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EP-4735906-A1 - SYSTEMS AND METHODS FOR HYPERPOLARIZED NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY AND MAGNETIC RESONANCE IMAGING

EP4735906A1EP 4735906 A1EP4735906 A1EP 4735906A1EP-4735906-A1

Abstract

The present disclosure describes systems and methods for enhancing spin-lattice (T 1 ) relaxation times in hyperpolarized molecules of interest during the period between a hyperpolarization procedure and the performance of a nuclear magnetic resonance (NMR) or magnetic resonance imaging (MRI) experiment. The systems and methods generally subject the hyperpolarized molecule to a relatively low magnetic field during the hyperpolarization procedure and/or during any purification procedures that follow the hyperpolarization procedure. At such relatively low magnetic fields, a hyperpolarizable nucleus may display a relatively long T 1 relaxation time constant at a nearly physiological pH. The T 1 relaxation time may be further enhanced by conducting the hyperpolarization procedure and/or the purification procedure in a deuterated water (D 2 O) solvent and/or in a solution containing a scavenging agent, such as ethylenediaminetetraacetic acid (EDTA). Such systems and methods may generate such long T 1 relaxation times that the hyperpolarized molecule retains substantial polarization during the NMR/MRI experiment.

Inventors

  • SCHWARTZ, Ilai
  • KNECHT, STEPHAN

Assignees

  • NVision Imaging Technologies GmbH

Dates

Publication Date
20260506
Application Date
20240620

Claims (20)

  1. 1. A method comprising: (a) obtaining a molecule of interest or a derivative of a molecule of interest dissolved in a solution characterized by a pH between 5 and 9, wherein the molecule of interest or the derivative of the molecule of interest comprises a hyperpolarizable nucleus, and wherein the hyperpolarizable nucleus is characterized by a spin-lattice (Ti) relaxation time of at least 60 second (s) in the solution at a magnetic field of at most 1 tesla (T) and a pH between 5 and 9; (b) subjecting the molecule of interest or the derivative of the molecule of interest to a nuclear spin hyperpolarization procedure to thereby generate a hyperpolarized molecule of interest and to thereby impart a first nuclear spin polarization to the hyperpolarizable nucleus; (c) subjecting the hyperpolarized molecule of interest to a purification procedure to thereby generate a purified hyperpolarized molecule of interest, thereby imparting a second nuclear spin polarization to the hyperpolarizable nucleus; (d) administering the hyperpolarized molecule of interest to a subject; and (e) performing a magnetic resonance spectroscopy (MRS) procedure on the subject.
  2. 2. The method of claim 1, further comprising, prior to (b), applying a first magnetic field of at most 1 T to the molecule of interest or the derivative of the molecule of interest.
  3. 3. The method of claim 1 or 2, further comprising, prior to (c), applying a second magnetic field of at most 1 T to the hyperpolarized molecule of interest.
  4. 4. The method of any one of claims 1-3, wherein the nuclear spin hyperpolarization procedure comprises a parahydrogen induced polarization (PHIP) procedure, a PHIP- sidearm hydrolysis (PHIP-SAH) procedure, a PHIP nuclear Overhauser effect system (PHIPNOESYS) procedure, or a signal amplification by reversible exchange (SABRE) procedure.
  5. 5. The method of any one of claims 1-4, wherein (a)-(e) are collectively performed in at most 60 s.
  6. 6. The method of any one of claims 1-5, wherein the second nuclear spin polarization is no less than 50% of the first nuclear spin polarization.
  7. 7. The method of any one of claims 1-6, wherein the second nuclear spin polarization is at least 10%.
  8. 8. The method of any one of claims 1-7, wherein the hyperpolarizable nucleus is characterized by a Ti relaxation time of at least 60 s in the solution at a pH between 5 and 9.
  9. 9. The method of any one of claims 1-8, wherein the molecule of interest comprises a carboxylate, a carbon- 13 -labeled carboxylate, a partially or fully deuterated carboxylate, or a carbon- 13 -labeled and partially or fully deuterated carboxylate.
  10. 10. The method of any one of claims 1-9, wherein the solution further comprises a scavenging agent selected from the group consisting of: ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 2,2’,2”,2”’-(l,4,7,10- tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid (DOTA), 1,7,10,16-tetraoxa- 4,13-diazacyclooctadecane (Kryptofix® 22), 1,4,7, 1013, 16-hexaazacyclooctadecane (Hexacyclen), and crown ethers.
  11. 11. The method of claim 10, wherein the solution comprises the scavenging agent at a concentration of at least 1%.
  12. 12. The method of claim 10 or 11, wherein the solution comprises the scavenging agent at a concentration of at most 10%.
  13. 13. The method of any one of claims 1-12, wherein the solution comprises a deuterated water (D2O) solvent.
  14. 14. The method of any one of claims 1-13, wherein the hyperpolarizable nucleus comprises a carbon- 13 ( 13 C) nucleus.
  15. 15. A composition comprising: a solution comprising: a solvent; and a hyperpolarized molecule of interest dissolved in the solvent, the hyperpolarized molecule comprising a hyperpolarizable nucleus; wherein the hyperpolarizable nucleus is characterized by a spin-lattice (Ti) relaxation time of at least 60 seconds (s) in the solution at a magnetic field of at most 1 tesla (T) and a pH between 5 and 9.
  16. 16. The composition of claim 15, wherein the hyperpolarizable nucleus of the hyperpolarized molecule of interest has a nuclear spin polarization of at least 10%.
  17. 17. The composition of claim 15 or 16, wherein the hyperpolarized molecule of interest comprises a hyperpolarized carboxylate, a hyperpolarized carbon- 13 -labeled carboxylate, a hyperpolarized partially or fully deuterated carboxylate, or a hyperpolarized carbon- 13 -labeled and partially or fully deuterated carboxylate.
  18. 18. The composition of any one of claims 15-17, wherein the solution further comprises a scavenging agent selected from the group consisting of: ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 2,2’,2”,2”’-(l,4,7,10- tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid (DOTA), 1,7,10,16-tetraoxa- 4,13-diazacyclooctadecane (Kryptofix® 22), 1,4,7, 1013, 16-hexaazacyclooctadecane (Hexacyclen), and crown ethers.
  19. 19. The composition of claim 18, wherein the solution comprises the scavenging agent at a concentration of at least 1%.
  20. 20. The composition of claim 18 or 19, wherein the solution comprises the scavenging agent at a concentration of at most about 10%.

Description

SYSTEMS AND METHODS FOR HYPERPOLARIZED NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY AND MAGNETIC RESONANCE IMAGING CROSS-REFERENCE [001] The present application claims priority to U.S. Provisional Patent Application No. 63/524,242, entitled “SYSTEMS AND METHODS FOR HYPERPOLARIZED NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY AND MAGNETIC RESONANCE IMAGING,” filed on June 30, 2023, which is incorporated herein by reference in its entirety for all purposes. TECHNICAL FIELD [002] The disclosed embodiments generally relate to the generation and purification of hyperpolarized materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications. BACKGROUND [003] Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are technologies with vital applications in chemistry, biology, and medical imaging. Despite these successes, it is recognized that magnetic resonance applications may often have limitations due to the minute nuclear polarization of analytes (typically on the order of 10'5). This minute nuclear polarization can result in limited sensitivity in comparison to other analytic techniques such as mass spectrometry. [004] Increasing nuclear spin polarization beyond its thermal equilibrium value can greatly improve magnetic resonance sensitivity. Nuclear spin polarization can be increased using known techniques like parahydrogen induced polarization (PHIP), PHIP-sidearm hydrogenation (PHIP-SAH), PHIP nuclear Overhauser effect system (PHIPNOESYS), signal amplification by reversible exchange (SABRE), and dynamic nuclear polarization (DNP), among others. Using such techniques, the nuclear spin polarization of a material can be drastically increased. For instance, the nuclear spin polarization of a material can sometimes be increased 10,000 times or more. The enhanced nuclear spin polarization can result in a proportional increase in the NMR/MRI signal. While this enhanced polarization decays over time due to the relaxation time of the nuclear spins in the polarized molecules, for many molecules the relaxation time can be many seconds, during which increased polarization can lead to a dramatic increase in NMR/MRI signal sensitivity. By enabling such a dramatic increase in NMR/MRI signal sensitivity, increased nuclear spin polarization can enable new applications, such as the imaging of in vivo metabolism using metabolites with increased nuclear spin polarization in an MRI scanner, accelerate NMR spectroscopy investigations, and enable visualization of previously unseen molecular dynamics and structures. BRIEF DESCRIPTION OF THE DRAWINGS [005] The accompanying drawings, which comprise a part of this specification, illustrate several embodiments and, together with the description, serve to explain certain principles and features of the disclosed embodiments. In the drawings: [006] FIG. 1 depicts a first exemplary process for generating polarized biorelevant imaging agents, in accordance with various embodiments. [007] FIG. 2 depicts a second exemplary process for generating polarized biorelevant imaging agents, in accordance with various embodiments. [008] FIG. 3 depicts a third exemplary process for generating polarized biorelevant imaging agents, in accordance with various embodiments. [009] FIG. 4 depicts an exemplary composition comprising hyperpolarized molecules of interest having a high nuclear spin polarization in a solution, in accordance with various embodiments. [010] FIG. 5 shows exemplary carbon- 13 (13C) spin-lattice (Ti) relaxation times associated with hyperpolarized pyruvate in water (H2O) and deuterated water (D2O) solvents at pH 7 in a variety of magnetic fields, in accordance with various embodiments. [OH] FIG. 6 shows exemplary 13C Ti relaxation times associated with hyperpolarized pyruvate in D2O solvent at two different pH values (5.5 and 7) in a variety of magnetic fields, in accordance with various embodiments. [012] FIG. 7 shows exemplary 13C Ti relaxation times associated with hyperpolarized pyruvate in D2O solvent in the absence and presence of ethylenediaminetetraacetic acid (EDTA) in a variety of magnetic fields, in accordance with various embodiments. DETAILED DESCRIPTION [013] Reference will now be made in detail to exemplary embodiments, discussed with regards to the accompanying drawings. Unless otherwise defined, technical and/or scientific terms have the meaning commonly understood by one of ordinary skill in the art. The disclosed embodiments are described in sufficient detail to enable those skilled in the art to practice the disclosed embodiments. It is to be understood that other embodiments may be utilized and that changes may be made without departing from the scope of the disclosed embodiments. Thus, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. [014] Recent work in the field of NMR and MRI has demonstrated that NMR and MRI signals associated with a variety of molecules of