifts. The hyperpolarization creates a large signal intensity, and the wide range of chemical shifts allows for identifying when the ¹²⁹Xe associates with molecules like hemoglobin. ¹²⁹Xe is preferred over ¹³¹Xe for MRI because ¹²⁹Xe has spin 1/2 (compared to 3/2 for ¹³¹Xe), a longer T1, and 3.4 times larger gyromagnetic ratio (11.78 MHz/T).

Uses

Medical uses

Xenon Xe 129 hyperpolarized

Clinical data
Trade names	Xenoview
License data	US DailyMed: Xenon Xe 129
Routes of administration	Inhalation
ATC code	None
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	13965-99-6
PubChem CID	10290811
UNII	726Q6M95ZA
KEGG	D12496

Xenon Xe 129 hyperpolarized, sold under the brand name Xenoview, is a hyperpolarized contrast agent indicated for use with magnetic resonance imaging (MRI) for evaluation of lung ventilation, and approved for people aged twelve years of age and older. It was approved for medical use in the US in December 2022.

The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.

The FDA approved Xenoview based on evidence from two clinical trials in 83 participants with various lung disorders who were being evaluated for possible lung resection or lung transplantation. The trials were conducted at five sites in the United States and assessed both efficacy and safety of Xenoview. Xenoview was evaluated in two clinical trials of 83 adults with pulmonary disorders who each underwent sequential lung ventilation imaging with Xenoview with MRI and an approved comparator, Xe 133 scintigraphy. In study 1, participants were imaged to help plan possible lung resection. To determine the benefit of Xenoview, estimates of the percentage of lung ventilation predicted to remain after surgery made with Xenoview with MRI and comparator imaging were evaluated for equivalence. In study 2, participants were imaged to help plan possible lung transplantation. To determine the benefit of Xenoview, estimates of the percentage of lung ventilation contributed by the right lung made with Xenoview with MRI and comparator imaging were evaluated for equivalence.

History

Hyperpolarized ¹²⁹Xe is achieved through spin-exchange optical pumping, a technique developed by Grover et al. in 1978 and improved by Happer et al. in 1984. Quantification of ¹²⁹Xe polarization was first described in 1982 by Bhaskar et al. The use of hyperpolarized ¹²⁹Xe gas in MRI ex-vivo was first described by Albert et al. in 1994 using excised rat lungs. The first in-vivo human studies with ¹²⁹Xe MRI were published by Mugler et al. in 1997.

¹²⁹Xe MRI has largely begun to replace ³He gas MRI, a very similar technology that uses hyperpolarized ³He molecules instead of ¹²⁹Xe. Grossman et al. began human clinical trials for ³He MRI in 1996. ³He was originally touted as the better gas for hyperpolarized gas MRI because it is more polarizable and has no effects on the body. However, ³He is mostly produced by the beta decay of tritium (³H), which is a product of nuclear warhead production. Additionally, ³He is widely used by the U.S. military to detect smuggled plutonium. These combination of increasing scarcity and increasing demand have combined to make ³He highly expensive, up to more than $1000 per liter.

Safety

¹²⁹Xe is an inert, non-radioactive, non-toxic, and non-teratogenic molecule that has shown no significant adverse health effects when inhaled for MR imaging. One potential area of concern is ¹²⁹Xe's anesthetic properties when a large volume is inhaled. Xenon shows blood and tissue solubility that allows it to diffuse through the lung membrane and affect the nervous system. The minimum alveolar concentration for 50% of motor response to be prevented (MAC) is 0.71, which is not reached during imaging. Further studies have shown that it provides good circulatory stability when dissolved in blood and does not affect body temperature.

Hyperpolarization

When applying an external magnetic field to gas, half of the nuclear spins of the gas atoms point towards the direction of the magnetic field whereas the other half point in the opposite direction. It is slightly more energetically favorable to be aligned with the magnetic field, meaning that one of the spin states is in slight excess of the other. This excess means that the two spin-states do not completely cancel each other out, creating a magnetic signal which can be observed with MRI. However, for traditional ¹H MRI, only about 4 ppm of the spin states do not cancel, so the signal is not particularly strong. This means that only regions with high densities of protons, like muscle tissue can be seen. Hyperpolarization is a means of flipping more of the atoms to have the same spin state so that less of the spin states cancel each other. In the case of ¹²⁹Xe, this leads to a 10⁴-10⁵ improvement in signal strength.

Polarization Transfer

Hyperpolarization of ¹²⁹Xe is usually performed using spin-exchange optical pumping (SEOP) using circularly polarized light to add angular momentum of the atoms. However, the polarized light cannot directly transfer angular momentum to the gas nuclei, thus, an alkali metal atom is used as an intermediary. Rubidium is often used to accomplish this, where the polarized light is tuned to provide exactly the necessary energy to excite rubidium's valence electron. This process is called optical pumping. In the next step, spin exchange, gas nuclei are introduced to the system and collide with the rubidium. They receive angular momentum in the collisions with rubidium valence electrons, which, by conservation of angular momentum, is in the same direction as the rubidium. Therefore, ¹²⁹Xe becomes hyperpolarized because there is a large excess of one spin state compared to the other. After this, the ¹²⁹Xe is extracted, the rubidium is polarized again, and the cycle continues.

Required modifications to conventional MRI

Traditional MR scanners need to be modified to detect ¹²⁹Xe, as ¹²⁹Xe has a lower gyromagnetic ratio of 11.77 MHz/T compared to that of protons, 42.5 MHz/T. Thus, the Larmor frequency of ¹²⁹Xe is much lower, which is difficult to detect with conventional narrow-band RF amplifiers set to proton's Larmor frequency. Therefore, a broad-band RF amplifier, for both excitation and receiving, is required. Additionally, the pulse sequence must also accommodate the difference in thermally-polarized protons and polarized ¹²⁹Xe. In proton MRI, a typical pulse sequence would involve a 90° flip then a subsequent T1 longitudinal relaxation to the external magnetic field. T1 relaxation in hyperpolarized gas involves the decay of magnetization and not the return to an external magnetic field, as in thermally-polarized protons. Therefore, after a 90° flip, a hyperpolarized gas nuclei's longitudinal relaxation is negligible, making the longitudinal magnetization remain zero after the flip. As a result, traditional 90° and 180° RF pulses are not desirable. A low-angle RF pulse is therefore used to only remove a portion of the total available magnetization of the hyperpolarized ¹²⁹Xe gas. This produces comparable longitudinal magnetization between protons and ¹²⁹Xe gas. Furthermore, as an image needs to be acquired within a breath-hold, a fast pulse-sequences, or fast-gradient echos, are used to adequately sample the k-space.

Applications

Ventilation MRI

After a patient inhales the hyperpolarized gas, the gas passes through the airways within the lungs. In a healthy lung, the gas is able to travel throughout the lungs. However, in a disease that obstructs airways, such as chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis, the hyperpolarized gas is unable to reach certain regions within the lung. Thus, a spin-density weighted image will produce high signals from normal areas and low signals from diseased regions. ³He was originally used for this type of image, but recently there has been a shift towards to ¹²⁹Xe due to its availability and cheaper price. Hyperpolarized ³He has historically produced superior images because it is easier to hyperpolarize, but current technology has improved gas polarization of ¹²⁹Xe to the point where the image quality is similar. Furthermore, ¹²⁹Xe is more sensitive to obstructions as it is a larger atom than ³He. In addition, an increased inhaled volume of ¹²⁹Xe results in a comparable SNR to that of ³He, up to 1 vs 0.1-0.3 liters.

Diffusion MRI

Diffusion MRI involves calculating the apparent diffusion coefficient (ADC) of the hyperpolarized gas. Diffusion-sensitizing gradients are applied to induce diffusion based attenuation to calculate the ADC. These gradients have an associated b-value, which represents the strength and duration of the gradients. At least 2 different b-value gradients are used to calculate the ADC. The ADC provides information regarding how the structure of the lung restricts the hyperpolarized gas diffusion. The value of the ADC increases in regions of increased space. For example, in healthy lungs, the ADC using ¹²⁹Xe might be around 0.04 cm²/s whereas the ADC for ¹²⁹Xe in an open space may be around 0.14 cm²/s. In emphysema, where alveolar structures enlarge, the gas is able to diffuse more freely, resulting in a higher ADC compared to normal regions providing information of disease areas. Ultimately, this is a novel imaging modality enabled by ¹²⁹Xe MRI, and its use is being investigated for Chronic Obstructive Pulmonary Disease, Asthma, Cystic Fibrosis, Long-COVID-19, and other diseases.

Partial pressure of oxygen

The longitudinal relaxation (T1) of the hyperpolarized gas is inversely proportional to the concentration of the oxygen in the lung. The interaction between paramagnetic oxygen significantly decreases the relaxation time, which offers insights into the partial pressure of oxygen (pO₂) within regions of the lung. Additionally, the ventilation to perfusion ratio can be calculated from these images. Most research has employed ³He, but improved technology has allowed for comparable results when using ¹²⁹Xe. However, due to the uptake of ¹²⁹Xe, its relaxation is much quicker than ³He resulting in higher apparent pO₂ if left unaccounted.

Research

Xe Gas MRI of Healthy and Diseased Lungs. Colors show different intensities of Xe Gas.

¹²⁹Xe gas MRI is being researched as a diagnostic test for respiratory diseases, such as COPD, asthma, and emphysema. Spirometry pulmonary function tests are used to determine the condition of lung function. However, this is a fairly basic, global assessment of lung function that does not provide specific information about the lung structure and physiology. For structural information, X-Ray CT is most commonly used, but it exposes the patient to high doses of ionizing radiation and it provides no functional information Conventional ¹H MRI is not effective in the lung airspace because of the minimal proton density. ¹²⁹Xe gas MRI provides detailed, specific information about lung structure and function that are not safely or efficiently obtainable by existing technologies.

Visualizing non-lung tissues

¹²⁹Xe gas is most commonly used to visualize the lung because it is a gas. However, small bubbles of xenon gas are capable of dissolving into the bloodstream at the alveoli. As these bubbles travel around the body, they can be used to gain insight into other regions of the body. ¹²⁹Xe gas is capable of crossing the blood brain barrier, allowing novel study of brain perfusion.r

Improving amount of hyperpolarization

Using hyperpolarized gas to image the lungs is not particularly novel, as the use of ³He was established in the early 2000s. ³He was originally chosen because it was easily hyperpolarized to a very large degree, and therefore generated a very strong signal. Recently, improvements in hyperpolarization techniques have been able to generate more hyperpolarized ¹²⁹Xe, enabling it to generate comparable images to ³He.