Toward Biocompatible Nuclear Hyperpolarization Using Signal Amplification by Reversible Exchange: Quantitative in Situ Spectroscopy and High-Field Imaging

Abstract

Signal amplification by reversible exchange (SABRE) of a substrate and parahydrogen at a catalytic center promises to overcome the inherent insensitivity of magnetic resonance. In order to apply the new approach to biomedical applications, there is a need to develop experimental equipment, in situ quantification methods, and a biocompatible solvent. We present results detailing a low-field SABRE polarizer which provides well-controlled experimental conditions, defined spins manipulations, and which allows in situ detection of thermally polarized and hyperpolarized samples. We introduce a method for absolute quantification of hyperpolarization yield in situ by means of a thermally polarized reference. A maximum signal-to-noise ratio of ∼103 for 148 μmol of substance, a signal enhancement of 106 with respect to polarization transfer field of SABRE, or an absolute 1H-polarization level of ≈10–2 is achieved. In an important step toward biomedical application, we demonstrate 1H in situ NMR as well as 1H and 13C high-field MRI using hyperpolarized pyridine (d3) and 13C nicotinamide in pure and 11% ethanol in aqueous solution. Further increase of hyperpolarization yield, implications of in situ detection, and in vivo application are discussed.

Delivering strong 1 H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

“…The efficiency of SABRE catalysis has been shown to be highly dependent on the solvent, with low hyperpolarization levels resulting in 100% D 2 O solutions despite the development of water-soluble catalysts (34,35,39,40). We suggest that hyperpolarization in an ethanol-d 6 solution followed by sample dilution to obtain a biocompatible bolus for injection reflects a sensible route to obtain the required signal strength for in vivo study.…”

In Situ and Ex Situ Low‐Field NMR Spectroscopy and MRI Endowed by SABRE Hyperpolarization

“…Although in situ SABRE detection at low magnetic field was already demonstrated by Hövener et al, [14b, 19] the entire proton NMR resonance line was assigned to HP pyridine, as the formation of HP o -H 2 and Ir–dihydride were not reported at that time. Nevertheless, to perform analytical measurements (i.e.…”

“…Recent progress in the development of SABRE catalysts in aqueous media is very encouraging and should facilitate the use of SABRE HP contrast agents in living organisms. [14] …”

“…Building on our demonstration of in situ PHIP [17] spectroscopic detection and ex situ SABRE [18] MRI detection and the recent work of others, [14b, 19] herein we present high-resolution MRI imaging and spectroscopy of a SABRE chemical-exchange reaction by using a combination of in situ and ex situ low-field NMR/MRI approaches. Ex situ NMR spectra and MRI images of a liquid solution after exchange with p -H 2 were obtained at 47.5 mT with sub-millimeter in-plane spatial resolution (pixel size 125 × 125 µm 2 ) and a large imaging matrix of up to 512 × 512.…”

Computational (DFT) and Experimental (EXAFS) Study of the Interaction of [Ir(IMes)(H)2(L)3] with Substrates and Co‐substrates Relevant for SABRE in Dilute Systems

“…[2b] Its potentialt op lay ar ole in the development of NMR spectroscopy for biomedical applications for the qualitative and quantitative analysis of complex mixturesi nabiomedical context is widely recognized, and this is broughtc loser by incorporation into 2D NMR spectroscopic methods [9] and the development of ab iocompatiblem odification for spectroscopy and imaging, [10] as well as of systems compatible with high magnetic fields [11] and with aqueous media. [12,13] Inborn errors of metabolism like those in the metabolism of the purinea nd pyrimidine nucleotides often lead to the accumulationo fd egradation products [14] and the characteristic 1 HNMR spectra of many metabolites related to such disorders have been compiled.…”