Spin‐lock imaging of exogenous exchange‐based contrast agents to assess tissue pH

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Iohexol is an iodinated X‐ray contrast agent commonly used in clinical CT imaging. It is a nonionic agent of low osmolality and low chemotoxicity that has demonstrated a very high safety profile in clinical practice 1. Some iodinated contrast agents have also been shown to generate MRI contrast in appropriate conditions. Different from CT imaging, which exploits the increased X‐ray atomic absorption of iodine to enhance images, MRI images may be affected by chemical exchange effects between the exchangeable protons of the iodinated agents and the water protons. Iodinated contrast agents were first used to enhance T2‐weighted images 3, and more recently were used to produce more specific contrast in chemical exchange saturation transfer (CEST) images by applying saturation pulses at the resonance frequencies of the exchangeable protons and detecting a subsequent decrease in the water signal 4. Suggested applications of CEST imaging of iodinated contrast agents include dynamic contrast‐enhanced imaging of tumors 11 and assessment of tumor acidosis 6.
Iodinated contrast agents (eg, iohexol, ioversol, iodixanol, iomeprol) often contain both amide and hydroxyl exchanging groups. The amide groups of iodinated contrast agents have a resonance frequency offset at approximately 4.3 to 4.4 ppm from water, and their exchange rates in physiological conditions are in the intermediate exchange regime 4. Previous CEST imaging of iodinated contrast agents applied saturation on these amide exchanging groups. The hydroxyl groups of iodinated contrast agents have resonance frequency offsets at approximately 0.6 ppm from water, and their exchange rates are in the fast exchange regime 12. Neither the amide nor hydroxyl protons in such X‐ray agents are in slow exchange with water, so that high irradiation powers are required to effectively saturate these groups, resulting in nonspecific direct saturation and semisolid magnetization transfer effects in tissues.
We have previously shown that spin‐lock sequences at high field are also sensitive to chemical exchange, and can be more suitable for detecting intermediate and fast exchanging groups than CEST 12. In addition, R1ρ, the spin‐lock relaxation rate obtained by comparing signals at a fixed locking power but at different locking times, is well estimated by linearly adding individual exchange contributions 13, whereas CEST signals from different exchanging pools have mutual interactions 14. These characteristics make the spin‐lock technique more suitable for quantifying exogenous contrast agents in complex biological tissues, where multiple exchanging pools are present. Moreover, the variation of R1ρ with locking power (the R1ρ dispersion) can be used to estimate specific exchange parameters and emphasize the effects of protons of a specific exchange rate 15.
In this paper, we demonstrate the ability of spin‐lock imaging to detect iohexol in tumor‐bearing rat brains. Two different metrics of MR contrast based on R1ρ are shown to depend separately on iohexol concentration and iohexol–water exchange rate, respectively, and were evaluated for assessing the effects of iohexol administration and extracellular acidification in tumors.

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