Imaging of Extracellular pH Using Hyperpolarized Molecules

Abstract

Many diseases can overrule natural pH regulatory mechanisms and alter the extracellular pH (pHe). A non‐invasive method that resolves pHe in vivo with high spatial and temporal resolution could therefore improve diagnosis and monitoring of diseases, contributing to the concept of precision medicine. During the last decades, several techniques have been proposed to image pHe non‐invasively. The majority of these methods rely on magnetic resonance because of its good spatial resolution, high penetration depth, non‐ionizing radiation and excellent complimentary soft tissue contrast. Dissolution dynamic nuclear polarization (DNP) is an emerging concept to enhance nuclear magnetic resonance (NMR) signals by more than four orders of magnitude, making it possible to observe in vivo metabolic processes in real‐time. Here, we summarize and review recent developments in pHe imaging techniques based on hyperpolarization methods and give an overview of recently discovered hyperpolarized pH sensor molecules that have been applied in vitro and in vivo.

Accurate pH Sensing using Hyperpolarized 129Xe NMR Spectroscopy

“…Different NMR approaches exist in that purpose, based either on endogenous or exogenous species and nuclei, but the crucial point is to overpass the sensitivity limitations of this modality. For one decade, the use of hyperpolarized agents, which nuclear polarization is transiently enhanced by several orders of magnitude, has been proposed . DNP‐hyperpolarized 13 C bicarbonate (DNP: dynamic nuclear polarization) enables the extraction of tissue pH through measurement of the intensity ratio between 13 C NMR signals of bicarbonate and CO 2 .…”

pH Dependence ofT1for13C‐Labelled Small Molecules Commonly Used for Hyperpolarized Magnetic Resonance Imaging

“…Interestingly, we observed a different pH-dependence for [1-13 C]lactate ( Figure 2). Its T 1 is relatively long at pH 1 indicating [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate. The T 1 of urea increases slightly but significantly with pH.…”

“…We further analysed the T 1 -dependence of HP [1-13 C] pyruvate and [1,[5][6][7][8][9][10][11][12][13] C 2 ]zymonic acid (ZA) in comparison to HP 13 C-urea. Note, that the radical was not filtered out for these experiments, as we used the standard dissolution procedure of our preclinical DNP polarizer.…”

“…HP urea has been established as perfusion marker and was applied for myocardial imaging. [11] Lately and among others, [12] [1,5-13 C 2 ]zymonic acid [13] has been discovered as pH sensor and was used to quantify extracellular pH in vivo.The recent design of sterile clinical polarizers [14] has led to the first use of pyruvate in patients [4] and to an increasing interest in hyperpolarization applications. Also, translation of HP applications to the clinic requires refinement of the underlying imaging and hyperpolarization methods.One of the most important properties of hyperpolarized probes is the spin-lattice relaxation time (T 1 ).…”

“…HP urea has been established as perfusion marker and was applied for myocardial imaging. [11] Lately and among others, [12] [1,5-13 C 2 ]zymonic acid [13] has been discovered as pH sensor and was used to quantify extracellular pH in vivo.…”