# US 12,110,270 B2 · Systems and methods for generation of hyperpolarized materials

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- Number: US 12,110,270 B2
- Document ID: US12110270B2
- Status: Granted
- Kind: B2
- Application number: 18/473,243
- Filed: 2023-09-23
- Published: 2024-01-18
- Granted: 2024-10-08
- Earliest claimed: 2021-03-23
- Assignees: Nvision Imaging Technologies GmbH
- Applicants: Nvision Imaging Technologies GmbH
- Inventors: Ilai Schwartz; Michael Keim; Stephan Knecht
- Web page: https://patentgrep.com/patent/US12110270B2

## CPC

- A61K 49/10: Organic compounds
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07C 67/40: by oxidation of primary alcohols
- C07C 69/716: Esters of keto-carboxylic acids {or aldehydo-carboxylic acids}
- C07C 69/73: of unsaturated acids
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure describes hyperpolarized materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications. The present disclosure describes methods for producing hyperpolarized materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications. The present disclosure describes precursor compounds for use in producing hyperpolarized materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications.

## Claims

### Claim 1

A composition comprising a compound of Formula (I):
wherein Z comprises: (i) a carbon-carbon double bond (—C═C—) which is substituted to include 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a carbon-carbon triple bond (—C≡C—);
R1 comprises a parahydrogen induced polarization (PHIP) transfer moiety;
R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine; and
R3 comprises a biorelevant imaging agent comprising a non-hydrogen nuclear spin and is at least partially isotopically labeled with the non-hydrogen nuclear spin;
wherein the PHIP transfer moiety comprises *CH2, *CH2—*CH2, *CHY, *C═Y, *CR4R5, *CR4Y, *C═Y, *CR6R7—* CR8R9, or any deuterated version thereof, wherein:
*C is a 12C or 13C carbon isotope;
R4 and R5 are each independently selected from: hydrogen, 1H, 2H, 3H, a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, a benzyl, a phenyl, a heteroaryl, and a haloalkyl group;
Y is selected from: a spin-1/2 atom, and a spin-1/2 atom covalently bonded to one or more chemical moiety chosen from: a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl group, or a heteroatom selected from the group consisting of N, O, S, optionally substituted with a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl group; and
R6, R7, R8, and R9 are each independently selected from: 1H, 2H, 3H, a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, a benzyl, a phenyl, a heteroaryl, and a haloalkyl group.

### Claim 2

A composition comprising a compound of Formula (I):
wherein Z comprises: (i) a carbon-carbon double bond (—C═C—) which is substituted to include 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a carbon-carbon triple bond (—C≡C—);
R1 comprises a parahydrogen induced polarization (PHIP) transfer moiety;
R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine; and
R3 comprises a biorelevant imaging agent comprising a non-hydrogen nuclear spin and is at least partially isotopically labeled with the non-hydrogen nuclear spin;
wherein: the PHIP transfer moiety includes at least one atom having a J-coupling with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz), or Z includes at least one atom having a J-coupling with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

### Claim 3

A composition comprising a compound of Formula (I):
wherein Z comprises: (i) a carbon-carbon double bond (—C═C—) which is substituted to include 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a carbon-carbon triple bond (—C≡C—);
R1 comprises a parahydrogen induced polarization (PHIP) transfer moiety;
R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine; and
R3 comprises a biorelevant imaging agent comprising a non-hydrogen nuclear spin and is at least partially isotopically labeled with the non-hydrogen nuclear spin;
wherein the biorelevant imaging agent comprises a compound of the formula R4C(═O)X—; wherein R4 is chosen from a linear, branched, or cyclic C1-C10 alkyl group, in which one or more C atoms are optionally replaced with C═C, CO, COH, CNH2, COOH, CH2COOH, CONH2, OC(═O); and X is chosen from NR5, S and O; wherein R5 is selected from hydrogen and an amino protecting group, optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butyl carbonate and benzyl.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the PHIP transfer moiety includes at least one atom having a J-coupling with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz), or Z includes at least one atom having a J-coupling with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

### Claim 5 (depends on 1)

The composition of claim 1, wherein R2 is selected from: a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an s-butyl group, a t-butyl group, an isobutyl group, a hydroxy group, a methyl alcohol group, an ethyl alcohol group, an n-propanol group, an isopropyl alcohol group, a propionic alcohol group, an n-butyl alcohol group, an s-butyl alcohol group, a t-butyl alcohol group, an isobutyl alcohol group, a methoxy group, an ethoxy group, a propoxy group, an isopropxy group, a propionic group, a butoxy group, a t-butoxy group, a s-butoxy group, an ester group, a phenyl group, a substituted phenyl group, a primary amine group, a secondary amine group, a tertiary amine group, a primary amide group, a secondary amide group, and a tertiary amide group.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the biorelevant imaging agent comprises a compound of the formula R10C(═O)X—; wherein R10 is chosen from a linear, branched, or cyclic C1-C10 alkyl group, in which one or more C atoms are optionally replaced with C═C, CO, COH, CNH2, COOH, CH2COOH, CONH2, OC(═O); and X is chosen from NR11, S and O; wherein R11 is selected from hydrogen and an amino protecting group, optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butyl carbonate and benzyl.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the biorelevant imaging agent is selected from: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the composition has a solubility in water of less than 50 millimolar (mM).

### Claim 9 (depends on 1)

The composition of claim 1, wherein the composition has a solubility in an organic solvent of less than 50 millimolar (mM); and wherein the organic solvent is acetone, ethanol, chloroform, or toluene.

### Claim 10 (depends on 1)

The composition of claim 1, wherein reacting the composition with parahydrogen results in a chemical yield of parahydrogenated product of at least 30%.

### Claim 11 (depends on 2)

The composition of claim 2, wherein the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.

### Claim 12 (depends on 2)

The composition of claim 2, wherein the PHIP transfer moiety comprises *CH2, *CH2—* CH2, *CHY, *C═Y, *CR4R5, *CR4Y, *C═Y, *CR6R7—* CR8R9, or any deuterated version thereof, wherein:
*C is a 12C or 13C carbon isotope;
R4 and R5 are each independently selected from: hydrogen, 1H, 2H, 3H, a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, a benzyl, a phenyl, a heteroaryl, and a haloalkyl group;
Y is selected from: a spin-1/2 atom, and a spin-1/2 atom covalently bonded to one or more chemical moiety chosen from: a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl group, or a heteroatom selected from the group consisting of N, O, S, optionally substituted with a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl group; and
R6, R7, R8, and R9 are each independently selected from: 1H, 2H, 3H, a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, a benzyl, a phenyl, a heteroaryl, and a haloalkyl group.

### Claim 13 (depends on 2)

The composition of claim 2, wherein R2 is selected from: a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an s-butyl group, a t-butyl group, an isobutyl group, a hydroxy group, a methyl alcohol group, an ethyl alcohol group, an n-propanol group, an isopropyl alcohol group, a propionic alcohol group, an n-butyl alcohol group, an s-butyl alcohol group, a t-butyl alcohol group, an isobutyl alcohol group, a methoxy group, an ethoxy group, a propoxy group, an isopropxy group, a propionic group, a butoxy group, a t-butoxy group, a s-butoxy group, an ester group, a phenyl group, a substituted phenyl group, a primary amine group, a secondary amine group, a tertiary amine group, a primary amide group, a secondary amide group, and a tertiary amide group.

### Claim 14 (depends on 2)

The composition of claim 2, wherein the biorelevant imaging agent comprises a compound of the formula R10C(═O)X—; wherein R10 is chosen from a linear, branched, or cyclic C1-C10 alkyl group, in which one or more C atoms are optionally replaced with C═C, CO, COH, CNH2, COOH, CH2COOH, CONH2, OC(═O); and X is chosen from NR11, S and O; wherein R11 is selected from hydrogen and an amino protecting group, optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butyl carbonate and benzyl.

### Claim 15 (depends on 2)

The composition of claim 2, wherein the biorelevant imaging agent is selected from: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.

### Claim 16 (depends on 2)

The composition of claim 2, wherein the composition has a solubility in water of less than 50 millimolar (mM).

### Claim 17 (depends on 2)

The composition of claim 2, wherein the composition has a solubility in an organic solvent of less than 50 millimolar (mM); and wherein the organic solvent is acetone, ethanol, chloroform, or toluene.

### Claim 18 (depends on 2)

The composition of claim 2, wherein reacting the composition with parahydrogen results in a chemical yield of parahydrogenated product of at least 30%.

### Claim 19 (depends on 3)

The composition of claim 3, wherein the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.

### Claim 20 (depends on 3)

The composition of claim 3, wherein the PHIP transfer moiety comprises *CH2, *CH2—* CH2, *CHY, *C═Y, *CR6R7, *CR6Y, *C═Y, *CR8R9—* CR10R11, or any deuterated version thereof, wherein:
*C is a 12C or 13C carbon isotope;
R6 and R7 are each independently selected from: hydrogen, 1H, 2H, 3H, a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, a benzyl, a phenyl, a heteroaryl, and a haloalkyl group;
Y is selected from: a spin-1/2 atom, and a spin-1/2 atom covalently bonded to one or more chemical moiety chosen from: a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl group, or a heteroatom selected from the group consisting of N, O, S, optionally substituted with a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl group; and
R8, R9, R10, and R11 are each independently selected from: 1H, 2H, 3H, a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, a C6 aryl, a benzyl, a phenyl, a heteroaryl, and a haloalkyl group.

### Claim 21 (depends on 3)

The composition of claim 3, wherein the PHIP transfer moiety includes at least one atom having a J-coupling with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz), or Z includes at least one atom having a J-coupling with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

### Claim 22 (depends on 3)

The composition of claim 3, wherein R2 is selected from: a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an s-butyl group, a t-butyl group, an isobutyl group, a hydroxy group, a methyl alcohol group, an ethyl alcohol group, an n-propanol group, an isopropyl alcohol group, a propionic alcohol group, an n-butyl alcohol group, an s-butyl alcohol group, a t-butyl alcohol group, an isobutyl alcohol group, a methoxy group, an ethoxy group, a propoxy group, an isopropxy group, a propionic group, a butoxy group, a t-butoxy group, a s-butoxy group, an ester group, a phenyl group, a substituted phenyl group, a primary amine group, a secondary amine group, a tertiary amine group, a primary amide group, a secondary amide group, and a tertiary amide group.

### Claim 23 (depends on 3)

The composition of claim 3, wherein the biorelevant imaging agent is selected from: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.

### Claim 24 (depends on 3)

The composition of claim 3, wherein the composition has a solubility in water of less than 50 millimolar (mM).

### Claim 25 (depends on 3)

The composition of claim 3, wherein the composition has a solubility in an organic solvent of less than 50 millimolar (mM); and wherein the organic solvent is acetone, ethanol, chloroform, or toluene.

### Claim 26 (depends on 3)

The composition of claim 3, wherein reacting the composition with parahydrogen results in a chemical yield of parahydrogenated product of at least 30%.