Preparation of isotopically labeled ketoglutarate and a method for hyperpolarization through signal amplification by reversible exchange (SABRE)

Abstract

Disclosed are compounds of formula (I), their pharma- ceutically acceptable salts, and methods for their preparation: [Formula 1] JPEG2025504653000086.jpg54115 (wherein R1, Xa, Xb, Xc, and Xd are as described in the specification). Further disclosed are isotopic mixtures of the compound of formula (I), as well as pharmaceutical compositions containing the hyperpolarized compound of formula (I). Also disclosed are methods of diagnosing or monitoring a patient suffering from cancer, comprising administering a pharmaceutical composition comprising an effective amount of a hyperpolarized ketoglutarate compound or a pharma- ceutically acceptable salt thereof, and measuring the hyperpolarization of the target compound in the patient. Further disclosed are methods of preparing the hyperpolarized ketoglutarate compound for use in the above methods.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support. The Government has certain rights in this invention.

[0002] CROSS REFERENCE TO PRIOR APPLICATION This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 303,190, filed January 26, 2022, which is incorporated by reference herein in its entirety. [Background technology]

[0003] 2. Background of the Invention Alpha-ketoglutarate (α-KG) is an important metabolite and signaling molecule in cancer cells, but the poor permeability of α-KG limits the study of α-KG-mediated effects in vivo. Cell-permeable mono- and diester α-KG derivatives have been synthesized for in vivo use, but many of these derivatives are not compatible with hyperpolarized carbon-13 nuclear magnetic resonance imaging (HPE-13C) imaging. 13 Certain isotopically labeled α-ketoglutaric acid compounds and their use as hyperpolarized contrast agents, therapeutic agents, or diagnostic agents, and methods for their preparation have been disclosed. See, for example, WO2021 / 146572A1; AbuSalim et al., “Simple Esterification of [1- 13 C]-Alpha-Ketoglutarate Enhances Membrane Permeability and Allows for Noninvasive Tracing of Glutamate and Glutamine Production,” ACS Chem. Biol. 2021, 16, 2144-2150 (Sept. 23, 2021).

[0004] However, HP- 13There remains an unmet need for isotopically labeled α-KG compounds with improved performance in C-MRI, e.g., increased T1 relaxivity of the carbonyl group, as well as methods for preparing such compounds, methods for preparing hyperpolarized isotope labeled α-KG compounds, and methods for detecting and / or monitoring patients for various diseases through the use of these compounds. Summary of the Invention

[0005] BRIEF SUMMARY OF THE INVETION The present invention is a 13 The present invention provides isotopically labeled α-KG compounds with improved performance in C-MRI, for example, increased T1 relaxivity, i.e., the time required for the z-component of M to reach (1-1 / e) or about 63% of its maximum (Mo). More specifically, the present invention provides isotopically labeled α-KG compounds having formula (I):

[0006] [ka]

[0007] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

[0008] The present invention also relates to a compound of formula (I):

[0009] [ka]

[0010] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium. or a pharma- ceutically acceptable salt thereof.

[0011] The invention further provides hyperpolarized compounds of formula (I), hyperpolarized compositions comprising an isotopic mixture of a compound of formula (I), pharmaceutical compositions comprising an effective amount of a hyperpolarized compound of formula I, and pharmaceutical compositions comprising a hyperpolarized isotopic mixture of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0012] The present invention further provides a method of diagnosing or monitoring a patient having or suspected of having cancer, the method comprising administering a hyperpolarized ketoglutarate compound, such as a hyperpolarized compound of formula (I), a hyperpolarized isotopic mixture of a compound of formula (I), or a compound of formula (IV):

[0013] [ka]

[0014] or a pharmaceutical composition comprising a hyperpolarized compound of formula (I), a hyperpolarized isotopic mixture of a compound of formula (I), or a hyperpolarized compound of formula (IV), and subjecting the patient to a hyperpolarized 13 This includes diagnosing or monitoring with C-MRI.

[0015] The present invention also provides methods for preparing compounds of formula (I), as well as methods for preparing hyperpolarised versions and isotopic mixtures thereof. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows a synthetic scheme for preparing mono-3-deuterated ketoglutaric acid according to an embodiment of the present invention. [Diagram 2] Figure 2 shows NMR results obtained for a compound according to one embodiment of the invention. The top scan shows a single-scan hyperpolarized (HP) 13C of [1-13C,5-12C] sodium ketoglutarate. The bottom scan shows a single-scan thermally polarized 13C signal from 4M [1-13C] sodium acetate. [Diagram 3] Figures 3A-3H provide results of the SABRE-SHEATH hyperpolarization process for [1-13C,5-12C;d4] α-ketoglutaric acid. Figure 3A is a schematic showing the SABRE-SHEATH hyperpolarization process and associated polarization transfer pathways for [1-13C,5-12C;d4] α-ketoglutaric acid. Figure 3B provides a 13C NMR spectrum of hyperpolarized [1-13C,5-12C;d4] α-ketoglutaric acid. Figure 3C provides a representative stacked variable temperature 13C NMR spectrum of 5 mM [1-13C,5-12C;d4] α-ketoglutaric acid. Figure 3D provides the corresponding 13C NMR spectrum of thermally polarized neat [1-13C] acetic acid. FIG. 3E provides a graph showing the enhancement and decay of the total 13C polarization of 13C-1 in [1-13C,5-12C;d4] α-ketoglutaric acid (i.e., integrating all bound and free resonances) at BT=0.42 μT. FIG. 3F provides a graph showing the corresponding 13C-1 T1 relaxation curves in the Earth's magnetic field and the 1.4 T magnetic field of a clinically relevant benchtop spectrometer. FIG. 3G provides a graph showing the total 13C polarization of 13C-1 [1-13C,5-12C;d4] α-ketoglutaric acid as a function of temperature. FIG. 3H provides a graph showing the total 13C polarization of 13C-1 [1-13C,5-12C;d4] α-ketoglutaric acid as a function of magnetic transfer field. [Figure 4]4A-4G provide results of the SABRE-SHEATH hyperpolarization process for naturally abundant disodium α-ketoglutarate. FIG. 4A is a schematic diagram showing the SABRE-SHEATH hyperpolarization process of disodium α-ketoglutarate and the associated polarization transfer pathway. FIG. 4B provides a representative 13C NMR spectrum of a 5.6 mM solution of natural-bundance disodium α-ketoglutarate obtained by performing SABRE-SHEATH in CD3OD at +10° C. FIG. 4C provides the corresponding 13C NMR spectrum of thermally polarized pure [1-13C] acetic acid. FIG. 4D provides a graph showing the enhancement and decay of total 13C polarization (i.e., integrating all bound and free resonances) in disodium α-ketoglutarate at BT=0.42 μT and TT=+10° C. Figure 4E provides a graph showing the total (bound + free) 13C polarization decay of disodium α-ketoglutarate in the Earth's magnetic field and in the 1.4 T magnetic field of a clinically relevant benchtop spectrometer. Figure 4F provides a graph showing the total 13C polarization of 13C-1 in naturally abundant disodium α-ketoglutarate as a function of temperature. Figure 4G provides a graph showing the total 13C polarization of 13C-1 in naturally abundant disodium α-ketoglutarate as a function of magnetic displacement field. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description of the Invention According to one aspect, the present invention provides a compound of formula (I):

[0018] [ka]

[0019] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

[0020] For example, the compound of formula (I) can be one of the following:

[0021] (i) Formula (Ia):

[0022] [ka]

[0023] Compounds in which one of Xa and Xb is deuterium and the other is hydrogen, and both Xc and Xd are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof,

[0024] (ii) Formula (Ib):

[0025] [ka]

[0026] Compounds in which one of Xc and Xd is deuterium and the other is hydrogen, and both Xa and Xb are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof,

[0027] (iii) Formula (Ic):

[0028] [ka]

[0029] Compounds in which one of Xa and Xb is deuterium and the other is hydrogen, and one of Xc and Xd is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof,

[0030] (iv) Formula (Id):

[0031] [ka]

[0032] Compounds in which both Xa and Xb are deuterium and both Xc and Xd are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof,

[0033] (v) Formula (Ie):

[0034] [ka]

[0035] Compounds in which both Xa and Xb are hydrogen and both Xc and Xd are deuterium, as shown in or a pharma- ceutically acceptable salt thereof,

[0036] (vi) Formula (If):

[0037] [ka]

[0038] Compounds in which both Xa and Xb are deuterium and one of Xc and Xd is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof,

[0039] (vii) Formula (Ig):

[0040] [ka]

[0041] Compounds in which both Xc and Xd are deuterium and one of Xa and Xb is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof, or

[0042] (viii) Formula (Ih):

[0043] [ka]

[0044] Compounds in which Xa, Xb, Xc, and Xd are deuterium as shown in Or a pharma- ceutically acceptable salt thereof.

[0045] In any of the embodiments of the compounds of formula (I) described herein (e.g., formulas (Ia)-(Ih)), each R1 can be independently selected from hydrogen, deuterium, a cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (aryl)C1-C6 alkyl. In some embodiments, each R1 is independently selected from C1-C6 alkyl, e.g., each R1 can be methyl, ethyl, propyl (e.g., isopropyl or n-propyl), butyl (e.g., isobutyl, n-butyl, tert-butyl, or sec-butyl), pentyl, or hexyl. In some embodiments, each R1 is independently selected from hydrogen, deuterium, and a cation. It will be readily understood by one of skill in the art that in embodiments in which R1 is a cation, the compound of Formula (I) (e.g., Formulas (Ia)-(Ih)) is a salt (e.g., a pharma- ceutically acceptable salt) in which the negative charge on the oxygen is balanced by a cation.

[0046] In another aspect, the present invention provides a compound of formula (I):

[0047] [ka]

[0048] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium. or a pharma- ceutically acceptable salt thereof. In other words, the present invention provides an isotopic mixture of a compound of formula (I), in which, on average, at least one of Xa+Xb+Xc+Xd is deuterium. When referring to a composition comprising an isotopic mixture, it will be understood that each compound in the composition comprising the isotopic mixture is structurally identical, apart from the isotopic label, i.e., each R1 is consistently defined. All other aspects of the compound of formula (I) (e.g., formulas (Ia)-(Ih)) in the composition comprising an isotopic mixture are as described herein.

[0049] In some embodiments of the isotopic mixture of the compound of formula (I), at least 25% of the total of deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium.For example, in the compound of formula (I), Xa can be hydrogen or deuterium, Xb can be hydrogen or deuterium, Xc can be hydrogen or deuterium, and Xd can be hydrogen or deuterium, and the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, at least one of Xa, Xb, Xc, and Xd is deuterium.In some embodiments of the isotopic mixture of the compound of formula (I), at least 50% of the total of deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium.In other words, the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, at least two of Xa, Xb, Xc, and Xd are deuterium. In another embodiment of the isotopic mixture of the compound of formula (I), at least 75% of the total of deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium.In other words, the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, at least three of Xa, Xb, Xc, and Xd are deuterium.In a particular embodiment of the isotopic mixture of the compound of formula (I), at least 95% of the total of deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium.In other words, the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, all or almost all of Xa, Xb, Xc, and Xd are deuterium. That is, a composition comprising an isotopic mixture of a compound of Formula (I) can have 25% to 100% (e.g., 25% to 95%, 25% to 75%, 25% to 50%, 50% to 100%, 50% to 95%, 50% to 75%, 75% to 100%, or 75% to 95%) of the total deuterium and hydrogen atoms defined by Xa, Xb, Xc, and Xd be deuterium.

[0050] In some embodiments of the isotopic mixture of the compound of formula (I), at least 50% of the total of deuterium and hydrogen atoms defined by Xa+Xb are deuterium.For example, in the compound of formula (I), Xa can be hydrogen or deuterium, and Xb can be hydrogen or deuterium, and the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, at least one of Xa and Xb is deuterium.In some embodiments of the isotopic mixture of the compound of formula (I), at least 75% of the total of deuterium and hydrogen atoms defined by Xa and Xb are deuterium.In other embodiments of the isotopic mixture of the compound of formula (I), at least 95% of the total of deuterium and hydrogen atoms defined by Xa+Xb are deuterium.In other words, the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, all or almost all of Xa and Xb are deuterium. That is, a composition comprising an isotopic mixture of a compound of Formula (I) can have 50% to 100% (e.g., 50% to 95%, 50% to 75%, 75% to 100%, or 75% to 95%) of the total deuterium and hydrogen atoms defined by Xa and Xb be deuterium.

[0051] Alternatively, or in addition, in some embodiments of the isotopic mixture of the compound of formula (I), at least 50% of the total of deuterium and hydrogen atoms defined by Xc+Xd are deuterium.For example, in the compound of formula (I), Xc can be hydrogen or deuterium, and Xd can be hydrogen or deuterium, and the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, at least one of Xc and Xd is deuterium.In some embodiments of the isotopic mixture of the compound of formula (I), at least 75% of the total of deuterium and hydrogen atoms defined by Xc and Xd are deuterium.In other embodiments of the isotopic mixture of the compound of formula (I), at least 95% of the total of deuterium and hydrogen atoms defined by Xc+Xd are deuterium.In other words, the isotopic mixture of the compound of formula (I) can have any combination of labels such that, on average, all or almost all of Xc and Xd are deuterium. That is, a composition comprising an isotopic mixture of a compound of formula (I) can have 50% to 100% (e.g., 50% to 95%, 50% to 75%, 75% to 100%, or 75% to 95%) of the total deuterium and hydrogen atoms defined by Xc and Xd be deuterium.

[0052] The invention further provides a pharmaceutical composition comprising a hyperpolarized compound of formula (I) (e.g., an effective amount of a hyperpolarized compound of formula (I)), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. All aspects relating to the compound of formula (I), and its hyperpolarization, are as described herein.

[0053] The present invention further provides a pharmaceutical composition comprising a hyperpolarized composition comprising an isotopic mixture of a compound of formula (I) (e.g., an effective amount of an isotopic mixture of a compound of formula (I)), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. As used herein, the phrase "hyperpolarized composition comprising an isotopic mixture of a compound of formula (I)" refers to a composition comprising an isotopic mixture of a compound of formula (I), in which one or more of the isotopes are hyperpolarized. In other words, a hyperpolarized composition comprising an isotopic mixture of a compound of formula (I) comprises a hyperpolarized isotopic mixture of a compound of formula (I). All aspects relating to the compound of formula (I), the isotopic mixture, and hyperpolarization thereof are as described herein.

[0054] The present invention further provides a method of diagnosing or monitoring a patient having or suspected of having cancer, the method comprising administering a hyperpolarized ketoglutarate compound or pharmaceutical composition as described above and treating the patient with a hyperpolarized 13 For example, a hyperpolarized composition comprising a hyperpolarized compound of formula (I) (e.g., an effective amount of a hyperpolarized compound of formula (I)) or an isotopic mixture of a compound of formula (I) (e.g., an effective amount of an isotopic mixture of a compound of formula (I)), or a pharmaceutical composition comprising the same, can be used in a method of diagnosing or monitoring a patient having or suspected of having cancer. For example, in some embodiments, the present invention provides the use of a hyperpolarized composition comprising a hyperpolarized compound of formula (I) (e.g., an effective amount of a hyperpolarized compound of formula (I)) or an isotopic mixture of a compound of formula (I) (e.g., an effective amount of an isotopic mixture of a compound of formula (I)), or a pharmaceutical composition comprising the same, in a method of diagnosing or monitoring a patient having or suspected of having cancer, the method comprising: 13In some embodiments, the method or the use comprises diagnosing or monitoring by C-MRI.In some embodiments, the method or the use comprises identifying the mutation or mutations that cause cancer.In certain embodiments, the method or the use identifies IDH1 mutation as the cause of cancer.In other words, the method or the use can be used to identify whether a patient has tumor, for example, IDH1 mutation.

[0055] The present invention further provides a method for preparing a compound of Formula (I) (e.g., Formulas (Ia)-(Ih)) or a pharma- ceutically acceptable salt thereof, as described herein, wherein each R1 is independently selected from hydrogen, deuterium, and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III):

[0056] [ka]

[0057] wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium, and Bn is benzyl; and (ii) reacting the compound of formula (III) with DCl and DO or HCl and HO to obtain a compound of formula (I) (e.g., formulas (Ia)-(Ih)) or a pharma- ceutically acceptable salt thereof. All other aspects of the compound of formula (I) are as described herein. In some embodiments, each R1 is hydrogen and the method comprises reacting the compound of formula (III) with HCl and HO. In some embodiments, each R1 is deuterium and the method comprises reacting the compound of formula (III) with DCl and DO. In some embodiments, each R1 is a cation and the method further comprises (iii) reacting the compound of formula (I) with a base.

[0058] The present invention further provides a method for preparing an isotopic mixture of a compound of formula (I) described herein, wherein each R is independently selected from hydrogen, deuterium, and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III):

[0059] [ka]

[0060] obtaining an isotopic mixture of a compound of the formula: wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total of the deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium; and (ii) reacting the isotopic mixture of the compound of formula (III) with DCl and DO or HCl and HO to obtain an isotopic mixture of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. All other aspects of the isotopic mixture of the compound of formula (I) are as described herein. In some embodiments, each R1 is hydrogen, and the method comprises reacting the compound of formula (III) with HCl and HO. In some embodiments, each R1 is deuterium, and the method comprises reacting the compound of formula (III) with DCl and DO. In some embodiments, each R1 is a cation, and the method further comprises (iii) reacting the compound of formula (I) with a base.

[0061] The present invention further provides a method for preparing a compound of Formula (I) (e.g., Formulas (Ia)-(Ih)) described herein, or a pharma- ceutically acceptable salt thereof, wherein each R1 is independently selected from hydrogen and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III):

[0062] [ka]

[0063] wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium, and Bn is benzyl; and (ii) reacting the compound of formula (III) with HCl and HO to obtain a compound of formula (I) (e.g., formulas (Ia)-(Ih)) or a pharma- ceutically acceptable salt thereof. All other aspects of the compound of formula (I) are as described herein. In some embodiments, each R is a cation, and the method further comprises (iii) reacting the compound of formula (I) with a base.

[0064] The present invention further provides a method for preparing an isotopic mixture of a compound of formula (I) as described herein, wherein each R is independently selected from hydrogen and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III):

[0065] [ka]

[0066] obtaining an isotopic mixture of a compound of the formula: wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total of the deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium; and (ii) reacting the isotopic mixture of the compound of formula (III) with HCl and HO to obtain the isotopic mixture of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. All other aspects of the isotopic mixture of the compound of formula (I) are as described herein. In some embodiments, each R1 is a cation, and the method further comprises (iii) reacting the compound of formula (I) with a base.

[0067] The present invention further comprises: (i) epoxidizing a compound of formula (A) to form a compound of formula (B):

[0068] [ka]

[0069] obtaining an epoxy compound of

[0070] (ii) deuterating the compound of formula (B) to obtain a compound of formula (C):

[0071] [ka]

[0072] and obtaining a compound of formula (iii) oxidizing the compound of formula (C) in an alkaline solution to obtain a compound of formula (D):

[0073] [ka]

[0074] In some embodiments, the compound of formula (B) is deuterated by reacting with NaBD4 in a solution of DO and lithium bromide. Alternatively, or in addition, in some embodiments, the alkaline solution in (iii) comprises 4-(dimethylamino)pyridine and sodium bicarbonate.

[0075] The present invention further relates to a compound of formula (L):

[0076] [ka]

[0077] wherein each R is independently H or alkyl, the method comprising: (i) reacting a compound of formula (E) with tert-butyldimethylsilyl chloride (TBSCl) bound to an imidazole, followed by reaction with catecholborane and water to give a compound of formula (F):

[0078] [ka]

[0079] obtaining a compound of (ii) reacting the compound of formula (F) with tris(dibenzylideneacetone)dipalladium ligand in a basic medium 12 The compound of formula (F) is esterified to obtain a compound of formula (G) by reacting with a bromomethyl ester having a C ester carbonyl group to obtain a compound of formula (G) (wherein R1 is H or alkyl):

[0080] [ka]

[0081] obtaining a compound of (iii) reacting the compound of formula (G) with tetrabutylammonium fluoride to obtain a compound of formula (H):

[0082] [ka]

[0083] obtaining a compound of (iv) epoxidizing the compound of formula (H) to obtain a compound of formula (J):

[0084] [ka]

[0085] obtaining a compound of (v) deuterating the compound of formula (J) by reacting the compound of formula (J) with lithium / copper deuteride to obtain a compound of formula (K):

[0086] [ka]

[0087] and obtaining a compound of formula (vi) oxidizing the compound of formula (K) to obtain the compound of formula (L). In some embodiments, epoxidation is carried out by reaction with an alkali metal tungstate and hydrogen peroxide. Alternatively, or in addition, in some embodiments, the compound of formula (B) is deuterated by reaction with NaBD4 in DO containing LiBr.

[0088] The present invention further relates to a compound of formula (L):

[0089] [ka]

[0090] wherein each R is H or alkyl, the method comprising: (i) reacting a compound of formula (M) with trimethylsilyl trifluoromethanesulfonate and palladium(0) to obtain a compound of formula (N):

[0091] [ka]

[0092] obtaining a compound of (ii) epoxidizing the compound of formula (N) to form a compound of formula (P):

[0093] [ka]

[0094] obtaining a compound of (iii) reacting the compound of formula (P) with sodium borodeuteride in DO with lithium bromide to obtain a compound of formula (Q):

[0095] [ka]

[0096] and obtaining a compound of formula (iv) oxidizing the compound of formula (Q) in an alkaline solution to obtain the compound of formula (L). The compound of formula (Q) can be oxidized by any suitable means to provide ketoglutaric acid. In some embodiments, the compound of formula (Q) is oxidized through Dess-Martin oxidation to form ketoglutaric acid. Alternatively, or in addition, in some embodiments, the epoxidation of the compound of formula (N) is carried out by reaction with a rare earth metal-biphenyldiol-Ph3-As=O complex. Alternatively, or in addition, in some embodiments, the compound of formula (B) is deuterated by reaction with NaBD4 in DO containing LiBr. Alternatively, or in addition, in some embodiments, the alkaline solution in (iv) comprises 4-(dimethylamino)pyridine and sodium bicarbonate.

[0097] An exemplary epoxidation method for the synthesis of mono-3-deuterated ketoglutaric acid according to an embodiment of the present invention is provided in FIG.

[0098] The present invention further comprises: (i) providing a SABRE polarization transfer precatalyst; (ii) combining the SABRE polarization transfer pre-catalyst with a ketoglutarate compound, parahydrogen, and optionally a co-ligand in a solvent to form a mixture comprising an active SABRE catalyst; and (iii) hyperpolarizing the mixture containing the active SABRE catalyst by exposing the mixture to a magnetic field or radio frequency excitation to transfer hyperpolarization from parahydrogen to the ketoglutarate compound to form a hyperpolarized ketoglutarate compound: The present invention provides a method for preparing a hyperpolarized ketoglutarate compound, comprising:

[0099] The ketoglutaric acid compound may be any suitable ketoglutaric acid compound, regardless of isotopic content. For example, the ketoglutaric acid compound may be deuterated, non-deuterated, or an isotopic mixture thereof. In general, the ketoglutaric acid compound is 13 C-labeled, and more specifically, at the C1 position 13 In some embodiments, the ketoglutarate compound is represented by formula (I) or (IV):

[0100] [ka]

[0101] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

[0102] Each R1 may be independently selected from hydrogen, deuterium, a cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (aryl)C1-C6 alkyl. In some embodiments, each R1 is independently selected from C1-C6 alkyl, for example, each R1 may be methyl, ethyl, propyl (e.g., isopropyl or n-propyl), butyl (e.g., isobutyl, n-butyl, tert-butyl, or sec-butyl), pentyl, or hexyl. In some embodiments, each R1 is independently selected from hydrogen, deuterium, and a cation. In embodiments where R1 is a cation, it will be readily understood by one of skill in the art that the compound of Formula (I) (e.g., Formulas (Ia)-(Ih)) is a salt (e.g., a pharma- ceutically acceptable salt) in which the negative charge on the oxygen is balanced by a cation. In certain embodiments, each R1 is independently a cation or C1-C6 alkyl.

[0103] In some embodiments, the ketoglutarate compound is an isotopic mixture of the compound of formula (I) described herein.

[0104] The method of preparing a hyperpolarized ketoglutarate compound includes providing a SABRE polarization transfer pre-catalyst. The SABRE (signal amplification by reversible exchange) polarization transfer pre-catalyst can be any suitable SABRE polarization transfer pre-catalyst, many of which are known in the art. In some embodiments, the SABRE polarization transfer pre-catalyst comprises a d-block element, such as, for example, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, and / or Hg. In certain embodiments, the SABRE polarization transfer pre-catalyst comprises an element from group 9 of the periodic table, i.e., Co, Rh, Ir, or Mt. In a preferred embodiment, the SABRE polarization transfer pre-catalyst comprises Ir or Co. For example, the SABRE polarization transfer precatalyst can be [Ir(COD)(IMes)(Cl)].

[0105] In some embodiments, the SABRE polarization transfer pre-catalyst may include one or more ligands, such as, for example, phosphine ligands, carbene ligands, imidazole ligands, and / or pincer ligands. Alternatively, the SABRE polarization transfer pre-catalyst may include a tridentate chelating ligand. In some embodiments, the SABRE polarization transfer pre-catalyst includes a phosphine ligand. In general, the phosphine ligands of the pre-catalyst are electron-rich and sterically demanding, and provide very high polarization transfer to pyridine protons. Examples of phosphine ligands include the following:

[0106] [ka]

[0107] Including, but not limited to:

[0108] In some embodiments, the SABRE polarization transfer precatalyst comprises a carbene ligand. In general, carbene ligands such as N-heterocyclic carbene (NHC) ligands can also provide very high polarization levels and even higher polarization than phosphine ligands due to the increased steric bulk and electron donating ability of NHC. Another advantage is that they provide faster substrate dissociation. Examples of NHCs are:

[0109] [ka]

[0110] In the formula, IMes is 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.

[0111] Alternatives to IMes include substituted IMes variants having para, meta, and / or ortho substitutions. Exemplary alternatives include the following para-substituted IMes:

[0112] [ka]

[0113] Ortho-substituted IMes:

[0114] [ka]

[0115] Meta-Substitution IMes:

[0116] [ka]

[0117] Other IMes:

[0118] [ka]

[0119] [ka]

[0120] Including, but not limited to:

[0121] In some embodiments, the SABRE polarization transfer pre-catalyst comprises a pincer chelate ligand. Exemplary pincer chelate ligands include the following SABRE polarization transfer pre-catalysts:

[0122] [ka]

[0123] These SABRE polarization transfer pre-catalysts may also be suitable for the methods described herein.

[0124] In some embodiments, the SABRE catalyst can be prepared using a water-soluble SABRE polarization transfer pre-catalyst. The water-soluble SABRE polarization transfer pre-catalyst can be prepared by any suitable method. For example, the water-soluble SABRE polarization transfer pre-catalyst can be prepared by adding a polar group, including a choline moiety or including an alkoxy (e.g., PEGylated) group, to the NHC ligand. Exemplary water-soluble SABRE polarization transfer pre-catalysts include the following:

[0125] [ka]

[0126] Including, but not limited to:

[0127] The SABRE polarization transfer pre-catalyst may also be a heterogeneous catalyst suitable for in vivo applications. For example, the SABRE polarization transfer pre-catalyst may be, for example, Polymer microbeads:

[0128] [ka]

[0129] Core-shell nanoparticles (or nano-SABRE catalysts):

[0130] [ka]

[0131] This is outlined below:

[0132] [ka]

[0133] Polymer Comb:

[0134] [ka]

[0135] Silica gel bound catalyst:

[0136] [ka]

[0137] The iridium catalyst may be immobilized on a solid support, such as

[0138] The active SABRE catalyst can be prepared by any suitable method. In general, the active SABRE catalyst is prepared by combining the SABRE polarization transfer pre-catalyst with a ketoglutaric acid compound, parahydrogen, and optionally a co-ligand in a solvent to form a mixture containing the active SABRE catalyst. In some embodiments, the active SABRE catalyst is prepared by combining the SABRE polarization transfer pre-catalyst with a ketoglutaric acid compound, parahydrogen, and a co-ligand in a solvent to form a mixture containing the active SABRE catalyst. The co-ligand, when included in the preparation of the active SABRE catalyst, can be combined with the SABRE polarization transfer pre-catalyst in any order and by any suitable means. For example, the co-ligand, when included in the preparation of the active SABRE catalyst, can be provided first to interact with the transfer pre-catalyst to promote the formation of the active SABRE catalyst. Alternatively, the co-ligand, when included in the preparation of the active SABRE catalyst, can be added together with the ketoglutaric acid compound to promote the formation of the active SABRE catalyst. In some embodiments, the co-ligand, ketoglutaric acid compound, and parahydrogen are essentially combined with the SABRE polarization transfer pre-catalyst simultaneously in a solvent to promote the formation of an active SABRE catalyst. In other embodiments, the ketoglutaric acid compound is first provided to interact with the transfer pre-catalyst to promote the formation of an active SABRE catalyst. In some embodiments, the co-ligand and ketoglutaric acid compound are combined with the SABRE polarization transfer pre-catalyst in a solvent, and parahydrogen is added (e.g., bubbled) to the resulting mixture. In other embodiments, the ketoglutaric acid compound is combined with the SABRE polarization transfer pre-catalyst in a solvent, and parahydrogen is added (e.g., bubbled) to the resulting mixture.

[0139] In some embodiments, the active SABRE catalyst is prepared by combining the SABRE polarization transfer precatalyst with a co-ligand in addition to the ketoglutaric acid compound and parahydrogen. Any suitable co-ligand can be used. For example, the co-ligand can be a compound containing a sulfoxide group. An example of a compound containing a sulfoxide group can be selected from the group consisting of DMSO, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, and dibutyl sulfoxide.

[0140] The method can be carried out in any suitable solvent. In some embodiments, the solvent comprises water (e.g., deionized water) and optionally one or more water-miscible organic solvents. In other embodiments, the solvent comprises one or more organic solvents. Examples of organic solvents that can be used in the method include alcohols such as propenyl alcohol, isopropyl alcohol, ethanol, 1-propanol, methanol, 1-hexanol, etc.; ketones such as acetone, diacetone alcohol, methyl ethyl ketone, etc.; esters such as ethyl formate, propyl formate, ethyl acetate, methyl acetate, methyl lactate, butyl lactate, ethyl lactate, etc.; ethers including sulfoxides such as dimethyl sulfoxide (DMSO), tetrahydrofuran, dioxane, diglyme, etc.; amides such as N,N-dimethylformamide, dimethylimidazolidinone, N-methylpyrrolidone, etc.; polyhydric alcohols and derivatives thereof such as ethylene glycol, glycerol, diethylene glycol, diethylene glycol monomethyl ether, etc.; and nitrogen-containing organic compounds such as acetonitrile, amylamine, isopropylamine, imidazole, dimethylamine, etc. In some embodiments, the solvent is water, i.e., without the presence of an organic solvent. The solvent can be a deuterated solvent or a non-deuterated solvent. In some embodiments, the solvent is a deuterated solvent. In other embodiments, the solvent is a non-deuterated solvent.

[0141] Parahydrogen can be combined with the SABRE polarization transfer pre-catalyst by any suitable means. For example, parahydrogen can be bubbled through a mixture containing the SABRE polarization transfer pre-catalyst, parahydrogen can be added as a gas blanket over a mixture containing the SABRE polarization transfer pre-catalyst, or the mixture containing the SABRE polarization transfer pre-catalyst can be placed under increasing pressures of parahydrogen. In some embodiments, parahydrogen is bubbled through a mixture containing the SABRE polarization transfer pre-catalyst. For example, an active SABRE catalyst can be prepared by the addition of parahydrogen to a pre-catalyst in the presence of an excess of substrate. In some embodiments, the SABRE catalyst is prepared by the addition of parahydrogen to a pre-catalyst in the presence of an excess of substrate.

[0142] [ka]

[0143] where IMes is 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.

[0144] As a result, the active SABRE (signal amplification by reversible exchange) catalyst comprises at least a d-block element, such as, for example, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, and / or Hg, parahydrogen, and a ketoglutarate compound. In certain embodiments, the active SABRE catalyst comprises an element from group 9 of the periodic table, i.e., Co, Rh, Ir, or Mt. In preferred embodiments, the active SABRE catalyst comprises Ir or Co. In some embodiments, the active SABRE catalyst comprises a ligand present on the SABRE polarization transfer pre-catalyst. For example, the active SABRE catalyst may comprise a phosphine ligand, a carbene ligand, an imidazole ligand, and / or a pincer ligand.

[0145] In some embodiments, the active SABRE catalyst comprises a co-ligand. Any suitable co-ligand can be used. For example, the co-ligand can be a compound containing a sulfoxide group. An example of a compound containing a sulfoxide group can be selected from the group consisting of DMSO, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, and dibutyl sulfoxide.

[0146] That is, in some embodiments, an active SABRE catalyst includes at least a d-block element (e.g., Ir or Co), para hydrogen, a ketoglutarate compound, and a co-ligand. In other embodiments, an active SABRE catalyst includes at least a d-block element (e.g., Ir or Co), para hydrogen, a ketoglutarate compound, a co-ligand, and one or more ligands.

[0147] In some embodiments, the active SABRE catalyst comprises a salt of a compound of formula (I) that is subjected to polarization transfer to obtain a hyperpolarized compound. Examples of active SABRE catalysts are:

[0148] [ka]

[0149] where R is a cation as described herein (e.g., Na + )is)is.

[0150] The method of preparing hyperpolarized ketoglutaric acid described herein comprises hyperpolarizing a mixture containing an active SABRE catalyst by exposing the mixture to a magnetic field or radio frequency excitation to transfer hyperpolarization from parahydrogen to the ketoglutaric acid compound to form the hyperpolarized ketoglutaric acid compound. It will be understood by those skilled in the art that initially the hyperpolarized ketoglutaric acid compound forms a complex with the hyperpolarized SABRE catalyst, however, the hyperpolarized ketoglutaric acid compound can be replaced by another ketoglutaric acid compound molecule, so the process can be repeated and free hyperpolarized ketoglutaric acid compound is produced.

[0151] The transfer of polarization from parahydrogen to the ketoglutaric acid compound to form the hyperpolarized ketoglutaric acid compound can occur under any suitable magnetic field or radio frequency excitation. For example, the transfer of polarization from parahydrogen to the carbon atom of the ketoglutaric acid compound can occur in a magnetic field below the magnetic field of the Earth. The appropriate level of magnetic field or radio frequency excitation required to transfer polarization from parahydrogen to the ketoglutaric acid compound to form the hyperpolarized ketoglutaric acid compound will be readily apparent to those skilled in the art.

[0152] In some embodiments, the method includes replenishing parahydrogen in the mixture during the step of hyperpolarizing a mixture containing an active SABRE catalyst by exposing the mixture to a magnetic field or radio frequency excitation to transfer hyperpolarization from parahydrogen to the ketoglutaric acid compound to form a hyperpolarized ketoglutaric acid compound. In other words, in some embodiments, the method includes bubbling parahydrogen through the mixture containing the active SABRE catalyst during the step of hyperpolarizing a mixture containing an active SABRE catalyst by exposing the mixture to a magnetic field or radio frequency excitation to transfer hyperpolarization from parahydrogen to the ketoglutaric acid compound to form a hyperpolarized ketoglutaric acid compound.

[0153] In some embodiments, the hyperpolarized ketoglutarate compound has formula (HP-I) or (HP-IV):

[0154] [ka]

[0155] (Wherein, the arrows in formula (HP-I) and formula (HP-IV) indicate hyperpolarization, Each R1 is independently selected from hydrogen, deuterium, a cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (aryl)C1-C6 alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

[0156] In this application, the term "alkyl" refers to a saturated hydrocarbon group having a specified number of carbon atoms, usually from 1 to about 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl (e.g., isopropyl or n-propyl), butyl (e.g., isobutyl, n-butyl, tert-butyl, or sec-butyl), pentyl, or hexyl.

[0157] In this application, the term "cycloalkyl" refers to a saturated hydrocarbon ring group having a specified number of carbon atoms, usually from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, as well as bridged or caged saturated ring groups such as norbornane or adamantane.

[0158] In this application, the term "cycloalkyl" refers to a saturated hydrocarbon ring group having a specified number of carbon atoms, usually from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, as well as bridged or caged saturated ring groups such as norbornane or adamantane.

[0159] The term "aryl" refers to a stable monocyclic or polycyclic, substituted or unsubstituted aromatic ring having from 5 to 60 ring carbon atoms, such as phenyl, tolyl, xylyl, naphthyl, phenanthryl, and anthracenyl.

[0160] The term "heteroaryl" refers to a stable monocyclic aromatic ring with the indicated number of ring atoms, containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, and the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring, containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, and the remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms, and in some embodiments, bicyclic heteroaryl groups are 9 to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms in which one 5 to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in a heteroaryl group is 2 or less. It is especially preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzofrijoxazolyl, benzofuranyl, benzothiazolyl, benzolhiophenyl, benzoxadiazolyl, dihydrobenzodioxinyl, furanyl, imidazolyl, indolyl, isothiazolyl, and isoxazolyl.

[0161] The term "heterocyclyl" refers to a saturated or unsaturated cyclic group having the indicated number of ring atoms containing from one to about three heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocyclyl groups include piperazine and thiazole groups.

[0162] The term "heterocycloalkyl" refers to a saturated cyclic group having the indicated number of ring atoms containing from 1 to about 3 heteroatoms selected from N, O, and 8, with the remaining ring atoms being carbon. Examples of heterocycloalkyl groups include tetrahydrofuranyl and pyrrolidinyl groups.

[0163] The term "pharmaceutical composition" refers to a composition that contains at least one active agent, such as a compound or salt of formula (I), and at least one other substance, such as a carrier, i.e., a diluent, excipient, or vehicle, with which the active compound is administered. "Pharmaceutically acceptable carrier" refers to a substance, such as an excipient, diluent, or vehicle, that is generally safe, non-toxic, and not biologically or otherwise undesirable, and is useful in preparing pharmaceutical compositions, and includes carriers that are acceptable for veterinary use and human pharmaceutical use. "Pharmaceutically acceptable carrier" includes both one and multiple such carriers.

[0164] The term "patient" refers to a human or non-human animal in need of medical care. Medical care can include treatment of an existing condition, such as disease treatment or disorder treatment or diagnostic treatment. In some embodiments, the patient is a human patient.

[0165] The term "treatment" or "treating" refers to providing an active compound to a patient in an amount sufficient to measurably reduce any symptoms of cancer, slow the progression of cancer, or cause regression of cancer. In certain embodiments, cancer treatment may begin before the patient exhibits symptoms of the disease.

[0166] The compounds of formula (I) may contain one or more asymmetric elements, such as asymmetric centers, asymmetric axes, for example, asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds may be, for example, racemic or optically active forms. For compounds with two or more asymmetric elements, these compounds may further be mixtures of diastereomers. For compounds with asymmetric centers, all optical isomers in pure form and their mixtures are encompassed. In these circumstances, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral HPLC column. All forms are contemplated herein, regardless of the method used to obtain them.

[0167] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds, where the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the compounds can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where possible. The salts of the present compounds further include the solvates of the compounds and the salts of the compounds.

[0168] Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; etc. The pharma- ceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2)n-COOH (wherein n is 0-4), and the like. Lists of additional suitable salts can be found, for example, in G, Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors, Wiley- VCH, 2002. The composition can further comprise at least one pharma- ceutically acceptable excipient. As used herein, pharma-ceutically acceptable excipient refers to non-active pharmaceutical ingredient ("API") substances, such as disintegrants, binders, fillers, and lubricants, used in formulating pharmaceutical products. Each of these substances is generally safe for human administration according to established government standards, including those promulgated by the United States Food and Drug Administration ("FDA").

[0169] The term "cation" as used herein refers to any positively charged ion capable of balancing the negative charge on the compound of formula (I). Generally, such cations are incorporated into salts (e.g., pharma- ceutically acceptable salts) of compounds of formula (I) by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K).

[0170] Disintegrants as used herein refer to one or more of, but are not limited to, agar-agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, gums, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, low-substituted hydroxypropylcellulose, and dioxypropylcellulose, sodium starch glycolate, and polyvinylpyrrolidone cross-linked with starch.

[0171] Binders as used herein refer to one or more of, but are not limited to, macrocrystalline cellulose, hydroxymethyl cellulose, and hydroxypropyl cellulose.

[0172] Fillers as used herein refer to one or more of, but are not limited to, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, sorbitol, starch, sucrose, sugar, and xylitol.

[0173] Lubricant as used herein refers to one or more of, but is not limited to, agar, calcium stearate, ethyl oleate, ethyl laurate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oils, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl, sorbitol, stearic acid, talc, and zinc stearate.

[0174] The composition according to the present invention can be administered to a patient by various routes.Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (e.g., topical), transmucosal, and rectal administration.In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans.Typically, the composition for intravenous administration is a solution in sterile isotonic aqueous buffer.

[0175] According to any of the embodiments, the composition according to the present invention can be orally administered to a subject in need thereof. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in a diluent, such as water, saline, or orange juice, and including additives, such as cyclodextrin or polyethylene glycol (e.g., PEG400); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, either as a solid or granules; (c) powders; (d) suspensions in suitable liquids; and (e) suitable emulsions and gels. Liquid formulations can contain diluents, such as water and alcohol, e.g., ethanol, benzyl alcohol, and polyethylene alcohol, either with or without the addition of a pharma- ceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be, for example, of the usual hard-shelled or soft-shelled gelatin type, containing surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, coloring agents, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms may contain flavors, the active ingredient in usually sucrose and acacia or tragacanth, and pastiles containing the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, etc., containing the active ingredient plus a carrier as known in the art.

[0176] Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may include suspending agents, solubilizing agents, thickening agents, stabilizers, and preservatives. Compositions according to the invention can be administered in a physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or mixture of liquids including water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, ethers such as glycerol ketals, poly(ethylene glycol) 400, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, or acetylated fatty acid glycerides, with or without the addition of a pharma- ceutically acceptable surfactant such as a soap or detergent, a suspending agent, or emulsifying agents and other pharmaceutical adjuvants such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose.

[0177] The oils that can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils.Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral.Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal salts, ammonium salts, and triethanolamine salts, and suitable detergents include (a) cationic detergents, such as, for example, dimethyldialkylammonium halides, and alkylpyridinium halides; (b) anionic detergents, such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; (c) nonionic detergents, such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers; (d) amphoteric detergents, such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.

[0178] Parenteral formulations will typically contain about 0.5 to about 25% by weight of the composition according to the invention in solution. Suitable preservatives and buffers can be used in such formulations. To minimize or eliminate irritation at the site of injection, such compositions can contain one or more non-ionic surfactants having a hydrophilic lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide with hydrophobic bases, formed by the condensation of propylene oxide with propylene glycol. Parenteral formulations can be presented in single- or multi-dose sealed containers, such as ampoules and vials, and for injections, can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, e.g., water, immediately prior to use.

[0179] The composition according to the present invention can be made into an injectable formulation. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those skilled in the art. See Pharmaceutics and Pharmacy Practice, JB Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250(1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630(1986).

[0180] The composition according to the present invention may be administered in an effective amount. "Effective amount" means an amount sufficient to show a meaningful benefit in a patient. The effective amount may vary depending on the biological effect desired in a patient, the condition to be treated, and / or the composition according to the present invention and the specific characteristics of the individual. In this regard, any suitable dose of the composition may be administered to a patient (e.g., a human) according to the type of biological effect desired or disease to be treated. Various general considerations to be taken into account in determining the "effective amount" are known to those skilled in the art and are described, for example, in Gilman et al, eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa., 1990, each of which is incorporated herein by reference. The dosage of the compositions according to the invention desirably comprises from about 0.1 mg per kilogram (kg) (mg / kg) to about 400 mg / kg (e.g., about 0.75 mg / kg, about 5 mg / kg, about 30 mg / kg, about 75 mg / kg, about 100 mg / kg, about 200 mg / kg, or about 300 mg / kg) of the patient's body weight. In another embodiment, the dose of a composition according to the present invention comprises about 0.5 mg / kg to about 300 mg / kg (e.g., about 0.75 mg / kg, about 5 mg / kg, about 50 mg / kg, about 100 mg / kg, or about 200 mg / kg), about 10 mg / kg to about 200 mg / kg (e.g., about 25 mg / kg, about 75 mg / kg, or about 150 mg / kg), or about 50 mg / kg to about 100 mg / kg (e.g., about 60 mg / kg, about 70 mg / kg, or about 90 mg / kg).

[0181] In one aspect, a dose of a composition according to the present invention desirably comprises from about 0.1 millimoles (mmol) per kilogram (kg) (mmol / kg) to about 10 mmol / kg (e.g., about 0.1 mmol / kg, about 0.5 mmol / kg, about 1 mmol / kg, about 1.5 mmol / kg, about 2 mmol / kg / kg, about 2.5 mmol / kg / kg, about 3 mmol / kg, about 4 mmol / kg, about 5 mmol / kg, about 6 mmol / kg, about 7 mmol / kg, about 8 mmol / kg, about 9 mmol / kg, or about 10 mmol / kg).

[0182] The diagnostic or monitoring methods include providing a patient with a particular dosage of the active agent. Dosage levels of about 0.1 millimoles (mmol) per kilogram (kg) of the patient's body weight (mmol / kg) to about 10 mmol / kg of each active agent per day are useful in the diagnostic or monitoring methods (e.g., about 0.1 mmol / kg, about 0.5 mmol / kg, about 1 mmol / kg, about 1.5 mmol / kg, about 2 mmol / kg / kg, about 2.5 mmol / kg / kg, about 3 mmol / kg, about 4 mmol / kg, about 5 mmol / kg, about 6 mmol / kg, about 7 mmol / kg, about 8 mmol / kg, about 9 mmol / kg, or about 10 mmol / kg).

[0183] Dosage levels of about 0.1 mg to about 140 mg of each active agent per kg of body weight per day are useful in the diagnostic or monitoring methods (about 0.5 mg to about 7 g per patient per day). The amount of compound that can be combined with carrier materials to produce a single dosage form will vary depending on the patient being treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg and about 500 mg of each active compound. In certain embodiments, 25 mg to 500 mg, or 25 mg to 200 mg of active agent are provided to the patient daily. The frequency of administration can also vary depending on the compound used and the particular diagnostic or monitoring method used. However, for many diagnostic or monitoring methods, a dosing schedule of four or fewer times per day can be used, and in certain embodiments, a dosing schedule of once or twice per day is used.

[0184] Aspects of the disclosure

[0185] The aspects, including embodiments, of the present invention described herein may be useful alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing, certain non-limiting aspects of the disclosure numbered 1-47 are provided below. As will be apparent to one of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or succeeding individually numbered aspects. This is intended to provide support for all such aspect combinations and is not limited to the aspect combinations explicitly provided below:

[0186] (1) Formula (I):

[0187] [ka]

[0188] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

[0189] (2) Formula (Ia):

[0190] [ka]

[0191] The compound of embodiment 1, wherein one of Xa and Xb is deuterium and the other is hydrogen, and both Xc and Xd are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

[0192] (3) Formula (Ib):

[0193] [ka]

[0194] The compound of embodiment 1, wherein one of Xc and Xd is deuterium and the other is hydrogen, and both Xa and Xb are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

[0195] (4) Formula (Ic):

[0196] [ka]

[0197] The compound of embodiment 1, wherein one of Xa and Xb is deuterium and the other is hydrogen, and one of Xc and Xd is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

[0198] (5) Formula (Id):

[0199] [ka]

[0200] The compound of embodiment 1, wherein both Xa and Xb are deuterium and both Xc and Xd are hydrogen as shown in or a pharma- ceutically acceptable salt thereof.

[0201] (6) Formula (Ie):

[0202] [ka]

[0203] The compound of embodiment 1, wherein both Xa and Xb are hydrogen and both Xc and Xd are deuterium as shown in or a pharma- ceutically acceptable salt thereof.

[0204] (7) Formula (If):

[0205] [ka]

[0206] The compound of embodiment 1, wherein both Xa and Xb are deuterium and one of Xc and Xd is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

[0207] (8) Formula (Ig):

[0208] [ka]

[0209] The compound of embodiment 1, wherein both Xc and Xd are deuterium and one of Xa and Xb is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

[0210] (9) Formula (Ih):

[0211] [ka]

[0212] The compound of embodiment 1, wherein Xa, Xb, Xc, and Xd are deuterium as shown in or a pharma- ceutically acceptable salt thereof.

[0213] (10) The compound of any one of embodiments 1-9, wherein each R1 is independently selected from hydrogen, 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.

[0214] (11) The compound of any one of embodiments 1-9, wherein each R1 is independently selected from C1-C6 alkyl. (12) The compound of any one of embodiments 1-9, wherein each R1 is hydrogen. (13) The compound of any one of aspects 1-9, wherein each R1 is deuterium. (14) The compound of any one of embodiments 1 to 9, wherein each R1 is a cation.

[0215] (15) Formula (I):

[0216] [ka]

[0217] wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium. or a pharma- ceutically acceptable salt thereof.

[0218] (16) The composition of embodiment 15, wherein at least 50% of the sum of deuterium atoms and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium. (17) The composition of embodiment 15, wherein at least 75% of the sum of deuterium atoms and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium. (18) The composition of embodiment 15, wherein at least 95% of the sum of deuterium atoms and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium. (19) The composition of any one of embodiments 15 to 18, wherein at least 50% of the sum of deuterium atoms and hydrogen atoms defined by Xa + Xb are deuterium. (20) The composition of any one of embodiments 15 to 18, wherein at least 75% of the sum of deuterium atoms and hydrogen atoms defined by Xa + Xb are deuterium.

[0219] (21) The composition of any one of embodiments 15 to 18, wherein at least 95% of the sum of deuterium atoms and hydrogen atoms defined by Xa + Xb are deuterium. (22) The composition of any one of embodiments 15 to 21, wherein at least 50% of the sum of deuterium atoms and hydrogen atoms defined by Xc + Xd are deuterium. (23) The composition of any one of embodiments 15-21, wherein at least 75% of the sum of deuterium atoms and hydrogen atoms defined by Xc+Xd are deuterium. (24) The composition of any one of embodiments 15 to 21, wherein at least 95% of the sum of deuterium atoms and hydrogen atoms defined by Xc + Xd are deuterium.

[0220] (twenty five) The composition of any one of embodiments 15-24, wherein each R1 is independently selected from hydrogen, 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.

[0221] (26) The composition of any one of embodiments 15-24, wherein each R1 is independently C1-C6 alkyl. (27) The composition of any one of aspects 15-24, wherein each R1 is hydrogen. (28) The composition of any one of aspects 15-24, wherein each R1 is deuterium. (29) The composition of any one of aspects 15 to 24, wherein each R1 is a cation.

[0222] (30) A pharmaceutical composition comprising the hyperpolarized compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. (31) A pharmaceutical composition comprising the hyperpolarized composition according to any one of aspects 15 to 29, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0223] (32) The pharmaceutical composition of embodiment 30 or embodiment 31 for use in a method for diagnosing or monitoring a patient having or suspected of having cancer, the method comprising treating the patient with hyperpolarized 13 2. A pharmaceutical composition, comprising: diagnosing or monitoring by C-MRI.

[0224] (33) The pharmaceutical composition for use according to embodiment 32, wherein the method comprises identifying the mutation(s) or mutations that are causative of cancer.

[0225] (34) The pharmaceutical composition for use according to embodiment 33, wherein the method identifies an IDH1 mutation.

[0226] (35) A method for preparing a compound of embodiment 1 or a pharma- ceutically acceptable salt thereof, wherein each R1 is independently selected from hydrogen, deuterium, and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III):

[0227] [ka]

[0228] wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium, and Bn is benzyl; and (ii) reacting said compound of formula (III) with DCl and DO or HCl and HO to obtain a compound of embodiment 1.

[0229] (36) A method for preparing the isotopic mixture of embodiment 15, wherein each R is independently selected from hydrogen, deuterium, and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III):

[0230] [ka]

[0231] obtaining an isotopic mixture of a compound of the formula: wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total of the deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium; and (ii) reacting the isotopic mixture of the compound of formula (III) with DCl and DO or HCl and HO to obtain the isotopic mixture of embodiment 15.

[0232] (37) (i) providing a SABRE polarization transfer precatalyst; (iii) combining the SABRE polarization transfer pre-catalyst with a ketoglutarate compound, parahydrogen, and optionally a co-ligand in a solvent to form a mixture comprising an active SABRE catalyst; and (iv) hyperpolarizing the mixture containing the active SABRE catalyst by exposing the mixture to a magnetic field or radio frequency excitation to transfer hyperpolarization from parahydrogen to the ketoglutarate compound to form a hyperpolarized ketoglutarate compound: 2. A method for preparing a hyperpolarized ketoglutarate compound comprising:

[0233] (38) The method of embodiment 37, wherein the ketoglutaric acid compound is a compound of any one of embodiments 1 to 14 or a pharma- ceutically acceptable salt thereof, or a composition of any one of embodiments 15 to 32.

[0234] (39) The method of embodiment 38, wherein each R1 is independently a cation or a C1-C6 alkyl.

[0235] (40) The hyperpolarized ketoglutarate compound has the formula (HP-I):

[0236] [ka]

[0237] (wherein the arrow in (HP-I) indicates hyperpolarization, Each R1 is independently selected from hydrogen, deuterium, a cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (aryl)C1-C6 alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; 40. The method of any one of aspects 37 to 39, wherein the compound is a medicament for treating a pulmonary circulation,

[0238] (41) A ketoglutaric acid compound having the formula (IV):

[0239] [ka]

[0240] and wherein each R is independently selected from hydrogen, deuterium, a cation, C-C alkyl, C-C cycloalkyl, (C-C cycloalkyl)C-C alkyl, (heterocycloalkyl)C-C alkyl, (heteroaryl)C-C alkyl, and (aryl)C-C alkyl; or a pharma- ceutically acceptable salt thereof.

[0241] (42) The hyperpolarized ketoglutarate compound has the formula (HP-IV):

[0242] [ka]

[0243] (wherein the arrow in (HP-IV) indicates hyperpolarization, and each R1 is independently selected from hydrogen, deuterium, a cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (aryl)C1-C6 alkyl; or a pharma- ceutically acceptable salt thereof.

[0244] (43) The method of any one of embodiments 37-42, wherein the SABRE polarization transfer pre-catalyst comprises a d-block element and one or more ligands.

[0245] (44) The method of embodiment 43, wherein the one or more ligands are selected from phosphine ligands, carbene ligands, imidazole ligands, pincer chelate ligands, and combinations thereof.

[0246] (45) The method of any one of aspects 37 to 44, wherein the active SABRE catalyst comprises a co-ligand.

[0247] (46) The method of embodiment 45, wherein the co-ligand is a compound containing a sulfoxide group.

[0248] (47) The method of embodiment 46, wherein the compound containing a sulfoxide group is selected from DMSO, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, and dibutyl sulfoxide.

[0249] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES

[0250] Example 1 This embodiment is a 1- 13 C-3-D2-4-D-5- 12 Demonstrate how to prepare C ketoglutaric acid:

[0251] [ka]

[0252] In a 20 mL vial, compound 1 (1.3 grams, 4.2 mmol) was dissolved in THF / D2O / Et3N (6 mL:3 mL:1 mL). The vial was sealed and heated at 65° C. overnight (14 hours). The reaction was cooled to room temperature and transferred to a 125 mL separatory funnel, and 10 mL D2O was added. It was worked up with CHCl2 (2×50 mL), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure to give compound 2 (1.2 grams, 92% yield with 95% D in C-3 and 50% D in C-4). 1 H NMR (400MHz, CdCl3) δ7.45-7.28 (m, 5H), 5.11 (s, 2H), 3.85-3.36 (m, 6H), 2.79-2.71 (m, 1H).

[0253] [ka]

[0254] To a 3 molar solution of DCl in D2O (50 mL) was added compound 2 (1.53 g, 5 mmol). The reaction mixture was stirred at 80 °C under an atmosphere of argon for 16 h. The solvent was removed in vacuo to give a syrup. The resulting crude product was purified by ion chromatography on formic acid resin (15 g, Bio-Rad AG 1-X8, 100-200 mesh). The column was adjusted with 4 M HCOOH and washed with D2O until a pH of 6.5 was observed. The resulting crude product was dissolved in D2O (10 mL) and loaded onto the column. The column was eluted using D2O (200 mL) followed by 3 M DCl in D2O (200 mL). The DCl phase was concentrated in vacuo and lyophilized from D2O. A yellow solid was obtained, which was crystallized from a minimum amount of EtOAc at -20 °C to give 3 (0.57 g, 75% yield). Any exposure of compound 3 to water leads to deuterium-hydrogen exchange of the carboxylic acid proton (i.e., R1) and in some cases deuterium-hydrogen exchange at carbon positions 3 and 4. The deuterated compounds were characterized by qualitative NMR using maleic acid as an internal standard. 13C NMR (101 MHz, Cd3CN) δ 169.13, 160.81. Compound 2 in CDCl3 1 H NMR:

[0255] [ka]

[0256] Example 2 This example illustrates the preparation of sodium 2-oxopentanedioate-5- 12 C-1- 13 The synthesis method of C is illustrated below.

[0257] [ka]

[0258] 2-Oxopentanedioic acid-5- 12 C-1- 13 C (16 mg, 0.11 mmol) was dissolved in 200 μL of deuterium oxide and 40% sodium deuteroxide in water (20 μL, 0.22 mmol) was added. The solution was lyophilized to give the desired product and was used further as is.

[0259] Example 3 This example illustrates a method for the synthesis of a SABRE catalyst according to one embodiment of the present invention.

[0260] In a glove box, a solution of 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene (1 g, 3 mmol, Aldrich) in 20 mL THF was added dropwise (over 15 min) to a stirred solution of [{Ir(μ-Cl)(COD)}2] (1 g, 1 mmol, Aldrich) in 3 mL THF.

[0261] The solution was stirred for 12 hours, then removed from the glove box and concentrated until about 20% of the solution volume remained. Dry, deoxygenated pentane was added to allow precipitation of the complex. The yellow precipitate was filtered and recrystallized (1.07 g, 99% yield).

[0262] Ultra-high purity hydrogen gas (Airgas) was fed into a parahydrogen (pH2) flow cryostat (Xeus technology LTD) and concentrated to approximately 50% parahydrogen at liquid nitrogen temperature (77 K) in the presence of a spin-exchange catalyst (Fe2O3). The pH2 flow was directed through a PTFE tubing to a mass flow controller (MFC, Sierra Instruments SmartTrak 100 series) set at 90 ssc / m and into a conventional 5 mm NMR tube (Norell) to allow bubbling through the sample. The entire pH2 line was pressurized to 96 psi.

[0263] Magnetic fields near or below approximately 1 μT were achieved using a home-built device consisting of a solenoid coil placed inside a mu-metal shield (Magnetic Shield Corporation model number ZG-206). At least once a day, the shield was demagnetized using an internal coil driven by a Variac. The solenoid had a diameter of 41 mm (40 mm core, 220 turns of AWG20 (0.9 mm) Cu wire and a 20 cm long winding with a 220 Ω resistor in series. The solenoid coil was powered by a commercial 1.5 V battery with a variable resistance decade box in series to provide finer control of the internal magnetic field inside the shield. Typical values ​​of the magnetic field inside the shield were between ±1.2 μT, and SABRE SHEATH experiments were typically between 0.5 μT and 0.8 μT in the sample area. Values ​​were monitored during the SABRE experiments using a Lakeshore Cryotronics Gaussmeter (model no. 475 DSP with a HMMA-2512-VR Hall Probe).

[0264] NMR experiments were carried out using a 1T Magritek Spinsolve benchtop NMR spectrometer. All 13 C NMR spectra were obtained throughout the duration of the experiment. 1 Acquisitions were performed with H decoupling turned off. The time required to manually transfer the sample from the shielded region to the magnet for low-field NMR acquisitions was typically less than 5 seconds.

[0265] From p-H2 derived hydrides [1- 13 C]ketoglutaric acid 13 Efficient hyperpolarization transfer to the C nuclear spins allows SABRE to synthesize [IrCl(H)2(DMSO)2(IMes)], [1- 13 This was made possible by using SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) using a solution mixture of [C]ketoglutaric acid and p-H2.

[0266] [ka]

[0267] All experiments were performed with 7.8 mM precatalyst, 45 mM DMSO and 10 mM [1- 13 C]ketoglutaric acid. The experiments were carried out at room temperature, with a p-H2 flow rate of about 100 sccm and a p-H2 overpressure of 96 PSI. The parahydrogen used in this example was generated from a low-cost 50% p-H2 generator.

[0268] For each experiment, p-H2 bubbling was applied for approximately 1 min, the sample was quickly transferred to the 1.4T NMR spectrometer for detection, the sample was then returned to the mu metal shield, and p-H2 bubbling was continued for the next experiment.

[0269] A schematic diagram of the catalytic system for SABRE-SHEATH hyperpolarization is shown below. The activated Ir complex catalyst, [Ir(H2)(η 2 -[1- 13 C]ketoglutaric acid (DMSO)(IMes)] transfers magnetization from p-H2 through a J-coupled spin network to [1- 13 C] ketoglutarate. Both p-H2 and ketoglutarate have weak, temporary bonds to the iridium complex.

[0270] [ka]

[0271] The results from the SABRE-SHEATH experiment are shown in Figure 2. The top scan is a single-scan HP selected from the SABRE-SHEATH experiment. 13 The C spectrum shows an enhancement ε of about 3,000 and a polarization of about P( 13 C) Approximately 0.24%. Sample: 10 mM [1- 13 C] Sodium ketoglutarate, 45 mM DMSO, 7.8 mM Ir-IMes catalyst in methanol-d4; spectra are shown in B T = -0.2μT, after 55s of p-H2 bubbling, acquired immediately after manual sample transfer to 1T.

[0272] The lower scan in Figure 2 shows a 4M [1- 13 C]Single-scan thermopolarization from sodium acetate 13 C signal is shown.

[0273] Example 4 This example illustrates the use of the SABRE catalyst, prepared in Example 1, [1- 13 C,5- 12 C;d4] of α-ketoglutarate hyperpolarization 13 C Provides the results of SABRE-SHEATH hyperpolarization.

[0274] 5 mM [1-13 C,5- 12 A sample composition was prepared containing [C;d4]α-ketoglutaric acid, 20 mM DMSO, 5 mM of the catalyst shown in FIG. 3A, and 0.5 M water. The sample was placed in a medium-walled NMR tube and argon was bubbled through the sample for 60 seconds to remove trapped air. The sample was then activated in a SABRE-SHEATH device, described in Example 3, by bubbling parahydrogen (p-H2) at a flow rate of 70 standard cubic centimeters per minute (sccm) and 100 PSI p-H2 overpressure (total p-H2 pressure of about 8 atmospheres) for about 5 minutes or more. For each experimental run, p-H2 was bubbled through the sample for 60 seconds and transferred to a 1.4 T benchtop SpinSolve NMR spectrometer for detection. The results are shown in FIGS. 3B-3H. All experiments were performed at 1000 Hz for 10 min, unless otherwise noted. T = +10°C, using a SpinSolve NMR spectrometer in CD3OD at 1.4T.

[0275] Figure 3B shows the hyperpolarized [1- 13 C,5- 12 C;d4] α-ketoglutaric acid 13 FIG. 3C provides a C NMR spectrum of 5 mM [1-C], demonstrating the interaction between the hyperpolarized complex 3b in FIG. 3A and the “free” peak as a function of temperature during the SABRE-SHEATH hyperpolarization process. 13 C,5- 12 C;d4] Representative stacking variable temperature of α-ketoglutaric acid 13 3C NMR spectrum of thermally polarized pure [1- 13 C]Acetic acid corresponding 13 C NMR spectrum of B T = 0.42μT [1- 13 C,5- 12 C;d4] in α-ketoglutarate 13 C-1 Total 13C polarization (i.e., integrating the overall bound and free resonances). Figure 3F shows the corresponding C polarization at Earth's magnetic field and at the 1.4 T magnetic field of a clinically relevant benchtop spectrometer. 13 C-1 T1 relaxation curve. FIG. 3G shows the T1 relaxation curve as a function of temperature. 13 C-1 [1- 13 C,5- 12 C;d4] total α-ketoglutaric acid 13 C polarization as a function of the magnetic moving field. 13 C-1 [1- 13 C,5- 12 C;d4] total α-ketoglutaric acid 13 C provides polarization.

[0276] In addition, the spin-lattice relaxation time was measured and found to be: T1 ([1- 13 C,5- 12 C;d4]α-ketoglutaric acid) = 97.1 ± 0.416 seconds (apparent T1 = 39.1 ± 0.414 seconds). [1- 13 C,5- 12 For comparison with [1-C;d4]α-ketoglutaric acid, the spin-lattice relaxation times were measured and found to be: T1 (after flip angle correction, 1-C;d4) in a 3T MR solution MRI system in a solution of DPBS with EDTA, prepared in Example 2, 13 C,5- 12 C]protonated α-ketoglutarate) = 63.0 ± 0.835 s (apparent T1 = 32.1 ± 0.824 s).

[0277] Example 5 This example illustrates the hyperpolarization of naturally abundant disodium α-ketoglutarate using the SABRE catalyst, shown in FIG. 4A. 13 C Provides the results of SABRE-SHEATH hyperpolarization.

[0278] A sample composition was prepared containing 5.6 mM naturally abundant disodium α-ketoglutarate in CD3OD, 20 mM DMSO, 5 mM of the catalyst shown in FIG. 4A, and 0.5 M water. The sample was placed in a medium-walled NMR tube and argon was bubbled through the sample for 60 seconds to remove trapped air. The sample was then activated in a SABRE-SHEATH device, described in Example 3, by bubbling parahydrogen (p-H2) at a flow rate of 70 standard cubic centimeters per minute (sccm) and 100 PSI p-H2 overpressure (total p-H2 pressure of about 8 atmospheres) for about 5 minutes or more. For each experimental run, p-H2 was bubbled through the sample for 60 seconds and transferred to a 1.4T benchtop SpinSolve NMR spectrometer for detection. The results are shown in FIGS. 4B-4G. All experiments were performed at 1000 K for 10 min, unless otherwise noted. T = +10°C, using a SpinSolve NMR spectrometer in CD3OD at 1.4T.

[0279] FIG. 4B shows a representative 5.6 mM solution of naturally abundant disodium α-ketoglutarate obtained by performing SABRE-SHEATH in CD3OD at +10° C. 13 4C provides the C NMR spectrum of thermally polarized pure [1- 13 C] acetic acid corresponding 13 C NMR spectrum of B T = 0.42μT and T T = Total in disodium α-ketoglutarate at +10°C 13 C polarization (i.e., integrating the total bound and free resonances). Figure 4E shows the total (bound + free) C polarization of disodium α-ketoglutarate at Earth's magnetic field and at a 1.4 T magnetic field on a clinically relevant benchtop spectrometer. 13 C polarization decay in naturally abundant disodium α-ketoglutarate as a function of temperature. 13 C-1 Total 13Figure 4G provides the C polarization in naturally abundant disodium α-ketoglutarate as a function of the magnetic field. 13 C-1 Total 13 C provides polarization.

[0280] The results from Examples 4 and 5 show that (i) the 1-position of α-ketoglutaric acid 13 C labeling allows for spectroscopic sensing, and (ii) deuteration at 3 and 4 positions allows for 3% deuteration in aqueous media. 13 (iii) maximizing the lifetime of the C-1 hyperpolarized state, and (iv) maximizing the 5-position of α-ketoglutarate. 12 C labeling is shown to minimize background signal from this resonance.

[0281] All references, including publications, patent applications, and patents, cited in this specification are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0282] Use of the terms "a" and "an" and "the" and "at least one" and similar referents in the context of describing the invention (particularly in the context of the claims below) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item (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 context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted. The recitation of ranges of values ​​herein is intended to serve as a simple way of referring to each separate value falling within the range individually, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be carried out in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary terms (e.g., "such as") provided herein is intended merely to better clarify the invention, and does not impose limitations on the scope of the invention unless otherwise stated in the claims. No terminology in this specification should be construed as indicating any element not recited in the claims as essential to the practice of the invention.

[0283] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that such variations will be utilized by those skilled in the art, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, each R １ are independently hydrogen, deuterium, cation, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

2. Formula (Ia): 【Chemistry 2】 2. The compound of claim 1, wherein one of Xa and Xb is deuterium and the other is hydrogen, and both Xc and Xd are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

3. Formula (Ib): 【Chemistry 3】 2. The compound of claim 1, wherein one of Xc and Xd is deuterium and the other is hydrogen, and both Xa and Xb are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

4. Formula (Ic): 【Chemistry 4】 2. The compound of claim 1, wherein one of Xa and Xb is deuterium and the other is hydrogen, and one of Xc and Xd is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

5. Formula (Id): 【Chemistry 5】 2. The compound of claim 1, wherein both Xa and Xb are deuterium and both Xc and Xd are hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

6. Formula (Ie): 【Chemistry 6】 2. The compound of claim 1, wherein both Xa and Xb are hydrogen and both Xc and Xd are deuterium, as shown in or a pharma- ceutically acceptable salt thereof.

7. Formula (If): 【Chemistry 7】 2. The compound of claim 1, wherein both Xa and Xb are deuterium and one of Xc and Xd is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

8. Formula (Ig): 【Chemistry 8】 2. The compound of claim 1, wherein both Xc and Xd are deuterium and one of Xa and Xb is deuterium and the other is hydrogen, as shown in or a pharma- ceutically acceptable salt thereof.

9. Formula (Ih): 【Chemistry 9】 The compound of claim 1, wherein Xa, Xb, Xc, and Xd are deuterium as shown in or a pharma- ceutically acceptable salt thereof.

10. Each R １ are independently hydrogen, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ The compound of any one of claims 1 to 9, wherein the aryl group is selected from alkyl.

11. Each R １ became independent and C １ -C ６ The compound of any one of claims 1 to 9, wherein the aryl group is selected from alkyl.

12. Each R １ The compound of any one of claims 1 to 9, wherein is hydrogen.

13. Each R １ The compound of any one of claims 1 to 9, wherein is deuterium.

14. Each R １ The compound of any one of claims 1 to 9, wherein is a cation.

15. Formula (I): 【Chemistry 10】 (In the formula, each R １ are independently hydrogen, deuterium, cation, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total of deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium; or a pharma- ceutically acceptable salt thereof.

16. 16. The composition of claim 15, wherein at least 50% of the sum of the deuterium and hydrogen atoms defined by Xa + Xb + Xc + Xd are deuterium.

17. 16. The composition of claim 15, wherein at least 75% of the sum of the deuterium and hydrogen atoms defined by Xa + Xb + Xc + Xd are deuterium.

18. 16. The composition of claim 15, wherein at least 95% of the sum of deuterium and hydrogen atoms defined by Xa + Xb + Xc + Xd are deuterium.

19. 19. The composition of any one of claims 15 to 18, wherein at least 50% of the sum of deuterium atoms and hydrogen atoms defined by Xa+Xb are deuterium.

20. 19. The composition of any one of claims 15 to 18, wherein at least 75% of the sum of deuterium atoms and hydrogen atoms defined by Xa+Xb are deuterium.

21. 19. The composition of any one of claims 15 to 18, wherein at least 95% of the sum of deuterium atoms and hydrogen atoms defined by Xa+Xb are deuterium.

22. 22. The composition of any one of claims 15 to 21, wherein at least 50% of the sum of deuterium atoms and hydrogen atoms defined by Xc + Xd are deuterium.

23. 22. The composition of any one of claims 15 to 21, wherein at least 75% of the sum of deuterium atoms and hydrogen atoms defined by Xc + Xd are deuterium.

24. 22. The composition of any one of claims 15 to 21, wherein at least 95% of the sum of deuterium atoms and hydrogen atoms defined by Xc + Xd are deuterium.

25. Each R １ are independently hydrogen, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ The composition of any one of claims 15 to 24, wherein the alkyl is selected from the group consisting of aryl, aryl, aryl and alkyl.

26. Each R １ became independent and C １ -C ６ The composition of any one of claims 15 to 24, wherein the alkyl is alkyl.

27. Each R １ The composition of any one of claims 15 to 24, wherein is hydrogen.

28. Each R １ The composition of any one of claims 15 to 24, wherein is deuterium.

29. Each R １ The composition of any one of claims 15 to 24, wherein is a cation.

30. A pharmaceutical composition comprising a hyperpolarised compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

31. A pharmaceutical composition comprising the hyperpolarized composition of any one of claims 15 to 29, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

32. 32. The pharmaceutical composition of claim 30 or claim 31 for use in a method of diagnosing or monitoring a patient having or suspected of having cancer, said method comprising treating said patient with hyperpolarized １３ 2. A pharmaceutical composition, including diagnosing or monitoring by C-MRI.

33. 33. The pharmaceutical composition for use according to claim 32, wherein the method comprises identifying the mutation or mutations that are causative of the cancer.

34. 34. The pharmaceutical composition for use according to claim 33, wherein the method identifies an IDH1 mutation.

35. 10. A method for preparing a compound of claim 1 or a pharma- ceutically acceptable salt thereof, comprising: １ are independently selected from hydrogen, deuterium, and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III): 【Chemistry 11】 wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium, and Bn is benzyl; and (ii) reacting the compound of formula (III) with DCl and D ２ O or HCl and H ２ O to obtain the compound of claim 1.

36. 16. The method of preparing the isotopic mixture of claim 15, wherein each R １ are independently selected from hydrogen, deuterium, and a cation, the method comprising: (i) reacting a compound of formula (II) with deuterium oxide in an organic solvent under basic conditions to obtain a compound of formula (III): 【Chemistry 12】 obtaining an isotopic mixture of a compound of the formula: wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and at least 25% of the total of the deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium; and (ii) reacting said isotopic mixture of compound of formula (III) with DCl and D ２ O or HCl and H ２ O to obtain the isotopic mixture of claim 15.

37. (i) providing a SABRE polarization transfer pre-catalyst; (ii) combining the SABRE polarization transfer pre-catalyst with a ketoglutarate compound, parahydrogen, and optionally a co-ligand in a solvent to form a mixture comprising an active SABRE catalyst; and (iii) hyperpolarizing the mixture containing the active SABRE catalyst by exposing the mixture to a magnetic field or radio frequency excitation to transfer hyperpolarization from parahydrogen to the ketoglutarate compound to form a hyperpolarized ketoglutarate compound; 2. A method for preparing a hyperpolarized ketoglutarate compound comprising:

38. 38. The method of claim 37, wherein the ketoglutarate compound is a compound of any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof, or a composition of any one of claims 15 to 32.

39. Each R １ are independently a cation or C １ -C ６ 40. The method of claim 38, wherein said alkyl is alkyl.

40. The hyperpolarized ketoglutarate compound has the formula (HP-I): 【Chemistry 13】 (wherein the arrow in (HP-I) designates hyperpolarization, Each R １ are independently hydrogen, deuterium, cation, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ alkyl; and Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, with the proviso that at least one of Xa, Xb, Xc, and Xd is deuterium; or a pharma- ceutically acceptable salt thereof.

41. The ketoglutaric acid compound has the formula (IV): 【Chemistry 14】 (and wherein each R １ are independently hydrogen, deuterium, cation, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ alkyl; or a pharma- ceutically acceptable salt thereof.

42. The hyperpolarized ketoglutarate compound has the formula (HP-IV): 【Chemistry 15】 (wherein the arrow in (HP-IV) designates hyperpolarization, And each R １ are independently hydrogen, deuterium, cation, C １ -C ６ Alkyl, C ３ -C ７ Cycloalkyl, (C ３ -C ７ Cycloalkyl)C １ -C ６ Alkyl, (heterocycloalkyl)C １ -C ６ Alkyl, (heteroaryl)C １ -C ６ Alkyl, and (aryl)C １ -C ６ alkyl; 42. The method of claim 37 or 41, wherein said compound is a phenylalanine or a phenylalanine compound, or a pharma- ceutically acceptable salt thereof.

43. The method of any one of claims 37 to 42, wherein the SABRE polarization transfer pre-catalyst comprises a d-block element and one or more ligands.

44. 44. The method of claim 43, wherein the one or more ligands are selected from phosphine ligands, carbene ligands, imidazole ligands, pincer chelate ligands, and combinations thereof.

45. The process of any one of claims 37 to 44, wherein the active SABRE catalyst comprises a co-ligand.

46. 46. ​​The method of claim 45, wherein the co-ligand is a compound containing a sulfoxide group.

47. 47. The method of claim 46, wherein the compound containing a sulfoxide group is selected from DMSO, phenylmethyl sulfoxide, phenylchloromethyl sulfoxide, diphenyl sulfoxide, dibenzoyl sulfoxide, and dibutyl sulfoxide.

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