Systems and methods for producing hyperpolarized materials

Abstract

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

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 375,392, entitled "SYSTEMS AND METHODS FOR GENERATION OF HYPERPOLARIZED MATERIALS," filed September 13, 2022, which is incorporated by reference in its entirety for all purposes.

[0002] Technical Field The disclosed embodiments relate generally to the production and purification of hyperpolarized materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications. [Background technology]

[0003] Parahydrogen-induced polarization (PHIP) is a low-cost, high-throughput method for polarizing metabolites for hyperpolarized (HP) magnetic resonance imaging (MRI). Parahydrogen-induced polarization with side-arm hydrogenation (PHIP-SAH) can be used to polarize metabolites, such as acetate molecules. However, existing PHIP-SAH polarization approaches may not be suitable for preclinical or clinical HP MRI applications. [Brief explanation of the drawings]

[0004] The accompanying drawings, which form a part of this specification, illustrate several embodiments and, together with the description, serve to explain certain principles and features of the disclosed embodiments.

[0005] [Figure 1] 1 illustrates a first exemplary process for producing a polarized biologically relevant imaging agent, according to various embodiments. [Figure 2] 1 illustrates a second exemplary process for producing a polarized biologically relevant imaging agent, according to various embodiments. [Figure 3]10 illustrates a third exemplary process for producing a polarized biologically relevant imaging agent, according to various embodiments. [Figure 4] 10 illustrates a fourth exemplary process for producing a polarized biologically relevant imaging agent, according to various embodiments. [Figure 5] FIG. 1 shows exemplary singlet lifetimes of (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate, (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D1, and (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D2, according to various embodiments. [Figure 6A] FIG. 1 shows an exemplary polarization transfer pulse sequence used to transfer spin order from the para-hydrogen-associated protons in (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate, (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D1, and (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D2 to the naturally abundant C nuclei present in (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate, (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D1, and (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D2, according to various embodiments. [Figure 6B] 6B shows exemplary 13C polarization achieved for (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D2 using various first periods tsweep in the polarization transfer pulse sequence of FIG. 6A, in accordance with various embodiments. [Figure 7A] 6A and 6B show exemplary 13C polarization levels of (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D2 after the polarization transfer procedure of FIGS. 6A and 6B, according to various embodiments. [Figure 7B] [Figure 8]1 shows exemplary 13C polarization levels of deuterated para-hydrogenated ester side arm derivatives of lactate, according to various embodiments. [Figure 9] 1 shows exemplary 13C polarization levels of deuterated parahydrogenated derivatives of monoethylketoglutarate, according to various embodiments. [Figure 10] 1 shows exemplary 13C polarization levels of deuterated parahydrogenated derivatives of Z-OMPD monomethyl ester, according to various embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0006] Exemplary embodiments will now be described in detail and discussed with reference to the accompanying drawings. Unless otherwise defined, technical and / or scientific terms have the meanings commonly understood by those skilled in the art. The disclosed embodiments are described in sufficient detail to enable those skilled in the art to practice the disclosed embodiments. It will be understood that other embodiments may be utilized and changes may be made without departing from the scope of the disclosed embodiments. Accordingly, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0007] Recent research in the fields of nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) has demonstrated that NMR and MRI signals associated with various biocontrast agents can be enhanced by orders of magnitude using various so-called hyperpolarization techniques. This signal enhancement allows for improved spectroscopic analysis of biocontrast agents as they are metabolized by various tissues at different locations within the body. Analysis of metabolic information determined by such spectroscopic imaging can enable noninvasive determination of the health of tissues within the body. For example, abnormal metabolism of biocontrast agents can indicate diseases such as cancer at several locations within the body.

[0008] Existing techniques for hyperpolarizing biologically relevant imaging agents include dissolution dynamic nuclear polarization (DNP), parahydrogen-induced polarization (PHIP), PHIP sidearm hydrogenation (PHIP-SAH), and signal amplification by reversible exchange (SABRE). In PHIP and PHIP-SAH, a precursor of the biologically relevant imaging agent is reacted with parahydrogen to form a parahydrogenated derivative of the precursor. Spin order is then transferred from the added proton via the parahydrogenation reaction to a nucleus of interest (e.g., carbon-13) contained within the biologically relevant imaging agent. In PHIP-SAH, the parahydrogenated derivative of the precursor is cleaved (e.g., hydrolyzed) to yield a hyperpolarized biologically relevant imaging agent. The biologically relevant imaging agent is then purified and used in NMR or MRI procedures. In PHIP-SAH, the precursor contains a biologically relevant imaging agent attached to a sidearm containing at least one unsaturated bond suitable for reaction with parahydrogen (e.g., at least one carbon-carbon double bond or at least one carbon-carbon triple bond). However, previous precursors have employed side arms that may not allow for the production of biorelevant contrast agents with clinically relevant polarization, concentration, volume, or purity. This behavior may be related to poor solubility of the precursor in organic solvents (where para-hydrogen is highly soluble), poor yield in the reaction between the unsaturated bond and para-hydrogen, poor transfer of spin order (e.g., from the side arm to the desired nucleus), or a variety of other factors. Therefore, there is a need for new PHIP-SAH precursors that produce hyperpolarized biorelevant contrast agents with clinically relevant polarization, concentration, volume, or purity.

[0009] The disclosed embodiments include systems and methods for producing biologically relevant imaging agents with clinically relevant polarization, concentration, volume, and purity. The disclosed embodiments provide technical improvements for polarizing biologically relevant imaging agents in solution. These technical improvements support increased biologically relevant imaging agent concentrations and biologically relevant degrees of polarization.

[0010] Hyperpolarization and Parahydrogen As used in this disclosure, hyperpolarization describes a state in which the absolute value of the difference between a population of spin states (e.g., nuclear spin states, proton spin states, etc.) in one state (e.g., spin up) and a population of spin states in another state (e.g., spin down) exceeds the absolute value of the corresponding difference at thermal equilibrium.

[0011] Parahydrogen can be used as a polarization source consistent with disclosed embodiments. Parahydrogen is a form of molecular hydrogen in which two proton spins are in a singlet state, as described herein. The disclosed embodiments are not limited to a particular method of producing parahydrogen. Parahydrogen can be formed in gaseous or liquid form. In some embodiments, parahydrogen is produced in gaseous form by flowing hydrogen gas at low temperature through a chamber using a catalyst (e.g., iron oxide or another suitable catalyst). The hydrogen gas can contain both parahydrogen and orthohydrogen. The low temperature can bring the hydrogen gas to thermodynamic equilibrium within the chamber, increasing the population of parahydrogen.

[0012] The disclosed embodiments are not limited to a specific parahydrogen production or use location. Parahydrogen can be produced at a first location and then transported to a second location for use. In some embodiments, the first location is a chamber that can be part of a container, bottle, holder, or other area capable of holding a gas or liquid. Such a chamber can be maintained at a suitable pressure or temperature. In some embodiments, the first location is a physical location such as a room, a laboratory, a specific warehouse, a hospital, or other location where parahydrogen is produced.

[0013] The disclosed embodiments are not limited to a specific para-hydrogen transportation method. The generated para-hydrogen can be transported in a chamber that can be different from the chamber in which the para-hydrogen was generated. The chamber that transports the para-hydrogen gas can be maintained at a suitable pressure or temperature that allows for transportation by vehicle or person. Transporting the para-hydrogen can involve moving the para-hydrogen from one container to a different container. Transporting the para-hydrogen can involve moving the para-hydrogen within the same location, such as from one part of a room to another part of a room. Transporting the para-hydrogen can involve moving the para-hydrogen from one room in a building to a different room in the same building, or to a nearby building. Transporting the para-hydrogen can involve moving the para-hydrogen to a different location in another part of the same city, or to a different city. Transporting the para-hydrogen can involve bringing the para-hydrogen near a polarizer, an NMR device, or an MRI device. Transporting the para-hydrogen can involve packaging or transporting the para-hydrogen in a suitable container.

[0014] In some embodiments, the population difference between two spin states is the difference between the populations of the two spin states divided by the total population of the two spin states. The population difference may be expressed as a fractional population difference or a percentage population difference. In some embodiments, the fractional population difference is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or more, up to about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or less, or within a range defined by any two of the foregoing values.

[0015] Hydrogen gas can exhibit a population difference between proton spin states at thermal equilibrium that significantly exceeds the population difference between the proton spin states. Parahydrogen can have a large population difference between either the singlet spin state and the triplet spin state. In the case of Iz1Iz2, for example, there is a large population difference between the spin state |↑>|↓> and the spin state |↑>|↑>. The population difference between the proton spin states can be at least about 0.1 (e.g., a 10% difference in spin states—55% of the parahydrogen molecules in a sample are in the singlet state and 45% are in the triplet state), 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or more, at most about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or less, or within a range defined by any two of the foregoing values.

[0016] Bio-related contrast agents Disclosed embodiments include systems and methods for producing and utilizing biorelevant imaging agents with clinically relevant polarization, concentration, volume, or purity. In some embodiments, the method is for preparing an NMR material. In some embodiments, the NMR material is suitable for use in NMR or MRI operations. In some embodiments, the NMR material increases the NMR or MRI signal and signal-to-noise ratio (SNR). In some embodiments, the NMR material is suitable for use in solution NMR spectroscopy. In some embodiments, the NMR material is a chemical compound. In some embodiments, the NMR material is a metabolite (e.g., a molecule with biorelevance, such as an amino acid, sugar, or derivative thereof), such as a metabolite suitable for use in NMR metabolomics applications. In some embodiments, the NMR material is suitable for in vitro probing of the metabolism of cell cultures or other biological tissues. In some embodiments, the NMR material is used in an NMR probe to investigate transient effects where high signal enhancement due to hyperpolarization is required, such as proton exchange between water and biomolecules. In some embodiments, the NMR material is a small molecule or metabolite suitable for injection into cells, tissues, or organisms for detection in MRI scans. In some embodiments, the NMR material is introduced into the chamber for further analysis by NMR or MRI operations. In some embodiments, the NMR material is introduced into the chamber for further analysis by NMR or MRI operations. 2 H) or carbon-13 ( 13 C) concentrated in atoms.

[0017] Consistent with disclosed embodiments, the NMR material may include a biorelevant contrast agent. In some embodiments, the biorelevant contrast agent may be suitable for use in NMR or MRI operations. In some embodiments, the biorelevant contrast agent may increase the NMR or MRI signal or signal-to-noise ratio (SNR). In some embodiments, the biorelevant contrast agent may be suitable for use in solution NMR spectroscopy. In some embodiments, the biorelevant contrast agent may be a metabolite (e.g., a molecule with biorelevance, such as an amino acid, sugar, or derivative thereof), such as a metabolite suitable for use in NMR metabolomics applications. In some embodiments, the biorelevant contrast agent is used for perfusion or contrast-enhanced imaging in MRI scans. In some embodiments, the biorelevant contrast agent may be suitable for in vitro probing of the metabolism of cell cultures or other biological tissues. In some embodiments, the biorelevant contrast agent is used for in vitro probing of the metabolism of cell cultures or other biological tissues. In some embodiments, the biorelevant contrast agent may be used in NMR probes to investigate transient effects where high signal enhancement due to hyperpolarization is required, such as proton exchange between water and biomolecules. In some embodiments, the biorelevant imaging agent may be a small molecule or metabolite suitable for injection into a cell, tissue, or organism for detection in an MRI scan. In some embodiments, the biorelevant imaging agent may be introduced into a chamber for further analysis by NMR or MRI operation. In some embodiments, the biorelevant imaging agent may be one or more 2 H or 13 It is enriched in C atoms.

[0018] In some embodiments, the biologically relevant imaging agent is pyruvate, lactate, alpha-ketoglutarate, bicarbonate, fumarate, urea, dehydroascorbate, glutamate, glutamine, acetate, dihydroxyacetone, acetoacetate, glucose, ascorbate, zymonate, alanine, fructose, imidazole, nicotinamide, nitroimidazole, pyrazinamide, isoniazid, conjugate acids of any of the above, natural and unnatural amino acids, esters thereof, or any of the foregoing. 2 H, 13C, or nitrogen-15( 15 In some embodiments, the biologically relevant imaging agent includes pyruvate, lactate, alpha-ketoglutarate. In some embodiments, the biologically relevant imaging agent includes pyruvate. In some embodiments, the biologically relevant imaging agent includes lactate. In some embodiments, the biologically relevant imaging agent includes alpha-ketoglutarate (e.g., ethyl alpha-ketoglutarate).

[0019] In some embodiments, the biologically relevant imaging agent comprises at least one non-hydrogen nuclear spin. In some embodiments, the non-hydrogen nucleus comprises at least one spin 1 / 2 atom. In some embodiments, the non-hydrogen nuclear spin is 13 C or 15 N. In some embodiments, the biologically relevant imaging agent is at least partially isotopically labeled with non-hydrogen nuclear spins. In some embodiments, the biologically relevant imaging agent is at least partially enriched in non-hydrogen nuclear spins compared to an analog of the biologically relevant imaging agent characterized by non-hydrogen nuclear spins at their natural abundance. In some embodiments, the biologically relevant imaging agent is at least partially enriched in non-hydrogen nuclear spins compared to an analog of the biologically relevant imaging agent characterized by non-hydrogen nuclear spins at their natural abundance. In some embodiments, the biologically relevant imaging agent is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, up to about 99%, 98%, 97%, 96%, Enriched to characterize non-hydrogen nuclear spins at abundances of 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less, or abundances within a range defined by any two of the foregoing values.

[0020] In some embodiments, the non-hydrogen nuclear spins are NMR inactive (i.e., spin 0) nuclei of an analog of a biologically relevant imaging agent that characterizes the non-hydrogen nuclear spins at their natural abundance (e.g., 12C or quadrupolar (i.e., spin >1 / 2) nuclei (e.g., nitrogen-14, 14 N) at their natural abundance. 13 The analogue of pyruvate that characterizes C has the structure H3C-C * (=O)-C * OOH either C * So, about 98.9% 12 C and about 1.1% 13 As a biorelevant imaging agent, pyruvate may contain one or both of the C * at any abundance described herein 13 To include C, instead 13 As used herein, * C and C * teeth, 12 C or 13 C describes carbon, which can be any of the carbon isotopes. 15 The analogue of urea that characterizes N is the structure H2N * -C(=O)- * Any N in NH2 * Approximately 99.6% 14 N and about 0.4% 15 As a biorelevant imaging agent, urea may contain one or both N * at any abundance described herein 15 To include N, instead 15 As used herein, * N and N * teeth, 14 N or 15 Describes nitrogen, which can be any of the nitrogen isotopes N.

[0021] Bio-relevant contrast agent precursors In some embodiments, the present disclosure describes a precursor (i.e., precursor compound) comprising a biologically relevant imaging agent and a side arm. In some embodiments, the biologically relevant imaging agent is covalently attached to the side arm. In some embodiments, the biologically relevant imaging agent is attached to the side arm via a transfer moiety, such as a PHIP transfer moiety, that is part of the side arm.

[0022] In some embodiments, the present disclosure describes precursors (i.e., precursor compounds) comprising a biologically relevant imaging agent (i.e., RC(=O)-) and an acyl derivative of a side arm. As used herein, the term "acyl derivative of a biologically relevant imaging agent" refers to a covalently linked derivative of a biologically relevant imaging agent in which the terminal acid moiety [RC(=O)OH)] of an unbound biologically relevant imaging agent is modified to an acyl group and a covalent bond [RC(=O)-)] in the bound biologically relevant imaging agent. In some embodiments, the acyl derivative of the biologically relevant imaging agent is covalently linked to the side arm. In some embodiments, the acyl derivative of the biologically relevant imaging agent is attached to the side arm via a transfer moiety, such as a PHIP transfer moiety, that is part of the side arm.

[0023] The side arms can be para-hydrogenated using para-hydrogen (e.g., by mixing the precursor and para-hydrogen). In some embodiments, the hydrogenation produces Iz1Iz2 order, which is the lower energy state between |↑>|↓>, |↓>|↑>, or singlet spin order of two hydrogen spins, depending on whether the hydrogenation is performed in a low or high magnetic field.

[0024] In some embodiments, the precursor is selected so that, after hydrogenation and other optional chemical reactions, the biologically relevant imaging agent is suitable for use in hyperpolarized NMR or MRI applications. In some embodiments, an additional chemical reaction after hydrogenation can be used to separate the biologically relevant imaging agent from the precursor. Such additional chemical reaction can include, for example, cleavage of the side arm of the precursor by hydrolysis. For example, the biologically relevant imaging agent can be a metabolite molecule, such that the precursor is a derivative of the metabolite molecule, and the derivative has the general chemical structure of Formula Ia or Formula Ib. The biologically relevant imaging agent can be polarized using the PHIP-SAH method (i.e., para-hydrogenation of the side arm and subsequent polarization transfer to the biologically relevant imaging agent). After hydrogenation and polarization transfer, the bond in the precursor (e.g., an ester bond) can be hydrolyzed to produce the polarized biologically relevant imaging agent and a separate side arm element.

[0025] As used herein, hydrolysis is defined as the cleavage of a molecule via a nucleophilic substitution reaction involving the addition of water. Hydrolysis can also be carried out under anhydrous conditions in the presence of hydroxide ions.

[0026] Consistent with the disclosed embodiments, precursors of the general chemical form presented in Formula Ia or Formula Ib can be used as precursors to PHIP-SAH. After hydrogenation of such precursors, two PHIP-SAHs exhibiting spin ordering are obtained. 1 The H spin is close (e.g., only 3, 4, or 5 bonds away) from the target carbon or nitrogen on the metabolite, which, as described herein, 13 C enrichment or 15 In some embodiments, the 13 C or 15 originating from N spin and parahydrogen 1High J-coupling between at least one of the H spins is achieved. In some embodiments, J-coupling is achieved at least about 0.1 Hertz (Hz), 0.2 Hz, 0.3 Hz, 0.4 Hz, 0.5 Hz, 0.6 Hz, 0.7 Hz, 0.8 Hz, 0.9 Hz, 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, or more, up to about 10 Hz, 9 Hz, 8 Hz, 7 Hz, 6 Hz, 5 Hz, 4 Hz, 3 Hz, 2 Hz, 1 Hz, 0.9 Hz, 0.8 Hz, 0.7 Hz, 0.6 Hz, 0.5 Hz, 0.4 Hz, 0.3 Hz, 0.2 Hz, 0.1 Hz, or less, or within a range defined by any two of the foregoing values. For example, in some embodiments, the J-coupling may be between 1 Hz and 2 Hz, 1 Hz and 3 Hz, 1 Hz and 4 Hz, 1 Hz and 5 Hz, 1 Hz and 6 Hz, 1 Hz and 7 Hz, 1 Hz and 8 Hz, 1 Hz and 9 Hz, 1 Hz and 10 Hz, 2 Hz and 3 Hz, 2 Hz and 4 Hz, 2 Hz and 5 Hz, 2 Hz and 6 Hz, 2 Hz and 7 Hz, 2 Hz and 8 Hz, 2 Hz and 9 Hz, 2 Hz and 10 Hz, 3 Hz and 4 Hz, 3 Hz and 5 Hz, 3 Hz and 6 Hz, 3 Hz and 7 Hz, 3 Hz and 8 Hz. Hz, 3Hz to 9Hz, 3Hz to 10Hz, 4Hz to 5Hz, 4Hz to 6Hz, 4Hz to 7Hz, 4Hz to 8Hz, 4Hz to 9Hz, 4Hz to 10Hz, 5Hz to 6Hz, 5Hz to 7Hz, 5Hz to 8Hz, 5Hz to 9Hz, 5Hz to 10Hz, 6Hz to 7Hz, 6Hz to 8Hz, 6Hz to 9Hz, 6Hz to 10Hz, 7Hz to 8Hz, 7Hz to 9Hz, 7Hz to 10Hz, 8Hz to 9Hz, 8Hz to 10Hz, or 9Hz to 10Hz. 13 This may allow for efficient polarization of the C spins.

[0027] The present invention relates to compounds of formula Ia, Ib, IIa, IIb, IIIa, IIIb, and IVa, their tautomers, deuterated derivatives of these compounds, and their tautomers, salts thereof, and to compounds having a tautomer structure at one or more positions within the molecule. 13 C or 15Novel precursors are disclosed, including N-enriched derivatives (which can then be subjected to hyperpolarization) and subsequent generation of precursors given by general formulas Ia, Ib, IIa, IIb, IIIa, IIIb, and IVa.

[0028] Precursors of Formula Ia and Formula Ib In some embodiments, the precursor comprises a compound of formula Ia, which includes the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions 13 C or 15 In some embodiments, Z in formula Ia is (i) 2 Formula Ia describes (ii) a carbon-carbon double bond (-C=C-) or (iii) a carbon-carbon triple bond (-C≡C-) that is fully substituted to include H (deuterium, also referred to as D) (i.e., -CD=CD-). In some embodiments, R1 of Formula Ia comprises a parahydrogen induced polarization (PHIP) transfer moiety as described herein. In some embodiments, R2 of Formula Ia comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine as described herein. In some embodiments, R3 of Formula Ia comprises a biorelevant imaging agent as described herein. In Formula Ia, all moieties to the right of the R3-R1 bond (i.e., -R1-Z-(C=O)-R2) may be collectively referred to as a side arm.

[0029] In some embodiments, the precursor comprises a compound of formula Ib, which includes the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions 13and C-enriched derivatives. In some embodiments, Z in Formula Ib represents an ethynyl (-C≡C-) group, a fully deuterated prop-2-ynyl (-CD2-C≡CD2-) group, a fully deuterated ethenyl (-CD=CD-) group, a fully deuterated prop-2-enyl (-CD2-CD=CD-) group, or a fully deuterated but-3-enyl (-CD2-CD2-CD=CD-) group. In some embodiments, R2 in Formula Ib comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group, as described herein. In some embodiments, R3 in Formula Ib comprises an acyl derivative of a biorelevant imaging agent, as described herein. In Formula Ib, all moieties to the right of the R3 group (i.e., -SZ-R2) may be collectively referred to as a side arm.

[0030] In some embodiments, the compound of Formula Ia or Formula Ib has a solubility in water of at least about 1 millimolar (mM), 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, 800 mM, 850 mM, 900 mM, 950 mM, 1,000 mM, or more, and up to about has a solubility in water of 1,000 mM, 950 mM, 900 mM, 850 mM, 800 mM, 750 mM, 700 mM, 650 mM, 600 mM, 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, 9 mM, 8 mM, 7 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2 mM, 1 mM, or less, or a solubility in water within a range defined by any two of the foregoing values.

[0031] In some embodiments, the compound of Formula Ia or Formula Ib is dissolved in at least about 1 millimolar (mM), 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, 800 mM, 850 mM, 900 mM, 950 mM, 1,000 mM, or more of an organic solvent (e.g., acetone, ethanol, chloroform, toluene, etc.). , 1000 mM, 950 mM, 900 mM, 850 mM, 800 mM, 750 mM, 700 mM, 650 mM, 600 mM, 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, 9 mM, 8 mM, 7 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2 mM, 1 mM, or less, or a solubility in an organic solvent within a range defined by any two of the foregoing values.

[0032] Para-hydrogenated precursors of formula IIa and formula IIb In some embodiments, the compound of formula Ia is para-hydrogenated (i.e., modified via addition of a para-hydrogenation proton across Z via a hydrogenation reaction between formula Ia and a para-hydrogen molecule) as described herein. In some embodiments, para-hydrogenation of the compound of formula Ia yields a compound of formula IIa, which includes the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions. 13 C or 15 In some embodiments, Z' of Formula IIa is (i) 2H (deuterium, also called D) (i.e., -CDH * -CDH * Para-hydrogenated carbon-carbon single bonds (-CH * -CH * -), or (ii) a para-hydrogenated carbon-carbon double bond (-CH * =CH * In some embodiments, H * represents hydrogen with spin order derived from para-hydrogen (i.e., a hydrogen atom or proton added across the carbon-carbon double bond or carbon-carbon triple bond Z via a hydrogenation reaction between a compound of Formula Ia as described herein and para-hydrogen). In some embodiments, H * indicates a hydrogen with spin order (e.g., before polarization transfer) derived from para-hydrogen. In some embodiments, R1 of Formula IIa comprises a PHIP transfer moiety as described herein. In some embodiments, R2 of Formula IIa comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine as described herein. In some embodiments, R3 of Formula IIa comprises a biorelevant imaging agent as described herein. In Formula IIa, all moieties to the right of the R3-R1 bond (i.e., -R1-Z'-(C=O)-R2) can be collectively referred to as a para-hydrogenated side arm.

[0033] In some embodiments, the compound of formula Ib is para-hydrogenated (i.e., modified via addition of a para-hydrogenation proton across Z via a hydrogenation reaction between formula Ib and a para-hydrogen molecule) as described herein. In some embodiments, para-hydrogenation of the compound of formula Ib yields a compound of formula IIb, which comprises the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions 13 In some embodiments, Z' of Formula IIb is a para-hydrogenated ethenyl (-CH* =CH * -) group, fully deuterated para-hydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, fully deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, fully deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or fully deuterated parahydrogen butanyl (-CD2-CD2-CH * =CH * In some embodiments, H * represents hydrogen with spin order derived from para-hydrogen (i.e., a hydrogen atom or proton added across the carbon-carbon double bond or carbon-carbon triple bond Z via a hydrogenation reaction between a compound of Formula Ib as described herein and para-hydrogen). In some embodiments, H * indicates a hydrogen with spin order (e.g., before polarization transfer) derived from para-hydrogen. In some embodiments, R2 of Formula IIb comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group, as described herein. In some embodiments, R3 of Formula IIb comprises an acyl derivative of a biorelevant imaging agent, as described herein. In Formula IIb, all moieties to the right of the R3 group (i.e., S-Z'-R2) may be collectively referred to as the para-hydrogenated side arm.

[0034] In some embodiments, the compound of Formula IIa or Formula IIb has a solubility in water of at least about 1 millimolar (mM), 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, 800 mM, 850 mM, 900 mM, 950 mM, 1,000 mM, or more. has a solubility in water of about 1,000 mM, 950 mM, 900 mM, 850 mM, 800 mM, 750 mM, 700 mM, 650 mM, 600 mM, 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, 9 mM, 8 mM, 7 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2 mM, 1 mM, or less, or a solubility in water within a range defined by any two of the foregoing values.

[0035] In some embodiments, the compound of Formula IIa or Formula IIb is dissolved in at least about 1 millimolar (mM), 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, 800 mM, 850 mM, 900 mM, 950 mM, 1,000 mM, or more of an organic solvent (e.g., acetone, ethanol, chloroform, thiamin ... In some embodiments, the compound has a solubility in an organic solvent (e.g., toluene) of up to about 1,000 mM, 950 mM, 900 mM, 850 mM, 800 mM, 750 mM, 700 mM, 650 mM, 600 mM, 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, 9 mM, 8 mM, 7 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2 mM, 1 mM, or less, or a solubility in an organic solvent within a range defined by any two of the foregoing values.

[0036] In some embodiments, when the composition of Formula Ia or Formula IIb reacts with parahydrogen, the chemical yield (e.g., the chemical yield of the compound of Formula IIa or Formula IIb) is at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, up to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or less, or within a range defined by any two of the foregoing values.For example, in some embodiments, when a composition of Formula Ia or Formula Ib is reacted with parahydrogen, the chemical yield is 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 30% to 55%, 30% to 60%, 30% to 65%, 30% to 70%, 30% to 75%, 30% to 80%, 30% to 85%, 30% to 90%, 30% to 95%, 35% to 40%, 35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, 35% to 65%, 35%~70%, 35%~75%, 35%~80%, 35%~85%, 35%~90%, 35%~95%, 40%~45%, 40%~50%, 40%~55%, 40%~60%, 40%~65%, 40%~70%, 40%~75%, 40%~80%, 40%~85%, 40%~90%, 40%~95%, 45%~50%, 45%~55%, 45%~60%, 45%~65%, 45%~70%, 45%~75%, 45%~80% , 45%~85%, 45%~90%, 45%~95%, 50%~55%, 50%~60%, 50%~65%, 50%~70%, 50%~75%, 50%~80%, 50%~85%, 50%~90%, 50%~95%, 55%~60%, 55%~65%, 55%~70%, 55%~75%, 55%~80%, 55%~85%, 55%~90%, 55%~95%, 60%~65%, 60%~70%, 60%~75%, 60%~80%, 60 % to 85%, 60% to 90%, 60% to 95%, 65% to 70%, 65% to 75%, 65% to 80%, 65% to 85%, 65% to 90%, 65% to 95%, 70% to 75%, 70% to 80%, 70% to 85%, 70% to 90%, 70% to 95%, 75% to 80%, 75% to 85%, 75% to 90%, 75% to 95%, 80% to 85%, 80% to 90%, 80% to 95%, 85% to 90%, 85% to 95%, or 90% to 95%.

[0037] Cleaved precursors of formula IIIa and formula IIIb In some embodiments, the compound of Formula IIa is cleaved (e.g., hydrolyzed) as described herein. In some embodiments, the compound of Formula IIa is cleaved (e.g., hydrolyzed) as described herein to provide a sidearm compound and the corresponding biorelevant imaging agent. In some embodiments, cleavage of the compound of Formula IIa results in a compound of Formula IIIa and the corresponding biorelevant imaging agent as described herein. Formula IIIa encompasses the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions 13 C or 15 In some embodiments, Z" of Formula IIIa is (i) 2 H (deuterium, also called D) (i.e., -CDH * -CDH * Para-hydrogenated carbon-carbon single bonds (-CH * -CH * -), or (ii) a para-hydrogenated carbon-carbon double bond (-CH * =CH * -). In some embodiments, R1' of Formula IIIa comprises a PHIP transfer moiety, as described herein. In some embodiments, R2 of Formula IIIa comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, as described herein. In Formula IIIa, all of the moieties R1-Z"-(C=O)-R2 may be collectively referred to as cleaved side arms or hydrolyzed side arms.

[0038] In some embodiments, the compound of Formula IIb is cleaved (e.g., hydrolyzed) as described herein. In some embodiments, the compound of Formula IIb is cleaved (e.g., hydrolyzed) as described herein to provide a sidearm compound and the corresponding biorelevant imaging agent. In some embodiments, cleavage of the compound of Formula IIb results in a compound of Formula IIIb and the corresponding biorelevant imaging agent, as described herein. Formula IIIb encompasses the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions 13 In some embodiments, Z″ of Formula IIIb is a para-hydrogenated ethenyl (—CH * =CH * -) group, fully deuterated para-hydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, fully deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, fully deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or fully deuterated parahydrogen butanyl (-CD2-CD2-CH * =CH * -) group. R2 in Formula IIIb includes an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group, as described herein. In Formula IIIb, all of the moieties HS-Z'-R2 can be collectively referred to as cleaved side arms or hydrolyzed side arms.

[0039] In some embodiments, the compound of Formula IIIa or Formula IIIb has a solubility in water of at least about 1 millimolar (mM), 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, 800 mM, 850 mM, 900 mM, 950 mM, 1,000 mM, or more. In some embodiments, the solubility in water is about 1,000 mM, 950 mM, 900 mM, 850 mM, 800 mM, 750 mM, 700 mM, 650 mM, 600 mM, 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, 9 mM, 8 mM, 7 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2 mM, 1 mM, or less, or a solubility in water within a range defined by any two of the foregoing values.

[0040] In some embodiments, the compound of Formula IIIa or Formula IIIb is dissolved in at least about 1 millimolar (mM), 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, 800 mM, 850 mM, 900 mM, 950 mM, 1,000 mM, or more of an organic solvent (e.g., acetone, ethanol, chloroform, toluene), a solubility in an organic solvent of up to about 1,000 mM, 950 mM, 900 mM, 850 mM, 800 mM, 750 mM, 700 mM, 650 mM, 600 mM, 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, 9 mM, 8 mM, 7 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2 mM, 1 mM, or less, or a solubility in an organic solvent within a range defined by any two of the foregoing values.

[0041] Formula IVa side arm In some embodiments, a biorelevant imaging agent and a side arm, such as a side arm compound of formula IVa, are conjugated as described herein to form a precursor compound, such as a compound of formula Ia, which includes the following structure: [ka] tautomers thereof, deuterated derivatives of these compounds and their tautomers, pharmaceutically acceptable salts thereof, and tautomers of these compounds at one or more positions 13 C or 15 In some embodiments, Z in formula IVa is (i) 2

[0023] Formula IVa describes a carbon-carbon double bond (-C=C-) or (ii) a carbon-carbon triple bond (-C≡C-) that is fully substituted to include H (deuterium, also referred to as D) (i.e., -CD=CD-). In some embodiments, R1 of Formula IVa comprises a parahydrogen induced polarization (PHIP) transfer moiety as described herein. In some embodiments, R2 of Formula IVa comprises a solubilizing moiety as described herein. In some embodiments, R2 of Formula IVa comprises an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine. In some embodiments, conjugation of a compound of Formula IVa with a biologically relevant imaging agent provides a compound of Formula Ia, as described herein.

[0042] PHIP moving part In some embodiments, the compositions of the present disclosure include a PHIP transfer moiety. In some embodiments, the compositions of the present disclosure include a PHIP transfer moiety between the Z, Z', or Z'' moiety and the sulfur atom of Formula Ib, Formula IIb, or Formula IIIb. In some embodiments, the PHIP transfer moieties described herein include one or more para-hydrogenated protons H * (For example, the sidearm H * ) from one or more non-hydrogen nuclear spins of a biologically relevant imaging agent (one or more of the biologically relevant imaging agents as described herein) 13 C or 15 In some embodiments, the PHIP transfer moiety comprises a chemical moiety configured to enable or enhance polarization transfer to a parahydrogenation proton H in the side arm of a compound of Formula IIa or Formula IIb. * to the non-hydrogen nuclear spins of the corresponding biologically relevant imaging agent of a compound of Formula IIa or IIb. In some embodiments, the PHIP transfer moiety transfers the para-hydrogen proton H in the side arm of the compound of Formula IIa or IIb after the para-hydrogenation reaction between the para-hydrogen and the compound of Formula Ia or IIb. * to the non-hydrogen nuclear spins of the corresponding biologically relevant imaging agent of the compound of Formula IIa or Formula IIb.

[0043] In some embodiments, the PHIP transfer moiety comprises a fully deuterated C1 hydrocarbon (ie, -CD2-) or a fully deuterated C2 hydrocarbon (ie, -CD2-CD2-).

[0044] In some embodiments, the PHIP translocation moiety is * In some embodiments, the compound includes a chemical moiety of the form CR4R5, or any fully deuterated version thereof. * C is 12 C carbon isotope. In some embodiments, R4 and R5 are each independently selected from: 2 H, fully deuterated straight-chain, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

[0045] In some embodiments, the PHIP translocation moiety is * CR6R7- * In some embodiments, the compound includes a chemical moiety of the form CR8R9, or any fully deuterated version thereof. * C is 12 C carbon isotope. In some embodiments, R6, R7, R8, and R9 are each independently selected from: 2 H, fully deuterated straight-chain, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

[0046] In some embodiments, the PHIP translocation moiety is * CH2, * CH2- * In some embodiments, the compound includes a chemical moiety of the form CH, or any fully deuterated version thereof. * C is 12 C carbon isotope.

[0047] In some embodiments, the compositions described herein comprise a first J-coupling, J, between a spin ½ atom described herein and a non-hydrogen nuclear spin described herein. 12 In some embodiments, the compositions described herein comprise a spin ½ atom as described herein and a para-hydrogenated proton, H * The second J-coupling between 13 In some embodiments, the compositions described herein comprise a non-hydrogen nuclear spin as described herein and a para-hydrogen proton H as described herein. * The third J-coupling between 23 In some embodiments, J 12 and / or J 13 J 23 In such cases, the PHIP transfer moiety may enable or enhance polarization transfer.

[0048] In some embodiments, the PHIP transfer moiety has a non-hydrogen nuclear spin of at least about 0.1 Hz, 0.2 Hz, 0.3 Hz, 0.4 Hz, 0.5 Hz, 0.6 Hz, 0.7 Hz, 0.8 Hz, 0.9 Hz, 1 Hz, or more, up to about 1 Hz, 0.9 Hz, 0.8 Hz, 0.7 Hz, 0.6 Hz, 0.5 Hz, 0.4 Hz, 0.3 Hz, 0.2 Hz, 0.1 Hz, or less. *Induce J-coupling between one or both of the H nuclear spins, or induce J-coupling with a non-hydrogen nuclear spin within the range defined by any two of the aforementioned values. For example, in some embodiments, the J-coupling may be in the range of 0.1 Hz to 0.2 Hz, 0.1 Hz to 0.3 Hz, 0.1 Hz to 0.4 Hz, 0.1 Hz to 0.5 Hz, 0.1 Hz to 0.6 Hz, 0.1 Hz to 0.7 Hz, 0.1 Hz to 0.8 Hz, 0.1 Hz to 0.9 Hz, 0.1 Hz to 1 Hz, 0.2 Hz to 0.3 Hz, 0.2 Hz to 0.4 Hz, 0.2 Hz to 0.5 Hz, 0.2 Hz to 0.6 Hz, 0.2 Hz to 0.7 Hz, 0.2 Hz to 0.8 Hz, 0.2 Hz to 0.9 Hz, 0.2 Hz to 1 Hz, 0.3 Hz to 0.4 Hz, 0.3 Hz to 0.5 Hz, 0.3 Hz to 0.6 Hz, 0.3 Hz to 0.7 Hz, 0.3 Hz to 0.8 Hz, 0.3 Hz to 0.9 Hz, 0.3 Hz to 1 Hz, 0.4 Hz to 0.5 Hz, 0.4 Hz to 0.6 Hz, 0.4 Hz to 0.7 Hz, 0.4 Hz to 0.8 Hz, 0.4 Hz to 0.9 Hz, 0.4 Hz to 1 Hz, 0.5 Hz to 0.6 Hz, 0.5 Hz to 0.7 Hz, 0.5 Hz to 0.8 Hz, 0.5 Hz to 0.9 Hz, 0.5 Hz to 1 Hz, 0.6 Hz to 0.7 Hz, 0.6 Hz to 0.8 Hz, 0.6 Hz to 0.9 Hz, 0.6 Hz to 1 Hz, 0.7 Hz to 0.8 Hz, 0.7 Hz to 0.9 Hz, 0.7 Hz to 1 Hz, 0.8 Hz to 0.9 Hz, 0.8 Hz to 1 Hz, or 0.9 Hz to 1 Hz.

[0049] Deuterated Compounds In some embodiments, the use of a deuterated Z, Z', or Z" group, or a PHIP transfer moiety, increases the duration of the spin order associated with the parahydrogen singlet state (referred to herein as the "singlet lifetime"). In some embodiments, the singlet lifetime associated with a compound containing a deuterated Z, Z', or Z" group, or a PHIP transfer moiety, increases the duration of the spin order associated with the parahydrogen singlet state (referred to herein as the "singlet lifetime"). * bond to hydrogen atoms 1 H, 13 C. 19 F, 31In some embodiments, the singlet lifetime associated with a compound containing a deuterated Z, Z', or Z" group or a PHIP transfer moiety described herein is increased relative to an analogous compound containing a nucleus such as P, or other nucleus. In some embodiments, the singlet lifetime associated with a compound containing a deuterated Z, Z', or Z" group or a PHIP transfer moiety described herein is increased relative to an analogous compound containing a deuterated Z, Z', or Z" group or a PHIP transfer moiety ... 15 seconds, 120 seconds or more, up to about 120 seconds, 115 seconds, 110 seconds, 105 seconds, 100 seconds, 95 seconds, 90 seconds, 85 seconds, 80 seconds, 75 seconds, 70 seconds, 65 seconds, 60 seconds, 55 seconds, 50 seconds, 45 seconds, 40 seconds, 35 seconds, 30 seconds, 25 seconds, 20 seconds, 15 seconds, 10 seconds, or less, or within a range defined by any two of the preceding values.

[0050] In some embodiments, the Z, Z′, or Z″ group, or the PHIP transfer moiety, is a H with spin order derived from parahydrogen as described herein. * bond to hydrogen atoms 1 H, 13 C. 19 F, 31 In some embodiments, the Z, Z', or Z'' group, or PHIP transfer moiety, contains up to 2, 1, or 0 nuclei, such as P, or other nuclei. 1 Contains H nuclei.

[0051] As used herein, the phrase "fully deuterated" refers to a compound having a hydroxyl group at each position of a chemical moiety. 1 H (proton) 2 refers to substitution with H (deuterium, also called D). Thus, for example, a fully deuterated straight chain alkyl hydrocarbon moiety is (-CD2) n -CD3, where n ranges from 0 to 9 for fully deuterated straight chain C1-C10 alkyl hydrocarbons. Similarly, a fully deuterated phenyl moiety has the form -CD6D5, a fully deuterated benzyl moiety has the form -CD2-CD6D5, etc.

[0052] R2 units In some embodiments, the R2 groups described herein include an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine. In some embodiments, the R2 groups described herein include an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine that functions as a solubilizing moiety. In some embodiments, the R2 groups described herein include a solubilizing moiety. In some embodiments, the solubilizing moiety includes any chemical moiety configured to enable or enhance the solubility of a compound, such as any of the compounds of Formula Ia, Ib, IIa, IIb, IIIa, IIIb, and / or IVa, in a solution in which a parahydrogenation reaction or a cleavage (e.g., hydrolysis) reaction is performed. In some embodiments, the enhanced solubility is measured with respect to a variant of the compound of Formula Ia, Ib, IIa, IIb, IIIa, IIIb, and / or IVa that utilizes one or more protons in place of the R2 group. In some embodiments, the solubility enhancement is measured with respect to variants of compounds of Formula Ia, Ib, IIa, IIb, IIIa, IIIb, and / or IVa that utilize a methyl group as the R2 group.

[0053] In some embodiments, the solubilizing moiety comprises a hydrophobic moiety or an organophilic moiety. In some embodiments, the solubilizing moiety comprises an organic solubilizing moiety. For example, in some embodiments, the solubilizing moiety comprises a hydrophobic moiety, an organophilic moiety, or an organic solubilizing moiety. In some embodiments, the solubilizing moiety comprises a hydrophilic moiety or an organophobic moiety.

[0054] In some embodiments, the R2 group comprises or is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, and tertiary amide. In some embodiments, the substituted phenyl group is selected from fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, toluene, cumene, ethylbenzene, styrene, ortho-xylene, meta-xylene, para-xylene, phenol, benzoic acid, benzaldehyde, acetophenone, methyl benzoate, anisole, aniline, nitrobenzene, benzonitrile, benzamide, benzenesulfonic acid, naphthalene, and anthracene.

[0055] R3 groups In some embodiments, the R3 groups described herein comprise a biorelevant imaging agent. In some embodiments, the biorelevant imaging agent has the formula R4C(=O)X-. In some embodiments, R4 is selected from a linear, branched, or cyclic C1-C10 alkyl group, wherein one or more C atoms are optionally substituted with CO, COOH, CH2COOH, CONH2, OH, amino (NR'R''), one or more halogen atoms, one or more haloalkyl groups, or one or more carbocycles, wherein the carbocycles are optionally substituted with one or more aliphatic or aromatic rings optionally substituted with one or more functional groups. In some embodiments, X is selected from NR''' and O. In some embodiments, R', R'', and R''' are each independently 1 H, 2 H, 3H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butylcarbonate, and benzyl. In some embodiments, the R group comprises any biologically relevant imaging agent described herein.

[0056] In some embodiments, the R groups described herein comprise acyl derivatives of biorelevant imaging agents. In some embodiments, the biorelevant imaging agents have the formula R9C(=O)O-. In some embodiments, R9 is selected from a linear, branched, or cyclic C1-C10 alkyl group, wherein one or more C atoms are optionally substituted with CO, COOH, CH2COOH, CONH2, OH, amino (NR'R''), one or more halogen atoms, one or more haloalkyl groups, or one or more carbocycles, wherein the carbocycles are optionally substituted with one or more aliphatic or aromatic rings, optionally substituted with one or more functional groups. In some embodiments, R' and R'' are each independently 1 H, 2 H, 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzyl, tert-butylcarbonate, and benzyl. In some embodiments, the R group comprises an acyl derivative of any of the biologically relevant imaging agents described herein.

[0057] In some embodiments, the R group comprises at least one non-hydrogen nuclear spin. In some embodiments, the non-hydrogen nucleus comprises at least one spin 1 / 2 atom. In some embodiments, the non-hydrogen nuclear spin is 13 C or 15N. In some embodiments, the R3 group is at least partially isotopically labeled with non-hydrogen nuclear spins. In some embodiments, the R3 group is at least partially enriched in non-hydrogen nuclear spins compared to an analog of the R3 group characterized by its natural abundance of non-hydrogen nuclear spins. In some embodiments, the R3 group is at least partially enriched in non-hydrogen nuclear spins compared to an analog of the R3 group characterized by its natural abundance of non-hydrogen nuclear spins. In some embodiments, the R3 group is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, up to about 99%, 98%, 97%, 96%, 95%, or more. %, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less abundance, or an abundance within a range defined by any two of the foregoing values.

[0058] In some embodiments, the non-hydrogen nuclear spins are NMR inactive (i.e., spin 0) nuclei of an analog of the R group that characterizes the non-hydrogen nuclear spins at their natural abundance, as described herein (e.g., 12 C or quadrupolar (i.e., spin >1 / 2) nuclei (e.g., 14 In some embodiments, the non-hydrogen nuclear spin is located no more than about one or two chemical bonds from the carbonyl (C=O) carbon in the R3 group.

[0059] Parahydrogenation In some embodiments, the non-hydrogen nuclear spins are NMR inactive (i.e., spin 0) nuclei of an analog of the R group that characterizes the non-hydrogen nuclear spins at their natural abundance, as described herein (e.g., 12 C or quadrupolar (i.e., spin >1 / 2) nuclei (e.g., 14 In some embodiments, the non-hydrogen nuclear spin is located no more than about one or two chemical bonds from the carbonyl (C=O) carbon in the R3 group.

[0060] Consistent with disclosed embodiments, precursors of biorelevant imaging agents (such as compounds of Formula Ia or Formula Ib as described herein) can be para-hydrogenated by combining the precursor, para-hydrogen, and a hydrogenation catalyst. The disclosed embodiments are not limited to a particular method of producing the para-hydrogenated precursor. In some embodiments, the precursor is added to a mixture containing para-hydrogen. In some embodiments, para-hydrogen gas is added to a solution containing the precursor (e.g., para-hydrogen gas can be bubbled into such a solution). In hydrogenating the precursor, para-hydrogen can create Iz1Iz2 ordering, a preferred population of lower energy states between |↑>|↓>, |↓>|↑>, or singlet spin ordering on the two hydrogen spins in the precursor.

[0061] The precursor can have unsaturated bonds (such as unsaturated carbon-carbon double bonds or unsaturated carbon-carbon triple bonds) that can be hydrogenated by parahydrogen gas. After combination of the precursor with parahydrogen, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the precursor can be hydrogenated, up to about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or less of the precursor, or a percentage of the precursor that is within a range defined by any two of the foregoing values.

[0062] In some embodiments, the para-hydrogenated precursor has a population difference in the para-hydrogenated proton spin state of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or within a range defined by any two of the foregoing values. For example, in some embodiments, the population difference is between 10% and 15%, 10% and 20%, 10% and 25%, 10% and 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% and 50%, 15% and 20%, 15% and 25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% and 50%, 20% and 25%, 20% and 30%, 20% and 35 ... The population difference may be 0% to 35%, 20% to 40%, 20% to 45%, 20% to 50%, 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 35% to 40%, 35% to 45%, 35% to 50%, 40% to 45%, 40% to 50%, or 45% to 50%. In some embodiments, the population difference is between the spin state containing the para-hydrogenated proton and another nuclear spin, e.g., a spin state containing an additional proton on the compound. In some embodiments, the para-hydrogenated precursor may contain a side arm, and the para-hydrogenated spin may be located on the side arm.

[0063] In some embodiments, the concentration of the hydrogenation catalyst during hydrogenation is at least about 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, or more, up to or less, or within a range defined by any two of the foregoing values.

[0064] Disclosed embodiments may include methods implemented by the disclosed systems for producing hyperpolarized biologically relevant imaging agents. The disclosed methods may include mixing (e.g., by a mixing mechanism) a solution including a precursor to the biologically relevant imaging agent and a hydrogenation catalyst. The mixing mechanism may be a device for introducing, holding, and facilitating a blend, mixture, or solution of two or more materials. In some embodiments, the mixing mechanism is disposed within a chamber, and mixing occurs within the chamber. In some embodiments, the solutions are mixed at a location remote from the chamber. The solution can be at least about 1 milliliter (ml), 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, or more in volume, up to 100 ml, 90 ml, 80 ml, 70 ml, 60 ml, 50 ml, 40 ml, 30 ml, 20 ml, 10 ml, 9 ml, 8 ml, 7 ml, 6 ml, 5 ml, 4 ml, 3 ml, 2 ml, 1 ml, or less in volume, or within a volume range defined by any two of the foregoing values.

[0065] In some embodiments, the mixing mechanism is a gas-liquid exchange mechanism. For example, the gas-liquid exchange mechanism can be a bubbler or a diffusion system. In some embodiments, the mixing mechanism includes a membrane adapted to allow diffusion of molecular hydrogen. In some embodiments, mixing can be performed using a spray chamber, where the solution is sprayed into a chamber filled with pressurized parahydrogen.

[0066] In some embodiments, the catalyst is a molecule, complex, or particle system that catalyzes hydrogenation. In some embodiments, the catalyst comprises a homogeneous metal catalyst, such as a rhodium complex or a ruthenium complex. Rhodium complexes can be used to prepare and activate precursor molecules and parahydrogen. In some embodiments, the heterogeneous metal catalyst is attached to nanoparticles.

[0067] Various embodiments of the present disclosure describe introducing a solution containing a precursor of a biologically relevant imaging agent and a hydrogenation catalyst into a chamber configured to hold the solution during polarization transfer. In some embodiments, the solution is mixed in the chamber. In some embodiments, the solution is hydrogenated in the chamber. In some embodiments, the chamber is within a magnetic shield (e.g., a mu-metal shield). A magnetic shield can reduce the effects of the Earth's magnetic field (or other external magnetic fields) and allow for modulation of the amplitude of a low-level magnetic field applied to the solution. Thus, placing the solution in the chamber can include placing the solution within a magnetic shield.

[0068] As described herein, in some embodiments, para-hydrogenation occurs prior to polarization transfer (e.g., before modulating the amplitude of a magnetic field, etc., applied to a solution, etc.). In some embodiments, para-hydrogenation occurs during polarization transfer. For example, para-hydrogen may be combined with a solution (e.g., flowed or bubbled through a solution) during modulation of the amplitude of a magnetic field.

[0069] In some embodiments, parahydrogen gas is combined with the solution in the hydrogenation chamber at a pressure. The pressure may be at least about 10 bar, 15 bar, 20 bar, 30 bar, 50 bar, or more, and may be up to about 50 bar, 30 bar, 20 bar, 15 bar, 10 bar, or less, or within a range defined by any two of the foregoing values. In some embodiments, the parahydrogen is combined with the solution in a metal chamber capable of withstanding the pressure. The parahydrogen may be combined with the solution over a time interval (or dissolution of the parahydrogen may occur in less than a time interval). The time interval can be up to about 90 seconds, 60 seconds, 30 seconds, 20 seconds, 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second, or less, at least about 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 20 seconds, 30 seconds, 60 seconds, 90 seconds, or more, or within a range defined by any two of the foregoing values. In some embodiments, hydrogenation is performed or occurs within the time interval.

[0070] Polarization transfer using radio frequency waveforms In some embodiments, the concentration of precursor or target molecule in solution prior to polarization transfer is at least about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 200 mM, 300 mM, 400 mM, 500 mM, 600 mM, 700 mM, 800 mM, 900 mM, 1,000 mM, or more. up to about 1,000 mM, 900 mM, 800 mM, 700 mM, 600 mM, 500 mM, 400 mM, 300 mM, 200 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, or less, or within a range defined by any two of the foregoing values. The volume of the solution may be at least about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 200 ml, 300 ml, 400 ml, 500 ml, 600 ml, 700 ml, 800 ml, 900 ml, 1000 ml, 2000 ml, or more, up to about 1 ml, 2000 ml, 3000 ml, 400 ml, 500 ml, 600 ml, 700 ml, 800 ml, 900 ml, 1000 ml, 2000 ml, or more. The volume may be 000ml, 900ml, 800ml, 700ml, 600ml, 500ml, 400ml, 300ml, 200ml, 100ml, 90ml, 80ml, 70ml, 60ml, 50ml, 40ml, 30ml, 20ml, 10ml, 9ml, 8ml, 7ml, 6ml, 5ml, 4ml, 3ml, 2ml, 1ml, or less, or within a range defined by any two of the foregoing values.

[0071] Various embodiments of the present disclosure describe applying a polarization-transfer magnetic perturbation intended to generate a magnetic field around a solution (e.g., around a solution comprising Formula IIa or Formula IIb described herein). In some embodiments, the magnetic field is at least about 0.1 Gauss (G), 0.2G, 0.3G, 0.4G, 0.5G, 0.6G, 0.7G, 0.8G, 0.9G, 1G, 2G, 3G, 4G, 5G, 6G, 7G, 8G, 9G, 10G, 20G, 30G, 40G, 50G, 60G, 70G, 80G, 90G, 100G, 200G, 300G, 400G, 500G, 600G, 700G, 800G, 900G, 1,000G, 2,000G, 3,000G, 4,000G, 5,000G, 6,000G, 7,000G, 8,000G, 9,000G, 10,000G, 20,000G, 30,000G, 40,000G, 50,000G, 60,000G, 70,000G, 80,000G, 90,000G, 100,000G, 200,000G or more, up to approximately 200 ,000G, 100,000G, 90,000G, 80,000G, 70,000G, 60,000G, 50,000G, 40,000G, 30,000G, 20,000G, 10,000G, 9,000G, 8,000G, 7,000G, 6,000G, 5,000G, 4,000G, 3,000G, 2,000G, 1,000G, 900G, 800G, 700G, 600G, 500G , 400G, 300G, 200G, 100G, 90G, 80G, 70G, 60G, 50G, 40G, 30G, 20G, 10G, 9G, 8G, 7G, 6G, 5G, 4G, 3G, 2G, 1G, 0.9G, 0.8G, 0.7G, 0.6G, 0.5G, 0.4G, 0.3G, 0.2G, 0.1G, or less, or within a range defined by any two of the foregoing values. In some embodiments, the magnetic field has a strength of 0.1G to 200,000G around the solution. The magnetic perturbation can be generated by an electromagnet or a permanent magnet. The magnetic field can be applied to the sample in pulses or continuous wave (CW). The magnetic perturbation can be static or time-varying.

[0072] The signal generator may be configured to generate one or more radio frequency (RF) waveforms that can be applied to the sample to transfer polarization. The signal generator may include another computing unit, processor, controller, associated memory, PC, computer service, or any device that can perform computational operations using inputs and generate outputs. In some embodiments, the RF coil may emit or "apply" a pulse sequence that includes the first RF waveform. In some embodiments, the RF coil may have one or more channels. A channel may be a pathway for an RF signal. At least one channel may be provided for each different type of NMR spectroscopy. In some embodiments, 1 H has at least one channel, 2 H, 13 C. 15 N, 19 F, and 31 For example, the first RF waveform is generated by one or more radio frequency coils (RF coils) disposed around the sample. 1 In some embodiments, the second RF waveform may be applied to the H channel of the RF coil. 13 In some embodiments, 1 H channel and 13 The RF waveform on the C channel is configured to apply a polarization transfer sequence such as PH-INEPT, Goldman's sequence, S2M, S2hM, SLIC, ADAPT, or ESOTERIC.

[0073] In some embodiments, the RF waveform is configured to support polarization transfer even in the presence of large proton full width at half maximum (FWHM). Such RF waveforms can include pulse sequences that can include tens to hundreds of RF pulses. The sequences can be configured so that the pulses protect against the deleterious effects of magnetic field inhomogeneities on polarization transfer.

[0074] In some embodiments, the polarization pulse sequence can be used to separate two unequal ions, for example, when the chemical shift difference is greater than the J-coupling between them. 1H. ESOTHERIC may be, for example, a pulse sequence suitable for polarization transfer in this regime.

[0075] In some embodiments, pulse sequences can be used to generate equivalent 1These pulse sequences are configured to transfer spin order from H hydrogen spins. These pulse sequences include pulses of at least about 0.01 millitesla (mT), 0.02 mT, 0.03 mT, 0.04 mT, 0.05 mT, 0.06 mT, 0.07 mT, 0.08 mT, 0.09 mT, 0.1 mT, 0.2 mT, 0.3 mT, 0.4 mT, 0.5 mT, 0.6 mT, 0.7 mT, 0.8 mT, 0.9 mT, 1 mT, 2 mT, 3 mT, 4 mT, 5 mT, 6 mT, 7 mT, 8 mT, 9 mT, 10 mT, 11 mT, 12 mT, 13 mT, 14 mT, 15 mT, 16 mT, 17 mT, 18 mT, 19 mT, 20 mT, 21 mT, 22 mT, 23 mT, 24 mT, 25 mT, 26 mT, 27 mT, 28 mT, 29 mT, 30 mT, 31 mT, 32 mT, 33 mT, 34 mT, 35 mT, 36 mT, 37 mT, 38 mT, 39 mT, 40 mT, 41 mT, 42 mT, 43 mT, 44 mT, 45 mT, 46 mT, 47 mT, 48 mT, 49 mT, 50 mT, 51 mT, 52 mT, 53 mT, 54 mT, 55 mT, 56 mT, 57 mT, 58 mT, 59 mT, 6 T, 9mT, 10mT, 20mT, 30mT, 40mT, 50mT, 60mT, 70mT, 80mT, 90mT, 100mT, 200mT, 300mT, 400mT, 500mT, 600mT, 700mT, 800mT, 900mT, 1,000mT, 2,000mT, 3,000mT, 4,000mT, 5,000mT, 6,000mT or more, up to about 6,000mT, 5,000mT, 4,000mT, 3,000mT, 2,000mT, 1,000mT, 900mT, 800mT, 700mT, 600mT, 500mT, 400mT, 300mT, 200mT , 100mT, 90mT, 80mT, 70mT, 60mT, 50mT, 40mT, 30mT, 20mT, 10mT, 9mT, 8mT, 7mT, 6mT, 5mT, 4mT, 3mT, 2mT, 1mT , 0.9 mT, 0.8 mT, 0.7 mT, 0.6 mT, 0.5 mT, 0.4 mT, 0.3 mT, 0.2 mT, 0.1 mT, 0.09 mT, 0.08 mT, 0.07 mT, 0.06 mT, 0.05 mT, 0.04 mT, 0.03 mT, 0.02 mT, 0.01 mT, or less, or within a range defined by any two of the foregoing values. Examples of such sequences may be the Goldman sequence (M. Goldman, H. Johannesson, CRPhys. 2005, 6, 575-581, which is incorporated herein by reference in connection with pulse sequence configurations for transferring spin order), the singlet-to-heteronuclear magnetization (S2hM) sequence, or other sequences used in singlet NMR (e.g., ADAPT, SLIC, etc.).

[0076] In some embodiments, the magnetic shielding can be designed to withstand a magnetic field applied to the solution of at least about 0 mG, 0.1 mG, 0.2 mG, 0.3 mG, 0.4 mG, 0.5 mG, 0.6 mG, 0.7 mG, 0.8 mG, 0.9 mG, 1 mG, 2 mG, 3 mG, 4 mG, 5 mG, 6 mG, 7 mG, 8 mG, 9 mG, 10 mG, 20 mG, 30 mG, 40 mG, 50 mG, 60 mG, 70 mG, 80 mG, 90 mG, 100 mG, or more, up to about 100 mG. The magnetic shield is configured to maintain a magnetic field applied to the solution of less than or equal to 0.9 mG, 90 mG, 80 mG, 70 mG, 60 mG, 50 mG, 40 mG, 30 mG, 20 mG, 10 mG, 9 mG, 8 mG, 7 mG, 6 mG, 5 mG, 4 mG, 3 mG, 2 mG, 1 mG, 0.9 mG, 0.8 mG, 0.7 mG, 0.6 mG, 0.5 mG, 0.4 mG, 0.3 mG, 0.2 mG, 0.1 mG, or a magnetic field within a range defined by any two of the foregoing values. The magnetic shield can maintain the magnetic field strength within the polarization chamber at such amplitudes during application of the polarizing waveforms to the one or more radio frequency coils.

[0077] Consistent with disclosed embodiments, an RF waveform may be applied to a solution containing a para-hydrogenated precursor.

[0078] Polarization transfer using magnetic field modulation In some embodiments, the polarization transfer magnetic perturbation is performed within a magnetic shield (e.g., a mu shield) to achieve a homogeneous low magnetic field. The magnetic shield provides a microtesla (μT) magnetic field, below the Earth's magnetic field. 13The low magnetic field may be at least about 0 mG, 0.1 mG, 0.2 mG, 0.3 mG, 0.4 mG, 0.5 mG, 0.6 mG, 0.7 mG, 0.8 mG, 0.9 mG, 1 mG, 2 mG, 3 mG, 4 mG, 5 mG, 6 mG, 7 mG, 8 mG, 9 mG, 10 mG, 20 mG, 30 mG, 40 mG, 50 mG, 60 mG, 70 mG, 80 mG, 90 mG, 100 mG, or more, up to about 100 mG, 9 mG, 100 mG, or more. The value may be 0mG, 80mG, 70mG, 60mG, 50mG, 40mG, 30mG, 20mG, 10mG, 9mG, 8mG, 7mG, 6mG, 5mG, 4mG, 3mG, 2mG, 1mG, 0.9mG, 0.8mG, 0.7mG, 0.6mG, 0.5mG, 0.4mG, 0.3mG, 0.2mG, 0.1mG, or less, or within a range defined by any two of the foregoing values.

[0079] In such a magnetic field, the polarization is determined by the proton spin and 2 H, 13 C. 15 N, 19 F, and 31 The polarization transfer is achieved by utilizing level pseudocrossings (LACs) between the spins of P and other spin species of interest, including P. In some embodiments, the magnetic field can be tuned to a specific field strength for LAC, as performed, for example, in the SABRE-SHEATH experiment. In various embodiments, the magnetic field strength can be temporally adjusted to enable robust polarization transfer in larger volumes of samples. For example, the magnetic field strength can be swept through LAC conditions. Alternatively, or additionally, the sample can be physically moved within the magnetic field. Such modulation can relax constraints on magnetic field homogeneity and field offset. Thus, robust polarization transfer can be performed in larger volumes with greater efficiency. Furthermore, relaxing constraints on magnetic field homogeneity and field offset can enable the use of less complex, accurate, or expensive polarization systems.

[0080] The lower limit of the magnetic field modulation may be at least about -10 μT, -9 μT, -8 μT, -7 μT, -6 μT, -5 μT, -4 μT, -3 μT, -2 μT, -1.9 μT, -1.8 μT, -1.7 μT, -1.6 μT, -1.5 μT, -1.4 μT, -1.3 μT, -1.2 μT, -1.1 μT, -1 μT, -0.9 μT, -0.8 μT, -0.7 μT, -0.6 μT, -0.5 μT, -0.4 μT, -0.3 μT, -0.2 μT, -0.1 μT, or more, up to about -0.1 μT, The value may be -0.2μT, -0.3μT, -0.4μT, -0.5μT, -0.6μT, -0.7μT, -0.8μT, -0.9μT, -1μT, -1.1μT, -1.2μT, -1.3μT, -1.4μT, -1.5μT, -1.6μT, -1.7μT, -1.8μT, -1.9μT, -2μT, -3μT, -4μT, -5μT, -6μT, -7μT, -8μT, -9μT, -10μT, or less, or within a range defined by any two of the foregoing values. The upper modulation limit may be at least about 0.1 μT, 0.2 μT, 0.3 μT, 0.4 μT, 0.5 μT, 0.6 μT, 0.7 μT, 0.8 μT, 0.9 μT, 1 μT, 1.1 μT, 1.2 μT, 1.3 μT, 1.4 μT, 1.5 μT, 1.6 μT, 1.7 μT, 1.8 μT, 1.9 μT, 2 μT, 3 μT, 4 μT, 5 μT, 6 μT, 7 μT, 8 μT, 9 μT, 10 μT, or more, up to about 10 μT, 9 μT , 8 μT, 7 μT, 6 μT, 5 μT, 4 μT, 3 μT, 2 μT, 1.9 μT, 1.8 μT, 1.7 μT, 1.6 μT, 1.5 μT, 1.4 μT, 1.3 μT, 1.2 μT, 1.1 μT, 1 μT, 0.9 μT, 0.8 μT, 0.7 μT, 0.6 μT, 0.5 μT, 0.4 μT, 0.3 μT, 0.2 μT, 0.1 μT, or less, or within a range defined by any two of the foregoing values.

[0081] The magnetic field may be applied to a volume of at least about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 200 ml, 300 ml, 400 ml, 500 ml, 600 ml, 700 ml, 800 ml, 900 ml, 1,000 ml, 2,000 ml, or more, and up to about 1,000 ml, 900 ml, 1000 ml, 2,000 ml, or more. The modulation may have such amplitude over a volume of 0 ml, 800 ml, 700 ml, 600 ml, 500 ml, 400 ml, 300 ml, 200 ml, 100 ml, 90 ml, 80 ml, 70 ml, 60 ml, 50 ml, 40 ml, 30 ml, 20 ml, 10 ml, 9 ml, 8 ml, 7 ml, 6 ml, 5 ml, 4 ml, 3 ml, 2 ml, 1 ml, or less, or a volume within a range defined by any two of the foregoing values. The modulation may be performed over a duration. The duration can be at least about 100 milliseconds (ms), 200 ms, 300 ms, 400 ms, 500 ms, 600 ms, 700 ms, 800 ms, 900 ms, 1 second (s), 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 20 seconds, 30 seconds, or more, up to about 30 seconds, 20 seconds, 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second, 900 ms, 800 ms, 700 ms, 600 ms, 500 ms, 400 ms, 300 ms, 200 ms, 100 ms, or less, or within a range defined by any two of the foregoing values.

[0082] Thus, the rate of change of the amplitude of the magnetic field is at least about 0.01 μT / sec, 0.015 μT / sec, 0.02 μT / sec, 0.025 μT / sec, 0.03 μT / sec, 0.035 μT / sec, 0.04 μT / sec, 0.045 μT / sec, 0.05 μT / sec, 0.055 μT / sec, 0.06 μT / sec, 0.065 μT / sec, 0.07 μT / sec, 0.075 μT / sec, 0.08 μT / sec, 0.085 μT / sec, 0.09 ... T / s, 0.095μT / s, 0.1μT / s, 0.15μT / s, 0.2μT / s, 0.25μT / s, 0.3μT / s, 0.35μT / s, 0.4μT / s, 0.45μT / s, 0.5μT / s, 0 .55μT / s, 0.6μT / s, 0.65μT / s, 0.7μT / s, 0.75μT / s, 0.8μT / s, 0.85μT / s, 0.9μT / s, 0.95μT / s, 1μT / s or higher, maximum At large, the results are approximately 1 μT / sec, 0.95 μT / sec, 0.9 μT / sec, 0.85 μT / sec, 0.8 μT / sec, 0.75 μT / sec, 0.7 μT / sec, 0.65 μT / sec, 0.6 μT / sec, 0.55 μT / sec, 0.5 μT / sec, 0.45 μT / sec, 0.4 μT / sec, 0.35 μT / sec, 0.3 μT / sec, 0.25 μT / sec, 0.2 μT / sec, 0.15 μT / sec, 0.1 μT / sec, 0.095 μT / sec, 0.09 μT / sec, 0. The upper limit of the rate of change of the amplitude of the magnetic field may be 0.08 μT / sec, 0.075 μT / sec, 0.07 μT / sec, 0.065 μT / sec, 0.06 μT / sec, 0.055 μT / sec, 0.05 μT / sec, 0.045 μT / sec, 0.04 μT / sec, 0.035 μT / sec, 0.03 μT / sec, 0.025 μT / sec, 0.02 μT / sec, 0.015 μT / sec, 0.01 μT / sec, or less, or within a range defined by any two of the foregoing values. The upper limit of the rate of change of the amplitude of the magnetic field may be determined by the capabilities of the equipment used to perform the sweep.

[0083] In some embodiments, when the magnetic field is within the upper and lower limits disclosed above, the spatial deviation of the magnetic field across the volume during modulation is less than about half (or one-quarter, or one-eighth, or one-tenth) of the amplitude of the magnetic field. For example, when the magnetic field strength is less than 2 μT (or greater than −2 μT), the spatial deviation of the magnetic field across the volume during modulation may be less than 1 μT. As a further example, when the magnetic field strength is less than 10 μT (or greater than −10 μT), the spatial deviation of the magnetic field across the volume during modulation may be less than 5 μT. Spatial deviation may be measured, for example, by taking at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or more spatially randomly sampled or spatially evenly distributed measurements of the magnetic field within the volume and calculating the standard deviation of the sampled magnetic field measurements. Such homogeneity can be achieved within a large homogeneous magnetic shield, for example, by having a large puncture solenoid valve through the magnetic shield, or by using a large Helmholtz coil with a large homogeneous region to generate the magnetic field amplitude modulation. In some embodiments, the modulation is a magnetic field sweep. In some embodiments, the magnetic field amplitude modulation includes a non-adiabatic jump, a monotonic amplitude change, or a combination thereof.

[0084] In some embodiments, following the polarization transfer step, a biologically relevant imaging agent (e.g., 13 C or 15The non-hydrogen nuclear spins of N) have a nuclear spin polarization of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more, a nuclear spin polarization of up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or a polarization within a range defined by any two of the foregoing values. For example, in some embodiments, following the polarization transfer step, the non-hydrogen nuclear spins of the biologically relevant imaging agent are 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to 40%, 10% to 45%, 10% to 50%, 15% to 20%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to 40%, 15% to 45%, 15% to 50%, 20% to 25%, 25% to 30%, 25% to 3 ... The nuclear spin polarization is 0% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 20% to 50%, 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 35% to 40%, 35% to 45%, 35% to 50%, 40% to 45%, 40% to 50%, or 45% to 50%.

[0085] In some embodiments, this polarization is achieved for a solution volume of at least about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 200 ml, 300 ml, 400 ml, 500 ml, or more, up to about 500 ml, 400 ml, 300 ml, 200 ml, 100 ml, 90 ml, 80 ml, 70 ml, 60 ml, 50 ml, 40 ml, 30 ml, 20 ml, 10 ml, 9 ml, 8 ml, 7 ml, 6 ml, 5 ml, 4 ml, 3 ml, 2 ml, 1 ml, or less, or a volume within a range defined by any two of the foregoing values.

[0086] In some embodiments, after polarization transfer, a portion of the population difference in the para-hydrogenated proton spin state is determined by the target of the biologically relevant imaging agent (e.g., 13 C or 15 N) nuclear spin polarization, which can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or within a range defined by any two of the foregoing values. For example, in some embodiments, this portion is 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to 40%, 10% to 45%, 10% to 50%, 15% to 20%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to 40%, 15% to 45%, 15% to 50%, 20% to 25%, 20% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 20% to 50%, 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 35% to 40%, 35% to 45%, 35% to 50%, 40% to 45%, 40% to 50%, or 45% to 50%.

[0087] In some embodiments, the magnetic field modulation includes a non-adiabatic jump of the magnetic field. The non-adiabatic jump can be performed to a magnetic field where a level pseudo-crossing occurs involving proton spins and non-proton spins. Considering J-coupling between nuclear spins in the system, this value can be analytically calculated or identified by plotting the energy levels of a Hamiltonian for different magnetic fields and identifying the LAC. In some embodiments, the duration for which the magnetic field amplitude remains in the LAC condition is at most about 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second, 0.9 seconds, 0.8 seconds, 0.7 seconds, 0.6 seconds, 0.5 seconds, 0.4 seconds, 0.3 seconds, 0.2 seconds, 0.1 seconds, or less, at least about 0.1 seconds, 0.2 seconds, 0.3 seconds, 0.4 seconds, 0.5 seconds, 0.6 seconds, 0.7 seconds, 0.8 seconds, 0.9 seconds, 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, or more, or within a range defined by any two of the foregoing values.

[0088] In some embodiments, modulating the amplitude of the magnetic field comprises varying the magnetic field amplitude monotonically (or monotonically over each of a limited number of intervals, such as 1-10 increasing intervals and / or 1-10 decreasing intervals). In some embodiments, modulating the amplitude of the magnetic field comprises varying the magnetic field amplitude linearly. The initial magnetic field amplitude of the sweep, the end magnetic field amplitude, and the total duration of the sweep can be optimized for the target molecule. In some embodiments, the magnetic field amplitude during the sweep is within a lower and upper bound. The lower limit is at least about -2μT, -1.9μT, -1.8μT, -1.7μT, -1.6μT, -1.5μT, -1.4μT, -1.3μT, -1.2μT, -1.1μT, -1μT, -0.9μT, -0.8μT, -0.7μT, -0.6μT, -0.5μT, -0.4μT, -0.3μT, -0.2μT, -0.1μT, or more, and up to about -0.1μT, -0. 2μT, -0.3μT, -0.4μT, -0.5μT, -0.6μT, -0.7μT, -0.8μT, -0.9μT, -1μT, -1.1μT, -1.2μT, -1.3μT, -1.4μT, -1.5μT, -1.6μT, -1.7μT, -1.8μT, -1.9μT, -2μT, or less, or within a range defined by any two of the foregoing values. The upper limit is at least about 0.1 μT, 0.2 μT, 0.3 μT, 0.4 μT, 0.5 μT, 0.6 μT, 0.7 μT, 0.8 μT, 0.9 μT, 1 μT, 1.1 μT, 1.2 μT, 1.3 μT, 1.4 μT, 1.5 μT, 1.6 μT, 1.7 μT, 1.8 μT, 1.9 μT, 2 μT, or more, up to about 2 μT, 1.9 μT , 1.8 μT, 1.7 μT, 1.6 μT, 1.5 μT, 1.4 μT, 1.3 μT, 1.2 μT, 1 μT, 1 μT, 0.9 μT, 0.8 μT, 0.7 μT, 0.6 μT, 0.5 μT, 0.4 μT, 0.3 μT, 0.2 μT, 0.1 μT, or less, or within a range defined by any two of the foregoing values.In some embodiments, the duration of the modulation can be at least about 100 ms, 200 ms, 300 ms, 400 ms, 500 ms, 600 ms, 700 ms, 800 ms, 900 ms, 1 s, 2 s, 3 s, 4 s, 5 s, 6 s, 7 s, 8 s, 9 s, 10 s, 20 s, 30 s, or more, up to about 30 s, 20 s, 10 s, 9 s, 8 s, 7 s, 6 s, 5 s, 4 s, 3 s, 2 s, 1 s, 900 ms, 800 ms, 700 ms, 600 ms, 500 ms, 400 ms, 300 ms, 200 ms, 100 ms, or less, or within a range defined by any two of the foregoing values. In some embodiments, the rate of amplitude change varies along an amplitude profile. In some embodiments, a constant adiabatic sweep is calculated by selecting a specific subset of level pseudo-crossings of the spin system. In some embodiments, the magnetic amplitude modulation includes a combination of non-adiabatic jumps, monotonic amplitude modulation, and rate-of-change sign reversals. In some embodiments, the precursors may be selected or designed such that, following hydrogenation and other potential chemical reactions, one of the products is a biologically relevant imaging agent usable in hyperpolarized NMR or MRI applications.

[0089] Hydrolysis, purification, and separation The present disclosure provides methods and systems for producing compositions (e.g., clinical dose compositions) comprising a hyperpolarized biologically relevant imaging agent (or a pharmaceutically acceptable salt thereof) in a solvent. In some embodiments, the biologically relevant imaging agent is produced by additional chemical reactions and / or processing steps after hydrogenation and polarization transfer according to the present disclosure. Such additional chemical reactions and / or processing steps may include, but are not limited to, (i) catalyst filtration and collection (e.g., filtration-collecting rhodium and / or iridium atoms), (ii) cleavage of the side arm of the biorelevant imaging agent precursor molecule (e.g., cleavage of a compound of Formula IIa or Formula IIb, as described herein), for example, by hydrolysis with aqueous sodium hydroxide, to form the biorelevant imaging agent and the side arm (e.g., a compound of Formula IIIa or Formula IIIb, as described herein), (iii) washing the solution with an organic solvent and separating any resulting aqueous mixture phase from the organic mixture phase, (iv) evaporative extraction of volatile organics from the aqueous mixture (e.g., using nitrogen gas bubbling), and (v) additional filtration / purification / concentration / polishing steps known in the art.

[0090] The volume of solution containing the biologically relevant imaging agent (e.g., after cleavage) and / or the concentration of the biologically relevant imaging agent produced can depend on the volume of solution used for polarization transfer and the concentration of precursors in that solution. Exemplary ranges of solution volumes and precursor concentrations are described herein. As a more specific example, at least about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, or more of solution, up to about 100 ml, 90 ml, 80 ml, 70 ml, 60 ml, 50 ml, 40 ml, 30 ml, 20 ml, 10 ml, 9 ml, 8 ml, 7 ml, 6 ml, 5 ml, 4 ml, 3 ml, 2 ml, 1 ml, or less of solution, or an amount of solution within a range defined by any two of the foregoing values, can be produced. In some embodiments, the solution may contain at least about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 200 mM, 300 mM, 400 mM, 500 mM, or more of a biologically relevant imaging agent, up to about 500 mM, 400 mM, 300 mM, 200 mM, 100 mM, 90 mM, 80 mM, 70 mM, 60 mM, 50 mM, 40 mM, 30 mM, 20 mM, 10 mM, or less of a biologically relevant imaging agent, or an amount of a biologically relevant imaging agent that is within a range defined by any two of the foregoing values.

[0091] In some embodiments, the present disclosure describes a multi-step liquid-liquid separation and purification process for producing a dose (e.g., a clinical dose) of an administration composition comprising a biologically relevant imaging agent (e.g., a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof).

[0092] In some embodiments (i.e., for PHIP-SAH procedures), following the polarization step, the side arm is cleaved from the target molecule precursor (e.g., biorelevant imaging agent precursor) (e.g., via hydrolysis with an aqueous mixture) to produce the target molecule (e.g., biorelevant imaging agent) and an unbound side arm (e.g., a compound of Formula IIIa described herein). In some embodiments, following the polarization step, the side arm is cleaved by mixing a solution (comprising the first organic solvent and the polarized product, e.g., a hyperpolarized biorelevant imaging agent or a pharmaceutically acceptable salt thereof) with a hydrolysis agent, such as a base (e.g., sodium hydroxide) in an aqueous solution. In some embodiments, the first organic solvent and the aqueous mixture (e.g., water) form a biphasic solution. In some embodiments, the first organic solvent and the aqueous mixture (e.g., water) form a biphasic solution, with a portion of the organic solvent being retained in the aqueous mixture. In some embodiments, the first organic solvent and the aqueous mixture (e.g., water) form a partial mixture.

[0093] Clinically relevant purity Consistent with the disclosed embodiments, processes, methods, and systems described herein, the hyperpolarized biologically relevant imaging agent can be separated from other substances in the original solution (e.g., catalyst, original solvent, reaction products, etc.) For example, most of the hydrogenation catalyst present in the original solution can be removed from the administered composition. In some embodiments, the administered composition contains up to about 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, or less of a hydrogenation catalyst, at least about 0.001%, 0.002%, 0.003%, or less. In some embodiments, the hydrogenation catalyst may be present in a range defined by any two of the foregoing values.Similarly, the administered composition may contain up to about 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, or less cleavage by-products (e.g., side arms or other residues of cleavage), at least about 0.01%. 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1% or more of the cleavage byproducts, or an amount of the cleavage byproducts that is within a range defined by any two of the foregoing values, may be retained.

[0094] In some embodiments, the methods and systems described herein produce administered compositions having a concentration of hyperpolarized biologically relevant imaging of at least about 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, or more, up to about 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, or less, or within a range defined by any two of the foregoing values.

[0095] In some embodiments, the methods and systems described herein produce administered compositions that have a polarization of hyperpolarized biologically relevant imaging that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or within a range defined by any two of the foregoing values. For example, in some embodiments, the methods and systems described herein may be configured to provide a method for determining whether the polarization of the hyperpolarized biologically relevant contrast is between 10% and 15%, 10% and 20%, 10% and 25%, 10% and 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% and 50%, 15% and 20%, 15% and 25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% and 50%, 20% and 25%. %, 20% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 20% to 50%, 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 35% to 40%, 35% to 45%, 35% to 50%, 40% to 45%, 40% to 50%, or 45% to 50%.

[0096] In some embodiments, the methods and systems described herein provide for concentrations of catalyst, precursor, or cleavage byproducts that are at most about 1 μM, 900 nanomolar (nM), 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or In some embodiments, the present invention produces a dosing composition that can be at or below about 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, or more, or within a range defined by any two of the preceding values. The methods and systems described herein produce administered compositions having a hyperpolarized biologically relevant imaging purity of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, up to about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, or less, or within a range defined by any two of the preceding values. In some embodiments, at least a fraction of the hyperpolarized compound is separated from cleaved side arms or other reaction by-products, if present.

[0097] transportation Consistent with disclosed embodiments, polarization transfer and use of a biologically relevant imaging agent can occur at different locations. In some embodiments, the administered composition is transported to different locations. In some embodiments, the administered composition is transported to different locations. The disclosed embodiments are not necessarily limited to any particular transport distance or duration. Instead, the maximum distance or duration can be determined based on the target molecule, the original degree or polarization, the desired final degree of polarization, and the transport conditions. In some embodiments, the administered composition is transported at least 1 meter with a suitable transport device.

[0098] Consistent with disclosed embodiments, the transport device may be configured to transport a sample of a precursor or a biologically relevant contrast agent. The transport device may be arranged and configured to simultaneously transport one or more samples (e.g., one or more administration compositions). The transport device may include a transport chamber configured to receive one or more samples. The transport device may be configured to maintain the transport chamber within a predetermined temperature range and a predetermined magnetic field strength. The transport device may be configured to maintain one or more samples in a magnetic field of at least about 10 G, 20 G, 30 G, 40 G, 50 G, 60 G, 70 G, 80 G, 90 G, 100 G, 200 G, 300 G, 400 G, 500 G, 600 G, 700 G, 800 G, 900 G, 1,000 G or more, up to about 1,000 G, 900 G, 800 G, 700 G, 600 G, 500 G, 400 G, 300 G, 200 G, 100 G, 90 G, 80 G, 70 G, 60 G, 50 G, 40 G, 30 G, 20 G, 10 G or less, or in a magnetic field within a range defined by any two of the foregoing values.

[0099] A permanent magnet or electromagnet included in the transport device can provide the magnetic field. In some embodiments, the permanent magnet or electromagnet is shielded to reduce the strength of the magnetic field outside the transport device. The transport device may also include a cooling system. The cooling system may be configured to maintain the sample at a predetermined temperature or within a predetermined temperature range during transport. For example, the cooling system may be configured to maintain the sample at a temperature below 270 K, below 80 K, or below 4 K. In some embodiments, the transport device is configured to maintain the sample at approximately liquid nitrogen temperature. The transport device may include thermal insulation between the cooling system and the exterior of the transport device to minimize heat exchange with the external environment. In some embodiments, the cooling system is configured to maintain the sample temperature using a cold gas flow. In some embodiments, the cooling system is configured to maintain the sample temperature using a coolant. In some embodiments, the transport device includes a dewar that provides cooling for the sample. To distribute the hyperpolarized sample over long distances, the container may be transported by standard transportation vehicles such as planes, trains, trucks, cars, and ships.

[0100] In some embodiments, the administration composition containing the hyperpolarized biologically-relevant imaging agent is transported in a transport device, in some embodiments, the relaxation time of the hyperpolarized biologically-relevant imaging agent in the transport device is at least about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more, up to about 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or less, or within a range defined by any two of the foregoing values.

[0101] Generation of polarized biorelevant contrast agents 1 shows a first exemplary process 100 for producing a polarized biologically relevant imaging agent, according to various embodiments. In some embodiments, the first process 100 includes providing a composition comprising a compound of Formula Ia at step 110. In some embodiments, the compound of Formula Ia is a compound selected from the group consisting of: (i) a methyl group, (ii) a methyl group, (iii) a methyl group, (iv) a methyl group, (v) a methyl group, (vi ... 2 a Z group containing (ii) a carbon-carbon double bond (-C=C-) fully substituted with H (deuterium, also referred to as D) (i.e., -CD=CD-), or a carbon-carbon triple bond (-C≡C-); an R group containing a PHIP transfer moiety, as described herein; an R group containing an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, or a solubilizing moiety, as described herein; and an R group containing a biorelevant imaging agent, as described herein.

[0102] In some embodiments, in step 120, the double or triple bond in the compound of Formula Ia is hydrogenated with para-hydrogen to form a para-hydrogenated derivative of the compound of Formula Ia, which is a compound having the structure of Formula IIa. In some embodiments, the compound of Formula IIa is 2 H (deuterium, also called D) (i.e., -CDH * -CDH * Para-hydrogenated carbon-carbon single bonds (-CH * -CH * -), or (ii) H * is a para-hydrogenated carbon-carbon double bond (-CH * =CH * and R1 group comprising a PHIP transfer moiety, as described herein; R2 group comprising an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, or a solubilizing moiety, as described herein; and R3 group comprising a biorelevant imaging agent, as described herein. In some embodiments, the compound of Formula Ia is parahydrogenated using the hydrogenation processes described herein.

[0103] In some embodiments, in step 130, a polarization transfer waveform is applied to convert at least one H in the side arm of the compound of Formula IIa, as described herein. * to any non-hydrogen nuclear spins in the biologically relevant imaging agent of the compound of Formula IIa, thereby forming a derivative of the compound of Formula IIa having a hyperpolarized biologically relevant imaging agent. In some embodiments, the nuclear spin order is transferred using any of the polarization transfer processes described herein.

[0104] 2 shows a second exemplary process 200 for producing a polarized biologically relevant imaging agent, according to various embodiments of the present disclosure. In some embodiments, the second process includes providing a composition comprising a compound of Formula IIa at step 210. In some embodiments, the compound of Formula IIa is prepared by reacting (i) 2 H (deuterium, also called D) (i.e., -CDH * -CDH * Para-hydrogenated carbon-carbon single bonds (-CH * -CH * -), or (ii) H, as described herein. * is a para-hydrogenated carbon-carbon double bond (-CH * =CH * -), an R1 group comprising a PHIP transfer moiety, as described herein, an R2 group comprising an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, or a solubilizing moiety, as described herein, and an R3 group comprising a biorelevant imaging agent, as described herein.

[0105] In some embodiments, in step 220, a polarization transfer waveform is applied to convert at least one H in the side arm of the compound of Formula IIa, as described herein. * from which nuclear spin order is transferred to any non-hydrogen nuclear spins in the biologically relevant imaging agent of the compound of formula IIa, thereby forming a derivative of the compound of formula IIa having a hyperpolarized biologically relevant imaging agent.

[0106] In some embodiments, the derivative compound of Formula IIa is hydrolyzed in step 230 to form a composition comprising a hyperpolarized biologically relevant imaging agent and a separate side arm compound of Formula IIIa. In some embodiments, the compound of Formula IIIa is a compound of (i) 2 H (deuterium, also called D) (i.e., -CDH * -CDH * Para-hydrogenated carbon-carbon single bonds (-CH * -CH * -), or (ii) a para-hydrogenated carbon-carbon double bond (-CH * =CH * -), an R1' group that includes a parahydrogen induced polarization (PHIP) transfer moiety, as described herein, and an R2 group that includes an optionally substituted hydrocarbon, alkoxy group, primary amine, secondary amine, or tertiary amine, or a solubilizing moiety, as described herein.

[0107] In some embodiments, the hyperpolarized biologically relevant imaging agent is washed one or more times with an organic solvent in step 240. In some embodiments, the non-hydrogen nuclear spins in the biologically relevant imaging agent have a non-hydrogen spin polarization after the washing step of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more, a non-hydrogen spin polarization after the washing step of up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less, or a non-hydrogen spin polarization within a range defined by any two of the foregoing values.

[0108] In some embodiments, the first or second process includes one or more additional steps or actions. In some embodiments, the first or second process omits one or more steps or actions. In some embodiments, one or more steps or actions of the first or second process are combined. In some embodiments, all steps or actions of the first or second process are combined to obtain a complete process for producing a hyperpolarized imaging agent from a precursor having the structure of Formula Ia.

[0109] 3 shows a third exemplary process 300 for producing a polarized biologically relevant imaging agent according to various embodiments. In the example shown, the process includes providing a composition comprising a compound of Formula Ib in step 310. In some embodiments, the compound of Formula Ib includes a Z group that includes an ethynyl (-C≡C-) group, a fully deuterated prop-2-ynyl (-CD2-C≡C-) group, a fully deuterated ethenyl (-CD=CD-) group, a fully deuterated prop-2-enyl (-CD2-CD=CD-) group, or a fully deuterated but-3-enyl (-CD2-CD2-CD=CD-) group, as described herein; an R2 group that includes an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or solubilizing moiety, as described herein; and an R3 group that includes an acyl derivative of a biologically relevant imaging agent, as described herein.

[0110] In some embodiments, in step 320, the double or triple bond in the compound of Formula Ib is hydrogenated with para-hydrogen to form a para-hydrogenated derivative of the compound of Formula Ib, which is a compound having the structure of Formula IIb. In some embodiments, the compound of Formula IIb can be prepared by the methods described herein. * is a hydrogen atom with spin ordering originating from para-hydrogen, * =CH * -) group, fully deuterated para-hydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, fully deuterated parahydrogenated ethanyl (-CDH * -CDH *-) group, fully deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or fully deuterated parahydrogen butanyl (-CD2-CD2-CH * =CH * and R2 group comprising an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group or a solubilizing moiety, as described herein. In some embodiments, the compound of Formula Ib is parahydrogenated using the hydrogenation processes described herein.

[0111] In some embodiments, in step 330, a polarization transfer waveform is applied to convert at least one H in the side arm of the compound of Formula IIb, as described herein. * to any non-hydrogen nuclear spins in the acyl derivative of the biologically relevant imaging agent of the compound of Formula IIb, thereby forming a derivative of the compound of Formula IIb having a hyperpolarized acyl derivative of the biologically relevant imaging agent. In some embodiments, the nuclear spin order is transferred using any of the polarization transfer processes described herein.

[0112] 4 shows a fourth exemplary process 400 for producing a polarized biologically relevant imaging agent according to various embodiments of the present disclosure. In the example shown, the process includes, in step 410, providing a composition comprising a compound of Formula IIb. In some embodiments, Formula IIb is a para-hydrogenated ethenyl (-CH) compound described herein, where H* is a hydrogen with spin order derived from the para-hydrogen. * =CH * -) group, fully deuterated para-hydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, fully deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, fully deuterated parahydrogenated propanyl (-CD2-CDH * -CDH *-) group or fully deuterated butanyl (-CD2-CD2-CH * =CH * a Z' group that includes a -) group; an R2 group that includes an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group or a solubilizing moiety, as described herein; and an R3 group that includes an acyl derivative of a biorelevant imaging agent, as described herein.

[0113] In some embodiments, in step 420, a polarization transfer waveform is applied to convert at least one H in the side arm of the compound of Formula IIb, as described herein. * from the compound of formula IIb, transferring nuclear spin order to any non-hydrogen nuclear spins in the acyl derivative of the biologically relevant imaging agent, thereby forming a derivative of the compound of formula IIb with the acyl derivative of the biologically relevant imaging agent hyperpolarized.

[0114] In some embodiments, in step 430, the derivative compound of Formula IIb is hydrolyzed to form a composition comprising a hyperpolarized biologically relevant imaging agent and a separate side arm compound of Formula IIIb. In some embodiments, the compound of Formula IIIb is a para-hydrogenated ethenyl (-CH) compound, as described herein. * =CH * -) group, fully deuterated para-hydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, fully deuterated parahydrogenated ethanyl (-CD * -CDH * -) group, fully deuterated parahydrogenated propanyl (-CD2-CDH * -CDH* * -) group, or fully deuterated parahydrogen butanyl (-CD2-CD2-CH * =CH * and an R group that includes an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group or a solubilizing moiety, as described herein.

[0115] In some embodiments, the hyperpolarized biologically relevant imaging agent is washed one or more times with an organic solvent in step 440. In some embodiments, the non-hydrogen nuclear spins in the biologically relevant imaging agent have a non-hydrogen spin polarization after the washing step of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more, a non-hydrogen spin polarization after the washing step of up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less, or a non-hydrogen spin polarization within a range defined by any two of the foregoing values.

[0116] In some embodiments, the third or fourth process includes one or more additional steps or operations. In some embodiments, the third or fourth process omits one or more steps or operations. In some embodiments, one or more steps or operations of the third or fourth process are combined. In some embodiments, all steps or operations of the third or fourth process are combined to obtain a complete process for producing a hyperpolarized imaging agent from a precursor having the structure of Formula Ib. [Example]

[0117] Example 1: Polarization transfer in non-deuterated, partially deuterated, and fully deuterated pyruvate derivatives To assess the effect of deuteration level on the PHIP transfer moiety in pyruvate, the following ester sidearm derivatives of pyruvate were prepared: (1) tert-butyl 4-((2-oxopropanoyl)oxy)but-2-ynoate (CH ester), (2) tert-butyl 4-((2-oxopropanoyl)oxy)but-2-ynoate-D (CDH ester), and (3) tert-butyl 4-((2-oxopropanoyl)oxy)but-2-ynoate-D (CD ester). Compounds (1), (2), and (3) were purified at natural abundance. 13C (approximately 1.1%). Compounds (1), (2), and (3) were reacted with parahydrogen. The reactions produced the parahydrogenated compounds: (4) (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate, (5) (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D1, and (6) (Z)-tert-butyl 4-((2-oxopropanoyl)oxy)but-2-enoate-D2, respectively. The singlet relaxation times T of the resulting compounds (4), (5), and (6) were s Figure 5 shows representative singlet lifetimes for compounds 4, 5, and 6. As shown in Figure 5, complete deuteration of the PHIP transfer moiety (compound 6) significantly reduced the singlet relaxation time T when compared to the non-deuterated PHIP transfer moiety (compound 4). s This resulted in a more than eight-fold increase in

[0118] Including, but not limited to, an increase in the singlet relaxation time T s is believed to be the most important factor in the performance enhancement achieved with the fully deuterated compounds described herein. s The spin order associated with parahydrogen is 13 C or 15 This increases the time that polarization can be transferred to other nuclei, such as N nuclei. Without being limiting, this increase in polarization transfer time allows for more efficient transfer of spin order to such nuclei.

[0119] FIG. 6A shows the natural abundance of protons present in compounds (4), (5), and (6) from the parahydrogen-related protons in compounds (4), (5), and (6). 13 Figure 6 shows a representative polarization transfer pulse sequence used to transfer spin order to C nuclei. Compounds (4), (5), and (6) were placed in a mu-metal magnetic shield and subjected to a magnetic field supplied by a solenoid coil. As shown in Figure 6A, the strength of magnetic field B1 was subjected to a first amplitude modulation by linearly varying the field strength from 1.0 μT to 1.3 μT. Magnetic field B1 was applied to the target during the first amplitude modulation.13 The first amplitude modulation occurs during the first period t sweep During the first amplitude modulation, the target 13 The magnetization of C is sweep was built over a period of

[0120] First period t sweep After that, the strength of the magnetic field B1 was subjected to a second amplitude modulation by linearly varying the magnetic field strength from 1.3 μT to 0 μT. The magnetic field B1 was then subjected to a second amplitude modulation by linearly varying the magnetic field strength from 1.3 μT to 0 μT. 13 It is linearly detuned from the Larmor frequency of the C nucleus.

[0121] FIG. 6B shows the polarization transfer pulse sequence of FIG. 6A with various first periods t sweep was achieved for compound (6) using 13 C polarization. As shown in Figure 6B, 13 The C polarization is performed during a first period t between about 10 seconds and about 12 seconds. sweep reached a maximum value at

[0122] FIG. 7A shows the polarization of compound (6) after the polarization transfer procedure of FIGS. 6A and 6B. 13 C polarization level. As shown in Figure 7A, up to 36% 13 C polarization level was achieved.

[0123] Figure 7B shows the highest densities achieved for compounds (4), (5), and (6). 13 C indicates the polarization level. As shown in Figure 7B, 13 The C polarization level increased with increasing deuteration.

[0124] Example 2: Polarization transfer in deuterated lactate derivatives To assess the effect of deuteration level on the PHIP transfer moiety in lactate, compound (7), an ester sidearm derivative of lactate was prepared. Compound (7) was then purified using a PHIP transfer moiety at natural abundance. 13C (approximately 1.1%). Hydrogenation of compound (7) was carried out in an NMR pressure tube using hydrogen gas containing >90% para-hydrogen enrichment at a flow rate of 0.5 standard liters per minute at 10 bar pressure. 50 mM of compound (7) was reacted with para-hydrogen in the presence of a 2.5 mM solution of Rh(dppb)(COD)BF catalyst in acetone-d6. The reaction produced the para-hydrogenated derivative of compound (7). Polarization transfer was 13 The experiment was carried out in a static magnetic field of 50 μT using a transverse magnetic field at the Larmor frequency of C. The field was ramped from 1.8 μT to 2.2 μT in 9 seconds. Figure 8 shows the results of the para-hydrogenated compound (7). 13 As shown in Figure 8, the maximum polarization level is 31%. 13 C polarization level was achieved. Compound (7): [ka]

[0125] Example 3: Polarization transfer in deuterated monoethylketoglutarate derivatives To assess the effect of deuteration level on the PHIP transfer moiety of monoethylketoglutarate, compound (8), an ester sidearm derivative of monoethylketoglutarate was prepared. Compound (8) was then purified using a 2000 NMR spectroscopy (DMSO) assay. 13 C (approximately 1.1%). Hydrogenation of compound (8) was carried out in an NMR pressure tube using hydrogen gas containing >90% para-hydrogen enrichment at a flow rate of 0.5 standard liters per minute at 10 bar pressure. 50 mM of compound (8) was reacted with para-hydrogen in the presence of a 2.5 mM solution of Rh(dppb)(COD)BF catalyst in acetone-d6. The reaction produced the para-hydrogenated derivative of compound (8). Polarization transfer was 13 The experiment was carried out in a static magnetic field of 50 μT using a transverse magnetic field at the Larmor frequency of C. The field was ramped from 1.8 μT to 2.2 μT in 9 seconds. Figure 8 shows the results of the para-hydrogenated compound (8). 13 As shown in Figure 8, the maximum polarization level is 31%. 13 As shown in Figure 9, polarization levels of up to 21% were achieved.13 C polarization level was achieved. Compound (8): [ka]

[0126] Example 4: Polarization transfer in Z-OMPD monomethyl ester derivatives To assess the effect of deuteration level on the PHIP transfer moiety in Z-OMPD monomethyl ester, compound (9), an ester sidearm derivative of Z-OMPD monomethyl ester, was prepared. Compound (9) was purified using a 2000 NMR spectroscopy (DMAC) assay. 13 C (approximately 1.1%). Hydrogenation of compound (9) was carried out in an NMR pressure tube using hydrogen gas containing >90% para-hydrogen enrichment at a flow rate of 0.5 standard liters per minute at 10 bar pressure. 220 mM of compound (9) was reacted with para-hydrogen in the presence of a 2.5 mM solution of Rh(dppb)(COD)BF catalyst in acetone-d6. This reaction produced the para-hydrogenated derivative of compound (9). Polarization transfer was 13 The experiment was carried out in a static magnetic field of 50 μT using a transverse magnetic field at the Larmor frequency of C. The field was ramped from 1.8 μT to 2.2 μT in 9 seconds. Figure 8 shows the results of the para-hydrogenated compound (9). 13 C polarization level of the para-hydrogenated compound (9). 13 As shown in Figure 10, the maximum polarization level is 24%. 13 C polarization level was achieved. Compound (9): [ka]

[0127] Enumeration of Embodiments Embodiment 1. A composition comprising a compound of formula Ia, [ka] During the ceremony, Z comprises a carbon-carbon double bond (-CD=CD-) or a carbon-carbon triple bond (-C≡C-) that is fully substituted to contain deuterium (D); R1 comprises a parahydrogen-induced polarization (PHIP) transfer moiety; R2 comprises an optionally substituted hydrocarbon or alkoxy group; A composition wherein R3 comprises a biologically relevant imaging agent containing non-hydrogen nuclear spins.

[0128] Embodiment 2. A composition comprising a compound of Formula IIa, [ka] During the ceremony, Z' is a parahydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. * -CDH * -) or para-hydrogenated carbon-carbon double bond (-CH * =CH * -) and H * is hydrogen with spin ordering derived from parahydrogen, R1 comprises a parahydrogen-induced polarization (PHIP) transfer moiety; R2 comprises an optionally substituted hydrocarbon or alkoxy group; A composition wherein R3 comprises a biologically relevant imaging agent containing non-hydrogen nuclear spins.

[0129] Embodiment 3. A composition comprising: (i) a biologically relevant imaging agent comprising non-hydrogen nuclear spins; and (ii) a compound of Formula IIIa: [ka] During the ceremony, Z'' is a parahydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. * -CDH * -) or para-hydrogenated carbon-carbon double bond (-CH * =CH * -) and H *is hydrogen with spin ordering derived from parahydrogen, R1' comprises a parahydrogen induced polarization (PHIP) transfer moiety; The composition wherein R2 comprises an optionally substituted hydrocarbon or alkoxy group.

[0130] Embodiment 4. A composition comprising: (i) a hyperpolarized biologically relevant imaging agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula IVa: [ka] During the ceremony, Z comprises a carbon-carbon double bond (-CD=CD-) or a carbon-carbon triple bond (-C≡C-) that is fully substituted to contain deuterium; R1' comprises a parahydrogen induced polarization (PHIP) transfer moiety; The composition wherein R2 comprises an optionally substituted hydrocarbon or alkoxy group.

[0131] Embodiment 5. The composition of any one of embodiments 1-4, wherein the PHIP transfer moiety comprises a fully deuterated C1 hydrocarbon (-CD2-) or a fully deuterated C2 hydrocarbon (-CD2-CD2-).

[0132] Embodiment 6. PHIP moving part, * CR4R5, * CR4Y, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, R4 and R5 are each independently selected from deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group; 6. The composition of any one of embodiments 1-5, wherein Y is selected from the group consisting of spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0133] Embodiment 7. PHIP moving part, * CR6R7- * CR8R9, or any fully deuterated version thereof, * C is, 12 C or 13 C is a carbon isotope, The composition of any one of embodiments 1 to 5, wherein R6, R7, R8, and R9 are each independently selected from deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

[0134] Embodiment 8. PHIP moving part, * CH2, * CH2- * CH2, * CHY, * C=Y, or any fully deuterated version thereof; H * is hydrogen with spin ordering derived from parahydrogen, * C is, 12 C or 13 C is a carbon isotope, 6. The composition of any one of embodiments 1-5, wherein Y is selected from the group consisting of spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0135] Embodiment 9. A spin 1 / 2 atom is 1 H, 13 C. 15 N, 19 F, or 31 The composition of embodiment 6 or 8, wherein the compound is selected from P.

[0136] Embodiment 10. The composition of any one of embodiments 1-9, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0137] Embodiment 11. The composition of any one of embodiments 1-10, wherein Z comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0138] Embodiment 12. The composition of any one of embodiments 1 to 11, wherein R2 comprises a solubilizing moiety.

[0139] Embodiment 13. The composition of any one of embodiments 1 to 12, wherein R2 comprises a hydrophobic and / or organophilic moiety.

[0140] Embodiment 14. The composition of embodiment 13, wherein R2 comprises an organic solubilizing moiety.

[0141] Embodiment 15. The composition of any one of embodiments 1 to 12, wherein R2 comprises a hydrophilic and / or organophobic moiety.

[0142] Embodiment 16. The composition of any one of embodiments 1 to 15, wherein R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, and tertiary amide.

[0143] Embodiment 17. The biologically relevant imaging agent is of formula R 10 C(═O)X—, wherein R 10 is selected from linear, branched or cyclic C1-C10 alkyl groups, in which one or more C atoms are optionally substituted with C=C, CO, COH, CNH2, COOH, CH2COOH, CONH2, OC(=O), and X is NR 11 , S, and O, wherein R 11 is selected from hydrogen and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butylcarbonate, and benzyl.

[0144] Embodiment 18. The composition of any one of embodiments 1 to 17, wherein the biologically relevant imaging agent is selected from pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and their conjugate acids.

[0145] Embodiment 19. The composition of any one of embodiments 1 to 18, wherein the composition has a solubility in water of less than 50 millimolar (mM).

[0146] Embodiment 20. The composition of any one of embodiments 1-19, wherein reacting the composition with para-hydrogen results in a chemical yield of para-hydrogenated product of at least 30%.

[0147] Embodiment 21. The composition of any one of embodiments 1 to 20, which is for use in a parahydrogen induced polarization (PHIP) process.

[0148] Embodiment 22. A method for preparing a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof, comprising: (a) providing a composition comprising a compound of formula Ia, [ka] During the ceremony, Z comprises a carbon-carbon double bond (-CD=CD-) or a carbon-carbon triple bond (-C≡C-) that is fully substituted to contain deuterium; R1 comprises a parahydrogen-induced polarization (PHIP) transfer moiety; R2 comprises an optionally substituted hydrocarbon or alkoxy group; R3 comprises a biologically relevant imaging agent containing non-hydrogen nuclear spins; (b) hydrogenating a double or triple bond in a compound of formula Ia with para-hydrogen to form a para-hydrogenated derivative of the compound of formula Ia, wherein the para-hydrogenated derivative has the structure of formula IIa: [ka] During the ceremony, Z' is a parahydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. * -CDH * -) or para-hydrogenated carbon-carbon double bond (-CH * =CH * -) and H * is hydrogen with spin ordering derived from parahydrogen, R1 comprises a parahydrogen-induced polarization (PHIP) transfer moiety; R2 comprises an optionally substituted hydrocarbon or alkoxy group; R3 comprises a biorelevant imaging agent containing non-hydrogen nuclear spins; (c) at least one H in the compound of formula IIa * and applying a polarization transfer waveform to transfer nuclear spin order from to non-hydrogen nuclear spins, thereby forming a derivative of Formula IIa having a hyperpolarized biologically relevant imaging agent.

[0149] Embodiment 23. A method for preparing a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof, comprising: (a) providing a composition comprising a compound of formula IIa, [ka] During the ceremony, Z' is a parahydrogenated carbon-carbon single bond (-CD H) that is fully substituted to contain deuterium. * -CDH * -) or para-hydrogenated carbon-carbon double bond (-CH * =CH * -) and H * is hydrogen with spin ordering derived from parahydrogen, R1 comprises a parahydrogen-induced polarization (PHIP) transfer moiety; R2 comprises an optionally substituted hydrocarbon or alkoxy group; R3 comprises a biologically relevant imaging agent containing non-hydrogen nuclear spins; (b) at least one H in the compound of formula IIa * and applying a polarization transfer waveform to transfer nuclear spin order from to non-hydrogen nuclear spins, thereby forming a derivative of Formula IIa having a hyperpolarized biologically relevant imaging agent.

[0150] Embodiment 24. Hydrolysis of a derivative of formula IIa to produce (i) a hyperpolarized biologically relevant imaging agent containing non-hydrogen nuclear spins and (ii) a compound of formula IIIa, [ka] During the ceremony, Z'' is a parahydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. * -CDH * -) or para-hydrogenated carbon-carbon double bond (-CH * =CH * -) and H * is hydrogen with spin ordering derived from parahydrogen, R1' comprises a parahydrogen induced polarization (PHIP) transfer moiety; 24. The method of embodiment 22 or 23, further comprising providing a composition comprising: a compound of Formula IIIa, wherein R2 comprises an optionally substituted hydrocarbon or alkoxy group.

[0151] Embodiment 25. The method of embodiment 24, further comprising washing the hyperpolarized biologically relevant imaging agent one or more times with an organic solvent.

[0152] Embodiment 26. The method of embodiment 25, wherein the non-hydrogen nuclear spins have a non-hydrogen nuclear spin polarization of greater than 10% after the washing step.

[0153] Embodiment 27. The method of any one of embodiments 22-26, wherein the PHIP transfer moiety comprises a fully deuterated C1 hydrocarbon (-CD2-) or a fully deuterated C2 hydrocarbon (-CD2-CD2-).

[0154] Embodiment 28. PHIP moving part, * CR4R5, * CR4Y, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, R4 and R5 are each independently selected from deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group; 27. The method of any one of embodiments 22-26, wherein Y is selected from spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0155] Embodiment 29. PHIP moving part, * CR6R7- * CR8R9, or any fully deuterated version thereof, * C is, 12 C or 13 C is a carbon isotope, The method of any one of embodiments 22 to 26, wherein R6, R7, R8, and R9 are each independently selected from the group consisting of deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

[0156] Embodiment 30. PHIP moving part, * CH2, * CH2- * CH2, * CHY, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, 27. The method of any one of embodiments 22-26, wherein Y is selected from spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0157] Embodiment 31. A spin 1 / 2 atom is 1 H, 13 C. 15 N, 19 F, or 31 The method of embodiment 28 or 30, wherein the compound is selected from P.

[0158] Embodiment 32. The method of any one of embodiments 22-31, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0159] Embodiment 33. The method of any one of embodiments 22-32, wherein Z or Z' comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0160] Embodiment 34. The method of any one of embodiments 22 to 33, wherein R2 comprises a solubilizing moiety.

[0161] Embodiment 35. The method of any one of embodiments 22 to 34, wherein R2 comprises a hydrophobic and / or organophilic moiety.

[0162] Embodiment 36. The method of embodiment 35, wherein R2 comprises an organic solubilizing moiety.

[0163] Embodiment 37. The method of any one of embodiments 22 to 33, wherein R2 comprises a hydrophilic and / or organophobic moiety.

[0164] Embodiment 38. The method of any one of embodiments 22 to 37, wherein R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic acid, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, and tertiary amide.

[0165] Embodiment 39. The biologically relevant imaging agent is represented by the formula R 10C(═O)X—, wherein R 10 is selected from linear, branched or cyclic C1-C10 alkyl groups, in which one or more C atoms are optionally substituted with C=C, CO, COH, CNH2, COOH, CH2COOH, CONH2, OC(=O), and X is NR 11 , S, and O, wherein R 11 The method of any one of embodiments 22-38, wherein is selected from hydrogen and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butyl carbonate, and benzyl.

[0166] Embodiment 40. The method of any one of embodiments 22 to 39, wherein the biologically relevant imaging agent is selected from pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and their conjugate acids.

[0167] Embodiment 41. A hyperpolarized biologically relevant imaging agent, or a pharmaceutically acceptable salt thereof, produced by the method of any one of Embodiments 22 to 40.

[0168] Embodiment 42. A composition comprising a compound of formula Ib, [ka] During the ceremony, Z comprises an ethynyl (-C≡C-) group, a fully deuterated prop-2-ynyl (-CD2-C≡CD2-) group, a fully deuterated but-3-ynyl (-CD2-CD2-C≡C-) group, a fully deuterated ethenyl (-CD=CD-) group, a fully deuterated prop-2-enyl (-CD2-CD=CD-) group, or a fully deuterated but-3-enyl (-CD2-CD2D2-CD=CD-) group; R1 comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group; A composition wherein R2 comprises an acyl derivative of a biologically relevant imaging agent, the biologically relevant imaging agent comprising non-hydrogen nuclear spins.

[0169] Embodiment 43. A composition comprising a compound of Formula IIb, [ka] During the ceremony, Z' is para-hydrogenated ethenyl (-CH * =CH * -) group, deuterated parahydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, deuterated para-hydrogenated but-3-enyl (-CD2-CD2-CH * =CH * -) group, deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or deuterated parahydrogen butanyl (-CD2-CD2-CDH * -CDH * -) group, H * is hydrogen with spin ordering derived from parahydrogen, R1 comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group; A composition wherein R2 comprises an acyl derivative of a biologically relevant imaging agent, the biologically relevant imaging agent comprising non-hydrogen nuclear spins.

[0170] Embodiment 44. A composition comprising: (i) a biologically relevant imaging agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula IIIb, [ka] During the ceremony, Z'' is para-hydrogenated ethenyl (-CH * =CH * -) group, deuterated parahydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, deuterated para-hydrogenated but-3-enyl (-CD2-CD2-CH * =CH * -) group, deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or deuterated parahydrogen butanyl (-CD2-CD2-CDH * -CDH * -) group, H * is hydrogen with spin ordering derived from parahydrogen, The composition, wherein R1 comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group.

[0171] Embodiment 45. The composition of any one of embodiments 42-44, wherein the composition further comprises a PHIP transfer moiety between the Z, Z', and Z'' moieties and the sulfur atom, and the PHIP transfer moiety comprises a fully deuterated C1 hydrocarbon (-CD2-) or a fully deuterated C2 hydrocarbon (-CD2-CD2-).

[0172] Embodiment 46. PHIP moving part, * CR3R4, * CR3Y, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, R3 and R4 are each independently selected from deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group; 46. ​​The composition of embodiment 45, wherein Y is selected from the group consisting of spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0173] Embodiment 47. PHIP moving part, * CR5R6- * CR7R8, or any fully deuterated version thereof, * C is, 12 C or 13 C is a carbon isotope, The composition of embodiment 45, wherein R5, R6, R7, and R8 are each independently selected from deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

[0174] Embodiment 48. PHIP moving part, * CH2, * CH2- * CH2, * CHY, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, 46. ​​The composition of embodiment 45, wherein Y is selected from the group consisting of spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0175] Embodiment 49. A spin 1 / 2 atom is 1 H, 13 C. 15 N, 19 F, or 31 The composition of embodiment 46 or 48, wherein the compound is selected from P.

[0176] Embodiment 50. The composition of any one of embodiments 45-49, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0177] Embodiment 51. The composition of any one of embodiments 42-50, wherein Z comprises at least one atom J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0178] Embodiment 52. A composition according to any one of embodiments 42 to 51, wherein R1 comprises a solubilizing moiety.

[0179] Embodiment 53. A composition according to any one of embodiments 42 to 52, wherein R1 comprises a hydrophobic and / or organophilic moiety.

[0180] Embodiment 54. The composition of embodiment 53, wherein R1 comprises an organic solubilizing moiety.

[0181] Embodiment 55. A composition according to any one of embodiments 42 to 52, wherein R1 comprises a hydrophilic and / or organophobic moiety.

[0182] Embodiment 56. The composition of any one of embodiments 42 to 55, wherein R1 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic acid, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, tertiary amide, and keto.

[0183] Embodiment 57. The composition of any one of embodiments 42 to 56, wherein the biologically relevant imaging agent comprises a compound of formula R9C(=O)O-, where R9 is selected from a linear, branched, or cyclic C1-C10 alkyl group, in which one or more C atoms are optionally substituted with C=C, CO, COH, CNH2, COOH, CH2COOH, CONH2, or OC(=O).

[0184] Embodiment 58. The composition of any one of embodiments 42 to 57, wherein the biologically relevant imaging agent is selected from pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, and their conjugate acids.

[0185] Embodiment 59. The composition of any one of embodiments 42 to 58, wherein the composition has a solubility in water of less than 50 millimolar (mM).

[0186] Embodiment 60. The composition of any one of embodiments 42-59, wherein reacting the composition with para-hydrogen provides a chemical yield of para-hydrogenated product of at least 30%.

[0187] Embodiment 61. The composition of any one of embodiments 42 to 60, which is for use in a parahydrogen induced polarization (PHIP) process.

[0188] Embodiment 62. A method for preparing a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof, the method comprising: (a) providing a composition comprising a compound of formula Ib, [ka] During the ceremony, Z comprises an ethynyl (-C≡C-) group, a fully deuterated prop-2-ynyl (-CD2-C≡C-) group, a fully deuterated but-3-ynyl (-CD2-CD2-C≡C-) group, a fully deuterated ethenyl (-CD=CD-) group, a fully deuterated prop-2-enyl (-CD2-CD=CD-) group, or a fully deuterated but-3-enyl (-CD2-CD2-CD=CD-) group; R1 comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group; R2 comprises an acyl derivative of a biologically relevant imaging agent, the biologically relevant imaging agent comprising a non-hydrogen nuclear spin; (b) hydrogenating the double or triple bond in the compound of formula Ib with para-hydrogen to form a para-hydrogenated derivative of the compound of formula Ib, wherein the para-hydrogenated derivative has the structure of formula IIb: [ka] During the ceremony, Z' is para-hydrogenated ethenyl (-CH * =CH * -) group, deuterated parahydrogenated prop-2-enyl (-CD2-CH * =CH *-) group, deuterated para-hydrogenated but-3-enyl (-CD2-CD2-CH * =CH * -) group, deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or deuterated parahydrogen butanyl (-CD2-CD2-CDH * -CDH * -) group, H * is hydrogen with spin ordering derived from parahydrogen, R1 comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group; R2 comprises an acyl derivative of a biologically relevant imaging agent, the biologically relevant imaging agent comprising non-hydrogen nuclear spins; (c) at least one H in the compound of formula IIb * and applying a polarization transfer waveform to transfer nuclear spin order from to non-hydrogen nuclear spins, thereby forming a derivative of Formula IIb having a hyperpolarized acyl derivative of a biologically relevant imaging agent.

[0189] Embodiment 63. A method for preparing a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof, the method comprising: (a) providing a composition comprising a compound of formula IIb, [ka] During the ceremony, Z' is para-hydrogenated ethenyl (-CH * =CH * -) group, deuterated parahydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, deuterated para-hydrogenated but-3-enyl (-CD2-CD2-CH * =CH * -) group, deuterated parahydrogenated ethanyl (-CDH * -CDH* -) group, deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or deuterated parahydrogen butanyl (-CD2-CD2-CDH * -CDH * -) group, H * is hydrogen with spin ordering derived from parahydrogen, R1 comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group; R2 comprises an acyl derivative of a biologically relevant imaging agent, the biologically relevant imaging agent comprising a non-hydrogen nuclear spin; (b) at least one H in the compound of formula IIb * and applying a polarization transfer waveform to transfer nuclear spin order from to non-hydrogen nuclear spins, thereby forming a derivative of Formula IIb having a hyperpolarized acyl derivative of a biologically relevant imaging agent.

[0190] Embodiment 64. Hydrolysis of a derivative of formula IIb to produce (i) a hyperpolarized biologically relevant imaging agent containing non-hydrogen nuclear spins and (ii) a compound of formula IIIb, [ka] During the ceremony, Z'' is para-hydrogenated ethenyl (-CH * =CH * -) group, deuterated parahydrogenated prop-2-enyl (-CD2-CH * =CH * -) group, deuterated para-hydrogenated but-3-enyl (-CD2-CD2-CH * =CH * -) group, deuterated parahydrogenated ethanyl (-CDH * -CDH * -) group, deuterated parahydrogenated propanyl (-CD2-CDH * -CDH * -) group, or deuterated parahydrogen butanyl (-CD2-CD2-CDH * -CDH *-) group, H * is hydrogen with spin ordering derived from parahydrogen, 64. The method of embodiment 62 or 63, further comprising providing a composition comprising: a compound of formula IIIb, wherein R comprises an optionally substituted hydrocarbon group, alkyl group, cyclic alkyl group, aryl group, carboxyl group, keto group, or alkoxy group.

[0191] Embodiment 65. The method of embodiment 64, further comprising washing the hyperpolarized biologically relevant imaging agent one or more times with an organic solvent.

[0192] Embodiment 66. The method of embodiment 65, wherein the non-hydrogen nuclear spins have a non-hydrogen nuclear spin polarization of greater than 10% after the washing step.

[0193] Embodiment 67. The method of any one of embodiments 62-66, wherein the composition further comprises a PHIP transfer moiety between the Z, Z', or Z'' moiety and the sulfur atom, and the PHIP transfer moiety comprises a fully deuterated C1 hydrocarbon (-CD2-) or a fully deuterated C2 hydrocarbon (-CD2-CD2-).

[0194] Embodiment 68. PHIP moving part, * CR3R4, * CR3Y, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, R3 and R4 are each independently selected from deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group; 68. The method of embodiment 67, wherein Y is selected from spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0195] Embodiment 69. PHIP moving part, * CR5R6- * CR7R8, or any fully deuterated version thereof, * C is, 12 C or 13 C is a carbon isotope, The method of embodiment 67, wherein R5, R6, R7, and R8 are each independently selected from the group consisting of deuterium, fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

[0196] Embodiment 70. PHIP moving part, * CH2, * CH2- * CH2, * CHY, * C=Y, or any fully deuterated version thereof; * C is, 12 C or 13 C is a carbon isotope, 68. The method of embodiment 67, wherein Y is selected from spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated linear, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

[0197] Embodiment 71. A spin 1 / 2 atom is 1 H, 13 C. 15 N, 19 F, or 31 The method of embodiment 68 or 70, wherein said compound is selected from P.

[0198] Embodiment 72 The method of any one of embodiments 67-71, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0199] Embodiment 73. The method of any one of embodiments 62-72, wherein Z or Z' comprises at least one atom that is J-coupled with a non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

[0200] Embodiment 74. The method of any one of embodiments 62 to 73, wherein R1 comprises a solubilizing moiety.

[0201] Embodiment 75. The method of any one of embodiments 62 to 74, wherein R1 comprises a hydrophobic and / or organophilic moiety.

[0202] Embodiment 76. The method of embodiment 75, wherein R1 comprises an organic solubilizing moiety.

[0203] Embodiment 77. The method of any one of embodiments 62 to 73, wherein R1 comprises a hydrophilic and / or organophobic moiety.

[0204] Embodiment 78. The method of any one of embodiments 62 to 77, wherein R1 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic acid, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, tertiary amide, and keto.

[0205] Embodiment 79. The method of any one of embodiments 62 to 78, wherein the biologically relevant imaging agent comprises a compound of formula R9C(=O)O-, wherein R9 is selected from a linear, branched, or cyclic C1-C10 alkyl group, in which one or more C atoms are optionally substituted with C=C, CO, COH, CNH2, COOH, CH2COOH, CONH2, OC(=O).

[0206] Embodiment 80. The method of any one of embodiments 62 to 79, wherein the biologically relevant imaging agent is selected from pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, and their conjugate acids.

[0207] Embodiment 81. A hyperpolarized biologically relevant imaging agent, or a pharmaceutically acceptable salt thereof, produced by the method of any one of embodiments 62 to 80.

Claims

1. A composition comprising a compound of formula Ia, 【Chemical 1】 During the ceremony, Z comprises a carbon-carbon double bond (-CD=CD-) or a carbon-carbon triple bond (-C≡C-) that is fully substituted to contain deuterium (D); R １ comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group; R ３ comprising a biologically relevant imaging agent comprising non-hydrogen nuclear spins.

2. 1. A composition comprising a compound of formula IIa, 【Chemistry 2】 During the ceremony, Z' is a para-hydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. ＊ -CDH ＊ -) or parahydrogenated carbon-carbon double bond (-CH ＊ =CH ＊ -) and H ＊ is hydrogen with spin ordering derived from parahydrogen, R １ comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group; R ３ comprising a biologically relevant imaging agent comprising non-hydrogen nuclear spins.

3. A composition comprising (i) a biologically relevant imaging agent containing non-hydrogen nuclear spins, and (ii) a compound of Formula IIIa, 【Chemistry 3】 During the ceremony, Z″ is a para-hydrogenated carbon-carbon single bond (—CDH) that is fully substituted to contain deuterium. ＊ -CDH ＊ -) or parahydrogenated carbon-carbon double bond (-CH ＊ =CH ＊ -) and H ＊ is hydrogen with spin ordering derived from parahydrogen, R １ ' comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group.

4. A composition comprising (i) a hyperpolarized biologically relevant imaging agent containing non-hydrogen nuclear spins, and (ii) a compound of formula IVa, 【Chemistry 4】 During the ceremony, Z comprises a carbon-carbon double bond (-CD=CD-) or a carbon-carbon triple bond (-C≡C-) that is fully substituted to contain deuterium; R １ ' comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group.

5. The PHIP transfer moiety is a fully deuterated C1 hydrocarbon (-CD ２ -) or fully deuterated C2 hydrocarbons (-CD ２ -CD ２ The composition according to any one of claims 1 to 4, comprising:

6. The PHIP transfer moiety is ＊ CR ４ R ５ , ＊ CR ４ Y. ＊ C=Y, or any fully deuterated version thereof; ＊ C is, １２ C or １３ C carbon isotope, R ４ and R ５ are each independently selected from deuterium, fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group; 6. The composition of any one of claims 1 to 5, wherein Y is selected from the group consisting of spin 1 / 2 atoms covalently bonded to one or more chemical moieties selected from fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

7. The PHIP transfer moiety is ＊ CR ６ R ７ - ＊ CR ８ R ９ or any fully deuterated version thereof, ＊ C is, １２ C or １３ C carbon isotope, R ６ , R ７ , R ８ , and R ９ are each independently selected from deuterium, fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

8. The PHIP transfer moiety is ＊ CH ２ , ＊ CH ２ - ＊ CH ２ , ＊ CHY, ＊ C=Y, or any fully deuterated version thereof; ＊ C is, １２ C or １３ C carbon isotope, 6. The composition of any one of claims 1 to 5, wherein Y is selected from the group consisting of spin 1 / 2 atoms covalently bonded to one or more chemical moieties selected from fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

9. the spin 1 / 2 atom is １ H. １３ C. １５ N. １９ F, or ３１ 9. The composition of claim 6 or 8, wherein the compound is selected from P.

10. 10. The composition of any one of claims 1 to 9, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

11. 11. The composition of any one of claims 1 to 10, wherein Z comprises at least one atom that is J-coupled with said non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

12. R ２ The composition of any one of claims 1 to 11, wherein comprises a solubilising moiety.

13. R ２ The composition of any one of claims 1 to 12, wherein comprises hydrophobic and / or organophilic moieties.

14. R ２ The composition of claim 13 , wherein comprises an organic solubilizing moiety.

15. R ２ The composition of any one of claims 1 to 12, wherein comprises hydrophilic and / or organophobic moieties.

16. R ２ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, and tertiary amide.

17. The biologically relevant imaging agent is of formula R １０ C(═O)X—, where R １０ However, one or more C atoms are C=C, CO, COH, CNH ２ , COOH, CH ２ COOH, CONH ２ , a linear, branched, or cyclic C1-C10 alkyl group optionally substituted with OC(=O), and X is selected from NR １１ , S, and O, wherein R １１ is selected from hydrogen and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butylcarbonate, and benzyl.

18. 18. The composition of any one of claims 1 to 17, 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 their conjugate acids.

19. 19. The composition of any one of claims 1 to 18, wherein the composition has a solubility in water of less than 50 millimolar (mM).

20. 20. The composition of any one of claims 1 to 19, wherein reacting the composition with para-hydrogen results in a chemical yield of para-hydrogenated product of at least 30%.

21. The composition of any one of claims 1 to 20, for use in a parahydrogen induced polarization (PHIP) process.

22. 1. A method for preparing a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof, comprising: (a) providing a composition comprising a compound of formula Ia, 【Chemistry 5】 During the ceremony, Z comprises a carbon-carbon double bond (-CD=CD-) or a carbon-carbon triple bond (-C≡C-) that is fully substituted to contain deuterium; R １ comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group; R ３ comprising a biologically relevant imaging agent containing non-hydrogen nuclear spins; (b) hydrogenating the double bond or the triple bond in the compound of formula Ia with para-hydrogen to form a para-hydrogenated derivative of the compound of formula Ia, wherein the para-hydrogenated derivative has the structure of formula IIa: 【Chemistry 6】 During the ceremony, Z' is a para-hydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. ＊ -CDH ＊ -) or parahydrogenated carbon-carbon double bond (-CH ＊ =CH ＊ -) and H ＊ is hydrogen with spin ordering derived from parahydrogen, R １ comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group; R ３ forming a biologically relevant imaging agent comprising non-hydrogen nuclear spins; (c) at least one H in the compound of formula IIa ＊ and applying a polarization transfer waveform to transfer nuclear spin order from to said non-hydrogen nuclear spins, thereby forming a derivative of Formula IIa having a hyperpolarized biologically relevant imaging agent.

23. 1. A method for preparing a hyperpolarized biologically relevant imaging agent or a pharmaceutically acceptable salt thereof, comprising: (a) providing a composition comprising a compound of formula IIa, 【Chemistry 7】 During the ceremony, Z' is a para-hydrogenated carbon-carbon single bond (-CDH) that is fully substituted to contain deuterium. ＊ -CDH ＊ -) or parahydrogenated carbon-carbon double bond (-CH ＊ =CH ＊ -) and H ＊ is hydrogen with spin ordering derived from parahydrogen, R １ comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ comprises an optionally substituted hydrocarbon or alkoxy group; R ３ comprising a biologically relevant imaging agent containing non-hydrogen nuclear spins; (b) at least one H in the compound of formula IIa ＊ and applying a polarization transfer waveform to transfer nuclear spin order from to said non-hydrogen nuclear spins, thereby forming a derivative of Formula IIa having a hyperpolarized biologically relevant imaging agent.

24. The derivative of formula IIa is hydrolyzed to produce (i) a hyperpolarized biologically relevant imaging agent containing non-hydrogen nuclear spins, and (ii) a compound of formula IIIa, 【Chemistry 8】 During the ceremony, Z″ is a para-hydrogenated carbon-carbon single bond (—CDH) that is fully substituted to contain deuterium. ＊ -CDH ＊ -) or parahydrogenated carbon-carbon double bond (-CH ＊ =CH ＊ -) and H ＊ is hydrogen with spin ordering derived from parahydrogen, R １ ' comprises a parahydrogen induced polarization (PHIP) transfer moiety; R ２ 24. The method of claim 22 or 23, further comprising providing a composition comprising: a compound of Formula IIIa, wherein: comprises an optionally substituted hydrocarbon or alkoxy group.

25. 25. The method of claim 24, further comprising washing the hyperpolarized biologically relevant imaging agent one or more times with an organic solvent.

26. 26. The method of claim 25, wherein the non-hydrogen nuclear spins have a non-hydrogen nuclear spin polarization of greater than 10% after the washing step.

27. The PHIP transfer moiety is a fully deuterated C1 hydrocarbon (-CD ２ -) or fully deuterated C2 hydrocarbons (-CD ２ -CD ２ -). The method according to any one of claims 22 to 26, comprising:

28. The PHIP transfer moiety is ＊ CR ４ R ５ , ＊ CR ４ Y. ＊ C=Y, or any fully deuterated version thereof; ＊ C is, １２ C or １３ C carbon isotope, R ４ and R ５ are each independently selected from deuterium, fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group; 27. The method of any one of claims 22 to 26, wherein Y is selected from spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

29. The PHIP transfer moiety is ＊ CR ６ R ７ - ＊ CR ８ R ９ or any fully deuterated version thereof, ＊ C is, １２ C or １３ C carbon isotope, R ６ , R ７ , R ８ , and R ９ are each independently selected from the group consisting of deuterium, fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbon, fully deuterated C6 aryl, fully deuterated benzyl, fully deuterated phenyl, fully deuterated heteroaryl, and fully deuterated haloalkyl group.

30. The PHIP transfer moiety is ＊ CH ２ , ＊ CH ２ - ＊ CH ２ , ＊ CHY, ＊ C=Y, or any fully deuterated version thereof; ＊ C is, １２ C or １３ C carbon isotope, 27. The method of any one of claims 22 to 26, wherein Y is selected from spin ½ atoms covalently bonded to one or more chemical moieties selected from fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups, or heteroatoms such as N, O, S, optionally substituted with fully deuterated straight chain, branched, or cyclic C1-C10 alkyl hydrocarbons, fully deuterated C6 aryls, fully deuterated benzyls, fully deuterated phenyls, fully deuterated heteroaryls, halogens, or fully deuterated haloalkyl groups.

31. the spin 1 / 2 atom is １ H. １３ C. １５ N. １９ F, or ３１ 31. The method of claim 28 or 30, wherein the aryl group is selected from P.

32. 32. The method of any one of claims 22 to 31, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled with the non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

33. 33. The method of any one of claims 22 to 32, wherein Z or Z' comprises at least one atom that is J-coupled with said non-hydrogen nuclear spin of at least 0.1 Hertz (Hz).

34. R ２ The method of any one of claims 22 to 33, wherein comprises a solubilising moiety.

35. R ２ The method of any one of claims 22 to 34, wherein comprises hydrophobic and / or organophilic moieties.

36. R ２ 36. The method of claim 35, wherein comprises an organic solubilizing moiety.

37. R ２ The method of any one of claims 22 to 33, wherein comprises hydrophilic and / or organophobic moieties.

38. R ２ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, hydroxy, methyl alcohol, ethyl alcohol, n-propanol, isopropyl alcohol, propionic acid, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, isobutyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, propionic acid, butoxy, t-butoxy, s-butoxy, ester, phenyl, substituted phenyl, primary amine, secondary amine, tertiary amine, primary amide, secondary amide, and tertiary amide.

39. The biologically relevant imaging agent is of formula R １０ C(═O)X—, where R １０ However, one or more C atoms are C=C, CO, COH, CNH ２ , COOH, CH ２ COOH, CONH ２ , a linear, branched, or cyclic C1-C10 alkyl group optionally substituted with OC(=O), and X is selected from NR １１ , S, and O, wherein R １１ is selected from hydrogen and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, tert-butyl carbonate, and benzyl.

40. 40. The method of any one of claims 22 to 39, wherein the biologically relevant imaging agent is selected from pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and their conjugate acids.

41. A hyperpolarised biologically relevant imaging agent, or a pharmaceutically acceptable salt thereof, produced by the method of any one of claims 22 to 40.

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