Achieving High Levels of NMR‐Hyperpolarization in Aqueous Media With Minimal Catalyst Contamination Using SABRE

Abstract

Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1H NMR signals in a range of substrates in aqueous media. To achieve this outcome, phase‐transfer catalysis is exploited, which leads to less than 1.5×10−6 mol dm−3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline‐based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called catalyst separated hyperpolarization through signal amplification by reversible exchange or CASH‐SABRE. We illustrate this method for the substrates pyrazine, 5‐methylpyrimidine, 4,6‐d 2‐methyl nicotinate, 4,6‐d 2‐nicotinamide and pyridazine achieving 1H signal gains of approximately 790‐, 340‐, 3000‐, 260‐ and 380‐fold per proton at 9.4 T at the time point at which phase separation is complete.

Signal Amplification by Reversible Exchange (SABRE): From Discovery to Diagnosis

“…This allows the catalyst to remain in the organic phase,and the aqueous phase,containing the hyperpolarized substrate,c an be separated as previously established for PHIP. [74] This led to up to 3000-fold signal enhancement at 9.4 Tw hen using methyl 4,6-d 2 -nicotinate.I mportantly,j ust 1.5 10 À6 m of the iridium catalyst and 0.06 %C DCl 3 contamination in the aqueous phase was observed. [74] This led to up to 3000-fold signal enhancement at 9.4 Tw hen using methyl 4,6-d 2 -nicotinate.I mportantly,j ust 1.5 10 À6 m of the iridium catalyst and 0.06 %C DCl 3 contamination in the aqueous phase was observed.…”

Catalyst‐Substrate Effects on Biocompatible SABRE Hyperpolarization

“…If a nominal, 1 g dosage of the contrast agent is used, this equates to a maximum 10 ppm iridium concentration in a single bolus. A number of methods for depleting the iridium content in solution have been reported, including bi‐phasic catalysis, ion‐exchange chromatography and solid phase scavengers …”

“…As an important last step, we wished to quantify the residual metal content after the catalyst had been removed either by ion exchange chromatography or biphasic catalysis . First, two SABRE active samples containing [IrCl(COD)(IMes)] (5 m m ) and either MN or Nam were quenched by the addition of 1.1 eq.…”

“…Conversely, the dominant factor in cell death was caused by the active SABRE catalyst, even at low concentration and exposure times. Importantly, this effect could be negated by removal of the catalyst using either catalyst deactivation and removal by ion exchange chromatography or bi‐phasic catalysis . Subsequently, catalyst capture using solid phase scavengers and subsequent filtration has proven an efficient method for catalyst depletion .…”

Multiple Quantum Coherences Hyperpolarized at Ultra‐Low Fields

“…SABRE at high magnetic field for high-resolution NMR encounters difficulties due to magnetic field inhomogeneity caused by pH 2 bubbling; [38] this is not a problem for ultra-low field (ULF) NMR and even allows continuous SABRE, [39] radiowave amplification by stimulated emission of radiation (RASER) [13] and QUASi-Resonance SABRE (QUASR). [41][42][43][44][45][46] When it comes to biomedical applications, usually, it is the goal to populate one dedicated spin state and, as a result, boost the MRI signal of the targeted nuclei. [41][42][43][44][45][46] When it comes to biomedical applications, usually, it is the goal to populate one dedicated spin state and, as a result, boost the MRI signal of the targeted nuclei.…”