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We describe here how the complexes Ir(COD)(NHC)Cl [NHC = IMes, SIMes, IPr, SIPr, ICy, IMe and ImMe2NPri2] provide significant insight into the catalytic process that underpins the hyperpolarization method signal amplification by reversible exchange (SABRE). These complexes react with pyridine and H2 to produce [Ir(H)2(NHC)(py)3]Cl which undergo lig...
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Reactions of (3,5-dimethylpyrazolylmethyl)pyridine (L1) and (3,5-diphenylpyrazolylmethyl)pyridine (L2) with either [PdCl2(NCMe)2] or [PdClMe(COD)] afforded the respective neutral palladium complexes, [PdCl2(L1)] (1), [PdCl2(L2)] (2) and [PdClMe(L1)] (3). Treatment of complex 1 with equimolar amounts of PPh3 or PPh3/NaBAr4 produced the corresponding...
Citations
... The hyperpolarization was conducted in three solvents: methanol-d 4 , acetone-d 6 , and benzene-d 6 , which exhibit various interactions with the Ir center of a catalyst. [38][39][40][41][42][43] A more detailed discussion about our choice of solvents can be found in the ESI. For the combinations of catalysts, solvents, and ligands, investigated in this study, see Table 1. ...
... The authors have cited additional references within the Supporting Information. [31,[38][39][40][41][42][43][48][49][50] Raw data concerned with this manuscript are available on the platform zenodo (DOI: 10.5281/zenodo.8058452). ...
The hydrogen molecule, which exists in two spin isomers (ortho‐ and parahydrogen), is a highly studied system due to its fundamental properties and practical applications. Parahydrogen is used for Nuclear Magnetic Resonance signal enhancement, which is hyperpolarization of other molecules, including biorelevant ones. Hyperpolarization can be achieved by using Signal Amplification by Reversible Exchange (SABRE). SABRE can also convert parahydrogen into orthohydrogen, and surprisingly, in some cases, it has been discovered that orthohydrogen's resonance has the Partially Negative Line (PNL) pattern. Here, an approach for obtaining orthohydrogen with a PNL signal is presented for two catalysts: Ir−IMes, and Ir−IMesBn. The type of solvent in which SABRE is conducted is crucial for the observation of PNL. Specifically, a PNL signal can be easily generated in benzene using both catalysts, but it is more intense for Ir−IMesBn. In acetone, PNL is observed only for Ir−IMesBn. In methanol, no PNL is detected. The PNL effect is only detectable during the initial steps of pre‐catalyst activation, and disappears as the activation process progresses. We have proposed a working hypothesis that explains our results. The presented data may facilitate the further investigation of PNL and its applications in material science and catalysis.
... Conversely, a slow exchange rate prevents bulk polarization to build up in the free molecule, leading to decay attributed to relaxation processes. 37,38 The optimum polarization transfer temperature for HP pyruvate with the present catalyst is found at a T T of −5°C, which is 15°C lower than that of the original IMes SABRE catalyst. Previous studies have shown that increasing the steric bulk of the NHC ligand leads to faster substrate dissociation. ...
... Previous studies have shown that increasing the steric bulk of the NHC ligand leads to faster substrate dissociation. 10,37,38 In the case of perfluorinated catalysts, the steric bulk of the substituents surrounding the metal centers significantly improves their stability and reactivity. 36,39 In addition, this increased hindrance lowered the 3b free energy (G) and rendered the pyruvate exchange more accessible; therefore, faster exchange takes place at lower temperatures when employing the perfluorinated Irf-sIMES catalyst compared with the IrIMes catalyst. ...
Hyperpolarized (HP) carbon-13 [¹³C] enables the specific investigation of dynamic metabolic and physiologic processes via in vivo MRI-based molecular imaging. As the leading HP metabolic agent, [1-¹³C]pyruvate plays a pivotal role due to its rapid tissue uptake and central role in cellular energetics. Dissolution dynamic nuclear polarization (d-DNP) is considered the gold standard method for the production of HP metabolic probes; however, development of a faster, less expensive technique could accelerate the translation of metabolic imaging via HP MRI to routine clinical use. Signal Amplification by Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) achieves rapid hyperpolarization by using parahydrogen (p-H2) as the source of nuclear spin order. Currently, SABRE is clinically limited due to the toxicity of the iridium catalyst, which is crucial to the SABRE process. To mitigate Ir contamination, we introduce a novel iteration of the SABRE catalyst, incorporating bis(polyfluoroalkylated) imidazolium salts. This novel perfluorinated SABRE catalyst retained polarization properties while exhibiting an enhanced hydrophobicity. This modification allows the easy removal of the perfluorinated SABRE catalyst from HP [1-¹³C]-pyruvate after polarization in an aqueous solution, using the ReD-SABRE protocol. The residual Ir content after removal was measured via ICP-MS at 177 ppb, which is the lowest reported to date for pyruvate and is sufficiently safe for use in clinical investigations. Further improvement is anticipated once automated processes for delivery and recovery are initiated. SABRE-SHEATH using the perfluorinated SABRE catalyst can become an attractive low-cost alternative to d-DNP to prepare biocompatible HP [1-¹³C]-pyruvate formulations for in vivo applications in next-generation molecular imaging modalities.
... 22−24 Subsequently, the spin order is spontaneously transferred through the J-coupling network without any changes in the substrate's covalent bonds. 25,26 Efficient and regenerative SABRE processes have been mostly carried out using homogeneous catalysts, which is hard to separate for reuse. 9 This is particularly disadvantageous for MRI due to the presence of a toxic organometallic catalyst in the solution after substrate polarization has been achieved. ...
A water-compatible and recyclable catalyst for nuclear magnetic resonance (NMR) hyperpolarization via signal amplification by reversible exchange (SABRE) was developed. The [Ir(COD)(IMes)Cl] catalyst was attached to a polymeric resin of bis(2-pyridyl)amine (heterogeneous SABRE catalyst, HET-SABRE catalyst), and it amplified the ¹H NMR signal of pyridine up to (−) 4455-fold (43.2%) at 1.4 T in methanol and (−) 50-fold (0.5%) in water. These are the highest amplification factors ever reported among HET-SABRE catalysts and for the first time in aqueous media. Moreover, the HET-SABRE catalyst demonstrated recyclability by retaining its activity in water after more than three uses. This newly designed polymeric resin-based heterogeneous catalyst shows great promise for NMR signal amplification for biomedical NMR and MRI applications in the future.
... ,17 have been demonstrated, until now they have not been studied in conjugation with each other. Without doubt, real-world applications The details of the activation process can be found in Ref.48 . Chemical mechanism of SABRE process, resulting in hyperpolarization of molecules (highlighted in red) using (b) Crabtree's catalyst and (d) Ir-IMes catalyst. ...
Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical tool used in modern science and technology. Its novel incarnation, based on measurements of NMR signals without external magnetic fields, provides direct access to intramolecular interactions based on heteronuclear scalar J-coupling. The uniqueness of these interactions makes each zero-field NMR spectrum distinct and useful in chemical fingerprinting. However, the necessity of heteronuclear coupling often results in weak signals due to the low abundance of certain nuclei (e.g., ¹⁵N). Hyperpolarization of such compounds may solve the problem. In this work, we investigate molecules with natural isotopic abundance that are polarized using non-hydrogenative parahydrogen-induced polarization. We demonstrate that spectra of hyperpolarized naturally abundant pyridine derivatives can be observed and uniquely identified whether the same substituent is placed at a different position of the pyridine ring or different constituents are placed at the same position. To do so, we constructed an experimental system using a home-built nitrogen vapor condenser, which allows for consistent long-term measurements, crucial for identifying naturally abundant hyperpolarized molecules at a concentration level of ~1 mM. This opens avenues for future chemical detection of naturally abundant compounds using zero-field NMR.
... SABRE method addresses both of these issues, allowing hyperpolarizing a broad range of molecular agents in a repetitive manner. [22][23][24] This becomes possible due to the reversible coordination of the parahydrogen and the substrate on a special organometallic catalyst, where polarization transfer between pH2 and the substrate occurs via network of nuclear scalar couplings. 25 A conventional SABRE experiment includes bubbling the sample containing the substrate and the catalyst with pH2, while ensuring the conditions for efficient polarization transfer in the SABRE complex. ...
Over the past decade, azobenzene-based molecular photoswitches have emerged as promising control devices in a range of fields, including chemistry, biology, materials science, physics, energy storage and pharmacology. Previous studies revealed that cis isomer of azobenzene gains strong nonequilibrium polarization (called hyperpolarization) of 15N nuclear spins through interaction with parahydrogen molecules (i.e., a dihydrogen isomer with protons having zero total spin, pH2) in the reversible exchange with Ir-complex. This technique, known as SABRE (Signal Amplification by Reversible Exchange), enhances inherently weak NMR signals by several orders of magnitude at relatively low operational cost. We demonstrate that performing SABRE in the presence of light irradiation allows to hyperpolarize trans-azobenzene, which direct coordination with the SABRE Ir-complex is sterically hindered. The proposed approach, which we called photo-SABRE, is robust and efficient, as well as non-destructive and reproducible. It combines coherent polarization transfer from pH2 to cis-azobenzene with the reversible cis-trans-photoisomerization. Moreover, using photo-SABRE, it is possible to hyperpolarize the long-lived spin order of 15N spin pair in trans-azobenzene, with a lifetime of about 25 minutes, which greatly exceeds the ordinary relaxation times T1 of its 15N nuclei at high (around 10 s) and low (around 200 s) magnetic fields. Photo-SABRE amplification of the NMR signals of cis-trans photoswitchable compounds has a potential to become a valuable tool in the ascending field of photopharmacology and novel light-controlled materials.
... Many factors influence the achievable SABRE hyperpolarization. They include exchange rates at the catalyst [11][12][13][14][15][16][17], the p-H 2 supply (i.e., flow, bubbling, and shaking), the solubility [12,14,16,[18][19][20], and the concentration [5,11,12,15,21,22] of the catalyst, hydrogen, and substrate in a chosen solvent. Further important parameters include the presence of co-substrates or additives [12,[23][24][25] and the exact control of the polarization transfer field [11][12][13][14][15]17,[26][27][28][29]. ...
... Many factors influence the achievable SABRE hyperpolarization. They include exchange rates at the catalyst [11][12][13][14][15][16][17], the p-H 2 supply (i.e., flow, bubbling, and shaking), the solubility [12,14,16,[18][19][20], and the concentration [5,11,12,15,21,22] of the catalyst, hydrogen, and substrate in a chosen solvent. Further important parameters include the presence of co-substrates or additives [12,[23][24][25] and the exact control of the polarization transfer field [11][12][13][14][15]17,[26][27][28][29]. ...
... They include exchange rates at the catalyst [11][12][13][14][15][16][17], the p-H 2 supply (i.e., flow, bubbling, and shaking), the solubility [12,14,16,[18][19][20], and the concentration [5,11,12,15,21,22] of the catalyst, hydrogen, and substrate in a chosen solvent. Further important parameters include the presence of co-substrates or additives [12,[23][24][25] and the exact control of the polarization transfer field [11][12][13][14][15]17,[26][27][28][29]. Another critical parameter that may often limit the hyperpolarization is the p-H 2 pressure applied to the sample [11][12][13][14]26,28,[30][31][32]. ...
Parahydrogen (p-H2)-based techniques are known to drastically enhance NMR signals but are usually limited by p-H2 supply. This work reports p-H2-based SABRE hyperpolarization at p-H2 pressures of hundreds of bar, far beyond the typical ten bar currently reported in the literature. A recently designed high-pressure setup was utilized to compress p-H2 gas up to 200 bar. The measurements were conducted using a sapphire high-pressure NMR tube and a 43 MHz benchtop NMR spectrometer. In standard methanol solutions, it could be shown that the signal intensities increased with pressure until they eventually reached a plateau. A polarization of about 2%, equal to a molar polarization of 1.2 mmol L−1, could be achieved for the sample with the highest substrate concentration. While the signal plateaued, the H2 solubility increased linearly with pressure from 1 to 200 bar, indicating that p-H2 availability is not the limiting factor in signal enhancement beyond a certain pressure, depending on sample composition. Furthermore, the possibility of using liquefied ethane and compressed CO2 as removable solvents for hyperpolarization was demonstrated. The use of high pressures together with quickly removable organic/non-organic solvents represents an important breakthrough in the field of hyperpolarization, advancing SABRE as a promising tool for materials science, biophysics, and molecular imaging.
... Using the SABRE method, the issue of the poor coordination of pyruvate to the iridium complex Ir(COD)(NHC)Cl (NHC = IMes) [40,41] had to be solved. This task was tackled by tuning the coordination capacity of the metal center by means of different ligands. ...
Parahydrogen‐induced polarization is a hyperpolarization method that exploits the spin order of hydrogen enriched in the para‐isomer, by means of a chemical reaction. Recently, its field of application has been extended significantly, through the introduction of non‐hydrogenative PHIP (i. e. SABRE) and of innovative h‐PHIP strategies that allowed to increase the intensity of the MR signals in molecules relevant for biological applications. This Concept article aims to show the potentialities of this hyperpolarization method in the field of diagnostics, through the discussion of some of the reported applications of parahydrogen polarized substrates. A section is also dedicated to the methods that have been introduced for the purification of parahydrogen polarized products, in order to make them suitable for biological studies.
... After warming the sample for 1 h at room temperature, further reaction to form two additional hydride-containing products takes place. Of these, [Ir(H) 2 78 and unlike the complexes formed in the absence of pyridine, pyridine-derived 5 A and 6 A proved stable when left at room temperature for >24 h. Given this stability, these species were suitable probes for rigorous assessment of their SABRE performance. ...
Here, we show how signal amplification by reversible exchange hyperpolarization of a range of 15N-containing synthons can be used to enable studies of their reactivity by 15N nuclear magnetic resonance (NO2- (28% polarization), ND3 (3%), PhCH2NH2 (5%), NaN3 (3%), and NO3- (0.1%)). A range of iridium-based spin-polarization transfer catalysts are used, which for NO2- work optimally as an amino-derived carbene-containing complex with a DMAP-d2 coligand. We harness long 15N spin-order lifetimes to probe in situ reactivity out to 3 × T1. In the case of NO2- (T1 17.7 s at 9.4 T), we monitor PhNH2 diazotization in acidic solution. The resulting diazonium salt (15N-T1 38 s) forms within 30 s, and its subsequent reaction with NaN3 leads to the detection of hyperpolarized PhN3 (T1 192 s) in a second step via the formation of an identified cyclic pentazole intermediate. The role of PhN3 and NaN3 in copper-free click chemistry is exemplified for hyperpolarized triazole (T1 < 10 s) formation when they react with a strained alkyne. We also demonstrate simple routes to hyperpolarized N2 in addition to showing how utilization of 15N-polarized PhCH2NH2 enables the probing of amidation, sulfonamidation, and imine formation. Hyperpolarized ND3 is used to probe imine and ND4+ (T1 33.6 s) formation. Furthermore, for NO2-, we also demonstrate how the 15N-magnetic resonance imaging monitoring of biphasic catalysis confirms the successful preparation of an aqueous bolus of hyperpolarized 15NO2- in seconds with 8% polarization. Hence, we create a versatile tool to probe organic transformations that has significant relevance for the synthesis of future hyperpolarized pharmaceuticals.
... 48 A microcontroller sets the desired parameters (e.g., p -H 2 bubbling time, mixing field, time to transfer, etc.) and timing, which is controlled within the pulse sequence. 49 Six catalyst precursors were tested with T[2,3-d ] P. [IrCl(COD)(IMes)], 50 and [IrCl(COD)(1,3-bis(2,3, 6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)], (Figure 6 ). The synthesis of the deuterated co-ligand is detailed in Supporting Information section 1. ...
... It has been demonstrated that SABRE signal enhancement levels are affected by the molar ratio of the substrate to catalyst. 50 To investigate the effect of substrate loading, samples were prepared using catalyst to substrate ratios 1:4, 1:6, and 1:8 for best performing T[2,3-d ]P. Figure 6B demonstrates that an optimum response was seen when four molar equivalents of substrate were present relative to the iridium precatalyst. This was also observed for T[3,4-d ]P (Supporting Information section 3). ...
... Six catalysts precursors were then tested with T[2,3-d ] P. [IrCl(COD)(IMes)] 50 Figure 6C ). ...
Purpose
Enabling drug tracking (distribution/specific pathways) with magnetic resonance spectroscopy requires manipulation (via hyperpolarization) of spin state populations and targets with sufficiently long magnetic lifetimes to give the largest possible window of observation. Here, we demonstrate how the proton resonances of a group of thienopyridazines (with known anticancer properties), can be amplified using the para‐hydrogen (p‐H2) based signal amplification by reversible exchange (SABRE) hyperpolarization technique.
Methods
Thienopyridazine isomers, including a ²H version, were synthesized in house. Iridium‐based catalysts dissolved in a methanol‐d4 solvent facilitated polarization transfer from p‐H2 gas to the target thienopyridazines. Subsequent SABRE ¹H responses of hyperpolarized thienopyridazines were completed (400 MHz NMR). Pseudo‐singlet state approaches were deployed to extend magnetic state lifetimes. Proof of principle spectral‐spatial images were acquired across a range of field strengths (7T‐9.4T MRI).
Results
¹H‐NMR signal enhancements of −10,130‐fold at 9.4T (~33% polarization) were achieved on thieno[2,3‐d]pyridazine (T[2,3‐d]P), using SABRE under optimal mixing/field transfer conditions. ¹H T1 lifetimes for the thienopyridazines were ~18‐50 s. Long‐lived state approaches extended the magnetic lifetime of target proton sites in T[2,3‐d]P from an average of 25‐40 seconds. Enhanced in vitro imaging (spatial and chemical shift based) of target T[2,3‐d]P was demonstrated.
Conclusion
Here, we demonstrate the power of SABRE to deliver a fast and cost‐effective route to hyperpolarization of important chemical motifs of anticancer agents. The SABRE approach outlined here lays the foundations for realizing continuous flow, hyperpolarized tracking of drug delivery/pathways.
... Recent developments towards a biocompatible SABRE solvent system have also been reported through approaches including the use of water-soluble catalysts and pre-activating 1 to endow water solubility [22,[28][29][30]. However, the highest enhancement levels have been reported when polarisation transfer occurs in a deuterated alcoholic solvent [31,32]. Therefore, a simple method suggested to generate a biologically compatible bolus is polarisation transfer in d 6 -ethanol, before dilution with D 2 O [33,34], with lower ethanol concentrations significantly decreasing mortality in mice [35]. ...
In recent years the NMR hyperpolarisation method signal amplification by reversible exchange (SABRE) has been applied to multiple substrates of potential interest for in vivo investigation. Unfortunately, SABRE commonly requires an iridium-containing catalyst that is unsuitable for biomedical applications. This report utilizes inductively coupled plasma-optical emission spectroscopy (ICP-OES) to investigate the potential use of metal scavengers to remove the iridium catalytic species from the solution. The most sensitive iridium emission line at 224.268 nm was used in the analysis. We report the effects of varying functionality, chain length, and scavenger support identity on iridium scavenging efficiency. The impact of varying the quantity of scavenger utilized is reported for the three scavengers with the highest iridium removed from initial investigations: 3-aminopropyl (S1), 3-(imidazole-1-yl)propyl (S4), and 2-(2-pyridyl) (S5) functionalized silica gels. Exposure of an activated SABRE sample (1.6 mg mL−1 of iridium catalyst) to 10 mg of the most promising scavenger (S5) resulted in <1 ppm of iridium being detectable by ICP-OES after 2 min of exposure. We propose that combining the approach described herein with other recently reported approaches, such as catalyst separated-SABRE (CASH-SABRE), would enable the rapid preparation of a biocompatible SABRE hyperpolarized bolus.
