In vitro singlet state and zero-quantum encoded magnetic resonance spectroscopy: Illustration with N-acetyl-aspartate

Abstract

Magnetic resonance spectroscopy (MRS) allows the analysis of biochemical processes non-invasively and in vivo. Still, its application in clinical diagnostics is rare. Routine MRS is limited to spatial, chemical and temporal resolutions of cubic centimetres, mM and minutes. In fact, the signal of many metabolites is strong enough for detection, but the resonances significantly overlap, exacerbating identification and quantification. Besides, the signals of water and lipids are much stronger and dominate the entire spectrum. To suppress the background and isolate selected signals, usually, relaxation times, J-coupling and chemical shifts are used. Here, we propose methods to isolate the signals of selected molecular groups within endogenous metabolites by using long-lived spin states (LLS). We exemplify the method by preparing the LLSs of coupled protons in the endogenous molecules N-acetyl-L-aspartic acid (NAA). First, we store polarization in long-lived, double spin states, followed by saturation pulses before the spin order is converted back to observable magnetization or double quantum filters to suppress background signals. We show that LLS and zero-quantum coherences can be used to selectively prepare and measure the signals of chosen metabolites or drugs in the presence of water, inhomogeneous field and highly concentrated fatty solutions. The strong suppression of unwanted signals achieved allowed us to measure pH as a function of chemical shift difference.

Single-scan measurements of nuclear spin singlet order decay rates

“…39 The quest for a biocompatible molecular marker that supports hyperpolarized long-lived spin order to be used for in vivo imaging applications is still open and has the potential to bring about important new possibilities in MRI. 40 At the core of all these developments is the measurement of the singlet order decay constant (T S ) and its theoretical modelling. 41 The intelligent design of molecules bearing singlet states has led to molecules displaying singlet order lifetimes of the order of hours.…”

Using optimal controlled singlet spin order to accurately target molecular signal in MRI and MRS

“…The longitudinal magnetization (the black line) is transferred to the spin order (I 1z + 2I 2x I 3x + 2I 2y I 3y ) with the highest efficiency. Comparing with the reported singlet-filtered methods for signal selection, including gM2S 43 , SUCCESS 36 , SISTEM 35 , the main advantage of the OC pulses lies on the accurate control of the spin dynamics of a multiple spin system, resulting in the high preparation efficiency of the singlet order of the multiple spin system (see Fig. S2 ).…”

“…More recently, a nuclear singlet spin state/order [28][29][30][31] has been used to select magnetic resonance signals from a specific group and/or molecule in vitro [32][33][34][35] . For example, DeVience et al 36 demonstrated a method known as 'Suppression of Undesired Chemicals using Contrast-Enhancing Singlet States (SUCCESS) to create, preserve and measure the target singlet state produces strong contrast relative to undesired spectral components when the spectra of two molecules nearly overlap.…”

“…Several molecules, such as N-acetyl-l-aspartic acid (NAA), dopamine (DA), and a tripeptide (alanine-glycine-glycine), have been used as target molecules in molecularly targeted MRI and MRS. Moreover, the analysis of the in vivo NAA targeted 1 H MRS spectrum of a human brain suggests a promising way to study important issues of molecular biology at the molecular level, e.g., measuring the local pH value of tissue in vivo, which is important for one to understand the molecular mechanism of biological processes 35,40,41 .…”

An Examination of Factors Influencing Small Proton Chemical Shift Differences in Nitrogen-Substituted Monodeuterated Methyl Groups

“…Tayler and Levitt incorporated 18 O isotopic labelling to engender a small 13 C chemical shift difference in a symmetric oxalate molecule [22]; (iii) Altering pH. Pravdivtsev et al adjusted the pH of their solution to tailor the chemical shift difference between the CH 2 group protons of N-acetyl-L-aspartic acid [23]; and (iv) Chemical reactions. Zhang et al forged a symmetrybreaking 1 H chemical shift difference and unlocked access to the LLS of dimethyl maleate by the addition of thiols [24].…”