SABRE catalysts containing fluorinated carbon chains for the delivery of metal-free MRI contrast agents

Abstract

Disclosed is a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, where the perfluorinated ligand is of formula (I): [L m -(NHC)-(Y-Z) q or a salt thereof. Also disclosed is a method of preparing a hyperpolarized substrate comprising a 1 / 2 spin nucleus or nuclei using a perfluorinated SABRE catalyst and isolating the resulting hyperpolarized substrate for administration to an animal. Further disclosed is a method of imaging tissue of an animal suspected of having a disease or condition.

Description

Technical Field

[0001] Statement Regarding Federally Sponsored Research or Development This invention was made with government support and the government has certain rights in this invention.

[0002] Cross - Reference to Prior Application This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328,545, filed Apr. 7, 2022, which is hereby incorporated by reference in its entirety.

Background Art

[0003] Background of the Invention Nuclear magnetic resonance spectroscopy (NMR) and magnetic resonance imaging (MRI) are powerful tools widely used in biomedical, chemical, and materials science applications. These methods rely on the population difference (called polarization) of nuclear spin energy levels created after applying a strong magnetic field. Spins aligned with or against the applied magnetic field produce a net polarization, which is detected. Unfortunately, nuclear polarization at thermal equilibrium (i.e., the normal state) is inherently poor and generally remains a limitation to the sensitivity and capabilities of magnetic resonance (Guenther, NMR Spectrosc. Basic Princ. Concepts Appl. Chem., 13 - 28 (2013)).

[0004] Hyperpolarization techniques have been developed to overcome this problem and enable orders of magnitude NMR / MRI signal enhancement. The most widely used hyperpolarization techniques utilize polarization transfer 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. U. S. A., 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 Schroeder et al., Science, 314, 446-449(2006)), or 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., C. R. Phys., 6, 575(2005); and Chekmenev et al., J. Am. Chem. Soc., 130, 4212(2008)). Hyperpolarized magnetic resonance (MR) is an emerging molecular imaging method for monitoring metabolism, enzyme turnover, or biochemical pathways that were previously inaccessible using MR.

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

[0006] The PHIP approach and its subcategory SABRE (Signal Amplification By Reversible Exchange) enable the transfer of 100% pure singlet spin-ordered 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, reversible exchange using SABRE leaves the hyperpolarized agent chemically unchanged. It is also not limited to one para H2 molecule per molecule and thus multiple spin transfer steps can lead to impressive levels of hyperpolarization. This effect has also been shown to transfer polarization to nuclei such as 1 H, 13 C, 19 F, 31 P and 15 N as well as / or 29 Si nuclei (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., 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] High polarization rate, short signal enhancement time, low cost, and scalability make SABRE a promising modality for studying in vivo metabolism using magnetic resonance spectroscopy technology.

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

[0009] Another obstacle to the successful implementation of the SABRE process is the lower solubility of para-hydrogen in water compared to its solubility in alcoholic solvents (the solubility of H2 in water is about 1.6 mg / L). SABRE hyperpolarization is mainly active in organic solvents, preferably methanol, which is not suitable for in vivo administration.

[0010] The foregoing indicates the need for an improved SABRE catalyst that can be easily separated from the hyperpolarized substrate so that the hyperpolarized substrate is free of heavy metals. Furthermore, there is a need for a method to separate the hyperpolarized substrate from the SABRE catalyst and / or the hyperpolarized SABRE catalyst complex containing heavy metals. There is also a need for a method to administer the hyperpolarized substrate in a solvent medium suitable for in vivo administration.

[0011] 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 present invention provided herein. SUMMARY OF THE INVENTION

[0012] The present invention provides a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand has the formula (I):

[0013]

Chem.

[0014] is of that kind, or a salt thereof, and 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 (NHC is bonded 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.

[0015] The present invention also provides a method for preparing a perfluorinated SABRE catalyst described herein, which includes 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 cyclooctadienyl).

[0016] The present invention further provides a method for preparing a hyperpolarized substrate, the method comprising: (i) providing a perfluorinated SABRE catalyst described herein; (ii) providing a coligand that interacts with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst; (iii) combining the active perfluorinated SABRE catalyst with parahydrogen and a substrate containing a 1 / 2 spin nucleus(s) or nucleus(nuclei) in a solvent to obtain a reaction mixture; and (iv) hyperpolarizing the mixture obtained in (iii) by exposing the mixture to a magnetic field or by high-frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate comprises

[0017] The present invention further provides a hyperpolarized substrate obtainable from the methods described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0018] The present invention further provides a method for obtaining a magnetic resonance image of a tissue in a subject, comprising administering to a subject having or suspected of having cancer or a harmful vascular condition the hyperpolarized substrate described herein, or a pharmaceutical composition comprising the same, and imaging the subject by magnetic resonance imaging.

[0019] The present invention further provides a compound of formula (III):

[0020]

Chemical formula

[0021] (wherein each Ar is independently selected from a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, each Ar f is independently selected from a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group, each Y is independently selected from a bond or a spacer group, X is an anion, and

[0022]

Chemical formula

[0023] is a single bond or a double bond), and a method for preparing the perfluorinated compound of formula (III).

Brief Description of the Drawings

[0024]

Figure 1

Figure 2

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Figure 7

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Figure 9

Figure 10A

Figure 10B

Figure 11

Figure 12

Figure 13

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Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

[0025] **Detailed Description of the Invention** The present invention provides a perfluorinated SABRE catalyst comprising a d - block element and a perfluorinated ligand, wherein the perfluorinated ligand is of formula (I):

[0026] **

Chemical formula

[0027] or a salt thereof, and 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 (NHC is bonded to the d - block element via the 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 (e.g., 1, 2, or 3).

[0028] The perfluorinated SABRE catalyst contains d-block elements 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 contains an element of Group 9 of the periodic table, namely, Co, Rh, Ir, or Mt. In a preferred embodiment, the perfluorinated SABER catalyst contains Ir or Co. For example, the perfluorinated SABER catalyst can be prepared from [Ir(COD)(IMes)(Cl)].

[0029] The perfluorinated SABER catalyst has the formula (I):

[0030]

Chemical formula

[0031] and includes a perfluorinated ligand of 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 group (NHC is bonded to the d-block element via the 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 (e.g., 1, 2, or 3).

[0032] In some embodiments, the NHC comprises an azolyl moiety, i.e., a 5-membered heterocyclic group having a nitrogen atom(s) and at least one other heteroatom selected from nitrogen, sulfur, and oxygen. That is, 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 carbene resulting from the treatment of a perfluorinated ligand having an imidazole, imidazoline, or thiazole nucleus.

[0033] In some embodiments, the 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, the NHC can be 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. Examples of the imidazolylidinyl moiety include N,N'-di-(2,4,6-trimethylphenyl)-imidazolylidinyl moiety, N,N'-di-(2,6-diisopropylphenyl)-imidazolidinyl moiety, N,N'-di-(2,6-dicyclohexyl)-imidazolidinyl moiety, N,N'-di-(2,6-t-butyl)-imidazolidinyl moiety, and N,N'-di-(1-adamantyl)-imidazolidinyl moiety.

[0034] In some embodiments, the perfluorinated ligand is of formula (Ia) or (Ib):

[0035]

Chemical formula

[0036] 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,

[0037]

Chemical formula

[0038] is a single bond or a double bond, and

[0039]

Chemical formula

[0040] represents a bond to a d-block element via a carbene.

[0041] In some embodiments, the perfluorinated ligand is of formula (Ic) or (Id):

[0042]

Chemical formula

[0043] or a salt thereof, and here, each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, a is from 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),

[0044]

Chemical formula

[0045] is a single bond or a double bond, and

[0046]

Chem.

[0047] represents a bond to a d-block element via a carbene. In some embodiments of formula (Ic) or (Id), a is from 4 to 10 (e.g., 4, 5, 6, 7, 8, 9, or 10).

[0048] In some embodiments, the perfluorinated ligand is of formula (Ie) or (If):

[0049]

Chem.

[0050] or a salt thereof, and where 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 1-6 alkenyl, or C 1-6 heteroalkyl, a is from 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,

[0051]

Chem.

[0052] is a single bond or a double bond, and

[0053]

Chem.

[0054] represents the bonding to the d-block element via a carbene. In some embodiments of formula (Ie) or (If), a is from 4 to 10 (for example, 4, 5, 6, 7, 8, 9, or 10).

[0055] In any of formulas (I) and (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 substitution) or unsubstituted aromatic ring having from 5 to 60 ring carbon atoms, such as phenyl, naphthyl, phenanthryl, and anthracenyl. As used herein, "substituted or unsubstituted heteroaromatic" has from 1 to 2 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon, and is substituted (e.g., C 1-6An alkyl-substituted or unsubstituted aromatic ring, or at least one 5- to 7-membered aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and which forms part of a stable bicyclic or tricyclic system. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms, and in some embodiments, bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms where 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 a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in a heteroaryl group is 2 or less. It is particularly preferred that the total number of S and O atoms in an aromatic heterocyclic ring is 1 or less. Heteroaryl groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzofrijoxazolyl, benzofuranyl, benzothiazolyl, benzolhiophenyl, benzoxadiazolyl, dihydrobenzodioxinyl, 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-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-di-isopropylphenyl, 2,5-di-isopropylphenyl, 2,6-di-isopropylphenyl, 3,5-di-isopropylphenyl, 2,4,6-tri-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-di-isobutylphenyl, 2,5-di-isobutylphenyl, 2,6-di-isobutylphenyl, 3,5-di-isobutylphenyl, 2,4,6-tri-isobutylphenyl, 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, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 2,4-di-t-butylphenyl, 2,5-di-t-butylphenyl, 2,6-di-t-butylphenyl, 3,5-di-t-butylphenyl, 2,4,6-tri-t-butylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2,4-di-cyclohexylphenyl, 2,5-di-cyclohexylphenyl, 2,6-di-cyclohexylphenyl, 3,5-di-cyclohexylphenyl, or 2,4,6-tri-cyclohexylphenyl.In certain embodiments of formulas (I) and (Ia)-(If), each L is independently hydrogen or 2,4,6-trimethylphenyl.

[0058] In any of formulas (I) and (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 group, a substituted or unsubstituted C 2-10 alkenyl group, a substituted or unsubstituted C 2-10 alkynyl group, a substituted or unsubstituted C 1-10 heteroalkyl group, a substituted or unsubstituted C 3-6 cycloalkyl group, a substituted or unsubstituted C 3-6 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 group, a substituted or unsubstituted C 2-10 alkenyl group, a substituted or unsubstituted C 2-10 alkynyl group, a substituted or unsubstituted C 1-10 heteroalkyl group, a substituted or unsubstituted C 3-6 cycloalkyl group, a substituted or unsubstituted C 3-6 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. In certain embodiments, each Y is independently a bond, a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10It is 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. In a preferred embodiment, each Y is independently a bond, a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10 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] The perfluorinated ligand contains a perfluorinated tag. For example, in any of formulas (I) and (Ia)-(If), each Z is a perfluorinated tag. The perfluorinated tag can be any perfluorinated group such as a perfluorinated alkyl (e.g., linear or branched), aryl, alkyarl, or arylalkyl group containing up to 60 carbon atoms. In some embodiments, the perfluorinated tag is a perfluorinated C 3-60 group containing only carbon atoms and fluorine atoms. In certain embodiments, the perfluorinated tag is a perfluorinated C 3-40 group containing only carbon atoms and fluorine atoms. In other embodiments, the perfluorinated tag is a perfluorinated C 3-20 group. For example, the perfluorinated tag can be selected from C4F9 group, 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, and each of them can be a linear or branched alkyl, aryl, alkyarl, or arylalkyl group.

[0061] In one aspect, Z is a straight-chain or branched perfluoroalkyl chain having a chain length of up to 60 or more carbon atoms. For example, the perfluoroalkyl chain has a chain length of 3 to 60, specifically 3 to 40, more specifically 3 to 20, and even more specifically 3 to 10 or more carbon atoms. For example, the perfluoroalkyl chain is selected from the group consisting of C4F9, C6F 13 , C7F 15 , C8F 17 , C9F 19 , and C 10 F 21 , and is preferably selected from the group consisting of C6F 13 , C8F 17 , and C 10 F 21 , each of which can be straight-chain, branched, or a combination thereof, where each of them can be straight-chain or branched.

[0062] In one aspect, the perfluorinated ligand is of formula (Ig):

[0063]

Chemical formula

[0064] or a salt thereof, and here, a is from 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,

[0065]

Chemical formula

[0066] is a single bond or a double bond, and

[0067]

Chemical formula

[0068] represents the bonding to the d-block element via a carbene. In some embodiments of formula (Ig), a is from 4 to 10 (e.g., 4, 5, 6, 7, 8, 9, or 10).

[0069] In one embodiment, the perfluorinated ligand is of formula (Ih):

[0070]

Chemical formula

[0071] or a salt thereof, and wherein a is from 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,

[0072]

Chemical formula

[0073] is a single bond or a double bond, and

[0074]

Chemical formula

[0075] represents the bonding to the d-block element via a carbene. In some embodiments of formula (Ig), a is from 4 to 10 (e.g., 4, 5, 6, 7, 8, 9, or 10).

[0076] Exemplary perfluorinated ligands are:

[0077]

Chemical formula

[0078] or a salt thereof, and wherein,

[0079] [Chemical formula]

[0080] is a single bond or a double bond, and

[0081] [Chemical formula]

[0082] represents a bond to a d-block element via a carbene.

[0083] The symbols used in this specification

[0084] [Chemical formula]

[0085] represents a single bond or a double bond. In some embodiments,

[0086] [Chemical formula]

[0087] is a single bond. In other embodiments,

[0088] [Chemical formula]

[0089] is a double bond.

[0090] [Chemical formula]

[0091] In embodiments where it is a single bond,

[0092]

Chemical formula

[0093] The orientation of the two substituents resulting from

[0094]

Chemical formula

[0095] when it is a single bond,

[0096]

Chemical formula

[0097] the orientation of the substituent resulting from

[0098] The symbols used in this specification

[0099]

Chemical formula

[0100] represent a bond to a d-block element via a carbene. In other words,

[0101]

Chemical formula

[0102] represent a bond to the metal of the catalyst.

[0103] 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 phosphine ligands, carbene ligands, imidazole ligands, pincer chelate ligands, and compounds containing 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:

[0104] [Chemical formula]

[0105] including, but not limited to these.

[0106] In some embodiments, the perfluorinated SABRE catalyst comprises a pincer chelate ligand. Generally, when the perfluorinated SABRE catalyst comprises a phosphine ligand or a pincer chelate ligand, the perfluorinated SABRE catalyst is in a pre-catalyst form. In some embodiments, the perfluorinated SABRE catalyst comprises a ligand that is a compound containing a sulfoxide group. Examples of compounds containing a sulfoxide group can be selected from the group consisting of dimethyl sulfoxide (DMSO), phenyltrifluoromethyl sulfoxide, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, and dibutyl sulfoxide. Generally, 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" can refer to an active perfluorinated SABER catalyst or a perfluorinated SABRE pre-catalyst.

[0107] The active perfluorinated SABRE catalyst can be prepared by any suitable method. Generally, the active perfluorinated SABRE catalyst is prepared by combining a perfluorinated SABRE precatalyst with a substrate, parahydrogen, and optionally a cosligand in a solvent to form a mixture containing the active perfluorinated SABRE catalyst. In some embodiments, the active perfluorinated SABRE catalyst is prepared by combining a perfluorinated SABRE precatalyst with a substrate, parahydrogen, and a cosligand in a solvent to form a mixture containing the active perfluorinated SABRE catalyst. When included in the preparation of the active perfluorinated SABRE catalyst, the cosligand can be combined with the perfluorinated SABRE precatalyst in any order and by any suitable means. For example, when included in the preparation of the active SABRE catalyst, the cosligand can be provided first and allowed to interact with the mobile precatalyst to facilitate the formation of the active perfluorinated SABRE catalyst. Alternatively, when included in the preparation of the active perfluorinated SABRE catalyst, the cosligand can be added together with the substrate to facilitate the formation of the active perfluorinated SABRE catalyst. In some embodiments, the cosligand, substrate, and parahydrogen are combined essentially simultaneously in a solvent with the perfluorinated SABRE precatalyst to facilitate the formation of the active perfluorinated SABRE catalyst. In other embodiments, the substrate is provided first and allowed to interact with the perfluorinated SABRE precatalyst to facilitate the formation of the active perfluorinated SABRE catalyst. In some embodiments, the cosligand and substrate are combined with the perfluorinated SABRE precatalyst in a solvent and parahydrogen is added to the resulting mixture (e.g., by bubbling through the mixture). In other embodiments, the substrate is combined with the perfluorinated SABRE precatalyst in a solvent and parahydrogen is added to the resulting mixture (e.g., by bubbling through the mixture). In some embodiments, the active perfluorinated SABRE catalyst is prepared by combining the perfluorinated SABRE precatalyst with a substrate and parahydrogen in addition to a cosligand.

[0108] In some embodiments, the active perfluorinated SABRE catalyst has the formula [Ir(H)2(F-IMes)(η 2 -SUBSTRATE)(coligand)] or [Ir(H)2(F-IMes)(η 1 -SUBSTRATE)(coligand)2] where SUBSTRATE is a target substrate that is hyperpolarized by the transfer of pure singlet spin-ordered parahydrogen by a spin transfer catalyst, preferably an atom having a 1 / 2 spin nucleus, such as 1 H, 13 C, 15 N, 19 F, 31 P and / or 29 Si-enriched target substrate. Without wishing to be bound by any particular theory, the coligand interacts with the spin transfer precatalyst to form an active polarization transfer catalyst and enhance the polarization transfer to the target substrate. F-IMes refers to a perfluorinated form of an N-heterocyclic carbene (NHC) ligand such as the 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene group.

[0109] In some embodiments, the perfluorinated SABRE catalyst (e.g., perfluorinated SABRE precatalyst) can be prepared by a method that includes reacting a perfluorinated compound with a base to form a carbene and reacting the carbene with [(d-block element)(COD)Cl]2, where COD represents cyclooctadienyl. In certain embodiments, the method includes 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

[0110]

Chemical formula

[0111] has the formula

[0112] [Chem.]

[0113] can be prepared by reacting the carbene with [Ir(COD)Cl]2.

[0114] Exemplary perfluorinated SABRE catalysts (e.g., perfluorinated SABRE precatalysts) are:

[0115] [Chem.]

[0116] [Chem.]

[0117] or a salt thereof.

[0118] The present invention further provides a method for preparing a hyperpolarized substrate, the method comprising: (i) providing a perfluorinated SABRE catalyst as described herein; (ii) providing a co-ligand that interacts with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst; (iii) combining the active perfluorinated SABRE catalyst with parahydrogen and a substrate comprising a 1 / 2 spin nucleus(s) in a solvent to obtain a reaction mixture; and (iv) hyperpolarizing the mixture obtained in (iii) by exposing the mixture to a magnetic field or by high frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate comprising.

[0119] The method of preparing a hyperpolarized substrate described herein involves polarizing a mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) by exposing the mixture to a magnetic field or radiofrequency excitation, and transferring the polarization from parahydrogen to the substrate to form a hyperpolarized substrate. Initially, the hyperpolarized substrate forms a complex with the hyperpolarized perfluorinated SABRE catalyst; however, since the hyperpolarized substrate can be replaced by another substrate molecule, the process can be repeated and a free hyperpolarized substrate bolus can be produced, as will be understood by those skilled in the art.

[0120] The transfer of polarization from parahydrogen to the substrate to form a hyperpolarized substrate can occur under any suitable magnetic field or radiofrequency excitation. For example, the transfer of polarization from parahydrogen to the substrate can occur at a magnetic field below that of the Earth's magnetic field. The appropriate level of magnetic field or radiofrequency excitation required to transfer the polarization from parahydrogen to the substrate to form a hyperpolarized substrate will be readily apparent to those skilled in the art.

[0121] In some embodiments, the method involves replenishing the parahydrogen in the mixture during the step of polarizing a mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) by exposing the mixture to a magnetic field or radiofrequency excitation and transferring the polarization from parahydrogen to the substrate to form a hyperpolarized substrate. In other words, in some embodiments, the method involves bubbling parahydrogen through the mixture comprising the perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) during the step of polarizing the mixture by exposing it to a magnetic field or radiofrequency excitation and transferring the polarization from parahydrogen to the substrate to form a hyperpolarized substrate.

[0122] Methods for preparing hyperpolarized substrates include providing a co-ligand that interacts with a perfluorinated SABRE catalyst to facilitate the formation of an active perfluorinated SABRE catalyst. The co-ligand can 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 containing a sulfoxide group. Examples of compounds containing a sulfoxide group can be selected from the group consisting of 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.

[0123] In embodiments of the method for preparing a hyperpolarized substrate, the magnetic field is an electromagnetic field. For example, the strength of the electromagnetic field can be in the range of 0 to 200 millitesla (mT). In some embodiments, the electromagnetic field can be at least partially provided by one or more permanent magnets applied to or in place of the coil. In some embodiments, the electromagnetic field can be an alternating magnetic field supplied at a frequency adapted to a particular atomic nucleus. The alternating magnetic field can change direction (i.e., alternate between positive and negative with respect to a positive direction). In some embodiments, the frequency can be a high frequency, and other frequencies outside this range are contemplated as being within the scope of the present disclosure, but can preferably be between 50 and 500 MHz.

[0124] A perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) is combined with parahydrogen and a substrate containing a 1 / 2 spin nucleus or nuclei 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, fluorinated solvents, or mixtures thereof. For example, the solvent can be ethanol-based or methanol-based, i.e., can include at least ethanol or methanol combined with water. In certain embodiments, the solvent includes a fluorinated solvent. In other embodiments, the solvent is deuterated such that a deuterated solvent can be prepared without deuterium-hydrogen exchange (i.e., with limited deuterium-hydrogen exchange).

[0125] A fluorinated solvent can be any organic solvent containing at least one compound having a fluorine atom. Without wishing to be bound by any particular theory, it is believed that fluorinated solvents increase the solubility of perfluorinated SABRE catalysts. In some embodiments, the solvent (e.g., a fluorinated solvent) is selected from a perfluorohexane / diethyl ether mixture, a methoxynonafluorobutane and ethyl acetate mixture 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, decafluoromethoxytri fluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkane, perfluorohexane, and methoxynonafluorobutane.

[0126] In some embodiments, the method of preparing a hyperpolarized substrate further includes 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 combinations thereof.

[0127] 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 the liquid containing the hyperpolarized substrate, where 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. For example, see FIG. 5. The solid-phase adsorbent can be any suitable adsorbent capable of preferentially adsorbing the perfluorinated SABRE catalyst over the hyperpolarized substrate. For example, the solid-phase adsorbent can be a Fluorous solid-phase adsorbent, a reverse-phase adsorbent (e.g., a C18 adsorbent, etc.), and a polyethylene-based filter (e.g., ultra-high molecular weight polyethylene). For example, see FIGS. 1 and 2. In certain embodiments, the method of preparing the hyperpolarized substrate further includes passing a fluorophobic solvent over the adsorbent and recovering the eluate containing the hyperpolarized substrate, where the eluate 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. The fluorophobic solvent can be any suitable solvent capable of preferentially washing the hyperpolarized substrate off the solid-phase adsorbent compared to the perfluorinated SABRE catalyst. For example, the fluorophobic solvent can include water and one or more of methanol, ethanol, acetonitrile, and dimethylformamide. Alternatively, or additionally, the method of preparing the hyperpolarized substrate further includes passing a fluorophilic solvent (e.g., an organic solvent selected from methanol, ethanol, acetonitrile, THF, ethyl acetate, chlorinated solvents (e.g., chlorinated alkanes such as methylene chloride, chloroform, and ethylene dichloride), and combinations thereof) over the adsorbent to recover, for example, the perfluorinated SABRE catalyst.Exemplary parent 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.

[0128] In some embodiments, the hyperpolarized substrate is isolated by treating the reaction mixture with a solid-phase adsorbent to adsorb the hyperpolarized substrate and recovering the liquid containing the perfluorinated SABRE catalyst, where 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 silica, alumina, etc. See, e.g., Figure 3. In certain embodiments, the method of preparing the hyperpolarized substrate further includes passing a parent fluorophilic solvent over the adsorbent and recovering the eluate containing the perfluorinated SABRE catalyst, where the eluate 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 parent fluorophilic solvent can be any suitable solvent capable of preferentially washing the perfluorinated SABRE catalyst off the solid-phase adsorbent compared to the hyperpolarized substrate. For example, the fluorophobic solvent can include 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 of preparing the hyperpolarized substrate can further include passing a fluorophobic solvent (e.g., a solvent containing water, methanol, ethanol, acetonitrile, dimethylformamide, or combinations thereof) over the adsorbent to recover, for example, the hyperpolarized substrate.

[0129] In any of the embodiments disclosed herein, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate may be present in a single-phase mixture or a two-phase mixture. The single-phase mixture or two-phase mixture may include any combination of the solvents described herein. For example, the two-phase mixture may include a polar solvent (e.g., water, methanol, and ethanol) combined with a nonpolar solvent (e.g., an organic solvent or a fluorinated solvent). In embodiments where the perfluorinated SABRE catalyst and / or the hyperpolarized substrate are present in a two-phase solvent, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be isolated by liquid / liquid extraction. For example, refer to Figure 4. That is, in some embodiments, the hyperpolarized substrate is isolated by liquid / liquid extraction, for example, by partitioning the perfluorinated SABER catalyst and the hyperpolarized substrate between a methanolic mixture and a fluorinated solvent, or by partitioning the perfluorinated SABER catalyst and the hyperpolarized substrate between a methanolic mixture and an organic solvent.

[0130] In some embodiments, the hyperpolarized substrate is isolated by precipitating the perfluorinated SABER catalyst and filtering to remove the precipitated perfluorinated SABER catalyst from the hyperpolarized substrate. Typically, the perfluorinated SABRE catalyst precipitates upon addition of a solvent in which the perfluorinated SABRE catalyst is insoluble (e.g., hexane, pentane, water, ethanol, etc.). In certain embodiments, the perfluorinated SABRE catalyst precipitates upon addition of water.

[0131] The perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be dried or concentrated (e.g., under reduced pressure, using a desiccant, heating, or combinations 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 hyperpolarization catalyst. Similarly, the hyperpolarized substrate can be dried or concentrated to remove the organic solvent and reconstituted in water for administration to a subject.

[0132] The substrate can be any compound containing a 1 / 2 spin nucleus or nuclei. For example, the substrate can 1 H, 13 C, 15 N, 19 F, 31 P, 29 Si, or combinations thereof. In some embodiments, the substrate further 2 contains D. That is, the methods described herein can be used to enhance the signal of the 1 H, 13 C, 15 N, 19 F, 31 P and / or 29 Si response of a target substrate. Generally, the spin polarization transfer described herein is based on the SABRE effect; however, the method can be extended to para-hydrogen induced polarization (PHIP).

[0133] In some embodiments, the substrate is selected from ketoglutaric acid, pyruvic acid, N-acetylcysteine, and salts or esters thereof. In certain embodiments, the substrate is 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 C-N-acetylcysteine, 15N2-isoniazide (i.e., pyridyl-4-carbo-bis- 15 N2-hydrazide), 13 C2, 15 N3 metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), their deuterated versions, and their salts.

[0134] In some embodiments, the substrate is of formula (II):

[0135]

Chemical formula

[0136] (wherein each R1 is independently selected from hydrogen, deuterium, a 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; 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), or a pharmaceutically acceptable salt thereof.

[0137] Each R1 can be independently selected from hydrogen, deuterium, a 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 (e.g., isopropyl or n-propyl), butyl (e.g., isobutyl, n-butyl, tert-butyl, or sec-butyl), pentyl, or hexyl. In some embodiments, each R1 is independently selected from hydrogen, deuterium, and a cation. In embodiments where R1 is a cation, it will be readily understood by those skilled in the art that the compound of formula (II) is a salt (e.g., a pharmaceutically acceptable salt) in which the negative charge on the oxygen is balanced by the cation. In certain embodiments, each R1 is independently a cation or C1-C6 alkyl.

[0138] The present invention further provides a hyperpolarized substrate, or a pharmaceutically acceptable salt thereof, obtained from any of the methods described herein, or a pharmaceutical composition comprising a hyperpolarized substrate, or a pharmaceutically acceptable salt thereof, 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 a water-soluble compound containing a hyperpolarized nucleus or nuclei, which imaging medium is particularly well-suited for nuclear magnetic resonance (NMR) spectroscopy and / or magnetic resonance imaging (MRI).

[0139] The present invention further provides a method for obtaining a magnetic resonance image of tissue in a subject, comprising administering to a subject having or suspected of having cancer or a harmful vascular condition the hyperpolarized substrate described herein, or a pharmaceutical composition thereof, and imaging the subject by magnetic resonance imaging. In one aspect, the subject has a cancer such as, for example, the cancer is selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer. In another aspect, the subject has a harmful vascular condition such as, for example, a vascular condition selected from myocardial infarction, stroke, and lung diseases (e.g., COPD, pulmonary fibrosis, long-term COVID-19 symptoms, and combinations thereof).

[0140] In some embodiments, the present invention provides a method for diagnosing or monitoring a patient having or suspected of having cancer, the method comprising administering the hyperpolarized substrate or pharmaceutical composition as described above and diagnosing or monitoring the patient by hyperpolarized 13 C-MRI. For example, the hyperpolarized substrate can be used in a method for diagnosing or monitoring a patient having or suspected of having cancer. In certain embodiments, the method or use comprises identifying the mutation(s) that cause 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, e.g., has an IDH1 mutation.

[0141] The present invention further provides a compound of formula (III):

[0142]

Chemical formula

[0143] (wherein, each Ar is independently selected from a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, Each Ar f is independently selected from a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group, each Y is independently selected from a bond or a spacer group, X is an anion, and

[0144]

Chemical formula

[0145] is a single bond or a double bond) provides a perfluorinated compound.

[0146] All embodiments of the perfluorinated compound of formula (III) are as described for any of formula (I) and (Ia)-(If). For example, Ar f is independently selected from a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group, where the substituted or unsubstituted aromatic group and the substituted or unsubstituted heteroaromatic group are as described for any of formula (I) and (Ia)-(If). In some embodiments of the perfluorinated compound of formula (III), (i) each Ar is independently selected from a substituted or unsubstituted aromatic group, (ii) each Ar f is independently selected from a perfluorinated substituted or unsubstituted aromatic group, and / or (iii) each Y is independently selected from a spacer group selected from C 1-5 alkyl and C 1-5 heteroalkyl.

[0147] In certain embodiments, the perfluorinated compound is of formula (IIIa):

[0148]

Chemical formula

[0149] (wherein, Each n is independently an integer from 0 to 4, X is an anion, and

[0150]

Chemical formula

[0151] is a single bond or a double bond).

[0152] In formulas (III) and (IIIa), X is an anion. X can be any suitable anion. For example, X can be a halide ion (e.g., fluoride, chloride, bromide, or iodide) or a fluorate ion (e.g., tetrafluoroborate or hexafluorophosphate).

[0153] The perfluorinated compound of formula (III) or (IIIa) can be prepared by any suitable means. For example, the perfluorinated compound can be: (i) reacting an α-bromo ketone containing a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group with an amidine containing a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group in the presence of a base to form an α-amino ketone, (ii) optionally reducing the α-amino ketone with a reducing agent to form an α-amino alcohol, and (iii) cyclizing the α-amino ketone or the α-amino alcohol to form a perfluorinated compound by a method including.

[0154] The perfluorinated compound of formula (III) or (IIIa) can be used in any suitable application. For example, the perfluorinated compound of formula (III) or (IIIa) can be used for catalysis (e.g., polymerization catalysis or SABRE catalysis). That is, in some embodiments, the present invention provides a catalyst (e.g., an olefin metathesis catalyst or a SABRE catalyst) comprising a d-block element and a perfluorinated compound of formula (III) or (IIIa) as a ligand, and a method of using the same. For example, an olefin metathesis catalyst comprising a perfluorinated compound of formula (III) or (IIIa) can be used in a method of polymerizing an olefin, the method comprising mixing the olefin metathesis catalyst and the olefin in a reaction mixture. Similarly, a SABRE catalyst comprising a perfluorinated compound of formula (III) or (IIIa) can be used in a method of hyperpolarizing a substrate as described herein.

[0155] Aspects of the disclosure Aspects of the invention described herein, including embodiments, may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing description, specific non-limiting aspects of the disclosure numbered 1-65 are provided below. As will be apparent to those skilled in the art upon reading this disclosure, each of the individually numbered aspects can be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to the combinations of aspects explicitly provided below:

[0156] (1) In aspect (1), a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand has the formula (I):

[0157]

Chemical formula

[0158] or a salt thereof, and 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 (NHC is bonded 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, A perfluorinated SABRE catalyst is provided.

[0159] (2) In embodiment (2), there is provided a perfluorinated SABRE catalyst according to embodiment 1, wherein NHC is a 5-membered N-heterocyclic carbene group.

[0160] (3) In embodiment (3), there is provided a perfluorinated SABRE catalyst according to embodiment 2, wherein the 5-membered N-heterocyclic carbene group is imidazole-based, imidazoline-based, or thiazole-based.

[0161] (4) In embodiment (4), there is provided a perfluorinated SABRE catalyst according to any one of embodiments 1 to 3, wherein 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.

[0162] (5) In embodiment (5), there is provided a perfluorinated SABRE catalyst according to any one of embodiments 1 to 4, wherein 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.

[0163] (6) In aspect (6), the perfluorinated ligand is of formula (Ia) or (Ib):

[0164]

Chem.

[0165] or a salt thereof, and 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,

[0166]

Chem.

[0167] is a single bond or a double bond, and

[0168]

Chem.

[0169] represents a bond to a d-block element via a carbene, providing a perfluorinated SABRE catalyst of aspect 1.

[0170] (7) In aspect (7), the perfluorinated ligand is of formula (Ic) or (Id):

[0171]

Chem.

[0172] or a salt thereof, and each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, a is from 4 to 20, b = 2a + 1 or b = a - 1, and each n is independently an integer from 0 to 4, and

[0173]

Chem.

[0174] is a single bond or a double bond, and

[0175]

Chem.

[0176] provides a perfluorinated SABRE catalyst of embodiment 1 that represents a bond to a d-block element via a carbene.

[0177] (8) In embodiment (8), the perfluorinated ligand is of formula (Ie) or (If):

[0178]

Chem.

[0179] or a salt thereof, and 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 1-6 alkenyl, or C 1-6 heteroalkyl, a is from 4 to 20, b = 2a + 1 or b = a - 1, and

[0180]

Chem.

[0181] is a single bond or a double bond, and

[0182] [Chemical formula]

[0183] provides a perfluorinated SABE catalyst of embodiment 1 that represents a bond to a d-block element via a carbene.

[0184] (9) In embodiment (9), a is from 4 to 10, providing a perfluorinated SABRE catalyst of embodiment 7 or embodiment 8.

[0185] In aspect (10), 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-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-di-isopropylphenyl, 2,5-di-isopropylphenyl, 2,6-di-isopropylphenyl, 3,5-di-isopropylphenyl, 2,4,6-tri-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-di-isobutylphenyl, 2,5-di-isobutylphenyl, 2,6-di-isobutylphenyl, 3,5-di-isobutylphenyl, 2,4,6-tri-isobutylphenyl, 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, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 2,4-di-t-butylphenyl, 2,5-di-t-butylphenyl, 2,6-di-t-butylphenyl, 3,5-di-t-butylphenyl, 2,4,6-tri-t-butylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2,4-di-cyclohexylphenyl, 2,5-di-cyclohexylphenyl, 2,6-di-cyclohexylphenyl, 3,5-di-cyclohexylphenyl, or 2,4,Provide a perfluorinated SABRE catalyst according to any one of aspects 1 to 9, which is 6-tri-cyclohexylphenyl.,

[0186] (11) In aspect (11), provide a perfluorinated SABRE catalyst according to any one of aspects 1 to 10, wherein each L is independently hydrogen or 2,4,6-trimethylphenyl.,

[0187] (12) In aspect (12), provide a perfluorinated SABRE catalyst according to any one of aspects 1 to 11, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10 alkenyl group, a substituted or unsubstituted C 2-10 alkynyl group, a substituted or unsubstituted C 1-10 heteroalkyl group, a substituted or unsubstituted C 3-6 cycloalkyl group, a substituted or unsubstituted C 3-6 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.,

[0188] (13) In aspect (13), provide a perfluorinated SABRE catalyst according to any one of aspects 1 to 11, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10 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.,

[0189] (14) In aspect (14), provide a perfluorinated SABRE catalyst according to any one of aspects 1 to 11, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10Provided is a perfluorinated SABRE catalyst according to any one of aspects 1 to 11, which is 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.

[0190] (15) In aspect (15), provided is a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is a perfluorinated C 3-60 group containing only carbon atoms and fluorine atoms.

[0191] (16) In aspect (16), provided is a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is a perfluorinated C 3-40 group containing only carbon atoms and fluorine atoms.

[0192] (17) In aspect (17), provided is a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is a perfluorinated C 3-20 group.

[0193] (18) In aspect (18), the perfluorinated tag is selected from the group consisting of a C4F9 group, a C5F 11 group, a C6F 13 group, a C7F 15 group, a C8F 17 group, a C9F 19 group, a C 10 F 21 group, a C6F5 group, a C4F7 group, a C5F9 group, a C6F 11 group, a C7F 13 group, a C8F 15 group, a C9F 17 group, and a C 10 F 19 group, and provided is a perfluorinated SABRE catalyst according to any one of aspects 1 to 14.

[0194] (19) In aspect (19), the perfluorinated ligand is

[0195] [Chemical formula]

[0196] or a salt thereof, and

[0197] [Chemical formula]

[0198] is a single bond or a double bond, and

[0199] [Chemical formula]

[0200] provides a perfluorinated SABE catalyst of embodiment 1 that represents a bond to a d-block element via a carbene.

[0201] (20) In embodiment (20), a d-block element is a transition metal, providing a perfluorinated SABRE catalyst of any one of embodiments 1 to 19.

[0202] (21) In embodiment (21), a d-block element is Co, Rh, Ir, Ru, Pd, Pt, or Mt, providing a perfluorinated SABRE catalyst of any one of embodiments 1 to 20.

[0203] (22) In embodiment (22), the SABRE catalyst further includes an additional ligand, providing a perfluorinated SABRE catalyst of any one of embodiments 1 to 21.

[0204] (23) In embodiment (23), the SABRE catalyst further includes an additional ligand selected from a phosphine ligand, a carbene ligand, an imidazole ligand, a pincer chelate ligand, and a compound containing a sulfoxide group, providing a perfluorinated SABRE catalyst of embodiment 22.

[0205] In embodiment (24), there is provided a method for preparing a perfluorinated SABRE catalyst of any one of embodiments 1 to 23, including 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 cyclooctadienyl).

[0206] In embodiment (25), there is provided the method of embodiment 24, wherein the d-block element is Co, Rh, Ir, Ru, Pd, Pt, or Mt.

[0207] In embodiment (26), there is provided a method for preparing a hyperpolarized substrate, the method comprising: (i) providing a perfluorinated SABRE catalyst according to any one of embodiments 1 to 23; (ii) providing a co-ligand that interacts with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst; (iii) combining the active perfluorinated SABRE catalyst with parahydrogen and a substrate containing a 1 / 2 spin nucleus(s) in a solvent to obtain a reaction mixture; and (iv) hyperpolarizing the mixture obtained in (iii) by exposing the mixture to a magnetic field or by high-frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate. The method is provided.

[0208] In embodiment (27), the substrate 1 is H, 13 C, 15 N, 19 F, 31 P, 29 Si, or a combination thereof, and there is provided the method of embodiment 26.

[0209] In embodiment (28), the substrate further 2 contains D, and there is provided the method of embodiment 27.

[0210] (29) In aspect (29), there is provided a method according to aspect 27 or aspect 28, wherein the co-ligand is a compound containing one or more sulfoxide groups, thioester groups, phosphine groups, amine groups, CO groups, isonitrile groups, nitrogen-containing heterocyclic groups, or combinations thereof.

[0211] (30) In aspect (30), there is provided a method according to any one of aspects 26 to 29, wherein the solvent comprises water, methanol, ethanol, a fluorinated solvent, or a mixture thereof.

[0212] (31) In aspect (31), there is provided a method according to any one of aspects 26 to 29, wherein the solvent comprises a solvent selected from a perfluorohexane / diethyl ether mixture, a methoxynonafluorobutane and ethyl acetate mixture having 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, perfluoroalkane, perfluorohexane, and methoxynonafluorobutane.

[0213] (32) In aspect (32), there is provided a method according to any one of aspects 26 to 31, wherein the solvent is deuterated.

[0214] (33) In aspect (33), there is provided a method according to any one of aspects 26 to 32, wherein the co-ligand is dimethyl sulfoxide or phenyltrifluoromethyl sulfoxide.

[0215] (34) In aspect (34), there is provided a method according to any one of aspects 26 to 33, further comprising (vi) isolating the hyperpolarized substrate.

[0216] (35) In aspect (35), the hyperpolarized substrate is isolated by treating the reaction mixture with a solid-phase adsorbent to adsorb the perfluorinated SABRE catalyst and recovering the liquid containing the hyperpolarized substrate, where the liquid is free or substantially free of the perfluorinated SABRE catalyst, providing the method of aspect 34.

[0217] (36) Aspect (36) further includes passing a fluorophobic solvent over the adsorbent and recovering the eluate containing the hyperpolarized substrate, where the eluate is free or substantially free of the perfluorinated SABRE catalyst, providing the method of aspect 35.

[0218] (37) In aspect (37), the fluorophobic solvent includes water and one or more of methanol, ethanol, acetonitrile, and dimethylformamide, providing the method of aspect 36.

[0219] (38) Aspect (38) further includes passing a profluorophilic solvent over the adsorbent, providing the method of aspect 36 or aspect 37.

[0220] (39) In aspect (39), the profluorophilic solvent includes an organic solvent selected from methanol, ethanol, acetonitrile, THF, ethyl acetate, a chlorinated solvent, and combinations thereof, providing the method of aspect 38.

[0221] (40) In aspect (40), the hyperpolarized substrate is isolated by treating the reaction mixture with a solid-phase adsorbent to adsorb the hyperpolarized substrate and recovering the liquid containing the perfluorinated SABRE catalyst, where the liquid is free or substantially free of the hyperpolarized substrate, providing the method of aspect 34.

[0222] In embodiment (41), the method further comprises passing a parent fluorinated solvent over an adsorbent and recovering an eluate containing the perfluorinated SABRE catalyst, wherein the eluate contains no or substantially no hyperpolarized substrate, providing the method of embodiment 40.

[0223] In embodiment (42), the parent fluorinated solvent comprises 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, providing the method of embodiment 41.

[0224] In embodiment (43), the hyperpolarized substrate is isolated by liquid / liquid extraction, providing the method of embodiment 34.

[0225] In embodiment (44), the liquid / liquid extraction comprises partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanolic mixture and a fluorinated solvent, providing the method of embodiment 43.

[0226] In embodiment (45), the liquid / liquid extraction comprises partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanolic mixture and an organic solvent, providing the method of embodiment 43.

[0227] In embodiment (46), the hyperpolarized substrate is isolated by precipitating the perfluorinated SABER catalyst, filtering to remove the precipitated perfluorinated SABER catalyst from the hyperpolarized substrate, providing the method of embodiment 34.

[0228] In embodiment (47), the perfluorinated SABRE catalyst is precipitated by addition of water, providing the method of embodiment 46.

[0229] In aspect (48), the substrate is selected from ketoglutaric acid, pyruvic acid, N-acetylcysteine, and their salts or esters, and provides any one of the methods of aspects 26 to 47.

[0230] (49) In aspect (49), the substrate is 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 C-N-acetylcysteine, 15 N2-isoniazid (i.e., pyridyl-4-carbo-bis- 15 N2-hydrazide), 13 C2, 15 N3 metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), their deuterated versions, and their salts, and provides any one of the methods of aspects 26 to 48.

[0231] (50) In aspect (50), the substrate is of formula (II):

[0232]

Chemical formula

[0233] (wherein each R1 is 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; 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), or a pharmaceutically acceptable salt thereof, and provides any one of the methods of aspects 26 to 48.

[0234] (51) In aspect (51), there is provided a hyperpolarized substrate obtained from any one of the methods of aspects 26 to 50, or a pharmaceutically acceptable salt thereof.

[0235] (52) In aspect (52), there is provided a pharmaceutical composition comprising the hyperpolarized substrate of aspect 51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0236] (53) In aspect (53), there is provided a method for obtaining a magnetic resonance image of tissue in a subject, comprising administering to a subject having or suspected of having cancer or a harmful vascular condition the hyperpolarized substrate described in aspect 51 or the pharmaceutical composition described in aspect 52, and imaging the subject by magnetic resonance imaging.

[0237] (54) In aspect (54), there is provided the method of aspect 53, wherein the subject has cancer.

[0238] (55) In aspect (55), there is provided the method of aspect 54, wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer.

[0239] (56) In aspect (56), there is provided the method of aspect 53, wherein the harmful vascular condition is selected from myocardial infarction, stroke, and lung disease.

[0240] (57) In aspect (57), there is provided the method of aspect 56, wherein the lung disease is selected from COPD, pulmonary fibrosis, long-term COVID-19 symptoms, and combinations thereof.

[0241] (58) In aspect (58), formula (III):

[0242]

Chemical formula

[0243] (wherein, Each Ar is independently selected from a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, each Ar f is independently selected from a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group, each Y is independently selected from a bond or a spacer group, X is an anion, and

[0244]

Chemical formula

[0245] is a single bond or a double bond) provides a perfluorinated compound.

[0246] (59) In aspect (59), there is provided a perfluorinated compound of aspect 58, wherein each Ar is independently selected from a substituted or unsubstituted aromatic group.

[0247] (60) In aspect (60), there is provided a compound of aspect 58 or aspect 59, wherein each Ar f is independently selected from a perfluorinated substituted or unsubstituted aromatic group.

[0248] (61) In aspect (61), there is provided a perfluorinated compound of any one of aspects 58 to 60, wherein each Y is independently selected from a spacer group selected from C 1-5 alkyl and C 1-5 heteroalkyl.

[0249] (62) In aspect (62), the perfluorinated compound is of formula (IIIa):

[0250]

Chemical formula

[0251] (wherein, Each n is independently an integer from 0 to 4, X is an anion, and

[0252] [Chemical formula]

[0253] is a single bond or a double bond), provides a perfluorinated compound of embodiment 58.

[0254] (63) In embodiment (63), a method for preparing a perfluorinated compound according to any one of embodiments 58 to 62, the method comprising: (i) reacting an alpha-bromoketone containing a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group with an amidine containing a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group in the presence of a base to form an alpha-aminoketone; (ii) optionally reducing the alpha-aminoketone with a reducing agent to form an alpha-aminoalcohol, and (iii) cyclizing the alpha-aminoketone or the alpha-aminoalcohol to form a perfluorinated compound is provided.

[0255] (64) In embodiment (64), an olefin metathesis catalyst is provided, which comprises a d-block element and a perfluorinated compound according to any one of embodiments 58 to 62 as a ligand.

[0256] (65) In embodiment (65), a method for polymerizing an olefin is provided, the method comprising combining the olefin metathesis catalyst of embodiment 64 and an olefin in a reaction mixture.

[0257] The following examples further illustrate the invention, but of course should not be construed as in any way limiting its scope.

Examples

[0258] Example 1 This example illustrates a method for preparing 1H,1H,2H,2H-perfluorooctyl-N,N'-bis(2,4,6-trimethylphenyl)-9,10-diamine:

[0259] [Chemical formula]

[0260] (where x = 6 and y = 13).

[0261] A 1.7 M solution of tert-butyllithium in pentane (5 mL, 9 mmol, 8 equivalents) was added to a solution of 1H,1H,2H,2H-perfluorooctyl chloride (2 g, 4 mmol, 4 equivalents) in dry Et2O (60 mL). The mixture was stirred at -78 °C for 20 minutes, and then solid N,N'-dimethyl ethanediamine (0.30 g, 1.03 mmol, 1 equivalent) was added portionwise. The reaction mixture was stirred for 4 hours. The reaction was warmed slowly to -30 °C and quenched with a saturated solution of ammonium chloride (0.6 mL).

[0262] 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 the diamine, diimine, and threo-diamine (0.6 g, 60% yield, white solid). 1 H NMR (400 MHz, CDCl3) δ 1.64 - 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= 10 Hz, 2H, CH), 6.82 (s, 4H, Ar-CH) ppm. 19 19F NMR (282.23 MHz, CDCl3) δ -83.8 (t, 3 J F-F = 10 Hz, 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 13C NMR (400 MHz, CDCl3) δ 18.3 (o-CH3), 20.3 (p-CH3), 21.7 (m, CF2CH2CH2), 29.2 (t, 2 J F-C = 22.2 Hz, CF2CH2), 57.1 (CH), 107 - 115 (m, 8CF2), 117.4 (qt, 1 J F-C = 288.3 Hz, 2 J F-C = 33.3 Hz, CF3), 118.7 (tt, 1 JF-C = 255.1 Hz, 2 JF-C = 31.0 Hz, 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).

[0263] Example 2 This example illustrates 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:

[0264] [Chemical formula]

[0265] is exemplified.

[0266] A mixture of 1H,1H,2H,2H-perfluorooctyl-N,N'-bis(2,4,6-trimethylphenyl)-9,10-diamine (0.250 g, 0.25 mmol), 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 hours. After cooling to room temperature, the solution was evaporated and the solid was triturated with diethyl ether (6 × 3 mL). The residue was redissolved in acetone, filtered, and concentrated to give dihydroimidazolium tetrafluoroborate. (0.2 g, 70% yield, yellowish solid). 1 H NMR (400 MHz, acetone-d6) δ 2.15 - 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 = 10 Hz, 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) δ 17.4 (o-CH3), δ 17.7 (o-CH3), 19.9 (p-CH3), 24.4 (m, CF2CH2CH2), 26.2 (t, 2 J F-C = 22.2 Hz, CF2CH2), 67.9 (CH), 105 - 118 (m, 8CF2), 118 (qt, 1 J F-C = 288.3 Hz, 2 J F-C = 33.3 Hz, CF3), 118.9 (tt, 1 JF-C = 254 Hz, 2JF-C = 31.0 Hz, 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 (N-C=N) ppm. MS (ESI) m / z (%): 999 [M+H] + (100).

[0267] Example 3 This example illustrates 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:

[0268]

Chemical formula

[0269] The synthesis of is exemplified.

[0270] Dihydroimidazolidium tetrafluoroborate salt (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 via TLC under UV. The solvent was removed and the resulting yellowish solid was dried with a vacuum pump to obtain the product (0.48 g, 99%). 1 1H NMR (400 MHz, acetone-d6) δ 2.15 - 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 19F NMR (400 MHz, acetone-d6) δ -81.8 (t, 4 J F-F= 10 Hz, 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 13C NMR (400 MHz, acetone-d6) δ 17.4 (o-CH3), δ 17.7 (o-CH3), 19.9 (p-CH3), 24.4 (m, CF2CH2CH2), 26.2 (t, 2 J F-C = 22.2 Hz, CF2CH2), 67.9 (CH), 105 - 118 (m, 8CF2), 118 (qt, 1 J F-C = 288.3 Hz, 2 J F-C = 33.3 Hz, CF3), 118.9 (tt, 1 JF-C = 254 Hz, 2 JF-C = 31.0 Hz, 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 (N-C=N) ppm. MS (ESI) m / z (%) : 999 [M+H] + (100).

[0271] Example 4 This example illustrates a method for synthesizing a fluorinated SABRE catalyst containing a transition metal according to one aspect of the present invention.

[0272] [Chemical formula]

[0273] 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) from Example 3 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 give the crude product, which was dried under vacuum overnight. This sample was dissolved in hexane and added to a 60 mL filter packed with SiO2 gel in hexane. The crude solution was adsorbed on top of the silica gel and then hexane was added to elute the compound, giving 104 mg (40% yield). 1 1H NMR (400 MHz, CDCl3) δ 1.04, 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 6.97 ppm. 19 19F NMR (400 MHz, CDCl3) δ -81.08, -114.33, -122.05, -123.07, -124.02, -126.39 ppm. 13 13C NMR (100 MHz, CDCl3) δ 18.7, 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, 206.72 ppm. MS (ESI) m / z (%): 1299 [M+H] + (100).

[0274] Example 5 This example illustrates a method for hyperpolarizing [1- 13 C] pyruvic acid according to one aspect of the present invention shown in Scheme 1.

[0275] Scheme 1. Hyperpolarization of [1- 13 C] pyruvic acid using phenyltrifluoromethyl sulfoxide as a co-ligand.

[0276]

Chemical formula

[0277] (In the formula, co-ligand = phenyltrifluoromethyl sulfoxide)

[0278] In the above reaction scheme, the hyperpolarization of [1- 13 C] pyruvic acid was carried out using the co-ligand approach developed by Duckett and colleagues (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)) 13 and adjusted for 13C nuclei (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017)) SABER 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)). Sodium [1- 13 C]-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 for this example was prepared according to Example 4. The active catalyst used in this example was 0.6 mL of methanol-d in a 5 mm NMR tube 4Prepared using a fixed ratio of substrate to the Ir(F-IMes)SABRE catalyst of Example 4 and phenyltrifluoromethyl sulfoxide (PTFSO) in the medium.

[0279] Para-hydrogen was generated using a Gas-Delivery Manifold. Ultra-high purity hydrogen gas (Airgas) was supplied into a para-hydrogen flow cryostat (Xeus technology LTD) and concentrated to approximately 50% para-hydrogen at liquid nitrogen temperature (77K) in the presence of a spin-exchange catalyst (Fe2O3). The flow of p-H2 was set to 90 scc / m via a PTFE tube through a mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) and directed towards a conventional 5 mm NMR tube (Norell) to enable bubbling through the sample. The entire pH2 line was pressurized to 100 psi.

[0280] The magnetic shielding conditions are as follows. A magnetic field of around 1 μT or below was achieved with a device consisting of a solenoid coil placed inside a mu-metal shield (Magnetic Shield Corporation, model number ZG-206). The shield was demagnetized using an internal self-made coil driven by a Variac when necessary. The solenoid had a diameter of 41 mm (a 40 mm core, 220 turns of AWG20 (0.9 mm) Cu wire and a 20 cm length of winding with a 220 Ω resistor in series. The solenoid coil was driven by a commercially available 1.5 V battery with a variable resistance decay box in series to provide finer control of the internal magnetic field inside the shield. Typical values of the magnetic field inside the shield were between ±1.2 μT, and SABRE SHEATH experiments were typically between -0.7 μT and +0.8 μT in the sample region. The values were monitored between SABRE experiments using a Lakeshore Cryotronics Gaussmeter (model number 475 DSP with an HMMA-2512-VR Hall Probe).

[0281] The MR experiments were carried out using a 1T Magritek Spinsolve benchtop NMR spectrometer. All 13 13C NMR spectra were acquired with 1H decoupling off throughout the course of the experiment. The time required to manually transfer the sample from the shielded region to the magnet for low-field NMR acquisition was typically less than 5 seconds. 1 The time required to manually transfer the sample from the shielded region to the magnet for low-field NMR acquisition was typically less than 5 seconds.

[0282] Efficient hyperpolarization transfer from the hydride of p-H2 in the generation period to the 13C nucleus of [1- 13 13C] pyruvic acid was achieved by using SABRE in a submicrotesla magnetic field and SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) using a solution mixture of [IrCl(H)2(PTFSO)2(F-IMes)], [1- 13 13C] pyruvic acid) and p-H2. Figure 6 shows, in the upper curve, the single-scan HP13C spectrum obtained for the hyperpolarized probe. The lower curve shows the single-scan thermal polarization 13C signal from 4M [1- 13 13C] sodium acetate using the same acquisition parameters. The enhancement is approximately ε = 9000, and the polarization is approximately P(13C) = 1%. 13 13C spectrum obtained for the hyperpolarized probe. The lower curve shows the single-scan thermal polarization 13C signal from 4M [1- 13 13C] sodium acetate using the same acquisition parameters. The enhancement is approximately ε = 9000, and the polarization is approximately P(13C) = 1%. 13 13C) = 1%. 13 13C) = 1%.

[0283] All experiments were performed using a solution containing a fluorinated catalyst, a co-ligand (phenyltrifluoromethyl sulfoxide), and [1- 13 13C] pyruvic acid in 0.6 mL of CD3OD. The ratios and concentrations can be further adjusted to achieve better enhancement and polarization. The results were obtained with 8 mM fluorinated catalyst, 16 mM phenyltrifluoromethyl sulfoxide (PTFSO), and 30 mM [1- 13C] pyruvate was obtained. The experiment was carried out at room temperature, a p-H2 flow rate of about 100 scc / m and a p-H2 overpressure of 96 PSI. The para-hydrogen used in this example was generated from a low-cost 50% p-H2 generator. For each experiment, p-H2 bubbling was applied for about 1 minute, and the sample was quickly transferred to a 1T NMR spectrometer for detection, and then the sample was returned to a mu-metal shield and p-H2 bubbling was continued for the next experiment. 13 The enhancement of the C signal is given by Equation 1:

[0284] [Number]

[0285] (where S HP and S REF are the 13 C signals from HP [1- 13 C] pyruvate and the thermal signal reference [1- 13 C] acetic acid, and C REF and C HP are the concentrations of the thermal signal reference [1- 13 C] acetic acid (4M) and HP [1- 13 C] pyruvate, respectively, and A REF and A HP are the effective cross-sectional areas of the NMR tubes for the thermal signal reference [1- 13 C] acetic acid sample and the HP [1- 13 C] pyruvate sample), respectively. The HP signal curve area under the curve (AUC) was calculated by comparing it with an external 13 C signal thermal signal reference (4M [1- 13 C] sodium acetate).

[0286] Example 6 This example illustrates a method for hyperpolarizing [1- 13 C] pyruvate according to one aspect of the present invention as shown in Scheme 2.

[0287] Scheme 2. Using the perfluorinated SABRE catalyst of Example 4 having dimethyl sulfoxide as a co-ligand [1- 13 C] hyperpolarization of pyruvic acid.

[0288]

Chemical Structure

[0289] In the reaction scheme above, [1- 13 C] hyperpolarization of pyruvic acid was performed using the co-ligand approach developed by Duckett and colleagues (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)) 13 and adjusted for 13C nuclei (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017)) SABER 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- 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 for this example was prepared according to Example 4. The active catalyst used in this example was a fixed ratio of substrate [1- 4 C] pyruvic acid, the Ir(F-IMes) SABRE catalyst of Example 4, and the co-ligand dimethyl sulfoxide (DMSO) in 0.6 mL of methanol-d 13 in a 5 mm NMR tube.

[0290] Para-hydrogen concentrated to about 70 to 95% was used and introduced into an NMR tube (Norell) with a 5 mm mid-wall through a PTFE tube into a mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) set between 50 and 120 scc / m to enable bubbling through the sample. The entire pH2 line was pressurized to a value between 50 psi and 110 psi.

[0291] The polarization transfer magnetic field was established as follows. A magnetic field of about 1 μT or less was achieved with a device consisting of a solenoid coil placed inside a three-layer mu-metal shield (6-inch inner diameter & 15-inch length, part number ZG-206, Magnetic Shield Corp., Bensenville, IL). The magnetic field was created using a custom-built solenoid coil and a triple independent channel DC power supply (KEITHLEY 2231A-30-3). The solenoid had a diameter of 41 mm (a 40 mm core, 220 turns of AWG20 (0.9 mm) Cu wire and a 20 cm length of winding with a 220 Ω resistor in series. The solenoid coil was driven with a decade box of variable resistors in series to provide finer control of the internal magnetic field inside the shield. Typical values of the magnetic field inside the shield were between ±1.2 μT, and the SABRE SHEATH experiments were typically between -0.7 μT and +0.8 μT in the sample region.

[0292] The MR experiments were carried out using an 80 MHz Magritek Spinsolve benchtop NMR spectrometer. The following acquisition parameters were used: Spectral width (SW) = 5 kHz; Dwell time (DT) = 150 μs; Number of scans (ns) = 1, Receiver gain = 16; Excitation pulse angle (a) = 90°; 13 C resonance frequency = 20.25232790 MHz.

[0293] All 13 C NMR spectra were acquired with 1H decoupling off throughout the course of the experiment. The time required to manually transfer the sample from the shielded region to the magnet for low-field NMR acquisition was typically less than 5 seconds. 1 The hyperpolarization transfer from the hydrogen of p-H2 to the 13C nucleus of [1-13C] pyruvate was achieved by using SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) with a solution mixture of [IrCl(H)2(DMSO)2(F-IMes)], [1-13C] pyruvate, co-ligand (dimethyl sulfoxide), and p-H2 in 0.5 mL of deuterated or non-deuterated methanol in a sub-microtesla magnetic field.

[0294] from iridium hydride derived from p-H2 to [1- 13 13C] pyruvate 13 The enhancement of the 13C signal is given by the formula: 13 (where S

[0295] 13 and S

[0296]

Number

[0297] are the 13C signals from HP [1- HP and S REF is the thermal signal reference [1- 13 13C] acetate, and C 13 is the concentration of thermal signal reference [1- 13 13C] acetate and C REF is the concentration of HP [1- HP 13C] pyruvate, and A 13 and A 13 are the areas of the thermal signal reference [1- REF 13C] acetate sample and HP [1- HP 13C] pyruvate sample, respectively, and 13 13C] acetate sample and HP [1- 13The area under the HP signal curve (AUC) was calculated using the external 13 C signal heat signal reference (4M [1- 13 C] sodium acetate). 13 Percentage of C polarization (%P 13 C ) is expressed by formula S2:(%P 13 C ), =ε 13 C *1.56181*10 -6 *Signal enhancement (ε 13 C ) at 1.81T 13 C nuclear spin polarization (1.5681*10 -4 %).

[0298] The activation of the fluorinated SABRE catalyst is shown in Figure 7. 13 C polarization fraction, which took less than 15 min and was carried out by bubbling approximately 95% p-H2 at a flow rate of 90 standard cubic centimeters per minute (scc / m) and a p-H2 partial pressure of 8 atm, leading to the formation of complex 2, complex 3a, complex 3b, and pyruvate, as shown in Figure 8, consistent with the notation introduced by Duckett and co-workers (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275(2019)). While not wishing to be bound by any particular theory, it is believed that complex 3B is the primary SABRE active species.

[0299] Example 7 This example shows the effect of the [1- 13 We demonstrate the effect of [1-C]pyruvate on the hyperpolarization of the fluorinated cations, as well as the effects of the magnetic transfer field, temperature, and the concentrations of the fluorination catalyst and DMSO. 13 The relaxation dynamics of [C]pyruvate was also studied.

[0300] [1-13 The hyperpolarization of pyruvate was repeated using SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) as described in Example 6 above, and the effects of the para-hydrogen pressure and flow rate, as well as the effects of the magnetic transfer field, temperature, and the concentration of the fluorinated catalyst and DMSO were studied.

[0301] The p-H2 parameters such as pressure and flow rate were evaluated, and the results of the polarization ratio are described in FIGS. 9A and 9B. 30 mM [1- 13 The NMR sample contained in 30 mM [1- C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst, and 40 mM dimethyl sulfoxide (DMSO), the mixed magnetic field was 0.4 μT and the temperature was 0 °C. As is clear from the results described in FIGS. 9A and 9B, as the flow rate and pressure of para-hydrogen increased, the polarization ratio also increased.

[0302] The temperature and magnetic field in the microtesla region were evaluated, and the 13C polarization level and the polarization transfer magnetic field at 0 °C are described in FIGS. 10A and 10B, respectively. 30 mM [1- 13 The NMR sample contained in 30 mM [1- C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst, and 40 mM dimethyl sulfoxide (DMSO), p-H2 flow and pressure 70 scc / m and 100 PSI. As is clear from the results described in FIGS. 10A and 10B, the best polarization transfer occurs at a temperature between -20 °C and 5 °C and a mixed magnetic field between 0.3 μT and 0.5 μT. The optimal temperature is -7.24 °C, and the optimal mixed magnetic field is 0.4 μT.

[0303] The perfluorinated SABRE catalyst and DMSO concentration were evaluated at a temperature of 0 °C, a magnetic field of 0.4 μT, a p-H2 flow of 90 scc / m, and a p-H2 pressure of 110 PSI, and the polarization ratios are described in FIGS. 11A and 11B. As is clear from the results described in FIG. 11A, the polarization ratio increases as the perfluorinated SABRE catalyst concentration increases. However, the polarization ratio remains relatively stable at concentrations above 20 mM.

[0304] As is clear from the results described in FIGS. 12A and 12B, the relaxation kinetics of [1- 13 C]-pyruvate show that the total P 13C (bound + free) enhancement time (T b = 6.6 ± 3.0 seconds) is significantly shorter than the corresponding T1 value of 16.1 ± 0.9 seconds, which enables reaching a P 13C level of up to 13.48%. Furthermore, the relaxation kinetics at the Earth's magnetic field and at 1.8 T are approximately the same as those of the non-fluorinated SABRE catalyst T1 = 28.9 ± 1.6 seconds and 66.5 ± 7 seconds, respectively.

[0305] Simultaneous exchange of p-H2 and [1- 13 C] pyruvate on the activated Ir(F-IMes) catalyst leads to an enhancement of 13 C hyperpolarization. In that regard, FIG. 13 shows an approximately 86,500-fold signal enhancement ε corresponding to approximately 13.48% P 13C of the NMR signal intensity compared to the reference sample, of 13 C-hyperpolarized [1- 13 C]-pyruvate. A representative spectrum of 13 C-hyperpolarized [1-

[0306] The temperature is [1- 13C] has a great influence on the exchange rate of pyruvic acid. In recent studies, Adelabu et al. (ChemPhysChem, 23, e202100839 (2022)) showed that the monotonic disappearance of 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- 13 C] The exchange with the polarization transfer complex of pyruvic acid is faster, leading to the overpolarization of both the free species and the bound 3b species at the expected pyruvic acid: precatalyst ratio. To rapidly release HP pyruvic acid from 3b, the HP solution was rapidly warmed and then the sample was inserted into the NMR detector (TomHon 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. 25 mM [1- 13 C] Sodium pyruvate, 6 mM perfluorinated SABRE catalyst, and an NMR sample (in deuterated methanol) contained in 47 mM dimethyl sulfoxide (DMSO), where the mixed magnetic field is 0.4 μT, and the para-hydrogen pressure and flow rate are set to 110 PSI and 90 scc / m, respectively.

[0307] As demonstrated by Figure 14, the exchange rate of complex 3b to the free state is faster even at low temperatures such as -10 °C, where most of the HP [1- 13 C] pyruvic acid is in the free state. 13 By lowering the temperature of the C SABRE-SHEATH to 0 °C, the maximum value of P 13C is achieved. The exchange remains fast enough to preferentially enhance the "free" HP [1- 13 C] pyruvic acid over complex 3b.

[0308] Example 8 This example illustrates an exemplary method for isolating hyperpolarized [1- 13 C] sodium pyruvate, including extraction and filtration.

[0309] [1- 13The hyperpolarization of sodium pyruvate was carried out using dimethyl sulfoxide (DMSO) as a co-ligand, the [IrCl(COD)(F-IMes)] SABRE catalyst, and parahydrogen concentrated to about 70 to 95% in deuterated methanol-d4 solvent as described in Examples 6 and 7. 13 It was carried out using SABRE (SABRE-SHEATH) in SABRE in SHield Enabled Alignment Transfer to Heteronuclei tuned for 13C nuclei. The SABRE sample was prepared in 0.5 mL CD3OD using 30 mM [1- 13 C] sodium pyruvate, 2.6 mM of the perfluorinated SABRE catalyst of Example 4, and 35 mM dimethyl sulfoxide (DMSO). The parahydrogen flow rate was established at 90 scc / m and pressurized to 8 bar, the mixing magnetic field was 0.4 μT, and the temperature was 0 °C.

[0310] After the hyperpolarization procedure was complete, the sample was quickly removed from the 0.40 μT magnetic 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 into a 1 mL plastic syringe attached to a Luer lock filter (Waters Oasis Prime HLB Plus Light Cartridge (part number: 186008866)), and the aqueous solution was led through the filter into a 5 mm NMR tube already positioned in an adjacent 1.8 T benchtop NMR spectrometer. The whole procedure took about 1.15 to 1.30 minutes, and no 13C signal was observed in any of the samples. The relaxation studies presented above indicate that the [1- 13 C]-T1 relaxation time of pyruvate in the Earth's magnetic field was substantially shorter (e.g., [1- 13 C]-T1 = 28.9 ± 1.6 s in the Earth's magnetic field). Automation and faster solution transfer should enable the observation of the HP [1- 13 C]-pyruvate signal in aqueous solution. 13 C]-pyruvate signal in aqueous solution.

[0311] Example 9 This example illustrates an exemplary method for isolating hyperpolarized [1- 13 C] sodium pyruvate, which involves extraction by precipitation using an organic solvent.

[0312] The precipitation and redissolution of HP [1- 13 C] pyruvic acid, which occurs in the same NMR tube as hyperpolarization, were performed (Schmidt et al., ACS Sensors, 7(11), 3430 - 3439(2022)). The SABRE sample was prepared in CD3OD using [1- 13 C] sodium pyruvate between 20 mM and 30 mM, 7.5 mM fluorinated SABRE catalyst, and 50 mM dimethyl sulfoxide (DMSO) as described in Examples 6 and 7. 100 μL of this solution was transferred into 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 inside a three-layer mu-metal with an inner diameter of 3’’ and a depth of 9’’ to shield the external magnetic field in combination with a custom-made solenoid, generating a static magnetic field B0 of 0.4 μT. The NMR tube was pressurized while bubbling p-H2 through the solution at a flow rate of 90 scc / m (110 psi, i.e., a total pressure of about 8 bar) to activate the catalyst and 13 C] sodium pyruvate solution was 13 C hyperpolarized. The activation of the catalyst was performed for 15 minutes at ambient temperature and magnetic field. For polarization enhancement, the sample was placed in a static magnetic field (typically about 0.4 μT) and a water bath, and the reaction temperature was adjusted to 0 °C. After polarization, the NMR tube was quickly transferred inside a 1.8 T NMR spectrometer and kept at room temperature. The precipitation of pyruvic acid was carried out by adding 400 μL of ethyl acetate (EtOAc) to the HP solution after decompression, and redissolved by adding 300 μL D2O to reconstitute pyruvic acid in water.

[0313] The NMR spectra were acquired immediately after reconstitution in water using a 1.8 T benchtop NMR and the results are depicted in the spectra above Figure 15. Further, the spectrum below Figure 15 shows the single scan thermal polarization 13 13C signal from 4 M sodium acetate. 13 The 13C signal is shown.

[0314] Furthermore, 13 the 13C-pyruvate concentration was determined by LCMS using a calibration curve for the naturally occurring isotope pyruvate. The pyruvate aqueous samples were further analyzed for iridium elemental content by ICP-MS (inductively coupled plasma multi-element scan) after the reconstituted SABRE-SHEATH method. The iridium content was determined to be only from about 150 ppb to about 300 ppm.

[0315] Example 10 This example illustrates a method for the synthesis of 2,2,2-trifluoro-N-(4-iodo-2,6-dimethylphenyl)acetamide:

[0316]

Chemical formula

[0317] is exemplified.

[0318] 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. The excess iodine was destroyed by the addition of 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 solution of sodium thiosulfate. The organic phase was evaporated to dryness in vacuo to give the product as a brown oil which solidified slowly under vacuum.

[0319] Hexane was added to dissolve the product, and the solution was filtered through celite and evaporated to dryness under vacuum. Further purification was not necessary. 1 1H NMR (400 MHz, CDCl3): δ = 7.14 (s, 2H), 4.45 (s, 2H), 2.04 (s, 6H).

[0320] Example 11 This example illustrates the method for 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:

[0321] [Chemical formula]

[0322] as an example.

[0323] In a glove box, palladium(II) acetate (0.16 g, 0.051 equiv, 0.71 mmol), sodium acetate (1.72 g, 1.50 equiv, 21.0 mmol), tricyclohexylphosphane (660 mg, 0.168 equiv, 2.35 mmol), tetrabutylammonium bromide (30 mg, 0.0067 equiv, 93 μmol) and 2,2,2-trifluoro-N-(4-iodo-2,6-dimethylphenyl)acetamide (4 g, 0.8 equiv, 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 equiv, 14.0 mmol) was added to the reaction mixture and heated to 120 °C. The solution was stirred for 19 h. 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 layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to give the crude product. Purification by column chromatography (hexane / DCM 4:1) gave 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, which was further crystallized (5 g, 70%, white needles).

[0324] Example 12 This example illustrates 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:

[0325] [Chemical formula]

[0326] as an example.

[0327] 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) in a glass autoclave was added 10% Pd / C (0.08 g, 0.07 mmol). The autoclave was evacuated and filled with hydrogen gas up 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.

[0328] Example 13 This example illustrates 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:

[0329]

Chemical formula

[0330] as an example.

[0331] 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 with sodium hydroxide (0.10 g, 250 mmol), and the reaction mixture was heated at 110 °C for 21 h. 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 solution of HCl (4 mL), saturated solution of NaHCO3 (4 mL), and brine (4 mL). The aqueous phase was neutralized and extracted with ethyl acetate (3×4 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).

[0332] Example 14 This example illustrates 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-diamine:

[0333] [Chemical formula]

[0334] as an example.

[0335] 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 a 40% aqueous solution of glyoxal (0.1 mL, 1 mmol) and a catalytic amount of formic acid (few drops). The reaction mixture was stirred at room temperature for 20 h during which a yellow precipitate formed. The solid was filtered and washed with cold ethanol (3 x 5 mL) to give neat 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).

[0336] Example 15 This example illustrates 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:

[0337] [ka]

[0338] The synthesis of the compound is illustrated below.

[0339] A flask was charged with 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). The mixture was cooled to 0° C. and a suspension of paraformaldehyde (262 mg, 2.91 mmol) and concentrated HCl (112 mg, 3.12 mmol) in dioxane (0.78 mL) was added slowly. The mixture was heated to reflux overnight. Purification was carried out by column chromatography. 11H NMR (400 MHz, CDCl3) δ 2.07, 2.55, 2.92, 7.37, 8.28, 9.65. MS (ESI) m / z (%): 1168.8 [M-TFA] + (100).

[0340] Example 16 This example illustrates the synthesis of a fluorinated SABRE catalyst according to one aspect of the present invention.

[0341] [Chemical formula]

[0342] Potassium tert-butoxide (2.5 equivalents) was added 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-ide, chloride (2.2 equivalents) in tetrahydrofuran at room temperature in a glove box. The resulting suspension was stirred for 30 minutes. A solution of [Ir(COD)Cl]2 (1.0 equivalent) was added and the resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain a crude product, which was dried under vacuum overnight. This sample was purified by flash chromatography on DCM / hexane (4:1) to obtain a fluorinated SABRE catalyst. MS (ESI) m / z (%): 1469 [M-Cl] + (100).

[0343] Example 17 This example illustrates the hyperpolarization of sodium pyruvate using the SABRE catalyst according to one aspect of the present invention shown in Scheme 3.

[0344] Scheme 3. Hyperpolarization of [1- 13 C] pyruvic acid using the perfluorinated SABRE catalyst of Example 16 having dimethyl sulfoxide as a co-ligand.

[0345] [Chemical formula]

[0346] In the above reaction scheme, from the hydride derived from p-H2 to [1- 13 C] pyruvic acid 13 The efficient hyperpolarization transfer to the 13C nuclear spin was achieved by using SABRE in a sub-microtesla magnetic field and SABER in SHIeld Enables Alignment Transfer (SABRE-SHEATH) using a mixed solution of [IrCl(H)2(DMSO)2(F-IMes)], [1- 13 C] pyruvic acid) and p-H2.

[0347] The SABRE sample was prepared in CD3OD using 40 mM sodium [1- 13 C] pyruvate, 6.6 mM of the perfluorinated SABRE catalyst of Example 16, and 50 mM dimethyl sulfoxide (DMSO). The SABRE sample was exposed to SABRE-SHEATH hyperpolarization conditions having the same setup and optimal conditions as described in Examples 6 and 7. The NMR tube was pressurized while bubbling p-H2 through the solution at a flow rate of 90 scc / m (110 psi, i.e., a total pressure of about 8 bar) to activate the catalyst and hyperpolarize the [1- 13 C] sodium pyruvate solution. 13 13C hyperpolarization was performed. The activation of the catalyst was carried out for 15 minutes at ambient temperature and magnetic field. For polarization enhancement, the sample was placed in a magnetic field (typically about 0.4 μT) and a water bath at 5 °C to adjust the reaction temperature. The spectrum was acquired immediately after manually transferring the sample to a 1.8 T benchtop NMR 5 seconds later, and the results are described in the spectrum above in Figure 16. Further, the spectrum below in Figure 16 shows the single-scan thermal polarization 13C signal from 4 M sodium [1- 13 C] acetate using similar acquisition parameters. 13 As is clear from the results described in Figure 16, the signal enhancement is ε about 16900, and the polarization is approximately P( 13C) It is about 2.17%.

[0348] Example 18 This example illustrates the method for 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:

[0349] [Chemical formula]

[0350] of.

[0351] 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), tricyclohexylphosphane (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 heated to 120 °C. The solution was stirred for 19 h. 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 layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to give the crude product. Purification by column chromatography (hexane / DCM 4:1) gave fluoroamide 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, which was further crystallized (5 g, 70%, white needles).

[0352] Example 19 This example illustrates the synthesis of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)aniline:

[0353]

Chemical formula

[0354] is exemplified.

[0355] A solution 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 (0.14 g, 250 μmol) in n-butanol (1.5 mL) was added with sodium hydroxide (0.10 g, 250 mmol), and the reaction mixture was heated at 110 °C for 21 h. 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 solution of HCl (4 mL), saturated solution of NaHCO3 (4 mL), and brine (4 mL). The aqueous phase was neutralized and extracted with ethyl acetate (3 × 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).

[0356] Example 20 This example illustrates 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-diamine:

[0357] [Chemical formula]

[0358] as an example.

[0359] 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 a 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 h, during which a yellow precipitate formed. The solid was filtered and washed with cold ethanol (3 × 5 mL) to afford pure 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-diamine (0.2 g, 20%, yellow powder).

[0360] Example 21 This example illustrates 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-ide, chloride salt:

[0361]

Chemical formula

[0362] is exemplified.

[0363] To a flask were added 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-diamine (2.40 g, 2.08 mmol) and tetrahydrofuran (80 mL). The mixture was cooled to 0 °C and a suspension of paraformaldehyde (262 mg, 2.91 mmol) and concentrated HCl (112 mg, 3.12 mmol) in dioxane (0.78 mL) was added slowly. The mixture was heated to reflux overnight. Purification was carried out by column chromatography. 1 1H NMR (400 MHz, CDCl3) δ 2.27, 6.71, 7.32, 7.36, 7.67, 8.16, 9.59 ppm. 1919F NMR (400 MHz, CDCl3) δ -82.43, -112.52, -122.59, -123.89, -124.17, -127.33 ppm. MS (ESI) m / z (%): 964.8 [M+H] + (100).

[0364] Example 22 This example illustrates the synthesis of a fluorinated SABRE catalyst according to one aspect of the present invention.

[0365]

Chemical Structure

[0366] Potassium tert-butoxide (2.5 equiv) was added 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-ide, chloride (2.2 equiv) in tetrahydrofuran at room temperature in a glove box. The resulting suspension was stirred for 30 minutes. A solution of [Ir(COD)Cl]2 (1.0 equiv) was added and the resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give a crude product, which was dried under vacuum overnight. This sample was purified by flash chromatography on DCM / hexane (4:1) to give the fluorinated SABRE catalyst. MS (ESI) m / z (%): 1266 [M-Cl] + (100).

[0367] Example 23 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.

[0368] Scheme 4. Hyperpolarization of [1- 13 13C]pyruvic acid using a perfluorinated SABRE catalyst having dimethyl sulfoxide as a co-ligand.

[0369]

Chemical Structure

[0370] In the reaction scheme above, efficient hyperpolarization transfer from the hydride derived from p-H2 to the 13 13C nucleus of pyruvic acid was achieved by using SABRE and SABER in SHIeld Enables Alignment Transfer (SABRE-SHEATH) in a sub-microtesla magnetic field with a mixed solution of [IrCl(H)2(DMSO)2(F-IMes)], 13 13C]pyruvic acid), and p-H2 in deuterated methanol. 13 The SABRE sample was prepared in CD3OD using 20 mM

[0371] 13C]sodium pyruvate, 7.6 mM of the perfluorinated SABER catalyst shown in Scheme 4, and 50 mM dimethyl sulfoxide (DMSO) as described in Examples 6 and 7. The SABRE sample was 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 while bubbling p-H2 through the solution at a flow rate of 90 scc / m (110 psi, i.e., a total pressure of about 8 bar) to activate the catalyst and 13 hyperpolarize the 13 13C]sodium pyruvate solution. The activation of the catalyst was carried out at ambient temperature and magnetic field for about 15 minutes. For polarization enhancement, the sample was placed in a magnetic field (typically about 0.4 μT) and a water bath at 5 °C to adjust the reaction temperature. The spectra were acquired immediately after manually moving the sample to a 1.8 T benchtop NMR 5 seconds later, and the results are described in the spectrum above in Figure 17. Further, the spectrum below in Figure 17 shows the single-scan thermal polarization 13 13C signal from 4 M 13 13C]sodium acetate using similar acquisition parameters. As is clear from the results described in Figure 17, the signal enhancement is ε about 19000, and the polarization is approximately P( 13 13C).13 C) is about 4.91%.

[0372] Example 24 This example illustrates a method for hyperpolarizing [1- 13 C] pyruvic acid according to one aspect of the present invention using a fluorinated mixture instead of deuterated methanol alone.

[0373] The hyperpolarization procedure of Example 6 was repeated using a mixture of nonafluorobutyl methyl ether (NFBME) and deuterated methanol instead of deuterated methanol alone.

[0374] Activation of the fluorinated SABRE catalyst takes less than 25 minutes at the 13 C polarization rate and is carried out 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. The NMR sample was at a mixed magnetic field of 0.4 μT and a temperature of 0 °C and contained about 25 mM [1- 13 C] sodium pyruvate, 7.4 mM of the perfluorinated SABRE catalyst of Example 4, and 40 mM dimethyl sulfoxide (DMSO) in 0.3 mL NFBME and 0.2 mL MeOD.

[0375] Example 25 This example demonstrates the effect on the hyperpolarization of [1- 13 C] pyruvic acid in a fluorinated mixture shown by changes in the pressure and flow rate of parahydrogen, as well as the effect of the magnetic transfer field. Furthermore, the relaxation kinetics of [1- 13 C] pyruvic acid were also studied.

[0376] [1- 13 C] pyruvic acid hyperpolarization was repeated using SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) as described in Example 24 above, and the effect of the parahydrogen flow rate and the effect of the magnetic transfer field were studied.

[0377] The p-H2 flow rate was evaluated, and the results of the polarization ratio are shown in Figure 19. The NMR sample was about 22 mM [1- 13 C] sodium pyruvate, 7.4 mM of the perfluorinated SABRE catalyst of Example 4, and 45 mM dimethyl sulfoxide (DMSO) in 0.3 mL NFBME and 0.2 mL MeOD at a mixed magnetic field of 0.4 μT and a temperature of 0 °C. As is clear from the results shown in Figure 19, as the flow rate of para-hydrogen increased, the polarization ratio also increased.

[0378] The magnetic field in the microtesla region was evaluated, and the 13 C polarization transfer magnetic field at 0 °C is shown in Figure 20. The NMR sample contained 22 mM [1- 13 C] sodium pyruvate, 7.4 mM of the perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO) in 0.2 mL NFBME and 0.2 mL MeOD. The flow rate and pressure of p-H2 were 50 ssc / m and 110 PSI, respectively. As is clear from the results shown in Figure 20, the best polarization transfer occurs at a mixed magnetic field between 0.3 μT and 0.5 μT. The optimal mixed magnetic field is 0.4 μT.

[0379] As is clear from the results shown in Figures 21A and 21B, the relaxation kinetics of [1- 13 C]-pyruvic acid show that the total P 13C (bound + free) enhancement time (T b = 3.0 ± 0.8 s) is significantly shorter than the corresponding T1 value of 11.3 ± 1.3 s, which enables reaching a P 13C level of up to 6.02%. Furthermore, the relaxation kinetics at the Earth's magnetic field and 1.8 T are approximately the same as those of the non-fluorinated SABRE catalyst T1 = 9.0 ± 1.9 s and 16.0 ± 1.4 s, respectively.

[0380] The simultaneous exchange of p-H2 and [1- 13 C] pyruvic acid on the activated Ir(F-IMes) catalyst is 13This leads to an enhancement of C hyperpolarization. In that regard, the spectrum above in Figure 22 is the reference sample of the NMR signal intensity (i.e., a single scan thermal polarization from 4M [1- 13 C] sodium acetate using similar acquisition parameters 13 C signal, the spectrum below in Figure 22), and is obtained through comparison with an approximately 6.02% P 13C corresponding to an approximately 38,600-fold signal enhancement ε 13 C-hyperpolarized [1- 13 C]-pyruvic acid. The NMR sample contained 23 mM [1- 13 C] sodium pyruvate, 7.4 mM of the perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO) in 0.2 mL NFBME and 0.2 mL MeOD. The flow rate and pressure of p-H2 were 90 ssc / m and 110 PSI, respectively, at a mixing magnetic field of 0.4 μT and a temperature of 0 °C.

[0381] Temperature has a significant impact on the exchange rate of [1- 13 C] pyruvic acid on complex 3b in Figure 7. In recent studies, Adelabu et al. (ChemPhysChem, 23, e202100839 (2022)) showed that the monotonic disappearance of the free HP resonance at low temperature occurs due to the slow exchange rate to the free state of complex 3b. At room temperature (e.g., 22 °C), the exchange of [1- 13 C] pyruvic acid with the polarization transfer complex is faster, leading to hyperpolarization of both the free species and the bound 3b species at the expected pyruvic acid:pre-catalyst ratio. To rapidly release HP pyruvic acid from 3b, the HP solution was rapidly warmed and then the sample was inserted into the NMR detector (TomHon 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. 23 mM [1- 13Sodium pyruvate, the perfluorinated SABRE catalyst of Example 4 at 7.4 mM, and an NMR sample (in nonafluorobutyl methyl ether (NFBME) and deuterated methanol) contained in 46 mM dimethyl sulfoxide (DMSO), where the mixed magnetic field was 0.4 μT, and the parahydrogen pressure and flow rate were set to 110 PSI and 90 scc / m, respectively.

[0382] As demonstrated by Figure 23, the exchange rate of complex 3b to the free state is faster even at low temperatures, such as -10 °C, where most of the [1- 13 C] pyruvate is in the free state. 13 By lowering the temperature of the C SABRE-SHEATH to 0 °C, the maximum value of P 13C is achieved. The exchange remains fast enough to preferentially enhance the "free" HP [1- 13 C] pyruvate over complex 3b.

[0383] Example 26 This example illustrates an exemplary method for isolating hyperpolarized [1- 13 C] sodium pyruvate involving biphasic extraction in an aqueous and fluorinated phase.

[0384] The hyperpolarization procedure of Example 6 was repeated using a mixture of nonafluorobutyl methyl ether (NFBME) and deuterated methanol instead of deuterated methanol alone. The SABRE sample was prepared with 23 mM [1- 13 C] sodium pyruvate, the perfluorinated SABRE catalyst of Example 4 at 7.4 mM, and 46 mM dimethyl sulfoxide (DMSO) in 0.2 mL NFBME and 0.2 mL MeOD, where the mixed magnetic field was 0.4 μT, and the parahydrogen pressure and flow rate were set to 110 PSI and 90 scc / m, respectively.

[0385] After the hyperpolarization procedure was completed, the sample was quickly removed from the 0.40 μT magnetic field and transferred inside the 1.8 T NMR spectrometer at room temperature. The NMR sample was depressurized and 400 μL of D2O was added to the solution to deliver [1- 13 C] sodium pyruvate in the aqueous phase. The pyruvate signal in the aqueous phase was collected, but the separation led to the formation of an emulsion, indicating the presence of both bound and free pyruvate. See Figure 24. In that regard, the upper spectrum in Figure 24 shows the reference sample of the NMR signal intensity (i.e., single scan thermal polarization from 4 M [1- 13 C] sodium acetate using similar acquisition parameters, the lower spectrum in Figure 24 showing the 13 C signal), and the representative spectrum of [1- 13C C]-hyperpolarized [1- 13 C]-pyruvate having a signal enhancement ε of about 10,800-fold corresponding to about 1.68% P 13 C is obtained through comparison with the reference sample.

[0386] [1- 13 C] sodium pyruvate-containing aqueous phase was drained and tested for iridium content and pyruvate concentration. ICP-MS studies showed an iridium content of 637 ppb, and LCMS showed that about 50 - 75% of the [1- 13 C] sodium pyruvate concentration was collected after filtration.

[0387] The fluorinated mixture containing the perfluorinated SABRE catalyst in NFBME and MeOD was reused for further [1- 13 C] sodium pyruvate hyperpolarization. After draining the aqueous phase, a solution containing 23 mM [1- 13 C] sodium pyruvate and 47 mM dimethyl sulfoxide in 0.2 mL CD3OD was added to the fluorinated mixture containing the perfluorinated SABRE catalyst from 4 days ago. The hyperpolarization of [1- 13 C] sodium pyruvate was repeated, and about 0.48% P obtained through comparison with the reference sample of the NMR signal intensity as shown in Figure 2513C corresponding to a signal enhancement ε of about 3090-fold for [1- 13 C]-pyruvic acid was shown. For [1- 13 C]pyruvic acid polarization was repeatable and showed nearly the same polarization level, demonstrating that the perfluorinated SABRE catalyst remained active for at least 4 days after its first use.

[0388] Example 27 This example is 1,3-dimesityl-4,5-bis(2-(perfluorophenyl)propyl)-4,5-dihydro-1H-imidazol-3-ium, triflate salt prepared according to the synthetic sequence described in Figure 26:

[0389]

Chemical formula

[0390] The synthesis of is illustrated.

[0391] 4-Pentafluorophenylbutanal (3). To a solution of alcohol (2) (4.8 g, 20.0 mmol) in DCM (40 mL), Dess-Martin periodinane (16.96 g, 40.0 mmol) was added portionwise at 0 °C with stirring under argon (5 min). The reaction was continued until the starting alcohol was consumed (2 h). 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 the product was obtained as a colorless oil by elution with 5% ethyl acetate in hexane. Yield: 3.33 g (70%). 1 1H NMR (CDCl3): 1 1H NMR (400 MHz, CDCl3) δ 9.71 (t, J = 1.3 Hz, 1H), 2.69 (tt, J = 7.9, 1.8 Hz, 2H), 2.44 (td, J = 7.3, 1.2 Hz, 2H), 1.86 (p, J = 7.3 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 200.89, 42.81, 21.49.

[0392] 1,2,3,4,5 - Pentafluoro - 6-(4 - iodobutyl)benzene (4). A solution of alcohol (2) (16.0 g, 66.67 mmol) in ice - cold was stirred under argon with imidazole (5.89 g, 86.67 mmol) and triphenylphosphine (20.96 g, 80.0 mmol) in DCM (100 mL). Iodine (20.32 g, 80.0 mmol) was added portionwise over a period of 15 minutes at 0 °C with vigorous stirring until a slight yellow color persisted. The reaction mixture was diluted with hexane (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 on silica gel (220 g). Elution with hexane gave compound (4) as a colorless oil. Yield: 21.0 g (90%). 1 H NMR (400 MHz, cdcl3) δ3.20 (t, J = 6.8 Hz, 1H), 2.73 (tt, J = 7.5, 1.8 Hz, 1H), 1.86 (dq, J = 8.6, 6.8 Hz, 1H), 1.76 - 1.66 (m, 1H). 13 C NMR (101 MHz, cdcl3) δ37.84, 30.01, 21.27, 5.39.

[0393] 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 h. The precipitated solid was filtered, washed with anhydrous ether, and dried under high vacuum for 20 h. Yield: 33.78 g (92%). 1 H NMR (400 MHz, 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). 1313C NMR (101 MHz, CDCl3) δ 135.23, 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.

[0394] Compound 6. To a solution of phosphonium salt (5) (6.79 g, 11 mmol) in anhydrous THF (40 mL) was added dropwise potassium tert-butoxide (2 M, 12.5 mL, 25.0 mmol) in THF, and the mixture was stirred under argon for 30 minutes. Aldehyde (3) (2.2 g, 9.24 mmol) in THF (5 mL) was added dropwise at room temperature, and the mixture was 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, a mixture of cis / trans isomers (90:10). Yield: 3.2 g (72%). 1 1H NMR (400 MHz, CDCl3) δ 5.41 (m, 2H), 2.72, 2.68 (m, 4H), 2.12, 2.10, 2.06 (m, 4H), 1.64 (m, 4H). 13 13C NMR (101 MHz, CDCl3) δ 129.46, 29.12, 26.76, 21.94

[0395] Compound 7. The olefin (6) (3.6 g, 8.1 mmol) in acetone (20 mL) and water (0.5 mL) was cooled to 0 °C, and dibromamine-T (2.93 g, 8.91 mmol, Org. Biomol. Chem., 8, 1424 - 1430 (2010)) was added with vigorous stirring. After the addition, the solution was brought to 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 completely disappeared. 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 on flash silica (80 g) and eluted with 10% EtOAc in hexane to give bromohydrin (7) as a mixture of diastereomers and as a colorless oil. Yield: 2.41 g (55%). 1 1H NMR (400 MHz, 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 13C NMR (101 MHz, CDCl3) δ 143.76, 138.35, 129.62, 126.82, 59.74, 57.12, 35.29, 34.50, 27.39, 25.48, 21.74, 21.34.

[0396] Compound 8. Bromohydrin (7) (2.2 g, 4.06 mmol) was dissolved in DCM (10.0 mL) and stirred with 5.0 g of molecular sieves. Dess - Martin reagent (3.44 g, 8.12 mmol) was added, and the mixture was stirred until the starting material was completely consumed (30 minutes). The whole 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 0 to 20% EtOAc in hexane over 20 minutes (80.0 mL / min; elution rate). Bromoketone (8) eluted as a colorless syrup with 5% EtOAc in hexane. Yield: 1.82 g (83%). 11H NMR (400 MHz, CDCl3) δ 4.25 (dd, J = 8.3, 6.0 Hz, 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). 13 13C NMR (101 MHz, CDCl3) δ 202.53, 52.19, 38.18, 32.31, 26.87, 23.21, 21.62, 21.45.

[0397] 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). Trimethylanilinium formamidine (0.94 g, 3.34 mmol) was then added as a solid to the stirred solution, and the reaction mixture was heated to 60 °C while excluding moisture. After consumption of the bromoketone (70 h), the reaction mixture was filtered, concentrated under reduced pressure, and chromatographed on flash silica (80 g). Elution with 20% DCM in hexane gave ketoamidine (10) as a colorless syrup. Yield: 1.2 g (49%). 1 1H NMR δ (CDCl3) 6.91 (s, 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 13C NMR (101 MHz, CDCl3) δ 208.19, 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].

[0398] Compound 11 (triflate salt). To an ice-cooled solution of ketoamidine (0.994 g, 1.35 mmol) in ethanol was added lithium borohydride (2 M in THF, 0.675 ml, 1.35 mmol), and the mixture was 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 above 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 the mixture was stirred under argon. Trifluoromethanesulfonic anhydride (1.104 g, 1.34 mmol) was then added dropwise and stirring was continued for 1 h. LC / MS showed 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 (3 s, 18H), 1.77 (m, 4H), 1.41 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 159.41, 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].

[0399] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety 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.

[0400] In the context of describing the present invention (particularly in the context of the following claims), the use of the terms "a", "an", "the", "at least one", and similar referents should be construed to cover both the singular and the plural forms, unless otherwise indicated 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 construed to mean 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 indicated herein or clearly contradicted by the context. The terms "comprising", "having", "including", and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. The recitation of a range of values herein is merely intended to be a convenient way of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any example, or exemplary language (e.g., "such as") provided herein is merely intended to better clarify the invention and does not impose a limitation on the scope of the invention unless otherwise claimed. No term in this specification should be construed as indicating that any non-recited element is essential for the practice of the invention.

[0401] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to employ such variations as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all alterations and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Further, any combination of the above-described elements in all possible variations thereof is included in the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand is of formula (I): 【Chemical 1】 or a salt thereof, and 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 (NHC is bonded to the d-block element via the 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 SABRE catalyst.

2. The perfluorinated SABRE catalyst according to claim 1, wherein NHC is a 5-membered N-heterocyclic carbene group.

3. The perfluorinated SABRE catalyst according to claim 2, wherein the 5-membered N-heterocyclic carbene group is imidazole-based, imidazoline-based, or thiazole-based.

4. The perfluorinated SABRE catalyst according to any one of claims 1 to 3, wherein NHC is a 5-membered N-heterocyclic carbene group of 4,5-disubstituted, 1,3-disubstituted, or 1,3,4,5-tetrasubstituted imidazole-based or imidazoline-based.

5. The perfluorinated SABRE catalyst according to any one of claims 1 to 4, wherein 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.

6. The perfluorinated ligand is of formula (Ia) or (Ib): [[Chemical 2]] or a salt thereof, and 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, 【Chemical Formula 3】 is a single bond or a double bond, and [Chemical Formula 4] represents the bond to the d-block element via the carbene, the perfluorinated SABRE catalyst according to claim 1.

7. The perfluorinated ligand is of formula (Ic) or (Id): [Chemical Formula 5] or a salt thereof, and Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, a is from 4 to 20, b = 2a + 1 or b = a - 1, each n is independently an integer from 0 to 4, [Chemical Formula 6] is a single bond or a double bond, and 【Chemical Formula 7】 represents a bond to a d-block element via a carbene, the perfluorinated SABRE catalyst of claim 1. **Claim 8** The perfluorinated ligand is of formula (Ie) or (If): [Chemical Formula 8] or a salt thereof, and 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 １－６ alkenyl, or C １－６ heteroalkyl, and a is from 4 to 20, b = 2a + 1 or b = a - 1, 【Chemical Formula 9】 is a single bond or a double bond, and 【Chemical Formula 10】 represents a bond to a d-block element via a carbene, the perfluorinated SABE catalyst of claim 1. **Claim 9** The perfluorinated SABRE catalyst of claim 7 or 8, wherein a is from 4 to 10. **Claim 10** 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-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-di-isopropylphenyl, 2,5-di-isopropylphenyl, 2,6-di-isopropylphenyl, 3,5-di-isopropylphenyl, 2,4,6-tri-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-di-isobutylphenyl, 2,5-di-isobutylphenyl, 2,6-di-isobutylphenyl, 3,5-di-isobutylphenyl, 2,4,6-tri-isobutylphenyl, 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, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 2,4-di-t-butylphenyl, 2,5-di-t-butylphenyl, 2,6-di-t-butylphenyl, 3,5-di-t-butylphenyl, 2,4,6-tri-t-butylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2,4-di-cyclohexylphenyl, 2,5-di-cyclohexylphenyl, 2,6-di-cyclohexylphenyl, 3,5-di-cyclohexylphenyl, or 2,4,6-tri-cyclohexylphenyl, the perfluorinated SABRE catalyst according to any one of claims 1 to 9.

11. The perfluorinated SABRE catalyst according to any one of claims 1 to 10, wherein each L is independently hydrogen or 2,4,6-trimethylphenyl.

12. Each Y is independently a bonded, substituted or unsubstituted C １－１０ alkyl group, a substituted or unsubstituted C ２－１０ alkenyl group, a substituted or unsubstituted C ２－１０ alkynyl group, a substituted or unsubstituted C １－１０ heteroalkyl group, a substituted or unsubstituted C ３－６ cycloalkyl group, a substituted or unsubstituted C ３－６ 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, the perfluorinated SABRE catalyst according to any one of claims 1 to 11.

13. Each Y is independently a bonded, substituted or unsubstituted C １－１０ alkyl group, a substituted or unsubstituted C ２－１０ 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, the perfluorinated SABRE catalyst according to any one of claims 1 to 11.

14. Each Y is independently a bonded, substituted or unsubstituted C １－１０ alkyl group, a substituted or unsubstituted C ２－１０ 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, the perfluorinated SABRE catalyst according to any one of claims 1 to 11.

15. The perfluorinated tag is a perfluorinated C group containing only carbon atoms and fluorine atoms, and the perfluorinated SABRE catalyst according to any one of claims 1 to 14. ３－６０ ​

16. The perfluorinated tag is a perfluorinated C group containing only carbon atoms and fluorine atoms, and the perfluorinated SABRE catalyst according to any one of claims 1 to 14. ３－４０ ​

17. The perfluorinated tag is a perfluorinated C ３－２０ group, and the perfluorinated SABRE catalyst according to any one of claims 1 to 14.

18. The perfluorinated tag is C ４ F ９ group, C ５ F １１ group, C ６ F １３ group, C ７ F １５ group, C ８ F １７ group, C ９ F １９ group, C １０ F ２１ group, C ６ F ５ group, C ４ F ７ group, C ５ F ９ group, C ６ F １１ group, C ７ F １３ group, C ８ F １５ group, C ９ F １７ group, and C １０ F １９ group, and the perfluorinated SABRE catalyst according to any one of claims 1 to 14, selected from

19. The perfluorinated ligand is 【Chemical 11】 or a salt thereof, and 【Chemical 12】 is a single bond or a double bond, and 【Chemical 13】 represents a bond to a d-block element via a carbene, the perfluorinated SABE catalyst of claim 1.

20. The perfluorinated SABRE catalyst according to any one of claims 1 to 19, wherein the d-block element is a transition metal.

21. The perfluorinated SABRE catalyst according to any one of claims 1 to 20, wherein the d-block element is Co, Rh, Ir, Ru, Pd, Pt, or Mt.

22. The perfluorinated SABRE catalyst according to any one of claims 1 to 21, wherein the SABRE catalyst further comprises an additional ligand.

23. The perfluorinated SABRE catalyst of claim 22, wherein the SABRE catalyst further comprises an additional ligand selected from a phosphine ligand, a carbene ligand, an imidazole ligand, a pincer chelate ligand, and a compound containing a sulfoxide group.

24. 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 cyclooctadienyl) to prepare a perfluorinated SABRE catalyst according to any one of claims 1 to 23.

25. The method of claim 24, wherein the d-block element is Co, Rh, Ir, Ru, Pd, Pt, or Mt.

26. A method for preparing a hyperpolarized substrate, the method comprising: (i) providing a perfluorinated SABRE catalyst according to any one of claims 1 to 23; (ii) providing a co-ligand that interacts with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst; (iii) combining the active perfluorinated SABRE catalyst with parahydrogen and a substrate containing a 1 / 2 spin nucleus(s) or nucleus(nuclei) in a solvent to obtain a reaction mixture; and (iv) hyperpolarizing the mixture obtained in (iii) by exposing the mixture to a magnetic field or by high-frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate comprising.

27. The substrate is １ H, １３ C, １５ N, １９ F, ３１ P, ２９ Si, or a combination thereof, the method of claim 26.

28. The substrate further ２ The method of claim 27, comprising D.

29. The method according to claim 27 or claim 28, wherein the co-ligand is a compound containing one or more sulfoxide groups, thioester groups, phosphine groups, amine groups, CO groups, isonitrile groups, nitrogen-containing heterocyclic groups, or combinations thereof.

30. The method according to any one of claims 26 to 29, wherein the solvent comprises water, methanol, ethanol, a fluorinated solvent, or a mixture thereof.

31. The method according to any one of claims 26 to 29, wherein the solvent comprises a solvent selected from a perfluorohexane / diethyl ether mixture, a methoxynonafluorobutane and ethyl acetate mixture having a nonpolar solvent, a perfluorohexane and ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, ether, a fluorocarbon derivative of THF FC 75, decafluoromethoxytri fluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkane, perfluorohexane, and methoxynonafluorobutane.

32. The method according to any one of claims 26 to 31, wherein the solvent is deuterated.

33. The method according to any one of claims 26 to 32, wherein the co-ligand is dimethyl sulfoxide or phenyltrifluoromethyl sulfoxide.

34. The method according to any one of claims 26 to 33, further comprising (vi) isolating the hyperpolarized substrate.

35. The method according to claim 34, wherein the hyperpolarized substrate is isolated by treating the reaction mixture with a solid-phase adsorbent to adsorb the perfluorinated SABRE catalyst and recovering the liquid containing the hyperpolarized substrate, wherein the liquid does not contain or substantially does not contain the perfluorinated SABRE catalyst.

36. The method according to claim 35, further comprising passing a fluorophobic solvent over the adsorbent and recovering an eluate containing the hyperpolarized substrate, wherein the eluate does not contain or substantially does not contain the perfluorinated SABRE catalyst.

37. The method according to claim 36, wherein the fluorophobic solvent comprises water and one or more of methanol, ethanol, acetonitrile, and dimethylformamide.

38. The method according to claim 36 or claim 37, further comprising passing a fluorophilic solvent over the adsorbent.

39. The method of claim 38, wherein the parent fluorophilic solvent comprises an organic solvent selected from methanol, ethanol, acetonitrile, THF, ethyl acetate, a chlorinated solvent, and combinations thereof.

40. The method of claim 34, wherein the hyperpolarized substrate is isolated 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 or substantially free of the hyperpolarized substrate.

41. The method of claim 40, further comprising passing the parent fluorophilic solvent over an adsorbent and recovering an eluate containing the perfluorinated SABRE catalyst, wherein the eluate is free or substantially free of the hyperpolarized substrate.

42. The method of claim 41, wherein the parent fluorophilic solvent comprises 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.

43. The method of claim 34, wherein the hyperpolarized substrate is isolated by liquid / liquid extraction.

44. The method of claim 43, wherein the liquid / liquid extraction comprises partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanolic mixture and a fluorinated solvent.

45. The method of claim 43, wherein the liquid / liquid extraction comprises partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanolic mixture and an organic solvent.

46. The method of claim 34, wherein the hyperpolarized substrate is isolated by precipitating the perfluorinated SABER catalyst, filtering to remove the precipitated perfluorinated SABER catalyst from the hyperpolarized substrate.

47. The method of claim 46, wherein the perfluorinated SABRE catalyst precipitates upon addition of water.

48. The method according to any one of claims 26 to 47, wherein the substrate is selected from ketoglutaric acid, pyruvic acid, N-acetylcysteine, and salts or esters thereof.

49. The substrate is 1- １３ C-ketoglutaric acid, 1- １３ C-5- １２ C-ketoglutaric acid, 1- １３ C-pyruvic acid, 1- １３ C-N-acetylcysteine, １５ N ２ -isoniazid (i.e., pyridyl-4-carbo-bis- １５ N ２ -hydrazide), １３ C ２ , １５ N ３ metronidazole, １５ N ２ -1-aminoisoquinoline (1-AIQ), their deuterated versions, and their salts, the method of any one of claims 26 to 48.

50. The substrate is of formula (II): 【Chemical Formula 14】 (wherein each R １ is independently hydrogen, deuterium, a cation, C １ - C ６ - alkyl, C ３ - C ７ - cycloalkyl, (C ３ - C ７ - cycloalkyl)C １ - C ６ - alkyl, (heterocycloalkyl)C １ - C ６ - alkyl, (heteroaryl)C １ - C ６ - alkyl, and (aryl)C １ - C ６ - 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). The method according to any one of claims 26 to 48, or a pharmaceutically acceptable salt thereof.

51. A hyperpolarized substrate obtained from the method according to any one of claims 26 to 50, or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition comprising the hyperpolarized substrate according to claim 51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

53. A method for obtaining a magnetic resonance image of tissue in a subject, comprising administering the hyperpolarized substrate according to claim 51 or the pharmaceutical composition according to claim 52 to a subject having or suspected of having cancer or a harmful vascular condition, and imaging the subject by magnetic resonance imaging.

54. The method according to claim 53, wherein the subject has cancer.

55. The method according to claim 54, wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer.

56. The method according to claim 53, wherein the harmful vascular condition is selected from myocardial infarction, stroke, and lung disease.

57. The method according to claim 56, wherein the lung disease is selected from COPD, pulmonary fibrosis, long-term COVID-19 symptoms, and combinations thereof.

58. Formula (III): 【Chemical Formula 15】 (wherein each Ar is independently selected from a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group, Each Ar ｆ is independently selected from a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group, each Y is independently selected from a bond or a spacer group, X is an anion, and 【Chemical Formula 16】 is a single bond or a double bond) a perfluorinated compound.

59. The perfluorinated compound according to claim 58, wherein each Ar is independently selected from a substituted or unsubstituted aromatic group.

60. Each Ar ｆ is independently selected from a perfluorinated or unsubstituted aromatic group, the perfluorinated compound of claim 58 or claim 59.

61. Each Y is independently, C １－５ alkyl and C １－５ A perfluorinated compound according to any one of claims 58 to 60, selected from spacer groups selected from heteroalkyl.

62. The perfluorinated compound is of formula (IIIa): 【Chemical 17】 (wherein each n is independently an integer from 0 to 4, X is an anion, and 【Chemical 18】 is a single bond or a double bond) the perfluorinated compound according to claim 58.

63. A method for preparing the perfluorinated compound according to any one of claims 58 to 62, the method comprising: (i) Reacting an α-bromoketone containing a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group with an amidine containing a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group in the presence of a base to form an α-aminoketone; (ii) Optionally reducing the α-aminoketone with a reducing agent to form an α-aminoalcohol; and (iii) Cyclizing the α-aminoketone or the α-aminoalcohol to form a perfluorinated compound A method comprising the above steps.

64. An olefin metathesis catalyst comprising a d-block element and a perfluorinated compound according to any one of claims 58 to 62 as a ligand.

65. A method for polymerizing an olefin, the method comprising combining the olefin metathesis catalyst of claim 64 and an olefin in a reaction mixture.

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