PH Dependence of T2 for Hyperpolarizable 13C-Labelled Small Molecules Enables Spatially Resolved pH Measurement by Magnetic Resonance Imaging.

Martin Grashei,Franz Schilling,Christian Hundshammer,Geoffrey J Topping,Frits H A Van Heijster

doi:10.3390/ph14040327

Abstract

Hyperpolarized 13C magnetic resonance imaging often uses spin-echo-based pulse sequences that are sensitive to the transverse relaxation time T2. In this context, local T2-changes might introduce a quantification bias to imaging biomarkers. Here, we investigated the pH dependence of the apparent transverse relaxation time constant (denoted here as T2) of six 13C-labelled molecules. We obtained minimum and maximum T2 values within pH 1–13 at 14.1 T: [1-13C]acetate (T2,min = 2.1 s; T2,max = 27.7 s), [1-13C]alanine (T2,min = 0.6 s; T2,max = 10.6 s), [1,4-13C2]fumarate (T2,min = 3.0 s; T2,max = 18.9 s), [1-13C]lactate (T2,min = 0.7 s; T2,max = 12.6 s), [1-13C]pyruvate (T2,min = 0.1 s; T2,max = 18.7 s) and 13C-urea (T2,min = 0.1 s; T2,max = 0.1 s). At 7 T, T2-variation in the physiological pH range (pH 6.8–7.8) was highest for [1-13C]pyruvate (ΔT2 = 0.95 s/0.1pH) and [1-13C]acetate (ΔT2 = 0.44 s/0.1pH). Concentration, salt concentration, and temperature alterations caused T2 variations of up to 45.4% for [1-13C]acetate and 23.6% for [1-13C]pyruvate. For [1-13C]acetate, spatially resolved pH measurements using T2-mapping were demonstrated with 1.6 pH units accuracy in vitro. A strong proton exchange-based pH dependence of T2 suggests that pH alterations potentially influence signal strength for hyperpolarized 13C-acquisitions.

Highlights

For [1,4-13 C2 ]fumarate, the T2 relaxation time constant was measured across the pH range
4–13, because its solubility strongly decreases for pH < 4
In the strongly acidic (T2 = 23.1 s, pH 1.02) and basic (T2 = 25.8 s, pH 12.97) regimes (Figure 1a), [1-13 C]acetate showed 13 C-T2 relaxation time constants in the order of its T1 at 14.1 T (T1 = 27 s, pH 1; T1 = 39 s, pH 13; [35]), with T2 values in the basic regime being slightly larger compared to the acidic regime

Summary

Introduction

[1-13 C]alanine and 13 C-bicarbonate has been investigated as an imaging biomarker for the detection and evaluation of various pathologies such as cancer [4], inflammation [5], and related changes in pH [6], as well as the functionality of various organs, such as the heart [7], liver [8], or kidney [9], and of perfusion [10] Inert compounds such as 13 C-urea and [13 C,15 N2 ]urea have been introduced, enabling the assessment of perfusion and kidney function from signal intensity maps [9]. Hyperpolarized 13 C-labelled molecules can be used as sensors of physicochemical properties by exploiting changes in longitudinal and transverse relaxation times or chemical shift, e.g., for the detection of metal ion concentrations [11] or pH [6,12] To sense these properties, the initially created hyperpolarized longitudinal magnetization must be excited in MRI experiments, thereby converting the longitudinal magnetization into transverse magnetization. This transverse magnetization precesses about the static magnetic field axis while decaying exponentially with a time constant T2 , Published: 2 April 2021

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Conclusion