Infusion device for making and delivering MRI probes

Abstract

A sterile MRI probe infusion device for preparing and administering a hyperpolarized MRI probe to a patient in need thereof is disclosed. The apparatus includes one or more reaction chambers where a hyperpolarized MRI probe is prepared, separated from the reaction mixture, concentrated, and prepared with a solution at a suitable concentration for administration to a patient. Also disclosed are methods of preparing and administering a hyperpolarized MRI probe to a patient in need thereof by using the device for diagnosing the stage of a disease or adverse condition or monitoring the progress of a treatment in a patient with a disease or adverse condition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 328,556, filed on April 7, 2022, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support and the government has certain rights in the invention. Background of the Invention

[0003] Nuclear magnetic resonance spectroscopy (NMR) and magnetic resonance imaging (MRI) methods are powerful tools widely used in biomedical, chemical and materials science applications. These methods rely on the overall difference in nuclear spin energy levels (called polarization) produced after applying a strong magnetic field. Spins aligned with or opposite to the applied field produce a net polarization that is detected. Unfortunately, nuclear polarization in thermal equilibrium (i.e., normal conditions) is inherently poor, and there is still a limit to the sensitivity and range of magnetic resonance capabilities (Günther, NMR Spectrosc. Basic Princ. Concepts Appl. Chem., 13-28 (2013)).

[0004] Hyperpolarization techniques have been developed to overcome this problem and allow NMR / MRI signal enhancements of orders of magnitude. The most widely used hyperpolarization techniques use signals from electrons (dynamic nuclear polarization, DNP) (Hausser et al., Adv. Magn. Opt. Reson., 3, 79-139 (1968); Abagam et al., Reports Prog. Phys., 41, 395-467 (1978) and Ardenkjaer-Larsen et al., Proc. Natl. Acad. Sci. USA, 100, 10158-10163 (2003)), photons (spin exchange optical pumping) (Bhaskar et al., Phys. Rev. Lett., 49, 25 (1982); Ebert et al., Lancet, 347, 1297 (1996); Albert et al., Nature, 370, 199-201 (1994); and et al., Science, 314, 446-449 (2006)) or polarization transfer of parahydrogen (parahydrogen-induced polarization, PHIP) (Bowers et al., Phys. Rev. Lett., 57, 2645 (1986); Bowers et al., J. Am. Chem. Soc., 109, 5541-5542 (1987); Eisenschmid et al., J. Am. Chem. Soc., 109, 8089 (1987); Haake et al., J. Am. Chem. Soc., 118, 8688 (1996); Goldman et al., CRPhys., 6, 575 (2005) and Chekmenev et al., J. Am. Chem. Soc., 130, 4212 (2008)). Hyperpolarized magnetic resonance (MR) is an emerging molecular imaging method to monitor metabolic, enzymatic transformations or biochemical pathways that were previously inaccessible using MR.

[0005] Current hyperpolarization imaging using dissolved DNPs and superconducting MRI scanners is very powerful due to its unique ability to track chemical transformations in vivo. However, DNP-based experiments are relatively tedious, slow and expensive.

[0006] The PHIP method and its subclass SABRE (Signal Amplification by Reversible Exchange) allow the transfer of 100% pure singlet spin order of parahydrogen (para-H2) into target molecules. The PHIP method is a traditional hydrogenation method and relies on a catalytic hydrogenation reaction in which a precursor in the form of a hydrogen acceptor is reduced and polarized by parahydrogen. In contrast, the reversible exchange using SABRE leaves the hyperpolarizer chemically unchanged. It is also not limited to one para-H2 molecule per molecule, so multiple spin transfer steps can lead to appreciable levels of hyperpolarization. This effect has also been shown to transfer polarization to nuclei in a wide range of biologically relevant molecules, such as 1 H. 13 C. 19 F. 31 P and 15 N and / or 29Si core (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017); Theis et al., J.Am.Chem.Soc., 137, 1404-1407 (2015); Shchepin et al., ChemPhysChem, 18, 1961-1965 (2017); Zhivonitko et al. al., Chem. Commun., 51, 2506-2509 (2015); Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019) and Gemeinhardt et al., Angew. Chemie Int. Ed., 59, 418-423 (2019)).

[0007] The high polarization percentage, short signal development time, low cost, and scalability make SABRE a promising approach to study metabolism in vivo using magnetic resonance spectroscopy.

[0008] Currently available hyperpolarized contrast agents are associated with spin transfer catalyst components containing heavy metals, such as transition metal atoms, necessary to achieve polarization transfer from secondary-H2 to substrates. When hyperpolarized contrast agents are administered in vivo, toxicity issues arise due to the presence of potentially toxic heavy metal-based complexes (e.g., the catalyst is typically an Ir-based organometallic compound) in solution with the hyperpolarized contrast agent.

[0009] Another obstacle to the success of the SABRE approach is the low solubility of parahydrogen in water (the solubility of H2 in water is about 1.6 mg / L) compared to its solubility in alcohol-based solvents. SABRE hyperpolarization is active primarily in organic solvents, preferably methanol, which is incompatible with in vivo administration.

[0010] The foregoing shows that there is a need for improved SABRE catalysts that can be easily separated from hyperpolarized substrates such that the hyperpolarized substrates are free of heavy metals. There is also a need for methods of separating hyperpolarized substrates from SABRE catalysts and / or hyperpolarized SABRE catalyst complexes containing heavy metals. There is also a need for methods of administering hyperpolarized substrates in a solvent medium suitable for in vivo administration.

[0011] Since hyperpolarized MRI probes have a very short useful life, there is an unmet need for devices that can generate hyperpolarized MRI probes in situ and administer them to patients in need. Devices that meet this need have been proposed in the prior art (Maslana et al., J. Autom. Methods Manag. Chem., 22 (6), 187-194 (2000); Kainz et al., "Synthesis of perfluoroalkyl-substituted aryl bromides and their purification over fluorous reverse phase silica," Synthesis (10), 1425-1427 (1998)); however, due to the disclosed methods of hyperpolarization and / or separation of the hyperpolarized probe from the reaction mixture, the proposed devices may not be effective. Previous attempts to automate and design instruments for generating hyperpolarized MRI probes or other molecules of interest have suffered from several limitations. Typically, the polarity of the Ir catalyst and the hyperpolarized MRI probe have similar solubility in methanol or other solvents in order to have effective hyperpolarization. Attempts to use extraction between the aqueous and organic layers have not always been able to separate the hyperpolarized MRI probe from the catalyst, as the activated catalyst is somewhat soluble in water (Iali et al., "Achieving High Levels of NMR-Hyperpolarization in Aqueous Media with Minimal Catalyst Contamination using SABRE," Chem.–A. Eur. J., 23, 10491-10495 (2017)). The Ir catalyst has been attached to silica gel to allow filtration, but the level of hyperpolarization has deteriorated.Ir catalysts have been captured by solid-supported thiols, but with mixed success (Barskiy et al., "Rapid Catalyst Capture Enables Metal-Free Parahydrogen-Based Hyperpolarized Contrast Agents," J. Phys. Chem. Lett. 9 (11), 2721-2724 (2018); Kidd et al., "Facile Removal of Homogenous SABRE Catalysts for Purifying Hyperpolarized Metronidazole, a Potential Hypoxia Sensor," J. Phys. Chem. 122, 16848-16852 (2018)). In addition, previous instruments lack clinical capabilities due to lack of control over purity and safety. In addition, the disclosed device for venting spent gases into a fume hood is not practical in a clinical setting where such a device would be useful.

[0012] The foregoing shows that there is a need for improved SABRE catalysts that can be easily separated from hyperpolarized substrates such that the hyperpolarized substrates are free of heavy metals. There is also a need for methods of separating hyperpolarized substrates from SABRE catalysts and / or hyperpolarized SABRE catalyst complexes containing heavy metals. There is also a need for methods of administering hyperpolarized substrates in a solvent medium suitable for in vivo administration.

[0013] The present invention provides such SABRE catalysts and methods.These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein. Brief Summary of the Invention

[0014] The present disclosure provides an MRI probe infusion device that satisfies the unresolved needs highlighted above. According to a first aspect of the present disclosure, an MRI probe infusion device is provided, comprising: (i) one or more reaction chambers, each reaction chamber comprising: (a) a structure configured to weaken a magnetic field from an external source within a reaction chamber, wherein a strength of the magnetic field from the external source within the reaction chamber is less than a threshold value; (b) one or more inlet ports; (c) a coil configured to generate an electromagnetic field within the reaction chamber; (d) one or more temperature control devices; and (e) one or more outlet ports; (ii) one or more MRI probe separators configured to receive a reaction mixture containing a perfluorinated SABRE catalyst, a solvent, and a hyperpolarized MRI probe from the one or more reaction chambers and extract the hyperpolarized MRI probe from the reaction mixture; and (iii) one or more MRI probe collectors configured to form a solution containing a desired concentration of hyperpolarized MRI probes.

[0015] According to an embodiment of the first aspect, the structure is a mu metal shield that attenuates a magnetic field from an external source in one or more reaction chambers to have a strength less than or equal to 10 nT.

[0016] According to an embodiment of the first aspect, the one or more inlet ports include one or more gas ports and one or more liquid ports.

[0017] According to an embodiment of the first aspect, each reaction chamber is configured to withstand a gas pressure of at least 10 bar.

[0018] According to an embodiment of the first aspect, the magnetic field in the reaction chamber induced by the coil is 0-200 millitesla.

[0019] According to a first aspect, the one or more temperature control devices include non-magnetic heating elements and / or cooling elements configured to maintain the temperature within the reaction chamber between -25°C and 100°C.

[0020] According to an embodiment of the first aspect, the one or more temperature control devices are configured to cycle the temperature within the reaction chamber between at least two different temperatures between -25°C and 100°C over a period of time.

[0021] According to an embodiment of the first aspect, one or more reaction chambers are configured to be hyperpolarized with a reaction mixture containing a perfluorinated SABRE catalyst, a solvent and a substrate to be hyperpolarized into a hyperpolarized MRI probe.

[0022] According to an embodiment of the first aspect, the solvent is a single-phase system or a two-phase system comprising water, methanol, ethanol, a fluorinated solvent or a mixture thereof.

[0023] According to an embodiment of the first aspect, the one or more MRI probe separators are configured to separate the hyperpolarized MRI probe from the perfluorinated SABRE catalyst by one of: filtration; extraction; or column chromatography.

[0024] According to an embodiment of the first aspect, the MRI probe infusion device further comprises a gas trap, a gas leak detector and / or an oxygen level monitor.

[0025] According to an embodiment of the first aspect, it also includes a processor configured to execute instructions that cause the processor to: control the flow of gas and / or liquid through the device, monitor safety measures of the device and / or environment, administer a desired amount of hyperpolarized MRI probe to the patient, or calculate the attenuation rate of the hyperpolarized MRI probe as a function of the flow rate of gas and / or liquid.

[0026] According to an embodiment of the first aspect, the one or more MRI probe collectors include one or more dryers.

[0027] According to an embodiment of the first aspect, the one or more reaction chambers include at least two reaction chambers, and the at least two reaction chambers are configured to be operable in series or in parallel.

[0028] According to an embodiment of the first aspect, the components of the MRI probe infusion device are made of non-magnetic material or plastic.

[0029] According to a second aspect of the present disclosure, there is provided a method of administering a hyperpolarized MRI probe to a patient in need thereof. The method comprises: (i) providing an MRI probe infusion device according to the first aspect, (ii) supplying a reaction mixture to one or more reaction chambers, the reaction mixture comprising a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, a solvent, a co-ligand, and a substrate to be hyperpolarized into an MRI probe, (iii) stirring the reaction mixture, wherein the stirring is provided by bubbling parahydrogen gas or a mixture of parahydrogen and nitrogen gas through the reaction mixture, (iv) applying a magnetic field suitable for hyperpolarization of the perfluorinated SABRE catalyst and the substrate to hyperpolarize the substrate into a hyperpolarized MRI probe, (v) separating the hyperpolarized MRI probe from the reaction mixture by at least one of filtration, extraction or column chromatography to obtain a solution containing the hyperpolarized MRI probe, (vi) concentrating the hyperpolarized MRI probe present in the solution obtained in step (v) to obtain a concentrate, and reconstituting the concentrate into a solution of the hyperpolarized MRI probe of a desired concentration for administration to a patient; (vii) analyzing at least one of the purity or concentration of the hyperpolarized MRI probe present in the solution; and (viii) administering a hyperpolarized MRI probe to the patient.

[0030] According to an embodiment of the second aspect, the solvent is selected from the group consisting of a perfluorohexane / diethyl ether mixture, a mixture of methoxynonafluorobutane and ethyl acetate with a non-polar solvent, a perfluorohexane and ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, ether, a fluorocarbon derivative of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkanes, perfluorohexane and methoxynonafluorobutane.

[0031] According to an embodiment of the second aspect, the substrate is selected from 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbon-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form and its salts.

[0032] According to an embodiment of the second aspect, the perfluorinated ligand is of formula (I): [L m -(NHC)-(YZ) q ] or a salt thereof, and wherein: Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, NHC is a 4- to 7-membered N-heterocyclic carbene radical, in which NHC is bound to a d-block element via a carbene. Each Y is independently selected from a bond or a spacer group, Each Z is a perfluorinated tag, m is an integer from 1 to 4, and q is an integer from 1 to 3.

[0033] According to an embodiment of the second aspect, the perfluorinated tag is one of the following: a perfluorinated C containing only carbon and fluorine atoms; 3-60 Group; Perfluorinated C containing only carbon and fluorine atoms 3-40 Group; or perfluorinated C 3-20 Group.

[0034] According to an embodiment of the second aspect, the perfluorinated ligand is selected from one of the following: or a salt thereof, and wherein is a single bond or a double bond, and represents a bond through a carbene to a d-block element. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 A reaction chamber and separator of a hyperpolarized MRI probe according to one aspect of the present disclosure are shown.

[0036] Figure 2 An internal structure of a reaction chamber according to one aspect of the present disclosure is shown.

[0037] Figure 3 Certain components and their arrangement of an MRI probe infusion device according to one aspect of the present disclosure are schematically illustrated.

[0038] Figure 4 An MRI probe infusion device equipped with multiple reaction chambers and separation of a hyperpolarized probe from each reaction chamber from a reaction mixture is shown according to one aspect of the present disclosure.

[0039] Figure 5 Some of the steps involved in a method of preparing an MRI probe for administration to a patient according to one aspect of the present disclosure are shown.

[0040] Figure 6 A fluorine solid phase extraction (F-SPE) process is shown, in which an organic fraction containing a hyperpolarized probe is separated from a fluorine fraction on fluorosilica gel using a fluorine-repellent solvent, i.e., through a fluorine-philic channel, thereby eluting the hyperpolarized probe into the fluorine fraction, and then the catalyst is recovered from the fluorosilica gel through the fluorine-philic channel. According to aspects of the present disclosure, recovering the catalyst from the fluorosilica gel through the fluorine-philic channel includes passing an aqueous / organic solvent such as methanol, ethanol, ethyl acetate, acetonitrile or THF through the silica gel.

[0041] Figure 7 According to one aspect of the present disclosure, Figure 6 Substrate polarization process and extraction of the probe through the fluorophilic channel are shown.

[0042] Figure 8 A "reverse" F-SPE process is shown, in which the probe is separated from the reaction mixture by a combination of a fluorophilic passage and a fluorophobic process. Thus, the reaction mixture is contacted with standard silica gel and a fluorophilic solvent, thereby retaining the probe on the silica gel. The probe is then recovered from the silica gel by elution with a standard organic solvent or by a fluorophobic passage.

[0043] Fig. 9The partitioning of the SABRE catalyst and the hyperpolarized substrate between two immiscible phases (a fluorinated solvent fraction and water or other water-immiscible solvent, such as a chlorinated solvent and water or other hydrophilic solvent) according to one aspect of the present disclosure is shown, which allows the principles of phase transfer catalysis to be used in conjunction with parahydrogen to produce high levels of hyperpolarization in the aqueous phase without catalyst contamination.

[0044] Fig.10 Shown is the hyperpolarization of a fluorinated SABRE catalyst containing a metal coordinated to a co-ligand and a substrate containing a half-spin core to form a metal-free hyperpolarized substrate according to one aspect of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0045] The present disclosure provides an MRI probe infusion device for producing a hyperpolarized MRI probe (i.e., a hyperpolarized substrate) and administering the hyperpolarized MRI probe to a patient. The MRI probe infusion device includes one or more reaction chambers, one or more MRI probe separators, and one or more MRI probe collectors. The MRI probe infusion device may also include a hyperpolarized MRI probe applicator for administering the hyperpolarized MRI probe to a patient. Each reaction chamber may also include: (a) a structure configured to weaken a magnetic field from an external source within a reaction chamber, wherein the strength of the magnetic field from the external source within the reaction chamber is less than a threshold value; (b) one or more inlet ports; (c) a coil configured to generate an electromagnetic field within the reaction chamber; (d) one or more temperature control devices; and (e) One or more outlet ports.

[0046] The present disclosure provides a method for administering a hyperpolarized MRI probe to a subject (e.g., a human or an animal). The method comprises: (i) providing an MRI probe infusion device according to the first aspect, (ii) supplying a reaction mixture to one or more reaction chambers, the reaction mixture comprising a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, a solvent, a co-ligand, and a substrate to be hyperpolarized into an MRI probe, (iii) stirring the reaction mixture, wherein the stirring is provided by bubbling parahydrogen gas or a mixture of parahydrogen and nitrogen gas through the reaction mixture, (iv) applying a magnetic field suitable for hyperpolarization of the perfluorinated SABRE catalyst and the substrate to hyperpolarize the substrate into a hyperpolarized MRI probe, (v) separating the hyperpolarized MRI probe from the reaction mixture by at least one of filtration, extraction or column chromatography to obtain a solution containing the hyperpolarized MRI probe, (vi) concentrating the hyperpolarized MRI probe present in the solution obtained in step (v) to obtain a concentrate, and reconstituting the concentrate into a solution of the hyperpolarized MRI probe of a desired concentration for administration to a patient; (vii) analyzing at least one of the purity or concentration of the hyperpolarized MRI probe present in the solution; and (viii) administering a hyperpolarized MRI probe to the patient.

[0047] The present disclosure also provides a perfluorinated SABRE catalyst introduced into a reaction chamber of at least one MRI probe infusion device, the perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand is of formula (I): [L m -(NHC)-(YZ) q ] Formula (I), or a salt thereof, and wherein Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, NHC is a 4- to 7-membered N-heterocyclic carbene radical, in which NHC is bound to a d-block element via a carbene. Each Y is independently selected from a bond or a spacer group, Each Z is a perfluorinated tag, m is an integer from 1 to 4 (e.g., 1, 2, 3, or 4), and q is an integer from 1 to 3 (eg, 1, 2 or 3).

[0048] The perfluorinated SABRE catalyst comprises a d-block element such as, for example, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au and / or Hg. In some embodiments, the d-block element is a transition metal such as, for example, Co, Rh, Ir, Ru, Pd, Pt or Mt. In certain embodiments, the perfluorinated SABRE catalyst comprises an element of Group 9 of the Periodic Table, i.e., Co, Rh, Ir or Mt. In preferred embodiments, the perfluorinated SABRE catalyst comprises Ir or Co. For example, the perfluorinated SABRE catalyst can be prepared from [Ir(COD)(IMes)(Cl)].

[0049] The perfluorinated SABRE catalyst comprises a perfluorinated ligand of formula (I) or a salt thereof: [L m -(NHC)-(YZ) q Formula (I), And among them Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, NHC is a 4- to 7-membered N-heterocyclic carbene radical, in which NHC is bound to a d-block element via a carbene. Each Y is independently selected from a bond or a spacer group, Each Z is a perfluorinated tag, m is an integer from 1 to 4 (e.g., 1, 2, 3, or 4), and q is an integer from 1 to 3 (eg, 1, 2 or 3).

[0050] In some aspects, the NHC comprises an oxazolyl moiety, i.e., a five-membered heterocyclic group having a nitrogen atom and at least one other heteroatom selected from nitrogen, sulfur, and oxygen. Thus, in some embodiments, the NHC is a 5-membered N-heterocyclic carbene group. For example, the 5-membered N-heterocyclic carbene group can be imidazole-based, imidazoline-based, or thiazole-based. In other words, the 5-membered N-heterocyclic carbene group can be a resulting carbene formed by treating a perfluorinated ligand having an imidazole, imidazoline, or thiazole core.

[0051] In some embodiments, NHC is a 4,5-disubstituted, 1,3-disubstituted or 1,3,4,5-tetrasubstituted imidazole-based or imidazoline-based 5-membered N-heterocyclic carbene group. For example, NHC can be a 4,5-disubstituted imidazolidinyl, a 1,3-disubstituted imidazolidinyl, a 1,3,4,5-tetrasubstituted imidazolidinyl, a 4,5-disubstituted 2,3-dihydro-imidazolyl, a 1,3-disubstituted 2,3-dihydro-imidazolyl or a 1,3,4,5-tetrasubstituted 2,3-dihydro-imidazolyl. Examples of the imidazolidinyl moiety include an N,N′-di-(2,4,6-trimethylphenyl)-imidazolidinyl moiety, an N,N′-di-(2,6-diisopropylphenyl)-imidazolidinyl moiety, an N,N′-di-(2,6-dicyclohexyl)-imidazolidinyl moiety, an N,N′-di-(2,6-tert-butyl)-imidazolidinyl moiety, and an N,N′-di-(1-adamantyl)-imidazolidinyl moiety.

[0052] In some embodiments, the perfluorinated ligand is of formula (Ia) or (Ib): or a salt thereof, and wherein Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, Each Y is independently a bond or a spacer group, Each Z is independently a perfluorinated tag, is a single bond or a double bond, and represents a bond through a carbene to a d-block element.

[0053] In some embodiments, the perfluorinated ligand is of formula (Ic) or (Id): or a salt thereof, and wherein Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), b = 2a + 1 or b = a - 1, Each n is independently an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4), is a single bond or a double bond, and represents a bond through a carbene to a d-block element. In some embodiments of Formula (Ic) or (Id), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0054] In some embodiments, the perfluorinated ligand is of formula (Ie) or (If): or a salt thereof, and wherein Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, Each Ar is independently a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, Each G is independently a key, C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 Heteroalkyl, a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), b = 2a + 1 or b = a - 1, is a single bond or a double bond, and represents a bond to a d-block element through a carbene. In some embodiments of Formula (Ie) or (If), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0055] In any of Formula (I) and Formulas (Ia)-(If), each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0056] As used herein, "substituted or unsubstituted aromatic" refers to a substituted (e.g., C 1-6 alkyl substituted) or unsubstituted aromatic rings, such as phenyl, naphthyl, phenanthrenyl and anthracenyl. As used herein, "substituted or unsubstituted heteroaromatic" refers to substituted (e.g., C 1-6 A substituted (or unsubstituted) or unsubstituted aromatic ring having 1 to 2 heteroatoms selected from N, O and S and the remaining ring atoms being carbon; or a stable bicyclic or tricyclic ring system containing at least one 5- to 7-membered aromatic ring containing 1 to 3, or in some aspects, 1 to 2 heteroatoms selected from N, O and S and the remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms, and in some aspects, bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms, in which one 5- to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl group does not exceed 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Heteroaromatic groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thienyl, triazolyl, henzofrijoxazolyl, benzofuranyl, benzothiazolyl, benzolhiophenyl, benzoxadiazolyl, dihydrobenzodioxetyl, furanyl, imidazolyl, indolyl, isothiazolyl, and isoxazolyl.

[0057] In some embodiments, each L is independently hydrogen, adamantyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,5-diethylphenyl, 2,4,6-trimethylphenyl, triethylphenyl, 2-n-propylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 2,4-di-n-propylphenyl, 2,5-di-n-propylphenyl, 2,6-di-n-propylphenyl, 3,5-di-n-propylphenyl, 2,4,6-tri-n-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-diisopropylphenyl, 2,5-diisopropylphenyl, 2,6-diisopropylphenyl, 3,5-diisopropylphenyl, 2,4,6-triisopropylphenyl phenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-diisobutylphenyl, 2,5-diisobutylphenyl, 2,6-diisobutylphenyl, 3,5-diisobutylphenyl, 2,4,6-triisobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2,4-di-sec-butylphenyl, 2,5-di-sec-butylphenyl, 2,6-di-sec-butylphenyl, 3,5-di-sec-butylphenyl, 2,4,6-tri-sec-butylphenyl In some embodiments, each L is independently hydrogen or 2,4,6-trimethylphenyl.

[0058] In any of Formula (I) and Formula (Ia)-(If), each Y is independently a bond or a spacer group. For example, Y can be a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6a heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, a substituted or unsubstituted arylalkyl group, or a linear or branched alkyleneoxy group (e.g., polyethylene oxide, polypropylene oxide, or a combination thereof).

[0059] In some embodiments, each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6 In some embodiments, each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 In a preferred embodiment, each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted arylalkyl group.

[0060] Perfluorinated ligands include perfluorinated tags. For example, in any of Formula (I) and Formula (Ia)-(If), each Z is a perfluorinated tag. The perfluorinated tag can be any perfluorinated group, such as, for example, a perfluorinated alkyl (e.g., linear or branched), aryl, alkaryl, or arylalkyl containing up to 60 carbon atoms. In some embodiments, the perfluorinated tag is a perfluorinated C containing only carbon and fluorine atoms. 3-60 In certain embodiments, the perfluorinated tag is a perfluorinated C 3-40 In other embodiments, the perfluorinated tag is a perfluorinated C 3-20 For example, the perfluorinated tag can be selected from the group C4F9, C5F 11 Group, C6F 13 Group, C7F 15 Group, C8F 17 Group, C9F19 Group, C 10 F 21 Group, C6F5 group, C4F7 group, C5F9 group, C6F 11 Group, C7F 13 Group, C8F 15 Group, C9F 17 Group and C 10 F 19 groups, each of which may be a straight-chain or branched alkyl group, an aryl group, an alkaryl group or an arylalkyl group.

[0061] In one aspect, Z is a linear or branched perfluoroalkyl chain having a chain length of up to 60 or more carbon atoms, for example, a perfluoroalkyl chain having a chain length of 3-60, particularly 3-40, more particularly 3-20, even more particularly 3-10 or more carbon atoms. For example, a perfluoroalkyl chain is selected from C4F9, C6F 13 、C7F 15 、C8F 17 、C9F 19 and C 10 F 21 , preferably selected from C6F 13 、C8F 17 and C 10 F 21 , each of which can be linear or branched, and combinations thereof, wherein each of which can be linear or branched.

[0062] In one aspect, the perfluorinated ligand is of formula (Ig): or a salt thereof, and wherein a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), b = 2a + 1 or b = a - 1, is a single bond or a double bond, and represents a bond through the carbene to the d-block element. In some embodiments of Formula (Ig), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0063] In one aspect, the perfluorinated ligand is of formula (Ih): or a salt thereof, and wherein a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), b = 2a + 1 or b = a - 1, is a single bond or a double bond, and represents a bond through the carbene to the d-block element. In some embodiments of Formula (Ig), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0064] Exemplary perfluorinated ligands include: or a salt thereof, and wherein is a single bond or a double bond, and represents a bond through a carbene to a d-block element.

[0065] As used herein, the symbol represents a single bond or a double bond. In some embodiments, is a single bond. In other embodiments, is a double bond. is a single bond embodiment, resulting from The orientation of the two substituents may have any suitable stereochemistry, i.e., may be cis or trans. In a preferred embodiment, when When it is a single bond, it comes from The stereochemistry of the substituent is trans.

[0066] As used herein, the symbol represents a bond through the carbene to a d-block element. In other words, Represents the bond to the metal of the catalyst.

[0067] In some embodiments, the perfluorinated SABRE catalyst further comprises an additional ligand. For example, the perfluorinated SABRE catalyst may further comprise an additional ligand selected from the group consisting of a phosphine ligand, a carbene ligand, an imidazole ligand, a pincerchelating ligand, and a compound comprising a sulfoxide group. In certain embodiments, the perfluorinated SABRE catalyst comprises one or more phosphine ligands. Examples of phosphine ligands include, but are not limited to, the following:

[0068] In some embodiments, the perfluorinated SABRE catalyst comprises a clamp chelating ligand. Typically, when the perfluorinated SABRE catalyst comprises a phosphine ligand or a clamp chelating ligand, the perfluorinated SABRE catalyst is in the form of a pre-catalyst. In some embodiments, the perfluorinated SABRE catalyst comprises a ligand, which is a compound comprising a sulfoxide group. Examples of compounds comprising sulfoxide groups can be selected from: dimethyl sulfoxide (DMSO), phenyltrifluoromethyl sulfoxide, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide and dibutyl sulfoxide. Typically, when the perfluorinated SABRE catalyst comprises a compound containing a sulfoxide group, the perfluorinated SABRE catalyst is in an active form. As used herein, "perfluorinated SABRE catalyst" may refer to an active perfluorinated SABRE catalyst or a perfluorinated SABRE pre-catalyst.

[0069] Active perfluorinated SABRE catalysts can be prepared by any suitable method. Typically, active perfluorinated SABRE catalysts are prepared by combining a perfluorinated SABRE precatalyst with a substrate, secondary hydrogen, and an optional co-ligand in a solvent to form a mixture comprising an active perfluorinated SABRE catalyst. In some embodiments, active perfluorinated SABRE catalysts are prepared by combining a perfluorinated SABRE precatalyst with a substrate, secondary hydrogen, and a co-ligand in a solvent to form a mixture comprising an active perfluorinated SABRE catalyst. When included in the preparation of an active perfluorinated SABRE catalyst, the co-ligand can be combined with the perfluorinated SABRE precatalyst in any order and by any suitable means. For example, when included in the preparation of an active SABRE catalyst, a co-ligand can first be provided to interact with the transfer precatalyst to promote the formation of an active perfluorinated SABRE catalyst. Alternatively, when included in the preparation of an active perfluorinated SABRE catalyst, a co-ligand can be added together with the substrate to promote the formation of an active perfluorinated SABRE catalyst. In some embodiments, the co-ligand, substrate and parahydrogen are substantially combined with the perfluorinated SABRE precatalyst in a solvent simultaneously to promote the formation of an active perfluorinated SABRE catalyst. In other embodiments, the substrate is first provided to interact with the perfluorinated SABRE precatalyst to promote the formation of an active SABRE catalyst. In some embodiments, the co-ligand and substrate are combined with the perfluorinated SABRE precatalyst in a solvent, and parahydrogen is added (e.g., by bubbling) to the resulting mixture. In other embodiments, the substrate is combined with the perfluorinated SABRE precatalyst in a solvent, and parahydrogen is added (e.g., by bubbling) to the resulting mixture. In some embodiments, the active perfluorinated SABRE catalyst is prepared by combining the perfluorinated SABRE precatalyst with a co-ligand except the substrate and parahydrogen.

[0070] In some embodiments, the active perfluorinated SABRE catalyst is of the formula [Ir(H)2(F-IMes)(η 2 -substrate)(co-ligand)] or [Ir(H)2(F-IMes)(η 1 -substrate)(co-ligand)2], wherein the substrate is a target substrate that is hyperpolarized by transferring pure singlet spin order of parahydrogen by a spin transfer catalyst, preferably a target substrate enriched in atoms having 1 / 2 spin nuclei, such as 1 H. 13 C. 15 N. 19 F. 31 P and / or 29 Si. Without wishing to be bound by any particular theory, the co-ligand interacts with the spin transfer precatalyst to form an activated polarization transfer catalyst and enhances polarization transfer to the target substrate. F-IMes refers to a perfluorinated form of N-heterocyclic carbene (NHC) ligand, such as 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazole-2-ylidene group.

[0071] In some embodiments, a perfluorinated SABRE catalyst (e.g., a perfluorinated SABRE precatalyst) can be prepared by a method comprising reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [(d-block element)(COD)Cl]2, wherein COD represents a cyclooctadienyl group. In certain embodiments, the method comprises reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [Ir(COD)Cl]2. For example, a perfluorinated SABRE catalyst of the formula It can be prepared by reacting a carbene of the formula:

[0072] Exemplary perfluorinated SABRE catalysts (e.g., perfluorinated SABRE precatalysts) include: or a salt thereof.

[0073] As used herein, the terms "hyperpolarized substrate" and "hyperpolarized MRI probe" are used interchangeably to refer to the desired hyperpolarized compound.

[0074] The method for preparing a hyperpolarized substrate described herein may include hyperpolarizing a mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) by exposing the mixture to a magnetic field or radio frequency excitation to transfer polarization from parahydrogen to the substrate to form a hyperpolarized substrate. First, the hyperpolarized substrate is compounded with the hyperpolarized perfluorinated SABRE catalyst; however, it will be understood by one of ordinary skill in the art that the hyperpolarized substrate can be replaced by another substrate molecule so that the process can be repeated and a free hyperpolarized substrate bolus is produced.

[0075] The transfer of polarization from the parahydrogen to the substrate to form a hyperpolarized substrate can occur under any suitable magnetic field or radio frequency excitation. For example, the transfer of polarization from the parahydrogen to the substrate can occur under a magnetic field that is less than the earth's magnetic field. The appropriate level of magnetic field or radio frequency excitation required to transfer polarization from the parahydrogen to the substrate to form a hyperpolarized substrate is readily apparent to one of ordinary skill in the art.

[0076] In some embodiments, the method includes replenishing parahydrogen in the mixture during the step of hyperpolarizing the mixture by exposing the mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) to a magnetic field or radio frequency excitation to transfer polarization from parahydrogen to a substrate to form a hyperpolarized substrate. In other words, in some embodiments, the method includes bubbling parahydrogen through a mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) during the step of hyperpolarizing the mixture by exposing the mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) to a magnetic field or radio frequency excitation to transfer polarization from parahydrogen to a substrate to form a hyperpolarized substrate.

[0077] The method for preparing a hyperpolarized substrate may include providing a co-ligand to interact with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst. The co-ligand may be any suitable compound containing one or more sulfoxide groups, thioester groups, phosphine groups, amine groups, CO groups, isonitrile groups, nitrogen-containing heterocyclic groups, or combinations thereof. In some embodiments, the co-ligand is a compound comprising a sulfoxide group. Examples of compounds comprising a sulfoxide group may be selected from: DMSO, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, phenyltrifluoromethyl sulfoxide, and dibutyl sulfoxide. In certain embodiments, the co-ligand is dimethyl sulfoxide or phenyltrifluoromethyl sulfoxide.

[0078] In some embodiments of the method for preparing a hyperpolarized substrate, the magnetic field is an electromagnetic field. For example, the intensity of the electromagnetic field can range from 0 to 200 millitesla (mT). In some embodiments, the electromagnetic field can be provided at least in part by one or more permanent magnets in addition to or in place of the coil. In some embodiments, the electromagnetic field can be an alternating magnetic field provided at a frequency suitable for a particular nucleus. The alternating magnetic field can change direction (i.e., alternate between positive and negative relative to the positive direction). In some embodiments, the frequency can be radio frequency, and is preferably 50 MHz to 500 MHz, although other frequencies outside this range are also considered to be within the scope of the present disclosure.

[0079] A perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) is combined with parahydrogen and a substrate comprising a 1 / 2 spin nucleus or nucleus in a solvent to obtain a reaction mixture. The solvent can be any suitable solvent capable of forming a heterogeneous or homogeneous mixture. In some embodiments, the solvent includes water, methanol, ethanol, a fluoro solvent, or a mixture thereof. For example, the solvent can be ethanolic or methanolic, that is, at least comprising ethanol or methanol in combination with water. In certain embodiments, the solvent includes a fluoro solvent. In other embodiments, the solvent is deuterated so that a deuterated solvent can be prepared without (i.e., with limited) deuterium-hydrogen exchange.

[0080] Fluorine solvent can be any organic solvent comprising at least one compound with fluorine atom. Without wishing to be bound by any particular theory, it is believed that fluorine solvent increases the solubility of perfluorinated SABRE catalyst. In some embodiments, solvent (e.g., fluorine solvent) is selected from perfluorohexane / diethyl ether mixture, methoxy nonafluorobutane and mixture of ethyl acetate and non-polar solvent, perfluorohexane and ether mixture, perfluorobutyl methyl ether and ethyl acetate mixture, ether, fluorocarbon derivative FC 75 of THF, decafluoromethoxy trifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethyl cyclohexane, perfluoroalkane, perfluorohexane and methoxy nonafluorobutane.

[0081] In some embodiments, the method of preparing a hyperpolarized substrate further comprises isolating the hyperpolarized substrate. The hyperpolarized substrate can be isolated by any suitable method. For example, the hyperpolarized substrate can be isolated by extraction, filtration, column chromatography, distillation, crystallization, or a combination thereof.

[0082] In some embodiments, the hyperpolarized substrate is isolated by treating the reaction mixture with a solid phase adsorbent to adsorb the perfluorinated SABRE catalyst and recovering a liquid containing the hyperpolarized substrate, wherein the liquid is free (i.e., undetectable) or substantially free (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) of the perfluorinated SABRE catalyst. See, e.g., Fig.10The solid phase adsorbent can be any suitable adsorbent that can preferentially adsorb the perfluorinated SABRE catalyst rather than the hyperpolarized substrate. For example, the solid phase adsorbent can be a fluorinated solid phase adsorbent, a reverse phase adsorbent (e.g., C18 adsorbent, etc.), and a polyethylene-based filter (e.g., ultra-high molecular weight polyethylene). See, for example, Figure 6 and Figure 7 . In certain embodiments, the method for preparing a hyperpolarized substrate further comprises passing a fluorophobic solvent through an adsorbent and recovering an eluate containing the hyperpolarized substrate, wherein the eluate is free of (i.e., undetectable) or substantially free of (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) a perfluorinated SABRE catalyst. The fluorophobic solvent can be any suitable solvent that can preferentially wash the hyperpolarized substrate from the solid phase adsorbent relative to the perfluorinated SABRE catalyst. For example, the fluorophobic solvent can comprise water and one or more of methanol, ethanol, acetonitrile, and dimethylformamide. Alternatively or additionally, the method for preparing a hyperpolarized substrate can further comprise passing a fluorophilic solvent (e.g., a solvent comprising an organic solvent selected from methanol, ethanol, acetonitrile, THF, ethyl acetate, a chlorinated solvent (e.g., a chlorinated alkane such as dichloromethane, chloroform, and dichloroethane) and combinations thereof) through an adsorbent, for example, to recover the perfluorinated SABRE catalyst. Exemplary fluorophilic solvent systems include perfluorohexane / diethyl ether mixtures, methoxynonafluorobutane and ethyl acetate mixtures, perfluorohexane and diethyl ether mixtures, perfluorobutyl methyl ether and ethyl acetate mixtures or diethyl ether.

[0083] In some embodiments, the hyperpolarized substrate is separated by treating the reaction mixture with a solid phase adsorbent to adsorb the hyperpolarized substrate and recovering a liquid containing the perfluorinated SABRE catalyst, wherein the liquid is free (i.e., undetectable) or substantially free (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) of the hyperpolarized substrate. The solid phase adsorbent can be any suitable adsorbent capable of preferentially adsorbing the hyperpolarized substrate over the perfluorinated SABRE catalyst. For example, the solid phase adsorbent can be a normal phase adsorbent such as, for example, silica, alumina, etc. See, for example, Figure 8. In certain embodiments, the method for preparing a hyperpolarized substrate further comprises passing a fluorophilic solvent through an adsorbent and recovering an eluate containing a perfluorinated SABRE catalyst, wherein the eluate is free of (i.e., undetectable) or substantially free of (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) the hyperpolarized substrate. The fluorophilic solvent can be any suitable solvent that can preferentially wash away the perfluorinated SABRE catalyst from the solid phase adsorbent relative to the hyperpolarized substrate. For example, the fluorophilic solvent can comprise a perfluorohexane / diethyl ether mixture, a methoxynonafluorobutane and ethyl acetate mixture, a perfluorohexane and diethyl ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, or diethyl ether. Alternatively or additionally, the method for preparing a hyperpolarized substrate can further comprise passing a fluorophilic solvent (e.g., a solvent comprising water, methanol, ethanol, acetonitrile, dimethylformamide, or a combination thereof) through an adsorbent, for example, to recover the hyperpolarized substrate.

[0084] In any of the embodiments disclosed herein, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate may be present in a single phase or a biphasic mixture. The single phase or biphasic mixture may contain any combination of solvents described herein. For example, a biphasic mixture may contain a combination of a polar solvent (e.g., water, methanol, and ethanol) and a non-polar solvent (e.g., an organic solvent or a fluorochemical solvent). In embodiments where the perfluorinated SABRE catalyst and / or the hyperpolarized substrate are present in a biphasic solvent, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate may be separated by liquid / liquid extraction. See, for example, Fig. 9 Thus, in some embodiments, the hyperpolarized substrate is separated by liquid / liquid extraction, for example, by partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanol mixture and a fluorous solvent, or partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanol mixture and an organic solvent.

[0085] In some embodiments, the hyperpolarized substrate is isolated by precipitating the perfluorinated SABRE catalyst and filtering and removing the precipitated perfluorinated SABRE catalyst from the hyperpolarized substrate. Typically, the perfluorinated SABRE catalyst is precipitated by adding a solvent in which the perfluorinated SABRE catalyst is insoluble (e.g., hexane, pentane, water, ethanol, etc.). In certain embodiments, the perfluorinated SABRE catalyst is precipitated by adding water.

[0086] The perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be dried or concentrated (e.g., under reduced pressure, using a desiccant, heating, or a combination thereof). Alternatively or additionally, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be diluted or reconstituted with a solvent (e.g., water) to provide a desired concentration. For example, the perfluorinated SABRE catalyst can be isolated and reused as a hyperpolarized catalyst. Similarly, the hyperpolarized substrate can be dried or concentrated to remove the organic solvent and reconstituted in water for administration to a subject.

[0087] The substrate can be any compound containing one or more 1 / 2 spin nuclei. For example, the substrate can include 1 H. 13 C. 15 N. 19 F. 31 P. 29 Si or a combination thereof. In some embodiments, the substrate further comprises 2 D. Therefore, the methods described herein can be used to enhance the 1 H. 13 C. 15 N. 19 F. 31 P and / or 29 The signal of Si response. In general, the spin polarization transfer described in this paper is based on the SABRE effect; however, the method can be extended to parahydrogen induced polarization (PHIP).

[0088] In some embodiments, the substrate is selected from ketoglutarate, pyruvate, N-acetylcysteine ​​and salts or esters thereof. 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbon-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form and its salts.

[0089] In some embodiments, the substrate is of formula (II) or a pharmaceutically acceptable salt thereof: wherein each R1 is independently selected from hydrogen, deuterium, a cation, a C1-C6 alkyl, a C3-C7 cycloalkyl, a (C3-C7 cycloalkyl)C1-C6 alkyl, a (heterocycloalkyl)C1-C6 alkyl, a (heteroaryl)C1-C6 alkyl, and a (aryl)C1-C6 alkyl; and wherein Xa, Xb, Xc and Xd are each independently hydrogen or deuterium, provided that at least one of Xa, Xb, Xc and Xd is deuterium.

[0090] Each R1 can be independently selected from hydrogen, deuterium, cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C6 alkyl, (heterocycloalkyl) C1-C6 alkyl, (heteroaryl) C1-C6 alkyl and (aryl) C1-C6 alkyl. In some embodiments, each R1 is independently selected from C1-C6 alkyl, for example, each R1 can be methyl, ethyl, propyl (for example, isopropyl or n-propyl), butyl (for example, isobutyl, n-butyl, tert-butyl or sec-butyl), pentyl or hexyl. In some embodiments, each R1 is independently selected from hydrogen, deuterium and cation. In the embodiment where R1 is a cation, it will be readily understood by those of ordinary skill in the art that the compound of formula (II) is a salt (for example, a pharmaceutically acceptable salt) in which the negative charge on oxygen is balanced by a cation. In certain embodiments, each R1 is independently a cation or C1-C6 alkyl.

[0091] The present disclosure also provides a hyperpolarized substrate or a pharmaceutically acceptable salt obtained from any of the methods described herein, or a pharmaceutical composition comprising a hyperpolarized substrate or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. In other words, the present invention provides an imaging medium (e.g., an aqueous imaging composition) having enhanced sensitivity to water-soluble compounds comprising one or more hyperpolarizable nuclei, the imaging medium being particularly suitable for nuclear magnetic resonance (NMR) spectroscopy and / or magnetic resonance imaging (MRI).

[0092] The present disclosure also provides a method for obtaining a magnetic resonance image of tissue of an object suffering from or suspected of suffering from cancer or an unfavorable vascular condition, the method comprising administering a hyperpolarized substrate as described herein or a pharmaceutical composition thereof to the object, and imaging the object by magnetic resonance imaging. On the one hand, the object suffers from cancer, such as, for example, a cancer selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer and thyroid cancer. On the other hand, the object suffers from an unfavorable vascular condition, such as, for example, a vascular condition selected from myocardial infarction, stroke and lung disease (e.g., COPD, pulmonary fibrosis, long-term COVID-19 symptoms and combinations thereof).

[0093] In some embodiments, the present disclosure provides a method of diagnosing or monitoring a patient having or suspected of having cancer, the method comprising administering a hyperpolarized substrate or pharmaceutical composition as described above and detecting the patient's cancer by hyperpolarization. 13 C-MRI diagnoses or monitors patients. For example, the hyperpolarized substrate can be used in a method for diagnosing or monitoring a patient suffering from or suspected of having cancer. In certain embodiments, the method or use comprises identifying one or more mutations that are the cause of the cancer. In certain embodiments, the method or use identifies an IDH1 mutation as the cause of the cancer. In other words, the method or use can be used to identify whether a patient has a tumor, for example, an IDH1 mutation.

[0094] The figures will now be described to illustrate various aspects of the disclosed MRI probe infusion device. It should be understood that features of any aspect of the disclosure are not intended to limit the scope of other aspects of the disclosure, and features from multiple aspects disclosed herein may be combined unless inconsistent with context.

[0095] Figure 1 1 shows a reaction chamber 110 and a separator 120 of a hyperpolarized MRI probe infusion device according to one aspect of the present disclosure. Figure 1 As shown, the reaction chamber 110 includes a plurality of inlet ports 112, 114 and a plurality of outlet ports 116, 118. According to one aspect, the reaction chamber 110 includes a first inlet port 112 for receiving a liquid input (e.g., a solvent, a catalyst, a substrate, etc.) and a second inlet port 114 for receiving a gas input (e.g., parahydrogen). The reaction chamber 110 also includes a first outlet port 116 for exhausting gas from the reaction chamber 110 and a second outlet port 118 for pumping the reaction mixture from the reaction chamber 110 into the separator 120.

[0096] According to one aspect, the first inlet port 112 can introduce a solution including one or more solvents, a catalyst, and a substrate into the reaction chamber. The solvent can include ethanol, a mixture of ethanol and a fluorinated solvent, methanol, or a mixture of methanol and a fluorinated solvent, for example, one or more solvents include ethanol and water. The substrate can include an element having a 1 / 2 spin nucleus selected from 13 C. 15 N. 19 F. 31 P and 29 Si and its deuterated form. Second inlet port 114 can introduce parahydrogen gas into the reaction chamber. Although not shown, one or more additional inlet ports can be included in reaction chamber 110 to introduce other liquids or gases into the reaction chamber. Alternatively, two or more components can be mixed in separate containers to form an intermediate solution and then introduced into reaction chamber 110 through one of inlet ports 112, 114.

[0097] According to one aspect, first outlet port 116 enables exhaust of gas from reaction chamber 110. A continuous flow of parahydrogen gas can be connected to inlet port 114 and exhausted from outlet port 116. Outlet port 116 can include a valve integrated therein or connected in series therewith to ensure that a desired pressure is maintained in reaction chamber 110. According to one aspect, reaction chamber 110 is configured to withstand gas pressures of up to 10 bar or more.

[0098] According to one aspect, the line connected to the outlet port 116 can be connected to a gas trap 122 and / or a storage tank 124 so that the gas exhausted from the reaction chamber 110 is not exhausted to the atmosphere in order to implement safety protocols. Although not explicitly shown, a compressor, valves, instrumentation, or other common air system components can be connected to the exhausted gas line to safely store the gas exhausted from the reaction chamber 110.

[0099] According to one aspect, after the reaction to produce the hyperpolarized MRI probe is complete, the second outlet port 118 enables the reaction mixture to be pumped out of the reaction chamber 110. The second outlet port 118 may include a valve integrated therein or connected in series therewith so that a vacuum can be created in the separator 120 and / or the collection container 130, which causes the liquid to rise along the tube in the reaction chamber 110 and enter the separator. While the reaction is proceeding, the valve can be closed to create a vacuum, and then opened once the reaction is complete to pump the reaction mixture out of the reaction chamber 110.

[0100] The separator 120 is configured to receive a reaction mixture containing a perfluorocarbon hyperpolarization transfer SABRE catalyst, a solvent, and a hyperpolarized MRI probe from a reaction chamber, and to separate the hyperpolarized MRI probe from the catalyst. According to one aspect, the separator 120 may include a filter medium, which may contain an adsorbent, such as fluorosilicone. The separator 120 may be configured to dilute the reaction mixture with water and / or ethanol before filtering the diluted mixture through the filter medium. The catalyst will be absorbed in the fluorosilicone and separated from the hyperpolarized probe in the solvent. According to another aspect, the filter medium may be omitted, and the mixture may be separated by stirring the mixture and extracting the ethanol layer from another layer containing the fluorosolvent-catalyst mixture. Optionally, the reaction mixture may be diluted with water before stirring and extracting, so that the water / ethanol layer is extracted from the column. Optionally, when methanol is used as a solvent, the above method may be adjusted by adding a step of concentration and redissolving with water. Finally, the separated reaction mixture 132 containing the hyperpolarized MRI probe is collected in a collection container 130, which may be, for example, a vacuum bottle or other device.

[0101] It should be understood that when extracted from the low magnetic field within the reaction chamber 110, the hyperpolarized MRI probe should be maintained in a high magnetic field to maintain polarization during separation, concentration, re-dissolution and administration. The high magnetic field can be provided by one or more permanent magnets or electromagnets (e.g., coils) near the separator 120 and the collection container 130. In some cases, the high magnetic field can be provided by the coils of an MRI machine located near the MRI probe infusion device. The strength of the high magnetic field can be determined based on the molecules being hyperpolarized.

[0102] Although not in Figure 1 10, but the reaction chamber 110 may include a plurality of internal components, such as a temperature control device and / or a coil (e.g., a solenoid) for generating an internal magnetic field within the reaction chamber 110, which are connected to an external controller via an interface 126. The controller is configured to execute software to control the temperature within the reaction chamber, control the flow of gases and liquids through the device, monitor the safety of the device and / or the environment, administer a desired amount of hyperpolarized probe to a patient, and / or calculate the decay rate of the hyperpolarized MRI probe as a function of the flow rate of the gas and / or liquid. The interface 126 may include electrical connections for providing control signals to the internal components and / or for receiving signals from one or more sensors (e.g., a temperature sensor, a magnetometer, a pressure gauge, etc.) connected to or located in the reaction chamber 110.

[0103] Some components of the device can be made of non-magnetic materials or plastics. For example, various connectors, sensors, valves, instruments, etc. can be made of brass or plastics to reduce any effect on the magnetic field induced in the reaction chamber.

[0104] Figure 2 1 shows the internal components of a reaction chamber 110 according to an aspect of the present disclosure. The reaction chamber 110 may include one or more metal layers 202, 204, 206 that are shaped to form a chamber configured to contain a volume and pressure of liquid and / or gas suitable for conducting the disclosed reactions therein. Figure 2As shown, the reaction chamber 110 may include three metal layers that form a substantially cylindrical shape. It should be understood that the reaction chamber is not limited to a cylindrical shape, and other desired shapes may also be considered for use as a reaction chamber. According to one aspect, the layers 202, 204, 206 include a ferromagnetic alloy. According to some aspects, one or more layers 202, 204, 206 may include a nickel-iron (Ni-Fe) alloy, such as Invar, Permalloy, or a mu alloy. At least one layer 202, 204, 206 is configured to shield the reaction chamber from magnetic fields associated with external sources, such as the earth's magnetic field or other electrical components that may emit EM radiation. According to one aspect, the layers 202, 204, 206 include a mu alloy shield that attenuates the magnetic field from the external source in one or more reaction chambers to have a strength less than or equal to a threshold. According to one aspect, the threshold is 10nT. According to some aspects, different layers may include different materials. For example, outer layer 202 may comprise a ferromagnetic alloy that serves to shield the interior of the chamber from external magnetic fields, while inner layer 206 may comprise a separate material that is non-reactive with solvents or chemicals introduced into the reaction chamber.

[0105] According to one aspect, the reaction chamber 110 further includes a coil 210 for generating an electromagnetic field in the reaction chamber in response to a current passing therethrough. According to some aspects, the coil is a high uniformity solenoid. The current can provide a constant or alternating magnetic field of 0-200 millitesla (mT) and / or a radio frequency of 0-500 MHz.

[0106] According to one aspect, the reaction chamber 110 further comprises a temperature control device 220, which may comprise a heating element and a cooling element. The temperature control device may comprise a non-magnetic (i.e., non-ferrous) material. According to one aspect, the cooling element comprises a liquid nitrogen bath outside at least the inner layer 206 of the reaction chamber, so that at least one surface of the layer 206 may be in contact with the liquid nitrogen. When heat is drawn from the reaction chamber through the surface, cooling is provided due to the evaporation of the liquid nitrogen. The nitrogen produced may be discharged into the atmosphere and / or discharged into the gas trap 122. The heating element may be a resistive heating element, such as a convection coil, which is inserted into the reaction chamber near the surface of the layer 206 or through a port in the reaction chamber. In operation, the temperature controller may be connected to a temperature sensor / probe and configured to operate the heating and cooling elements to adjust the temperature of the reaction chamber 110. According to one aspect, the temperature control device 220 is configured to maintain the temperature of one or more reaction chambers at -25°C to 100°C. According to other aspects, the temperature of the reaction chamber may be cycled up to 10-20 times between two or more different temperatures within a time period of 1 minute to 5 minutes. For example, in operation, liquid nitrogen can be dispensed into the bath to cool the reaction chamber to a desired low temperature. Once the reaction chamber 110 has reached a low temperature and / or the liquid nitrogen has boiled into nitrogen gas, the heating element can be turned on to heat the reaction chamber 110 to a desired high temperature. This cycle can be repeated multiple times during the reaction process.

[0107] Figure 3 Components and their arrangement of an MRI probe infusion device according to one aspect of the present disclosure are schematically shown. The MRI probe infusion device comprises at least one reaction chamber 110, a separator 120, a collection and measurement device 320, and an MRI probe applicator device 330. The reaction chamber 110, the collection and measurement device 320, and the MRI probe applicator device 330 are connected to a controller 310. The infusion device is also equipped with a dryer or concentrator 322 and an analyzer 332 for analyzing at least one of the purity or concentration of the hyperpolarized MRI probe in the solution.

[0108] According to one aspect, the controller 310 includes software and / or hardware for operating the MRI probe infusion device. The controller 310 may include a computer device including at least one processor, a memory, and one or more input / output devices. The software stored in the memory may be executed by the processor to control the functions of the MRI probe infusion device. According to one aspect, the controller 310 includes a processor configured to execute instructions that cause the processor to: control the flow of gas and / or liquid through the device, monitor safety metrics of the device and / or environment, administer a desired amount of hyperpolarized MRI probe to the patient, and / or calculate the decay rate of the hyperpolarized MRI probe as a function of the flow rate of the gas and / or liquid.

[0109] Although not explicitly shown, the controller 310 can receive input from one or more sensors that provide feedback in order to control the operation of the MRI probe infusion device. For example, the sensor may include a temperature sensor for monitoring the temperature of the reaction chamber and controlling the temperature control device (i.e., heating and / or cooling element). The sensor may also include a pressure transducer, a flow meter, or other types of sensors to monitor the flow of liquid and / or gas flowing into or out of the reaction chamber 110. The sensor may also include a gas leak detector and / or an oxygen level monitor to maintain a safety protocol when operating the device. For example, a gas leak detector can monitor the surrounding environment around the device to monitor the level of hydrogen that may leak from the reaction chamber and / or any related gas pipelines or storage tanks. The oxygen level monitor can detect the level of oxygen in the room to prevent accidental suffocation caused by nitrogen leaks. It should be understood that any other necessary sensors, such as encoders, limit switches, proximity sensors, optical sensors, etc., can be included in the device to monitor one or more operating characteristics or states of any component or actuator integrated therein.

[0110] The controller 310 may also include an interface for human input, such as a touch screen display, a keypad or keyboard, a switch, a button, etc. The interface may allow a technician to manually operate the device. Optionally, the interface may include a wired or wireless interface so that the controller can communicate with an external terminal (e.g., a computer device, a server device, a tablet device, etc.) for controlling the operation of the MRI probe infusion device. For example, the controller 310 may include a network interface that enables the device to be connected to another terminal via a wired or wireless interface. The terminal may display a graphical user interface that enables the technician to interact with various menus to control the operation of the device.

[0111] like Figure 3 As shown, in one aspect, the MRI probe infusion device includes a collection and measurement device 320. In a clinical environment, the mixture containing the hyperpolarized MRI probe can be analyzed and further processed to facilitate the automatic generation of the hyperpolarized MRI probe and the administration to a patient (e.g., a human or an animal) being treated. According to one aspect, the collection and measurement device 320 may include a dryer 322, which is configured to concentrate the solution or emulsion containing the hyperpolarized MRI probe received from one or more MRI probe separators 120 to form a concentrate. The dryer 322 may include a spray dryer and / or an evaporative dryer. In one aspect, one or more evaporative dryers form one or more azeotropes with an inert solvent, resulting in a lower temperature of the evaporative dryer.

[0112] For example, a spray dryer including a container and a nozzle can be implemented, the nozzle being configured to evaporate the solvent so that the hyperpolarized MRI probe is deposited on the container wall. The solvent vapor can be discharged to a gas trap and / or a storage tank. The solid hyperpolarized MRI probe can be dissolved in a buffer solution (e.g., saline or a mixture of saline and ethanol) to form a solution containing a desired concentration of hyperpolarized MRI probe. The collection and measurement device 320 can also include an analyzer 324 and / or other measuring tools for analyzing the reaction mixture before and / or after concentration and dilution to determine the reaction efficacy in the reaction chamber and / or for adjusting operating parameters to produce a buffer solution of a hyperpolarized MRI probe of a desired concentration. For example, after analyzing the buffer solution, the controller 310 can use the measured concentration of the hyperpolarized MRI probe in the buffer solution to distribute additional buffer solution to reach the target concentration. On the one hand, the analyzer 324 can include a liquid chromatograph / mass spectrometer (LC / MS) and / or a nuclear magnetic resonance (NMR) spectrometer.

[0113] Applicator 330 may include any equipment required for metering and delivering a hyperpolarized MRI probe to a patient. Applicator 330 is configured to administer a dose of a solution containing a desired concentration of a hyperpolarized MRI probe to an animal or patient in need. According to one aspect, applicator 330 may include, but is not limited to, a peristaltic pump, fluid lines, and the like. In one aspect, applicator 330 may include a power injector commonly used for other MRI or X-ray contrast agents. In another aspect, applicator 330 may include an aerosol delivery accessory for pulmonary administration.

[0114] Likewise, it will be appreciated that the separator 120, the collection and measurement device 320, and the applicator 330 should be maintained in a high magnetic field during extraction and preparation of the hyperpolarized MRI probe prior to delivery to the patient. The magnetic field may be provided by one or more permanent magnets or electromagnets, which may be included near the device and / or provided by a separate device (e.g., an MRI machine).

[0115] Figure 4 An MRI infusion device equipped with multiple reaction chambers and a hyperpolarized probe from each reaction chamber separated from a reaction mixture is shown according to one aspect of the present disclosure. Figure 4As shown, the MRI infusion device 400 may include two or more reaction chambers 402, 404, 406 to facilitate multiple reactions of different hyperpolarized MRI probes substantially simultaneously and / or to increase the total volume of a single hyperpolarized MRI probe by multiple independent reactions performed in parallel. For example, if it takes 10 minutes to produce a single dose of hyperpolarized MRI probe from a particular reactor, multiple reaction chambers may be used, such as using a 2-chamber or 3-chamber system to produce separate doses every 5 minutes or 3.3 minutes, respectively. As described above, each reaction chamber 402, 404, 406 may be associated with a separate and different separator 120, collection and measurement device 320, and / or applicator 330. Alternatively, multiple reaction chambers may share a single separator 120, collection and measurement device 320, and / or applicator 330.

[0116] It should be understood that in some cases, one or more reaction chambers are configured to be operable in series. For example, a reaction mixture produced based on a reaction performed in a first reaction chamber can be provided to a second reaction chamber, where a second reaction can be performed. The reactions can be the same reaction or different reactions (e.g., by introducing different gases or chemical compounds in, for example, the second reaction chamber).

[0117] Figure 5 Some steps involved in a method of preparing a hyperpolarized MRI probe for administration to a patient according to one aspect of the present disclosure are shown. At step 502, a reaction mixture is supplied to one or more chambers of an MRI probe infusion device. Again, the reaction mixture may include a perfluorinated SABRE catalyst containing a d-block element and a perfluorinated ligand, a solvent, a co-ligand, and a substrate to be hyperpolarized into an MRI probe.

[0118] According to one aspect of the present disclosure, the substrate may be selected from one of the following: 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbon-bis-15N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form and its salts.

[0119] According to one aspect of the present disclosure, the perfluorinated ligand is of formula (I): [L m -(NHC)-(YZ) q] or a salt thereof. In formula (I), each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group; NHC is a 4-membered to 7-membered N-heterocyclic carbene group, wherein NHC is bound to a d-block element via a carbene; each Y is independently selected from a bond or a spacer group; each Z is a perfluorinated tag; m is an integer from 1 to 4; and q is an integer from 1 to 3. The perfluorinated tag is one of the following: a perfluorinated C containing only carbon and fluorine atoms; 3-60 Group; Perfluorinated C containing only carbon and fluorine atoms 3-40 Group; or perfluorinated C 3-20 Group.

[0120] According to one aspect of the present disclosure, the perfluorinated ligand is selected from one of the following: or a salt thereof, and wherein single or double bonds, and represents a bond through a carbene to a d-block element.

[0121] At 504, the reaction mixture is stirred by injecting parahydrogen or a mixture of parahydrogen and nitrogen. For example, the inlet port 114 connected to the parahydrogen can be connected to a tube that descends to the bottom of the reaction chamber 110 so that the gas entering the reaction chamber is bubbled through a solution containing a solvent, a catalyst, and a substrate. According to one aspect, the coil 210 and / or the temperature control device 220 can be controlled to maintain a target temperature of the reaction chamber 110, or the temperature is cycled between two or more temperatures to promote a reaction that produces a hyperpolarized MRI probe. According to one aspect, a magnetic field is applied within the reaction chamber using a coil 210, which is suitable for hyperpolarization of a perfluorinated SABRE catalyst and a substrate to hyperpolarize the substrate into a hyperpolarized MRI probe.

[0122] At step 506, the solution containing the hyperpolarized MRI probe is extracted from the reaction chamber. The hyperpolarized MRI probe is separated from the reaction mixture by at least one of filtration, extraction or column chromatography, and the solution can be separated into at least two parts to obtain a solution containing the hyperpolarized MRI probe. According to one aspect, the solution is filtered by a separator 120 to separate the catalyst from the hyperpolarized MRI probe dissolved in the solvent, and the solvent includes ethanol, a mixture of ethanol and water, methanol or a mixture of ethanol and methanol. According to one aspect of the present disclosure, the solvent can be selected from one of the following: a perfluorohexane / diethyl ether mixture, a mixture of methoxynonafluorobutane and ethyl acetate and a non-polar solvent, a perfluorohexane and ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, ether, a fluorocarbon derivative of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, a perfluoroalkane, perfluorohexane or methoxynonafluorobutane.

[0123] At step 508, the solution is concentrated to obtain a concentrate. The solution can be dried using one or more dryers to evaporate the solvent and increase the concentration of the hyperpolarized MRI probe in the solution. In some cases, all of the solvent is removed so that a powder, solid residue, or viscous liquid containing the hyperpolarized MRI probe remains on the surface of the dryer.

[0124] At step 510, a buffer solution is added to the concentrate to obtain a solution of a desired concentration. According to one aspect, saline or a saline and ethanol solution can be added to the concentrate to produce a buffer solution having a desired concentration of hyperpolarized MRI probe.

[0125] At step 512, the purity and / or concentration of the hyperpolarized MRI probe in the buffer solution is analyzed. In some aspects, the analysis can be performed using at least one of a liquid chromatograph / mass spectrometer or an NMR spectrometer. According to some aspects, the results of the analysis can be used to further dilute the solution with additional buffer solution to adjust the concentration of the hyperpolarized MRI probe in the solution.

[0126] The hyperpolarized MRI probe may be administered to a subject (eg, a patient or an animal) at step 514. The hyperpolarized MRI probe may be administered using the applicator 330 at a desired dose and / or at desired intervals.

[0127] Likewise, it should be understood that step 504 is performed in a low magnetic field within the reaction chamber and steps 506-512 are performed in a high magnetic field (e.g., several orders of magnitude greater than the low magnetic field within the reaction chamber) provided by one or more permanent magnets and / or electromagnets outside the reaction chamber.

[0128] In one aspect, the hyperpolarized MRI probe can be separated from the reaction mixture in an MRI separator by means of fluorine-repellent passage through a filter medium, such as Figure 6 As shown and further described in Example 8.

[0129] Figure 7 Aspects of hyperpolarization, separation of the probe, and recovery of the SABRE catalyst are shown.

[0130] On the other hand, the hyperpolarized MRI probe can be separated from the reaction mixture in an MRI separator by passing through a fluorine-repelling channel, which is preceded by a fluorine-philic channel, such as Figure 8 As shown and further described in Example 9.

[0131] On the other hand, Fig. 9 The process of separation of the probe and injection into a subject (eg, an animal or patient) is shown.

[0132] Aspects of the present disclosure including embodiments may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the above description, certain non-limiting aspects of the present disclosure numbered 1-47 are provided below. As will be apparent to those skilled in the art upon reading the present disclosure, each individually numbered aspect may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all combinations of these aspects, and is not limited to the combinations of aspects explicitly provided below:

[0133] (1) In aspect (1), there is provided an MRI probe infusion device comprising: (i) one or more reaction chambers, each reaction chamber comprising: (a) a structure configured to weaken a magnetic field from an external source within a reaction chamber, wherein the strength of the magnetic field from the external source within the reaction chamber is less than a threshold value; (b) one or more inlet ports; (c) a coil configured to generate an electromagnetic field within the reaction chamber; (d) one or more temperature control devices; and (e) one or more outlet ports; (ii) one or more MRI probe separators configured to receive a reaction mixture comprising a perfluorinated SABRE catalyst, a solvent, and a hyperpolarized MRI probe from the one or more reaction chambers and extract the hyperpolarized MRI probe from the reaction mixture; and (iii) one or more MRI probe collectors configured to form a solution containing a desired concentration of hyperpolarized MRI probes.

[0134] (2) In aspect (2), structure (a) is a mu metal shield that attenuates a magnetic field from an external source in one or more reaction chambers to have a strength less than or equal to 10 nT.

[0135] (3) In aspect (3), the one or more inlet ports include one or more gas ports and one or more liquid ports.

[0136] (4) In aspect (4), each reaction chamber is configured to withstand a gas pressure of at least 10 bar.

[0137] (5) In aspect (5), the magnetic field in the reaction chamber induced by the coil is 0-200 millitesla.

[0138] (6) In aspect (6), the one or more temperature control devices include non-magnetic heating elements and / or cooling elements, which are configured to provide temperature cycling of the reaction chamber.

[0139] (7) In aspect (7), one or more temperature control devices provide cooling using nitrogen gas evaporated from liquid nitrogen and heating by convection coils.

[0140] (8) In aspect (8), the one or more temperature control devices are configured to provide temperature cycling or maintain the temperature of each reaction chamber at -25°C to 100°C.

[0141] (9) In aspect (9), the one or more reaction chambers are configured to be hyperpolarized with a reaction mixture containing a perfluorinated SABRE catalyst, a solvent, and a substrate to be hyperpolarized into a hyperpolarized MRI probe.

[0142] (10) In aspect (10), the solvent is a single-phase system or a two-phase system comprising water, methanol, ethanol, a fluorinated solvent or a mixture thereof.

[0143] (11) In aspect (11), the one or more MRI probe separators are configured to separate the hyperpolarized MRI probe from the perfluorinated SABRE catalyst by one of the following: filtration; extraction; or column chromatography.

[0144] (12) In aspect (12), the MRI probe infusion device further comprises a gas trap, a gas leak detector and / or an oxygen level monitor.

[0145] (13) In aspect (13), the MRI probe infusion device also includes a processor configured to execute instructions that cause the processor to: control the flow of gas and / or liquid through the device, monitor safety measures of the device and / or environment, administer a desired amount of hyperpolarized MRI probe to the patient, or calculate the attenuation rate of the hyperpolarized MRI probe as a function of the flow rate of gas and / or liquid.

[0146] (14) In aspect (14), one or more MRI probe concentrators include one or more dryers.

[0147] (15) In aspect (15), the one or more dryers include an evaporative dryer that forms one or more azeotropes with the inert solvent, resulting in a lower temperature in the evaporative dryer.

[0148] (16) In aspect (16), the one or more reaction chambers include at least two reaction chambers, and the at least two reaction chambers are configured to be operable in series or in parallel.

[0149] (17) In aspect (17), the components of the MRI probe infusion device are made of non-magnetic material or plastic.

[0150] (18) In aspect (18), a method of administering a hyperpolarized MRI probe to a patient in need thereof is provided, the method comprising: (i) providing an MRI probe infusion device, (ii) supplying a reaction mixture to one or more reaction chambers, the reaction mixture comprising a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, a solvent, a co-ligand, and a substrate to be hyperpolarized into an MRI probe, (iii) stirring the reaction mixture, wherein the stirring is provided by bubbling parahydrogen gas or a mixture of parahydrogen and nitrogen gas through the reaction mixture, (iv) applying a magnetic field suitable for hyperpolarization of the perfluorinated SABRE catalyst and the substrate to hyperpolarize the substrate into a hyperpolarized MRI probe, (v) separating the hyperpolarized MRI probe from the reaction mixture by at least one of filtration, extraction or column chromatography to obtain a solution containing the hyperpolarized MRI probe, (vi) concentrating the hyperpolarized MRI probe present in the solution obtained in step (v) to obtain a concentrate, and reconstituting the concentrate into a solution of the hyperpolarized MRI probe of a desired concentration for administration to a patient; (vii) analyzing at least one of the purity or concentration of the hyperpolarized MRI probe present in the solution; and (viii) administering a hyperpolarized MRI probe to the patient.

[0151] (19) In aspect (19), the solvent comprises water, methanol, ethanol, a fluorinated solvent or a mixture thereof.

[0152] (20) In aspect (20), the solvent is selected from a perfluorohexane / diethyl ether mixture, a mixture of methoxynonafluorobutane and ethyl acetate with a non-polar solvent, a perfluorohexane and ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, ether, a fluorocarbon derivative of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkanes, perfluorohexane and methoxynonafluorobutane.

[0153] (21) In aspect (21), the substrate comprises 1 H. 13 C. 15 N. 19 F. 31 P. 29 Si or a combination thereof.

[0154] (22) In aspect (22), the substrate further comprises 2 D.

[0155] (23) In aspect (23), the substrate is selected from 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbon-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form and its salts.

[0156] (24) In aspect (24), the substrate is of formula (II) or a pharmaceutically acceptable salt thereof: wherein each R1 is independently selected from hydrogen, deuterium, a cation, C 1-C6 C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl and (aryl)C1-C6 alkyl; and wherein Xa, Xb, Xc and Xd are each independently hydrogen or deuterium, provided that at least one of Xa, Xb, Xc and Xd is deuterium.

[0157] (25) In aspect (25), the perfluorinated ligand is of formula (I): [L m -(NHC)-(YZ) q ] or a salt thereof, and wherein: each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, NHC is a 4- to 7-membered N-heterocyclic carbene group, wherein NHC is bound to the d-block element via a carbene, each Y is independently selected from a bond or a spacer group, each Z is a perfluorinated tag, m is an integer from 1 to 4, and q is an integer from 1 to 3.

[0158] (26) In aspect (26), NHC is a 5-membered N-heterocyclic carbene group.

[0159] (27) In aspect (27), the 5-membered N-heterocyclic carbene group is imidazole-based, imidazoline-based or thiazole-based.

[0160] (28) In aspect (28), NHC is a 4,5-disubstituted, 1,3-disubstituted or 1,3,4,5-tetrasubstituted imidazole-based or imidazoline-based 5-membered N-heterocyclic carbene group.

[0161] (29) In aspect (29), NHC is 4,5-disubstituted imidazolidinyl, 1,3-disubstituted imidazolidinyl, 1,3,4,5-tetrasubstituted imidazolidinyl, 4,5-disubstituted 2,3-dihydro-imidazolyl, 1,3-disubstituted 2,3-dihydro-imidazolyl or 1,3,4,5-tetrasubstituted 2,3-dihydro-imidazolyl.

[0162] (30) In aspect (30), the perfluorinated ligand is of formula (Ia) or (Ib): or a salt thereof, and wherein: each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, each Y is independently a bond or a spacer group, each Z is independently a perfluorinated tag, is a single bond or a double bond, and represents a bond through a carbene to a d-block element.

[0163] (31) In aspect (31), the perfluorinated ligand is of formula (Ic) or (Id): or a salt thereof, and wherein: each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, a is 4 to 20, b=2a+1 or b=a-1, each n is independently an integer from 0 to 4, is a single bond or a double bond, and represents a bond through a carbene to a d-block element.

[0164] (32) In aspect (32), the perfluorinated ligand is of formula (Ie) or (If): or a salt thereof, and wherein: each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, each Ar is independently a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, each G is independently a bond, C 1-6 Alkyl, C 1-6Alkenyl or C 1-6 heteroalkyl, a is 4 to 20, b = 2a + 1 or b = a-1, is a single bond or a double bond, and represents a bond through a carbene to a d-block element.

[0165] (33) In aspect (33), each L is independently hydrogen, adamantyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,5-diethylphenyl, 2,4,6-trimethylphenyl, 6-triethylphenyl, 2-n-propylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 2,4-di-n-propylphenyl, 2,5-di-n-propylphenyl, 2,6-di-n-propylphenyl, 3,5-di-n-propylphenyl, 2,4,6-tri-n-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-diisopropylphenyl, 2,5-diisopropylphenyl, 2,6-diisopropylphenyl, 3,5-diisopropylphenyl, 2,4,6-triisopropylphenyl Propylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-diisobutylphenyl, 2,5-diisobutylphenyl, 2,6-diisobutylphenyl, 3,5-diisobutylphenyl, 2,4,6-triisobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2,4-di-sec-butylphenyl, 2,5-di-sec-butylphenyl, 2,6-di-sec-butylphenyl, 3,5-di-sec-butylphenyl, 2,4,6-tri-sec-butylphenyl Phenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2,4-di-tert-butylphenyl, 2,5-di-tert-butylphenyl, 2,6-di-tert-butylphenyl, 3,5-di-tert-butylphenyl, 2,4,6-tri-tert-butylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2,4-dicyclohexylphenyl, 2,5-dicyclohexylphenyl, 2,6-dicyclohexylphenyl, 3,5-dicyclohexylphenyl or 2,4,6-tricyclohexylphenyl.

[0166] (34) In aspect (34), each L is independently hydrogen or 2,4,6-trimethylphenyl.

[0167] (35) In aspect (35), each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6 a heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, a substituted or unsubstituted arylalkyl group, or a linear or branched alkyleneoxy group.

[0168] (36) In aspect (36), the perfluorinated tag is a perfluorinated C containing only carbon and fluorine atoms. 3-60 Group.

[0169] (37) In aspect (37), the perfluorinated tag is a perfluorinated C containing only carbon and fluorine atoms. 3-40 Group.

[0170] (38) In aspect (38), the perfluorinated tag is a perfluorinated C 3-20 Group.

[0171] (39) In aspect (39), the perfluorinated tag is selected from the group consisting of C4F9, C5F 11 Group, C6F 13 Group, C7F 15 Group, C8F 17 Group, C9F 19 Group, C 10 F 21 Group, C6F5 group, C4F7 group, C5F9 group, C6F 11 Group, C7F 13 Group, C8F 15 Group, C9F 17 Group and C 10 F 19 Group.

[0172] (40) In aspect (40), the perfluorinated ligand is one of: or a salt thereof, and wherein: is a single bond or a double bond, and represents a bond through a carbene to a d-block element.

[0173] (41) In aspect (41), the d-block element is a transition metal.

[0174] (42) In aspect (42), the d-block element is one of Co, Rh, Ir, Ru, Pd, Pt or Mt.

[0175] (43) In aspect (43), the method further comprises using the hyperpolarized MRI probe to diagnose the stage of a disease or to monitor the progress of treatment in a patient suffering from the disease.

[0176] (44) In aspect (44), the disease is cancer or an adverse vascular condition.

[0177] (45) In aspect (45), the cancer is selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer and thyroid cancer.

[0178] (46) In aspect (46), the adverse vascular condition is selected from myocardial infarction, stroke and lung disease.

[0179] (47) In aspect (47), the lung disease is selected from COPD, pulmonary fibrosis, long-term COVID-19 symptoms, or a combination thereof.

[0180] The following examples further illustrate various aspects of the disclosure, but should of course not be construed as limiting the scope thereof in any way. Example 1

[0181] This example shows a method for preparing 1H,1H,2H,2H-perfluorooctyl-N,N'-bis(2,4,6-trimethylphenyl)-9,10-diamine: Where x=6 and y=13.

[0182] A 1.7 M solution of tert-butyl lithium in pentane (5 mL, 9 mmol, 8 equiv) was added to a solution of 1H,1H,2H,2H-perfluorooctyl iodide (2 g, 4 mmol, 4 equiv) in anhydrous Et2O (60 mL) at -78°C. After the mixture was stirred at -78°C for 20 minutes, solid N,N'-dimesitylethanediimine (0.30 g, 1.03 mmol, 1 equiv) was added in portions. The reaction mixture was stirred for 4 hours. The reaction was slowly warmed to -30°C and quenched with saturated ammonium chloride solution (0.6 mL).

[0183] Water (20 mL) was added, the organic layer was separated, and the aqueous layer was extracted with diethyl ether (3×15 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The crude product was purified by flash column chromatography (4:1 hexane / dichloromethane (DCM)) to give diamine, diimine and threo-diamine (0.6 g, 60% yield, white solid). 1H NMR (400MHz, CDCl3) δ1.64-1.82 (m, 2H, CH2CHHCH (NHAr)), 2.00 (s, 12H, o-CH3), 2.07-2.27 (m, 4H, CHHCHHCH(NHAr)), 2.33(s, 6H, p-CH3), 2.67-2.91(m, 2H, CHHCH2CH(NHAr)), 2.95(br s, 2H, NH), 3.23(br d, 3 J H-H =10Hz, 2H, CH), 6.82 (s, 4H, Ar-CH)ppm. 19 F NMR(282.23MHz, CDCl3)δ-83.8(t, 3 J F-F =10Hz, 6F, CF3), -114.4 (m, 4F, CF2CH2), -121.9 (m, 4F, CF2CF2CH2), -122.8 (m, 4F, CF3CF2CF2CF2), -123.4 (m, 4F, CF3CF2CF2), -126.1 (m, 4F, CF3CF2)ppm. 13 C NMR (400MHz, CDCl3) δ18.3(o-CH3), 20.3(p-CH3), 21.7(m, CF2CH2CH2), 29.2(t, 2 J F-C =22.2Hz, CF2CH2), 57.1(CH), 107-115(m, 8CF2), 117.4(qt, 1 J F-C =288.3Hz, 2 J F-C =33.3Hz, CF3), 118.7(tt, 1 JF-C = 255.1 Hz, 2 JF-C=31.0Hz, CF2CH2), 128.6(Ar-C), 129.9(Ar-CH), 131.4(Ar-C), 140.4(Ar-C)ppm. MS (ESI), m / z (%): 990 [M+H] + (100). Example 2

[0184] This example shows the synthesis of trans-4,5-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium tetrafluoroborate:

[0185] A mixture of 1H,1H,2H,2H-perfluorooctyl-N,N'-bis(2,4,6-trimethylphenyl)-9,10-diamine (0.250 g, 0.25 mmol) from Example 1, ammonium tetrafluoroborate (about 10% molar excess) (0.030 g, 0.25 mmol) and triethyl orthoformate (0.5 mL) was heated to 125 °C and stirred for 15 h. After cooling to room temperature, the solution was evaporated and the solid was triturated with diethyl ether (6 x 3 mL). The residue was redissolved in acetone, filtered and concentrated to give dihydroimidazolium tetrafluoroborate. (0.2 g, 70% yield, light yellow solid). 1 H NMR (400MHz, acetone-d6) δ2.15-2.70 (m, 8H, CF2CH2CH2), 2.34 (s, 6H, p-CH3), 2.51 (s, 6H, o-CH3), 2.94 (br s, 2H, NH), 5.16 (m, 2H, CH2CH2CH), 7.17 (s, 4H, Ar-CH), 9.06 (s, 1H, N-CH=N) ppm. 19 F NMR (400 MHz, acetone-d6) δ-81.6 (t, 4 J F-F =10Hz, 6F, CF3), -115.1 (m, 4F, CF2CF2CH2), -122.5 (m, 4F, CF2CF2CH2), -123.6 (m, 4F, CF3CF2CF2CF2), -124.5 (m, 4F, CF3CF2CF2), -126.9 (m, 4F, CF3CF2CF2), -150.9 (4F, BF4)ppm. 13 C NMR (400 MHz, acetone-d6) δ17.4 (o-CH3), δ17.7 (o-CH3), 19.9 (p-CH3), 24.4 (m, CF2CH2CH2), 26.2 (t, 2 J F-C =22.2Hz, CF2CH2), 67.9(CH), 105-118(m, 8CF2), 118(qt, 1 J F-C =288.3Hz, 2 J F-C =33.3Hz, CF3), 118.9(tt, 1 JF-C = 254 Hz, 2JF-C=31.0Hz, CF2CH2), 129.5(Ar-C), 130.1(Ar-CH), 130.5(Ar-CH), 135.8(Ar-C), 136(Ar-C), 140.8(Ar-C) ppm, 159.7 (NC=N) ppm. MS (ESI) m / z (%): 999 [M+H] + (100). Example 3

[0186] This example shows the synthesis of trans-4,5-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium chloride:

[0187] Dihydroimidazolium tetrafluoroborate (0.5 g, 0.46 mmol) was dissolved in MeOH (1.5 mL) and passed through a short column of ion exchange resin Amberlite 400. The column was washed with MeOH until no spots were visible by TLC under UV. The solvent was removed and the resulting pale yellow solid was dried with a vacuum pump to obtain the product (0.48 g, 99%). 1 H NMR (400MHz, acetone-d6) δ2.15-2.70 (m, 8H, CF2CH2CH2), 2.34 (s, 6H, p-CH3), 2.51 (s, 6H, o-CH3), 2.94 (br s, 2H, NH), 5.16 (m, 2H, CH2CH2CH), 7.17 (s, 4H, Ar-CH), 9.06 (s, 1H, N-CH=N) ppm. 19 F NMR (400 MHz, acetone-d6) δ-81.8 (t, 4 J F-F =10Hz, 6F, CF3), -115.1 (m, 4F, CF2CF2CH2), -122.5 (m, 4F, CF2CF2CH2), -123.6 (m, 4F, CF3CF2CF2CF2), -124.5 (m, 4F, CF3CF2CF2), -127 (m, 4F, CF3CF2CF2)ppm. 13 C NMR (400 MHz, acetone-d6) δ17.4 (o-CH3), δ17.7 (o-CH3), 19.9 (p-CH3), 24.4 (m, CF2CH2CH2), 26.2 (t, 2 J F-C=22.2Hz, CF2CH2), 67.9(CH), 105-118(m, 8CF2), 118(qt, 1 J F-C =288.3Hz, 2 J F-C =33.3Hz, CF3), 118.9(tt, 1 JF-C = 254 Hz, 2 JF-C=31.0Hz, CF2CH2), 129.5(Ar-C), 130.1(Ar-CH), 130.5(Ar-CH), 135.8(Ar-C), 136(Ar-C), 140.8(Ar-C)ppm, 159.7 (NC=N) ppm. MS(ESI) m / z (%): 999 [M+H] + (100). Example 4

[0188] This example illustrates a method for synthesizing a transition metal-containing fluorinated SABRE catalyst according to one aspect of the present invention.

[0189] Potassium tert-butoxide (112 mg, 1.00 mmol, 2.5 equiv) was added to a stirred solution of trans-4,5-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium chloride (320 mg, 0.88 mmol, 2.2 equiv) in tetrahydrofuran (10 mL) at room temperature in a glove box. The resulting suspension was stirred for 30 minutes. A solution of [Ir(COD)Cl]2 (268 mg, 0.40 mmol, 1.0 equiv) was added and the resulting solution was stirred at room temperature overnight (Cowley et al., J. Am. Chem. Soc., 133, 6134-6137 (2011)). The solvent was removed under reduced pressure to obtain a crude product and dried overnight under vacuum. The sample was dissolved in hexane and added to a 60 mL filter filled with SiO2 gel in hexane. The crude solution was adsorbed on the top of the silica gel and hexane was then added to elute the compound to obtain 104 mg of the compound (40% yield). 1 H NMR (400MHz, CDCl3) δ1.04, 1.18, 1.49, 1.76, 2.13, 2.22, 2.25, 2.4, 2.48, 2.66, 2.94, 3.73, 4.01, 4.2, 6.84, 6.91 6.97ppm. 19F NMR (400MHz, CDCl3) δ-81.08, -114.33, -122.05, -123.07, -124.02, -126.39ppm. 13 C NMR (100MHz, CDCl3) δ18.7, 20.95, 21.07, 21.34, 26.45, 27.21, 29.83, 30.74, 31.42, 49.93, 55.12, 68.11, 68.47, 83.26, 86.69, 108.32, 111.0 , 112.95, 115.85, 117.75, 118.69, 129.02, 129.3, 130.36, 130.55, 134. 71, 134.8, 135.32, 136.33, 137.92, 138.28, 138.45, 138.5, 206.72ppm. MS (ESI) m / z (%): 1299 [M+H] + (100). Example 5

[0190] This example shows a hyperpolarization method according to one aspect of the present disclosure. 13 C] pyruvate, as shown in Scheme 1. Scheme 1. [1- 13 C] Hyperpolarization of pyruvate. Wherein the co-ligand = phenyl trifluoromethyl sulfoxide.

[0191] In the above reaction scheme, [1- 13 Hyperpolarization of C]pyruvate was performed using the coligand method developed by Duckett and coworkers (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)) using 13 C core customization (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017)) was performed by SABRE in SHield Enabled Alignment Transfer to Heteronuclei (SABRE-SHEATH) (Theis et al., J. Am. Chem. Soc., 137, 1404-1407 (2015) and Truong et al., J. Phys. Chem. C, 119, 8786-8797 (2015)). [1- 13C]-Sodium pyruvate and deuterated methanol-d4 solvent were purchased from Sigma-Aldrich and used without any further purification. The [IrCl(COD)(F-IMes)]SABRE catalyst used in this example was prepared according to Example 4. The active catalyst used herein was prepared with a fixed ratio of substrate to the Ir(F-IMes)SABRE catalyst of Example 4 and phenyltrifluoromethylsulfoxide (PTFSO) in 0.6 mL methanol-d4 in a 5 mm NMR tube.

[0192] Parahydrogen was generated using a Gas-Delivery Manifold. Ultra-high purity hydrogen (Airgas) was fed into a parahydrogen flow cryostat (Xeus technology LTD) at liquid nitrogen temperature (77K) in the presence of a spin exchange catalyst (Fe2O3) and enriched to about 50% parahydrogen. The p-H2 flow was directed through PTFE tubing to a mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) set to 90 scc / m and to a conventional 5 mm NMR tube (Norell) to allow bubbling through the sample. The entire pH2 line was pressurized to 100 psi.

[0193] The magnetic shielding conditions are as follows. Magnetic fields close to or below about 1 μT were achieved using an apparatus consisting of a solenoid coil placed in a highly permeable alloy shield (Magnetic Shield Corporation, Model ZG-206). The shield was degaussed when necessary using an in-house homemade coil driven by a Variac. The solenoid had a 41 mm (40 mm) core in diameter, a 20 cm long winding with 220 turns of AWG20 (0.9 mm) Cu wire, and a 220 Ω series resistor. The solenoid coil was driven by a commercial 1.5 V battery with a variable resistor decade box in series to provide finer control of the internal magnetic field within the shield. Typical values ​​for the field within the shield were ±1.2 μT, and SABRE SHEATH experiments were typically -0.7 μT to +0.8 μT in the sample area. This value was monitored using a Lakeshore Cryotronics Gaussmeter (Model 475DSP with a HMMA-2512-VR Hall probe) between SABRE experiments.

[0194] MR experiments were performed using a 1T Magritek Spinsolving benchtop NMR spectrometer. 13 C NMR spectrum was closed during the entire experiment 1The time required to manually transfer the sample from the shielded area to the magnet for low-field NMR acquisition is typically <5 s.

[0195] From the newly generated p-H2 source hydride to [1- 13 C]pyruvic acid 13 The efficient hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(PTFSO)2(F-IMes)], [1- 13 C] A solution mixture of pyruvate and p-H2 in deuterated methanol obtained by SABRE in shield-enabled alignment transfer into heteronuclei (SABRE-SHEATH) in a sub-microtesla magnetic field. Figure 6 The single scan HP obtained for the hyperpolarized probe is depicted in the top curve 13 C spectrum. The bottom curve shows the spectrum from 4M [1- 13 C] sodium acetate single scan thermal polarization 13 C signal. The enhancement is ε~9000, and the polarization is about P( 13 C)~1%.

[0196] All experiments were performed with a fluorination catalyst, a coligand (phenyl trifluoromethyl sulfoxide) and [1- 13 C] pyruvic acid in 0.6 mL CD3OD. The ratio and concentration can be further adjusted to obtain better enhancement and polarization. For 8 mM fluorinated catalyst, 16 mM phenyl trifluoromethyl sulfoxide (PTFSO) and 30 mM [1- 13 The results were obtained with pyruvic acid [C] at room temperature, a p-H2 flow rate of ~100 scc / m and a p-H2 overpressure of 96 PSI. The parahydrogen used in this example was from a low-cost 50% p-H2 generator. For each experiment, the p-H2 sparge was applied for about 1 minute, the sample was quickly transferred to the 1T NMR spectrometer for detection, and then the sample was returned to the mu metal shield to continue the p-H2 sparge for the next experiment. The area under the HP signal curve (AUC) was compared to the external 13 C signal thermal signal reference (4M[1- 13 C] sodium acetate) to calculate 13 C signal enhancement: Where S HP and S REF It is from HP[1- 13 C] pyruvate and heat signal reference [1- 13 C] acetate 13 C signal, C REF and C HPThey are the thermal signal reference [1- 13 C] acetate (4M) and HP[1- 13 C] pyruvate concentration, and A REF and A HP is used for thermal signal reference [1- 13 C] acetate and HP[1- 13 C] Effective cross section of the NMR tube for the pyruvate sample. Example 6

[0197] This example shows a hyperpolarized 13 C] pyruvate, as shown in Scheme 2. Scheme 2. [1- 13 C] Hyperpolarization of pyruvate.

[0198] In the above reaction scheme, [1- 13 Hyperpolarization of C]pyruvate was performed using the coligand method developed by Duckett and coworkers (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)) using 13 C core customization (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017)) was carried out by SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) (Theis et al., J. Am. Chem. Soc., 137, 1404-1407 (2015) and Truong et al., J. Phys. Chem. C, 119, 8786-8797 (2015)). [1- 13 C]-Sodium pyruvate and deuterated methanol-d4 solvent were purchased from Sigma-Aldrich and used without any further purification. The [IrCl(COD)(F-IMes)]SABRE catalyst used in this example was prepared according to Example 4. The active catalyst used herein was reacted with a fixed ratio of substrate [1- 13 C] Pyruvic acid, the Ir(F-IMes)SABRE catalyst of Example 4, and the co-ligand dimethyl sulfoxide (PTFSO) were prepared in 0.6 mL of methanol-d4 in a 5 mm NMR tube.

[0199] Parahydrogen enriched to about 70% to 95% was used and directed through PTFE tubing into a mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) set at 50 scc / m to 120 scc / m, into a medium wall 5 mm NMR tube (Norell) to allow bubbling through the sample. The pressure value of the entire pH2 line was 50 psi to 110 psi.

[0200] The polarization transfer magnetic field was established as follows. Magnetic fields approaching or below about 1 μT were achieved using an apparatus consisting of a solenoid coil placed within a three-layer mu metal shield (6-inch inner diameter and 15-inch long, part number ZG-206, Magnetic Shield Corp., Bensenville, IL). The magnetic field was generated using a custom-made solenoid coil and a triple independent channel DC power supply (KEITHLEY 2231A-30-3). The solenoid had a 41 mm diameter (40 mm core, a 20 cm long winding with 220 turns of AWG20 (0.9 mm) Cu wire, and a 220 Ω series resistor. The solenoid coil was driven by a series variable resistor decade box to provide finer control of the internal magnetic field within the shield. Typical values ​​for the field within the shield were ±1.2 μT, with SABRE SHEATH experiments typically ranging from -0.7 μT to +0.8 μT in the sample area.

[0201] MR experiments were performed using an 80 MHz Magritek Spinsolve benchtop NMR spectrometer. The following acquisition parameters were used: Spectral width (SW) = 5kHz; Dwell time (DT) = 150 μs; Scan times (ns) = 1, Receiver gain = 16; Excitation pulse angle (a) = 90°; 13 C resonance frequency = 20.25232790 MHz.

[0202] all 13 C NMR spectrum was closed during the entire experiment 1 The time required to manually transfer the sample from the shielded area to the magnet for low-field NMR acquisition is typically <5 s.

[0203] From iridium hydride from p-H2 to [1- 13 C]pyruvic acid 13 The hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(DMSO)2(F-IMes)], [1- 13C] A solution mixture of pyruvate, co-ligand (dimethyl sulfoxide) and p-H2 in 0.5 mL of deuterated or non-deuterated methanol was obtained by SABRE in shield-enabled alignment transfer into heteronuclei (SABRE-SHEATH) in a sub-microtesla magnetic field.

[0204] The following equation was used to compare the area under the curve (AUC) of the HP signal with that of the external 13 C signal thermal signal reference (4M[1- 13 C] sodium acetate) to calculate 13 C signal enhancement: Where S HP and S REF It is from HP[1- 13 C] pyruvate and heat signal reference [1- 13 C] acetate 13 C signal, C REF and C HP They are the thermal signal reference [1- 13 C] acetate (4M) and HP[1- 13 C] pyruvate concentration, and A REF and A HP is used for thermal signal reference [1- 13 C] acetate and HP[1- 13 C] The effective cross section of the NMR tube for the pyruvic acid sample. According to the following equation S2, the signal enhancement (ε 13 C ) multiplied by the heat at 1.81T 13 C nuclear spin polarization (1.5681*10 -4 %) to calculate 13 The percentage of C polarization (%P 13 C ):(%P 13 C ), = ε 13 C *1.56181*10 -6 *100.

[0205] The fluorinated SABRE catalyst takes less than 15 minutes to activate. 13 C polarization percentage Figure 7 As shown, and by bubbling about 95% p-H2 at a flow rate of 90 standard cubic centimeters per minute (scc / m) at a p-H2 partial pressure of 8 atm, which resulted in the formation of complex 2, complex 3a, complex 3b and pyruvate, as shown Figure 8As shown, it is consistent with the comments introduced by Duckett and colleagues (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)). Without wishing to be bound by any particular theory, it is believed that complex 3B is the main SABRE active species. Example 7

[0206] This example demonstrates that [1- 13 The effects of hyperpolarization of [1-C]pyruvate on the parahydrogen pressure and flow rate as well as the effects of magnetic transfer field, temperature and the concentrations of fluorination catalyst and DMSO were investigated. 13 C] Relaxation kinetics of pyruvate.

[0207] As described in Example 6 above, SABRE (SABRE-SHEATH) repeats [1- 13 C] hyperpolarization of pyruvic acid and studied the effects of hydrogen partial pressure and flow rate, as well as the effects of magnetic transfer field, temperature, and the concentrations of fluorination catalyst and DMSO.

[0208] p-H2 parameters such as pressure and flow rate were evaluated and the polarization percentage results were Fig. 9 A and Fig. 9 B shows the NMR sample contained in 30 mM [1- 13 C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst and 40 mM dimethyl sulfoxide (DMSO), the mixing field was 0.4 μT, and the temperature was 0°C. Fig. 9 A and Fig. 9 As is apparent from the results shown in Figure B, as the parahydrogen flow rate and pressure increase, the polarization percentage also increases.

[0209] The temperature and magnetic field in the microtesla system were evaluated and the 13 The C polarization level and polarization transfer magnetic field are shown in Fig.10 A and Fig.10 B. NMR samples contained 30 mM [1- 13 C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst and 40 mM dimethyl sulfoxide (DMSO), pH 2 flow rate was 70 scc / m and pressure was 100 PSI. Fig.10 A and Fig.10 As is evident from the results shown in B, the best polarization transfer occurs at temperatures between -20°C and 5°C and mixing fields between 0.3 μT and 0.5 μT. The optimum temperature is -7.24°C and the optimum mixing field is 0.4 μT.

[0210] The perfluorinated SABRE catalyst and DMSO concentration were evaluated at a temperature of 0°C, a magnetic transfer field of 0.4 μT, a pH flow rate of 90 scc / m, and a pH pressure of 110 PSI, and the polarization percentages are shown in Figures 11A and 11B. As is apparent from the results shown in Figure 11A, the polarization percentage increases with increasing concentration of the perfluorinated SABRE catalyst. However, the polarization percentage remains relatively consistent at concentrations above 20 mM.

[0211] As is apparent from the results shown in FIG. 12A and FIG. 12B , [1- 13 C]-pyruvate relaxation kinetics showed that total P 13C (Bound + Free) Formation Time (T b =6.6±3.0s) is significantly shorter than the corresponding T1 value of 16.1±0.9s, which allows to achieve a P value of up to 13.48%. 13C Furthermore, the relaxation kinetics at geomagnetic field and 1.8 T are roughly the same as those of the non-fluorinated SABRE catalyst T1, which are equal to 28.9 ± 1.6 s and 66.5 ± 7 s, respectively.

[0212] Simultaneous exchange of p-H2 and [1- 13 C] pyruvate leads to 13 C hyperpolarization formation. In this regard, Figure 13 shows 13 C-hyperpolarized [1- 13 Representative spectrum of [C]-pyruvic acid, the 13 C-hyperpolarized [1- 13 The signal enhancement of [C]-pyruvic acid was about 86500 times, corresponding to about 13.48% of P obtained by comparing the NMR signal intensity with the reference sample. 13C The NMR samples were contained in 20 mM [1- 13 C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst and 40 mM dimethyl sulfoxide (DMSO), the mixing field was 0.4 μT and the temperature was 0°C, and the parahydrogen pressure and flow rate were 110 PSI and 90 scc / m, respectively.

[0213] Temperature Figure 7 On the complex 3b [1- 13 C] pyruvate exchange rate has a profound impact. In recent work, Adelabu et al. (ChemPhysChem, 23, e202100839 (2022)) showed that the monotonic disappearance of the free HP resonance at low temperatures occurs due to the slow exchange rate of complex 3b to the free state. At room temperature (e.g., 22 ° C), [1- 13C] The exchange of pyruvate with the polarization transfer complex is faster, resulting in hyperpolarization of free and bound 3b species at the expected pyruvate: pre-catalyst ratio. In order to quickly release HP pyruvate from 3b, the HP solution is quickly heated and the sample is then inserted into the NMR detector (Tom Hon et al., J. Am. Chem. Soc., 144 (1) 282-287 (2022)). Figure 14 shows a variable temperature SABRE-SHEATH experiment using the saturated perfluorinated SABRE catalyst of Example 4. The NMR sample (in deuterated methanol) contained 25 mM [1- 13 C] sodium pyruvate, 6 mM perfluorinated SABRE catalyst, and 47 mM dimethyl sulfoxide (DMSO) with a mixing field of 0.4 μT and parahydrogen pressure and flow rate set to 110 PSI and 90 scc / m, respectively.

[0214] As shown in Figure 14, even in most HP[1- 13 C] At low temperatures (e.g. -10°C) when pyruvate is in the free state, the exchange rate of complex 3b to the free state is also faster. 13 C SABRE-SHEATH temperature is reduced to 0℃, reaching P 13C The exchange is kept fast enough to preferentially form "free" HP[1- 13 C] pyruvate. Example 8

[0215] This example shows the method for separating hyperpolarized [1- 13 C] An exemplary method of sodium pyruvate, the method comprising extraction and filtration.

[0216] Using dimethyl sulfoxide (DMSO) in deuterated methanol-d4 solvent as a co-ligand, [IrCl(COD)(F-IMes)]SABRE catalyst and para-hydrogen enriched to about 70% to 95%, the reaction was carried out using a reaction mixture directed to 13 C core customized shield-enabled alignment transfer to heterogeneous core SABRE (SABRE-SHEATH) [1- 13 C] sodium pyruvate hyperpolarization as described in Examples 6 and 7. Using 30 mM [1- 13 C] SABRE samples were prepared in 0.5 mL CD3OD with sodium pyruvate, 2.6 mM perfluorinated SABRE catalyst of Example 4, and 35 mM dimethyl sulfoxide (DMSO). The parahydrogen flow rate was set to 90 scc / m and pressurized to 8 bar, the mixing field was 0.4 μT, and the temperature was 0°C.

[0217] After the hyperpolarization process was completed, the sample was quickly removed from the 0.40 μT field, depressurized, and 20% volume (125 μL) of D2O was added to the solution to precipitate the perfluorinated SABRE catalyst. The resulting mixture was transferred to a 1 mL plastic syringe mounted on a Luer-locked filter (Waters Oasis Prime HLB Plus Light Cartridge (Part Number: 186008866)) and the aqueous solution was directed through the filter into a 5 mm NMR tube that was already located in an adjacent 1.8 T benchtop NMR spectrometer. The entire process took approximately 1.15 minutes to 1.30 minutes, and no HP was observed in any of the samples. 13 C signal. The relaxation studies presented above show that the [1- 13 C]-T1 relaxation time is significantly shorter (for example, in the geomagnetic field [1- 13 C]-T1=28.9±1.6s). Automation and faster solution transfer should allow observation of HP[1- 13 C]-pyruvate signal. Example 9

[0218] This example shows the method for separating hyperpolarized [1- 13 C] An exemplary method of sodium pyruvate, the method comprising extraction by precipitation with an organic solvent.

[0219] HP[1- 13 Precipitation and redissolution of [1-C]pyruvate were performed in the same NMR tube as the hyperpolarization (Schmidt et al., ACS Sensors, 7(11), 3430-3439(2022)). 20 mM to 30 mM [1- 13 C] sodium pyruvate, 7.5 mM fluorinated SABRE catalyst and 50 mM dimethyl sulfoxide (DMSO), SABRE samples were prepared in CD3OD as described in Examples 6 and 7. 100 μl of this solution was transferred to a 5 mm NMR tube and exposed to SABRE-SHEATH hyperpolarization conditions with the same setup and optimal conditions as described in Examples 6 and 7. The solution was located within a 3-layer high-permeability alloy of 3” inner diameter and 9” deep to shield from external magnetic fields, combined with a custom-made solenoid to generate a static magnetic field B0 of 0.4 μT. The NMR tube was pressurized (110 psi, i.e., about 8 bar total pressure) with pH 2 bubbled through the solution at a flow rate of 90 scc / m to activate the catalyst, and 13 C-hyperpolarization [1- 13C] sodium pyruvate solution. The activation of the catalyst was carried out at ambient temperature and magnetic field for 15 minutes. In order to polarize the formation, the sample was placed in a static magnetic field (usually about 0.4 μT) and a water bath to adjust the reaction temperature to 0°C. After polarization, the NMR tube was quickly transferred to an NMR spectrometer at 1.8T and kept at room temperature. After decompression, pyruvic acid was precipitated by adding 400 μL of ethyl acetate (EtOAc) to the HP solution and re-dissolved by adding 300 μL of D2O to reconstitute pyruvic acid in water.

[0220] NMR spectra were collected immediately after reconstitution in water using a 1.8T benchtop NMR and are shown in the top spectrum of Figure 15. In addition, the bottom spectrum of Figure 15 shows the NMR spectra from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal.

[0221] also, 13 The C-pyruvic acid concentration was determined by LCMS using a calibration curve of naturally occurring isotopic pyruvic acid. After the SABRE-SHEATH method was reconstructed, the pyruvic acid aqueous solution samples were further analyzed for iridium content by ICP-MS (inductively coupled plasma multi-element scanning). The iridium content was determined to be only about 150 ppb to about 300 ppm. Example 10

[0222] This example shows the synthesis of 2,2,2-trifluoro-N-(4-iodo-2,6-dimethylphenyl)acetamide:

[0223] To a stirred solution of 2,6-diisopropylaniline (4.92 mL, 40.00 mmol, 1.0 equiv) in diethyl ether (50 mL) was added iodine (11.17 g, 44.00 mmol, 1.1 equiv) and saturated sodium bicarbonate solution (30 mL). The solution was stirred at room temperature for 3 hours and gas evolution was observed. Excess iodine was eliminated by adding sodium thiosulfate (1.33 g, 8.40 mmol). The phases were separated and the aqueous phase was further extracted with diethyl ether (2×20 mL). The combined organic phases were washed with water (200 mL) and saturated sodium thiosulfate solution. The organic phase was evaporated to dryness in vacuo to obtain the product as a brown oil, which slowly became a solid under vacuum.

[0224] Hexane was added to dissolve the product, and the solution was filtered through Celite, evaporated, and dried under vacuum. No additional purification was required. 1 HNMR (400MHz, CDCl3): δ=7.14 (s, 2H), 4.45 (s, 2H), 2.04 (s, 6H). Embodiment 11

[0225] This example shows the synthesis of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooct-1-en-1-yl)phenyl)-2,2,2-trifluoroacetamide:

[0226] In a glove box, palladium (II) acetate (0.16 g, 0.051 eq., 0.71 mmol), sodium acetate (1.72 g, 1.50 eq., 21.0 mmol), tricyclohexylphosphine (660 mg, 0.168 eq., 2.35 mmol), tetrabutylammonium bromide (30 mg, 0.0067 eq., 93 μmol) and 2,2,2-trifluoro-N-(4-iodo-2,6-dimethylphenyl)acetamide (4 g, 0.8 eq., 0.01 mol) were added to a Schlenk flask with 10 mL of dimethylformamide. The Schlenk flask was warmed to 90 ° C, and then 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooct-1-ene (4.84 g, 1 equivalent, 14.0 mmol) was added to the reaction mixture and further heated to 120 ° C. The solution was stirred for 19 hours. After cooling, the mixture was filtered through Celite and washed with diethyl ether (50 mL). Water (50 mL) and diethyl ether (30 mL) were added, the organic phase was separated, and the aqueous phase was extracted with Et2O (3×15 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (hexane / DCM 4:1) gave further crystallized fluoroamide N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooct-1-en-1-yl)phenyl)-2,2,2-trifluoroacetamide (5 g, 70%, white needles). Example 12

[0227] This example shows the synthesis of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)-2,2,2-trifluoroacetamide:

[0228] In a glass autoclave, to a solution of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooct-1-en-1-yl)phenyl)-2,2,2-trifluoroacetamide (0.40 g, 0.70 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (0.08 g, 0.07 mmol). The autoclave was evacuated, filled with hydrogen to 500 kPa, and stirred at room temperature for 5 hours. The mixture was filtered through Celite and washed with EtOAc (30 mL). The solvent was removed on a vacuum rotary evaporator to give N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10- tridecafluorooctyl)phenyl)-2,2,2-trifluoroacetamide. Example 13

[0229] This example shows the synthesis of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)aniline:

[0230] To a solution of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)-2,2,2-trifluoroacetamide (0.14 g, 250 μmol) in n-butanol (1.5 mL) was added sodium hydroxide (0.10 g, 250 mmol) and the reaction mixture was heated to 110°C for 21 hours. After cooling to room temperature, water (4 mL) and ethyl acetate (4 mL) were added and the organic phase was separated and washed with 1 M HCl solution (4 mL), saturated solution of NaHCO3 (4 mL) and brine (4 mL). The aqueous phase was neutralized and extracted with ethyl acetate (3 times x 4 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)aniline (0.50 g, 92%, brown crystals). Embodiment 14

[0231] This example shows the synthesis of N,N'-bis[2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl]ethane-1,2-diimine:

[0232] To a solution of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)aniline (0.5 g, 1 mmol) in ethanol (5 mL) was added 40% aqueous solution of glyoxal (0.1 mL, 1 mmol) and a catalytic amount of formic acid (a few drops). The reaction mixture was stirred at room temperature for 20 hours, during which a yellow precipitate formed. The solid was filtered and washed with cold ethanol (3×5 mL) to give clean N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)ethane-1,2-diimine (0.2 g, 20%, yellow powder). Embodiment 15

[0233] This example shows the synthesis of 1,3-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)-1H-imidazol-3-ium-2-ide chloride salt:

[0234] N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-tridecafluorooctyl)phenyl)ethane-1,2-diimine (2.40 g, 2.08 mmol) and tetrahydrofuran (80 mL) were charged into a flask. The mixture was cooled to 0°C and a suspension of paraformaldehyde (262 mg, 2.91 mmol) and concentrated hydrochloric acid (112 mg, 3.12 mmol) in dioxane (0.78 mL) was slowly added. The mixture was heated to reflux overnight. Purification was performed by column chromatography. 1 HNMR (400MHz, CDCl3) δ2.07, 2.55, 2.92, 7.37, 8.28, 9.65. MS(ESI)m / z(%): 1168.8[M-TFA] + (100). Example 16

[0235] This example illustrates the synthesis of a fluorinated SABRE catalyst according to one aspect of the invention.

[0236] To a stirred solution of 1,3-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)-1H-imidazol-3-ium-2-ylidene(2-ide) chloride (2.2 eq.) in tetrahydrofuran was added potassium tert-butoxide (2.5 eq.) at room temperature in a glove box. The resulting suspension was stirred for 30 minutes. A solution of [Ir(COD)Cl]2 (1.0 eq.) was added and the resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the crude product, which was dried under vacuum overnight. The sample was purified by flash chromatography DCM / hexane (4:1) to obtain the fluorinated SABRE catalyst. MS (ESI) m / z (%): 1469 [M-Cl] + (100). Embodiment 17

[0237] This example illustrates the hyperpolarization of sodium pyruvate using a SABRE catalyst according to one aspect of the present invention, as shown in Scheme 3. Scheme 3. [1- 13 C] Hyperpolarization of pyruvate.

[0238] In the above reaction scheme, from the hydride of p-H2 source to [1- 13 C]pyruvic acid 13 The efficient hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(DMSO)2(F-IMes)], [1- 13 C] A solution mixture of pyruvate and p-H2 in deuterated methanol obtained by SABRE in shield-enabled alignment transfer into heteronuclei (SABRE-SHEATH) in a sub-microtesla magnetic field.

[0239] Use 40 mM [1- 13 C] sodium pyruvate, 6.6 mM perfluorinated SABRE catalyst of Example 16, and 50 mM dimethyl sulfoxide (DMSO) were used to prepare SABRE samples in CD3OD as described in Examples 6 and 7. The SABRE samples were exposed to SABRE-SHEATH hyperpolarization conditions with the same setup and optimal conditions as described in Examples 6 and 7. The NMR tube was pressurized (110 psi, i.e., about 8 bar total pressure) with pH 2 bubbling through the solution at a flow rate of 90 scc / m to activate the catalyst, and 13 C-hyperpolarization [1- 13C] sodium pyruvate solution. The activation of the catalyst was carried out at ambient temperature and in a magnetic field for about 15 minutes. For polarization formation, the sample was placed in a magnetic field (usually about 0.4 μT) and a 5°C water bath to adjust the reaction temperature. The spectrum was collected immediately after the sample was manually transferred to a 1.8T benchtop NMR after 5 seconds, and the results are shown in the top spectrum of Figure 16. In addition, the bottom spectrum of Figure 16 shows the spectrum from 4M[1- 13 Single-scan thermal polarization of sodium acetate 13 As is apparent from the results shown in FIG16 , the signal enhancement is ε~16900 and the polarization is about P( 13 C)~2.17%. Embodiment 18

[0240] This example shows the synthesis of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-en-1-yl)phenyl)-2,2,2-trifluoroacetamide:

[0241] In a glove box, palladium (II) acetate (0.16 g, 0.051 eq., 0.71 mmol), sodium acetate (1.72 g, 1.50 eq., 21.0 mmol), tricyclohexylphosphine (660 mg, 0.168 eq., 2.35 mmol), tetrabutylammonium bromide (30 mg, 0.0067 eq., 93 μmol) and 2,2,2-trifluoro-N-(4-iodo-2,6-dimethylphenyl)acetamide (4 g, 0.8 eq., 0.01 mol) were added to a Schlenk flask with 10 mL of dimethylformamide. The Schlenk flask was warmed to 90°C, and then 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene (4.84 g, 1 eq., 14.0 mmol) was added to the reaction mixture and further heated to 120°C. The solution was stirred for 19 hours. After cooling, the mixture was filtered through Celite and washed with diethyl ether (50 mL). Water (50 mL) and diethyl ether (30 mL) were added, the organic phase was separated, and the aqueous phase was extracted with Et2O (3×15 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain a crude product. Further crystallized fluoroamide N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene-1-yl)phenyl)-2,2,2-trifluoroacetamide (5 g, 70%, white needles) was obtained by column chromatography (hexane / DCM4:1). Embodiment 19

[0242] This example shows the synthesis of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)aniline:

[0243] To a solution of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8-tridecafluorooct-1-en-1-yl)phenyl)-2,2,2-trifluoroacetamide (0.14 g, 250 μmol) in n-butanol (1.5 mL) was added sodium hydroxide (0.10 g, 250 mmol) and the reaction mixture was heated to 110°C for 21 hours. After cooling to room temperature, water (4 mL) and ethyl acetate (4 mL) were added, and the organic phase was separated and washed with 1 M HCl solution (4 mL), saturated NaHCO3 solution (4 mL) and brine (4 mL). The aqueous phase was neutralized and extracted with ethyl acetate (3 times x 4 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)aniline (0.50 g, 92%, brown crystals). Embodiment 20

[0244] This example shows the synthesis of N,N'-bis[2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-en-1-yl)phenyl]ethane-1,2-diimine:

[0245] To a solution of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-en-1-yl)aniline (0.5 g, 1 mmol) in ethanol (5 mL) was added 40% aqueous solution of glyoxal (0.1 mL, 1 mmol) and a catalytic amount of formic acid (a few drops). The reaction mixture was stirred at room temperature for 20 hours, during which a yellow precipitate formed. The solid was filtered and washed with cold ethanol (3×5 mL) to give clean N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)phenyl)ethane-1,2-diimine (0.2 g, 20%, yellow powder). Embodiment 21

[0246] This example shows the synthesis of 1,3-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-en-1-yl)-1H-imidazol-3-ium-2-ylidene(2-ide) chloride salt:

[0247] N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene-1-yl)phenyl)ethane-1,2-diimine (2.40 g, 2.08 mmol) and tetrahydrofuran (80 mL) were charged into a flask. The mixture was cooled to 0°C and a suspension of paraformaldehyde (262 mg, 2.91 mmol) and concentrated hydrochloric acid (112 mg, 3.12 mmol) in dioxane (0.78 mL) was slowly added. The mixture was heated to reflux overnight. Purification was performed by column chromatography. 1 H NMR (400MHz, CDCl3) δ2.27, 6.71, 7.32, 7.36, 7.67, 8.16, 9.59ppm. 19 F NMR (400MHz, CDCl3) δ-82.43, -112.52, -122.59, -123.89, -124.17, -127.33ppm. MS(ESI)m / z(%):964.8[M+H] + (100). Embodiment 22

[0248] This example illustrates the synthesis of a fluorinated SABRE catalyst according to one aspect of the invention. To a stirred solution of 1,3-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-en-1-yl)phenyl)-1H-imidazol-3-ium-2-ylidene(2-ide) chloride (2.2 eq.) in tetrahydrofuran was added potassium tert-butoxide (2.5 eq.) at room temperature in a glove box. The resulting suspension was stirred for 30 minutes. A solution of [Ir(COD)Cl]2 (1.0 eq.) was added and the resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the crude product, which was dried under vacuum overnight. The sample was purified by flash chromatography DCM / hexane (4:1) to obtain the fluorinated SABRE catalyst. MS (ESI) m / z (%): 1266 [M-Cl] + (100). Embodiment 23

[0249] This example illustrates the hyperpolarization of sodium pyruvate using a SABRE catalyst according to one aspect of the present invention, as shown in Scheme 4. Scheme 4. [1- 13C] Hyperpolarization of pyruvate.

[0250] In the above reaction scheme, from the hydride of p-H2 source to [1- 13 C]pyruvic acid 13 The efficient hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(DMSO)2(F-IMes)], [1- 13 C] A solution mixture of pyruvate and p-H2 in deuterated methanol obtained by SABRE in shield-enabled alignment transfer into heteronuclei (SABRE-SHEATH) in a sub-microtesla magnetic field.

[0251] Use 20 mM [1- 13 C] sodium pyruvate, 7.6 mM perfluorinated SABRE catalyst shown in Scheme 4, and 50 mM dimethyl sulfoxide (DMSO) were used to prepare SABRE samples in CD3OD as described in Examples 6 and 7. The SABRE samples were exposed to SABRE-SHEATH hyperpolarization conditions with the same setup and optimal conditions as described in Examples 6 and 7. The NMR tube was pressurized (110 psi, i.e., about 8 bar total pressure) with pH 2 bubbling through the solution at a flow rate of 90 scc / m to activate the catalyst, and 13 C-hyperpolarization [1- 13 C] sodium pyruvate solution. The activation of the catalyst was carried out at ambient temperature and under a magnetic field for about 15 minutes. For polarization formation, the sample was placed in a magnetic field (usually about 0.4 μT) and a 5°C water bath to adjust the reaction temperature. The spectrum was collected immediately after the sample was manually transferred to a 1.8T benchtop NMR after 5 seconds, and the results are shown in the top spectrum of Figure 17. In addition, the bottom spectrum of Figure 17 shows the spectrum from 4M[1- 13 Single-scan thermal polarization of sodium acetate 13 As is apparent from the results shown in FIG17 , the signal enhancement is ε ˜19000 and the polarization is about P( 13 C)~4.91%. Embodiment 24

[0252] This example shows a hyperpolarized 13 C] pyruvic acid method, which uses a fluorinated mixture instead of just deuterated methanol.

[0253] The hyperpolarization process of Example 6 was repeated using a mixture of nonafluorobutyl methyl ether (NFBME) and deuterated methanol instead of deuterated methanol alone.

[0254] The fluorinated SABRE catalyst activation takes less than 25 minutes.13 The C polarization percentages are shown in FIG18 and were performed by bubbling about 95% p-H2 at a flow rate of 90 standard cubic centimeters per minute (scc / m) at 8 atm p-H2 partial pressure. The NMR sample contained about 25 mM [1- 13 C] Sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst from Example 4 and 40 mM dimethyl sulfoxide (DMSO) with a mixing field of 0.4 μT and a temperature of 0°C. Embodiment 25

[0255] This example demonstrates the effect of [1- 13 The effects of hyperpolarization of [1-C]pyruvate on the parahydrogen pressure and flow rate as well as the effect of the magnetic transfer field were investigated. 13 C] Relaxation kinetics of pyruvate.

[0256] As described in Example 24 above, SABRE (SABRE-SHEATH) repeats [1- 13 C] hyperpolarization of pyruvic acid, and the effect of the parahydrogen flow rate as well as the effect of the magnetic transfer field were studied.

[0257] The p-H2 flow rate was evaluated and the polarization percentage results are shown in Figure 19. The NMR sample contained approximately 22 mM [1- 13 C] Sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4, and 45 mM dimethyl sulfoxide (DMSO), the mixing field was 0.4 μT, and the temperature was 0° C. As is apparent from the results shown in FIG19 , as the parahydrogen flow rate increases, the polarization percentage also increases.

[0258] The magnetic field in the microtesla system was evaluated and the 13 The C polarization transfer magnetic field is shown in Figure 20. The NMR sample contained 22 mM [1- 13 C] sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO). The p-H2 flow rate and pressure were 50 ssc / m and 110 PSI, respectively. As is apparent from the results shown in FIG20 , the best polarization transfer occurs at a mixing field of 0.3 μT to 0.5 μT. The best mixing field was 0.4 μT.

[0259] As is apparent from the results shown in FIG. 21A and FIG. 21B , [1- 13C]-pyruvate relaxation kinetics showed that total P 13C (Bound + Free) Formation Time (T b =3.0±0.8s) is significantly shorter than the corresponding T1 value of 11.3±1.3s, which allows to achieve a P value of up to 6.02%. 13C Furthermore, the relaxation kinetics at geomagnetic field and 1.8 T are roughly the same as those of the non-fluorinated SABRE catalyst T1, which are equal to 9.0 ± 1.9 s and 16.0 ± 1.4 s, respectively.

[0260] Simultaneous exchange of p-H2 and [1- 13 C] pyruvate leads to 13 C hyperpolarization formation. In this regard, the top spectrum of Figure 22 shows 13 C-hyperpolarization [1- 13 Representative spectrum of [C]-pyruvic acid, the 13 C-hyperpolarization [1- 13 The signal enhancement ε of [1-C]-pyruvate is about 38,600 times, corresponding to the NMR signal intensity compared to the reference sample (i.e., the bottom spectrum of Figure 22, which shows the signal enhancement ε of [1-C]-pyruvate using similar acquisition parameters). 13 Single-scan thermal polarization of sodium acetate 13 C signal) compared with the P 13C The NMR sample contained 23 mM [1- 13 C] Sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4 and 46 mM dimethyl sulfoxide (DMSO). The p-H2 flow rate and pressure were 90 ssc / m and 110 PSI, respectively, the mixing field was 0.4 μT and the temperature was 0°C.

[0261] Temperature Figure 7 On the complex 3b [1- 13 C] pyruvate exchange rate has a profound impact. In recent work, Adelabu et al. (ChemPhysChem, 23, e202100839 (2022)) showed that the monotonic disappearance of the free HP resonance at low temperatures occurs due to the slow exchange rate of complex 3b to the free state. At room temperature (e.g., 22 ° C), [1- 13C] The exchange of pyruvate with the polarization transfer complex is faster, resulting in hyperpolarization of free and bound 3b species at the expected pyruvate: pre-catalyst ratio. In order to quickly release HP pyruvate from 3b, the HP solution is quickly heated and the sample is then inserted into the NMR detector (Tom Hon et al., J. Am. Chem. Soc., 144 (1) 282-287 (2022)). Figure 23 shows a variable temperature SABRE-SHEATH experiment using the saturated perfluorinated SABRE catalyst of Example 4. The NMR samples (in nonafluorobutyl methyl ether (NFBME) and deuterated methanol) contained 23 mM [1- 13 C] sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO), with a mixing field of 0.4 μT and parahydrogen pressure and flow rate set to 110 PSI and 90 scc / m, respectively.

[0262] As shown in Figure 23, even in most HP[1- 13 C] At low temperatures (e.g. -10°C) where pyruvate is in the free state, the exchange rate of complex 3b to the free state is also faster. 13 C SABRE-SHEATH temperature is reduced to 0℃, reaching P 13C The exchange is kept fast enough to form "free" HP[1- 13 C] pyruvate. Embodiment 26

[0263] This example shows the method for separating hyperpolarized [1- 13 C] An exemplary method for preparing sodium pyruvate, the method comprising performing a two-phase extraction with an aqueous phase and a fluorinated phase.

[0264] The hyperpolarization process of Example 6 was repeated using a mixture of nonafluorobutyl methyl ether (NFBME) and deuterated methanol instead of deuterated methanol alone. 23 mM [1- 13 C] SABRE samples were prepared with sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO), with a mixing field of 0.4 μT, and parahydrogen pressure and flow rate set to 110 PSI and 90 scc / m, respectively.

[0265] After the hyperpolarization process was completed, the sample was quickly removed from the 0.40 μT field and transferred to the NMR spectrometer at 1.8 T at room temperature. The NMR sample was depressurized and 400 μL of D2O was added to the solution to drive the hyperpolarization [1- 13C] sodium pyruvate enters the aqueous phase. The pyruvate signal in the aqueous phase is collected, but separation results in the formation of an emulsion, indicating the presence of bound pyruvate and free pyruvate. See Figure 24. In this regard, the top spectrum of Figure 24 shows 13 C-hyperpolarization [1- 13 Representative spectrum of [C]-pyruvic acid, the 13 C-hyperpolarization [1- 13 The signal enhancement ε for [1-C]-pyruvate is about 10,800-fold, corresponding to the NMR signal intensity compared to the reference sample (i.e., the bottom spectrum of FIG24 ), which shows the signal enhancement ε for [1-C]-pyruvate using similar acquisition parameters. 13 Single-scan thermal polarization of sodium acetate 13 C signal) compared with the P of about 1.68% 13C .

[0266] Will contain [1- 13 The aqueous phase of sodium pyruvate was evacuated and tested for iridium content and pyruvic acid concentration. ICP-MS showed an iridium content of 637 ppb, and LCMS showed that the [1- 13 C] Sodium pyruvate concentration is about 50-75%.

[0267] The fluorine mixture containing the perfluorinated SABRE catalyst in NFBME and MeOD was reused for further [1- 13 After the aqueous phase was emptied, 0.2 mL of CD3OD containing 23 mM [1- 13 C] A solution of sodium pyruvate and 47 mM dimethyl sulfoxide was added to the fluorinated mixture containing the perfluorinated SABRE catalyst. 13 C] sodium pyruvate, and showed [1- 13 C] pyruvate polarization, the [1- 13 The signal enhancement ε of [C] pyruvate is about 3090 times, corresponding to about 0.48% of P obtained by comparison of the NMR signal intensity with the reference sample. 13C , as shown in Figure 25. [1- 13 The polarization of [C] pyruvate was reproducible and showed approximately the same polarization level, indicating that the perfluorinated SABRE catalyst remained active for at least 4 days after initial use. Embodiment 27

[0268] This example shows the synthesis of 1,3-dimesityl-4,5-bis(2-(perfluorophenyl)propyl)-4,5-dihydro-1H-imidazol-3-ium trifluoromethanesulfonate: It was prepared according to the synthetic sequence shown in FIG26 .

[0269] 4-Pentafluorophenylbutyraldehyde (3). To a solution of alcohol (2) (4.8 g, 20.0 mmol) in DCM (40 mL) was added Dess-Martin periodinane (16.96 g, 40.0 mmol) in portions at 0°C while stirring under argon (5 minutes). The reaction was continued until the starting ethanol was consumed (2 hours). The resulting solution was concentrated to about 10.0 mL, adsorbed onto 10.0 g of silica and dried to a free-flowing powder. The silica with the crude product was applied to a silica column (120.0 g) and eluted with 5% ethyl acetate in hexane to give the product as a colorless oil. Yield: 3.33 g (70%). 1 H NMR (CDCl3): 1 H NMR (400MHz, CDCl3) δ9.71 (t, J=1.3Hz, 1H), 2.69 (tt, J=7.9, 1.8Hz, 2H), 2.44 (td, J=7.3, 1.2Hz, 2H), 1.86 (p, J=7.3Hz, 2H). 13 C NMR (101MHz, CDCl3) δ200.89, 42.81, 21.49.

[0270] 1,2,3,4,5-Pentafluoro-6-(4-iodobutyl)benzene (4). An ice-cold solution of ethanol (2) (16.0 g, 66.67 mmol) was stirred with DCM (100 mL) containing imidazole (5.89 g, 86.67 mmol) and triphenylphosphine (20.96 g, 80.0 mmol) under argon. Iodine (20.32 g, 80.0 mmol) was added in portions over 15 minutes at 0°C with vigorous stirring until a slightly yellow color persisted. The reaction mixture was diluted with hexanes (300 mL) and filtered. The filtrate was washed with saturated sodium thiosulfate (3×50 mL), water (3×100 mL), and dried over sodium sulfate. The clear solution was filtered and concentrated to an oil, which was chromatographed over silica gel (220 g). Elution with hexanes gave compound (4) as a colorless oil. Yield: 21.0 g (90%). 1 HNMR (400MHz, cdcl3) δ3.20 (t, J=6.8Hz, 1H), 2.73 (tt, J=7.5, 1.8Hz, 1H), 1.86 (dq, J=8.6, 6.8Hz, 1H), 1.76–1.66 (m, 1H). 13 C NMR (101MHz, cdcl3) δ37.84, 30.01, 21.27, 5.39.

[0271] Iodo-(4-(pentafluorophenyl)butyl)triphenyl-λ 5 -phosphane (5). A solution of iodobutane (4) (21.0 g, 60.0 mmol) and triphenylphosphine (17.29 g, 66.0 mmol) was refluxed under argon for 24 hours. The precipitated solid was filtered, washed with anhydrous ether and dried under high vacuum for 20 hours. Yield: 33.78 g (92%). 1 H NMR (400MHz, CDCl3) δ7.73 (m, 15H), 3.92, 3.86 (m, 2H), 2.76, 2.74 (m, 2H), 2.07, 2.025 (m, 2H), 1.6 (m, 2H). 13 C NMR (101MHz, CDCl3) δ135.23, 135.20, 133.75, 133.65, 130.65, 130.53, 118.32, 117.46, 29.43, 29.27, 23.05, 22.55, 21.78, 21.74, 21.66.

[0272] Compound 6. To a solution of phosphonium salt (5) (6.79 g, 11 mmol) in anhydrous THF (40 mL) was added dropwise THF (2 M, 12.5 mL, 25.0 mmol) containing potassium tert-butoxide and stirred under argon for 30 minutes. THF (5 mL) containing acetaldehyde (3) (2.2 g, 9.24 mmol) was added dropwise at room temperature and stirred for 3 hours. The solution was concentrated and purified on flash silica (120 g). Elution with hexane gave the product as a colorless oil as a mixture of cis / trans isomers (90:10). Yield: 3.2 g (72%). 1 H NMR (400MHz, CDCl3) δ5.41 (m, 2H), 2.72, 2.68 (m, 4H), 2.12, 2.10, 2.06 (m, 4H), 1.64 (m, 4H). 13 C NMR (101MHz, CDCl3) δ129.46, 29.12, 26.76, 21.94.

[0273] Compound 7. Acetone (20 mL) and water (0.5 mL) containing olefin (6) (3.6 g, 8.1 mmol) were cooled to 0 ° C, and dibromoamine-T (2.93 g, 8.91 mmol, Org. Biomol. Chem., 8, 1424-1430 (2010)) was added under vigorous stirring. After addition, the solution was allowed to reach room temperature and stirred until the starting material disappeared (30 minutes). The solution was quenched with solid sodium thiosulfate (2.0 g) and stirred until the color of bromine disappeared completely. The mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed over flash silica gel (80 g) and eluted with hexane containing 10% EtOAc to give bromohydrin (7) as a mixture of diastereomers and a colorless oil. Yield: 2.41 g (55%). 1 H NMR (400MHz), CDCl3) δ 4.02 (m, 1H), 3.48 (m, 1H), 2.73 (4H, CH2-C6F5), 1.6–2.0 (m, 9H, -CH2- and OH)). 13 C NMR (101MHz, CDCl3) δ143.76, 138.35, 129.62, 126.82, 59.74, 57.12, 35.29, 34.50, 27.39, 25.48, 21.74, 21.34.

[0274] Compound 8. Bromohydrin (7) (2.2 g, 4.06 mmol) was dissolved in DCM (10.0 mL) and stirred with 5.0 g molecular sieves. Dess-Martin reagent (3.44 g, 8.12 mmol) was added and stirred until the starting material was completely consumed (30 minutes). The entire mixture was adsorbed onto flash silica (20.0 g) and dried to a free-flowing powder. The silica with the crude product was loaded onto a flash silica (80.0 g) column and eluted with hexane containing 0 to 20% EtOAc over 20 minutes (80.0 mL / min; elution rate). Bromoketone (8) was eluted with hexane containing 5% EtOAc as a colorless slurry. Yield: 1.82 g (83%). 1 H NMR (400MHz, CDCl3) δ4.25 (dd, J=8.3, 6.0Hz, 1H), 2.94–2.81 (m, 1H), 2.80–2.68 (m, 4H), 2.67–2.52 (m, 1H), 2.09–1.86 (m, 4H), 1.86–1.59 (m, 2H). 13C NMR (101MHz, CDCl3) δ202.53, 52.19, 38.18, 32.31, 26.87, 23.21, 21.62, 21.45.

[0275] Compound 9. Sodium bicarbonate (0.56 g, 6.68 mmol) was added to a stirred solution of bromoketone (8) (1.8 g, 3.34 mmol) in anhydrous acetonitrile (10.0 mL). Solid trimethylaniline formamidine (0.94 g, 3.34 mmol) was then added to the stirred solution and the reaction mixture was heated to 60° C., excluding water. After the bromoketone was consumed (70 hours), the reaction mixture was filtered, concentrated under reduced pressure, and chromatographed over flash silica (80 g). Elution with hexane containing 20% ​​DCM gave ketoamidine (10) as a colorless syrup. Yield: 1.2 g (49%). 1 HNMRδ(CDCl3)6.91 9s, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 6.68 (s, 2H), 4.53 (m, 1H), 3.08 (m, 1H), 2.57 (m, 2h), 2.43 (m , 2H), 2.35(m, 2H), 2.36(s, 3h), 2.2(s, 3H), 2.13(s, 3H), 2.01(s, 3H), 1.92(s, 6H), 1.8(m, 2H). 13 C NMR (101MHz, CDCl3) δ208.19, 151.90, 138.19, 131.45, 129.47, 128.74, 64. 33, 60.38, 41.49, 28.39, 25.50, 22.96, 20.56, 18.44, 18.41, 18.23, 14.18. MS:739.1[M+H].

[0276] Compound 11 (trifluoromethanesulfonate). To an ice-cold solution of ketone amidine (0.994 g, 1.35 mmol) in ethanol was added lithium borohydride (2M in THF, 0.675 ml, 1.35 mmol) and stirred at 0-5 ° C for 24 h under argon. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to a paste at room temperature. The paste was dissolved in 5.0 ml of anhydrous benzene and cooled to 0 ° C. DIPEA (0.523 g, 4.05 mmol) was added and stirred under argon. Trifluoromethanesulfonic anhydride (1.104 g, 1.34 mmol) was then added dropwise and stirring was continued for 1 hour. LC / MS indicated complete consumption of the peak corresponding to 741. The mixture was adsorbed onto 10.0 g of silica gel and dried to a free-flowing powder. The silica with the crude product was loaded onto an empty loading column placed on top of an 80.0 g silica column and chromatographed. Elution with 4% MeOH in DCM gave the product as a mixture of cis / trans isomers and as a brown paste. Yield: 0.338 g (33%). 1 H NMR (CDCl3) δ 8.82 (s, 1H), 6.93 (s, 4H), 4.15 (m, 2H), 2.61 (m, 4H), 2.25, 2.23, 2.21 (3S, 18H), 1.77 (m, 4H), 1.41 (m, 4H). 13 C NMR (101MHz, CDCl3) δ159.41, 141.00, 135.66, 134.43, 130.60, 129.96, 128.58, 68.76, 66.17, 32.48, 26.91, 24.65, 21.71, 20.97, 18.38, 18.11. MS:723.0[M+H].

[0277] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0278] The use of the terms "a" and "an" and "the" and "at least one" and similar references in the context of describing the present invention (especially in the context of the appended claims) should be interpreted as covering both the singular and the plural, unless otherwise specified herein or clearly contradicted by the context. The use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be interpreted as meaning one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise specified herein or clearly contradicted by the context. Unless otherwise specified, the terms "comprising", "having", "including" and "containing" should be interpreted as open terms (i.e., meaning "including but not limited to"). Unless otherwise specified herein, the description of numerical ranges herein is intended only to be used as a shorthand method of referring to each individual value falling within the range, respectively, and each individual value is incorporated into the specification as if it were individually described herein. Unless otherwise noted herein or otherwise clearly contradictory to the context, all methods described herein may be performed in any suitable order. Unless otherwise claimed, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention. Any language in the specification should not be interpreted as indicating that any unclaimed element is essential for implementing the present invention.

[0279] Preferred embodiments of the present invention are described herein, including the best mode known to the inventor for implementing the present invention. After reading the foregoing description, variations of those preferred embodiments can become apparent to those of ordinary skill in the art. The inventor of the present application expects that such variations will be appropriately adopted by those skilled in the art, and the inventor of the present application intends to practice the present invention in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter recorded in the appended claims as allowed by applicable law. In addition, unless otherwise noted herein or otherwise clearly contradictory to the context, the present invention encompasses any combination of the above-mentioned elements in all possible variations thereof.

Claims

1. An MRI probe infusion device, comprising: (i) one or more reaction chambers, each reaction chamber comprising: (a) a structure configured to weaken a magnetic field from an external source within the reaction chamber, wherein the strength of the magnetic field from the external source within the reaction chamber is less than a threshold value; (b) one or more inlet ports; (c) a coil configured to generate an electromagnetic field within the reaction chamber; (d) one or more temperature control devices; and (e) one or more outlet ports; (ii) one or more MRI probe separators configured to receive a reaction mixture containing a perfluorinated SABRE catalyst, a solvent, and a hyperpolarized MRI probe from the one or more reaction chambers, and to extract the hyperpolarized MRI probe from the reaction mixture; and (iii) one or more MRI probe collectors configured to form a solution containing a desired concentration of the hyperpolarized MRI probes.

2. The MRI probe infusion device of claim 1, wherein the structure is a mu metal shield that attenuates the magnetic field from the external source to a strength less than or equal to 10 nT in the one or more reaction chambers.

3. The MRI probe infusion device of claim 1, wherein the one or more inlet ports include one or more gas ports and one or more liquid ports.

4. The MRI probe infusion device of claim 1, wherein each reaction chamber is configured to withstand a gas pressure of at least 10 bar.

5. The MRI probe infusion device according to claim 1, wherein the magnetic field in the reaction chamber induced by the coil is 0-200 millitesla.

6. The MRI probe infusion device of claim 1, wherein the one or more temperature control devices comprise non-magnetic heating elements and / or cooling elements configured to maintain the temperature of the reaction chamber at -25°C to 100°C.

7. The MRI probe infusion device of claim 1, wherein the one or more reaction chambers are configured to be hyperpolarized with a reaction mixture containing the perfluorinated SABRE catalyst, the solvent, and a substrate to be hyperpolarized into the hyperpolarized MRI probe.

8. The MRI probe infusion device according to claim 7, wherein the solvent is a single-phase system or a two-phase system comprising water, methanol, ethanol, a fluorine solvent or a mixture thereof.

9. The MRI probe infusion device of claim 1 , wherein the one or more MRI probe separators are configured to separate the hyperpolarized MRI probe from the perfluorinated SABRE catalyst by one of: filter; extraction; or Column chromatography.

10. The MRI probe infusion device of claim 1, further comprising a gas trap, a gas leak detector, and / or an oxygen level monitor.

11. The MRI probe infusion device of claim 1 , further comprising a processor configured to execute instructions causing the processor to: Controlling the flow of gases and / or liquids through the device, monitoring security metrics of the device and / or environment, administering a desired amount of the hyperpolarized MRI probe to the patient, or The decay rate of the hyperpolarized MRI probe is calculated as a function of the flow rate of the gas and / or the liquid.

12. The MRI probe infusion device of claim 1, wherein the one or more MRI probe collectors comprise one or more dryers.

13. The MRI probe infusion device of claim 1, wherein the one or more reaction chambers include at least two reaction chambers, and the at least two reaction chambers are configured to be operable in series or in parallel.

14. The MRI probe infusion device of claim 1, wherein components of the device are made of non-magnetic materials or plastics.

15. A method of administering a hyperpolarized MRI probe to a patient in need thereof, the method comprising: (i) providing an MRI probe infusion device according to claim 1, (ii) supplying a reaction mixture to one or more of the reaction chambers, the reaction mixture comprising a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, a solvent, a co-ligand, and a substrate to be hyperpolarized into an MRI probe, (iii) stirring the reaction mixture, wherein the stirring is provided by bubbling parahydrogen gas or a mixture of parahydrogen and nitrogen gas through the reaction mixture, (iv) applying a magnetic field suitable for hyperpolarization of the perfluorinated SABRE catalyst and the substrate to hyperpolarize the substrate into a hyperpolarized MRI probe, (v) separating the hyperpolarized MRI probe from the reaction mixture by at least one of filtration, extraction or column chromatography to obtain a solution containing the hyperpolarized MRI probe, (vi) concentrating the hyperpolarized MRI probe present in the solution obtained in step (v) to obtain a concentrate, and reconstituting the concentrate into a solution of the hyperpolarized MRI probe of a desired concentration for administration to the patient; (vii) analyzing at least one of the purity or concentration of the hyperpolarized MRI probe present in the solution; and (viii) administering the hyperpolarized MRI probe to the patient.

16. The method according to claim 15, wherein the solvent is selected from the group consisting of a perfluorohexane / diethyl ether mixture, a mixture of methoxynonafluorobutane and ethyl acetate with a nonpolar solvent, a perfluorohexane and ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, ether, a fluorocarbon derivative of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkanes, perfluorohexane and methoxynonafluorobutane.

17. The method according to claim 15, wherein the substrate is selected from 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbon-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form and its salts.

18. The method according to claim 15, wherein the perfluorinated ligand is of formula (I): [L m -(NHC)-(YZ) q ] or a salt thereof, and wherein: Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, NHC is a 4- to 7-membered N-heterocyclic carbene radical, in which NHC is bound to a d-block element via a carbene. Each Y is independently selected from a bond or a spacer group, Each Z is a perfluorinated tag, m is an integer from 1 to 4, and q is an integer from 1 to 3.

19. The method of claim 18, wherein the perfluorinated tag is one of: Perfluorinated C containing only carbon and fluorine atoms 3-60 Group; Perfluorinated C containing only carbon and fluorine atoms 3-40 group; or Perfluorinated C 3-20 Group.

20. The method of claim 15, wherein the perfluorinated ligand is selected from one of the following: or a salt thereof, and wherein: is a single bond or a double bond, and represents a bond through the carbene to the d-block element.

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