Hyperpolarized Xenon-129 Chemical Exchange Saturation Transfer (HyperCEST) Molecular Imaging: Achievements and Future Challenges.

Molecular magnetic resonance imaging (MRI) is an emerging field that is set to revolutionize our perspective of disease diagnosis, treatment efficacy monitoring, and precision medicine in full concordance with personalized medicine. A wide range of hyperpolarized (HP) 129Xe biosensors have been recently developed, demonstrating their potential applications in molecular settings, and achieving notable success within in vitro studies. The favorable nuclear magnetic resonance properties of 129Xe, coupled with its non-toxic nature, high solubility in biological tissues, and capacity to dissolve in blood and diffuse across membranes, highlight its superior role for applications in molecular MRI settings. The incorporation of reporters that combine signal enhancement from both hyperpolarized 129Xe and chemical exchange saturation transfer holds the potential to address the primary limitation of low sensitivity observed in conventional MRI. This review provides a summary of the various applications of HP 129Xe biosensors developed over the last decade, specifically highlighting their use in MRI. Moreover, this paper addresses the evolution of in vivo applications of HP 129Xe, discussing its potential transition into clinical settings.

Cucurbit[6]uril Hyperpolarized Chemical Exchange Saturation Transfer Pulse Sequence Parameter Optimization and Detectability Limit Assessment at 3.0T.

The front cover artwork is provided by Prof. Mitchell S. Albert's group at Lakehead University. The image shows the hyperpolarized chemical exchange saturation transfer (HyperCEST) effect in cucurbit[6]uril molecular biosensors within a blood vessel. Read the full text of the Research Article at 10.1002/cphc.202300346.

Cucurbit[6]uril Hyperpolarized Chemical Exchange Saturation Transfer Pulse Sequence Parameter Optimization and Detectability Limit Assessment at 3.0T.

Molecular imaging is the future of personalized medicine; however, it requires effective contrast agents. Hyperpolarized chemical exchange saturation transfer (HyperCEST) can boost the signal of Hyperpolarized 129 Xe MRI and render it a molecular imaging modality of high efficiency. Cucurbit[6]uril (CB6) has been successfully employed in vivo as a contrast agent for HyperCEST MRI, however its performance in a clinical MRI scanner has yet to be optimized. In this study, MRI pulse sequence parameter optimization was first performed in CB6 solutions in phosphate-buffered saline (PBS), and subsequently in whole sterile citrated bovine blood. The performance of four different depolarization pulse shapes (sinusoidal, 3-lobe sinc (3LS), rectangular (block), and hyperbolic secant (hypsec) was optimized. The detectability limits of CB6 in a clinical 3.0T MRI scanner was assessed using the optimized pulse sequences. The 3LS depolarization pulses performed best, and demonstrated 24 % depletion in a 25 µM solution of CB6 in PBS. It performed similarly in blood. The CB6 detectability limit was found to be 100 µM in citrated bovine blood with a correspondent HyperCEST depletion of 30 % ±9 %. For the first time, the HP 129 Xe HyperCEST effect was observed in red blood cells (RBC) and had a similar strength as HyperCEST in plasma.

Revealing a Third Dissolved-Phase Xenon-129 Resonance in Blood Caused by Hemoglobin Glycation.

Hyperpolarized (HP) xenon-129 (129Xe), when dissolved in blood, has two NMR resonances: one in red blood cells (RBC) and one in plasma. The impact of numerous blood components on these resonances, however, has not yet been investigated. This study evaluates the effects of elevated glucose levels on the chemical shift (CS) and T2* relaxation times of HP 129Xe dissolved in sterile citrated sheep blood for the first time. HP 129Xe was mixed with sheep blood samples premixed with a stock glucose solution using a liquid-gas exchange module. Magnetic resonance spectroscopy was performed on a 3T clinical MRI scanner using a custom-built quadrature dual-tuned 129Xe/1H coil. We observed an additional resonance for the RBCs (129Xe-RBC1) for the increased glucose levels. The CS of 129Xe-RBC1 and 129Xe-plasma peaks did not change with glucose levels, while the CS of 129Xe-RBC2 (original RBC resonance) increased linearly at a rate of 0.015 ± 0.002 ppm/mM with glucose level. 129Xe-RBC1 T2* values increased nonlinearly from 1.58 ± 0.24 ms to 2.67 ± 0.40 ms. As a result of the increased glucose levels in blood samples, the novel additional HP 129Xe dissolved phase resonance was observed in blood and attributed to the 129Xe bound to glycated hemoglobin (HbA1c).

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

Hyperpolarized 129 Xe imaging of the brain: Achievements and future challenges.

Hyperpolarized (HP) xenon-129 (129 Xe) brain MRI is a promising imaging modality currently under extensive development. HP 129 Xe is nontoxic, capable of dissolving in pulmonary blood, and is extremely sensitive to the local environment. After dissolution in the pulmonary blood, HP 129 Xe travels with the blood flow to the brain and can be used for functional imaging such as perfusion imaging, hemodynamic response detection, and blood-brain barrier permeability assessment. HP 129 Xe MRI imaging of the brain has been performed in animals, healthy human subjects, and in patients with Alzheimer's disease and stroke. In this review, the overall progress in the field of HP 129 Xe brain imaging is discussed, along with various imaging approaches and pulse sequences used to optimize HP 129 Xe brain MRI. In addition, current challenges and limitations of HP 129 Xe brain imaging are discussed, as well as possible methods for their mitigation. Finally, potential pathways for further development are also discussed. HP 129 Xe MRI of the brain has the potential to become a valuable novel perfusion imaging technique and has the potential to be used in the clinical setting in the future.

Hyperpolarized 129 Xe multi-slice imaging of the human brain using a 3D gradient echo pulse sequence.

PURPOSE: To demonstrate the possibility of performing multi-slice in-vivo human brain MRI using hyperpolarized (HP) xenon-129 (129 Xe) in two different orientations and to calculate the signal-to-noise ratio (SNR). METHODS: Two healthy female participants were imaged during a single breath-hold of HP 129 Xe using a Philips Achieva 3.0T MRI scanner (Philips, Andover, MA). Each HP 129 Xe multi-slice brain image was acquired during separate HP 129 Xe breath-holds using 3D gradient echo (GRE) imaging. The acquisition started 10 s after the inhalation of 1 L of HP 129 Xe. Overall, four sagittal and three axial images were acquired (seven imaging sessions per participant). The SNR was calculated for each slice in both orientations. RESULTS: The first ever HP 129 Xe multi-slice images of the brain were acquired in axial and sagittal orientations. The HP 129 Xe signal distribution correlated well with the gray matter distribution. The highest SNR values were close in the axial and sagittal orientations (19.46 ± 3.25 and 18.76 ± 4.94, respectively). Additionally, anatomical features, such as the ventricles, were observed in both orientations. CONCLUSION: The possibility of using multi-slice HP 129 Xe human brain magnetic resonance imaging was demonstrated for the first time. HP 129 Xe multi-slice MRI can be implemented for brain imaging to improve current diagnostic methods.

The effects of an initial depolarization pulse on dissolved phase hyperpolarized 129 Xe brain MRI.

PURPOSE: To evaluate the effect of an initial 90° depolarization RF pulse on the dissolved-phase hyperpolarized (HP) xenon-129 (129 Xe) brain imaging and to compare the SNR variability of HP 129 Xe images acquired without an initial depolarization RF pulse to those following the initial depolarization pulse. METHODS: Five cognitive normal healthy volunteers were imaged using a Philips Achieva 3.0T MRI scanner during a single breath-hold following inhalation of 1 L of HP 129 Xe. Each participant underwent six HP 129 Xe scans. Three scans were performed using conventional single-slice projection HP 129 Xe brain imaging, and the other three scans were performed using the HP 129 Xe time-of-flight imaging with an initial rectangular depolarization pulse. RESULTS: Although the utilization of an initial depolarization results in the reduction of the mean image SNR, the presence of an initial depolarization RF pulse reduces the SNR variability of the HP 129 Xe brain image by a factor of 2.26. The highest SNR variability was observed from the posterior brain region, where the anterior region possessed the lower level of signal variability. CONCLUSION: An initial 90° depolarization RF pulse, applied prior to the HP 129 Xe image acquisition, reduced the HP 129 Xe signal variability more than two times between the different breath-hold images.

Evaluation of fluorine-19 magnetic resonance imaging of the lungs using octafluorocyclobutane in a rat model.

PURPOSE: To test octafluorocyclobutane (OFCB) as an inhalation contrast agent for fluorine-19 MRI of the lung, and to compare the image quality of OFCB scans with perfluoropropane (PFP) scans THEORY AND METHODS: After normalizing for the number of signal averages, a theoretical comparison between the OFCB signal-to-noise ratio (SNR) and PFP SNR predicted the average SNR advantage of 90% using OFCB during gradient echo imaging. The OFCB relaxometry was conducted using single-voxel spectroscopy and spin-echo imaging. A comparison of OFCB and PFP SNRs was performed in vitro and in vivo. Five healthy Sprague-Dawley rats were imaged during single breath-hold and continuous breathing using a Philips Achieva 3.0T MRI scanner (Philips, Andover, MA). The scan time was constant for both gases. Statistical comparison between PFP and OFCB scans was conducted using a paired t test and by calculating the Bayes factor. RESULTS: Spin-lattice (T1 ) and effective spin-spin ( T2∗ ) relaxation time constants of the pure OFCB gas were determined as 28.5 ± 1.2 ms and 10.5 ± 1.8 ms, respectively. Mixing with 21% of oxygen decreased T1 by 30% and T2∗ by 20%. The OFCB in vivo images showed 73% higher normalized SNR on average compared with images acquired using PFP. The statistical significance was shown by both paired t test and calculated Bayes factors. The experimental results agree with theoretical calculations within the error of the relaxation parameter measurements. CONCLUSION: The quality of the lung images acquired using OFCB was significantly better compared with PFP scans. The OFCB images had higher a SNR and were artifact-free.

Molecular Imaging of Fluorinated Probes for Tau Protein and Amyloid-ß Detection.

Alzheimer's disease (AD) is the most common form of dementia and results in progressive neurodegeneration. The incidence rate of AD is increasing, creating a major public health issue. AD is characterized by neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and senile plaques composed of amyloid-ß (Aß). Currently, a definitive diagnosis of AD is accomplished post-mortem. Thus, the use of molecular probes that are able to selectively bind to NFTs or Aß can be valuable tools for the accurate and early diagnosis of AD. The aim of this review is to summarize and highlight fluorinated molecular probes that can be used for molecular imaging to detect either NFTs or Aß. Specifically, fluorinated molecular probes used in conjunction with 19F MRI, PET, and fluorescence imaging will be explored.

Cyclodextrin-Based Contrast Agents for Medical Imaging.

Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits. CDs are widely used in host-guest chemistry and biochemistry due to their structural advantages, biocompatibility, and ability to form inclusion complexes. Recently, CDs have become of high interest in the field of medical imaging as a potential scaffold for the development of a large variety of the contrast agents suitable for magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, positron emission tomography, single photon emission computed tomography, and computed tomography. The aim of this review is to summarize and highlight the achievements in the field of cyclodextrin-based contrast agents for medical imaging.

R3-Noria-methanesulfonate: A Molecular Cage with Superior Hyperpolarized Xenon-129 MRI Contrast.

Hyperpolarized (HP) xenon-129 (129Xe) magnetic resonance imaging (MRI) has the potential to be used as a molecular imaging modality. For this purpose, numerous supramolecular cages have been developed and evaluated in the past. Herein, we report a novel and unique macrocycle that can be successfully utilized for xenon MRI, the resorcinarene trimer methanesulfonate (R3-Noria-MeSO3H). This molecule is capable of two different contrast mechanisms for xenon-MRI, resulting from an increase in the effective spin-spin relaxation and hyperpolarized chemical exchange saturation transfer (HyperCEST). We have demonstrated a superior negative contrast caused by R3-Noria-MeSO3H on HP 129Xe MRI at 3.0 T as well as HyperCEST imaging of the studied macrocycle. Additionally, we have found that the complex aggregation behaviors of R3-Noria-methanesulfonate and its impact on xenon-129 relaxivity are an area for future study.

Hyperpolarized 129Xe Time-of-Flight MR Imaging of Perfusion and Brain Function.

Perfusion measurements can provide vital information about the homeostasis of an organ and can therefore be used as biomarkers to diagnose a variety of cardiovascular, renal, and neurological diseases. Currently, the most common techniques to measure perfusion are 15O positron emission tomography (PET), xenon-enhanced computed tomography (CT), single photon emission computed tomography (SPECT), dynamic contrast enhanced (DCE) MRI, and arterial spin labeling (ASL) MRI. Here, we show how regional perfusion can be quantitively measured with magnetic resonance imaging (MRI) using time-resolved depolarization of hyperpolarized (HP) xenon-129 (129Xe), and the application of this approach to detect changes in cerebral blood flow (CBF) due to a hemodynamic response in response to brain stimuli. The investigated HP 129Xe Time-of-Flight (TOF) technique produced perfusion images with an average signal-to-noise ratio (SNR) of 10.35. Furthermore, to our knowledge, the first hemodynamic response (HDR) map was acquired in healthy volunteers using the HP 129Xe TOF imaging. Responses to visual and motor stimuli were observed. The acquired HP TOF HDR maps correlated well with traditional proton blood oxygenation level-dependent functional MRI. Overall, this study expands the field of HP MRI with a novel dynamic imaging technique suitable for rapid and quantitative perfusion imaging.

Decacationic Pillar[5]arene: A New Scaffold for the Development of 129Xe MRI Imaging Agents.

A decacationic water-soluble pillar[5]arene possessing a nonsolvated hydrophobic core has been designed and synthesized. This supramolecular host is capable of binding xenon, as evidenced by hyperCEST depletion experiments. Fluorescence-based studies also demonstrate that xenon binds into the cavity of the pillararene with an association constant of 4.6 × 103 M-1. These data indicate that the water-soluble pillararene is a potential scaffold for building contrast agents that can be detected by xenon-129 magnetic resonance imaging.

In-Vivo Retention of 5-Fluorouracil Using 19F Magnetic Resonance Chemical Shift Imaging in Colorectal Cancer in a Murine Model.

Colorectal cancer is the third leading cause of cancer death worldwide. 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapies for treatment of solid tumours, including colorectal cancer. The efficacy of treatment is dependent on tumour type and can only be determined six weeks after beginning chemotherapy, with only 40-50% of patients responding positively to the 5-FU therapy. In this paper, we demonstrate the potential of using Magnetic Resonance (MR) Chemical Shift Imaging (CSI) for in-vivo monitoring of 5-FU tumor-retention in two different colorectal tumour types (HT-29 & H-508). Time curves for 5-FU signals from the liver and bladder were also acquired. We observed significant differences (p < 0.01) in 5-FU signal time dependencies for the HT-29 and H-508 tumours. Retention of 5-FU occurred in the H-508 tumour, whereas the HT-29 tumour is not expected to retain 5FU due to the observation of the negative b time constant indicating a decline in 5FU within the tumour. This study successfully demonstrates that CSI may be a useful tool for early identification of 5-FU responsive tumours based on observed tumour retention of the 5-FU.

Cyclodextrin-Based Pseudorotaxanes: Easily Conjugatable Scaffolds for Synthesizing Hyperpolarized Xenon-129 Magnetic Resonance Imaging Agents.

Hyperpolarized (HP) xenon-129 (Xe) magnetic resonance (MR) imaging has the potential to detect biological analytes with high sensitivity and high resolution when coupled with xenon-encapsulating molecular probes. Despite the development of numerous HP Xe probes, one of the challenges that has hampered the translation of these agents from in vitro demonstration to in vivo testing is the difficulty in synthesizing the Xe-encapsulating cage molecule. In this study, we demonstrate that a pseudorotaxane, based on a γ-cyclodextrin macrocycle, is easily synthesized in one step and is detectable using HyperCEST-enhanced 129Xe MR spectroscopy.