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JP-7855006-B2 - System and method for generating hyperpolarized materials

JP7855006B2JP 7855006 B2JP7855006 B2JP 7855006B2JP-7855006-B2

Inventors

  • イライ シュバルツ
  • ミヒャエル カイム
  • シュテファン クネヒト

Assignees

  • エヌビジョン イメージング テクノロジーズ ゲゼルシャフト ミット ベシュレンクテル ハフツング

Dates

Publication Date
20260507
Application Date
20220323
Priority Date
20210323

Claims (8)

  1. A composition comprising a compound of formula (I), In the formula, Z includes (i) a carbon-carbon double bond (-C=C-) substituted with (i) 1 H (proton), 2 H (deuterium), or a combination thereof, or (ii) a carbon-carbon triple bond (-C≡C-), R1 includes a para-hydrogen-induced polarization (PHIP) transfer portion, R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine. R3 comprises a bio-related contrast agent that includes non-hydrogen nuclear spins and is at least partially isotope-labeled with said non-hydrogen nuclear spins, The PHIP moving portion includes * CH2 , * CH2- * CH2 , *CHY, *C= Y , * CR4R5 , * CR4Y , *C= Y , * CR6R7- * CR8R9 , or any deuterated version thereof. *C is the carbon isotope 12C or 13C . R4 and R5 are each independently selected from hydrogen, 1H , 2H , 3H , linear, branched, or cyclic C1-C10 alkyl hydrocarbons, C6 aryls, benzyls, phenyls, heteroaryls, and haloalkyl groups. Y is selected from a spin 1/2 atom and a spin 1/2 atom covalently bonded to one or more chemical parts selected from the group consisting of N, O, and S, which are optionally substituted with a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, C6 aryl, benzyl, phenyl, heteroaryl, halogen, or haloalkyl group, and the spin 1/2 atom is 1H , 13C , 15N , 19F , or 31P . A composition in which R6 , R7 , R8 , and R9 are each independently selected from ¹H , ²H , ³H , linear, branched, or cyclic C1-C10 alkyl hydrocarbons, C6 aryls, benzyls, phenyls, heteroaryls, and haloalkyl groups.
  2. The composition according to claim 1, wherein the PHIP moving portion contains at least one atom that is J-coupled with the non-hydrogen nucleus spin at least 0.1 Hertz (Hz), or Z contains at least one atom that is J-coupled with the non-hydrogen nucleus spin at least 0.1 Hertz (Hz).
  3. The composition according to 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 hydroxyl group, a methyl alcohol group, an ethyl alcohol group, an n-propanol group, an isopropyl alcohol group, an alcohol propionic acid 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, an ethoxy group, an isopropoxy group, an alcohol propionic acid group, a butoxy group, a t-butoxy group, an 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.
  4. The composition according to claim 1, wherein the bio-related contrast agent comprises a compound of formula R 10 C(=O)X-, where R 10 is selected from linear, branched, or cyclic C1-C10 alkyl groups, one or more C atoms are optionally substituted with C=C, CO, COOH, CNH₂ , COOH, CH₂COOH , CONH₂ , OC(=O), and X is selected from NR 11 , S, and O, where R 11 is selected from hydrogen and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butyl carbonate, and benzyl.
  5. The composition according to claim 1, wherein the bio-related contrast agent is selected from pyruvate, glutamate, glutamine, lactic acid, acetic acid, acetoacetic acid, zymonate, alanine, fructose, fumaric acid, bicarbonate, urea, dehydroascorbic acid, α-ketoglutaric acid, dihydroxyacetone, glucose, ascorbic acid, and their conjugate acids.
  6. The composition according to claim 1, wherein the composition has a solubility in water of less than 50 mmol (mM).
  7. The composition according to claim 1, wherein the composition has a solubility in an organic solvent of less than 50 mmol (mM), and the organic solvent is acetone, ethanol, chloroform, or toluene.
  8. The composition according to claim 1, wherein reacting the composition with parahydrogen yields a chemical yield of at least 30% of the parahydrogenated product.

Description

Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63/164,585 filed on 23 March 2021, U.S. Provisional Patent Application No. 63/260,631 filed on 27 August 2021, and U.S. Provisional Patent Application No. 63/266,986 filed on 21 January 2022, each of which is incorporated herein by reference in whole for all purposes. The disclosed embodiments generally relate to the production of hyperpolarized materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications. Para-hydrogen-induced polarization (PHIP) is a low-cost, high-throughput method for polarization of metabolites for hyperpolarized (HP) magnetic resonance imaging (MRI). Para-hydrogen-induced polarization with a side arm (PHIP-SAH) can be used to polarize metabolites, such as acetic acid molecules. However, existing PHIP-SAH polarization approaches may not be suitable for preclinical or clinical HP MRI applications. In some embodiments, the present disclosure relates to a composition comprising a compound of formula (I), The composition described herein comprises a formula in which Z comprises (i) a carbon-carbon double bond (-C=C-) substituted to include (i) 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a carbon-carbon triple bond (-C≡C-), R1 comprises a para-hydrogen-induced polarization (PHIP) transfer moiety, R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, and R3 comprises a bio-related contrast agent containing a non-hydrogen nuclear spin. In some embodiments, the present disclosure relates to a composition comprising a compound of formula (II), The composition is described in which Z' is (i) a parahydrogenated carbon-carbon single bond (-CH*-CH*-) substituted to include 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a parahydrogenated carbon-carbon double bond (-CH*=CH*-) substituted to include 1H (proton), 2H (deuterium), or a combination thereof, and in the formula H* is a hydrogen having a spin order derived from parahydrogen, R1 includes a parahydrogen-induced polarization (PHIP) transfer moiety, R2 includes an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, and R3 includes a bio-related contrast agent containing a non-hydrogen nuclear spin. In some embodiments, the present disclosure relates to a composition comprising (i) a bio-relevant contrast agent containing non-hydrogen nuclear spins and (ii) a compound of formula (III), The composition described is one in which Z'' is (i) a parahydrogenated carbon-carbon single bond (-CH*-CH*-) substituted to include 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a parahydrogenated carbon-carbon double bond (-CH*=CH*-) substituted to include 1H (proton), 2H (deuterium), or a combination thereof, R1 ' comprises a parahydrogen-induced polarization (PHIP) transfer moiety, and R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine. In some embodiments, the present disclosure relates to a composition comprising (i) a hyperpolarized bio-relevant contrast agent containing non-hydrogen nuclear spins and (ii) a compound of formula (IV), The following describes a composition in which Z comprises (i) a carbon-carbon double bond (-C=C-) substituted to include (i) 1H (proton), 2H (deuterium), or a combination thereof, or (ii) a carbon-carbon triple bond (-C≡C-), R1 ' comprises a para-hydrogen-induced polarization (PHIP) transfer moiety, and R2 comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine. In some embodiments, this disclosure describes compounds of formula I, formula II, formula III, or formula IV that include a PHIP transfer moiety. In some embodiments, the PHIP transfer moiety includes an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon. In some embodiments, the PHIP transfer portion comprises * CR4R5 , * CR4Y , *C=Y, or any deuterated version thereof, where *C is a carbon isotope of 12C or 13C , R4 and R5 are each independently selected from 1H , 2H , 3H, linear, branched, or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, and haloalkyl groups, and Y is selected from a spin 1/2 atom and a spin 1/2 atom covalently bonded to one or more chemical portions selected from a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, C6 aryl, benzyl, phenyl, heteroaryl, halogen, or haloalkyl group, or a heteroatom such as N, O, S that is optionally substituted with a linear, branched, or cyclic C1-C10 alkyl hydrocarbon, C6 aryl, benzyl, phenyl, heteroaryl, halogen, or haloalkyl group. In some embodiments, the PHIP transfer portion includes * CR6R7- * CR8R9 , or any deuterated version thereof, where *C is a carbon isotope of 12C or 13C . R6 , R7 , R8 , and R9 are each independen