Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this area's most compelling outcomes. Methods to optimize the low-cost parahydrogen-based approach signal amplification by reversible exchange with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2 H labeling in both the agent and catalyst and achieve polarization lifetimes of ca. 2 min with 50% polarization in the case of methyl-4,6-d 2 -nicotinate. Because a 1.5-T hospital scanner has an effective 1 H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this technique's generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine, and isonicotinamide analogs that feature as building blocks in biochemistry and many disease-treating drugs.
The
hyperpolarization (HP) method signal amplification by reversible exchange
(SABRE) uses para-hydrogen to sensitize substrate
detection by NMR. The catalyst systems [Ir(H)2(IMes)(MeCN)2(R)]BF4 and [Ir(H)2(IMes)(py)2(R)]BF4 [py = pyridine; R = PCy3 or PPh3; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene],
which contain both an electron-donating N-heterocyclic carbene and
a phosphine, are used here to catalyze SABRE. They react with acetonitrile
and pyridine to produce [Ir(H)2(NCMe)(py)(IMes)(PPh3)]BF4 and [Ir(H)2(NCMe)(py)(IMes)(PCy3)]BF4, complexes that undergo ligand exchange on
a time scale commensurate with observation of the SABRE effect, which
is illustrated here by the observation of both pyridine and acetonitrile
HP. In this study, the required symmetry breaking that underpins SABRE
is provided for by the use of chemical inequivalence rather than the
previously reported magnetic inequivalence. As a consequence, we show
that the ligand sphere of the polarization transfer catalyst itself
becomes hyperpolarized and hence that the high-sensitivity detection
of a number of reaction intermediates is possible. These species include
[Ir(H)2(NCMe)(py)(IMes)(PPh3)]BF4, [Ir(H)2(MeOH)(py)(IMes)(PPh3)]BF4, and [Ir(H)2(NCMe)(py)2(PPh3)]BF4. Studies are also described that employ the deuterium-labeled
substrates CD3CN and C5D5N, and the
labeled ligands P(C6D5)3 and IMes-d22, to demonstrate that dramatically improved
levels of HP can be achieved as a consequence of reducing proton dilution
and hence polarization wastage. By a combination of these studies
with experiments in which the magnetic field experienced by the sample
at the point of polarization transfer is varied, confirmation of the
resonance assignments is achieved. Furthermore, when [Ir(H)2(pyridine-h5)(pyridine-d5)(IMes)(PPh3)]BF4 is examined,
its hydride ligand signals are shown to become visible through para-hydrogen-induced polarization rather than SABRE.
Signal amplification by reversible exchange (SABRE) turns typically weak magnetic resonance responses into strong signals making previously impractical measurements possible. This technique has gained significant popularity because of its speed and simplicity. This Minireview tracks the development of SABRE from the initial hyperpolarization of pyridine in 2009 to the point in which 50 % H polarization levels have been achieved in a di-deuterio-nicotinate, a key step in the pathway to potential clinical use. Simple routes to highly efficient N hyperpolarization and the creation of hyperpolarized long-lived magnetic states are illustrated. To conclude, we describe how the recently reported SABRE-RELAY approach offers a route for parahydrogen to hyperpolarize a much wider array of molecular scaffolds, such as amides, alcohols, carboxylic acids, and phosphates, than was previously thought possible. We predict that collectively these developments ensure that SABRE will significantly impact on both chemical analysis and the diagnosis of disease in the future.
Iridium N-heterocyclic carbene (NHC) complexes catalyse the para-hydrogen-induced hyperpolarization process, Signal Amplification by Reversible Exchange (SABRE). This process transfers the latent magnetism of para-hydrogen into a substrate, without changing its chemical identity, to dramatically improve its nuclear magnetic resonance (NMR) detectability. By synthesizing and examining over 30 NHC containing complexes, here we rationalize the key characteristics of efficient SABRE catalysis prior to using appropriate catalyst-substrate combinations to quantify the substrate’s NMR detectability. These optimizations deliver polarizations of 63% for 1H nuclei in methyl 4,6-d2-nicotinate, 25% for 13C nuclei in a 13C2-diphenylpyridazine and 43% for the 15N nucleus of pyridine-15N. These high detectability levels compare favourably with the 0.0005% 1H value harnessed by a routine 1.5 T clinical MRI system. As signal strength scales with the square of the number of observations, these low cost innovations offer remarkable improvements in detectability threshold that offer routes to significantly reduce measurement time.
SABRE catalysts [Ir(H)2(η2-pyruvate)(sulfoxide)(NCH) transfer magnetisation from para-hydrogen to pyruvate yielding hyperpolarised 13C NMR signals enhanced by >2000-fold. Properties of the catalyst control efficiency.
We report on a strategy for using
SABRE (signal amplification by
reversible exchange) for polarizing 1H and 13C nuclei of weakly interacting ligands which possess biologically
relevant and nonaromatic motifs. We first demonstrate this via the
polarization of acetonitrile, using Ir(IMes)(COD)Cl as the catalyst
precursor, and confirm that the route to hyperpolarization transfer
is via the J-coupling network. We extend this work
to the polarization of propionitrile, benzylnitrile, benzonitrile,
and trans-3-hexenedinitrile in order to assess its
generality. In the 1H NMR spectrum, the signal for acetonitrile
is enhanced 8-fold over its thermal counterpart when [Ir(H)2(IMes)(MeCN)3]+ is the catalyst. Upon addition
of pyridine or pyridine-d5, the active
catalyst changes to [Ir(H)2(IMes)(py)2(MeCN)]+ and the resulting acetonitrile 1H signal enhancement
increases to 20- and 60-fold, respectively. In 13C NMR
studies, polarization transfers optimally to the quaternary 13C nucleus of MeCN while the methyl 13C is hardly polarized.
Transfer to 13C is shown to occur first via the 1H–1H coupling between the hydrides and the methyl
protons and then via either the 2J or 1J couplings to the respective 13Cs, of which the 2J route is more efficient.
These experimental results are rationalized through a theoretical
treatment which shows excellent agreement with experiment. In the
case of MeCN, longitudinal two-spin orders between pairs of 1H nuclei in the three-spin methyl group are created. Two-spin order
states, between the 1H and 13C nuclei, are also
created, and their existence is confirmed for Me13CN in
both the 1H and 13C NMR spectra using the Only
Parahydrogen Spectroscopy protocol.
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