Fluorinated carbon chain-containing SABRE catalysts for delivery of metal-free MRI contrast agents

Abstract

A perfluorinated SABRE catalyst is disclosed comprising a d-region element and a perfluorinated ligand wherein the perfluorinated ligand has the formula (I): [Lm-(NHC)-(Y-Z) q] or a salt thereof. Also disclosed are methods of preparing a hyperpolarized substrate comprising one or more 1 / 2 spin nuclei using the perfluorinated SABRE catalyst and separating the resulting hyperpolarized substrate for administration to an animal. Methods of imaging tissue of an animal suspected of having a disease or condition are also disclosed.

Description

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

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

[0003] Cross-reference to priority application

[0004] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328,545, filed on April 7, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0005] Nuclear magnetic resonance spectroscopy (NMR) and magnetic resonance imaging (MRI) methods are powerful tools widely used in biomedical, chemical and material science applications. These methods rely on the overall difference in nuclear spin energy levels (called polarization) produced after applying a strong magnetic field. Spins aligned with or opposite to the applied field produce a net polarization that is detected. Unfortunately, nuclear polarization under thermal equilibrium (i.e. normal conditions) is inherently poor, and there are still limitations on the sensitivity and range of capabilities of magnetic resonance in general (Günther, NMR Spectrosc. Basic Princ. Concepts Appl. Chem., 13-28 (2013)).

[0006] Hyperpolarization techniques have been developed to overcome this problem and allow NMR / MRI signal enhancements of orders of magnitude. The most widely used hyperpolarization techniques employ photons (dynamic nuclear polarization, DNP) (Hausser et al., Adv. Magn. Opt. Reson., 3, 79-139 (1968); Abagam et al., Reports Prog. Phys., 41, 395-467 (1978); and Ardenkjaer-Larsen et al., Proc. Natl. Acad. Sci. USA, 100, 10158-10163 (2003)), photons (spin exchange optical pumping) (Bhaskar et al., Phys. Rev. Lett., 49, 25 (1982); Ebert et al., Lancet, 347, 1297 (1996); Albert et al., Nature, 370, 199-201 (1994); and et al., Science, 314, 446-449 (2006)) or polarization transfer of parahydrogen (parahydrogen induced polarization, PHIP) (Bowers et al., Phys. Rev. Lett., 57, 2645 (1986); Bowers et al., J. Am. Chem. Soc., 109, 5541-5542 (1987); Eisenschmid et al., J. Am. Chem. Soc., 109, 8089 (1987); Haake et al., J. Am. Chem. Soc., 118, 8688 (1996); Goldman et al., CRPhys., 6, 575 (2005); and Chekmenev et al., J. Am. Chem. Soc., 130, 4212 (2008)). Hyperpolarized magnetic resonance (MR) is an emerging molecular imaging method for monitoring metabolism, enzymatic transformations, or biochemical pathways that were previously inaccessible using MR.

[0007] Current hyperpolarization imaging with dissolved DNPs and superconducting MRI scanners is very powerful due to its unique ability to track chemical transformations in vivo. However, DNP-based experiments are relatively cumbersome, slow, and expensive.

[0008] The PHIP method and its subclass SABRE (Signal Amplification by Reversible Exchange) allow the singlet spin order transfer of 100% pure parahydrogen (paraH2) into a target molecule. The PHIP method is a traditional hydrogenation method and relies on a catalytic hydrogenation reaction in which a precursor in the form of a hydrogen acceptor is reduced and polarized by parahydrogen. In contrast, the reversible exchange using SABRE leaves the hyperpolarizing reagent chemically unchanged. It is also not limited to one paraH2 molecule per molecule, and therefore multiple spin transfer steps can lead to significant levels of hyperpolarization. This effect has also been shown to transfer polarization to nuclei in a wide range of biologically relevant molecules, such as 1 H. 13 C. 19 F. 31 P and 15 N and / or 29Si core (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017); Theis et al., J.Am.Chem.Soc., 137, 1404-1407 (2015); Shchepin et al., ChemPhysChem, 18, 1961-1965 (2017); Zhivonitko et al., 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)).

[0009] The high polarization percentage, short signal settling time, low cost, and scalability make SABRE a promising approach to study metabolism in vivo using magnetic resonance spectroscopy.

[0010] Currently available hyperpolarized contrast agents are associated with spin transfer catalyst components containing heavy metals (e.g., transition metal atoms) necessary to transfer polarization from secondary H2 to the substrate. Due to the presence of potentially toxic heavy metal-based complexes (e.g., the catalyst is typically an iridium-based organometallic compound) in solution with the hyperpolarized contrast agents, toxicity issues arise when the hyperpolarized contrast agents are administered in vivo.

[0011] Another obstacle to the successful implementation of the SABRE method is the low solubility of parahydrogen in water (the solubility of H2 in water is about 1.6 mg / L) compared to its solubility in alcohol-based solvents. SABRE hyperpolarization is mainly active in organic solvents, preferably methanol, which is incompatible with in vivo administration.

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

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

[0014] The present invention provides a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand has formula (I):

[0015] [L m -(NHC)-(YZ) q ]

[0016] Formula (I),

[0017] or a salt thereof, and wherein

[0018] Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0019] NHC is a 4- to 7-membered N-heterocyclic carbene radical, wherein the NHC is bonded to the d-block element via a carbene,

[0020] Each Y is independently selected from a bond or a spacer group,

[0021] Each Z is a perfluorinated tag,

[0022] m is an integer from 1 to 4, and

[0023] q is an integer from 1 to 3.

[0024] The present invention also provides a method for preparing the perfluorinated SABRE catalyst described herein comprising reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [(d-block element)(COD)Cl]2, wherein COD represents cyclooctadienyl.

[0025] The present invention also provides a method for preparing a hyperpolarized substrate, the method comprising:

[0026] (i) providing a perfluorinated SABRE catalyst as described herein;

[0027] (ii) providing a co-ligand to interact with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst;

[0028] (iii) combining the active perfluorinated SABRE catalyst with parahydrogen and a substrate comprising a 1 / 2 spin core or a plurality of 1 / 2 spin cores in a solvent to obtain a reaction mixture; and

[0029] (iv) hyperpolarizing the mixture obtained in (iii) by exposing it to a magnetic field or by radio frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate.

[0030] The present invention also provides a hyperpolarized substrate obtained by the method described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the hyperpolarized substrate.

[0031] The present invention also provides a method of obtaining a magnetic resonance image of tissue in an individual having or suspected of having cancer or an adverse vascular condition, comprising administering to the individual a hyperpolarized substrate described herein or a pharmaceutical composition comprising the hyperpolarized substrate, and imaging the individual by magnetic resonance imaging.

[0032] The present invention also provides a perfluoro compound of formula (III):

[0033]

[0034] wherein each Ar is independently selected from a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0035] Each Ar f are independently selected from perfluorinated substituted or unsubstituted aromatic groups, or perfluorinated substituted or unsubstituted heteroaromatic groups,

[0036] Each Y is independently selected from a bond or a spacer group,

[0037] X is an anion, and

[0038] The present invention also provides a method for preparing the perfluoro compound of formula (III). BRIEF DESCRIPTION OF THE DRAWINGS

[0039] According to one aspect of the present invention, Figure 1 A fluorinated solid phase extraction (F-SPE) method is exemplified, wherein an organic fraction containing the hyperpolarized substrate is separated from a fluorinated fraction on fluorinated silica gel using a fluorphobic solvent or a fluorophobic process, followed by recovery of the fluorinated fraction containing the perfluorinated SABRE catalyst using an aqueous / organic solvent or a fluorophilic process.

[0040] According to one aspect of the present invention, Figure 2 The substrate polarization process and its use through a fluorophilic process, such as using methanol or ethanol, from Figure 1 The SABRE catalyst was extracted from the fluorinated silica gel exemplified in FIG.

[0041] According to one aspect of the present invention, Figure 3 A 'reverse' F-SPE method is exemplified, in which the fluorinated fraction is separated from the aqueous / organic fraction on standard silica gel using a fluorophilic solvent or a fluorophilic process. The hyperpolarized substrate present in the organic fraction is recovered from the silica gel by extraction with a standard organic solvent or by a fluorophilic process.

[0042] According to one aspect of the present invention, Figure 4The partitioning of a perfluorinated SABRE catalyst and a hyperpolarized substrate between two immiscible phases (a fluorinated solvent fraction and water, or another water-immiscible solvent (e.g., a chlorinated solvent) and water or other hydrophilic solvent) is demonstrated, which allows the principles of phase transfer catalysis to be used in conjunction with parahydrogen to produce high levels of hyperpolarization in the aqueous phase without catalyst contamination.

[0043] According to one aspect of the present invention, Figure 5 Hyperpolarization of a metal-containing fluorinated SABRE catalyst coordinated with a co-ligand and a substrate containing a half-spin core to form a hyperpolarized substrate free of or substantially free of a perfluorinated SABRE catalyst is demonstrated.

[0044] Figure 6 The top curve depicts the reaction of 30 mM [1- 13 Single scan HP obtained from SABRE-SHEATH experiment with activation of sodium pyruvate, 42 mM p-trifluoromethylphenyl sulfoxide (PTFSO), and 7.8 mM Ir-F-Imes 13 C spectra. Spectra were acquired immediately after manual transfer of the sample to a 1T benchtop NMR after bubbling 50% p-H2 for 55 seconds at BT = -0.7 μT. The bottom curve shows the spectra from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal. The enhancement is ε~1250, and the polarization is about P( 13 C)~0.1%.

[0045] Figure 7 A graph showing activation time for a perfluorinated SABRE catalyst as described in Example 6 is provided.

[0046] Figure 8 A schematic diagram showing the formation of complex 2, complex 3a, complex 3b and pyruvate as described in Example 6 is provided.

[0047] Fig.9A and Fig. 9B A graph showing the polarization (%) as a function of parahydrogen flow rate and pressure, respectively, as described in Example 7 is provided.

[0048] Fig. 10A and Fig. 10B Provided are graphs showing the temperature and magnetic field as a function of Example 7, respectively. 13 C Diagram of polarization transfer levels.

[0049] Fig.11A and Fig. 11BGraphs showing polarization (%) as a function of perfluorinated SABRE catalyst concentration and DMSO concentration, respectively, as described in Example 7 are provided.

[0050] Fig. 12A and Fig. 12B Provided is a method showing that [1- 13 C]-pyruvate relaxation kinetics, where Fig. 12A shows the accumulation and relaxation at 0.4 μT, and Fig. 12B Relaxation at 1.81 T and Earth field is shown.

[0051] Fig.13 As described in Example 7, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig.13 The bottom spectrum of Fig.13 The top spectrum of 13C , with a signal enhancement of ∼86,500-fold 13 C-hyperpolarization [1- 13 Comparison of representative spectra of [C]-pyruvate.

[0052] Fig.14 A variable temperature SABRE-SHEATH experiment using the saturated perfluorinated SABRE catalyst of Example 4, as described in Example 7, is shown.

[0053] Fig.15 As described in Example 9, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig.15 The bottom spectrum of Fig.15 The top spectrum of 13C , with a ~9000-fold signal enhancement ε after reconstitution in water 13 C-hyperpolarization [1- 13 Comparison of representative spectra of [C]-pyruvate.

[0054] Fig.16 As described in Example 17, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig.16 The bottom spectrum of Fig.16 The top spectrum of 13C, with a signal enhancement of 16900 times 13 C-hyperpolarization [1- 13 Comparison of representative spectra of [C]-pyruvate.

[0055] Fig.17 As described in Example 23, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig.17 The bottom spectrum of Fig.17 The top spectrum of 13C , with a signal enhancement of ∼19,000-fold 13 C-hyperpolarization [1- 13 Comparison of representative spectra of [C]-pyruvate.

[0056] Fig.18 A graph showing the activation time of a perfluorinated SABRE catalyst in a fluorination mixture as described in Example 24 is provided.

[0057] Fig.19 A graph showing polarization (%) as a function of parahydrogen flow rate in a fluorination mixture as described in Example 25 is provided.

[0058] Fig. 20 Provided is a graph showing that, in a fluorinated mixture as described in Example 25, the 13 C Diagram of polarization transfer levels.

[0059] Fig.21A and Fig. 21B Provided is a fluorinated mixture prepared by the method described in Example 25, [1- 13 C]-pyruvate relaxation kinetics, where Fig.21A shows the accumulation and relaxation at 0.4 μT, and Fig. 21B Relaxation at 1.81 T and Earth field is shown.

[0060] Fig. 22 As described in Example 25, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig. 22 The bottom spectrum of Fig. 22 The top spectrum of 13C , with a signal enhancement of ∼38,600-fold in the fluorinated mixture 13 C-hyperpolarization [1- 13Comparison of representative spectra of [C]-pyruvate.

[0061] Fig.23 A variable temperature SABRE-SHEATH experiment using the saturated perfluorinated SABRE catalyst of Example 4 in a fluorination mixture as described in Example 25 is shown.

[0062] Fig.24 As described in Example 26, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig.24 The bottom spectrum of Fig.24 The top spectrum of 13C , with ~10800-fold signal enhancement ε 13 C-hyperpolarization [1- 13 Comparison of representative spectra of [C]-pyruvate.

[0063] Fig.25 As described in Example 26, the results from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal Fig.25 The top spectrum of Fig.25 The bottom two spectra show that the P 13C , prepared from the reused catalyst with a signal enhancement of ε of ∼3090 times 13 C-hyperpolarization [1- 13 Comparison of representative spectra of [C]-pyruvate.

[0064] Fig.26 An exemplary synthesis of 1,3-dimesityl-4,5-bis(2-(perfluorophenyl)ethyl)-4,5-dihydro-1H-imidazol-3-ium, triflate salt as described in Example 27 is shown. DETAILED DESCRIPTION

[0065] The present invention provides a perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand has formula (I):

[0066] [L m -(NHC)-(YZ) q ]

[0067] Formula (I),

[0068] or a salt thereof, and wherein

[0069] Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0070] NHC is a 4- to 7-membered N-heterocyclic carbene radical, wherein the NHC is bonded to a d-block element via a carbene,

[0071] Each Y is independently selected from a bond or a spacer group,

[0072] Each Z is a perfluorinated tag,

[0073] m is an integer from 1 to 4 (e.g., 1, 2, 3, or 4), and

[0074] q is an integer from 1 to 3 (eg, 1, 2 or 3).

[0075] The perfluorinated SABRE catalyst comprises a d-block element, such as 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 Co, Rh, Ir, Ru, Pd, Pt or Mt. In certain embodiments, the perfluorinated SABRE catalyst comprises an element of Group 9 of the Periodic Table, i.e., Co, Rh, Ir or Mt. In preferred embodiments, the perfluorinated SABRE catalyst comprises Ir or Co. For example, the perfluorinated SABRE catalyst can be prepared from [Ir(COD)(IMes)(Cl)].

[0076] The perfluorinated SABRE catalyst comprises a perfluorinated ligand of formula (I):

[0077] [L m -(NHC)-(YZ) q ]

[0078] Formula (I),

[0079] or a salt thereof, and wherein

[0080] Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0081] NHC is a 4- to 7-membered N-heterocyclic carbene radical, wherein the NHC is bonded to a d-block element via a carbene,

[0082] Each Y is independently selected from a bond or a spacer group,

[0083] Each Z is a perfluorinated tag,

[0084] m is an integer from 1 to 4 (e.g., 1, 2, 3, or 4), and

[0085] q is an integer from 1 to 3 (eg, 1, 2 or 3).

[0086] In some aspects, NHC comprises an azolyl moiety, i.e. a five-membered heterocyclic group having a nitrogen atom and at least one other heteroatom selected from nitrogen, sulfur and oxygen. Thus, in some embodiments, NHC is a 5-membered N-heterocyclic carbene group. For example, a 5-membered N-heterocyclic carbene group can be imidazole-based, imidazoline-based or thiazole-based. In other words, a 5-membered N-heterocyclic carbene group can be a carbene formed by treating a perfluorinated ligand having an imidazole, imidazoline or thiazole core.

[0087] In some embodiments, NHC is a 4,5-disubstituted, 1,3-disubstituted or 1,3,4,5-tetrasubstituted imidazole-based or imidazoline-based 5-membered N-heterocyclic carbene group. For example, NHC can be a 4,5-disubstituted imidazolidinyl, a 1,3-disubstituted imidazolidinyl, a 1,3,4,5-tetrasubstituted imidazolidinyl, a 4,5-disubstituted 2,3-dihydro-imidazolyl, a 1,3-disubstituted 2,3-dihydro-imidazolyl or a 1,3,4,5-tetrasubstituted 2,3-dihydro-imidazolyl. Examples of the imidazolidinyl moiety include an N,N′-di(2,4,6-trimethylphenyl)-imidazolidinyl moiety, an N,N′-di(2,6-diisopropylphenyl)-imidazolidinyl moiety, an N,N′-di(2,6-dicyclohexyl)-imidazolidinyl moiety, an N,N′-di(2,6-tert-butyl)-imidazolidinyl moiety, and an N,N′-di(1-adamantyl)-imidazolidinyl moiety.

[0088] In some embodiments, the perfluorinated ligand has formula (Ia) or (Ib):

[0089]

[0090] or a salt thereof, and wherein

[0091] Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0092] Each Y is independently a bond or a spacer group,

[0093] Each Z is independently a perfluorinated tag,

[0094] is a single bond or a double bond, and

[0095] represents bonding to a d-block element via a carbene.

[0096] In some embodiments, the perfluorinated ligand has formula (Ic) or (Id):

[0097]

[0098] or a salt thereof, and wherein

[0099] Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0100] a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20),

[0101] b = 2a + 1 or b = a – 1,

[0102] Each n is independently an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4),

[0103] is a single bond or a double bond, and

[0104] represents bonding to the d-block element via a carbene. In some embodiments of Formula (Ic) or Formula (Id), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0105] In some embodiments, the perfluorinated ligand has formula (Ie) or (If):

[0106]

[0107] or a salt thereof, and wherein

[0108] Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0109] Each Ar is independently a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0110] Each G is independently a bond, C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 Heteroalkyl,

[0111] a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20),

[0112] b = 2a + 1 or b = a – 1,

[0113] is a single bond or a double bond, and

[0114] = represents bonding to the d-block element via a carbene. In some embodiments of Formula (Ie) or Formula (If), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0115] In any of Formula (I) and Formula (Ia) to Formula (If), each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0116] As used herein, "substituted or unsubstituted aromatic" refers to a substitution having 5 to 60 ring carbon atoms (e.g., C 1-6 As used herein, "substituted or unsubstituted heteroaromatic" refers to a substitution having 1 to 2 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon (e.g., C 1-6 The term "heteroaryl" refers to a cycloheteroaryl group, which is a cycloheteroaryl group which is a cycloheteroaryl group having at least one cycloheteroaryl group, a ... Heteroaromatic groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thienyl, triazolyl, henzofrijoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, isothiazolyl, and isoxazolyl.

[0117] In some embodiments, each L is independently hydrogen, adamantyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,5-diethylphenyl, 2,4,6-trimethylphenyl, triethylphenyl, 2-n-propylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 2,4-di-n-propylphenyl, 2,5-di-n-propylphenyl, 2,6-di-n-propylphenyl, 3,5-di-n-propylphenyl, 2,4,6-tri-n-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-diisopropylphenyl, 2,5-diisopropylphenyl, 2,6-diisopropylphenyl, 3,5-diisopropylphenyl, 2,4,6-triisopropylphenyl phenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-diisobutylphenyl, 2,5-diisobutylphenyl, 2,6-diisobutylphenyl, 3,5-diisobutylphenyl, 2,4,6-triisobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2,4-di-sec-butylphenyl, 2,5-di-sec-butylphenyl, 2,6-di-sec-butylphenyl, 3,5-di-sec-butylphenyl, 2,4,6-tri-sec-butylphenyl In some embodiments of formula (I) and formula (Ia) to formula (If), each L is independently hydrogen or 2,4,6-trimethylphenyl.

[0118] In any of Formula (I) and Formula (Ia) to Formula (If), each Y is independently a bond or a spacer group. For example, Y can be a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6a heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, a substituted or unsubstituted arylalkyl group, or a linear or branched alkyleneoxy group (e.g., polyethylene oxide, polypropylene oxide, or a combination thereof).

[0119] In some embodiments, each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6 In some embodiments, each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 In a preferred embodiment, each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted arylalkyl group.

[0120] Perfluorinated ligands include perfluorinated tags. For example, in any of Formula (I) and Formula (Ia) to Formula (If), each Z is a perfluorinated tag. The perfluorinated tag can be any perfluorinated group, for example, a perfluorinated alkyl (e.g., linear or branched), aryl, alkaryl, or arylalkyl group containing up to 60 carbon atoms. In some embodiments, the perfluorinated tag is a perfluorinated C containing only carbon and fluorine atoms. 3-60 In certain embodiments, the perfluorinated tag is a perfluorinated C 3-40 In other embodiments, the perfluorinated tag is a perfluorinated C 3-20 For example, the perfluorinated tag can be selected from the group C4F9, C5F 11 Group, C6F 13 Group, C7F 15 Group, C8F 17 Group, C9F 19 Group, C 10F 21 Group, C6F5 group, C4F7 group, C5F9 group, C6F 11 Group, C7F 13 Group, C8F 15 Group, C9F 17 Group and C 10 F 19 groups, each of which may be a straight-chain or branched alkyl, aryl, alkaryl or arylalkyl group.

[0121] In one aspect, Z is a linear or branched perfluoroalkyl chain having a chain length of up to 60 or more carbon atoms, for example, the perfluoroalkyl chain has a chain length of 3 to 60, particularly 3 to 40, more particularly 3 to 20, even more particularly 3 to 10 or more carbon atoms. For example, the perfluoroalkyl chain is selected from C4F9, C6F 13 、C7F 15 、C8F 17 、C9F 19 and C 10 F 21 , preferably selected from C6F 13 、C8F 17 and C 10 F 21 , each of which can be linear or branched, and combinations thereof, each of which can be linear or branched.

[0122] In one aspect, the perfluorinated ligand has formula (Ig):

[0123]

[0124] or a salt thereof, and wherein

[0125] a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20),

[0126] b = 2a + 1 or b = a – 1,

[0127] is a single bond or a double bond, and

[0128] represents bonding to the d-block element via a carbene. In some embodiments of Formula (Ig), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0129] In one aspect, the perfluorinated ligand has formula (Ih):

[0130]

[0131] or a salt thereof, and wherein

[0132] a is 4 to 20 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20),

[0133] b = 2a + 1 or b = a – 1,

[0134] is a single bond or a double bond, and

[0135] represents bonding to the d-block element via a carbene. In some embodiments of Formula (Ig), a is 4 to 10 (eg, 4, 5, 6, 7, 8, 9, or 10).

[0136] Exemplary perfluorinated ligands include:

[0137]

[0138]

[0139] or a salt thereof, and wherein is a single bond or a double bond, and represents bonding to a d-block element via a carbene.

[0140] As used in this article, the symbol represents a single bond or a double bond. In some embodiments, is a single bond. In other embodiments, is a double bond. is a single bond, derived from The orientation of the two substituents may have any suitable stereochemistry, i.e., may be cis or trans. In a preferred embodiment, when When it is a single bond, it comes from The stereochemistry of the substituent is trans.

[0141] As used in this article, the symbol represents bonding to a d-block element via a carbene. In other words, Indicates bonding to the metal of the catalyst.

[0142] 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 a phosphine ligand, a carbene ligand, an imidazole ligand, a pincer chelate ligand, and a compound comprising a sulfoxide group. In certain embodiments, the perfluorinated SABRE catalyst comprises one or more phosphine ligands. Examples of phosphine ligands include, but are not limited to, the following:

[0143]

[0144] In some embodiments, the perfluorinated SABRE catalyst comprises a pincer chelate ligand. Typically, when the perfluorinated SABRE catalyst comprises a phosphine ligand or a pincer chelate ligand, the perfluorinated SABRE catalyst is in the form of a pre-catalyst. In some embodiments, the perfluorinated SABRE catalyst comprises a ligand, which is a compound comprising a sulfoxide group. Examples of compounds comprising sulfoxide groups can be selected from dimethyl sulfoxide (DMSO), phenyltrifluoromethyl sulfoxide, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide and dibutyl sulfoxide. Typically, when the perfluorinated SABRE catalyst comprises a compound containing a sulfoxide group, the perfluorinated SABRE catalyst is in an active form. As used herein, "perfluorinated SABRE catalyst" may refer to an active perfluorinated SABRE catalyst or a perfluorinated SABRE pre-catalyst.

[0145] Active perfluorinated SABRE catalysts can be prepared by any suitable method. Typically, active perfluorinated SABRE catalysts are prepared by combining a perfluorinated SABRE precatalyst with a substrate, secondary hydrogen, and an optional co-ligand in a solvent to form a mixture comprising an active perfluorinated SABRE catalyst. In some embodiments, active perfluorinated SABRE catalysts are prepared by combining a perfluorinated SABRE precatalyst with a substrate, secondary hydrogen, and a co-ligand in a solvent to form a mixture comprising an active perfluorinated SABRE catalyst. When a co-ligand is included in the preparation of an active perfluorinated SABRE catalyst, the co-ligand can be combined with a perfluorinated SABRE precatalyst in any order and by any suitable means. For example, when a co-ligand is included in the preparation of an active SABRE catalyst, a co-ligand can be first provided to interact with a transfer precatalyst to promote the formation of an active perfluorinated SABRE catalyst. Alternatively, when a co-ligand is included in the preparation of an active perfluorinated SABRE catalyst, the co-ligand can be added together with the substrate to promote the formation of an active perfluorinated SABRE catalyst. In some embodiments, the co-ligand, substrate and secondary hydrogen are combined with the perfluorinated SABRE precatalyst in a solvent substantially simultaneously to promote the formation of an active perfluorinated SABRE catalyst. In other embodiments, a substrate is first provided to interact with the perfluorinated SABRE precatalyst to promote the formation of an active SABRE catalyst. In some embodiments, the co-ligand and substrate are combined with the perfluorinated SABRE precatalyst in a solvent, and secondary hydrogen is added to (e.g., bubbled through) the resulting mixture. In other embodiments, the substrate is combined with the perfluorinated SABRE precatalyst in a solvent, and secondary hydrogen is added to (e.g., bubbled through) the resulting mixture. In some embodiments, the active perfluorinated SABRE catalyst is prepared by combining the perfluorinated SABRE precatalyst with a co-ligand except the substrate and secondary hydrogen.

[0146] In some embodiments, the active perfluorinated SABRE catalyst has the formula

[0147] [Ir(H)2(F-IMes)(η 2 -SUBSTRATE)(coligand)] or

[0148] [Ir(H)2(F-IMes)(η 1 -SUBSTRATE)(co-ligand)2],

[0149] Wherein SUBSTRATE is a target substrate that is hyperpolarized by transfer of pure singlet spin-ordered parahydrogen by a spin transfer catalyst, preferably having a substrate rich in 1 / 2 spin nuclei (e.g. 1 H. 13 C. 15 N. 19F. 31 P and / or 29 The target substrate is an atom of Si). Without wishing to be bound by any particular theory, the co-ligand interacts with the spin transfer pre-catalyst to form an activated polarization transfer catalyst and enhances the polarization transfer to the target substrate. F-IMes refers to a perfluorinated form of N-heterocyclic carbene (NHC) ligand, such as 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazole-2-ylidene group.

[0150] In some embodiments, a perfluorinated SABRE catalyst (e.g., a perfluorinated SABRE precatalyst) can be prepared by a process comprising reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [(d-block element)(COD)Cl]2, wherein COD represents a cyclooctadienyl group. In certain embodiments, the process comprises reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [Ir(COD)Cl]2. For example, a catalyst having the formula

[0151]

[0152] The perfluorinated SABRE catalyst can be prepared by making a catalyst having the formula

[0153] Prepared by reacting carbene with [Ir(COD)Cl]2.

[0154] Exemplary perfluorinated SABRE catalysts (e.g., perfluorinated SABRE precatalysts) include:

[0155]

[0156]

[0157] or a salt thereof.

[0158] The present invention also provides a method for preparing a hyperpolarized substrate, the method comprising:

[0159] (i) providing a perfluorinated SABRE catalyst as described herein;

[0160] (ii) providing a co-ligand to interact with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst;

[0161] (iii) combining an active perfluorinated SABRE catalyst with parahydrogen and a substrate comprising a 1 / 2 spin nucleus or a plurality of 1 / 2 spin nuclei in a solvent to obtain a reaction mixture; and

[0162] (iv) hyperpolarizing the mixture obtained in (iii) by exposing it to a magnetic field or by radio frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate.

[0163] The method for preparing a hyperpolarized substrate described herein comprises hyperpolarizing a mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) by exposing the mixture to a magnetic field or radio frequency excitation to transfer polarization from parahydrogen to the substrate to form a hyperpolarized substrate. Initially, the hyperpolarized substrate is complexed with the hyperpolarized perfluorinated SABRE catalyst; however, it will be understood by one of ordinary skill in the art that the hyperpolarized substrate can be replaced by another substrate molecule so that the process can be repeated and free hyperpolarized substrate groups can be generated.

[0164] The transfer of polarization from the parahydrogen to the substrate to form a hyperpolarized substrate can occur under any suitable magnetic field or radio frequency excitation. For example, the transfer of polarization from the parahydrogen to the substrate can occur under a magnetic field below the earth's magnetic field. Suitable levels of magnetic field or radio frequency excitation required to transfer polarization from the parahydrogen to the substrate to form a hyperpolarized substrate will be apparent to those of ordinary skill in the art.

[0165] In some embodiments, the method includes replenishing parahydrogen in the mixture during the step of hyperpolarizing the mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) by exposing the mixture comprising a perfluorinated SABRE catalyst to a magnetic field or radio frequency excitation to transfer polarization from parahydrogen to a substrate to form a hyperpolarized substrate. In other words, in some embodiments, the method includes bubbling parahydrogen through the mixture comprising a perfluorinated SABRE catalyst during the step of hyperpolarizing the mixture comprising a perfluorinated SABRE catalyst by exposing the mixture comprising a perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) to a magnetic field or radio frequency excitation to transfer polarization from parahydrogen to a substrate to form a hyperpolarized substrate.

[0166] The method for preparing the hyperpolarized substrate comprises providing a co-ligand to interact with the perfluorinated SABRE catalyst to promote the formation of the 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 comprising a sulfoxide group. Examples of compounds comprising a sulfoxide group can be selected from DMSO, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, phenyltrifluoromethyl sulfoxide and dibutyl sulfoxide. In certain embodiments, the co-ligand is dimethyl sulfoxide or phenyltrifluoromethyl sulfoxide.

[0167] In an embodiment of the method for preparing a hyperpolarized substrate, the magnetic field is an electromagnetic field. For example, the intensity of the electromagnetic field can be 0-200 millitesla (mT). In some embodiments, the electromagnetic field can be provided at least in part by one or more permanent magnets in addition to or in place of the coil. In some embodiments, the electromagnetic field can be an alternating magnetic field provided at a frequency suitable for a particular nucleus. The alternating magnetic field can change direction (i.e., alternate between positive and negative relative to the positive direction). In some embodiments, the frequency can be radio frequency, and is preferably 50 to 500 MHz, although other frequencies outside this range are also considered to be within the scope of the present disclosure.

[0168] A perfluorinated SABRE catalyst (e.g., an active perfluorinated SABRE catalyst) is combined with parahydrogen and a substrate comprising a 1 / 2 spin core or multiple 1 / 2 spin cores in a solvent to obtain a reaction mixture. The solvent can be any suitable solvent capable of forming a heterogeneous or homogeneous mixture. In some embodiments, the solvent includes water, methanol, ethanol, a fluorinated solvent, or a mixture thereof. For example, the solvent can be ethanolic or methanolic, i.e., at least comprising ethanol or methanol combined with water. In certain embodiments, the solvent includes a fluorinated solvent. In other embodiments, the solvent is deuterated so that a deuterated solvent can be prepared without (i.e., with limited) deuterium-hydrogen exchange.

[0169] Fluorinated solvents can be any organic solvents comprising at least one compound with fluorine atoms. 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, solvents (e.g., fluorinated solvents) are selected from perfluorohexane / diethyl ether mixtures, methoxy nonafluorobutane and ethyl acetate mixtures with nonpolar solvents, perfluorohexane and ether mixtures, perfluorobutyl methyl ether and ethyl acetate mixtures, ethers, fluorocarbon derivatives of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkanes, perfluorohexane, and methoxy nonafluorobutane.

[0170] In some embodiments, the method of preparing a hyperpolarized substrate further comprises isolating the hyperpolarized substrate. The hyperpolarized substrate can be isolated by any suitable method. For example, the hyperpolarized substrate can be isolated by extraction, filtration, column chromatography, distillation, crystallization, or a combination thereof.

[0171] In some embodiments, the hyperpolarized substrate is isolated by treating the reaction mixture with a solid phase adsorbent to adsorb the perfluorinated SABRE catalyst and recovering a liquid containing the hyperpolarized substrate, wherein the liquid is free (i.e., undetectable) or substantially free (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) of the perfluorinated SABRE catalyst. See, e.g., Figure 5 The solid phase adsorbent can be any suitable adsorbent that can preferentially adsorb the perfluorinated SABRE catalyst over the hyperpolarized substrate. For example, the solid phase adsorbent can be a fluorinated solid phase adsorbent, a reverse phase adsorbent (e.g., C18 adsorbent, etc.), and a polyethylene-based filter (e.g., ultra-high molecular weight polyethylene). See, for example, Figure 1 and Figure 2 . In certain embodiments, the method for preparing a hyperpolarized substrate further comprises passing a fluorophilic solvent through an adsorbent and recovering an eluent containing the hyperpolarized substrate, wherein the eluent is free of (i.e., undetectable) or substantially free of (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) a perfluorinated SABRE catalyst. The fluorophilic solvent may be any suitable solvent that is capable of preferentially washing the hyperpolarized substrate from the solid phase adsorbent relative to the perfluorinated SABRE catalyst. For example, the fluorophilic solvent may include one or more of water and methanol, ethanol, acetonitrile, and dimethylformamide. Alternatively or additionally, the method for preparing a hyperpolarized substrate may further comprise, for example, passing a fluorophilic solvent (e.g., a solvent comprising an organic solvent selected from methanol, ethanol, acetonitrile, THF, ethyl acetate, a chlorinated solvent (e.g., a chlorinated alkane such as dichloromethane, chloroform, and dichloroethane) and combinations thereof) through an adsorbent to recover the perfluorinated SABRE catalyst. Exemplary fluorophilic solvent systems include perfluorohexane / diethyl ether mixtures, methoxynonafluorobutane and ethyl acetate mixtures, perfluorohexane and diethyl ether mixtures, perfluorobutyl methyl ether and ethyl acetate mixtures or diethyl ether.

[0172] In some embodiments, the hyperpolarized substrate is separated by treating the reaction mixture with a solid phase adsorbent to adsorb the hyperpolarized substrate and recovering a liquid containing the perfluorinated SABRE catalyst, wherein the liquid is free (i.e., undetectable) or substantially free (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) of the hyperpolarized substrate. The solid phase adsorbent can be any suitable adsorbent capable of preferentially adsorbing the hyperpolarized substrate over the perfluorinated SABRE catalyst. For example, the solid phase adsorbent can be a normal phase adsorbent, such as silica, alumina, and the like. See, e.g., Figure 3. In certain embodiments, the method for preparing a hyperpolarized substrate further comprises passing a fluorophilic solvent through an adsorbent and recovering an eluent containing a perfluorinated SABRE catalyst, wherein the eluent is free of (i.e., undetectable) or substantially free of (e.g., less than 100 ppm, less than 50 ppm, less than 10 ppm, less than 5 ppm, or less than 1 ppm) the hyperpolarized substrate. The fluorophilic solvent may be any suitable solvent that is capable of preferentially washing the perfluorinated SABRE catalyst from the solid phase adsorbent relative to the hyperpolarized substrate. For example, a fluorophobic 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. Alternatively or additionally, the method for preparing a hyperpolarized substrate may further comprise, for example, passing a fluorophobic solvent (e.g., a solvent comprising water, methanol, ethanol, acetonitrile, dimethylformamide, or a combination thereof) through an adsorbent to recover the hyperpolarized substrate.

[0173] In any of the embodiments disclosed herein, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be present in a single phase or a biphasic mixture. The single phase or biphasic mixture can contain any combination of solvents described herein. For example, a biphasic mixture can contain a combination of a polar solvent (e.g., water, methanol, and ethanol) and a non-polar solvent (e.g., an organic solvent or a fluorinated solvent). In embodiments where the perfluorinated SABRE catalyst and / or the hyperpolarized substrate are present in a biphasic solvent, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be separated by liquid / liquid extraction. See, for example, Figure 4 Thus, in some embodiments, the hyperpolarized substrate is separated by liquid / liquid extraction, for example, by partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanol mixture and a fluorinated solvent, or partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanol mixture and an organic solvent.

[0174] In some embodiments, the hyperpolarized substrate is isolated by precipitating the perfluorinated SABRE catalyst and filtering and removing the precipitated perfluorinated SABRE catalyst from the hyperpolarized substrate. Typically, the perfluorinated SABRE catalyst is precipitated by adding a solvent in which the perfluorinated SABRE catalyst is not soluble (e.g., hexane, pentane, water, ethanol, etc.). In certain embodiments, the perfluorinated SABRE catalyst is precipitated by adding water.

[0175] The perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be dried or concentrated (e.g., under reduced pressure, using a desiccant, heating, or a combination thereof). Alternatively or additionally, the perfluorinated SABRE catalyst and / or the hyperpolarized substrate can be diluted or reconstituted with a solvent (e.g., water) to provide the desired concentration. For example, the perfluorinated SABRE catalyst can be separated and reused as a hyperpolarized catalyst. Similarly, the hyperpolarized substrate can be dried or concentrated to remove the organic solvent and reconstituted in water for administration to an individual.

[0176] The substrate may be any compound containing a 1 / 2 spin nucleus or multiple 1 / 2 spin nuclei. For example, the substrate may contain 1 H. 13 C. 15 N. 19 F. 31 P. 29 Si or a combination thereof. In some embodiments, the substrate further comprises 2 D. Therefore, the methods described herein can be used to enhance the 1 H. 13 C. 15 N. 19 F. 31 P and / or 29 The signal of the Si response. In general, the spin polarization transfer described herein is based on the SABRE effect; however, the approach can be extended to parahydrogen induced polarization (PHIP).

[0177] In some embodiments, the substrate is selected from ketoglutarate, pyruvate, N-acetylcysteine, and salts or esters thereof. 13 C-ketoglutarate, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbonyl-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form, and its salts.

[0178] In some embodiments, the substrate has formula (II):

[0179]

[0180] wherein each R1 is independently selected from hydrogen, deuterium, a cation, a C1-C6 alkyl, a C3-C7 cycloalkyl, a (C3-C7 cycloalkyl)C1-C6 alkyl, a (heterocycloalkyl)C1-C6 alkyl, a (heteroaryl)C1-C6 alkyl, and a (aryl)C1-C6 alkyl; and

[0181] 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,

[0182] or a pharmaceutically acceptable salt thereof.

[0183] Each R1 can be independently selected from hydrogen, deuterium, cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C6 alkyl, (heterocycloalkyl) C1-C6 alkyl, (heteroaryl) C1-C6 alkyl and (aryl) C1-C6 alkyl. In some embodiments, each R1 is independently selected from C1-C6 alkyl, for example, each R1 can be methyl, ethyl, propyl (for example, isopropyl or n-propyl), butyl (for example, isobutyl, n-butyl, tert-butyl or sec-butyl), pentyl or hexyl. In some embodiments, each R1 is independently selected from hydrogen, deuterium and cation. In the embodiment where R1 is a cation, it will be readily understood by those of ordinary skill in the art that the compound of formula (II) is a salt (for example, a pharmaceutically acceptable salt) in which the negative charge on oxygen is balanced by a cation. In certain embodiments, each R1 is independently a cation or C1-C6 alkyl.

[0184] The present invention also provides a hyperpolarized substrate or a pharmaceutically acceptable salt obtained from any of the methods described herein, or a pharmaceutical composition comprising a hyperpolarized substrate or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. In other words, the present invention provides an imaging medium (e.g., an aqueous imaging composition) having enhanced sensitivity to a water-soluble compound or a hyperpolarizable nucleus comprising a hyperpolarizable nucleus, the imaging medium being particularly suitable for use in nuclear magnetic resonance (NMR) spectroscopy and / or magnetic resonance imaging (MRI).

[0185] The present invention also provides a method for obtaining a magnetic resonance image of a tissue in an individual suffering from or suspected of suffering from cancer or an adverse vascular condition, the method comprising administering a hyperpolarized substrate described herein or a pharmaceutical composition thereof to the individual, and imaging the individual by magnetic resonance imaging. In one aspect, the individual suffers from cancer, such as a cancer selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer. On the other hand, the individual suffers from an adverse vascular condition, such as a vascular condition selected from myocardial infarction, stroke, and lung disease (e.g., COPD, pulmonary fibrosis, long-term COVID-19 symptoms, and combinations thereof).

[0186] 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 a hyperpolarized substrate or pharmaceutical composition as described above, and 13 C-MRI diagnoses or monitors patients. For example, the hyperpolarized substrate can be used in a method for diagnosing or monitoring a patient suffering from or suspected of having cancer. In certain embodiments, the method or use comprises identifying one or more mutations that cause cancer. In certain embodiments, the method or use identifies an IDH1 mutation as causing cancer. In other words, the method or use can be used to identify whether a patient has a tumor, for example, an IDH1 mutation.

[0187] The present invention also provides a perfluoro compound of formula (III):

[0188]

[0189] in

[0190] Each Ar is independently selected from a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0191] Each Ar f are independently selected from perfluorinated substituted or unsubstituted aromatic groups, or perfluorinated substituted or unsubstituted heteroaromatic groups,

[0192] Each Y is independently selected from a bond or a spacer group,

[0193] X is an anion, and

[0194] Is a single bond or a double bond.

[0195] All aspects of the perfluorinated compound of formula (III) are as described for any one of formula (I) and formula (Ia) to formula (If). f is independently selected from a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group, wherein the substituted or unsubstituted aromatic group and the substituted or unsubstituted heteroaromatic group are as described for any one of Formula (I) and Formula (Ia) to Formula (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 independently selected from perfluorinated substituted or unsubstituted aromatic groups, and / or (iii) each Y is independently selected from a spacer group selected from C 1-5 Alkyl and C 1-5 Heteroalkyl.

[0196] In certain embodiments, the perfluorinated compound has formula (IIIa):

[0197]

[0198] in

[0199] Each n is independently an integer from 0 to 4,

[0200] X is an anion, and

[0201] Is a single bond or a double bond.

[0202] In formula (III) and formula (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 fluoride salt ion (e.g., tetrafluoroborate or hexafluorophosphate).

[0203] The perfluoro compound of formula (III) or formula (IIIa) can be prepared by any suitable method. For example, the perfluoro compound can be prepared by the following method, including:

[0204] (i) reacting an α-bromoketone comprising a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group with an amidine comprising a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group in the presence of a base to form an α-aminoketone,

[0205] (ii) optionally reducing the α-amino ketone with a reducing agent to form an α-amino alcohol, and

[0206] (iii) Cyclizing an α-amino ketone or α-amino alcohol to form a perfluorinated compound.

[0207] The perfluoro compound of formula (III) or formula (IIIa) can be used in any suitable manner. For example, the perfluoro compound of formula (III) or formula (IIIa) can be used for catalysis (e.g., polymerization catalysis or SABRE catalysis). Therefore, in some embodiments, the present invention provides a catalyst (e.g., olefin metathesis catalyst or SABRE catalyst) of a perfluoro compound comprising a d-block element and a ligand as a ligand. For example, an olefin metathesis catalyst comprising a perfluoro compound of formula (III) or formula (IIIa) can be used in a method for polymerizing olefins, the method comprising combining an olefin metathesis catalyst with an olefin in a reaction mixture. Similarly, a SABRE catalyst comprising a perfluoro compound of formula (III) or formula (IIIa) can be used in a method for hyperpolarizing a substrate as described herein.

[0208] Aspects of the Disclosure

[0209] The aspects of the invention described herein (including embodiments) may be beneficial alone, or may be beneficial in combination with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure numbered 1 to 65 are provided below. It will be apparent to those skilled in the art after reading this disclosure that each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for such combinations of all aspects, and is not limited to the combinations of aspects explicitly provided below:

[0210] (1) In aspect (1), a perfluorinated SABRE catalyst is provided, comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand has formula (I):

[0211] [L m -(NHC)-(YZ) q ]

[0212] Formula (I),

[0213] or a salt thereof, and wherein

[0214] Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0215] NHC is a 4- to 7-membered N-heterocyclic carbene radical, wherein the NHC is bonded to a d-block element via a carbene,

[0216] Each Y is independently selected from a bond or a spacer group,

[0217] Each Z is a perfluorinated tag,

[0218] m is an integer from 1 to 4, and

[0219] q is an integer from 1 to 3.

[0220] (2) In aspect (2), there is provided the perfluorinated SABRE catalyst of aspect 1, wherein NHC is a 5-membered N-heterocyclic carbene group.

[0221] (3) In aspect (3), there is provided the perfluorinated SABRE catalyst of aspect 2, wherein the 5-membered N-heterocyclic carbene group is imidazole-based, imidazoline-based or thiazole-based.

[0222] (4) In aspect (4), a perfluorinated SABRE catalyst according to any one of aspects 1 to 3 is provided, 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.

[0223] (5) In aspect (5), a perfluorinated SABRE catalyst according to any one of aspects 1 to 4 is provided, wherein NHC is a 4,5-disubstituted imidazolidinyl, a 1,3-disubstituted imidazolidinyl, a 1,3,4,5-tetrasubstituted imidazolidinyl, a 4,5-disubstituted 2,3-dihydro-imidazolyl, a 1,3-disubstituted 2,3-dihydro-imidazolyl or a 1,3,4,5-tetrasubstituted 2,3-dihydro-imidazolyl.

[0224] (6) In aspect (6), a perfluorinated SABRE catalyst of aspect 1 is provided, wherein the perfluorinated ligand has formula (Ia) or formula (Ib):

[0225]

[0226] or a salt thereof, and wherein

[0227] Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0228] Each Y is independently a bond or a spacer group,

[0229] Each Z is independently a perfluorinated tag,

[0230] is a single bond or a double bond, and

[0231] represents bonding to a d-block element via a carbene.

[0232] (7) In aspect (7), a perfluorinated SABRE catalyst of aspect 1 is provided, wherein the perfluorinated ligand has formula (Ic) or formula (Id):

[0233]

[0234] or a salt thereof, and wherein

[0235] Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0236] a is 4 to 20,

[0237] b = 2a + 1 or b = a – 1,

[0238] Each n is independently an integer from 0 to 4,

[0239] is a single bond or a double bond, and

[0240] represents bonding to a d-block element via a carbene.

[0241] (8) In aspect (8), a perfluorinated SABRE catalyst of aspect 1 is provided, wherein the perfluorinated ligand has formula (Ie) or formula (If):

[0242]

[0243] or a salt thereof, and wherein

[0244] Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0245] Each Ar is independently a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0246] Each G is independently a key, C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 Heteroalkyl,

[0247] a is 4 to 20,

[0248] b = 2a + 1 or b = a – 1,

[0249] is a single bond or a double bond, and

[0250] represents the bonding to the d-block element via a carbene.

[0251] (9) In aspect (9), a perfluorinated SABRE catalyst according to aspect 7 or aspect 8 is provided, wherein a is 4 to 10.

[0252] (10) In aspect (10), a perfluorinated SABRE catalyst according to any one of aspects 1 to 9 is provided, wherein 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-diisopropylphenyl, 2,5-diisopropylphenyl, 2,6-diisopropylphenyl, 3,5-di-n-propylphenyl, 2,4,6-tri-n-propylphenyl Isopropylphenyl, 2,4,6-triisopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-diisobutylphenyl, 2,5-diisobutylphenyl, 2,6-diisobutylphenyl, 3,5-diisobutylphenyl, 2,4,6-triisobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2,4-di-sec-butylphenyl, 2,5-di-sec-butylphenyl, 2,6-di-sec-butylphenyl, 3,5-di-sec-butylphenyl, 2,4 ,6-tri-sec-butylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2,4-di-tert-butylphenyl, 2,5-di-tert-butylphenyl, 2,6-di-tert-butylphenyl, 3,5-di-tert-butylphenyl, 2,4,6-tri-tert-butylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2,4-dicyclohexylphenyl, 2,5-dicyclohexylphenyl, 2,6-dicyclohexylphenyl, 3,5-dicyclohexylphenyl or 2,4,6-tricyclohexylphenyl.

[0253] (11) In aspect (11), provided is the perfluorinated SABRE catalyst of any one of aspects 1 to 10, wherein each L is independently hydrogen or 2,4,6-trimethylphenyl.

[0254] (12) In aspect (12), there is provided 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 groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6a heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, a substituted or unsubstituted arylalkyl group, or a linear or branched alkyleneoxy group.

[0255] (13) In aspect (13), there is provided 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 groups, substituted or unsubstituted C 2-10 an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted arylalkyl group.

[0256] (14) In aspect (14), a perfluorinated SABRE catalyst according to any one of aspects 1 to 11 is provided, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted arylalkyl group.

[0257] (15) In aspect (15), there is provided a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is a perfluorinated C containing only carbon and fluorine atoms. 3-60 Group.

[0258] (16) In aspect (16), there is provided a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is a perfluorinated C containing only carbon and fluorine atoms. 3-40 Group.

[0259] (17) In aspect (17), there is provided a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is a perfluorinated C 3-20 Group.

[0260] (18) In aspect (18), there is provided a perfluorinated SABRE catalyst according to any one of aspects 1 to 14, wherein the perfluorinated tag is selected from a C4F9 group, a 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 13Group, C8F 15 Group, C9F 17 Group and C 10 F 19 Group.

[0261] (19) In aspect (19), there is provided the perfluorinated SABRE catalyst of aspect 1, wherein the perfluorinated ligand is

[0262]

[0263] or a salt thereof, and wherein

[0264] is a single bond or a double bond, and

[0265] represents bonding to a d-block element via a carbene.

[0266] (20) In aspect (20), there is provided the perfluorinated SABRE catalyst of any one of aspects 1 to 19, wherein the d-block element is a transition metal.

[0267] (21) In aspect (21), a perfluorinated SABRE catalyst according to any one of aspects 1 to 20 is provided, wherein the d-block element is Co, Rh, Ir, Ru, Pd, Pt or Mt.

[0268] (22) In aspect (22), there is provided the perfluorinated SABRE catalyst of any one of aspects 1 to 21, wherein the perfluorinated SABRE catalyst further comprises an additional ligand.

[0269] (23) In aspect (23), there is provided the perfluorinated SABRE catalyst of aspect 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 comprising a sulfoxide group.

[0270] (24) In aspect (24), a method for preparing the perfluorinated SABRE catalyst of any one of aspects 1 to 23 is provided, comprising reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [(d-block element)(COD)Cl]2, wherein COD represents cyclooctadienyl.

[0271] (25) In aspect (25), the method of aspect 24 is provided, wherein the d-block element is Co, Rh, Ir, Ru, Pd, Pt or Mt.

[0272] (26) In aspect (26), a method for preparing a hyperpolarized substrate is provided, the method comprising:

[0273] (i) providing a perfluorinated SABRE catalyst according to any one of aspects 1 to 23;

[0274] (ii) providing a co-ligand to interact with the perfluorinated SABRE catalyst to promote the formation of an active perfluorinated SABRE catalyst;

[0275] (iii) combining an active perfluorinated SABRE catalyst with parahydrogen and a substrate comprising a 1 / 2 spin nucleus or a plurality of 1 / 2 spin nuclei in a solvent to obtain a reaction mixture; and

[0276] (iv) hyperpolarizing the mixture obtained in (iii) by exposing the mixture to a magnetic field or by radio frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate.

[0277] (27) In aspect (27), the method of aspect 26 is provided, wherein the substrate comprises 1 H. 13 C. 15 N. 19 F. 31 P. 29 Si or a combination thereof.

[0278] (28) In aspect (28), the method of aspect 27 is provided, wherein the substrate further comprises 2 D.

[0279] (29) In aspect (29), a method of aspect 27 or 28 is provided, 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 a combination thereof.

[0280] (30) In aspect (30), the method of any one of aspects 26 to 29 is provided, wherein the solvent comprises water, methanol, ethanol, a fluorinated solvent or a mixture thereof.

[0281] (31) In aspect (31), a method according to any one of aspects 26 to 29 is provided, wherein the solvent comprises a solvent selected from a perfluorohexane / diethyl ether mixture, a methoxynonafluorobutane and ethyl acetate mixture with a non-polar solvent, a perfluorohexane and ether mixture, a perfluorobutyl methyl ether and ethyl acetate mixture, ether, a fluorocarbon derivative of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkanes, perfluorohexane and methoxynonafluorobutane.

[0282] (32) In aspect (32), there is provided the method of any one of aspects 26 to 31, wherein the solvent is deuterated.

[0283] (33) In aspect (33), a method according to any one of aspects 26 to 32 is provided, wherein the co-ligand is dimethyl sulfoxide or phenyltrifluoromethyl sulfoxide.

[0284] (34) In aspect (34), the method of any one of aspects 26 to 33 is provided, further comprising (vi) isolating the hyperpolarized substrate.

[0285] (35) In aspect (35), a method of aspect 34 is provided, wherein the hyperpolarized substrate is separated by treating the reaction mixture with a solid phase adsorbent to adsorb the perfluorinated SABRE catalyst and recovering a liquid containing the hyperpolarized substrate, wherein the liquid contains no or substantially no perfluorinated SABRE catalyst.

[0286] (36) In aspect (36), the method of aspect 35 is provided, further comprising passing the fluorophobic solvent through the adsorbent and recovering an eluent containing the hyperpolarized substrate, wherein the eluent contains no or substantially no perfluorinated SABRE catalyst.

[0287] (37) In aspect (37), the method of aspect 36 is provided, wherein the fluorine-repellent solvent comprises water, and one or more of methanol, ethanol, acetonitrile and dimethylformamide.

[0288] (38) In aspect (38), the method of aspect 36 or aspect 37 is provided, further comprising passing the fluorophilic solvent through an adsorbent.

[0289] (39) In aspect (39), the method of aspect 38 is provided, wherein the fluorophilic solvent comprises an organic solvent selected from the group consisting of methanol, ethanol, acetonitrile, THF, ethyl acetate, chlorinated solvents, and combinations thereof.

[0290] (40) In aspect (40), a method of aspect 34 is provided, wherein the hyperpolarized substrate is separated by treating the reaction mixture with a solid phase adsorbent to adsorb the hyperpolarized substrate and recovering a liquid containing the perfluorinated SABRE catalyst, wherein the liquid contains no or substantially no hyperpolarized substrate.

[0291] (41) In aspect (41), the method of aspect 40 is provided, further comprising passing the fluorophilic solvent through the adsorbent and recovering an eluate containing the perfluorinated SABRE catalyst, wherein the eluate is free of or substantially free of the hyperpolarized substrate.

[0292] (42) In aspect (42), the method of aspect 41 is provided, wherein the 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.

[0293] (43) In aspect (43), the method of aspect 34 is provided, wherein the hyperpolarized substrate is separated by liquid / liquid extraction.

[0294] (44) In aspect (44), the method of aspect 43 is provided, wherein the liquid / liquid extraction comprises partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanol mixture and a fluorinated solvent.

[0295] (45) In aspect (45), the method of aspect 43 is provided, wherein the liquid / liquid extraction comprises partitioning the perfluorinated SABRE catalyst and the hyperpolarized substrate between a methanol mixture and an organic solvent.

[0296] (46) In aspect (46), the method of aspect 34 is provided, wherein the hyperpolarized substrate is isolated by precipitating the perfluorinated SABRE catalyst and filtering, and removing the precipitated perfluorinated SABRE catalyst from the hyperpolarized substrate.

[0297] (47) In aspect (47), the method of aspect 46 is provided, wherein the perfluorinated SABRE catalyst is precipitated by adding water.

[0298] (48) In aspect (48), a method according to any one of aspects 26 to 47 is provided, wherein the substrate is selected from ketoglutarate, pyruvate, N-acetylcysteine ​​and salts or esters thereof.

[0299] (49) In aspect (49), the method of any one of aspects 26 to 48 is provided, wherein the substrate is selected from 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbonyl-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form, and its salts.

[0300] (50) In aspect (50), the method of any one of aspects 26 to 48 is provided, wherein the solvent has formula (II):

[0301]

[0302] wherein each R1 is independently selected from hydrogen, deuterium, a cation, a C1-C6 alkyl, a C3-C7 cycloalkyl, a (C3-C7 cycloalkyl)C1-C6 alkyl, a (heterocycloalkyl)C1-C6 alkyl, a (heteroaryl)C1-C6 alkyl, and a (aryl)C1-C6 alkyl; and

[0303] 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,

[0304] or a pharmaceutically acceptable salt thereof.

[0305] (51) In aspect (51), provided is a hyperpolarized substrate obtained by the method of any one of aspects 26 to 50, or a pharmaceutically acceptable salt thereof.

[0306] (52) In aspect (52), a pharmaceutical composition is provided, comprising the hyperpolarized substrate of aspect 51 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0307] (53) In aspect (53), a method for obtaining a magnetic resonance image of tissue in an individual suffering from or suspected of suffering from cancer or an adverse vascular condition is provided, comprising administering to the individual a hyperpolarized substrate according to aspect 51 or a pharmaceutical composition according to aspect 52, and imaging the individual by magnetic resonance imaging.

[0308] (54) In aspect (54), the method of aspect 53 is provided, wherein the individual suffers from cancer.

[0309] (55) In aspect (55), the method of aspect 54 is provided, wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, bladder cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer and thyroid cancer.

[0310] (56) In aspect (56), the method of aspect 53 is provided, wherein the adverse vascular condition is selected from myocardial infarction, stroke and lung disease.

[0311] (57) In aspect (57), the method of aspect 56 is provided, wherein the lung disease is selected from COPD, pulmonary fibrosis, long-term COVID-19 symptoms, and combinations thereof.

[0312] (58) In aspect (58), a perfluoro compound of formula (III) is provided:

[0313]

[0314] in

[0315] Each Ar is independently selected from a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

[0316] Each Ar f are independently selected from perfluorinated substituted or unsubstituted aromatic groups, or perfluorinated substituted or unsubstituted heteroaromatic groups,

[0317] Each Y is independently selected from a bond or a spacer group,

[0318] X is an anion, and

[0319] Is a single bond or a double bond.

[0320] (59) In aspect (59), the perfluoro compound of aspect 58 is provided, wherein each Ar is independently selected from a substituted or unsubstituted aromatic group.

[0321] (60) In aspect (60), a compound of aspect 58 or aspect 59 is provided, wherein each Ar f Independently selected from perfluorinated substituted or unsubstituted aromatic groups.

[0322] (61) In aspect (61), the perfluoro compound of any one of aspects 58-60 is provided, wherein each Y is independently selected from a spacer group selected from C 1-5 Alkyl and C 1-5 Heteroalkyl.

[0323] (62) In aspect (62), the perfluoro compound of aspect 58 is provided, wherein the perfluoro compound has formula (IIIa):

[0324]

[0325] in

[0326] Each n is independently an integer from 0 to 4,

[0327] X is an anion, and

[0328] Is a single bond or a double bond.

[0329] (63) In aspect (63), there is provided a method for preparing a perfluoro compound according to any one of aspects 58 to 62, the method comprising:

[0330] (i) reacting an α-bromoketone comprising a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group with an amidine comprising a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group in the presence of a base to form an α-aminoketone,

[0331] (ii) optionally reducing the α-amino ketone with a reducing agent to form an α-amino alcohol, and

[0332] (iii) Cyclizing an α-amino ketone or α-amino alcohol to form a perfluorinated compound.

[0333] (64) In aspect (64), there is provided an olefin metathesis catalyst comprising a d-block element and a perfluoro compound according to any one of aspects 58 to 62 as a ligand.

[0334] (65) In aspect (65), a method for polymerizing an olefin is provided, the method comprising combining the olefin metathesis catalyst of aspect 64 with an olefin in a reaction mixture.

[0335] The following examples further illustrate the invention but should, of course, not be construed as limiting its scope in any way.

[0336] Example 1

[0337] This example illustrates the preparation of 1H,1H,2H,2H-perfluorooctyl-N,N'-bis(2,4,6-trimethylphenyl)-9,10-diamine:

[0338]

[0339] Where x=6, and y=13.

[0340] At -78 ° C, a 1.7 M solution of tert-butyl lithium in pentane (5 mL, 9 mmol, 8 eq) was added to a solution of 1H, 1H, 2H, 2H-perfluorooctyl iodide (2 g, 4 mmol, 4 eq) in dry Et2O (60 mL). After the mixture was stirred for 20 minutes at -78 ° C, solid N, N'-dimethylethylenediimine (0.30 g, 1.03 mmol, 1 eq) was added in batches. The reaction mixture was stirred for 4 hours. The reaction was slowly warmed to -30 ° C and quenched with saturated ammonium chloride solution (0.6 mL).

[0341] Water (20 mL) was added, the organic layer was separated, and the aqueous layer was extracted with diethyl ether (3×15 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The crude product was purified by flash column chromatography (4:1 hexane / dichloromethane (DCM)) to give diamine, diimine and threo diamine (0.6 g, 60% yield, white solid). 1H NMR(400MHz, CDCl3)δ1.64-1.82(m,2H,CH2CHHCH(NHAr)),2.00(s,12H,o-CH3),2.07-2.27 (m,4H,CHHCHHCH(NHAr)),2.33(s,6H,p-CH3),2.67-2.91(m,2H,CHHCH2CH(NHAr)),2.95(br s,2H,NH),3.23(br d, 3 J H-H =10Hz,2H,CH),6.82(s,4H,Ar-CH)ppm. 19 F NMR(282.23MHz, CDCl3)δ-83.8(t, 3 J F-F =10Hz,6F,CF3),-114.4(m,4F,CF2CH2),-121.9(m,4F,CF2CF2CH2),-122.8(m,4F,CF3CF2CF2CF2),-123.4(m,4F,CF3CF2CF2),-126.1(m,4F,CF3CF2)ppm. 13 C NMR(400MHz, CDCl3)δ18.3(o-CH3),20.3(p-CH3),21.7(m,CF2CH2CH2),29.2(t, 2 J F-C =22.2Hz,CF2CH2),57.1(CH),107-115(m,8CF2),117.4(qt, 1 J F-C =288.3Hz, 2 J F-C =33.3Hz,CF3),118.7(tt, 1 JF-C=255.1Hz, 2 JF-C=31.0Hz, CF2CH2), 128.6(Ar-C), 129.9(Ar-CH), 131.4(Ar-C), 140.4(Ar-C)ppm. MS(ESI),m / z(%):990[M+H] + (100).

[0342] Example 2

[0343] 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:

[0344]

[0345] A mixture of 1H,1H,2H,2H-perfluorooctyl-N,N'-bis(2,4,6-trimethylphenyl)-9,10-diamine (0.250 g, 0.25 mmol) from Example 1, ammonium tetrafluoroborate (-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 x 3 mL). The residue was redissolved in acetone, filtered and concentrated to give dihydroimidazolium tetraborate. (0.2 g, 70% yield, slightly yellow solid). 1 H NMR (400MHz, acetone-d6) δ2.15-2.70(m,8H,CF2CH2CH2),2.34(s,6H,p-CH3),2.51(s,6H,o-CH3),2.94(br s, 2H, NH), 5.16 (m, 2H, CH2CH2CH), 7.17 (s, 4H, Ar-CH), 9.06 (s, 1H, N-CH=N) ppm. 19 F NMR (400MHz, acetone-d6) δ-81.6 (t, 4 J F-F =10Hz,6F,CF3),-115.1(m,4F,CF2CF2CH2),-122.5(m,4F,CF2CF2CH2),-123.6(m,4F,CF3 CF2CF2CF2),-124.5(m,4F,CF3CF2CF2),-126.9(m,4F,CF3CF2CF2),-150.9(4F,BF4)ppm. 13 C NMR (400MHz, acetone-d6) δ17.4 (o-CH3), δ17.7 (o-CH3), 19.9 (p-CH3), 24.4 (m, CF2CH2CH2), 26.2 (t, 2 J F-C =22.2Hz,CF2CH2),67.9(CH),105-118(m,8CF2),118(qt, 1 J F-C =288.3Hz, 2 J F-C =33.3Hz,CF3),118.9(tt, 1 JF-C=254Hz, 2JF-C=31.0Hz, CF2CH2), 129.5(Ar-C), 130.1(Ar-CH), 130.5(Ar-CH), 135.8(Ar-C), 136(Ar-C), 140.8(Ar-C)ppm, 159.7(NC=N)ppm. MS(ESI)m / z(%):999[M+H] + (100).

[0346] Example 3

[0347] 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:

[0348]

[0349] Dihydroimidazolium tetraborate (0.5 g, 0.46 mmol) was dissolved in MeOH (1.5 mL) and passed through a short column of ion exchange resin Amberlite 400. The column was washed with MeOH until no spots were visible by TLC under UV. The solvent was removed and the resulting yellowish solid was dried with a vacuum pump to give the product (0.48 g, 99%). 1 H NMR (400MHz, acetone-d6) δ2.15-2.70(m,8H,CF2CH2CH2),2.34(s,6H,p-CH3),2.51(s,6H,o-CH3),2.94(br s, 2H, NH), 5.16 (m, 2H, CH2CH2CH), 7.17 (s, 4H, Ar-CH), 9.06 (s, 1H, N-CH=N) ppm. 19 F NMR (400MHz, acetone-d6) δ-81.8 (t, 4 J F-F =10Hz,6F,CF3),-115.1(m,4F,CF2CF2CH2),-122.5(m,4F,CF2CF2CH2),-123.6(m,4F,CF3CF2CF2CF2),-124.5(m,4F,CF3CF2CF2),-127(m,4F,CF3CF2CF2)ppm. 13 C NMR (400MHz, acetone-d6) δ17.4 (o-CH3), δ17.7 (o-CH3), 19.9 (p-CH3), 24.4 (m, CF2CH2CH2), 26.2 (t, 2 J F-C=22.2Hz,CF2CH2),67.9(CH),105-118(m,8CF2),118(qt, 1 J F-C =288.3Hz, 2 J F-C =33.3Hz,CF3),118.9(tt, 1 JF-C=254Hz, 2 JF-C=31.0Hz, CF2CH2), 129.5(Ar-C), 130.1(Ar-CH), 130.5(Ar-CH), 135.8(Ar-C), 136(Ar-C), 140.8(Ar-C)ppm, 159.7(NC=N)ppm. MS(ESI)m / z(%):999[M+H] + (100).

[0350] Example 4

[0351] This example illustrates the synthesis of a fluorinated SABRE catalyst containing a transition metal according to one aspect of the present invention.

[0352]

[0353] At room temperature, in a glove box, 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-tridecafluorooctyl)-1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium chloride (320 mg, 0.88 mmol, 2.2 equiv) in tetrahydrofuran (10 mL) from Example 3. 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 a crude product, and dried overnight under vacuum. The sample was dissolved in hexanes and added to a 60 mL filter packed with SiO2 gel in hexanes. The crude solution was adsorbed on top of silica gel and hexanes were then added to elute the compound to afford 104 mg (40% yield). 1 H NMR (400MHz, CDCl3) δ1.04,1.18,1.49,1.76,2.13,2.22,2.25,2.4,2.48,2.66,2.94,3.73,4.01,4.2,6.84,6.91 6.97ppm. 19F NMR (400MHz, CDCl3) δ -81.08, -114.33, -122.05, -123.07, -124.02, -126.39ppm. 13 C NMR (100MHz, CDCl3) δ18.7,20.95,21.07,21.34,26.45,27.21,29.83,30.74,31.42,49.93,55.12,68.11,68.47,83.26,86.69,108.32,111.0 ,112.95,115.85,117.75,118.69,129.02,129.3,130.36,130.55,134. 71,134.8,135.32,136.33,137.92,138.28,138.45,138.5,206.72ppm. MS (ESI) m / z (%): 1299 [M+H] + (100).

[0354] Example 5

[0355] This example illustrates the use of [1- 13 C] Methods for pyruvate hyperpolarization.

[0356] Scheme 1. [1- 13 C] Hyperpolarization of pyruvate.

[0357]

[0358] Wherein the co-ligand = phenyl trifluoromethyl sulfoxide.

[0359] In the above reaction scheme, the co-ligand method developed by Duckett and colleagues (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)) was used. 13 SHIELD ENABLED ALIGNMENT TRANSFER TO HETERONUCLEI (SABRE-SHEATH) [1- 13 C] Hyperpolarization of pyruvate (Theis et al., J. Am. Chem. Soc., 137, 1404-1407 (2015) and Truong et al., J. Phys. Chem. C, 119, 8786-8797 (2015)).13 C]-Sodium pyruvate and deuterated methanol-d4 solvent were purchased from Sigma-Aldrich and used without any further purification. The [IrCl(COD)(F-IMes)]SABRE catalyst used in this example was prepared according to Example 4. The active catalyst used herein was prepared in a 5 mm NMR tube with a fixed ratio of substrate to the Ir(F-IMes)SABRE catalyst of Example 4 and 0.6 mL of phenyltrifluoromethyl sulfoxide (PTFSO) in methanol-d4.

[0360] Use gas delivery manifold (Gas-Delivery Manifold) to generate parahydrogen.Under liquid nitrogen temperature (77K), in the presence of spin exchange catalyst (Fe2O3), ultra-high purity hydrogen (Airgas) is supplied to parahydrogen flow cryostat (Xeus technology LTD) and enriched to about 50% parahydrogen. Via PTFE tube, p-H2 flow is directed to the mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) set to 90scc / m and is directed to conventional 5mm NMR tube (Norell) to allow bubbling by sample. Whole pH2 pipeline is pressurized to 100psi.

[0361] Magnetic shielding conditions are as follows. Magnetic fields approaching or below ~1 μT were achieved using an apparatus consisting of an electromagnetic coil placed inside a mu-metal shield (Magnetic Shielding, Inc., Model ZG-206). The shield was degaussed when necessary using an in-house homemade coil driven by a Variac. The solenoid had a 41 mm diameter (40 mm core, 20 cm long winding with 220 turns of AWG20 (0.9 mm) Cu wire and a 220 Ω series resistor. The solenoid coil was driven by a commercial 1.5 V battery with a variable resistor decade box in series to provide finer control of the internal magnetic field inside the shield. Typical values ​​of the field inside the shield were between ±1.2 μT, and SABRE SHEATH experiments were typically -0.7 μT to +0.8 μT in the sample area. Values ​​were monitored between SABRE experiments using a Lakeshore Cryotronics Gaussmeter (Model 475DSP with a HMMA-2512-VR Hall probe).

[0362] MR experiments were performed using a 1T Magritek Spinsolving benchtop NMR spectrometer. The 1 H decoupled to collect all 13 C NMR spectroscopy. The time required to manually transfer the sample from the shielded area to the magnet for low-field NMR acquisition was typically <5 seconds.

[0363] From nascent p-H2-derived hydrides to [1- 13 C]pyruvate 13 The efficient hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(PTFSO)2(F-IMes)], [1- 13 C] A solution mixture of pyruvate and p-H2 in deuterated methanol was subjected to SABRE in a sub-microtesla magnetic field using a shield to transfer alignment to the heteronucleus (SABRE-SHEATH). Figure 6 The top curve depicts a single scan HP acquired with the hyperpolarized probe. 13 C spectrum. The bottom curve shows the spectrum from 4M[1- 13 Single-scan thermal polarization of sodium acetate 13 C signal. The enhancement is ε~9000, and the polarization is about P( 13 C)~1%.

[0364] All experiments were performed with a fluorination catalyst containing 0.6 mL, a co-ligand (phenyl trifluoromethyl sulfoxide) and [1- 13 C] pyruvate CD3OD solution. The ratio and concentration can be further adjusted to obtain better enhancement and polarization. For 0.6 mL of 8 mM fluorination catalyst, 16 mM phenyl trifluoromethyl sulfoxide (PTFSO) and 30 mM [1- 13 C] Results for pyruvate CD3OD solutions. The experiments were performed at room temperature, ~100 scc / m p-H2 flow rate, and 96 PSI p-H2 overpressure. The parahydrogen used in this example came from a low-cost 50% p-H2 generator. For each experiment, p-H2 bubbling was applied for about 1 minute, the sample was quickly transferred to a 1T NMR spectrometer for detection, and then the sample was returned to the μ-metal shield to continue p-H2 bubbling for the next experiment. By using Equation 1: Comparison of the area under the curve (AUC) of the HP signal with that of the external 13 C signal thermal signal reference (4M[1- 13 C] sodium acetate) to calculate 13 C signal enhancement, where S HP and S REF It is from HP[1- 13 C]pyruvate and heat signal reference [1- 13 C] acetate 13 C signal, C REF and C HP They are the thermal signal reference [1- 13 C] acetate (4M) and HP[1- 13 C] pyruvate concentration, and AREF and A HP is used for thermal signal reference [1- 13 C] acetate and HP[1- 13 C] Effective cross section of the NMR tube for the pyruvate sample.

[0365] Example 6

[0366] This example illustrates the use of [1- 13 C] Methods for pyruvate hyperpolarization.

[0367] Scheme 2. Use of the perfluorinated SABRE catalyst of Example 4 with dimethyl sulfoxide as a co-ligand to 13 C] Pyruvate hyperpolarization.

[0368]

[0369] In the above reaction scheme, the co-ligand method developed by Duckett and colleagues (Iali et al., Angew. Chemie-Int. Ed., 58, 10271-10275 (2019)) was used. 13 Shielding of C core tailoring (Barskiy et al., ChemPhysChem, 18, 1493-1498 (2017)) enables SABRE transfer to heteronuclei (SABRE-SHEATH) [1- 13 C] Hyperpolarization of pyruvate (Theis et al., J. Am. Chem. Soc., 137, 1404-1407 (2015) and Truong et al., J. Phys. Chem. C, 119, 8786-8797 (2015)). 13 C]-Sodium pyruvate and deuterated methanol-d4 solvent were purchased from Sigma-Aldrich and used without any further purification. The [IrCl(COD)(F-IMes)]SABRE catalyst used in this example was prepared according to Example 4. In a 5 mm NMR tube, 0.6 mL of a fixed ratio substrate [1- 13 C] The active catalyst used in this article was prepared by reacting pyruvate with the Ir(F-IMes)SABRE catalyst of Example 4 and a co-ligand dimethyl sulfoxide (DMSO) in methanol-d4.

[0370] Parahydrogen enriched to about 70% to 95% was used and directed via PTFE tubing into a mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) set at 50 to 120 scc / m into a medium wall 5 mm NMR tube (Norell) to allow bubbling through the sample. The pressure value throughout the pH 2 line was 50 to 110 psi.

[0371] The polarization transfer magnetic field was established as follows. Magnetic fields approaching or below ~1 μT were achieved using an apparatus consisting of a solenoid coil placed within a three-layer μ-metal shield (6-inch inner diameter and 15-inch long part number ZG-206, Magnetic Shield Corp., Bensenville, IL). The magnetic field was generated using a custom-made solenoid coil and a triple independent channel DC power supply (KEITHLEY 2231A-30-3). The solenoid had a 41 mm diameter (40 mm core, 20 cm long winding with 220 turns of AWG20 (0.9 mm) Cu wire and a 220 Ω series resistor. The solenoid coil was driven by a variable resistor decade box in series to provide finer control of the internal magnetic field within the shield. Typical values ​​for the field within the shield were between ±1.2 μT, and SABRE SHEATH experiments were typically -0.7 μT to +0.8 μT in the sample area.

[0372] MR experiments were performed using an 80 MHz Magritek Spinsolving benchtop NMR spectrometer. The following acquisition parameters were used:

[0373] Spectral width (SW) = 5kHz;

[0374] Dwell time (DT) = 150 μs;

[0375] Scan times (ns) = 1,

[0376] Receiver gain = 16;

[0377] Excitation pulse angle (α) = 90°;

[0378] 13 C resonance frequency = 20.25232790 MHz.

[0379] Closed during the entire experiment 1 H decoupled to collect all 13 C NMR spectroscopy. The time required to manually transfer the sample from the shielded area to the magnet for low-field NMR acquisition was typically <5 seconds.

[0380] From p-H2-derived iridium hydride to [1- 13C]pyruvate 13 The hyperpolarization transfer of C nuclear spins was carried out by using 0.5 mL of [IrCl(H)2(DMSO)2(F-IMes)], [1- 13 C] A solution mixture of pyruvate, a coligand (dimethyl sulfoxide) and p-H2 in deuterated or non-deuterated methanol was subjected to SABRE in a sub-microtesla magnetic field using shielding to transfer alignment to the heteronuclear (SABRE-SHEATH).

[0381] The area under the curve (AUC) of the HP signal was compared with that of the external 13 C signal thermal signal reference (4M[1- 13 C] sodium acetate) to calculate 13 C signal enhancement:

[0382]

[0383] Where S HP and S REF It is from HP[1- 13 C]pyruvate and heat signal reference [1- 13 C] acetate 13 C signal, C REF and C HP They are the thermal signal reference [1- 13 C] acetate (4M) and HP[1- 13 C] pyruvate concentration, and A REF and A HP is used for thermal signal reference [1- 13 C] acetate and HP[1- 13 C] The effective cross section of the NMR tube for the pyruvate sample. According to Equation S2: (% P 13 C ), = ε 13 C *1.56181*10 -6 *100 By increasing the signal (ε 13 C ) multiplied by 1.81T(1.5681*10 -4 %) 13 C nuclear spin polarization, calculated 13 The percentage of C polarization (%P 13 C ).

[0384] Activation of the fluorinated SABRE catalyst takes less than 15 minutes, where 13 C polarization percentage Figure 7and was performed by bubbling ˜95% p-H2 at a flow rate of 90 standard cubic centimeters per minute (scc / m) at a p-H2 partial pressure of 8 atm, which resulted in the formation of a marker introduced by Duckett and co-workers (Iali et al., Angew. Chemie-Int. Ed., 58, 10271–10275 (2019)), as Figure 8 Complex 2, complex 3a, complex 3b and pyruvate are shown in FIG. Without wishing to be bound by any particular theory, it is believed that complex 3B is the major SABRE active species.

[0385] Example 7

[0386] This example demonstrates that the changes in parahydrogen pressure and flow rate have an important influence on the 13 C] pyruvate hyperpolarization, and the effects of magnetic transfer field, temperature, and the concentrations of fluorination catalyst and DMSO on [1- 13 In addition, the effects of [1- 13 C] Relaxation kinetics of pyruvate.

[0387] As described in Example 6 above, the SABRE (SABRE-SHEATH) repeats [1- 13 C] hyperpolarization of pyruvate, and the effects of parahydrogen pressure and flow rate, as well as the effects of magnetic transfer field, temperature, and the concentrations of fluorination catalyst and DMSO were studied.

[0388] The p-H2 parameters such as pressure and flow rate are evaluated, and the polarization percentage results are as follows Fig.9A and Fig. 9B The NMR samples were contained in 30 mM [1- 13 C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst and 40 mM dimethyl sulfoxide (DMSO), the mixing field was 0.4 μT, and the temperature was 0°C. Fig.9A and Fig. 9B It is evident from the results described in that as the parahydrogen flow rate and pressure increase, the polarization percentage also increases.

[0389] The temperature and magnetic field in the microtesla system were evaluated and Fig. 10A and Fig. 10B The 13 C polarization level and polarization transfer magnetic field. The NMR sample contained 30 mM [1- 13 C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst and 40 mM dimethyl sulfoxide (DMSO), with a p-H2 flow rate and pressure of 70 scc / m and 100 PSI. Fig. 10A and Fig. 10B It is evident from the results described in that the best polarization transfer occurs at temperatures between -20°C and 5°C and at mixing fields between 0.3 μT and 0.5 μT. The optimum temperature is -7.24°C and the optimum mixing field is 0.4 μT.

[0390] The perfluorinated SABRE catalyst and DMSO concentration were evaluated at a temperature of 0°C, a magnetic transfer field of 0.4 μT, a p-H2 flow of 90 scc / m, and a p-H2 pressure of 110 PSI, and the polarization percentage was Fig.11A and Fig. 11B From Fig.11A The results shown clearly show that the percent polarization increases with increasing concentration of the perfluorinated SABRE catalyst. However, the percent polarization remains relatively consistent above 20 mM concentration.

[0391] from Fig. 12A and Fig. 12B The results shown clearly show that [1- 13 C]-pyruvate relaxation kinetics revealed that total P 13C (Bound + Free) Cumulative Time (T b =6.6±3.0s) is significantly shorter than the corresponding T1 value of 16.1±0.9s, which allows to achieve a P value of up to 13.48%. 13C In addition, the relaxation kinetics at geomagnetic field and 1.8 T are roughly the same as those of the non-fluorinated SABRE catalyst with T1 = 28.9 ± 1.6 s and 66.5 ± 7 s, respectively.

[0392] p-H2 and [1- 13 C] The simultaneous exchange of pyruvate leads to 13 C is the accumulation of hyperpolarization. In this regard, Fig.13 Shows 13 C-hyperpolarized [1- 13 Representative spectrum of [C]-pyruvate, corresponding to ∼13.48% of P obtained by comparing the NMR signal intensity with a reference sample 13C The signal enhancement ε is ∼86500 times. The NMR sample contained 20 mM [1- 13 C] sodium pyruvate, 2.6 mM fluorinated SABRE catalyst and 40 mM dimethyl sulfoxide (DMSO), the mixing field was at 0.4 μT and the temperature was at 0°C, the parahydrogen pressure and flow rate were 110 PSI and 90 scc / m respectively.

[0393] Temperature Figure 7 The [1- 13C] pyruvate exchange rate has a profound effect. In recent work, Adelabu et al. (ChemPhysChem, 23, e202100839 (2022)) showed that the monotonic disappearance of the free HP resonance at low temperatures is 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 of pyruvate with the polarization transfer complex is faster, resulting in hyperpolarization of both free and bound 3b species in the expected pyruvate: pre-catalyst ratio. In order to quickly release HP pyruvate from 3b, the HP solution is quickly warmed and the sample is then inserted into the NMR detector (Tom Hon et al., J. Am. Chem. Soc., 144 (1) 282-287 (2022)). Fig.14 A variable temperature SABRE-SHEATH experiment is shown using the saturated perfluorinated SABRE catalyst of Example 4. The NMR sample (in deuterated methanol) contained 25 mM [1- 13 C] sodium pyruvate, 6 mM perfluorinated SABRE catalyst, and 47 mM dimethyl sulfoxide (DMSO) with a mixing field of 0.4 μT and parahydrogen pressure and flow rate set to 110 PSI and 90 scc / m, respectively.

[0394] like Fig.14 As shown, even in most HP[1- 13 C] pyruvate is in the free state at low temperatures, such as -10 ° C, and the exchange rate of complex 3b to the free state is also faster. 13 C SABRE-SHEATH temperature is reduced to 0℃ and reaches P 13C The exchange is kept fast enough to preferentially form "free" HP[1- 13 C] pyruvate, but not complex 3b.

[0395] Example 8

[0396] This example illustrates the use of a method for separating hyperpolarized [1- 13 C] An exemplary method of sodium pyruvate, comprising extraction and filtration.

[0397] As described in Examples 6 and 7, using 13 Tailored shielding of the C core enables alignment transfer to the heteronuclear SABRE (SABRE-SHEATH) using dimethyl sulfoxide (DMSO) as a coligand, [IrCl(COD)(F-IMes)]SABRE catalyst, and parahydrogen enriched to about 70% to 95% in deuterated methanol-d4 solvent [1- 13 C] sodium pyruvate. 30 mM [1- 13C] SABRE samples were prepared in 0.5 mL CD3OD with sodium pyruvate, 2.6 mM perfluorinated SABRE catalyst of Example 4, and 35 mM dimethyl sulfoxide (DMSO). Parahydrogen flow rate was established at 90 scc / m and pressurized to 8 bar, mixing field was 0.4 μT, and temperature was 0°C.

[0398] After the hyperpolarization process was completed, the sample was quickly removed from the 0.40 μT field, depressurized, and 20 volume % (125 μL) of D2O was added to the solution to precipitate the perfluorinated SABRE catalyst. The resulting mixture was transferred to a 1 mL plastic syringe mounted on a Luer lock filter (Waters Oasis Prime HLB Plus Light Cartridge (Part No.: 186008866) and the aqueous solution was directed through the filter into a 5 mm NMR tube already in an adjacent 1.8 T benchtop NMR spectrometer. The entire process took approximately 1.15 to 1.30 minutes, and no HP was observed in any of the samples. 13 C signal. The relaxation studies presented above show that pyruvate in the [1- 13 C]-T1 relaxation time is significantly shorter (e.g., under Earth's field, [1- 13 C]-T1=28.9±1.6s). Automation and faster solution transfer should allow observation of HP[1- 13 C]-pyruvate signal.

[0399] Example 9

[0400] This example illustrates the use of a method for separating hyperpolarized [1- 13 C] An exemplary method of sodium pyruvate comprising extraction by precipitation with an organic solvent.

[0401] HP[1- 13 C] pyruvate precipitation and redissolution (Schmidt et al., ACS Sensors, 7(11), 3430-3439(2022)). As described in Examples 6 and 7, 20 to 30 mM [1- 13SABRE samples were prepared in CD3OD with sodium pyruvate, 7.5 mM fluorinated SABRE catalyst, and 50 mM dimethyl sulfoxide (DMSO). 100 μL of this solution was transferred to a 5 mm NMR tube and exposed to SABRE-SHEATH hyperpolarization conditions with the same setup and optimal conditions as described in Examples 6 and 7. The solution was placed in 3 layers of μ-metal at 3″ ID and 9″ deep to shield the external magnetic field, combined with a custom-made solenoid to generate a static magnetic field B0 of 0.4 μT. The NMR tube was pressurized (110 psi, i.e., approximately 8 bar total pressure) by bubbling through the solution with p-H2 at a flow rate of 90 scc / m to activate the catalyst and [1- 13 C] Sodium pyruvate solution 13 C-hyperpolarization. The activation of the catalyst was carried out for 15 minutes at ambient temperature and magnetic field. For polarization accumulation, the sample was placed in a static magnetic field (usually about 0.4 μT) and a water bath to adjust the reaction temperature at 0 ° C. After polarization, the NMR tube was quickly transferred to an NMR spectrometer at 1.8 T and kept at room temperature. After decompression, 400 μL of ethyl acetate (EtOAc) was added to the HP solution to precipitate pyruvate, and 300 μL of D2O was added to redissolve the pyruvate in the reconstructed water.

[0402] NMR spectra were acquired using a 1.8T benchtop NMR immediately after reconstitution in water and the results are shown in Fig.15 In addition, Fig.15 The bottom spectrum shows the spectrum from 4M[1- 13 Single-scan thermal polarization of sodium acetate 13 C signal.

[0403] In addition, the pyruvate concentration was determined by LCMS using a calibration curve of naturally occurring isotopes of pyruvate. 13 C-pyruvate concentration. After reconstructing the SABRE-SHEATH methodology, the pyruvic acid aqueous solution samples were further analyzed for iridium content by ICP-MS (inductively coupled plasma multi-element scanning). The iridium content was determined to be only about 150 ppb to about 300 ppm.

[0404] Example 10

[0405] This example illustrates the synthesis of 2,2,2-trifluoro-N-(4-iodo-2,6-dimethylphenyl)acetamide:

[0406]

[0407] Iodine (11.17 g, 44.00 mmol, 1.1 equivalents) and saturated sodium bicarbonate solution (30 mL) were added to a stirred solution of 2,6-diisopropylaniline (4.92 mL, 40.00 mmol, 1.0 equivalents) in diethyl ether (50 mL). The solution was stirred at room temperature for 3 hours and gas evolution was observed. Excess iodine was destroyed by adding sodium thiosulfate (1.33 g, 8.40 mmol). The phases were separated and the aqueous phase was further extracted with diethyl ether (2 × 20 mL). The combined organic phases were washed with water (200 mL) and saturated sodium thiosulfate solution. The organic phase was evaporated to dryness in a vacuum to obtain the product as a brown oil that slowly became a solid under vacuum.

[0408] Hexane was added to dissolve the product, and the solution was filtered through celite, evaporated and dried under vacuum. No further purification was required. 1 H NMR (400MHz, CDCl3): δ = 7.14 (s, 2H), 4.45 (s, 2H), 2.04 (s, 6H).

[0409] Embodiment 11

[0410] 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-tridecafluorooct-1-en-1-yl)phenyl)-2,2,2-trifluoroacetamide:

[0411]

[0412] 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 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-13fluorooct-1-ene (4.84 g, 1 equivalent, 14.0 mmol) was added to the reaction mixture and further heated to 120 ° C. The solution was stirred for 19 hours. After cooling, the mixture was filtered through diatomaceous earth and washed with diethyl ether (50 mL). Water (50 mL) and diethyl ether (30 mL) were added, the organic phase was separated, and the aqueous phase was extracted with Et2O (3 × 15 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (hexane / DCM 4:1) gave 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).

[0413] Example 12

[0414] 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:

[0415]

[0416] In a glass autoclave, 10% Pd / C (0.08 g, 0.07 mmol) was added 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-ene-1-yl)phenyl)-2,2,2-trifluoroacetamide (0.40 g, 0.70 mmol) in ethyl acetate (10 mL). The autoclave was evacuated, filled to 500 kPa with hydrogen, and stirred at room temperature for 5 hours. The mixture was filtered through diatomaceous earth 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.

[0417] Example 13

[0418] 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:

[0419]

[0420] To a solution of N-(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)-2,2,2-trifluoroacetamide (0.14 g, 250 μmol) in n-butanol (1.5 mL) was added sodium hydroxide (0.10 g, 250 mmol) and the reaction mixture was heated to 110 °C for 21 hours. After cooling to room temperature, water (4 mL) and ethyl acetate (4 mL) were added, and the organic phase was separated and washed with 1 M HCl solution (4 mL), saturated NaHCO3 solution (4 mL) and brine (4 mL). The aqueous phase was neutralized and extracted with ethyl acetate (3 times x 4 mL). The organic layers were combined and 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).

[0421] Embodiment 14

[0422] 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-diimine:

[0423]

[0424] To a solution of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)aniline (0.5 g, 1 mmol) in ethanol (5 mL) was added 40% aqueous glyoxal (0.1 mL, 1 mmol) and a catalytic amount of formic acid (a few drops). The reaction mixture was stirred at room temperature for 20 hours, during which time a yellow precipitate formed. The solid was filtered and washed with cold ethanol (3×5 mL) to give clean N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)ethane-1,2-diimine (0.2 g, 20%, yellow powder).

[0425] Embodiment 15

[0426] This example illustrates the synthesis of 1,3-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)phenyl)-1H-imidazol-3-ium-2-chloride:

[0427]

[0428] The 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 a solution of concentrated HCl (112 mg, 3.12 mmol) in dioxane (0.78 mL) were slowly added. The mixture was heated to reflux overnight. Purification was performed by column chromatography. 1 H NMR (400MHz, CDCl3) δ2.07, 2.55, 2.92, 7.37, 8.28, 9.65. MS(ESI)m / z(%):1168.8[M-TFA] + (100).

[0429] Example 16

[0430] This example illustrates the synthesis of a fluorinated SABRE catalyst according to one aspect of the present invention.

[0431]

[0432] Potassium tert-butoxide (2.5 equiv) was added to a stirred solution of 1,3-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorooctyl)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 for 2 hours at room temperature. The solvent was removed under reduced pressure to give the crude product, and dried under vacuum overnight. The sample was purified by flash chromatography DCM / hexane (4:1) to obtain the fluorinated SABRE catalyst. MS (ESI) m / z (%): 1469 [M-Cl] + (100).

[0433] Embodiment 17

[0434] This example illustrates the hyperpolarization of sodium pyruvate using a SABRE catalyst according to one aspect of the present invention as shown in Scheme 3.

[0435] Scheme 3. Use of the perfluorinated SABRE catalyst of Example 16 and dimethyl sulfoxide as a co-ligand to make [1- 13 C] Pyruvate hyperpolarization.

[0436]

[0437] In the above reaction scheme, the hydride derived from p-H2 to [1- 13 C]pyruvate 13 The efficient hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(PTFSO)2(DMSO)], [1- 13 C] A solution mixture of pyruvate and p-H2 in deuterated methanol was subjected to SABRE in a sub-microtesla magnetic field using SABRE-SHEATH to transfer alignment to the heteronucleus.

[0438] As described in Examples 6 and 7, 40 mM [1- 13SABRE samples were prepared in CD3OD with sodium pyruvate, 6.6 mM perfluorinated SABRE catalyst of Example 16, and 50 mM dimethyl sulfoxide (DMSO). The SABRE samples were exposed to SABRE-SHEATH hyperpolarization conditions with the same setup and optimal conditions as described in Examples 6 and 7. The NMR tube was pressurized (110 psi, i.e., approximately 8 bar total pressure) by bubbling pH 2 at a flow rate of 90 scc / m through the solution to activate the catalyst and to allow [1- 13 C] Sodium pyruvate solution 13 C-hyperpolarization. The activation of the catalyst was carried out at ambient temperature and in a magnetic field for about 15 minutes. For polarization accumulation, the sample was placed in a magnetic field (usually about 0.4 μT) and a 5°C water bath to adjust the reaction temperature. The spectrum was obtained immediately after the sample was manually transferred to a 1.8T benchtop NMR after 5 seconds, and the results are shown in Fig.16 In addition, Fig.16 The bottom spectrum shows the spectrum from 4M[1- 13 Single-scan thermal polarization of sodium acetate 13 C signal. Fig.16 As can be clearly seen from the results shown in , the signal enhancement ε is ∼16900 and the polarization is about P( 13 C)~2.17%.

[0439] Embodiment 18

[0440] This example illustrates 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:

[0441]

[0442] 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 further heated to 120°C. The solution was stirred for 19 hours. After cooling, the mixture was filtered through diatomite and washed with diethyl ether (50mL). Water (50mL) and diethyl ether (30mL) were added, the organic phase was separated, and the aqueous phase was extracted with Et2O (3 × 15mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain a crude product. Fluoramide N- (2,6- dimethyl -4- (3,3,4,4,5,5,6,6,7,7,8,8,8- 13 fluorooct-1-ene-1-yl) phenyl) -2,2,2- trifluoroacetamide was obtained by column chromatography (hexane / DCM 4:1), which was further crystallized (5g, 70%, white needles).

[0443] Embodiment 19

[0444] 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:

[0445]

[0446] To 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 sodium hydroxide (0.10 g, 250 mmol) and the reaction mixture was heated to 110 °C for 21 hours. After cooling to room temperature, water (4 mL) and ethyl acetate (4 mL) were added, and the organic phase was separated and washed with 1 M HCl solution (4 mL), saturated NaHCO3 solution (4 mL) and brine (4 mL). The aqueous phase was neutralized and extracted with ethyl acetate (3 times x 4 mL). The organic layers were combined and 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).

[0447] Embodiment 20

[0448] 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-diimine:

[0449]

[0450] To a solution of 2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-en-1-yl)aniline (0.5 g, 1 mmol) in ethanol (5 mL) was added 40% aqueous glyoxal (0.1 mL, 1 mmol) and a catalytic amount of formic acid (a few drops). The reaction mixture was stirred at room temperature for 20 hours, during which time a yellow precipitate formed. The solid was filtered and washed with cold ethanol (3×5 mL) to give clean N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)phenyl)ethane-1,2-diimine (0.2 g, 20%, yellow powder).

[0451] Embodiment 21

[0452] 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-chloride:

[0453]

[0454] The flask was charged with N,N-bis(2,6-dimethyl-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene-1-yl)phenyl)ethane-1,2-diimine (2.40 g, 2.08 mmol) and tetrahydrofuran (80 mL). The mixture was cooled to 0 °C, and a suspension of paraformaldehyde (262 mg, 2.91 mmol) and a solution of concentrated HCl (112 mg, 3.12 mmol) in dioxane (0.78 mL) were slowly added. The mixture was heated to reflux overnight. Purification was performed by column chromatography. 1 H NMR (400MHz, CDCl3) δ2.27, 6.71, 7.32, 7.36, 7.67, 8.16, 9.59ppm. 19 F NMR (400MHz, CDCl3) δ-82.43,-112.52,-122.59,-123.89,-124.17,-127.33ppm. MS(ESI)m / z(%):964.8[M+H] + (100).

[0455] Embodiment 22

[0456] This example illustrates the synthesis of a fluorinated SABRE catalyst according to one aspect of the present invention.

[0457]

[0458] Potassium tert-butoxide (2.5 eq.) 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-chloride (2.2 eq.) 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 eq.) was added and the resulting solution was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure to give the crude product, and dried under vacuum overnight. The sample was purified by flash chromatography DCM / hexane (4:1) to obtain the fluorinated SABRE catalyst. MS (ESI) m / z (%): 1266 [M-Cl] + (100).

[0459] Embodiment 23

[0460] 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.

[0461] Scheme 4. Use of the perfluorinated SABRE catalyst shown with dimethyl sulfoxide as a co-ligand to synthesize [1-13 C] Pyruvate hyperpolarization.

[0462]

[0463] In the above reaction scheme, the hydride derived from p-H2 to [1- 13 C]pyruvate 13 The efficient hyperpolarization transfer of C nuclear spins was achieved by using [IrCl(H)2(PTFSO)2(DMSO)], [1- 13 C] A solution mixture of pyruvate and p-H2 in deuterated methanol was subjected to SABRE in a sub-microtesla magnetic field using a shield to transfer alignment to the heteronucleus (SABRE-SHEATH).

[0464] As described in Examples 6 and 7, 20 mM [1- 13 SABRE samples were prepared in CD3OD with sodium pyruvate, 7.6 mM perfluorinated SABRE catalyst shown in Scheme 4, and 50 mM dimethyl sulfoxide (DMSO). The SABRE samples were exposed to SABRE-SHEATH hyperpolarization conditions with the same setup and optimal conditions as described in Examples 6 and 7. The NMR tube was pressurized (110 psi, i.e., approximately 8 bar total pressure) by bubbling pH 2 at a flow rate of 90 scc / m through the solution to activate the catalyst and to allow [1- 13 C] Sodium pyruvate solution 13 C-hyperpolarization. The activation of the catalyst was carried out at ambient temperature and in a magnetic field for about 15 minutes. For polarization accumulation, the sample was placed in a magnetic field (usually about 0.4 μT) and a 5°C water bath to adjust the reaction temperature. The spectrum was obtained immediately after the sample was manually transferred to a 1.8T benchtop NMR after 5 seconds, and the results are shown in Fig.17 In addition, Fig.17 The bottom spectrum shows the spectrum from 4M[1- 13 Single-scan thermal polarization of sodium acetate 13 C signal. Fig.17 As can be clearly seen from the results shown in , the signal enhancement ε is ∼19000 and the polarization is about P( 13 C)~4.91%.

[0465] Embodiment 24

[0466] This embodiment illustrates the method of making [1- 13 C] A method for the hyperpolarization of pyruvate using a fluorinated mixture instead of deuterated methanol alone.

[0467] The hyperpolarization process of Example 6 was repeated using a mixture of nonafluorobutyl methyl ether (NFBME) and deuterated methanol instead of deuterated methanol alone.

[0468] Activation of the fluorinated SABRE catalyst takes less than 25 minutes, where 13 C polarization percentage Fig.18 The NMR samples were prepared by bubbling 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 samples contained approximately 25 mM [1- 13 C] Sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst from Example 4, and 40 mM dimethyl sulfoxide (DMSO).

[0469] Embodiment 25

[0470] This example illustrates the effect of fluorinated mixtures [1- 13 The effects of hyperpolarization of [1-C]pyruvate, which is manifested by changes in parahydrogen pressure and flow rate, and the influence of the magnetic transfer field, were also studied. 13 C] Relaxation kinetics of pyruvate.

[0471] As described in Example 24 above, the SABRE repeats [1- 13 C] hyperpolarization of pyruvate, and the effect of the parahydrogen flow rate, as well as the effect of the magnetic transfer field, were studied.

[0472] The p-H2 flow rate was evaluated and the polarization percentage results were as follows Fig.19 The NMR sample contained approximately 22 mM [1- 13 C] sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4 and 45 mM dimethyl sulfoxide (DMSO). Fig.19 It is clear from the results shown in that as the parahydrogen flow rate increases, the polarization percentage also increases.

[0473] Evaluate the magnetic field in the microtesla regime and Fig. 20 The 13 C polarization transfer magnetic field. The NMR sample contained 22 mM [1- 13C] sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4 and 46 mM dimethyl sulfoxide (DMSO). The p-H2 flow rate and pressure were 50 ssc / m and 110 PSI, respectively. Fig. 20 It is clear from the results shown that the best polarization transfer occurs at a mixing field of 0.3 μT to 0.5 μT. The best mixing field is 0.4 μT.

[0474] from Fig.21A and Fig. 21B The results shown in the figure clearly show that [1- 13 C]-pyruvate relaxation kinetics revealed that total P 13C (Bound + Free) Cumulative Time (T b =3.0±0.8s) is significantly shorter than the corresponding T1 value of 11.3±1.3s, which allows to achieve a P value of up to 6.02%. 13C In addition, the relaxation kinetics at geomagnetic field and 1.8 T are roughly the same as those of the non-fluorinated SABRE catalyst, with T1 = 9.0 ± 1.9 s and 16.0 ± 1.4 s, respectively.

[0475] p-H2 and [1- 13 C] The simultaneous exchange of pyruvate leads to 13 C is the accumulation of hyperpolarization. In this regard, Fig. 22 The top spectrum shows 13 C hyperpolarization [1- 13 C]-pyruvate, with a signal enhancement ε of ∼38,600-fold, corresponding to the NMR signal intensity compared to a reference sample (i.e., Fig. 22 The bottom spectrum shows the spectrum from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal) compared with the obtained ~6.02% P 13C The NMR samples contained 23 mM [1- 13 C] Sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4 and 46 mM dimethyl sulfoxide (DMSO). At a mixing field of 0.4 μT and a temperature of 0°C, the p-H2 flow rate and pressure were 90 ssc / m and 110 PSI, respectively.

[0476] Temperature Figure 7 The [1- 13C] pyruvate exchange rate has a profound effect. In recent work, Adelabu et al. (ChemPhysChem, 23, e202100839 (2022)) showed that the monotonic disappearance of the free HP resonance at low temperatures is 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 of pyruvate with the polarization transfer complex is faster, resulting in hyperpolarization of both free and bound 3b species in the expected pyruvate: pre-catalyst ratio. To quickly release HP pyruvate from 3b, the HP solution is quickly warmed and the sample is then inserted into the NMR detector (Tom Hon et al., J. Am. Chem. Soc., 144 (1) 282-287 (2022)). Fig.23 A variable temperature SABRE-SHEATH experiment is shown using the saturated perfluorinated SABRE catalyst of Example 4. The NMR samples (in nonafluorobutyl methyl ether (NFBME) and deuterated methanol) contained 23 mM [1- 13 C] sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO), with a mixing field of 0.4 μT, and parahydrogen pressure and flow rate set to 110 PSI and 90 scc / m, respectively.

[0477] like Fig.23 As shown, even in most HP[1- 13 C] pyruvate is in the free state at low temperatures, such as -10 ° C, and the exchange rate of complex 3b to the free state is also faster. 13 C SABRE-SHEATH temperature is reduced to 0℃ and reaches P 13C The exchange is kept fast enough to preferentially form "free" HP[1- 13 C] pyruvate, but not complex 3b.

[0478] Embodiment 26

[0479] This example illustrates the use of a method for separating hyperpolarized [1- 13 C] An exemplary method for sodium pyruvate, which comprises a two-phase extraction with an aqueous phase and a fluorinated phase.

[0480] The hyperpolarization process of Example 6 was repeated using a mixture of nonafluorobutyl methyl ether (NFBME) and deuterated methanol instead of deuterated methanol alone. 23 mM [1- 13C] SABRE samples were prepared with sodium pyruvate, 7.4 mM perfluorinated SABRE catalyst of Example 4, and 46 mM dimethyl sulfoxide (DMSO), with a mixing field of 0.4 μT, and parahydrogen pressure and flow rate set to 110 PSI and 90 scc / m, respectively.

[0481] After the hyperpolarization process was completed, the sample was quickly removed from the 0.40 μT field and transferred to the NMR spectrometer at 1.8 T at room temperature. The NMR sample was depressurized and 400 μL of D2O was added to the solution to convert the hyperpolarized [1- 13 C] Sodium pyruvate is driven into the aqueous phase. The pyruvate signal is collected in the aqueous phase, but separation results in the formation of an emulsion, indicating the presence of both bound and free pyruvate. See Fig.24 .in this regard, Fig.24 The top spectrum shows 13 C hyperpolarization [1- 13 Representative spectrum of [C]-pyruvate, with a signal enhancement ε of ∼10,800-fold, corresponding to the NMR signal intensity compared to a reference sample (i.e., Fig.24 The bottom spectrum shows the spectrum from 4M [1- 13 Single-scan thermal polarization of sodium acetate 13 C signal) compared to the ~1.68% P 13C .

[0482] Will contain [1- 13 The aqueous phase of the sodium pyruvate was evacuated 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 [1- 13 C] Sodium pyruvate concentration.

[0483] The fluorination mixture containing the perfluorinated SABRE catalyst in NFBME and MeOD was reused for further [1- 13 C] sodium pyruvate hyperpolarization. After the aqueous phase was emptied, starting from the first 4 days, a solution containing 23 mM [1- 13 C] A 0.2 mL CD3OD solution of sodium pyruvate and 47 mM dimethyl sulfoxide was added to the fluorination mixture containing the perfluorinated SABRE catalyst. Repeat [1- 13 C] sodium pyruvate, and showed [1- 13 C] pyruvate polarization, with a ∼3090-fold signal enhancement ε, corresponding to e.g. Fig.25 The ~0.48% P 13C , which is obtained by comparing the NMR signal intensity with that of a reference sample. [1- 13The polarization of [C] pyruvate was reproducible and showed approximately the same polarization level, indicating that the perfluorinated SABRE catalyst remained active for at least 4 days after initial use.

[0484] Embodiment 27

[0485] This example illustrates the synthesis of 1,3-dimesityl-4,5-bis(2-(perfluorophenyl)propyl)-4,5-dihydro-1H-imidazol-3-ium, triflate salt:

[0486]

[0487] Its basis Fig.26 Prepared according to the synthetic sequence shown in .

[0488] 4-Pentafluorophenylbutyraldehyde (3). To a solution of alcohol (2) (4.8 g, 20.0 mmol) in DCM (40 mL) at 0°C, Dess-Martin periodinane (16.96 g, 40.0 mmol) was added in portions while stirring under argon (5 minutes). The reaction was continued until the starting alcohol was consumed (2 hours). The resulting solution was concentrated to about 10.0 mL and adsorbed onto 10.0 g of silica and dried to a free-flowing powder. The silica with the crude product was applied to a silica column (120.0 g) and eluted with 5% ethyl acetate in hexane to produce the product as a colorless oil. Yield: 3.33 g (70%). 1 H NMR(CDCl3): 1 H NMR (400MHz, CDCl3) δ9.71 (t, J = 1.3 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 C NMR (101MHz, CDCl3) δ200.89, 42.81, 21.49.

[0489] 1,2,3,4,5-pentafluoro-6-(4-iodobutyl)benzene (4). An ice-cooled solution of alcohol (2) (16.0 g, 66.67 mmol) was stirred with imidazole (5.89 g, 86.67 mmol) and triphenylphosphine (20.96 g, 80.0 mmol) in DCM (100 mL) under argon. Iodine (20.32 g, 80.0 mmol) was added in portions at 0°C over a period of 15 minutes while stirring vigorously until a slightly 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 over silica gel (220 g). Elution with hexane gave compound (4) as a colorless oil. Yield: 21.0 g (90%). 1 H NMR (400MHz, cdcl3) δ3.20(t,J=6.8Hz,1H),2.73(tt,J=7.5,1.8Hz,1H),1.86(dq,J=8.6,6.8Hz,1H),1.76–1.66(m,1H). 13 C NMR (101MHz, cdcl3) δ37.84, 30.01, 21.27, 5.39.

[0490] Iodo-(4-(pentafluorophenyl)butyl)triphenyl-λ 5 -phosphine (5). A solution of iodobutane (4) (21.0 g, 60.0 mmol) and triphenylphosphine (17.29 g, 66.0 mmol) was refluxed under argon for 24 hours. The precipitated solid was filtered and washed with anhydrous ether and dried under high vacuum for 20 hours. Yield: 33.78 g (92%). 1 H NMR (400MHz, CDCl3) δ7.73(m,15H),3.92,3.86(m,2H),2.76,2.74(m,2H),2.07,2.025(m,2H),1.6(m,2H). 13 CNMR (101MHz, CDCl3) δ135.23,135.20,133.75,133.65,130.65,130.53,118.32,117.46,29.43,29.27,23.05,22.55,21.78,21.74,21.66.

[0491] Compound 6. To a solution of phosphonium salt (5) (6.79 g, 11 mmol) in anhydrous THF (40 mL) was added a solution of potassium tert-butoxide in THF (2 M, 12.5 mL, 25.0 mmol) and stirred under argon for 30 minutes. A solution of aldehyde (3) (2.2 g, 9.24 mmol) in THF (5 mL) was added dropwise at room temperature and stirred for 3 hours. The solution was concentrated and purified on flash silica (120 g). Elution with hexane gave the product as a colorless oil, a mixture of cis / trans isomers (90:10). Yield: 3.2 g (72%). 1 H NMR (400MHz, CDCl3) δ5.41(m,2H),2.72,2.68(m,4H),2.12,2.10,2.06(m,4H),1.64(m,4H). 13 C NMR (101MHz, CDCl3) δ129.46, 29.12, 26.76, 21.94.

[0492] Compound 7. A solution of olefin (6) (3.6 g, 8.1 mmol) in acetone (20 mL) and water (0.5 mL) was cooled to 0 ° C, and dibromoamine-T (2.93 g, 8.91 mmol, Org. Biomol. Chem., 8, 1424-1430 (2010)) was added under vigorous stirring. After addition, the solution was allowed to reach room temperature and stirred until the starting material disappeared (30 minutes). The solution was quenched with solid sodium thiosulfate (2.0 g) and stirred until the color of bromine was completely discharged. The mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on flash silica (80 g) and eluted with 10% EtOAc hexane solution to produce bromohydrin (7), which is a mixture of diastereomers and a colorless oil. Yield: 2.41 g (55%). 1 H NMR (400MHz), CDCl3) δ4.02(m,1H),3.48(m,1H),2.73(4H,CH2-C6F5),1.6–2.0(m,9H,-CH2-andOH)). 13 C NMR (101MHz, CDCl3) δ143.76,138.35,129.62,126.82,59.74,57.12,35.29,34.50,27.39,25.48,21.74,21.34.

[0493] Compound 8. Bromohydrin (7) (2.2 g, 4.06 mmol) was dissolved in DCM (10.0 mL) and stirred with 5.0 g molecular sieves. Dess-Martin reagent (3.44 g, 8.12 mmol) was added and stirred until the starting material was completely consumed (30 minutes). The entire mixture was adsorbed onto flash silica (20.0 g) and dried to a free-flowing powder. The silica with the crude product was loaded onto a flash silica (80.0 g) column and eluted with 0 to 20% EtOAc in hexane for 20 minutes (80.0 mL / min; elution rate). Bromoketone (8) was eluted in 5% EtOAc in hexane as a colorless slurry. Yield: 1.82 g (83%). 1 H NMR (400MHz, CDCl3) δ4.25(dd,J=8.3,6.0Hz,1H),2.94–2.81(m,1H),2.80–2.68(m,4H),2.67–2.52(m,1H),2.09–1.86(m,4H),1.86–1.59(m,2H). 13 CNMR (101MHz, CDCl3) δ202.53,52.19,38.18,32.31,26.87,23.21,21.62,21.45.

[0494] 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). Trimethylaniline 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, excluding moisture. After the bromoketone was consumed (70 hours), the reaction mixture was filtered, concentrated under reduced pressure, and chromatographed over rapid silica (80 g). Eluted with a hexane solution of 20% DCM to give ketoamidine (10) as a colorless slurry. Yield: 1.2 g (49%). 1 H NMRδ(CDCl3)6.91 9s,1H),6.81(s,1H),6.71(s,1H),6.68(s,2H),4.53(m,1H),3.08(m,1H),2.57(m,2h),2.43(m ,2H),2.35(m,2H),2.36(s,3h),2.2(s,3H),2.13(s,3H),2.01(s,3H),1.92(s,6H),1.8(m,2H). 13C NMR (101MHz, CDCl3) δ208.19,151.90,138.19,131.45,129.47,128.74,64. 33,60.38,41.49,28.39,25.50,22.96,20.56,18.44,18.41,18.23,14.18. MS:739.1[M+H].

[0495] Compound 11 (trifluoromethanesulfonate). To an ice-cold solution of ketone amidine (0.994g, 1.35mmol) in ethanol, lithium borohydride (2M in THF, 0.675ml, 1.35mmol) was added and stirred at 0-5°C for 24 hours under argon. The reaction mixture was poured into 50ml water and extracted with ethyl acetate (3×50ml). The combined organic layer was dried (sodium sulfate) and filtered, and concentrated to a paste at room temperature. The above paste was dissolved in 5.0ml anhydrous benzene and cooled to 0°C. DIPEA (0.523g, 4.05mmol) was added and stirred under argon. Trifluoromethanesulfonic anhydride (1.104g, 1.34mmol) was then added dropwise and stirring was continued for 1 hour. LC / MS indicated complete consumption of the peak corresponding to 741. The mixture was adsorbed onto 10.0g silica gel and dried to a free-flowing powder. The silica with the crude product was loaded onto an empty 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 as a brown paste. Yield: 0.338 g (33%). 1 H NMR(CDCl3)δ8.82(s,1H),6.93(s,4H),4.15(m,2H),2.61(m,4H),2.25,2.23,2.21(3S,18H),1.77(m,4H),1.41(m,4H). 13 C NMR (101MHz, CDCl3) δ159.41,141.00,135.66,134.43,130.60,129.96,128.58,68.76,66.17,32.48,26.91,24.65,21.71,20.97,18.38,18.11. MS:723.0[M+H].

[0496] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0497] In the context of describing the present invention (particularly in the context of the following claims), the use of the terms "a" and "an" and "the" and "at least one" and similar references should be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. The term "at least one" followed by one or more items in a list (e.g., "at least one of A and B") should be interpreted as meaning one item (A or B) selected from the listed items 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 interpreted as open terms (i.e., meaning "including but not limited to"), unless otherwise stated. References to ranges of values ​​herein are intended only as a shorthand method of individually referencing each individual value falling within the range, unless otherwise stated herein, and each individual value is incorporated into the specification as if it were individually cited herein. All methods described herein can be performed in any suitable order, unless otherwise stated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. Language in this specification should not be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0498] Preferred embodiments of the present invention are described herein, including the best mode known to the inventor for implementing the present invention. For those of ordinary skill in the art, after reading the foregoing description, changes in these preferred embodiments are obvious. The inventor expects that those skilled in the art will appropriately adopt such changes, and the inventor intends to practice the present invention in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter described in the appended claims as allowed by applicable law. In addition, the present invention includes any combination of the above-mentioned elements in all possible variations thereof, unless otherwise stated herein or clearly contradictory to the context.

Claims

1. A perfluorinated SABRE catalyst comprising a d-block element and a perfluorinated ligand, wherein the perfluorinated ligand has formula (I): <h2 style=";text-align:left;direction:ltr">[L<h2 style=";text-align:left;direction:ltr"> m <h2 style=";text-align:left;direction:ltr"> -(NHC)-(YZ)<h2 style=";text-align:left;direction:ltr"> q <h2 style=";text-align:left;direction:ltr"> ] Formula (I), or a salt thereof, and wherein Each L is independently selected from hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, NHC is a 4- to 7-membered N-heterocyclic carbene radical, wherein the NHC is bonded to the d-block element via a carbene, Each Y is independently selected from a bond or a spacer group, Each Z is a perfluorinated tag, m is an integer from 1 to 4, and q is an integer from 1 to 3.

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

3. The perfluorinated SABRE catalyst of 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 4,5-disubstituted, 1,3-disubstituted or 1,3,4,5-tetrasubstituted imidazole-based or imidazoline-based 5-membered N-heterocyclic carbene group.

5. The perfluorinated SABRE catalyst according to any one of claims 1 to 4, wherein NHC is a 4,5-disubstituted imidazolidinyl, a 1,3-disubstituted imidazolidinyl, a 1,3,4,5-tetrasubstituted imidazolidinyl, a 4,5-disubstituted 2,3-dihydro-imidazolyl, a 1,3-disubstituted 2,3-dihydro-imidazolyl or a 1,3,4,5-tetrasubstituted 2,3-dihydro-imidazolyl.

6. The perfluorinated SABRE catalyst of claim 1, wherein the perfluorinated ligand has formula (Ia) or formula (Ib): or a salt thereof, and wherein Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, Each Y is independently a bond or a spacer group, Each Z is independently a perfluorinated tag, is a single bond or a double bond, and represents bonding to the d-block element via the carbene.

7. The perfluorinated SABRE catalyst of claim 1, wherein the perfluorinated ligand has formula (Ic) or formula (Id): or a salt thereof, and wherein Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, a is 4 to 20, b = 2a + 1 or b = a – 1, Each n is independently an integer from 0 to 4, is a single bond or a double bond, and represents the bonding to the d-block element via the carbene.

8. The perfluorinated SABRE catalyst of claim 1, wherein the perfluorinated ligand has formula (Ie) or formula (If): or a salt thereof, and wherein Each L is independently hydrogen, adamantyl, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, Each Ar is independently a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, Each G is independently a bond, C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 Heteroalkyl, a is 4 to 20, b = 2a + 1 or b = a – 1, is a single bond or a double bond, and represents the bonding to the d-block element via the carbene.

9. The perfluorinated SABRE catalyst according to claim 7 or 8, wherein a is 4 to 10.

10. The perfluorinated SABRE catalyst according to any one of claims 1 to 9, wherein 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 phenyl, 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-diisopropylphenyl, 2,5-diisopropylphenyl, 2,6-diisopropylphenyl, 3,5-diisopropylphenyl Phenyl, 2,4,6-triisopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2,4-diisobutylphenyl, 2,5-diisobutylphenyl, 2,6-diisobutylphenyl, 3,5-diisobutylphenyl, 2,4,6-triisobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2,4-di-sec-butylphenyl, 2,5-di-sec-butylphenyl, 2,6-di-sec-butylphenyl, 3,5-di-sec-butylphenyl, 2,4,6 -tri-sec-butylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2,4-di-tert-butylphenyl, 2,5-di-tert-butylphenyl, 2,6-di-tert-butylphenyl, 3,5-di-tert-butylphenyl, 2,4,6-tri-tert-butylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2,4-dicyclohexylphenyl, 2,5-dicyclohexylphenyl, 2,6-dicyclohexylphenyl, 3,5-dicyclohexylphenyl or 2,4,6-tricyclohexylphenyl.

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

12. The perfluorinated SABRE catalyst of any one of claims 1 to 11, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl groups, substituted or unsubstituted C 2-10 Alkynyl group, substituted or unsubstituted C 1-10 Heteroalkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted C 3-6 a heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, a substituted or unsubstituted arylalkyl group, or a linear or branched alkyleneoxy group.

13. The perfluorinated SABRE catalyst of any one of claims 1 to 11, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted arylalkyl group.

14. The perfluorinated SABRE catalyst of any one of claims 1 to 11, wherein each Y is independently a bond, a substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted arylalkyl group.

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

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

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

18. The perfluorinated SABRE catalyst according to any one of claims 1 to 14, wherein the perfluorinated tag is selected from the group consisting of C4F9, C5F 11 Group, C6F 13 Group, C7F 15 Group, C8F 17 Group, C9F 19 Group, C 10 F 21 Group, C6F5 group, C4F7 group, C5F9 group, C6F 11 Group, C7F 13 Group, C8F 15 Group, C9F 17 Group and C 10 F 19 Group.

19. The perfluorinated SABRE catalyst of claim 1, wherein the perfluorinated ligand is or a salt thereof, and wherein is a single bond or a double bond, and represents the bonding to the d-block element via the carbene.

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

21. The perfluorinated SABRE catalyst of 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 of any one of claims 1 to 21, wherein the perfluorinated 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 the group consisting of a phosphine ligand, a carbene ligand, an imidazole ligand, a pincer chelating ligand, and a compound comprising a sulfoxide group.

24. A method of preparing a perfluorinated SABRE catalyst as claimed in any one of claims 1 to 23 comprising reacting a perfluorinated compound with a base to form a carbene, and reacting the carbene with [(d-block element)(COD)Cl]2, wherein COD represents cyclooctadienyl.

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 to interact 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 core or a plurality of 1 / 2 spin cores in a solvent to obtain a reaction mixture; and (iv) hyperpolarizing the mixture obtained in (iii) by exposing it to a magnetic field or by radio frequency excitation to obtain a hyperpolarized active perfluorinated SABRE catalyst-substrate and / or a hyperpolarized substrate.

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

28. The method of claim 27, wherein the substrate further comprises 2 D.

29. The method according to claim 27 or 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 of 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 the group consisting of perfluorohexane / diethyl ether mixtures, methoxynonafluorobutane and ethyl acetate mixtures with non-polar solvents, perfluorohexane and ether mixtures, perfluorobutyl methyl ether and ethyl acetate mixtures, ethers, fluorocarbon derivatives of THF FC 75, decafluoromethoxytrifluoromethylpentane, hexafluoropropanol, nonafluorobutyl methyl ether, perfluoromethylcyclohexane, perfluoroalkanes, perfluorohexane, and methoxynonafluorobutane.

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

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

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

35. The method of 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 a liquid containing the hyperpolarized substrate, wherein the liquid is free or substantially free of the perfluorinated SABRE catalyst.

36. The method of claim 35, further comprising passing a fluorine-repellent solvent through the adsorbent and recovering an eluate containing the hyperpolarized substrate, wherein the eluate is free or substantially free of the perfluorinated SABRE catalyst.

37. The method of claim 36, wherein the fluorine-repellent solvent comprises water, and one or more of methanol, ethanol, acetonitrile and dimethylformamide.

38. The method of claim 36 or 37, further comprising passing a fluorophilic solvent through the adsorbent.

39. The method of claim 38, wherein the fluorophilic solvent comprises an organic solvent selected from the group consisting of methanol, ethanol, acetonitrile, THF, ethyl acetate, chlorinated solvents, 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 a fluorophilic solvent through the 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 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 methanol 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 methanol mixture and an organic solvent.

46. ​​The method of claim 34, wherein the hyperpolarized substrate is isolated by precipitating the perfluorinated SABRE catalyst and filtering, and removing the precipitated perfluorinated SABRE catalyst from the hyperpolarized substrate.

47. The process of claim 46, wherein the perfluorinated SABRE catalyst is precipitated by the addition of water.

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

49. The method according to any one of claims 26 to 48, wherein the substrate is selected from 1- 13 C-ketoglutaric acid, 1- 13 C-5- 12 C-ketoglutaric acid, 1- 13 C-pyruvic acid, 1- 13 CN-acetylcysteine, 15 N2-isoniazid (or pyridyl-4-carbonyl-bis- 15 N2-hydrazide), 13 C2, 15 N3-Metronidazole, 15 N2-1-aminoisoquinoline (1-AIQ), its deuterated form, and its salts.

50. The method of any one of claims 26 to 48, wherein the substrate has formula (II): wherein each R1 is independently selected from hydrogen, deuterium, a cation, a C1-C6 alkyl, a C3-C7 cycloalkyl, a (C3-C7 cycloalkyl)C1-C6 alkyl, a (heterocycloalkyl)C1-C6 alkyl, a (heteroaryl)C1-C6 alkyl, and a (aryl)C1-C6 alkyl; and wherein Xa, Xb, Xc and Xd are each independently hydrogen or deuterium, provided that at least one of Xa, Xb, Xc and Xd is deuterium, or a pharmaceutically acceptable salt thereof.

51. A hyperpolarized substrate obtained by 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 of obtaining a magnetic resonance image of tissue in an individual suffering from or suspected of suffering from cancer or an adverse vascular condition, comprising administering to the individual a hyperpolarized substrate according to claim 51 or a pharmaceutical composition according to claim 52, and imaging the individual by magnetic resonance imaging.

54. The method of claim 53, wherein the individual has cancer.

55. The method of 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's lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer.

56. The method of claim 53, wherein the adverse vascular condition is selected from the group consisting of myocardial infarction, stroke, and lung disease.

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

58. Perfluoro compounds of formula (III): in Each Ar is independently selected from a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, Each Ar f are independently selected from perfluorinated substituted or unsubstituted aromatic groups, or perfluorinated substituted or unsubstituted heteroaromatic groups, Each Y is independently selected from a bond or a spacer group, X is an anion, and Is a single bond or a double bond.

59. The perfluorinated compound of claim 58, wherein each Ar is independently selected from substituted or unsubstituted aromatic groups.

60. The perfluorinated compound according to claim 58 or 59, wherein each Ar f Independently selected from perfluorinated substituted or unsubstituted aromatic groups.

61. The perfluorinated compound according to any one of claims 58 to 60, wherein each Y is independently selected from a spacer group selected from C 1-5 Alkyl and C 1-5 Heteroalkyl.

62. The perfluoro compound of claim 58, wherein the perfluoro compound has formula (IIIa): in Each n is independently an integer from 0 to 4, X is an anion, and Is a single bond or a double bond.

63. A method for preparing a perfluorinated compound according to any one of claims 58 to 62, the method comprising: (i) reacting an α-bromoketone comprising a perfluorinated substituted or unsubstituted aromatic group or a perfluorinated substituted or unsubstituted heteroaromatic group with an amidine comprising 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-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 the perfluoro compound.

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 of polymerizing an olefin, the method comprising combining the olefin metathesis catalyst of claim 64 with the olefin in a reaction mixture.

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