Order‐Unity ¹³C Nuclear Polarization of [1‐¹³C]Pyruvate in Seconds and the Interplay of Water and SABRE Enhancement

Abstract

Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE‐SHEATH) is investigated to achieve rapid hyperpolarization of 13C1 spins of [1‐13C]pyruvate, using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co‐ligation of DMSO and H2O. Order‐unity 13C (>50 %) polarization of catalyst‐bound [1‐13C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1‐13C]pyruvate at lower temperatures. On the catalyst bound pyruvate, 39 % polarization is measured using a 1.4 T NMR spectrometer, and extrapolated to >50 % at the end of build‐up in situ. The highest measured polarization of a 30‐mM pyruvate sample, including free and bound pyruvate is 13 % when using 20 mM DMSO and 0.5 M water in CD3OD. Efficient 13C polarization is also enabled by favorable relaxation dynamics in sub‐microtesla magnetic fields, as indicated by fast polarization buildup rates compared to the T1 spin‐relaxation rates (e. g., ∼0.2 s−1 versus ∼0.1 s−1, respectively, for a 6 mM catalyst‐[1‐13C]pyruvate sample). Finally, the catalyst‐bound hyperpolarized [1‐13C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water, paving the way to future biomedical applications of hyperpolarized [1‐13C]pyruvate produced via comparatively fast and simple SABRE‐SHEATH‐based approaches.

Rapid 13C Hyperpolarization of the TCA Cycle Intermediate α-Ketoglutarate via SABRE-SHEATH

“…The optimum values of B T and T T (and maximum total P 13C ) for 13 C-1 in α-KG isotopologues are nearly identical to those of [1- 13 C]pyruvate reported recently, 47 indicating that our SABRE-SHEATH polarization transfer approach may be universally tailored to this structural motif of α-ketocarboxylate in other biologically relevant biomolecules, such as [1-13 C]αketoisocaproate. 80 The main biomedical limitation of the presented study is the production of the HP substrate in an alcohol-based solution in the presence of an iridium-based catalyst, which may be considered toxic.…”

“…The HP free (i.e., not catalyst bound) is negligible compared to the HP 3b resonance because the substrate exchange is too slow on the time scale of the experiment. 47 SABRE-SHEATH polarization at an elevated temperature leads to the rise of the resonances from HP-free species with an optimal polarization transfer temperature T T of 6−10 °C (Figures 1g and 2f) for both isotopologues studied. At this temperature, the exchange rate of the substrate is likely matched to the size of the spin−spin coupling between the parahydrogen-derived hydrides and the 13 C-1 nucleus.…”

“…The standard precatalyst used for SABRE [IrCl(COD) (IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2ylidene; COD = cyclooctadiene), 51,56 and catalyst 1 (6 mM) was activated with p-H 2 bubbling in the presence of ∼5 mM α-KG, 20 mM DMSO, and 0.5 M H 2 O in CD 3 OD (Figure 1, top), corresponding to our previously optimized protocol for preparation of HP [1-13 C]pyruvate (P 13C = 13%). 47 We used a low α-KG concentration (5 mM) because of the low α-KG solubility in CD 3 OD. Fast activation (<5 min) leads to the formation of species 2, 3a, and 3b in accord with the notation introduced by Duckett and co-workers (in the context of pyruvate SABRE).…”

“…The reader is also directed to several recent reviews for detailed descriptions of leading HP technologies. 9,12,26,27,45,46 We and others have recently demonstrated a series of innovations (including the use of water as an additional potential coligand 47,48 and temperature cycling 37,49 ), demonstrating that catalyst-bound [1-13 C]pyruvate 13 C polarization (P 13C ) may reach order-unity values, 47 and 13 C bulk P 13C of up to 13% can be obtained.…”

Understanding Parahydrogen Hyperpolarized Urine Spectra: The Case of Adenosine Derivatives

“…Furthermore, the complexity of published hyperpolarized urine spectra [6][7][8][9] demonstrates that even the catalyst's limited chemical scope allows for the detection of large numbers of metabolites. The list of known 2 binding analytes is growing and includes, on top of nitrogenous heteroaromatics, pyruvate [10], tagged oligopeptides [11,12], amino acids [13,14], nitriles [15], and sulfur heteroaromatics [16], suggesting the chemoselectivity envelope is wide.…”