Using bidirectional chemical exchange for improved hyperpolarized [¹³C]bicarbonate pH imaging

Abstract

Purpose: Rapid chemical exchange can affect SNR and pH measurement accuracy for hyperpolarized pH imaging with [ 13 C]bicarbonate. The purpose of this work was to investigate chemical exchange effects on hyperpolarized imaging sequences to identify optimal sequence parameters for high SNR and pH accuracy. Methods: Simulations were performed under varying rates of bicarbonate-CO 2 chemical exchange to analyze exchange effects on pH quantification accuracy and SNR under different sampling schemes. Four pulse sequences, including 1 new technique, a multiple-excitation 2D EPI (multi-EPI) sequence, were compared in phantoms using hyperpolarized [ 13 C]bicarbonate, varying parameters such as tip angles, repetition time, order of metabolite excitation, and refocusing pulse design. In vivo hyperpolarized bicarbonate-CO 2 exchange measurements were made in transgenic murine prostate tumors to select in vivo imaging parameters. Results: Modeling of bicarbonate-CO 2 exchange identified a multiple-excitation scheme for increasing CO 2 SNR by up to a factor of 2.7. When implemented in phantom imaging experiments, these sampling schemes were confirmed to yield high pH accuracy and SNR gains. Based on measured bicarbonate-CO 2 exchange in vivo, a 47% CO 2 SNR gain is predicted. Conclusion: The novel multi-EPI pulse sequence can boost CO 2 imaging signal in hyperpolarized 13 C bicarbonate imaging while introducing minimal pH bias, helping to surmount a major hurdle in hyperpolarized pH imaging. K E Y W O R D S bicarbonate, chemical exchange, hyperpolarized 13 C, MRI, NMR spectroscopy pH imaging 960 | KORENCHAN Et Al. | 961 KORENCHAN Et Al.

Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer

“…Another is the relatively slow kinetic conversion between bicarbonate and CO 2 , which requires sufficient time to reach equilibrium pH and depends upon expression and localization of carbonic anhydrase (CA) isoforms. We have previously measured the characteristic exchange rate constant for bicarbonate-CO 2 to be 1.56 s -1 in high-grade TRAMP tumors [53], which suggests that pH equilibrium is reached (95%) in ~2 s. Bicarbonate-CO 2 exchange might be slower in low-grade tumors if extracellular CA isoforms are not as strongly expressed, although we have not measured either exchange or CA expression in low-grade tumors. Some HP bicarbonate and CO 2 in a given voxel may also distribute between erythrocytes, blood plasma, and tumor cytoplasm, meaning that the measured pH is not strictly extracellular.…”

“…Moreover, the method produced high quality, high-resolution maps of pH e (Figure 5). Finally, recent advances in pulse sequence acquisition promise to increase the signal-to-noise ratio of this method [53]. Taken together, these observations suggest the potential feasibility and utility of using hyperpolarized 13 C pH e imaging for detecting aggressive disease in men with localized prostate cancer.…”

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

“…17 Although in this way the dependency on PDH activity is eliminated, 17 the uncertainty in intracellular versus extracellular pH, and the dependency on CA activity, remain. 18 Hyperpolarized [1,5-13 C 2 ]zymonic acid has been shown to be a sensitive extracellular pH marker that is independent of enzymatic activity 19 and was found useful in vivo in the rat bladder, kidney, and in adenocarcinoma. 20 Several other enzymatically independent hyperpolarized pH reporters have also been investigated, [21][22][23][24][25][26][27] but were only tested in vitro.…”

Cardiac pH-Imaging With Hyperpolarized MRI

“…Most work in this area has focused on obtaining metabolic information from [1- 13 C]pyruvate, neglecting the carbon dioxide resonance necessary for pH-calculation. As one of the few studies aiming to improve hyperpolarized pH-imaging, Korenchan et al reported a significant signal-to-noise increase for hyperpolarized 13 C-bicarbonate using multi flip angle echo-planar imaging ( 35 ). In a similar manner, Lau et al optimized pH-imaging of hyperpolarized [1- 13 C]pyruvate ( 21 ).…”