Long-lived states of methylene protons in achiral molecules

Abstract

In nuclear magnetic resonance (NMR), the lifetimes of long-lived states (LLSs) are exquisitely sensitive to their environment. However, the number of molecules where such states can be excited has hitherto been rather limited. Here, it is shown that LLSs can be readily excited in many common molecules that contain two or more neighboring CH 2 groups. Accessing such LLSs does not require any isotopic enrichment, nor does it require any stereogenic centers to lift the chemical equivalence of CH 2 protons. LLSs were excited in a variety of metabolites, neurotransmitters, vitamins, amino acids, and other molecules. One can excite LLSs in several different molecules simultaneously. In combination with magnetic resonance imaging, LLSs can reveal a contrast upon noncovalent binding of ligands to macromolecules. This suggests new perspectives to achieve high-throughput parallel drug screening by NMR.

Paramagnetic relaxivity of delocalized long-lived states of protons in chains of CH2 groups

“…The results support simulations that show that different LLSs are excited depending on the SLIC sequence and the number of adjacent methylene units. SLIC methods have also been shown to be efficient for other achiral molecules containing neighboring CH 2 groups, such as dopamine, γ -aminobutyric acid (GABA), ethanolamine, and β-alanine (Sonnefeld et al, 2022a). All of these molecules contain aliphatic chains, so the effects of paramagnetic polarizing agents like TEMPOL should be similar to what is reported in this work.…”

“…The intensities of the LLS-derived signals are typically about 5 % for single SLIC experiments and up to 10 % for poly-SLIC experiments. The theoretical maximum efficiency of LLS excitation and reconversion in a four-spin -CH 2 -CH 2 -moiety was calculated to be 14 % for single SLIC and 28 % for double SLIC experiments (Sonnefeld et al, 2022a). Simulations of the contributions of different LLS terms to the observed signals were performed using SpinDynamica (Bengs and Levitt, 2018).…”

“…The coefficients of the first two bilinear terms are always equal, i.e., λ AA = λ XX , while the four-spin term is always proportional to the leading bilinear terms, with a weight λ AA XX = 8/3λ AA (Sonnefeld et al, 2022a). This state corresponds to the imbalance between the singlet-singlet state and the triplet-triplet manifold and is therefore expected to decay monoexponentially.…”

“…Therefore, one can transfer samples with hyperpolarized LLSs to an NMR spectrometer for detection without significant loss of polarization. For small molecules, the ratio T LLS /T 1 ranges typically from 2 to 6 for LLSs in CH 2 groups in non-degassed samples (Sonnefeld et al, 2022a), although it is possible to achieve a ratio T LLS /T 1 > 30 in some degassed samples containing isolated pairs of protons (Sarkar et al, 2007) or carbon-13 nu- clei (Pileio et al, 2012;Stevanato et al, 2015). In this work, we carried out a systematic analysis of relaxivities, i.e., of the dependence of the relaxation rate constants of LLSs and longitudinal magnetization on the concentration of the paramagnetic species 4-hydroxy-2,2,6,6-tetramethylpiperidin-1oxyl (TEMPOL).…”

Multiple Stroboscopic Detection of Long-Lived Nuclear Magnetization for Glutathione Oxidation Kinetics

“…We preserved magnetization in symmetry-adapted long-lived spin states in GSH/GSSG Gly-(H α1,α2 ) and Cys-(H α H β1,β2 ) aliphatic protons (Figure A) in order to ensure the lifetimes necessary for on-the-fly stroboscopic detection. Methods to excite long-lived nuclear spin states on protons have been developed − for several endogenous molecules − to act as magnetization carriers while circumventing costly molecular enrichment in carbon-13 or nitrogen-15. Herein, long-lived states were excited and detected using a stroboscopic version of the “SELLS” procedure we have proposed recently. , The detection starts by a small flip-angle pulse used to convert a fraction of the singlet state into detectable magnetization (Figure B).…”