Systems and methods for generating hyperpolarizing materials

Abstract

A system and method for increasing the nuclear spin polarization of a target compound are disclosed. [Solution] According to this system and method, a first non-thermal equilibrium nuclear spin polarization may be conferred to a source atom of at least one source compound, the source atom having a nuclear gyromagnetic ratio of at least 12 megahertz (MHz / T) per tesla. A first solution containing the source compound and the target compound can be obtained. At least one source atom can be present in the first solution at a source concentration of at least 0.1 moles (M). At least 0.01% of a second non-thermal equilibrium nuclear spin polarization can be conferred to at least one target atom of the target compound via nuclear Overhauser effect (NOE) transfer of the first non-thermal equilibrium nuclear spin polarization to at least one target atom.

Description

[Technical Field]

[0001] Reference to related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 143,794, filed on 30 January 2021. This application claims the benefits of U.S. Provisional Patent Application No. 63 / 147,263, filed on 9 February 2021. This application claims the benefits of U.S. Provisional Patent Application No. 63 / 164,675, filed on 23 March 2021. This application claims the benefits of U.S. Provisional Patent Application No. 63 / 201,153, filed on 15 April 2021. This application claims the benefits of U.S. Provisional Patent Application No. 63 / 260,174, filed on 11 August 2021. This application claims the benefits of U.S. Provisional Patent Application No. 63 / 261,152, filed on 14 September 2021. Each of these applications is incorporated herein by reference in its entirety.

[0002] The disclosed embodiments generally relate to the generation of hyperpolarizing materials for use in nuclear magnetic resonance, magnetic resonance imaging, or similar applications. [Background technology]

[0003] Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are technologies with important applications in chemistry, biology, and medical imaging. Despite these successes, nuclear magnetic resonance applications face challenges in detecting minute nuclear polarization (typically 10°) of analytes. -5 It is recognized that there are limitations due to the order of magnitude. This minute nuclear polarization can result in limited sensitivity compared to other analytical techniques such as mass spectrometry.

[0004] By increasing the nuclear spin polarization beyond the thermal equilibrium value, the magnetic resonance sensitivity can be improved. The nuclear spin polarization can be increased using known techniques such as dynamic nuclear polarization. Using such techniques, the nuclear spin polarization of a material can be increased by more than 10,000 times. The enhanced nuclear spin polarization can result in a proportional increase in the NMR / MRI signal. This enhanced polarization decays over time due to the relaxation time of the nuclear spins in the polarized molecules, but for many molecules, the relaxation time can be on the order of seconds to minutes, during which time the increase in polarization can result in a dramatic increase in the NMR / MRI signal sensitivity. By enabling such a dramatic increase in the NMR / MRI signal sensitivity, the increase in nuclear spin polarization enables new applications such as imaging of in vivo metabolism using metabolites with increased nuclear spin polarization in an MRI scanner, accelerates the investigation of signal NMR spectroscopy, and enables visualization of molecular dynamics and structures that were previously invisible.

Summary of the Invention

[0005] According to the present disclosure, the intermolecular nuclear Overhauser effect can be used to transfer polarization from a polarization source compound to a target compound. The polarized target compound can then be used in nuclear magnetic resonance (NMR) spectroscopy or magnetic resonance imaging (MRI) applications.

[0006] The disclosed embodiments include a method for increasing the nuclear spin polarization of a target compound. The method can include the act of imparting at least 1% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of a source compound, the source atom having a nuclear gyromagnetic ratio of at least 12 megahertz (MHz / T) per tesla. The method can include the act of obtaining a first solution. The first solution can include the source compound and the target compound. At least one source atom can be present in the first solution at a source concentration of at least 0.1 molar (M). The method can include the act of imparting at least 0.01% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound via nuclear Overhauser effect (NOE) transfer of the first non-thermal equilibrium nuclear spin polarization to the at least one target atom.

[0007] The disclosed embodiments include a system for increasing the nuclear spin polarization of a target compound. The system can include a first solution receiving module configured to receive a first solution. The first solution can include a source compound dissolved therein, the source compound including at least one source atom, at least one source non-carbon atom being present in the first solution at a source concentration of at least 0.1 molar (M). The system can include a polarization module coupled to the first solution receiving module, the polarization module being configured to impart at least 1% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of the source compound. The system can include a second solution receiving module configured to receive a second solution. The second solution can include a target compound dissolved therein. The system can include a mixing module fluidly coupled to the polarization module and the second solution receiving module, the mixing module being configured to mix the first solution and the second solution, thereby allowing the first non-thermal equilibrium nuclear spin polarization to be transferred to at least one target atom of the target compound via nuclear Overhauser effect (NOE) transfer, thereby imparting at least 0.01% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound.

[0008] The disclosed embodiments may include a system for increasing the nuclear spin polarization of a target compound. The system may include a container. The container may include an internal volume configured to contain a source compound. The source compound may include at least one PETS portion. The container may include a first magnetic field source configured to at least partially surround the internal volume and generate a first magnetic field within the internal volume. The container may include at least one optical window configured to be coupled to a light source and thereby allow the optical polarization of at least one PETS portion. The container may include at least one container port configured to allow the passage of the source compound through it. The system may include a solution preparation system. The source preparation system may include a dissolution vessel coupled to at least one container port and configured to receive the source compound after it has passed through the at least one container port, and to receive a first solution containing a pressurized gas and the compound dissolved therein. The source preparation system may include a second magnetic field source configured to at least partially surround the dissolution vessel and generate a second magnetic field within the dissolution vessel. The source preparation system may include a grinding head located within a dissolution vessel and configured to grind the source compound, thereby allowing the source compound to dissolve in a first solution, and thereby producing a second solution. The source preparation system may include at least one solution port configured to allow the passage of the second solution through it.

[0009] It should be understood that both the general description above and the detailed description below are illustrative and explanatory, and do not limit the disclosed embodiments as requested.

[0010] The accompanying drawings, including portions of this specification, illustrate several embodiments and, together with this specification, serve to illustrate the principles and features of the disclosed embodiments. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows an exemplary process 100 for the preparation and use of a target compound in NMR spectroscopy or MRI applications according to the disclosed embodiments. [Figure 2A] Figure 2A shows the incorporation of a pentacene dopant into a naphthalene crystal according to the disclosed embodiment. [Figure 2B] Figure 2B shows a pentacene-doped naphthalene crystal according to the disclosed embodiment. [Figure 3A] Figure 3A shows a spin transfer in an exemplary dynamic nuclear polarization (DNP) method that achieves spin transfer using solid-state effects, according to the disclosed embodiment. [Figure 3B] Figure 3B shows a spin transfer in an exemplary dynamic nuclear polarization (DNP) method that achieves spin transfer using solid-state effects, according to the disclosed embodiment. [Figure 4] Figure 4 shows exemplary sequences of light irradiation, magnetic field sweep, and electromagnetic irradiation suitable for inducing polarization in a compound, according to the disclosed embodiments. [Figure 5] Figure 5 shows NMR signal readings from the compound before and after the repetition of the polarization sequence shown in Figure 4, according to the disclosed embodiment. [Figure 6] Figure 6 shows an exemplary para-hydrogen-induced polarization (PHIP) precipitation transfer process according to the disclosed embodiment. [Figure 7A] Figure 7A shows the measurement of the target thermal T1 = 1 / ρ relaxation time using a standard non-selective reverse recovery sequence of napasalen and acetone according to the disclosed embodiment. [Figure 7B] Figure 7B shows the steady-state saturation transfer of naphthalene to acetone according to the disclosed embodiment. [Figure 8A] Figure 8A shows the measurement of the target thermal T1=1 / ρ relaxation time using a standard non-selective inversion recovery sequence for naptalene and 1,1,2,2-trichloroethylene (TCE) according to the disclosed embodiment. [Figure 8B] Figure 8B shows the steady-state saturation transfer of naphthalene to TCE according to the disclosed embodiment. [Figure 9A] Figure 9A shows the accumulation and decay of acetone polarization at 1.45 T when the naphthalene source is optically polarized before dissolution in the target solution, according to the disclosed embodiment. [Figure 9B] Figure 9B shows the frequency shift of the acetone resonance according to the disclosed embodiment. [Figure 10A] Figure 10A shows the accumulation and decay of TCE polarization at 1.45T when the naphthalene source is optically polarized before dissolution in the target solution according to the disclosed embodiment. [Figure 10B] Figure 10B shows the frequency shift of the TCE resonance according to the disclosed embodiment. [Figure 10C] Figure 10C shows a post-processing method according to the disclosed embodiment for separating the effects of the sample magnetic field and source compound signals from the rest of the acquired NMR spectrum. [Figure 10D] Figure 10D shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10E] Figure 10E shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10F] Figure 10F shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10G] Figure 10G shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10H] Figure 10H shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10I] Figure 10I shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10J] Figure 10J shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 10K] Figure 10K shows the effect of the steps of the method in Figure 10C on an exemplary acquired NMR spectrum according to the disclosed embodiment. [Figure 11] Figure 11 shows an exemplary PHIP precipitation system and process, consistent with the disclosed embodiments. [Figure 12] Figure 12 shows an overview of the setup and components of a photo-excited triplet state (PETS) polarizer according to the disclosed embodiment. [Figure 13] Figure 13 shows an exemplary transport system consistent with the disclosed embodiments. [Figure 14] Figure 14 shows an exemplary system for automatically combining a solid source compound with a target compound, consistent with the disclosed embodiments. [Figure 15] Figure 15 shows a series of NMR spectra obtained after the injection of the hyperpolarized solution into a spectrometer according to the disclosed embodiment. [Figure 16A] Figure 16A shows the relationship between the phase of the target resonance and the width of the radiation attenuation signal according to the disclosed embodiment. [Figure 16B] Figure 16B shows the enhancement curves estimated for each proton site using the preceding procedure according to the disclosed embodiment. [Figure 17] Figure 17 shows the spectrum acquired 35 seconds after injection into the spectrometer, compared to the thermal spectrum with an average flip angle of 90 degrees according to the disclosed embodiment. [Figure 18A] Figure 18A shows the accumulation curve of propargyl acetate probed at a 1-degree flip angle according to the disclosed embodiment. [Figure 18B] Figure 18B shows the hyperpolarized spectrum of propargyl acetate compared to the thermal spectrum with an average flip angle of 90 degrees according to the disclosed embodiment. [Figure 18C] Figure 18C shows the time-dependent polarization enhancement of a solution containing TCE, dichloromethane (DCM), tetrahydrofuran (THF), and acetone according to the disclosed embodiments. [Figure 18D]Figure 18D shows the hyperpolarized spectrum of the solution in Figure 18C, compared to the thermal spectrum at an average, 90-degree flip angle according to the disclosed embodiment. [Figure 19] Figure 19 shows the single-shot hyperpolarized spectrum of propargyl acetate following a 2° flip-angle pulse, using PHIP-polarized methyl maleate as the source, compared to the single-shot thermal equilibrium spectrum of the same mixture obtained after a 90° flip-angle pulse according to the disclosed embodiment. [Modes for carrying out the invention]

[0012] Herein, exemplary embodiments are described in detail and discussed with respect to the accompanying drawings. In some examples, the same reference numerals are used throughout the drawings, and the following description refers to identical or similar parts. Unless otherwise defined, technical and / or scientific terms have meanings that are generally 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. Naturally, other embodiments may be used and modifications may be made without departing from the scope of the disclosed embodiments. Thus, the materials, methods, and examples are illustrative and not necessarily intended to be limiting.

[0013] NMR spectroscopy can be used in applications ranging from determining the chemical structure of synthetic intermediates to determining the atomic-level structure and dynamics of proteins and nucleic acids. However, the sensitivity of NMR spectroscopy can be limited due to the combination of the tiny size of the nuclear magnetic moment and the corresponding small polarization in thermal equilibrium. This limited sensitivity may prevent the use of NMR spectroscopy in some applications and can make other applications of NMR spectroscopy unrealistically time-consuming or material-intensive.

[0014] NMR sensitivity can be improved by using higher magnetic fields and optimized detection systems. However, an alternative approach is to increase NMR sensitivity by significantly increasing nuclear spin polarization to a level above thermal equilibrium. Such hyperpolarization techniques can enable new NMR spectroscopy applications, such as the observation of low-gamma nuclei or low-concentration analytes.

[0015] Nuclear spin polarization can be increased using a variety of techniques, including dynamic nuclear polarization (DNP), para-hydrogen-induced polarization (PHIP), spin-exchange optical pumping (SEOP), optically initialized electronic triplet states (also referred herein as photo-excited triplet states (PTES)), and other suitable methods. DNP can increase nuclear spin polarization in a wide range of materials, but may require equipment capable of generating cryogenic and high magnetic fields (e.g., dissolution dynamic nuclear polarization) or equipment that provides only limited signal enhancement (e.g., Oberhauser DNP). Para-hydrogen-induced polarization (PHIP) and spin-exchange optical pumping (SEOP) can generate high levels of polarization, but only in specific suitable materials.

[0016] Polarization via optically initialized electronic triplet states (e.g., in organic molecular crystals, or in nitrogen vacancies (NVs), or in other defect centers) can produce high levels of polarization in certain suitable materials. Such optical polarization methods also benefit from reduced equipment requirements and enable the fabrication of polarized materials with long relaxation times. Optical polarization can generate nuclear spin polarization of several tens of percent or more at room temperature and low magnetic fields (<1T). The polarization rate can be controlled by the optical pump speed. The relaxation time of nuclear spins after polarization can be very long because paramagnetic electrons can only exist under laser irradiation. For example, in pentacene-doped naphthalene crystals... 1 The H nucleus is polarized to a maximum of 80%, has a lifetime of approximately 50 hours at liquid nitrogen temperature, and is long enough to be transported to remote facilities.

[0017] A convenient method of polarization transfer can enable the separation of an originally polarized material (e.g., a source compound) from a material used in NMR spectroscopy (e.g., a target compound). The originally polarized material, referred to herein as the source compound, may include a source molecule or source material. The material used in NMR spectroscopy, referred herein as the target compound, may include a target molecule or target material. The source compound can then be selected based on the polarization method (e.g., DNP, PHIP, SEOP, optical polarization, etc.), relaxation time, ease of preparation, ease of separation from the target compound, ease of transport, or other technical concerns. The target compound can be selected based on the intended NMR spectroscopy application. Therefore, separating the technical requirements of polarization from the technical requirements of NMR spectroscopy can address the technical problem of obtaining high nuclear spin polarization in a suitable target compound.

[0018] The disclosed embodiments utilize the intermolecular nuclear Overhauser effect (NOE) to transfer polarization. The disclosed embodiments can provide NMR signal enhancement for a variety of source and target compounds. The disclosed polarization transfer from the source compound to the target compound can occur on a timescale of less than a few minutes, and in some embodiments, cryogenic temperatures are not required. Furthermore, because no paramagnetic contaminants are present, high-resolution NMR spectra can be generated using target compounds polarized using the disclosed embodiments. Unlike conventional polarization transfer systems, the disclosed embodiments can be automated, operate at room temperature, and be used with existing equipment.

[0019] As described herein, the disclosed embodiments can be used with polarizing molecules and molecular mixtures. Signal enhancement of more than 200 times and up to 1730 times, and even more (corresponding to 0.86% polarization or more), can be achieved for the benchmark molecule propargyl acetate at a magnetic field strength of 1.45 T.

[0020] "Polarization" may involve an imbalance in electron or nuclear spin orientation. In some embodiments, polarization can be a normalized, approximate difference obtained by subtracting the number of spins in the opposite direction from the number of spins in the first direction. In non-limiting embodiments, 200,000 1 Assuming a nuclear spin for H, a 2% polarization can correspond to 102,000 spins in the first direction and 98,000 spins in the opposite direction. In some embodiments, "hyperpolarization" may include polarization of a species (e.g., nuclear, selective, or homogeneous) that exceeds the typical polarization level of that species observed in thermal equilibrium when exposed to a particular magnetic field. In non-limiting embodiments, 1 A sample in a 1T magnetic field at thermal equilibrium with H nuclear spin polarization exceeding 0.000341% has substantially higher polarization than 0.000341% at thermal equilibrium (e.g., at least one or more orders of magnitude higher). 1 It can be hyperpolarized to have H nuclear spin polarization. As an additional non-limiting example, greater than 0.000257% 13 A sample with C spin polarization in a 3T magnetic field at thermal equilibrium can be hyperpolarized. As a further non-limiting example, greater than 0.000103% 15 A sample with N spin polarization in a 3T magnetic field at thermal equilibrium can be hyperpolarized.

[0021] PETS (Photo-excited Triplet State) materials may contain polarized molecules having electron spins of 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more when exposed to appropriate light radiation. In some embodiments, polarizable materials may have triplet spin states. In some embodiments, appropriate light irradiation can induce electron polarization by an initial selected population of triplet spin states. In various embodiments, appropriate light radiation can induce electron polarization via differential decay rates in triplet spin states. In some embodiments, appropriate light irradiation can induce electron polarization via a combination of inversion pulses and differential decay rates during the triplet state after light irradiation.

[0022] In some embodiments, the nuclear spins of a PETS material can be adapted for polarization using spin-polarized electron triplet states in the PETS material. For example, in some embodiments, the spin order associated with the spin-polarized electron triplet states in the PETS material can be shifted to the nuclei within the PETS material. Spin-polarized photo-excited electron triplet states can provide on-demand electron polarization over a wide range of magnetic fields and temperatures, even for combinations where thermionic polarization is orders of magnitude smaller than units. Furthermore, photo-excitable triplet states can have singlet grounding levels at which they decay. Thus, whenever electrons are not excited to an excited state, it is not a paramagnetic center and does not cause relaxation. Consequently, PETS materials can have nuclear relaxation times of more than 1 hour, more than 2 hours, more than 5 hours, more than 10 hours, more than 20 hours, more than 50 hours, or more above liquid nitrogen temperature in the absence of light irradiation. In some embodiments, the PETS material may include a combination of a polarizable material and a host material. The host material may be, for example, naphthalene.

[0023] A “porous” material can be a material containing voids. In some embodiments, the ratio of the surface area of ​​voids in the amount of porous material to the surface area of ​​the amount of porous material may be greater than 1, 10, 100, 1000, 10000, or 10000. Accessible voids are voids accessible from the envelope surface of the amount of porous material (e.g., open cells as opposed to closed cells).

[0024] "Microparticles" can be particles smaller than 1000 micrometers (μm), 500 μm, 200 μm, 100 μm, 50 μm, 20 μm, 10 μm, 5 μm, 2 μm, or 1 μm in at least one dimension (e.g., less than 200 μm in two or three dimensions). In some embodiments, microparticles can be spherical. In various embodiments, microparticles can have a single dimension that is significantly larger than other dimensions. For example, in some embodiments, microparticles can be rod-shaped or fibrous. In such embodiments, the length of the rod- or fiber-like microparticles may be smaller than 1000 μm, 500 μm, 200 μm, 100 μm, 50 μm, 20 μm, 10 μm, 5 μm, 2 μm, or 1 μm. Similarly, “nanoparticles” can be particles smaller than 1000 nanometers (nm), 500 nm, 200 nm, 100 nm, 50 nm, 20 nm, 10 nm, 5 nm, 2 nm, or 1 nm in at least one dimension (e.g., smaller than 200 nm in two or three dimensions). In some embodiments, nanoparticles can be spherical. In various embodiments, nanoparticles can have a single dimension that is significantly larger than other dimensions. For example, in some embodiments, nanoparticles can be rod-shaped or fibrous. In such embodiments, the length of the rod- or fibrous nanoparticles may be smaller than 1000 nm, 500 nm, 200 nm, 100 nm, 50 nm, 20 nm, 10 nm, 5 nm, 2 nm, or 1 nm. In some embodiments, microparticles or nanoparticles may be densely packed, thereby creating a semi-polycrystalline structure. As used herein, unless otherwise specified, “particles” can be nanoparticles or microparticles. The semi-polycrystalline structure may be porous and have accessible voids.

[0025] overview

[0026] Figure 1 shows an exemplary process 100 for the preparation and use of a target compound in NMR spectroscopy and MRI applications according to the disclosed embodiments. Process 100 separates the initial polarization of a source compound from the polarization of a target compound to be used in NMR spectroscopy or MRI applications. Instead, the source compound is polarized, and then the polarization is transferred to the target compound. Process 100 may optionally include transporting the polarized source compound and separating the polarized target compound from the source compound before using the target compound in a spectroscopic or imaging application. Process 100 can allow for greater flexibility in the selection of polarization methods, source materials, target materials, and polarization positions. Thus, process 100 can improve NMR spectroscopy or MRI by enabling the generation of more highly polarized target materials and increasing NMR or MRI sensitivity.

[0027] In step 110 of process 100, a polarization source compound can be obtained. In some embodiments, obtaining a source compound may include generating a source compound. Consistent with the disclosed embodiments, obtaining a polarization source compound may include placing the source compound in a solution. In some embodiments, the source compound can be present in a solution at a source compound concentration of at least 0.01 mol(M), 0.02 M, 0.05 M, at least 0.1 M, at least 0.2 M, at least 0.5 M, 1 M, at least 2 M, at least 5 M, or at least 10 M. The concentration of the source compound can be selected to allow substantial polarization of the source compound. In some embodiments, the source compound may contain at least one source atom. In some embodiments, the source atom can be present in a solution at a source atom concentration of at least 0.01 M, 0.02 M, 0.05 M, 0.1 M, at least 0.2 M, at least 0.5 M, at least 1 M, at least 2 M, at least 5 M, or at least 10 M. In step 110, polarizing the source compound may include polarizing at least one source atom. In some embodiments, the ability of NOE to shift polarization between the source atom and the target atom may depend on the gyromagnetic ratio of the source atom, with a higher gyromagnetic ratio enhancing the polarization shift. In such embodiments, the source atom may have a gyromagnetic ratio of at least 12 megahertz / tesla (MHz / T), at least 14 MHz / T, at least 16 MHz / T, at least 18 MHz / T, at least 20 MHz / T, at least 22 MHz / T, at least 24 MHz / T, at least 26 MHz / T, at least 28 MHz / T, at least 30 MHz / T, at least 32 MHz / T, at least 34 MHz / T, at least 36 MHz / T, at least 38 MHz / T, at least 40 MHz / T, at least 42 MHz / T, or at least 44 MHz / T.For example, the source atom can be a hydrogen atom (e.g., a gyromagnetic ratio of 42.58 MHz / T), a tritium atom (e.g., a gyromagnetic ratio of 45.42 MHz / T), a fluorine-19 atom (e.g., a gyromagnetic ratio of 40.08 MHz / T), a phosphorus-31 atom (e.g., a gyromagnetic ratio of 17.25 MHz / T), or the like.

[0028] In some embodiments, the source compound can be a molecule, and the source atom can be part of that molecule. For example, if the source compound is naphthalene, the source atom can be 1 H. As an additional example, if the source compound is fluorostyrene, the source atom can be 19 F. As a further example, if the source compound is triphenylphosphine, the source atom can be 31 P. In various embodiments, the source compound can be a combination of molecules, and the source atom can be part of one of these molecules. For example, the source compound can be a crystalline host that can contain dopant molecules. The source atom can be part of the dopant molecule. In some embodiments, the crystalline host can be or can include naphthalene, p-terphenyl, or benzoic acid. In various embodiments, the dopant can be or can include pentacene.

[0029] In some embodiments, the solution can be an organic solution. In some embodiments, the organic solution is a common organic solution used in NMR spectroscopy, such as acetone, chloroform, DMSO, toluene, ethyl acetate, benzene, methanol, ethanol, other short alcohols, or their deuterated versions. In some embodiments, the solution is an aqueous solution. In some embodiments, the solution can be selected such that the source compound is at least partially soluble in the solution. For example, if the source compound is naphthalene, the solution can be deuterated acetone, DMSO, methanol, or chloroform.

[0030] In accordance with the disclosed embodiments, obtaining a polarized source compound may include polarizing the source compound. The disclosed embodiments are not limited to any particular method for polarizing the source compound. In some embodiments, the source compound may be polarized using dynamic nuclear polarization (DNP), optical polarization, para-hydrogen induced polarization (PHIP), or para-hydrogen induced polarization by side-arm hydrogenation (PHIP-SAH), signal amplification by reversible exchange (SABRE), or another suitable method.

[0031] In accordance with the disclosed embodiments, the source compound can be polarized using DNP at low temperatures and high magnetic fields. In some embodiments, free electron spins in radicals or paramagnetic defects of the source compound can be highly polarized in thermodynamic equilibrium at temperatures below 4 K and magnetic fields above 1 T. Using the DNP protocol, this high thermal polarization of electrons can be transferred to nuclear spins in the source compound. In some embodiments, after polarization, the compound can be dissolved in a solution using dissolution DNP.

[0032] In accordance with the disclosed embodiments, the source compound can be optically polarized. In some embodiments, optical polarization can be achieved by using optical defects such as color centers. In these methods, optically active defects in semiconductors such as diamond and silicon carbide can be used to polarize the surrounding nuclear spins. In various embodiments, optical polarization can hyperpolarize the nuclear spins in the PETS compound by polarization transfer from optically polarizable electron spins to nuclear spins in the PETS polarized molecule. Figures 2–5 show the generation of polarized source compounds using optically initialized electron triplet states.

[0033] In accordance with the disclosed embodiments, the source compound may be polarized using PHIP, PHIP-SAH, or SABRE. Parahydrogen, orthodeurium, or paratritium can be used to induce an electron spin order in the source compound, which can be converted to nuclear spin polarization (e.g., via the application of a suitable RF pulse sequence). In the SABRE embodiment, the catalyst can be bound to the source compound and parahydrogen, orthodeurium, or paratritium. The source compound may be polarized while bound to the catalyst. In the PIP or PHIP-SAH embodiment, the precursor compound may be hydrogenated to form a parahydrogenation, orthodeuterination, or paratotritiation precursor, respectively (e.g., using parahydrogenation, orthodeurium, or paratritium). In the PHIP embodiment, the hydrogenation precursor may be polarized to form the source compound, while in the PHIP-SAH embodiment, the hydrogenation precursor may be polarized and its side arms cleaved to form the source compound. In some embodiments, the hydrogenation catalyst and / or reaction byproducts can be separated from the source compound. In some embodiments, the source compound can be precipitated or solidified. Figure 6 shows the generation of a polarization source compound using PHIP.

[0034] In some embodiments, the polarization of the source compound may include hyperpolarizing at least one source atom of the source compound. As described herein, such hyperpolarization may include increasing the polarization level of at least one source atom above the level observed at thermal equilibrium. In some embodiments, the non-thermal equilibrium polarization imparted to at least one source atom may exceed at least 1%. In various embodiments, the non-thermal equilibrium polarization imparted to at least one source atom may exceed at least 2%, 5%, 10%, 20%, or 50%.

[0035] In the optional step 120, if the source compound is polarized in solution (for example, if the source compound is polarized using PHIP, PHIP-SAH, or SABRE), the source compound may be extracted from the solution, or undesirable solutes may be removed from the solution. Such undesirable solutes may include hydrogenation catalysts and reaction byproducts. The disclosed embodiments are not limited to any particular method for separating the source compound. In some embodiments, the concentration of the compound increases during the separation. In some embodiments, the separation is carried out by liquid-liquid separation. In various embodiments, the source compound (or undesirable solute) may be extracted from the solution by precipitation or solidification. Such precipitation or solidification may be induced to reduce the solubility of the source compound in the solution. In some embodiments, the solution may be modified (for example, by adding pH, temperature, other solvents or similar substances to the solution). In various embodiments, electromagnetic stimulation (e.g., light emission such as ultraviolet or light emission at another suitable wavelength or wavelength) or mechanical stimulation (e.g., ultrasound, stirring, or another suitable mechanical stimulation), addition of another solute or solvent to the solution, or application of another suitable method. In some embodiments, the precursor molecule can be modified relative to the source compound. For example, the side arms of the precursor molecule can be cleaved to form the source compound. The source compound becomes less soluble in solution than the precursor, which can cause the source compound to precipitate. In some embodiments, after precipitation, the precipitated source compound can be separated from the solution (e.g., using a filter, centrifuge, or another suitable method).

[0036] In any step 130 of process 100, the polarization source compound can be transported. In some embodiments, the polarization source compound can be prepared at a facility separate from the facility where NMR spectroscopy is performed beforehand. For example, the polarization source compound may be produced at a facility dedicated to the production of polarization source compounds, while NMR spectroscopy is performed at one of many facilities that require a polarized target compound. Thus, scale efficiency can be achieved in the production of the source compound. In some embodiments, the polarization source compound can be transported for a period of time exceeding 30 minutes, or 1 hour, or 2 hours, or 5 hours, or 10 hours or more. The polarization source compound can be transported in a cryogenic container. The polarization source compound can be subjected to a predetermined magnetic field during transport. In some embodiments, the predetermined magnetic field may be greater than the Earth's magnetic field. Figure 9 shows an exemplary container for transporting the polarization source compound.

[0037] In step 130 of step 100, polarization may be transferred to the target compound. As preparation for polarization transfer, the target compound and the source compound can be combined. In some embodiments, the source compound can be combined in solid form. The solid source compound can be combined with the solid target compound. The combined compounds can then be mixed in a solution. The solid source compound can be redissolved in the solution. This solution may contain the target compound, or the target compound may be added later.

[0038] As can be understood, by precipitating and redissolving the source compound, separate preparations of the solution in which the source compound is polarized (first solution) and the solution in which polarization transfer occurs (second solution) are possible. The properties of the first solution (e.g., biocompatibility, concentration, volume, temperature, pH, polarity, or other relevant properties) may differ from those of the second solution. For example, the concentrations of the source compound may differ between the original solution and the subsequent solution. A lower concentration of the source compound in the original solution in step 110 allows for greater polarization of the source compound. A higher concentration of the source compound in the subsequent solution in step 140 allows for greater polarization transfer from the source compound to the target compound.

[0039] In some embodiments, the source compound or target compound may remain solid, semi-solid, or suspended in solution. For example, the source compound or target compound may be incorporated into a surface, solid, film, nanoparticles, or microparticles. In such embodiments, polarization of the target atom may then occur by cross-relaxation at the liquid-solid interface.

[0040] In some embodiments, the source compounds can be combined in a solution. In such embodiments, the optional step 120 may be omitted. The source compounds may remain in the solution of step 110. The target compound can be dissolved in the source compound solution, or a solution containing the target compound can be added to the source compound solution.

[0041] In some embodiments, the target compound can be, or may include, small molecules (e.g., molecules having molecular weights of 1000, 900, 800, 700, 600, 500, 400, 300, 200, or less than 100 daltons), peptides, polypeptides, proteins, nucleic acids, ribonucleic acid, deoxyribonucleic acid, carbohydrates, polymers, or other suitable target compounds. In some embodiments, the target compound may be particles suspended in a solution or particles impregnated with a solution. In some embodiments, the target compound may be the surface of a solid or thin material in contact with the solution. In some embodiments, the target compound may be an amorphous structure in contact with the solution, such as a gel, membrane, polymer, or porous material. Transferring polarization to the target compound may include transferring polarization from at least one source atom of the source compound to the nuclear spin polarization of at least one target atom of the target compound. The target atom may be selected based on the intended NMR spectroscopy application. In some embodiments, the target atom may be hydrogen, tritium, carbon-13, nitrogen-15, fluorine-19, silicon-29, phosphorus-31, iron-57, selenium-77, yttrium-89, rhodium-103, silver-107, silver-109, cadmium-111, cadmium-113, tin-117, tin-119, tellurium-123, tellurium-125, thulium-169, ytterbium-171, tungsten-183, osmium-187, platinum-195, mercury-199, thallium-203, thallium-205, lead-207, polonium-209, or plutonium-239. In some embodiments, the target atom may have a nuclear spin of 1 / 2. In other embodiments, the target atom may have one or more nuclear spins.

[0042] In some embodiments, the ability to transfer polarization from a source atom to the nuclear spin polarization of a target atom may depend on the electron cloud size of the target atom (e.g., a lower electron cloud size improves the ability to transfer polarization by reducing the minimum distance to other molecules) and the gyromagnetic ratio of the target atom (e.g., increasing the gyromagnetic ratio improves the ability to transfer polarization). In some embodiments, the target atom is at least 2 MHz / T, at least 4 MHz / T, at least 6 MHz / T, at least 8 MHz / T, at least 10 MHz / T, at least 12 MHz / T, at least 14 MHz / T, at least 16 MHz / T, at least 18 MHz / T, at least 20 MHz / T, at least 22 MHz / T, at least 24 MHz / T, at least 26 MHz / T, at least 28 MHz / T, at least 30 MHz / T, at least 32 MHz / T, at least 34 MHz / T, at least 36 MHz / T, at least 38 MHz / T, at least 40 MHz / T, at least 42 MHz / T, or at least It may have a gyromagnetic ratio that is greater than or within the range defined by any two of the following values: 44 MHz / T, maximum 44 MHz / T, maximum 42 MHz / T, maximum 40 MHz / T, maximum 38 MHz / T, maximum 36 MHz / T, maximum 34 MHz / T, maximum 32 MHz / T, maximum 30 MHz / T, maximum 28 MHz / T, maximum 26 MHz / T, maximum 24 MHz / T, maximum 22 MHz / T, maximum 20 MHz / T, maximum 18 MHz / T, maximum 16 MHz / T, maximum 14 MHz / T, maximum 12 MHz / T, maximum 10 MHz / T, maximum 8 MHz / T, maximum 6 MHz / T, maximum 4 MHz / T, and maximum 2 MHz / T.

[0043] In some embodiments, the target compound may be a molecule, and the target atom may be a part of that molecule. For example, if the target compound is a metabolite, the target atom is 1 H, 13 C, 15 It can be N. As an additional example, if the target compound is a silicate, the target atom is 29It can be Si. In various embodiments, the target compound may be a combination of molecules, and the target atom may be part of one of these molecules.

[0044] In accordance with the disclosed embodiments, polarization can be moved using SPINOE. Nuclear spins on a target atom can be polarized by cross-relaxation from a polarized source atom. In some embodiments, the source compound containing the source atom can be in a solution containing the target compound containing the target atom. In some embodiments, the concentration of the target compound in the solution can be 1,000 mmol (mM), 500 mM, 200 mM, 100 mM, 50 mM, 20 mM, 10 mM, 5 mM, 2 mM, 1 mM, 500 micromoles (μM), 200 μM, 100 μM, 50 μM, 20 μM, 10 μM, 5 μM, 2 μM, 1 μM, 500 nanomoles (nM), 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, or less in the first solution.

[0045] In some embodiments, at least one target atom may be hyperpolarized via polarization transfer. As described herein, such hyperpolarization may involve increasing the polarization level of at least one target atom above the thermal equilibrium polarization level observed at thermal equilibrium. In some embodiments, at least 0.01% of non-thermal equilibrium polarization may be imparted to at least one target atom via polarization transfer. In various embodiments, the non-thermal equilibrium polarization imparted to at least one target atom may be at least 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 5%, or more than 10%.

[0046] In an optional step 140 of process 100, the target compound can be separated from the source compound. The disclosed embodiments are not limited to any particular method for separating the target compound from the source compound. In some embodiments, the target compound can be separated from the source compound using liquid-liquid separation. The target compound and source compound can be selected such that the polarity of the target compound differs from the polarity of the source compound (e.g., a polar target compound and a non-polar source compound). In some embodiments, a solution of the source compound, target compound, and a first solvent can be combined with a second solvent. For example, if the target compound and source compound are mixed in a cavity, the second solvent can be introduced into the cavity. The source compound may be more soluble in the first solvent, while the target compound may be more soluble in the second solvent. In some embodiments, the first and second solvents may be immiscible. The first solvent can be separated from the second solvent to separate the target compound from the source compound. For example, the source compound may be selected to preferentially dissolve in an organic solvent, and the target compound may be selected to preferentially dissolve in an aqueous solvent (or vice versa). Next, the separation of the target compound from the source compound can be carried out by separating the aqueous solution from the organic solution.

[0047] In various embodiments, the target compound may be crystallized or precipitated from the solution. The disclosed embodiments are not limited to any specific method for inducing such precipitation. For example, such precipitation may be induced by changes in temperature or pH, electromagnetic stimulation (e.g., optical emission such as ultraviolet or optical emission at another suitable wavelength or multiple wavelengths), mechanical stimulation (e.g., ultrasound, stirring, or another suitable mechanical stimulation), addition of another solute or solvent to the solution, or another suitable method, or any combination thereof. In some embodiments, after precipitation, the target compound may be separated from the solution (e.g., using a filter or another suitable method). In some embodiments, the target compound may then be combined with or redissolved in another solution. This second solution may have desirable properties for the intended imaging application (e.g., biocompatibility, concentration, volume, temperature, pH, polarity, or other relevant properties, or any combination thereof).

[0048] In step 150 of process 100, the target compound can be used for imaging or spectroscopic applications. In some embodiments, at least a portion of the target compound can be injected into a subject or patient. In various embodiments, at least a portion of the target compound can be used in NMR spectroscopy. During the execution of step 150, at least one NMR or MRI pulse sequence can be applied to the target compound. In some embodiments, the signal from the source molecule is reduced by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% for spectroscopic applications. In some embodiments, source polarization is reduced before the detection scheme. In some embodiments, a pulse sequence is utilized to reduce the transverse vibration signal of the source molecule compared to the target molecule. In some embodiments, a signal post-processing scheme is applied to the signal to reduce the influence of the highly polarized source molecule, including removing the signal from the source molecule and improving the phase and frequency of the target molecule, and improving the phase and frequency of the target molecule to best match its phase and frequency without the influence of the highly polarized source molecule. In some embodiments, at least one NMR or MRI pulse sequence may include at least one radiation attenuation procedure configured to reduce the radiation attenuation of a target compound by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a pulse sequence that does not use at least one radiation attenuation procedure. Such radiation attenuation procedures may include at least one Q-switching procedure or at least one detuning procedure. At least one Q-switching procedure or at least one detuning procedure may be applied to an induction coil configured to receive an NMR or MRI signal from the target compound. In some embodiments, at least one Q-switching procedure or at least one detuning procedure includes changing the quality (Q) coefficient of the induction coil from a first value of at least 100, at least 50, at least 20, or at least 10 during the application of a hard excitation pulse to the molecule, and (ii) from a second value of up to 1, up to 0.5, up to 0.2, or up to 0.1 during the application of a frequency-selective pulse to the molecule.

[0049] In some embodiments (not shown in Figure 1), the target compound and the source compound can be combined in solution in step 110 before polarization of the source compound. In some such embodiments, the combination of the target compound and the polarization source compound can be transported as described in any step 130. This combination can be transported in solution, as a precipitate, or in some other suitable form. In some embodiments, the steps of polarizing the source compound (e.g., using SABRE), transferring the polarization to the target compound, and detecting the target compound signal can be repeated. In such embodiments, the source compound can repeatedly increase the polarization of the target compound, allowing a number of hyperpolarization signals to be obtained from the target molecule. Such repeated polarization transfers can be used for signal averaging or to perform spectroscopy in two or more dimensions. In some embodiments, the target compound can be separated in step 150 (e.g., via liquid-liquid separation or precipitation). The separated target compound can be used in step 160 for NMR spectroscopy or imaging applications.

[0050] PETS source compound preparation and polarization

[0051] As described above with respect to step 110 of step 100, the source compound can be a PETS material. As described herein, many organic molecules exhibit the phenomenon that, when excited at a specific wavelength of light or ultraviolet (UV) spectrum, electrons in the low-level singlet state S0 of the molecule are excited to a higher-level singlet electronic state S1. From this state, radiative decay can return to the singlet state, or intersystem crossing (ISC) to a triplet state can occur. These triplet states exhibit two main characteristics: firstly, they are long-lived (e.g., on the order of microseconds to seconds) and can therefore be dealt with on a reasonable timescale; and secondly, the collection of triplet states between the three spin levels is heterogeneous for many molecules, thereby generating polarized states.

[0052] Some polarized molecules suitable for inclusion in PET materials (e.g., acridine, pentacene, benzophenone, etc.) may possess one of the more than 90% of spin states introduced. Such polarized molecules may exhibit nearly uniform polarization at temperature and magnetic field, where the thermodynamic polarization of electron spin is otherwise orders of magnitude smaller. Furthermore, these polarized molecules may also possess different triplet spin states exhibiting different decay times for the singlet state, thereby generating another process through which a differential set of spin states, and therefore polarization, can be obtained.

[0053] A key aspect of these optically excited triplet states is the decay of electrons from the triplet state to the singlet ground state. Free electrons can be the primary source of nuclear relaxation at lower temperatures. Thus, when electrons in a molecule decay back to the singlet state (and therefore have no free electron spins), the molecule no longer contains paramagnetic impurities due to free electron spins that can relax the surrounding nuclear spins. Consequently, nuclear spin polarization can reach higher levels, and the material can have significantly longer relaxation times after the polarization sequence. Thus, optically excited triplet states can serve as long-term sources of polarization target compounds via SPINOE.

[0054] Polarized molecules can be incorporated into PETS materials to form source compounds in several different ways. In some embodiments, the source compound may be a crystal grown from the melt. The disclosed embodiments are not limited to any particular method for growing crystals from the melt. In some embodiments, the crystals can be grown using rapid temperature reduction, the Bridgman growth method, the Czochralski method, the cell method, another suitable crystal growth method, or any combination thereof. The polarized molecules may be included in a melt-in concentration selected to produce a suitable source compound (e.g., a source compound having desired polarization properties).

[0055] In some embodiments, the source compound may be a crystal grown using another suitable method, such as from a solution, gel, or vapor. Exemplary suitable crystal growth methods are disclosed in Penn, Benjamin G, et al., “Growth of Bulk Single Crystals of Organic Materials for Nonlinear Optical Devices: An Overview,” which is incorporated herein by reference in its entirety for all purposes. Relevant portions of this specification describe methods for molecular crystal growth and purification, including growth by physical vapor transport, growth from melts by the Bridgman-Stockbarger method, Czochralski Growth, or Kyropoulos method, and growth from solutions including slow cooling processes, solvent evaporation processes, and temperature difference processes.

[0056] In some embodiments, the source compound may be a Shpolsky matrix incorporating a suitable polarization molecule. For example, pentacene can be incorporated into n-heptane, n-nonane, n-decane, n-dodecane, n-tetradecane, and n-hexadecane Shpolsky matrices. Methods for such incorporation are disclosed by Banasiewicz, M., I. Deperasiska, and B. Kozankiewicz in "Spectroscopic Properties of Pentacene in Shpolsky Matrices," which is incorporated herein by reference in its entirety for all purposes. As described in this paper, the liquid sample can be foamed with argon to remove oxygen and gently heated to increase the solubility of the host. The liquid sample can then be rapidly frozen in liquid nitrogen and subsequently inserted into a polarizer cryostat.

[0057] In some embodiments, the source compound may be a pentacene:naphthalene crystal. As shown in Figure 2A, the pentacene dopant may be incorporated into the crystal lattice of the naphthalene crystal in two possible orientations. The presence of these defined orientations can enable hyperpolarization in relatively high amounts, up to about 10. -4Naphthalene crystals can be doped with mol / mol of pentacene. An example of such a pentacene:naphthalene crystal is shown in Figure 2B.

[0058] In some embodiments, pentacene:naphthalene crystals can be grown using the self-seeding vertical Bridgman method. A variation of Bridgman growth uses a double-walled ampoule with an inner wall that has capillaries opening towards the space between the walls. The ampoule is filled with naphthalene and pentacene and can then be moved through a steep temperature gradient, including the melting temperature of naphthalene. This temperature gradient can be achieved by a bath having two liquid phases heated to different temperatures. As the ampoule descends into the upper and warmer portion of the bath, the pentacene-naphthalene mixture dissolves into a homogeneous liquid. When the bottom of the ampoule reaches the phase separation of the heated bath, crystallization begins in the space between the ampoule walls. Here, solidification occurs with multiple nuclei, leading to a polycrystalline region in the space between the walls. By slowly moving the ampoule within that region, the number of nucleation events can be kept to a minimum, resulting in polycrystals with relatively large grains. As the ampoule is lowered further, the capillaries of the inner wall come into contact with the polycrystals. Ideally, only a single crystal orientation is formed within the capillary. This self-seeding process supports the emergence of a single crystal within the inner wall of the ampoule.

[0059] Consistent with the disclosed embodiments, the DNP can be used in step 110 of process 100 to transfer polarization from electron spin to the nuclear spin of a source atom of a source compound. The DNP can transfer electron spin to nuclear spin using electromagnetic irradiation (e.g., microwave or radio frequency irradiation) or magnetic field tuning. In some embodiments, the polarization transfer can be achieved via level avoidance crossing (LAC) or other suitable phenomena. The DNP protocol can exploit at least one of the interactions between electron spin or the underlying physical mechanism (e.g., satisfying resonance conditions such as Hartman-Hahn states, or excitation of selective transitions such as irradiation at a frequency matching the energy gap between two quantum states). The DNP protocol may differ in the configuration used to achieve these conditions. The DNP protocol may also differ in the use of microwave pulses or continuous microwave radiation.

[0060] In some embodiments, DNP can be used in conjunction with the PETS material in step 110 of process 100 to obtain a polarization source compound. In some embodiments, high nuclear polarization can be obtained with the PETS material using DNP (e.g., >10%, >20%, >30%, >40%, >50%, >60%, >70%, or >80%). However, the disclosed embodiments are not limited to the use of DNP in conjunction with the PETS compound. DNP can be used in conjunction with other compounds, and the PETS material can be polarized using other methods.

[0061] In accordance with the disclosed embodiments, preferred DNP protocols include "Hyperpolarization of Nuclear Spins in Bulk at Room Temperature" by Kenichiro Tateishi et al. (e.g., for pentacene:p-terphenyl), "High Proton Spin Polarization by DNP Using the Triplet State of Pentacene-d14" by Eichhorn, TR et al. (e.g., for pentacene:naphthalene), and "Light in Polycrystalline Samples" by Kazuyuki Takeda, K. Takekoshi, Takehiko Terao et al. (e.g., polycrystalline pentacene sample:naphthalene with random crystal orientation). This is discussed in “Dynamic Nuclear Polarization by Excited Triplet Electron Spin”. A suitable DNP method is also disclosed in Section II of “Dynamic Nuclear Polarization in High Magnetic Fields” by Maly, Thorsten, et al. In addition, sophisticated DNP sequences such as “Robust Optical Polarization of Nuclear Spin Buses Using Hamiltonian Engineering for Nitrogen-Vacancy Center Quantum Dynamics” disclosed by Schwartz, Ilai, et al. can enable fast polarization transfer. Suitable DNP methods disclosed in “Dynamic Nuclear Polarization Using Multicolor Control of Color Centers in Diamond” by Yang, Pengcheng, Martin B Plenio, and Jianming Cai, and in “Enhanced Dynamic Nuclear Polarization via a Sweeping Microwave Frequency Comb” by Ajoy, A, et al. can enable nuclear polarization transfer in nanocrystals, polycrystalline source materials, and bulk samples (e.g., using color centers in nanodiamonds). The DNP protocols and preparation techniques disclosed in these references are incorporated herein by reference in their entirety for all purposes.

[0062] In accordance with the disclosed embodiments, the DNP protocol may include a polarization sequence. Such a polarization sequence may include a polarization step and a subsequent transfer step. In the polarization step, the source compound can be exposed to a strong light pulse. The duration of the light pulse can be at least about 10 nanoseconds (ns), 20 ns, 50 ns, 100 ns, 200 ns, 500 ns, 1 microsecond (μs), 2 μs, 5 μs, 10 μs, 20 μs, 50 μs, 100 μs, or longer. The duration of the light pulse may be up to about 100 μs, 50 μs, 20 μs, 10 μs, 5 μs, 2 μs, 1 μs, 500 ns, 200 ns, 100 ns, 50 ns, 20 ns, 10 ns, or less. The duration of the light pulse can be within a range defined by any two preceding values, such as 100 ns to 10 μs. The energy of the light pulse can be at least about 0.1 millijoules (mJ), 0.2 mJ, 0.5 mJ, 1 mJ, 2 mJ, 5 mJ, 10 mJ, or more. The energy of the light pulse can be at most about 10 mJ, 5 mJ, 2 mJ, 1 mJ, 0.5 mJ, 0.2 mJ, 0.1 mJ, or less. The energy of the light pulse can be within a range defined by any two preceding values, such as between 0.1 mJ and 10 mJ, or more. The energy and duration of the light pulse can be selected to induce a triplet state of polarized molecules in the source compound in a polarized manner.

[0063] In some embodiments, electron spins can be transferred to hydrogen nucleus spins in the source compound during the transfer step using integrated solid-state effects (ISE). Other types of nuclear spins may be affected by changing the parameters of the transfer step. In some embodiments, for example, electron spins in the compound can be transferred by using different B1 microwave (MW) fields. 13The electron spin can be transferred to the nuclear spin. In some embodiments, the B1 microwave field is applied laterally to the magnetization field B0 on ​​which the compound is located. In various embodiments, the electron spin can be transferred to the nuclear spin in the transfer step using an alternative to ISE. For example, spin transfer can be performed using solid-state effects, cross-effects, or low-field thermal mixing (for very high concentrations of PETS molecules). As an additional embodiment, spin transfer can be performed using pulsed DNP methods such as electron spin lock (NOVEL) sequences or nuclear spin orientation via dress-state solid-state effects.

[0064] Figures 3A and 3B show the spin transfer that occurs during an exemplary DNP protocol that achieves spin transfer using solid-state effects. This exemplary method shifts polarization from electron spin to nuclear spin, increasing nuclear polarization while decreasing electron polarization. Figures 3A and 3B show the different electron / nuclear spin states in the source atom of the source compound as four levels, with black bars representing the population in the source compound at each level. Before the initiation of spin transfer, as shown in Figure 3A, the source compound exhibits electron spin polarization greater than nuclear spin polarization. Thus, the two lower levels are shown as larger populations than the two upper levels. Using microwave or RF irradiation, the state

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[0065] In some embodiments, the polarization of electron spins can be transferred to nuclear spins using interactions involving at least two electron spins and nuclear spins (e.g., using cross-effects and low-field thermal mixed DNP protocols). Such interactions may depend on several allowable transitions between electron spins and nuclear spins, including homogeneously or heterogeneously extended electron paramagnetic resonance (EPR) lines. If two or more electron spins and nuclear spins flip simultaneously, energy can be saved in the broadening of the EPR line.

[0066] In various embodiments, electron spins can be transferred to nuclear spins using a variation of the integrated solid-state effect (ISE), in which a "comb" of multi-frequency microwaves sweeps several microwave frequencies in parallel. Such techniques may be particularly suitable for transferring polarization in nanocrystals, polycrystalline source materials, or bulk samples.

[0067] In some embodiments, the triplet lifetime can be extended and the polarization of the compound increased by preparing the triplet state prior to the DNP protocol. This can be done to different spin states with longer relaxation times via collective transfer between excited state sublevels (e.g., by resonating with the transition frequency and a 180-degree pulse). Further details on preparing the triplet state prior to the DNP protocol are provided by Eichhorn and Tim Rolf in "Dynamic Nuclear Polarization with Photoexcitation-Generated Paramagnetic Centers," which is incorporated herein by reference in whole for all purposes.

[0068] In some embodiments, polarization transfer from electron spin to nuclear spin can be achieved without the use of microwaves by aligning the external magnetic field to the level avoidance crossing (LAC) of the electron spin. Further details of the polarization transfer are provided in "Dynamic Nuclear Polarization with Photoexcitation-Generated Paramagnetic Centers" by Eichhorn and Tim Rolf, which is incorporated herein by reference in whole for all purposes.

[0069] In some embodiments, the external magnetic field can be selected according to the desired application. For example, for polarization of a target compound in hyperpolarization MRI applications, or for NMR spectroscopy with an external spectrometer, the magnetic field may be less than 5 Tesla (T). In some embodiments, an external magnetic field with a low magnetic flux density (e.g., less than 2T, less than 1T, less than 0.5T, less than 0.2T, less than 0.1T, less than 0.05T, less than 0.02T, less than 0.01T, or less) may be used. Advantageously, such magnetic flux densities can be achieved using permanent magnets or electromagnets without the need for cryogenic superconducting materials. Furthermore, such magnetic fields can be measured using conventional methods (e.g., using a Gaussmeter). Thus, the equipment requirements (and therefore costs) for such methods can be reduced compared to other methods for polarizing source compounds.

[0070] In accordance with the disclosed embodiments, the induced relaxation of nuclear spins in the source compound can be reduced by actively separating the nuclear spins from possible electron spins on the surface of the source compound (e.g., electron spins arising from contaminants on the surface of the source compound). Such separation can be achieved by using microwave or radio frequency irradiation to drive electron spins at their Larmor frequency or energy transition frequency (e.g., strong hyperfine resolution or in the presence of spin-1 electron spins), or under electron-nuclear zero-quantum or double quantum resonance conditions.

[0071] In some embodiments (e.g., NMR spectroscopy applications), it may be advantageous to perform the polarization transfer from optically polarizable electron spins to nuclear spins in situ (e.g., in an NMR apparatus). In such embodiments, steps 110, 130, and 150 of process 100 can be performed in situ. Thus, using the same magnet, the source compound can be obtained (e.g., through the polarization transfer of the source compound to nuclear spins), and NMR spectroscopy can be performed. For polycrystalline, single-crystal, or single-crystal compounds in the form of micro or nanoparticles, low magnetic fields (e.g., less than 1000 millitesla (mT), 500 mT, 200 mT, 100 mT, 50 mT, 20 mT, 10 mT, 5 mT, 2 mT, 1 mT, or another suitable field) can allow for addressing many of the orientations of PETS electron spins.

[0072] Figure 4 shows exemplary sequences of optical and magnetic interactions (e.g., polarization sequences) suitable for inducing polarization in the source compound. In this example, the source compound is a pentacene-d14:naphthalene-h8 crystalline sample. The sample is 100–300 mm. 3The size can be such that... In some embodiments, the sample can be cooled to below 100 Kelvin (K) while being placed in a magnetic field of at least 1 kilogauss (kG), 2 kG, 5 kG, 10 kG, 20 kG, 50 kG, or 100 kG, oriented along the long axis of the pentacene molecule. The sequence can include multiple repetitions of optical pulses followed by a magnetic field sweep. In each repetition, one or more optical pulses (e.g., laser pulses) can excite the pentacene molecule to a short-lived triplet state. This can be achieved by introducing an optical pulse (e.g., optical pulse 410) to a higher singlet state, each optical pulse having an optical pulse amplitude 411 and an optical pulse duration 413, where a slower transition from singlet to triplet state is performed. In some embodiments, the optical pulse amplitude has pulse energies of at least about 1 mJ, 2 mJ, 5 mJ, 10 mJ, 20 mJ, 50 mJ, 100 mJ, 200 mJ, 500 mJ, 1000 mJ or more, and at most about 1000 mJ, 500 mJ, 200 mJ, 100 mJ, 50 mJ, 20 mJ, 10 mJ, 5 mJ, 2 mJ, 1 mJ or less, or within the range defined by any two of the preceding values. In some embodiments, the pulse duration is at least about 10 ns, 20 ns, 50 ns, 100 ns, 200 ns, 500 ns, 1 μs, 2 μs, 5 μs, 10 μs, 20 μs, 50 μs, 100 μs, or greater, and at most about 100 μs, 50 μs, 20 μs, 10 μs, 5 μs, 2 μs, 1 μs, 500 ns, 200 ns, 100 ns, 50 ns, 20 ns, 10 ns, or less, or within the range defined by any two of the preceding values. After a delay 415, the previously ramped-up magnetic field 420 sweeps the electron spin resonance linewidth (e.g., magnetic field sweep amplitude 421) of all triplets, while irradiating with a microwave pulse 430 having a microwave pulse duration 431 to facilitate Hartman-Hahn matching of all spin packets in the line.In some embodiments, the delay is at least about 10 ns, 20 ns, 50 ns, 100 ns, 200 ns, 500 ns, 1000 ns or more, and at most about 1000 ns, 500 ns, 200 ns, 100 ns, 50 ns, 20 ns, 10 ns or less, or within a range defined by any two of the preceding values. After repeating this sequence N times, the proton signal can be read out via the free induction decay 441 of a resonant radio frequency pulse 443 having a non-destructive small tip angular amplitude. As shown in Figure 5, this sequence of optical and magnetic interactions can increase the polarization in the sample by more than 50%.

[0073] Figure 5 shows the NMR signals read from the compound before and after repeating the polarization sequence as shown in Figure 4. In Figure 5, the X-axis is the frequency of the NMR signal, and the illustrated y-axis is the signal intensity. The first trace shows the NMR signal from the compound at thermal equilibrium (multiplied by 16,000). The second trace shows the NMR signal read from the compound with 4% polarization (multiplied by 4). The third trace shows the NMR signal read from the compound with 50% polarization. The increase in polarization is a result of repeating the polarization sequence shown in Figure 4.

[0074] Source compound generation and polarization using spin order

[0075] In accordance with the disclosed embodiments, the electron spin order is transferred to the nuclear spin of the source atom of the source compound in step 110 of process 100, thereby polarizing the source compound. Such methods (e.g., PHIP, PHIP-SAH, SABRE, etc.) are described herein in relation to parahydrogen for convenience of this disclosure, but are similarly applicable to orthodeterium and paratritium.

[0076] Figure 6 shows a process 600 for generating and isolating a polarization source compound using PHIP, PHIP-SAH, or SABRE polarization. In some embodiments, such generation and isolation can be carried out as part of step 110 of process 100. In various embodiments, the polarization source compound may optionally be separated from the hydrogenation catalyst or reaction byproduct (e.g., as in step 120 of process 100) and / or transported from where it was generated to another location for use (e.g., as in step 130 of process 100). The polarization source compound can be combined with a target compound (e.g., as in step 140 of process 100).

[0077] In step 610 of process 600, parahydrogen can be generated and optionally transported. Parahydrogen is a form of molecular hydrogen. In this form of molecular hydrogen, the two proton spins are in a singlet state. In some embodiments, parahydrogen can be formed in gaseous or liquid form. For example, in some embodiments, parahydrogen can be generated in gaseous form by flowing hydrogen gas through a chamber with a catalyst. In some embodiments, the hydrogen gas can be subjected to low temperatures such as up to about 100K, 90K, 80K, 70K, 60K, 50K, 40K, 30K, 20K, 10K, 9K, 8K, 7K, 6K, 5K, 4K, 3K, or lower. In some embodiments, the catalyst may be iron oxide. In some embodiments, the hydrogen gas contains both parahydrogen and orthohydrogen, and the low temperature brings the hydrogen gas to thermodynamic equilibrium in the chamber, during which a population of parahydrogen grows.

[0078] In some embodiments, the gas may be generated at a first location and then transported to a second location for use. In some embodiments, the first location may be a chamber, which may be part of a container, bottle, holder, or other area capable of holding the gas or liquid. Such a chamber may be maintained at appropriate pressure, temperature, or a combination thereof. In some embodiments, the first location may refer to a physical location such as a room, laboratory, specific warehouse, hospital, or other place where parahydrogen may be generated.

[0079] In some embodiments, the generated parahydrogen may be transported in a chamber different from the chamber in which it was generated. The chamber transporting the parahydrogen gas may be maintained at an appropriate pressure or temperature, and this may be transported by vehicle or by person. In some embodiments, the transport of parahydrogen may involve moving the parahydrogen from one container to a different container. In some embodiments, the transport of parahydrogen may involve moving the parahydrogen within the same location, such as from one part of a room to another part of a room. In some embodiments, the transport of parahydrogen may involve moving the parahydrogen from one room in a building to another room in the same building or to a nearby building. In some embodiments, the transport of parahydrogen may involve moving the parahydrogen to a different part of the same city or to a different location in a different city. For example, the transport of parahydrogen may involve bringing the parahydrogen near a polarizer or NMR / MRI equipment. In other embodiments, in some embodiments, the transport of parahydrogen may involve packaging or shipping the parahydrogen into appropriate containers, as shown in Figure 10.

[0080] In step 620 of process 600, the source compound can be produced using parahydrogen. In some embodiments, the solution may be formed by combining a precursor molecule (or the source compound in the SABRE embodiment), a solvent, and a catalyst for hydrogenation (e.g., a hydrogenation catalyst). The solution may be formed in a mixing mechanism, which may be configured to introduce, hold, or promote a blend, mixture, or solution of two or more materials. In some embodiments, the mixing mechanism may be located in a chamber, and mixing may occur within the chamber. In some embodiments, the solution may be mixed at a location away from the chamber. In some embodiments, the volume of the solution may be at least 10 microliters (μL), 20 μL, 50 μL, 100 μL, 200 μL, 500 μL, 1000 μL, or more. The concentration of the precursor molecule may be at least 10 mmol (mM), 20 mM, 50 mM, 100 mM, 200 mM, 500 mM, 1 M, 2 M, 5 M, or more. In some embodiments, the mixing mechanism may be a gas-liquid exchange mechanism. For example, the gas-liquid exchange mechanism may be a bubbler or a diffusion system. In some embodiments, the mixing mechanism may include a membrane adapted to allow the diffusion of molecular hydrogen. In some embodiments, the mixture may be formed when parahydrogen gas is bubbled into the mixture.

[0081] In some embodiments, the hydrogenation catalyst may be any molecule, complex, or particle system that catalyzes the hydrogenation reaction (for PHIP or PHIP-SAH processes) or catalyzes the polarized transfer from para-hydrogen (for SABRE processes). In some embodiments, homogeneous metal catalysts, such as rhodium or ruthenium complexes, may be used to prepare and activate the precursor molecules and para-hydrogen. In embodiments utilizing SABRE, iridium complexes may be used as homogeneous catalysts. In some embodiments, heterogeneous metal catalysts attached to nanoparticles may be used to prepare and activate the precursor molecules and para-hydrogen.

[0082] In some embodiments, the precursor molecule may have an unsaturated bond that can be hydrogenated by para-hydrogen gas. In the PHIP embodiment, the hydrogenation precursor molecule may be the source compound. In the PHIP-SAH embodiment, the hydrogenation precursor molecule may be a para-hydrogenation precursor of the source compound. Preferably, after bubbling the para-hydrogen gas, more than 50%, more than 80%, or almost all of the molecule may be hydrogenated. In some embodiments, the hydrogenation may produce a low-energy state on the two hydrogen spins of the hydrogenation molecule of the order Iz1Iz2, between |↑>|↓> and |↓>|↑>, or singlet spin order. In such embodiments, the hydrogenation precursor molecule can act as the source compound in process 100.

[0083] In some embodiments, polarization occurs via non-hydrogenated PHIP, also known as signal amplification by reversible exchange (SABRE). In such embodiments, the hydrogenation and polarization transfer steps described may occur by polarization transfer from parahydrogen to the source compound, while both are bonded to the catalyst. The source compound, e.g., pyridine, can be reversibly bonded to the catalyst. Bubble parahydrogen gas may also be reversibly bonded to the catalyst, allowing spin order or polarization transfer to the source compound. Preferably, at the end of the process, the mean polarization (or spin order) of the source atoms of the source compound is at least 1%, 2%, 5%, 10%, 20%, 50%, or more.

[0084] In accordance with the disclosed embodiments, the generation of the source compound in step 620 may involve a polarization transfer from electron spin to nuclear spin. Such a polarization transfer can be carried out in a magnetic field, and electromagnetic irradiation can be used. In some embodiments, the polarization transfer may involve the application of at least one RF waveform to the parahydrogenation precursor molecule.

[0085] In some embodiments, at least one RF waveform may be generated by a waveform generator. The waveform generator may further include one or more computing units, processors, controllers, associated memory, PCs, computer services, or any device capable of carrying out computational processing using inputs and generating outputs.

[0086] At least one RF waveform can be applied to the source compound using an RF coil. The RF coil can be positioned around the chamber where parahydrogenation is performed, or around another polarization-moving chamber. The RF coil may have one or more channels. These channels can be pathways for applying the RF signal to the source compound. At least one channel may be provided for each different type of nuclear spin species. In some embodiments, another nuclear spin species (e.g., 3 H, 13 C, 19 F, 31 For P, or other suitable species, at least one proton ( 1 H) Channels and at least one additional channel (e.g., an additional channel) may exist. In some embodiments, 1 The RF waveform applied to the H channel and each of the additional channels may be different. In some embodiments, at least one proton channel is hydrogenated 1 It is used to selectively address one of the H spins. In some embodiments, 1 H Channel and additional Channels (for example, 13 The RF waveform on the C channel is configured to apply a polarization shift sequence such as PH-INEPT, Goldman's sequence, S2M, S2hM, or ESOTERIC.

[0087] In some embodiments, the polarization shift is at least 1 microtesla (μT), 2 μT, 5 μT, 10 μT, 20 μT, 50 μT, 100 μT, 200 μT, 500 μT, 1 mT, 2 mT, 5 mT, 10 mT, 20 mT, 50 mT, 100 mT, 200 mT, 500 mT, 1000 mT, 2000 mT, 5000 mT, or more, up to approximately 5000 mT, 2000 mT, 10 The process may be carried out using a magnetic field with an intensity of 00mT, 500mT, 200mT, 100mT, 50mT, 20mT, 10mT, 5mT, 2mT, 1mT, 500μT, 200μT, 100μT, 50μT, 20μT, 10μT, 5μT, 2μT, 1μT, or less, or using a magnetic field intensity within a range defined by any two preceding values, such as 10μT to 2000mT. The magnetic field may be generated by an electromagnet or a permanent magnet. The magnetic field may be applied to the sample in pulses or continuously. The magnetic field may be static or vary over time. The applied magnetic field may be non-uniform. The non-uniformity of the magnetic field may be characterized in parts per million (ppm) over the diameter of the spherical volume. In some embodiments, the applied magnetic field may have heterogeneity of at least about 1 ppm, 2 ppm, 5 ppm, 10 ppm, 20 ppm, 50 ppm, 100 ppm, or more, and at most about 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, or less, or within a range defined by any two of the preceding values.

[0088] In such a magnetic field, at least one RF waveform can be applied to the source compound to shift the polarization between the parahydrogen and the nuclear spin of the source compound (e.g., the nuclear spin of the source atom). The at least one RF waveform may include a sequence of elements. An element in the sequence of elements may be an RF pulse. For example, an element in the sequence of elements may be an excitation pulse. An excitation pulse may be an RF pulse that modifies the energy level or spin phase of the material (e.g., to increase the detectable polarization signal in the source compound), such as a 90-degree (or approximately 90-degree pulse). An element in the sequence of elements may be a separation sequence. In some embodiments, the separation sequence may include one or more pulses, or a group of one or more RF pulses (e.g., described herein as a block of RF pulses or pulse block).

[0089] In other embodiments, polarization shift can be carried out using a magnetic field of less than 0.1 G. In such a magnetic field, polarization is performed with respect to the proton spin, 13 C, 15 N, 19 F, or 31 P can be moved by utilizing level avoidance crossings (LACs) with other target spin species, including P. The magnetic field can be tuned to the exact field of the LAC, for example, to sweep the LAC state, or it can be varied over time.

[0090] In various embodiments utilizing SABRE, spin order shifts can occur in a magnetic field that allows for the natural movement between para-hydrogen atoms and selected molecules, or, for example, by signal amplification through reversible exchange in a shield, enabling alignment shifts to heteronuclei (SABRE-SHEATH). The spin order of para-hydrogen atoms can be shifted to a polarization on the molecule or to a spin order on the molecule.

[0091] In various embodiments, SABRE, PHIP, or PHIP-SAH are used 1The polarization of the H molecule can be transferred to another molecule by chemical exchange, for example, using the SABRE-RELAY method. Such other molecules can form the source compounds described herein with respect to Figure 1.

[0092] In various embodiments, the spin order on a proton spin is not transferred to other spin species, but instead converted to polarization on the proton spin. This can be done, for example, by singlet to a magnetization conversion pulse, e.g., by S2M, or by using spin-lock induced crossover (iSLIC) similar to the method used in singlet NMR. In another embodiment, the spin order is converted to polarization by a PHIP-echo sequence in a high magnetic field.

[0093] In some embodiments, the spin order on protons can be converted to polarization via the application of a pulse sequence. In some embodiments, the spin order on protons of a molecule having a chemical shift difference between hydrogenation spins can be converted to polarization by first hydrogenating the molecule in a low magnetic field and then moving the molecule in a high magnetic field, i.e., by using adiabatic longitudinal transport after dissociation has generated a net alignment (ALTADENA) sequence. The spin order of the two protons due to hydrogenation can then be converted to the ALTADENA order, i.e., most spins adiabatically move from the singlet state to the |↑>|↓> state (or alternatively, most spins move to the |↓>|↑> state). To convert this spin order to polarization, since the spins are separated by chemical shift, a selective pulse can be applied to reverse only one of the two spins. In another specific embodiment, molecules having hydrogenated protons with the same chemical shift are hydrogenated in a high or low magnetic field, and the singlet order is converted to magnetization using a pulse sequence (e.g., S2M, PulsePol) or RF irradiation (e.g., iSLIC).

[0094] In some embodiments, the application of a selective pulse or pulse sequence can induce substantial radiation attenuation using a high concentration of the source compound and the high electron or nuclear spin polarization of the source compound. In some embodiments, the radiation attenuation effect during the transition of spin order to polarization occurs during the application of a selective pulse or pulse sequence of spins 1 The effective quality factor Q of the polarizer (e.g., NMR spectrometer) in H resonance can be reduced to less than 20, 10, 5, 1, 0.5, 0.2, or 0.1. In some embodiments, this is achieved by reducing the probe circuit (e.g., the NMR probe circuit of an NMR spectrometer) 1 This is done by a controllable readjustment of the resonance from the H resonance to the demodulated value, thereby 1 This reduces the amplification factor of the polarizer RF coil (e.g., the NMR coil in an NMR spectrometer) at H resonance. In some embodiments, the quality factor Q of the probe circuit can be reduced by neutralizing the voltage in the receiver coil induced by a strong NMR signal via an electron feedback circuit.

[0095] In some embodiments, the shift in spin order to magnetization can be achieved using radiation decay. For example, non-equivalent 1 In the ALTADENA experiment with H spins, for example, if there is a sufficiently large splitting due to chemical shift, the application of an excitation pulse (even a pulse with a small flip angle) induces radiation decay, and both 1 This can result in a net magnetization of the H spin. In some embodiments, radiation decay can be induced without an excitation pulse (e.g., by statistical fluctuations).

[0096] The disclosed embodiments describe a spin order on the source compound prior to the combination of the source compound and the target compound. 1 The embodiment is not limited to the one in which the nuclear spin is converted on the H source atom. In some embodiments, the source compound may be combined with a target compound, and then the spin order is 1This can be converted into nuclear spin polarization of the H source atom. This nuclear spin polarization can then be transferred to the target atom using NOE as described herein.

[0097] Source compound precipitation

[0098] As described above with respect to step 120 of process 100, the polarization source compound can be isolated at least partially according to the disclosed embodiments. In some embodiments, the polarization source compound may be induced to solidify and precipitate, thereby producing a polarized or spin-order-containing crystal. As used herein, spin order generally refers to an excess population in certain electronic or nuclear states (e.g., spin-1 / 2 electron or specific spin eigenstates of the nucleus, or singlet or triplet states of a spin-1 system such as a PETS system). In some embodiments, such precipitation may be induced by reducing the solubility of the polarized or spin-order-containing source compound. Solubility of the source compound in solution can be reduced by modifying the solvent (or mixture or solvent) in which the source compound is dissolved. Solidification and precipitation of the polarization source compound can enable efficient mechanical separation of the source compound.

[0099] Solid hyperpolarization source compound particles can be used in multiple applications. Hyperpolarization source compound microparticles configured to be insoluble in aqueous solutions can be used as NMR / MRI tracers. Hyperpolarization source compound precipitates can also provide a source for transferring polarization to a target compound, as described herein.

[0100] As a non-limiting example, fumaric acid polarized by PHIP can precipitate in aqueous solution. Disodium fumarate and fumaric acid exhibit a large difference in solubility in aqueous solution (e.g., 1.42 M vs. 60 mM, respectively). Disodium fumarate was polarized and dissolved in water at a concentration of 1.2 M. Upon addition of acid (HCl), the resulting fumaric acid rapidly precipitated, forming microcrystals.

[0101] In accordance with the disclosed embodiments, organic solvents can be used for precipitation of the polarization source compound. In some embodiments, parahydrogen-induced polarization occurs in organic solvents. Parahydrogens are typically more soluble in organic solvents than in aqueous solvents, and therefore hydrogenation can occur more efficiently in organic solvents.

[0102] In various embodiments, polarization transfer can be carried out in aqueous solution by hydrogenation and, optionally, by aqueous solution. The aqueous solution can be mixed with a miscible organic solvent to induce precipitation. In organic solvents, carboxylic acids are typically well soluble to PHIP concentrations. For example, fumaric acid is soluble in acetone at about 220 mM at room temperature. However, salts of these acids are usually very insoluble (e.g., 1 mM, 0.1 mM, 0.01 mM, or less). Thus, precipitates in organic solvents can be used at source compound concentrations suitable for achieving high polarization using PHIP or SABRE.

[0103] In accordance with the disclosed embodiments, solidification or precipitation can separate the polarized source compound (or polarized molecule) from the hydrogenation catalyst used to hydrogenate the precursor molecule (or, in the SABRE implementation, to facilitate polarization transfer). As described herein, the polarized source compound (or polarized molecule) can be solidified or precipitated into crystals, amorphous solid particles, or polycrystalline materials. After solidification or precipitation, the source compound (or polarized molecule) can be separated from the solution containing the hydrogenation catalyst (e.g., through filtration of the precipitate and washing steps with a solvent that does not dissolve the source compound). In some embodiments, a large portion of the hydrogenation catalyst can be separated from the polarized molecules in the sample by solidification. For example, more than 99% by weight of the hydrogenation catalyst (or 99.99%, 99.999%, or more) can be separated from the source compound (or polarized molecule).

[0104] In some embodiments, forming a polarization source compound may involve cleaving the side arms of a polarization molecule (e.g., as found in PHIP-SAH). The side arms of the polarization molecule can be cleaved by hydrolysis. In some embodiments, the cleaving of the side arms can be carried out in a solvent in which the polarization molecule is more soluble than the polarization source compound (e.g., the polarization molecule without side arms). Thus, the cleaving of the side arms may cause precipitation of the polarization source compound. In some embodiments, the solvent may be an organic solvent, and the cleaving can be carried out under basic conditions. After cleaving, the less soluble polarization source compound can undergo rapid solidification while maintaining its polarization. In various embodiments, hydrogenation, polarization transfer, and side arm cleaving can be carried out in the same solvent. In some embodiments, hydrogenation and polarization transfer can be carried out in a first solution, and then a second solution can be added to the first solution before cleaving the side arms. For example, a basic solution (e.g., an aqueous solution of sodium hydroxide) can be added to cleave the side arms.

[0105] In some of these embodiments, precipitation of the polarization precursor molecule can occur before cleavage, resulting in the polarized precursor molecule retaining its side arms while solidifying (e.g., still in ester form). Such embodiments may be used, for example, when the polarization precursor molecule (e.g., having side arms) is more stable than the polarization source compound (e.g., not having side arms). Such precipitation can be carried out by modifying the pH of the solvent to reduce the solubility of the polarization molecule, or by mixing it in a solution or other compound that reduces the solubility of the polarization molecule, or by any combination thereof. In these embodiments, cleavage may be carried out after redissolution of the polarization molecule or polarization source compound in another solvent (e.g., a more biocompatible solvent).

[0106] In some embodiments, precipitation may occur after the cleavage of side arms from the polarization molecules (thereby forming the polarization source compound). Such precipitation can be carried out by modifying the pH of the solvent so as to reduce the solubility of the polarization source compound, or by mixing it in a solution or other compound that reduces the solubility of the polarization source compound, or by any combination thereof.

[0107] In some embodiments, the conversion to spin-order polarization may occur before the polarization molecule or polarization source compound is solidified and precipitated. In other embodiments, this conversion occurs after the redissolution of the solidified source compound with the target compound.

[0108] Source compound transport

[0109] As described herein with respect to Figure 1, the polarized compound (e.g., source compound or target compound) can be transported from a base location to a destination location (e.g., in step 130 of process 100). Consistent with the disclosed embodiments, the compound may have a long nuclear relaxation time. Thus, the polarized compound can be stored and transported without undergoing unacceptable depolarization (e.g., depolarization greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%). Since the polarization of the source compound or target compound can be carried out independently of any further processing of the source compound or target compound, polarization and further processing can be carried out by separate apparatus optimized for different purposes. Furthermore, the production of polarized compounds for a sufficient number of end users can be carried out in a central facility, enabling greater efficiency and economies of scale.

[0110] In some embodiments, the polarized source compound may be transported to a destination location and then processed into microparticles or nanoparticles before transferring its polarization from the polarized source compound to the target compound. In some embodiments, the polarized source compound may be processed into microparticles or nanoparticles before being transported to a destination location. In various embodiments, the polarized target compound may be transported to a destination location and then dissolved in a solvent suitable for use in the intended NMR spectroscopy or MRI application.

[0111] The transport device may be configured to transport a polarization source compound or a polarized target compound. The transport device may be arranged and configured to transport one or more samples of a polarization source compound or a polarized target compound (or multiple polarization source compounds or target compounds) simultaneously. The transport device may be configured to maintain one or more samples in a magnetic field of at least 1 Gauss (G), 2G, 5G, 10G, 20G, 50G, 100G, 200G, 500G, or 1000G.

[0112] Permanent magnets or electromagnets included in the transport device can provide a magnetic field. Furthermore, in some embodiments, the permanent magnets or electromagnets can be 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 less than 270K, less than 80K, or less than 4K. In some embodiments, the transport device may be configured to maintain the sample at the approximate temperature of dry ice, liquid nitrogen, or liquid helium. The transport device may include insulation between the cooling system and the outside of the transport device to minimize heat exchange with the external environment. In some embodiments, the cooling system may be configured to maintain the sample temperature using a cold gas flow. In various embodiments, the cooling system may be configured to maintain the sample temperature using a solid or liquid coolant such as dry ice, liquid nitrogen, or liquid helium. In various embodiments, the transport device may include a dewar to provide cooling for the sample. To distribute polarized samples over long distances, it is preferable that the containers be transported by standard transport vehicles such as airplanes, trains, trucks, automobiles, and ships.

[0113] combination of source compound and target compound

[0114] As described herein with respect to Figure 1, the polarization source compound can be combined with the target compound (for example, as described in step 140 of process 100). Such combinations are not limited to any particular method of polarizing the source compound. In various embodiments, the source compound is polarized using PHIP, PHIP-SAH, or SABRE, using DNP (for example, dissolved DNP as described herein), source 1 H, 19 F, or 31 It can be polarized using P atoms, PETS, or another suitable method.

[0115] In accordance with the disclosed embodiments, the polarization source compound can be combined with the target compound in solution. In some embodiments, the solution can be produced by dissolving the polarization source compound in a solution. This solution may already contain the target compound. Alternatively, the target compound can be added to this solution (e.g., in solid form, dissolved in another solution). In some embodiments, the source compound (or target compound) may be treated into microparticles before dissolution (e.g., pulverized, ground, cut, etc.) to increase the dissolution rate. In some embodiments, the source compound may be polarized in a first solution, and the target compound can be added to this first solution (e.g., in solid form, dissolved in another solution, etc.).

[0116] In accordance with the disclosed embodiments, the source compound may be soluble in the solvent and may be selected to retain polarization after dissolution. For example, a source compound such as disodium fumarate, when dissolved at room temperature or at other temperatures in the range of -150°C to -200°C, has a long relaxation time, allowing dissolution while maintaining the polarization of the source atom. Possible solvents may depend on the selected source compound. In a non-limiting example, if the polarization source compound is disodium fumarate or pyridinium sodium crystals, candidate solvents may include aqueous solutions, glycerol, dimethyl sulfoxide (DMSO), and alcohols. In another non-limiting example, if the polarization source compound is pentacene:naphthalene, pentacene:p-terphenyl, or 3-phenylpropanoate crystals, potential solvents may include organic solvents such as toluene, ether, ethanol, carboxylic acids, chloroform, hexane, acetic acid, butyric acid, DMSO, and mixtures thereof or derivatives thereof. In some embodiments, the solvent is deuterated to at least 50%, 60%, 70%, 80%, 90%, or more.

[0117] In some embodiments, the dissolution and mixing of the source and target compounds are carried out by an automated system. In some embodiments, the automated polarization transfer system includes a transport magnet to maintain the polarization of the source compound. The source compound is then loaded into a container for grinding and dissolution. The transfer system includes a mechanism for mechanically breaking down the source compound into smaller particles for faster dissolution, for example, by a grinding head, pestle, or ultrasonic probe. In the dissolution container, a solution that may contain the target compound is mixed with the ground source compound for rapid dissolution. A separator, such as a frit, is used to separate the dissolved source compound from the solid particles, and the solution is pumped into an NMR spectrometer.

[0118] In some embodiments, the concentration of the source compound in solution can be selected for efficient polarization transfer to the target compound. This concentration can be at least 100 mM, 200 mM, 500 mM, 1 M, 1.5 M, 2 M, 3 M, 4 M, 5 M, 6 M, or higher. Such high concentrations can enable efficient polarization transfer from at least one source atom of the source compound to at least one target atom of the target compound. As can be understood, the concentration of the source compound in solution during polarization transfer to the target compound (e.g., step 140 of process 100) may differ from the concentration of the source compound during the initial polarization of the source compound (e.g., in step 110 of process 100). In some embodiments, high source compound concentrations can inhibit initial polarization, so the source compound concentration during polarization transition may be much higher than the source compound concentration during initial polarization (e.g., 250 mM or less, 200 mM or less, 150 mM or less, 100 mM or less, 50 mM or less, 20 mM or less, or 10 mM or less).

[0119] In some embodiments, the concentration of the source compound may be greater than or equal to the concentration of the target compound. For example, the concentration ratio of at least one source atom to at least one target atom may be at least 1:1, 2:1, 5:1, 10:1, 20:1, 50:1, 100:1, 200:1, 500:1, 1000:1 or greater, and at most 1000:1, 500:1, 200:1, 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1 or less, or within the range defined by any two of the preceding values. When a source compound is polarized using the PHIP or SABRE process, the concentration of any hydrogenation catalyst (or reaction byproduct such as a cleavage arm) in the solution of the source and target compounds may be within the range defined by 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, or less, greater than 1 nM, 2 nM, 5 nM, 10 nM, 20 nM, 50 nM, 100 nM, 200 nM, 500 nM, 1 μM, or any two of the preceding values. Such reductions in concentration can be achieved by separating the polarized source compound from the hydrogenation catalyst (or reaction byproduct) (e.g., using a filter, liquid-liquid separation, or other suitable method).

[0120] Nuclear polarization shift

[0121] As described herein with respect to Figure 1, nuclear spin polarization can be transferred from the polarized source atoms of the source compound to the target atoms of the target compound (for example, as described with respect to step 140 of process 100). In accordance with the disclosed embodiments, nuclear spin polarization may be transferred by cross-relaxation (for example, spin-polarization-induced nuclear Overhauser effect, or SPINOE).

[0122] In accordance with the disclosed embodiments, the source compound may be selected to improve polarization transfer. In some embodiments, the polarized source atom may be selected to have a high gyromagnetic ratio, thereby inducing a high cross-relaxation rate for the target atom. In some embodiments, the ratio of the cross-relaxation of at least one nuclear spin of the target compound induced by the source molecule to the total relaxation of the same nuclear spin is at least 0.001, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.3, 0.5, or higher. In some embodiments, the polarization of at least one nuclear spin on the target compound after cross-relaxation is at least 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 5%, 10%, or higher.

[0123] In some embodiments, the source compound is modified, for example, by selective deuteration of a portion of the source compound, or by slow deuteration. 1 By selecting molecules with H spin, it is possible to choose those that have low intramolecular relaxation relative to the polarized source atom.

[0124] In some embodiments, the source compound can be selected such that polarized source atoms protrude from the source compound and are therefore well exposed to the surrounding environment. For example, polarized source atoms may be located on a portion of the source molecule that is well exposed to the surrounding environment, such as at or near the end of a side chain or arm of the source molecule. Such configurations can increase cross-relaxation with the target atom.

[0125] In some embodiments, the cross-relaxation rate can be increased by the choice of solvent in which the source and target compounds are combined, the temperature of the solvent, the magnetic field that generates the NOE, and / or the viscosity of the solvent.

[0126] In some embodiments, the source compound may be selected to have a longer relaxation time compared to the time required to transfer the intended amount of polarization to the target compound (e.g., to achieve the polarization of the target compound described herein). The transfer time may depend on factors including the diffusion rate, the concentration of the source molecule, the concentration of the target molecule, and the cross-relaxation rate. In some embodiments, the relaxation time of the source compound may be at least 10 seconds, 20 seconds, 30 seconds, 50 seconds, 100 seconds, or longer.

[0127] In some embodiments, RF irradiation (e.g., a rotating-frame Overhauser-enhanced spectroscopy (ROESY) NMR pulse sequence) may be provided to carry out polarization shift.

[0128] In some embodiments, a first magnetic field may be applied during polarization transfer, and a second, different magnetic field may be applied during NMR spectroscopy. In some embodiments, the first magnetic field may be selected to achieve high NOE polarization between the source compound and the target compound. The different magnetic fields can be implemented using a magnetic field cycle or physical transport of the solution from the first to the second magnetic field.

[0129] Intermolecular NOE in liquids can be understood as the transfer of magnetization between nuclear spins on adjacent molecules, induced by the stochastic regulation of dipole-dipole coupling via their relative motion. Intramolecular NOE enhancement is commonly measured by NMR analysis, while smaller intermolecular enhancements are sensitive to mean molecular distance and have applications in the study of intermolecular interactions. 129 Similar transfer mechanisms for hyperpolarized systems have been observed in solutions containing Xe and a source polarized via dissolved DNP, as well as PHIP. However, 129 Previous attempts at polarization transfer via SPINOE from sources polarized via Xe, soluble DNP, and PHIP have typically resulted in only slight enhancement of the target compound signal.

[0130] Magnetization transfer from source spin S to target spin I is performed by an auto-relaxation rate

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[0131]

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[0132] It should be noted that the magnetization transfer curve follows the accumulation of an initial straight line in the opposite direction of the magnetization of the hyperpolarized source. While fitting only equation (1) does not allow for independent determination of the cross-relaxation rate and source polarization, both parameters can be decomposed using standard (thermal polarization) measurements of the NOE. In such experiments, the source spin can be saturated by continuous RF irradiation, resulting in a steady-state enhancement of the target spin given by equation (2).

[0133]

number

[0134] A separate measurement T1 can then clearly determine σ.

[0135] In accordance with the disclosed embodiments, NOE can be demonstrated in a solution containing high concentrations (e.g., 10% v / v, 20% v / v, 50% v / v, or similar) of naphthalene-h8 as a source compound in CDCl3. Such solutions may further contain low concentrations of acetone, 1,1,2,2-tetrachloroethane (TCE), tetrahydrofuran (THF), toluene, and / or acetone as target compounds for spin polarization transfer. Since both naphthalene and the target compounds have T1 relaxation times exceeding 10 seconds, the polarization accumulation time becomes long enough to be easily monitored by small flip angle experiments. Acetone and TCE can be selected as target compounds because acetone has a shorter T1 relaxation time of 13.5 seconds than the source relaxation time, while TCE has a longer T1 relaxation time of 35.6 seconds.

[0136] For thermally polarized samples, the cross-relaxation rate σ is ρ1 and

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[0137] Figures 9A (pentacene:napasalen and acetone) and 10A (pentacene:napasalen and TCE) show polarization accumulation and decay at 1.45 T when the pentacene:naphthalene source compound is optically polarized before dissolving in a target solution containing 20% ​​v / v pentacene:naphthalene in CDCl3 and either 25 mM acetone or 100 mM TCE. The acetone concentration differs between the thermal and hyperpolarization experiments, but this is unlikely to affect the estimated cross-relaxation rate because the source concentration effectively determines the average intermolecular separation in solution, since the pentacene:naphthalene concentration is much higher than either target compound concentration. The polarization transfer curves generally agree with the characteristic profile expected from equation (1), although there is some deviation in the short term. To obtain a better agreement, the fitting function can be modified to include the offset time t0 and the extension coefficient β in equation (1), thereby yielding equation (3).

[0138]

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[0139] The polarization of the source compound in solution at the initiation of NOE accumulation is described herein and as shown in Figures 9B and 10B.

number

[0140] In another experiment, 38 milligrams (mg) of pentacene:naphthalene crystals were measured in an optical polarizer at approximately 25%. 1 The crystals were polarized to H polarization. After polarization, the crystals were transferred to a transport system and placed in a mixed dissolution chamber. In the chamber, the crystals were dissolved and mixed for 8 seconds in DMSO-d6 (99.96%) solvent containing 100 mM caffeine and an equivalent amount of acetone. The mixture was transferred to a 60 megahertz (MHz) spinsolve spectrometer for measurement. A selective Gaussian pulse centered at 3.2 ppm was used to significantly reduce the signal from the naphthalene nuclear spin. Hyperpolarization peaks from acetone, caffeine, and residual DMSO protons were observed. NMR spectra were measured approximately every 10 seconds. The first spectrum was measured approximately 12 seconds after the end of mixing. The enhancements for acetone and caffeine were 120–170.

[0141] Optimized detection and NMR spectra

[0142] As described herein with respect to Figure 1, combinations of source and target compounds can be used in NMR spectroscopy or MRI applications. In some embodiments, selective reduction of the source compound NMR signal can be permitted to improve the detection of the target compound signal. This selective reduction can prevent the NMR signal generated by the highly enriched and polarized source compound from masking the NMR signal generated by the target compound. In the absence of such selective reduction, target compounds having NMR spectral features (e.g., peaks) that overlap with the NMR spectral features of the source compound may be difficult to identify or characterize.

[0143] In accordance with the disclosed embodiments, selective reduction of the source compound NMR signal can be achieved by reducing the polarization of the source compound. Such reduction can be achieved by selecting the source compound, selecting a specific pulse sequence for acquiring the NMR spectrum, or by post-processing the acquired NMR spectrum.

[0144] In some embodiments, the source compound may be selected to contain at least one fast-relaxing atom (e.g., deuterium, which has short relaxation times in both low and high magnetic fields). The solution containing the source compound can be placed in an ultra-low magnetic field (e.g., less than 1 uT, less than 100 nT, or less) where the Larmer frequency difference between the source atom spin and the fast-relaxing atom spin is sufficiently small (e.g., less than 10 Hz or less than 1 Hz). The coupling between the source atom spin and the fast-relaxing atom spin can then induce selective relaxation of the source atom. In some embodiments, the solution containing the source compound can be moved non-adiabatically to an ultra-low electric field, thereby inducing relaxation of the source atom.

[0145] In some embodiments, the relaxation of the source atom spin via coupling with a fast-relaxing atom spin can be enhanced using RF irradiation. For example, such RF irradiation can establish a Hartman-Hahn resonance within a rotational frame between the source atom spin and the fast-relaxing atom spin. In an additional embodiment, an INEPT pulse sequence can shift the polarization between the source atom spin and the fast-relaxing atom spin. For example, the source compound may be at least partially deuterated, while the target compound is not. The enhancement of relaxation through interaction with the deuterium spin selectively affects the at least partially deuterated source compound, allowing for a reduction in the masking effect of the source molecule on the NMR spectrum.

[0146] In some embodiments, the pulse sequence may be selected to reduce the polarization or signal of the source compound according to any suitable NMR solvent suppression technique. In some embodiments, the selected pulse sequence may depend on a specific J-coupling of the polarized spin of the source compound. For example, if the source compound has the same chemical shift, 1 If H nuclear spin is present (for example, when the source compound is polarized using PHIP or SABRE), apply an S2M or iSLIC pulse. 1 Convert the H nuclear spin into electron spin, thereby 1 The spin polarization of the H nucleus can be reduced. The use of such pulse sequences can reduce the polarization of the source compound, and therefore the detected source compound signal. In some embodiments, sequences utilizing selective pulses are used.

[0147] In some embodiments, the NMR spectrum may be post-processed to correct for the magnetic field generated by the high magnetization of the source compound. This magnetic field can cause significant drift in the resonances of the target and source atoms, and thus the frequencies of the detected peaks. For a long cylinder magnetized transversely to its axis of symmetry, the magnetic field in a small spherical cavity inside the cylinder is B M =μ0M / 2-2μ0M / 3=-μ0M6, nuclear magnetization

number

number

number

[0148] NMR spectra can also be post-processed to correct for the influence of the source compound signal. These influences may include large, broad peaks centered at the source compound frequency. This expansion may be due to the reverse action of the detection circuit on the source compound spin, generating negative feedback, which is referred to in NMR as "radiation attenuation." In some implementations, positive feedback may be possible, such as the so-called "laser" effect (radio amplification by stimulated emission of radiation), when the source is depolarized.

[0149] The source compound signal may be strong enough to influence other spin species. Relatively short-lived magnetic fields induced by process spin and radiation decay can couple to other spins. These magnetic fields act similarly to weak RF pulses and can induce frequency-dependent phase shifts on other resonances. These magnetic fields may be associated with radiation decay signals measured by a spectrometer. Thus, the phase of the target compound resonance depended almost linearly to the magnitude of the naphthalene signal at the target resonance frequency. In some embodiments, the fit of the source compound signal can be multiplied by a constant to define frequency-dependent phase corrections for other spin species (e.g., spin species associated with the target compound).

[0150] The width of the radiation attenuation signal may be related to the magnitude of the magnetization of the source compound and the intensity of the radiation attenuation itself, and therefore the phase of the target resonance and the width of the radiation attenuation signal may be related.

[0151] Figure 10C shows a post-processing method 1000 according to a disclosed embodiment for separating the effects of the sample magnetic field and source compound signal from the rest of the acquired NMR spectrum. In this way, the performance of method 1100 can improve the detection of the 1D NMR spectrum of the target compound. Method 1100 can be performed using multiple NMR spectra acquired repeatedly or periodically by an NMR spectrometer. As can be understood, the NMR spectrum produced by method 1000 can be analyzed in the same manner as conventional NMR spectra. In some embodiments, the order of operation of method 1000 can be changed. For example, the phase shift due to the magnetization of the source compound can be determined before subtracting the signal of the source compound (e.g., step 1030 can be performed before one or more of steps 1010 and 1020).

[0152] In step 1010, the source compound signal can be removed from each acquired NMR spectrum in accordance with the disclosed embodiments. In some embodiments, the source compound signal can be fitted to a complex Lorentzian (or sum of Lorentzian) linear shape. Such a Lorentzian shape may have the following equation:

[0153]

number

[0154] Figure 10D shows an exemplary spectrum with mask data used for fitting, where peaks from the target molecule are excluded from the fit calculation. Figure 10E shows a complex Lorentz-type fit. The linear shape of the source compound can be subtracted from the NMR spectrum to produce the spectrum shown in Figure 10F. Any residual distortion in the NMR spectrum baseline can be corrected using moving averages or other standard techniques.

[0155] In step 1020, a nonlinear phase correction is applied based on the fit of the source compound signal, followed by standard zero-order and first-order phase corrections. In addition to the standard zero-order and first-order phase corrections, a second-order correction can be estimated by multiplying the normalized Lorentz type (A=1) of the source background by a constant ψ². The phase and background subtracted spectra are given by ψS(v), where S(v) is the background subtracted spectrum and ψ is the phase correction including zero-order, first-order, and second-order terms.

[0156]

number

[0157] Applying zero-order, first-order, and second-order phase correction yields the results shown in Figure 10G, where the baseline is nearly flat and only the narrow features of the naphthalene source signal remain.

[0158] In step 1030, the NMR spectra can be aligned to match the disclosed embodiments. In some implementations, a complex Lorentzian (or sum of Lorentzian) lineform can be fitted to the target compound signal for each NMR spectrum. In the example shown in Figure 10H, the complex Lorentzian fits to the higher frequency peaks of the THF. Examples of this fit are shown for 32.9 sec, 49.3 sec, 65.7 sec, and 82.2 sec. Real and virtual components are labeled in each plot. The center frequencies of each target compound lineform can be extracted. These center frequencies can then be fitted to a decay index, as shown in Figure 10I, to obtain the exponential decay of the phase shift due to the naphthalene source compound magnetization decaying over time. Alternatively, the center frequencies of the source compound lineform can be extracted from step 1010. In either implementation, the decay index can define the frequency shift required to align the NMR spectra. When determining the frequency shift using the source compound lineform, some additional manual alignment adjustments can be performed. Once the phase shift of each spectrum is determined, each spectrum can be shifted by the determined amount to align the spectra and correct the chemical shift axis of each spectrum. Figure 10J shows the spectra before chemical shift axis correction, while Figure 10K shows the spectra after chemical shift axis correction.

[0159] In some embodiments, radiation decay can be utilized to enable several polarization shifts and repeated detections. Due to the very high magnetization of the source compound, after the excitation pulse, radiation decay rapidly rotates the magnetization / polarization of the source back to the z-axis, preferably in less than 100 milliseconds, 50 milliseconds, 30 milliseconds, 10 milliseconds, or 5 milliseconds. This rate is the rate of decoherence of the source compound (T2 or T2). *Since this can be faster than ), even with an excitation pulse angle of 90 degrees, a considerable amount of source polarization is maintained after the excitation pulse. Therefore, a large signal can be obtained from the target molecule without significant polarization loss of the source compound. This can be used for repeated measurements before the source compound relaxes and returns to thermal equilibrium, enabling signal averaging or multidimensional spectroscopy.

[0160] In some embodiments, long relaxation times of source compounds can be used to detect signals from target compounds having short relaxation times, such as less than 10 seconds, less than 5 seconds, less than 2 seconds, less than 1 second, less than 500 milliseconds, less than 200 milliseconds, less than 100 milliseconds, less than 50 milliseconds, less than 10 milliseconds, or less. These target compounds are typically very difficult to polarize outside the NMR spectrometer using methods that result in polarization, such as dissolved DNP, due to rapid relaxation between the transport and detection of the molecule to the NMR spectrometer. However, in the disclosed embodiments, since the target compound can remain in a constant NOE interaction with the source compound, the polarization accumulation of the target compound can remain for the duration of the source molecule's relaxation time, thereby enabling the detection of polarization in fast-relaxing target compounds. Furthermore, since the maximum value of polarization accumulation can be limited by the short relaxation time of the target compound, several excitation pulses close to the maximum polarization accumulation can be used within the longer relaxation time of the source compound, enabling signal averaging or multidimensional spectroscopy. In some embodiments, ultrafast 2D sequencing can be used in two-dimensional spectroscopy, as described in "Ultrafast Two-Dimensional NMR: A Novel Tool in Analytical Spectroscopy" by P. Giraudeau and L. Frydman, which is incorporated herein by reference in its entirety for all purposes.

[0161] Source compound and target compound

[0162] As described herein with respect to Figure 1, after polarization transfer, the target compound can be separated from the source compound. In some embodiments, such a separation step can produce a mixture containing the target compound, while some trace concentrations of the source compound (e.g., 1 mM, 500 micromoles (μM), 200 μM, 100 μM, 50 μM, 20 μM, 10 μM, 5 μM, 2 μM, 1 μM, 500 nanomoles (nM), 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 500 picomoles (pM), 200 pM, 100 pM, 50 pM, 20 pM, 10 pM, 5 pM, 2 pM, or less than 1 pM) remain in the mixture. In some embodiments, such separation may involve removing at least 90% (e.g., at least 99%, 99.9%, 99.99%, or more) of the source compound from a mixture of the source compound and the target compound.

[0163] In accordance with the disclosed embodiments, the source compound may not be suitable for use in certain NMR spectroscopy or imaging applications. Separation of the source compound from the target compound enables the use of the resulting mixture in such applications. For example, the source compound may be a non-biocompatible material or may contain a non-biocompatible material, while the target compound may be biocompatible. After polarization transfer, the polarized biocompatible target compound can be separated from the non-biocompatible compound to produce a polarized biocompatible mixture. The resulting mixture can be used as a magnetic resonance probe. As a further example, the target compound can be used to detect tissue metabolism in vitro or in vivo (e.g., hyperpolarized MRI applications). In such applications, toxicity, biocompatibility, or regulatory requirements may necessitate the separation of the source compound from the target compound. Furthermore, process control and reproducibility requirements may necessitate the separation of the source compound from the target compound. As an additional example, the resulting mixture may be used in applications (e.g., NMR spectroscopy) where the magnetic resonance signal of the source compound may otherwise mask the magnetic resonance signal of the target compound, making it difficult to distinguish between the two signals.

[0164] In accordance with the disclosed embodiments, the separation of the source and target compounds may be carried out in close proximity to an MRI or NMR apparatus, as the relaxation time of the target compound may be short (e.g., on the order of minutes or seconds). In some embodiments, the target compound may be used in a liquid state (e.g., by injection or probe). In such embodiments, the mixture of the source and target compounds may be dissolved before the extraction of the target compound. In some embodiments, the dissolution step may be carried out by heating the mixture or by introducing an additional solvent to dissolve the target compound. In various embodiments of the present invention, the compound may be separated from the solution by filtering out the compound particles (e.g., using mechanical filtration such as a commercially available sterile filter) or by centrifugation of the mixture to remove the compound particles.

[0165] When the source and target compounds are solutes in solution, the compounds can be removed from the solution by liquid-liquid extraction, high-performance liquid chromatography (HPLC) (e.g., separation of polar and nonpolar molecules), introduction of an agent that undergoes a chemical reaction with the compound to enable the separation pathway, or other suitable methods. Separation of the source and target compounds can be achieved using methods similar to those used for separating the source compound from a hydrogenation catalyst or reaction by-product (e.g., sidearms) when using PHIP, PHIP-SAH, or SABRE polarization methods as described herein. For example, if the source compound is better soluble in the target compound in the organic and aqueous phases, liquid-liquid extraction between the aqueous and organic phases can facilitate rapid purification of the target compound. In some embodiments, one or more rapid iterations of liquid-liquid extraction can be performed depending on the required purity of the target compound. In various embodiments, liquid-liquid extraction may be performed in 2 minutes, 1 minute, 20 seconds, 10 seconds, 5 seconds, or less than 1 second. In some embodiments, liquid-liquid extraction may be performed as an additional purification step following other extraction and separation methods.

[0166] Exemplary PHIP polarization and mobile device

[0167] Figure 11 shows an exemplary PHIP precipitation system and process in accordance with the disclosed embodiments. The magnetic field generator 1101 (e.g., a permanent magnet, a permanent magnet array, or an electromagnet) can be configured to generate a magnetic field within a range defined by any two of the preceding values, such as at least about 1 mT, 2 mT, 5 mT, 10 mT, 20 mT, 50 mT, 1000 mT, 200 mT, 500 mT, 1000 mT, 2000 mT, 5000 mT, or more, and at most about 5000 mT, 2000 mT, 1000 mT, 500 mT, 200 mT, 100 mT, 50 mT, 20 mT, 10 mT, 5 mT, 2 mT, 1 mT, or less, or between 10 mT and 5000 mT. In some embodiments, the magnetic field generated by the magnetic field generator 1101 may have magnetic field heterogeneity greater than 1 ppm and less than 1000 ppm over volumes of 1 ml (mL), 2 mL, 5 mL, 10 mL, 20 mL, 50 mL, 100 mL, or more. Magnetic field heterogeneity can be measured as the dispersion of the magnetic field over volume, or according to any other statistical indicator. In some embodiments, the magnetic field generator 1101 can generate a magnetic field with the aforementioned heterogeneity without active shimming.

[0168] The polarization chamber 1102 may be configured to contain a solution. During use, a precursor of the source compound can be dissolved in the solution and then chemically reacted with parahydrogen (e.g., parahydrogenation) to form a parahydrogenation precursor. In some embodiments, parahydrogen may be aerated into the solution via a connection to the parahydrogen container 1103 (e.g., a gas line). In some embodiments, parahydrogenation may be carried out outside the polarization chamber 1102 (and optionally outside the magnetic field established by the magnetic field generator 1101). For example, in a separate parahydrogenation chamber (not shown in Figure 11), parahydrogen may be aerated into the solution via a gas line, or the solution may be sprayed into a parahydrogen environment via a liquid transport line. The waveform generator 1104 may generate RF pulses (or voice frequency pulses in a relatively low magnetic field) that can be applied to the polarization chamber 1102 using the RF coil 1105. The waveform generator 1104 may be any waveform generator, or may optionally include a waveform generator, and may generate a sequence of RF pulses suitable for converting the spin order in the superhydrogenation precursor to nuclear polarization. In some embodiments, the RF coil 1105 may be an NMR probe for performing NMR measurements, may be connected to it, or may include it. Such NMR measurements can be used for monitoring and quality control of the polarization of the source compound. The heating element 1106 may be configured to control the temperature in the polarization chamber 1102. For example, to improve hydrogenation, the solution temperature may be raised above 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, or higher. In some embodiments, the heating element 1106 controls the temperature using light, microwaves, or RF energy. In some embodiments, the heating element 1106 controls the temperature using temperature-controlled fluid air.

[0169] The precipitation chamber 1107 may be configured to separate the polarization source compound from any hydrogenation catalyst or reaction byproduct (e.g., sidearms). During use, the solution containing the polarization source compound may be automatically, semi-automatically, or manually transferred to the precipitation chamber 1107. Precipitation can be initiated in the precipitation chamber 1107 using any of the methods described herein. For example, the compound can be added to the solution to initiate precipitation. In some embodiments, the compound may be a base. If the polarized parahydrogenation precursor is an ester of the source compound, the added compound can cleave the ester and initiate precipitation of the polarization source compound. The precipitation chamber 1107 may also be configured to allow separation of the precipitate from the supernatant, thereby separating the polarization source compound from the catalyst and solvent (e.g., organic solvent) used for hydrogenation and polarization of the precursor, thereby forming the source compound. Furthermore, such precipitation can change the concentration of the source compound (e.g., from a low concentration suitable for polarization of the source compound to a high concentration suitable for polarization transfer to the target compound using NOE).

[0170] In some embodiments, a further purification step may occur within the precipitation chamber 1107, during which the concentration of the hydrogenation catalyst may be reduced from the range of 0.1 to 100 mM to less than 1 micrometer, less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 2 nM, less than 1 nM, or less. Such reductions may be achieved by washing the precipitated polarization source compound with a biocompatible solvent. The biocompatible solvent may be selected such that the precipitated polarization source compound is insoluble in this solvent.

[0171] In some embodiments, the hydrogenation, polarization transfer, and precipitation steps of the new precursor molecule may be repeated within a predetermined period. In some embodiments, the predetermined period may be within the relaxation time of the target nuclear spin in the solid phase. In some embodiments, the hydrogenation, polarization transfer, and precipitation steps may be performed rapidly, on the order of minutes or seconds, to allow for the collection of larger quantities of solid polarized particles. In some embodiments, these steps may be performed in a continuous flow system. In some other embodiments, these steps may be performed in several separate steps.

[0172] After precipitation and purification, the hyperpolarized particles can be stored and transported in a transport device 1108. The transport device may include permanent magnets or electromagnets for generating a magnetic field greater than 10 mT. Preferably, the transport device includes a coolant for cooling the temperature of the hyperpolarized particles to 273.15 K or less, 150 K or less, 80 K or less, and 30 K or less. A suitable transport device is described herein with respect to Figure 13.

[0173] After precipitation and transfer, the source compound 1109 can be mixed with a solution containing the target compound 1110 in the polarization transfer system 1111. In some embodiments, polarization can be transferred from the source atom of the source compound 1109 to the target atom of the target compound 1110 by SPINOE. In some embodiments, the polarization transfer system 1111 can be temperature-controlled to increase the polarization transfer efficiency or polarization transfer rate. In some embodiments, the solution containing the source and target compounds can then be used by an NMR spectrometer or MRI apparatus 1112 for hyperpolarization NMR or MRI. In some embodiments, after the transfer of polarization to the target atom, another transfer may follow, for example, by an INEPT sequence, from the target atom to different nuclear spins on the target compound. In some embodiments, the polarization transfer system 1111 may be part of the NMR spectrometer or MRI apparatus 1112.

[0174] Exemplary PETS polarization and mobile device

[0175] Figure 12 shows an overview of the setup and components of a PETS polarizer according to the disclosed embodiment. The PETS polarizer may include a container 1210 and a solution preparation system 1220. The container 1210 may include a p-polarizing chamber 1211 and a magnetic field generator 1212. The solution preparation system 1220 may include a dissolution container 1221, a magnetic field generator 1223, and processing means 1225.

[0176] The polarization chamber 1211 may be configured to contain a solution within its internal volume. During use, a source compound containing at least one PETS portion may be contained within the polarization chamber 1211. In some embodiments, the source compound may be a dopant-doped crystalline host. In various embodiments, the crystalline host may contain at least one of naphthalene, p-terphenyl, or benzoic acid. In some embodiments, the dopant may be pentacene. In some embodiments, the polarization chamber 1211 may include at least one optical window 1213. The optical window 1213 may be configured to be coupled to a light source (not shown in Figure 12). During use, the light source may provide light for the optical polarization of at least one PETS portion. Consistent with the disclosed embodiments, the polarization chamber 1211 may include at least one container port 1215. At least one container port 1215 may allow the automatic, semi-automatic, or manual passage of the source compound from the internal volume, through the at least one container port, and into the solution preparation system. For example, the source compound can exit the polarized chamber 1211 into a transporter 1216 (e.g., a transporter as shown in Figure 13 or 14) through at least one container port 1215. The transporter 1216 can then transport the source compound to a solution preparation system 1220 and to a solution preparation system 1220. In an additional embodiment, a manifold or conveyor can transport the source compound (e.g., automatically or semi-automatically in response to user input) from the polarized chamber 1211 into a dissolution vessel 1221 through at least one container port 1215.

[0177] The magnetic field generator 1213 can at least partially surround the internal volume of the polarization chamber 1211. The magnetic field generator 1213 (e.g., a permanent magnet, a permanent magnet array, or an electromagnet) can be configured to generate a magnetic field of at least about 1 mT, 2 mT, 5 mT, 10 mT, 20 mT, 50 mT, 100 mT, 200 mT, 500 mT, 1000 mT, 2000 mT, 5000 mT, or more, and at most about 5000 mT, 2000 mT, 1000 mT, 500 mT, 200 mT, 100 mT, 50 mT, 20 mT, 10 mT, 5 mT, 2 mT, 1 mT, or less, or within the internal volume of the polarization chamber 1211, defined by any two of the preceding values, such as between 10 mT and 5000 mT. In some embodiments, the magnetic field generator 1213 may be or include at least one solenoid. In some embodiments, the magnetic field generated by the magnetic field generator 1213 may have magnetic field heterogeneity within a range defined by 1 ppm, 2 ppm, 5 ppm, 10 ppm, 20 ppm, 50 ppm, 100 ppm, 200 ppm, 500 ppm, 1000 ppm or more, 1000 ppm, 500 ppm, 200 ppm, 100 ppm, 50 ppm, 20 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm or less, or any two of the preceding values. In some embodiments, magnetic field heterogeneity is measured over a volume of 1 ml, 2 ml, 5 ml, 10 ml, 20 ml, 50 ml, 100 ml or more. In some embodiments, the magnetic field generator 1213 may generate a magnetic field with the aforementioned heterogeneity without active shimming.

[0178] In some embodiments, the dissolution vessel 1221 may be configured to be coupled to at least one container port 1215. In various embodiments, the dissolution vessel 1221 is configured to receive a source compound to be transported to a transporter 1216 (e.g., a transporter as shown in Figures 13 and 14). When in use, the dissolution vessel 1221 can receive the source compound (e.g., after the source compound has passed through at least one container port 1215 and after automatic, semi-automatic, or manual transport of the source compound). The dissolution vessel 1221 may be configured to receive a pressurized gas and a solution. The dissolution vessel 1221 may be configured to receive a solution through port 1227. When in use, the target compound can be dissolved in the first solution. The dissolution vessel 1221 can receive pressurized gas from a gas container 1230. The pressurized gas may be an inert gas. In some embodiments, the pressurized gas may be nitrogen, argon, or any combination thereof. In accordance with the disclosed embodiments, the polarization chamber 1211 may include a port 1229 that can allow the automatic, semi-automatic, or manual passage of the solution from the dissolution vessel 1221 through port 1229 to the NMR tube. In some embodiments, port 1129 may be coupled to a flow system. In some embodiments, the flow system may be a tube or manifold (e.g., using a pump) that allows or causes the flow of the solution to the NMR tube (which may be inside or outside the hole of the NMR magnet). For example, the solution may flow from port 1129 through the manifold into a tube inside the NMR magnet. In another embodiment, port 1129 may be directly connected to the NMR tube, which may be transported to the NMR magnet or shuttled to it (e.g., mechanically, aerially, manually, etc.). The disclosed embodiments are not limited to a particular flow system.

[0179] During use, the flow system may be configured to receive a second solution formed by combining the pulverized source compound with the solution added to the dissolution chamber 1221, and to transport this second solution to an NMR tube 1241 (not shown in Figure 12) located within the NMR spectrometer 1240.

[0180] The magnetic field generator 1223 can at least partially surround the dissolution container 1221. The magnetic field generator 1223 (for example, a permanent magnet, such as a permanent magnet array or electromagnet) can be configured to generate a magnetic field of at least about 1 mT, 2 mT, 5 mT, 10 mT, 20 mT, 50 mT, 100 mT, 200 mT, 500 mT, 1000 mT, 2000 mT, 5000 mT, or more, and at most about 5000 mT, 2000 mT, 1000 mT, 500 mT, 200 mT, 100 mT, 50 mT, 20 mT, 10 mT, 5 mT, 2 mT, 1 mT, or less, or within a range defined by any two of the preceding values, such as between 10 mT and 5000 mT inside the dissolution container 1221. In some embodiments, the magnetic field generator 1223 may be at least one solenoid, or may include one.

[0181] Processing means 1225 (not shown in Figure 12) may be at least partially located within the dissolution container 1221. Processing means 1225 may be configured to process the source compound into pieces of desired size (e.g., crush, grind, cut, grind, etc.). In use, processing means 1225 can process the source compound, thereby allowing or accelerating the dissolution of the source compound in the solution received through the solution port, thereby producing a second solution.

[0182] In some embodiments, the processing means may be an ultrasonic probe. In some embodiments, the processing means may include a cutting, grinding, or crushing head (e.g., a processing head) for mechanically processing the source compound. The processing head may be mechanically coupled to a shaft. In some embodiments, the shaft may be configured to allow movement within the dissolution vessel. In some embodiments, the movement may include movement along the axis of the shaft. The shaft advances within the dissolution vessel 1221, causing the processing head to process the source compound (e.g., against the wall of the dissolution vessel 1221). In some embodiments, the movement may include movement around the axis of the shaft and / or around a second axis parallel to the axis of the shaft. This movement may rotate the processing head within the dissolution vessel, causing the processing head to process the source compound. In some embodiments, the processing head may press the source compound against a filter (e.g., frit) so that particles of the source compound pass through the filter. In some embodiments, the shaft may be mechanically coupled to a rotary motor. The rotary motor may be configured to provide movement to the processing head via the shaft, thereby processing the source compound.

[0183] Examples of transport equipment

[0184] Figure 13 describes an exemplary transport device 1300 in accordance with the disclosed embodiments. In some embodiments, the device 1300 may include a base 1310, a container 1320, and a magnet 1330. The device may further include a canister 1340, a cartridge 1350, and a seal 1360.

[0185] The base 1310 may be configured to support the container 1320. The magnets 1330 may be attached to the base 1310 and arranged around the container 1320. In some embodiments, the magnets 1330 may include multiple magnets spaced apart around the container 1320. The magnets 1330 may be configured to maintain a magnetic field of intensity between 0.1 and 4 Tesla inside the container 1320 (or inside the receptacle 1327 of the container 1320) when the container 1320 is placed inside the magnets 1330 on the base 1310.

[0186] The container 1320 may include an insulating layer 1321, an absorbent material layer 1323, an inlet 1325, and a receptacle 1327. The insulating layer 1321 may be configured to insulate the inside of the container 1320 from the external environment. The insulating layer 1321 can be any suitable insulating material. The absorbent material layer 1323 may be configured to absorb a liquid coolant. For example, the absorbent material layer 1323 may be suitable for absorbing liquid nitrogen or a similar cryogenic liquid. The receptacle 1327 may be a void formed in the absorbent material layer 1323 below the inlet 1325. In some embodiments, the void may be cylindrical. The inlet 1325 may allow access to the inside of the container 1320 through the insulating layer 1321.

[0187] Container 1320 may be configured to allow a liquid coolant (e.g., liquid nitrogen) to be poured into the receptacle 1327 and absorbed into the absorbent material layer 1323. As long as sufficient liquid coolant remains, the temperature inside the receptacle 1327 will approximate the temperature of the liquid coolant. In some embodiments, container 1320 may be a cryogenic dry transport container such as a cryostat (e.g., a dewar, vacuum flask, etc.).

[0188] The canister 1340 may be configured to support the cartridge 1350 within the receptacle 1327. In some embodiments, the canister 1340 may include a handle 1341 that allows the canister 1340 to be placed inside the receptacle 1327 through an inlet 1325 and to be removed from the receptacle 1327. The cartridge 1350 may be configured to hold one or more holders 1351. The cartridge 1350 may be configured and arranged so that each holder 1351 may be separately removable from the cartridge 1350. Each holder 1351 may be configured to hold a sample of the polarized compound. The cartridge 1350 is configured within the canister and can be lowered into the container 1320. The seal 1360 may be configured to seal the container 1320 and prevent evaporation of the coolant.

[0189] In some embodiments, the device 1300 may not include a base 1310. In such embodiments, the magnet 1330 may be placed inside the container 1320. The magnet 1330 may be placed around the receptacle 1327. In some embodiments, an absorbent material layer 1323 may be placed between the magnet 1330 and the receptacle 1327. In various embodiments, the absorbent material layer 1323 may be placed between the magnet 1330 and the inner surface of the insulating layer 1321. In such embodiments, for example, the receptacle 1327 may be a void at least partially defined by the inner surface of the magnet 1330.

[0190] Exemplary apparatus for combining source and target compounds

[0191] Figure 14 shows an exemplary system 1400 for automatically combining a solid source compound with a target compound, consistent with the disclosed embodiments. In some embodiments, system 1400 can serve the role of the solution preparation system 1220 in Figure 12 or the polarized transfer system 1111 in Figure 11.

[0192] In some embodiments, the system 1400 may include a transport container 1410. The transport container 1410 may be configured to store a solid (e.g., crystalline) source compound during transport from the polarizer to the system 1400. The transport 1410 may include magnets 1411 (e.g., permanent magnets, electromagnetic devices, etc.) placed around the transport container 1413 to maintain the polarization of the source compound. The magnet 1411 can generate a magnetic field in the transport container 1413 of at least about 1 mT, 2 mT, 5 mT, 10 mT, 20 mT, 50 mT, 100 mT, 200 mT, 500 mT, 1000 mT, 2000 mT, 5000 mT, or more, and at most about 5000 mT, 2000 mT, 1000 mT, 500 mT, 200 mT, 100 mT, 50 mT, 20 mT, 10 mT, 5 mT, 2 mT, 1 mT, or less, or within a range defined by any two of the preceding values, such as between 10 mT and 2000 mT. In some embodiments, the transport 1410 may include a temperature control system (e.g., a cryogenic storage unit, a dewar, or other suitable method) for maintaining the temperature of the source compound.

[0193] In some embodiments, the system 1400 may include a dissolution vessel 1420. The dissolution vessel 1420 may be connected to a source compound loading port 1421. The source compound loading port 1421 may be connected to a transport container 1413 and may provide a channel for solid source compounds in the transport container 1413 to move to a source compound position 1423 in the dissolution vessel 1420 (e.g., by gravity and / or by compressed gas). A target compound loading port 1422 may allow the addition of target compounds, solvents, solutions of target compounds and solvents, pressurized gases, or any combination or sequence of the foregoing to the dissolution vessel 1420. In some embodiments, the target compound loading port 1410 may be connected to a manifold, which is successively connected to a pressurized gas source, a target compound or target compound solution container, a solvent container, or similar.

[0194] In accordance with the disclosed embodiments, the dissolution vessel 1420 may incorporate a mechanism for mechanically breaking down a solid source compound into smaller particles for faster dissolution. As shown in Figure 14, such a mechanism can be implemented using a grinding head 1424 connected to a shaft 1425 driven by a rotary motor 1426. In some embodiments, the rotary motor 1426, shaft 1425, and grinding head 1423 may be advanced and withdrawn within the dissolution vessel 1420. In this way, the source compound may be positioned within the source compound position 1423 before the grinding head 1424 is advanced and rotated (e.g., for 1 to 10 seconds or more), thereby breaking down the source compound. Similarly, the grinding head 1424 may be withdrawn before adding the target compound or a solution containing the target compound. Alternatively, the solution containing the target compound may be added through the target compound port 1422 while the grinding head 1424 is advanced (e.g., while the grinding head 1424 is rotating). In these embodiments, the rotation of the grinding head 1424 may serve to mix the target solution with the source compound. While shown as a rotating grinding head 1424 driven by a rotary motor 1426 through a shaft 1425, the disclosed embodiments are not limited to this arrangement. In some embodiments, a mechanism for mechanically decomposing a solid source compound may be implemented using a mortar and pestle arrangement or an ultrasonic probe.

[0195] In accordance with the disclosed embodiments, the separator 1427 may be positioned adjacent to the source compound position 1423 (e.g., below or around the source compound position 1423, or at another suitable location). The separator 1427 can be used to separate the solution resulting from the addition of the solvent or target solution to the dissolution vessel 1420 through the target compound loading port 1422. The separator 1427 may be a frit, membrane, filter, or similar. In some examples, the separator 1427 can separate the dissolved source compound (or additionally dissolved target compound) from solid particles (e.g., undissolved particles of the source or target compound). In some embodiments, the solution may be forced through the separator 1427. The solution may be forced through the separator 1427 using a gas (e.g., nitrogen gas, argon gas, and / or another suitable inert gas) introduced through the target compound loading port 1422. The solution may be forced to an outlet port 1428 which can be fluidly connected to the dissolution vessel 1420. In some embodiments, there may be a delay between the cessation of rotation by the grinding head 1424 and the introduction of gas to push the solution through the separator 1427 (at least about 1 millisecond (ms), 2 ms, 5 ms, 10 ms, 20 ms, 50 ms, 100 ms, 200 ms, 500 ms, 1000 ms, or more, up to about 1000 ms, 500 ms, 200 ms, 100 ms, 50 ms, 20 ms, 10 ms, 5 ms, 2 ms, 1 ms, or less, or within the range defined by any two of the preceding values). Such delays can allow polarized migration from the source atoms of the source compound to the target atoms of the target compound.

[0196] In some embodiments, the outlet port 1428 may be connected to a container for collecting the solution (e.g., an NMR tube, or another suitable container), or to the inlet port of an NMR or MRI device.

[0197] In some embodiments, the magnet 1429 may be positioned around the dissolution vessel 1420 or attached to the dissolution vessel 1420 (and optionally, at least partially around the source compound loading port 1421 and the target compound loading port 1422, as shown in Figure 14). Such magnets may be permanent magnets, electromagnets, or similar. Such magnets can generate a magnetic field within the dissolution vessel 1420 of at least about 1 mT, 2 mT, 5 mT, 10 mT, 20 mT, 50 mT, 100 mT, 200 mT, 500 mT, 1000 mT, 2000 mT, 5000 mT, or more, and at most about 5000 mT, 2000 mT, 1000 mT, 500 mT, 200 mT, 100 mT, 50 mT, 20 mT, 10 mT, 5 mT, 2 mT, 1 mT, or less, or within the range defined by any two of the preceding values.

[0198] Exemplary polarization transfer from pentacene-doped napasalen in solution

[0199] The transfer of polarization from spin-polarized pentacene-doped naphthalene crystals dissolved in solution to target compounds via intermolecular NOEs was investigated at room temperature and under a moderate magnetic field (1.45 T). NMR signals were enhanced by 200–1,730 times (corresponding to up to 0.86% polarization) for various small molecules. The entire polarization process took less than a minute, did not require cryogenic temperatures, and therefore yielded high-resolution NMR spectra due to the absence of paramagnetic contaminants.

[0200] Hyperpolarization of source molecules Pentacene-doped naphthalene crystals were optically polarized to 20%–25% proton polarization. The polarized crystals were then transferred to a polarization transfer device at room temperature within a handheld permanent magnet assembly, where they were placed in a dissolution vessel under an inert atmosphere, crushed, and dissolved in the target solution. Finally, the sample was injected into a 1.45T benchtop spectrometer for measurement. For time-dependent studies, small-angle (approximately 1 degree) RF pulses were applied every 3.3 seconds to monitor source and target signals. Alternatively, a single 90-degree pulse could be applied after waiting for the polarization transfer to obtain maximum signal intensity.

[0201] The proton spin of naphthalene-H8 was polarized via triplet-DNP in single crystals doped with deuterated pentacene (as shown in T. Eichorn et al., "Apparatus for pulsed ESR and DNP experiments using optically excited triplet states down to liquid helium temperature," J. Magn. Reson. 2013, 234, 58-66, the whole is incorporated herein for all purposes by reference). The latter photo-excited triplet state exhibited high electron polarization of approximately 90%, largely independent of magnetic field and temperature. Naphthalene was extensively purified by zone refinement to minimize contamination, particularly from paramagnetic sources, and to maximize T1 relaxation time and triplet-DNP yield. Material quality was periodically probed by delayed fluorescence during the purification process. Triplet state lifetimes of naphthalene exceeding 300 milliseconds were obtained at room temperature. Pentacene-doped naphthalene crystals were grown using the self-seeding Bridgman method (see S. Selvakumar et al., "Growth and Characterization of High-Quality Naphthalene Single Crystals by Selective Self-Seeding Vertical Bridgman Method (SSVBT)," Crystal Growth, 2005, 282, 370-375, the whole of which is incorporated herein for all purposes). The pentacene doping concentration was preferentially selected to be close to the saturation level (on the order of 10 ppm to 100 ppm) to maximize the triplet-DNP accumulation rate.

[0202] In the polarization shift experiment, the crystal axis was identified by optical birefringence, the sample was cut into approximately 40 mg pieces, and placed in a custom-made polarizer characterized by cooling with liquid nitrogen to a temperature of around 150°C. Polarizer control, reading, and analysis were performed using the software suite Qudi. The sample was rotated to its canonical orientation (B0 magnetic field parallel to the pentacene X-axis) and shuttled between an electron spin resonance (ESR) cavity and an NMR coil, both immersed in an electromagnet field, typically maintained at 0.22 T for ESR / DNP operation and tilted to a maximum of 0.8 T for NMR readout. The crystal was aligned based on the optically detected magnetic resonance (ODMR) of the pentacene fluorescence signal using an optical pump-probe scheme. The photo-excited triplet state was initialized with a pulsed laser, and microwaves were synthesized by an arbitrary waveform generator (AWG), enabling the performance of an advanced DNP protocol with microwave frequency and phase sweeps.

[0203] Polarization was constructed using an optimal controlled-enhancement transfer scheme. Here, the initial assumption for the optimization algorithm was the "standard" integrated solid effect (as shown in "Enhancement of Dynamic Nuclear Polarization by Integrated Solid Effects" by A. Henstra et al., Physics Letters A, 1988, 134, 134-136, the whole of which is incorporated herein for all purposes by reference). The optimized sequence typically reaches polarization accumulation rates in the range of 0.1% / min to 1% / min (depending on doping concentration and sample thickness) and is equalized between 20-25% on average for a 40 mg sample (assuming heterogeneous polarization along the laser direction due to the high-absorption crosssection). The hyperpolarization values ​​of naphthalene were calibrated by comparing them to the thermally relaxed polarization signal.

[0204] Thermal NMR measurement The experiments described herein utilized two benchtop spectrometers. One was included in a polarization-shift setup (1.45T) to monitor polarization shift and thermal calibration, and the other was used to perform saturation shift measurements to measure the cross-relaxation rate (1.88T). Intermolecular NOE enhancement was obtained via differential measurements, where the enhancement signal was acquired in the same pulse sequence but compared to a reference signal having a saturation frequency set at an equal offset opposite the target resonance.

[0205] Polarized transfer to the target compound To bring the polarized source into contact with the selected target compound, the polarized crystal was transported from the optical polarizer to a ceramic grinding and mixing vessel via a handheld magnetic assembly (B0 approximately 150 mT). The crystal was placed on titanium frit with a pore size on the order of 5 μm. To maximize polarization transfer efficiency, the average distance between the source and the target compound should be reduced as much as possible. Therefore, naphthalene was dissolved in solution at a concentration of 1.6 mol(M) to 1.8 M, which is not far from the saturation point in chloroform at room temperature. To achieve a concentration close to 20%(v / v) naphthalene, approximately 160 μL of the target solution was poured into the vessel.

[0206] The dissolution of the crystals was achieved by lowering a motor-controlled ceramic shaft into the ceramic container. The grinding shaft began motor-controlled rotation, first descending onto the crystals just above the frit, and then rotating to a predetermined position to continue the dissolution. Grinding and mixing were carried out for 6 seconds until most of the polarized naphthalene crystals had dissolved.

[0207] Next, the material was pushed through titanium frit and injected over 2–8 seconds into a 3 mm NMR tube positioned in a benchtop NMR spectrometer to monitor the hyperpolarization signal over time. The hyperpolarization signal was monitored with small flip-hard pulse excitations, typically 1–3 degrees, to minimize the effects of radiation attenuation while providing a suitable SNR for low-concentration target compound signals. The pulses were spaced with acquisition periods of either 1.7 seconds or 3.3 seconds.

[0208] The experiments described herein used the following target solutions: (1) 100 mmol (mM) of propargyl acetate (Sigma Aldrich) in 99.8% D-CDCl3, (2) 50 mM TCE or a mixture of small molecules in 99.8% D-CDCl3, and (3) 25 mM acetone, 100 mM dichloromethane, 160 mM chloroform, 100 mM THF, and 100 mM TCE in 99.8% D-CDCl3. Each target solution was frothed with N2 gas for 120 seconds before nuclear experiments to evacuate any paramagnetic O2 to minimize the source of nuclear spin self-relaxation. An inert atmosphere of N2 gas was maintained during the process of crushing and dissolving the crystals, and the hyperpolarized mixtures were injected into an NMR spectrometer using pressurized N2 gas.

[0209] Results and Analysis Figure 14 shows a series of NMR spectra acquired every 3.3 seconds after the hyperpolarized solution was injected into the spectrometer (i.e., every 3 scans, for clarity). Three traces are referred to as traces 1410, 1420, and 1430. The sample considered in this example contained approximately 1.8 M naphthalene (20% v / v) and 100 mM dichloromethane in deuterated chloroform CDCl3.

[0210] With respect to Figure 10C, as described above, the spectrum exhibits many features related to nuclear magnetization. Firstly, the sample magnetic field produced significant drifts in the source and target compound resonances, clearly indicated by the change in the position of dichloromethane and the expansion of the naphthalene resonance over time. The magnetic field of the benchtop NMR spectrometer was 1.45 T, and a shift of -1.00 ppm corresponds to a 5.73% proton polarization. Secondly, the spectrum is dominated by a large, broad peak centered at the naphthalene resonance frequency. Figure 16A shows the relationship between the phase of the target resonance and the width of the radiation-attenuated signal. Figure 16B shows the enhancement curves estimated for each proton site using the preceding procedure according to the disclosed embodiment. Figure 17 compares the 90-degree excitation of the hyperpolarized dichloromethane signal, measured after approximately 35 seconds and post-processed according to Method 1000, with the thermal spectrum of a single shot.

[0211] The efficiency of the dissolved NOE polarization transfer approach was benchmarked using a mixture of 20% v / v naphthalene and 300 mM propargyl acetate in CDCl3. The propargyl acetate spectrum consists of three distinct proton resonances well separated from the naphthalene resonance. The accumulation curves probed at a 1-degree flip angle are shown in Figure 18A. These curves show the highest enhancement achieved with propargyl acetate, estimated to be -1730 ± 60 times at 1.45 T, corresponding to approximately 1% polarization. The CH proton has a long duration of approximately 60 seconds. 1 This exhibits an HT1 relaxation time, leading to particularly high polarization shifts, as predicted from equation (2). Both CH2 and CH3 resonances are approximately 10 seconds long. 1 It has H T1s, reaching maximum signal enhancement of -250±10 and -360±1, respectively.

[0212] The hyperpolarized spectra are compared to the averaged 90-degree flip angle thermal spectra of Figure 18B. The acquisition time selected for this comparison was the approximate time observed to show maximum enhancement of the -CH resonance (e.g., 35 - 40 seconds). These curves show the highest enhancement achieved from propargyl acetate, which is estimated to be 1820 ± 60 times at 1.45T corresponding to a polarization of approximately 1%. The CH proton shows a proton T1 relaxation time of approximately 60 seconds and has particularly brought about a high degree of polarization transfer. Both the CH2 and CH3 resonances have T1 times of approximately 10 seconds for protons and reached maximum signal enhancements of approximately 260 ± 10 and 380 ± 10, respectively.

[0213] To show the applicability of the polarization transfer method to more complex NMR spectra, this procedure was applied to a CDCl3 solution containing 100 mM of 1,1,2,2-tetrachloroethane (TCE), 100 mM of dichloromethane (DCM), 100 mM of tetrahydrofuran (THF), 5 - 10 mM of toluene, and 25 mM of acetone. The polarization enhancement of this solution over time is shown in Figure 18C. The hyperpolarized spectra are compared to the averaged 90-degree flip angle thermal spectra of Figure 18D. Signal enhancements greater than 200-fold relative to thermal polarization at 1.45T were observed for all resonances from 20 - 40 seconds after injection.

[0214] Exemplary polarization transfer from PHIP-polarized diethyl maleate in solution

[0215] Via the intermolecular nuclear Overhauser effect (NOE), the transfer of polarization from spin-polarized deuterated and 13 13C-labeled diethyl maleate-1- 13 13C-d 10 to the target compound was investigated at room temperature and at 1.9T). The NMR signal was enhanced approximately 6-fold relative to ethyl acetate in solution.

[0216] 2M of diethyl acetylenedicarboxylate-1- 13 13C-d 10A 0.5 mL sample of 15 mM [1,4-bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I) tetrafluoroborate was prepared in acetone-d6. 25 μL of ethyl acetate was added to the PHIP precursor solution. A pressure-capable 5 mm NMR tube was filled with the solution and sealed with a glass capillary extending to the bottom. The solution was heated to 60 °C and para-hydrogen gas was bubbled into the solution at 15 bar for 15 s through the capillary. The chemical reaction caused hydrogenation of the precursor of diethyl maleate-1- 13 C-d 10 Immediately afterwards, the NMR tube containing the solution was placed inside a mu-metal shield of a solenoid electromagnet that provided a constant 50 μT magnetic field. A transverse oscillating magnetic field was applied and tilted in intensity to convert the proton singlet order of diethyl maleate-1- 13 C-d 10 to proton magnetization. The sample was extracted from the mu-metal shield and placed in a 1.9 T benchtop NMR spectrometer for signal acquisition after a 2° flip angle rf pulse.

[0217] Results and Analysis Diethyl maleate-1- 13 C-d 10 showed a large and broad resonance at 6.5 ppm, and ethyl acetate showed enhanced NMR resonances centered at 1.3, 2.0, and 4.1 ppm corresponding to three proton sites. Figure 19 shows the hyperpolarized spectrum 1910 above the thermal equilibrium spectrum 1920 acquired after a 90° flip angle pulse after the hyperpolarized signal had relaxed. The ethyl acetate lines in the hyperpolarized spectrum are negatively enhanced as expected from the NOE effect.

[0218] The foregoing description is provided for illustrative purposes only. It is not exhaustive and is not limited to the exact forms or embodiments disclosed. Modifications and adaptations of embodiments will be apparent from consideration of the specification and implementation of the disclosed embodiments. For example, while the described implementations include hardware, systems and methods consistent with this disclosure can be implemented using hardware and software. Furthermore, while certain components are described as being combined with one another, such components may be integrated with one another or distributed in any suitable manner.

[0219] Furthermore, while exemplary embodiments are described herein, the scope includes any and all embodiments having equivalent elements, modifications, omissions, combinations (e.g., aspects across various embodiments), adaptations, or alterations based on this disclosure. The elements of the claims should be interpreted broadly in accordance with the language used in the claims, and not limited to the examples described herein or in the application of the application, and such examples should be interpreted as non-exclusive. Furthermore, the steps of the methods of this disclosure can be modified in any way, including reordering steps, or inserting or deleting steps.

[0220] The features and advantages of this disclosure are evident from the detailed specification, and therefore the attached claims are intended to cover all systems and methods that fall within the true spirit and scope of this disclosure. Where used herein, the indefinite articles "a" and "an" mean "one or more." Similarly, the use of plural words does not necessarily mean plural unless ambiguous in a given context. Furthermore, since numerous modifications and variations readily arise from the study of this disclosure, it is undesirable to limit the exact structure and operation of this disclosure to examples and descriptions only. Accordingly, all suitable modifications and equivalents may be utilized so as to fall within the scope of this disclosure.

[0221] Embodiments may be further described using the following clauses.

[0222] Article 1 A method for increasing the nuclear spin polarization of a target compound, comprising: (a) imparting at least 1% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of a source compound such that the source atom has a nuclear gyromagnetic ratio of at least 12 megahertz per tesla (MHz / T); (b) obtaining a first solution comprising a source compound and a target compound, wherein at least one source atom is present in the first solution at a source concentration of at least 0.1 mol (M); and (c) imparting at least 0.01% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound via nuclear Overhauser effect (NOE) transfer of the first non-thermal equilibrium nuclear spin polarization to at least one target atom.

[0223] Article 2 The method according to clause 1, further comprising placing the source compound in the first solution before (b).

[0224] Article 3 The method according to clause 1 or 2, further comprising placing the target compound in the first solution prior to (b).

[0225] Article 4 The method described in any one of clauses 1 to 3, wherein (a) occurs before (b).

[0226] Article 5 (a) is a method of any one of the provisions 1 to 3 that occurs following (b).

[0227] Article 6 (d) The method according to any one of the claims 1 to 5, further comprising extracting the target compound from the first solution and placing the target compound in the second solution.

[0228] Article 7 (d) The method according to Clause 6, wherein the method comprises carrying out a liquid-liquid extraction procedure using the first solution and the second solution.

[0229] Article 8 (d) The method according to paragraph 6, comprising crystallizing the target compound from the first solution and disposing the target compound in the second solution.

[0230] Clause 9 The method according to any one of Clauses 1 to 8, further comprising performing at least one nuclear magnetic resonance (NMR) or magnetic resonance imaging (MRI) pulse sequence on the target compound.

[0231] Clause 10 The method according to Clause 9, wherein at least one NMR or MRI pulse sequence comprises at least one radiation attenuation procedure configured to reduce the radiation attenuation of the target compound by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to a pulse sequence that does not use at least one radiation attenuation procedure.

[0232] Clause 11 The method according to Clause 10, wherein at least one radiation attenuation procedure comprises at least one Q-switching procedure or at least one detuning procedure.

[0233] Clause 12 The method according to Clause 11, wherein at least one Q-switching procedure or at least one detuning procedure is applied to an induction coil configured to receive an NMR signal or an MRI signal from the target compound.

[0234] Clause 13 The method according to Clause 12, wherein at least one Q-switching procedure or at least one detuning procedure comprises changing the quality (Q) factor of the induction coil from (i) a first value of at least 20 during the application of a hard excitation pulse to the molecule to (ii) a second value of at most 1 during the application of a frequency selective pulse to the molecule.

[0235] Clause 14 The method according to any one of Clauses 1 to 13, wherein the source compound comprises at least one photoexcited triplet state (PTS) moiety.

[0236] Article 15 The method according to Clause 14, wherein (a) optically excites the triplet state of the PETS portion.

[0237] Article 16 The method according to any one of claims 1 to 15, wherein the source compound comprises a dopant-doped crystalline host.

[0238] Article 17 The method according to Clause 16, wherein the crystalline host comprises naphthalene, p-terphenyl, or benzoic acid.

[0239] Article 18 The method described in Clause 16 or 17, wherein the dopant comprises pentacene.

[0240] Article 19 The method according to any one of the claims 1 to 18, wherein the source compound comprises a parahydrogenated or paratotritiated source compound.

[0241] Article 20 The method according to Clause 19, wherein the source compound comprises a PHIP-polarized parahydrogenated or paratotritiated source compound.

[0242] Article 21 The method according to Clause 19, wherein the source compound comprises a PHIP-SAH-polarized parahydrogenated or paratotritiated source compound.

[0243] Article 22 The method according to Clause 19, wherein the source compound comprises a SABRE-polarized parahydrogenated or paratotritiated source compound.

[0244] Article 23 The method according to Clause 19, further comprising repeating (a) and (c) to impart additional polarization to the target compound.

[0245] Article 24 The method according to any one of claims 1 to 22, wherein at least one source atom comprises hydrogen, tritium, fluorine-19, or phosphorus-31.

[0246] Article 25 The method according to any one of the claims 1 to 24, wherein at least one target atom has a nuclear spin equal to 1 / 2.

[0247] Article 26 The method according to Clause 25, wherein at least one target atom comprises hydrogen, tritium, carbon-13, nitrogen-15, fluorine-19, silicon-29, phosphorus-31, iron-57, selenium-77, yttrium-89, rhodium-103, silver-107, silver-109, cadmium-111, cadmium-113, tin-117, tin-119, tellurium-123, tellurium-125, thulium-169, ytterbium-171, tungsten-183, osmium-187, platinum-195, mercury-199, thallium-203, thallium-205, lead-207, polonium-209, or plutonium-239.

[0248] Article 27 The method according to any one of the claims 1 to 26, wherein at least one target atom has a nuclear spin greater than 1 / 2.

[0249] Article 28 At least one target atom is deuterium, lithium-6, lithium-7, beryllium-9, boron-10, boron-11, nitrogen-14, oxygen-17, sodium-23, magnesium-25, aluminum-27, sulfur-33, chlorine-35, chlorine-37, potassium-39, potassium-41, calcium-43, scandium-45, titanium-47, titanium-49, vanadium-50, vanadium-51, chromium-53, manganese-55, cobalt-59, nickel-61, copper-63, copper-65, zinc-67, gallium-69, gallium-71, germanium-73, arsenic-75, bromine-79, bromine-81, rubidium-85, rubidium-87, strontium The method according to Clause 27, comprising rontium-87, zirconium-91, niobium-93, molybdenum-95, molybdenum-97, ruthenium-99, ruthenium-101, palladium-105, indium-113, indium-115, antimony-121, antimony-123, iodine-127, cesium-133, barium-135, barium-137, lanthanum-138, lanthanum-139, hafnium-177, hafnium-179, tantalum-181, rhenium-185, rhenium-187, osmium-189, iridium-191, iridium-193, gold-197, mercury-201, bismuth-209, or uranium-235.

[0250] Article 29 The method according to any one of the claims 1 to 28, wherein at least one source atom is present in the first solution at a source concentration of at least 0.2 M, 0.5 M, 1 M, 2 M, 5 M, or 10 M.

[0251] Article 30 The method according to any one of the claims 1 to 29, wherein (a) imparts at least 2%, 5%, 10%, 20%, or 50% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of the source compound.

[0252] Article 31 The method according to any one of the claims 1 to 30, wherein (c) imparts at least 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 5%, or 10% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound.

[0253] Article 32 The method according to any one of the claims 1 to 31, wherein the cross-relaxation term between the source atom and at least one target atom is at most 1 Hz, 0.5 Hz, 0.2 Hz, 0.1 Hz, 0.05 Hz, 0.02 Hz, 0.01 Hz, 0.005 Hz, 0.002 Hz, or 0.001 Hz.

[0254] Article 33 The method according to any one of claims 1 to 32, wherein the target compound is present in the first solution at a target concentration of up to 1,000 mmol (mM), 500 mM, 200 mM, 100 mM, 50 mM, 20 mM, 10 mM, 5 mM, 2 mM, 1 mM, 500 micromoles (μM), 200 μM, 100 μM, 50 μM, 20 μM, 10 μM, 5 μM, 2 μM, 1 μM, 500 nanomoles (nM), 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, or less.

[0255] Article 34 The method according to any one of claims 1 to 33, wherein the target compound is incorporated into a surface, solid, film, nanoparticles, or microparticles.

[0256] Article 35 The method according to any one of claims 1 to 34, wherein the target compound comprises a small molecule, peptide, polypeptide, protein, nucleic acid, ribonucleic acid, deoxyribonucleic acid, carbohydrate, or polymer.

[0257] Article 36 A system for increasing the nuclear spin polarization of a target compound, comprising: a first solution receiving module configured to receive a first solution containing a source compound, wherein the source compound is dissolved therein, and the source noncarbon atom is present in the first solution at a source concentration of at least 0.1 mol(M); a polarization module coupled to the first solution receiving module, configured to impart at least 1% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of the source compound; a second solution receiving module configured to receive a second solution containing a target compound dissolved therein; and a mixing module fluidly coupled to the polarization module and the second solution receiving module, configured to mix the first solution and the second solution, thereby allowing the first non-thermal equilibrium nuclear spin polarization to be transferred to at least one target atom of the target compound via nuclear Overhauser effect (NOE) transfer, thereby imparting at least 0.01% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound.

[0258] Article 37 The system according to Clause 36, further comprising a chamber fluidly coupled to a first solution receiving module, wherein the chamber is configured to receive a source compound and a liquid, and to mix the source compound and the liquid to form a first solution.

[0259] Article 38 The system according to Clause 36 or 37, wherein the polarization module includes a para-hydrogen polarization module.

[0260] Article 39 The system described in Clause 36 or 37, wherein the polarization module includes a PETS module.

[0261] Article 40 The system described in any one of clauses 36 to 39, further configured to perform the method described in any one of clauses 1 to 35.

[0262] Article 41 A system for increasing the nuclear spin polarization of a target compound, comprising: a system for increasing the nuclear spin polarization of a target compound, the system comprising: an internal volume configured to contain a source compound having at least one PETS portion therein; a first magnetic field source at least partially surrounding the internal volume and configured to generate a first magnetic field within the internal volume; a container including at least one optical window coupled to a light source and configured to allow optical polarization of at least one PETS portion; and at least one container port configured to allow passage of the source compound; a dissolution vessel coupled to at least one container port and configured to receive the source compound after it has passed through the at least one container port, and to receive a first solution containing pressurized gas and the compound dissolved therein; a second magnetic field source at least partially surrounding the dissolution vessel and configured to generate a second magnetic field within the dissolution vessel; a grinding head located within the dissolution vessel and configured to grind the source compound, thereby allowing the dissolution of the source compound in the first solution, thereby producing a second solution; and at least one solution port configured to allow passage of the second solution through it.

[0263] Article 42 The system according to Clause 41, wherein the source compound comprises a dopant-doped crystalline host.

[0264] Article 43 The system according to Clause 42, wherein the crystalline host comprises naphthalene, p-terphenyl, or benzoic acid.

[0265] Article 44 A system as described in Clause 42 or 43, wherein the dopant includes pentacene.

[0266] Article 45 The system according to any one of the clauses 41 to 44, wherein the first magnetic field source or the second magnetic field source includes at least one solenoid.

[0267] Article 46 The system according to any one of the clauses 41 to 45, wherein the first or second magnetic field has an intensity of at least about 1 mT, 2 mT, 5 mT, or 10 mT.

[0268] Article 47 A system as described in any one of clauses 41 to 46, wherein the first or second magnetic field has a maximum intensity of approximately 5000 mT, 2000 mT, 1000 mT, 500 mT, 200 mT, or 100 mT.

[0269] Article 48 A system as described in any one of the clauses 41 to 47, wherein the pressurized gas includes nitrogen, argon, or any combination thereof.

[0270] Article 49 The system according to any one of the clauses 41 to 48, further comprising a shaft mechanically coupled to a grinding head and configured to allow the movement of the grinding head, thereby grinding the source compound.

[0271] Article 50 The system according to Clause 49, further comprising a rotary motor mechanically coupled to a shaft and configured to provide movement to a grinding head via the shaft, thereby grinding a source compound.

[0272] Article 51 The system according to any one of clauses 41 to 50, wherein the solution port is configured to be coupled to an NMR tube configured to receive a second solution therein.

[0273] Article 52 The system according to any one of clauses 41 to 51, wherein the solution port is configured to be coupled to a flow system configured to receive a second solution and transport the second solution to an NMR tube located within an NMR spectrometer.

[0274] As used herein, unless otherwise stated, the term "or" encompasses all possible combinations, unless impractical. For example, if it is stated that a component may include A or B, then unless otherwise stated or impractical, the component may include A, or B, or A and B. As a second embodiment, if it is stated that a component may include A, B, or C, then unless otherwise stated, the component may include A, or B, or C, or A and B, or C, or C, or B.

Claims

1. A method for increasing the nuclear spin polarization of a target compound, (a) imparting at least 1% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of the source compound such that the source atom has a nuclear gyromagnetic ratio of at least 12 megahertz per tesla (MHz / T), (b) The source compound wherein at least one source atom is present in the first solution at a source concentration of at least 0.1 moles (M), To obtain a first solution containing the target compound, (c) Conferring at least 0.01% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound via the transfer of the first non-thermal equilibrium nuclear spin polarization to the at least one target atom of the target compound via the nuclear Overhauser effect (NOE) transfer of the first non-thermal equilibrium nuclear spin polarization to the at least one target atom, Methods that include...

2. The method according to claim 1, further comprising placing the source compound in the first solution before (b).

3. The method according to claim 1, further comprising placing the target compound in the first solution before (b).

4. The method according to claim 1, wherein (a) occurs before (b).

5. The method according to claim 1, wherein (a) occurs following (b).

6. (d) The method according to claim 1, further comprising extracting the target compound from the first solution and placing the target compound in a second solution.

7. The method according to claim 6, wherein (d) is to carry out a liquid-liquid extraction procedure using the first solution and the second solution.

8. The method according to claim 6, wherein (d) crystallizes the target compound from the first solution and places the target compound in the second solution.

9. The method according to claim 1, further comprising performing at least one nuclear magnetic resonance (NMR) or magnetic resonance imaging (MRI) pulse sequence on the target compound.

10. The method according to claim 9, wherein the at least one NMR or MRI pulse sequence includes at least one radiation attenuation procedure configured to reduce the radiation attenuation of the target compound by at least 50% compared to a pulse sequence that does not use the at least one radiation attenuation procedure.

11. The method according to claim 10, wherein the at least one radiation attenuation procedure includes at least one Q-switching procedure or at least one detuning procedure.

12. The method according to claim 11, wherein the at least one Q-switching procedure or the at least one detuning procedure is applied to an induction coil configured to receive an NMR signal or an MRI signal from the target compound.

13. The method according to claim 12, wherein the at least one Q-switching procedure or the at least one detuning procedure includes changing the quality (Q) coefficient of the induction coil from a first value of at least 20 during the application of a hard excitation pulse to the molecule to a second value of up to 1 during the application of a frequency-selective pulse to the molecule.

14. The method according to claim 1, wherein the source compound comprises at least one photoexcited triplet state (PETS) moiety.

15. The method according to claim 14, wherein (a) optically excites the triplet state of the PETS portion.

16. The method according to claim 1, wherein the source compound comprises a dopant-doped crystalline host.

17. The method according to claim 16, wherein the crystalline host comprises naphthalene, p-terphenyl, or benzoic acid.

18. The method according to claim 16, wherein the dopant comprises pentacene.

19. The method according to claim 1, wherein the source compound comprises a parahydrogenated or paratotritiated source compound.

20. The method according to claim 19, wherein the source compound comprises a PHIP polarized parahydrogenated or paratotritiated source compound.

21. The method according to claim 19, wherein the source compound comprises a PHIP-SAH-polarized parahydrogenated or paratotritiated source compound.

22. The method according to claim 19, wherein the source compound comprises a SABRE polarized parahydrogenated or paratotritiated source compound.

23. The method according to claim 19, further comprising repeating (a) and (c) to impart additional polarization to the target compound.

24. The method according to claim 1, wherein the at least one source atom comprises hydrogen, tritium, fluorine-19, or phosphorus-31.

25. The method according to claim 1, wherein the at least one target atom has a nuclear spin equal to 1 / 2.

26. The method according to claim 25, wherein the at least one target atom comprises hydrogen, tritium, carbon-13, nitrogen-15, fluorine-19, silicon-29, phosphorus-31, iron-57, selenium-77, yttrium-89, rhodium-103, silver-107, silver-109, cadmium-111, cadmium-113, tin-117, tin-119, tellurium-123, tellurium-125, thulium-169, ytterbium-171, tungsten-183, osmium-187, platinum-195, mercury-199, thallium-203, thallium-205, lead-207, polonium-209, or plutonium-239.

27. The method according to claim 1, wherein at least one target atom has a nuclear spin greater than 1 / 2.

28. The at least one target atom is deuterium, lithium-6, lithium-7, beryllium-9, boron-10, boron-11, nitrogen-14, oxygen-17, sodium-23, magnesium-25, aluminum-27, sulfur-33, chlorine-35, chlorine-37, potassium-39, potassium-41, calcium-43, scandium-45, titanium-47, titanium-49, vanadium-50, vanadium-51, chromium-53, manganese-55, cobalt-59, nickel-61, copper-63, copper-65, zinc-67, gallium-69, gallium-71, germanium-73, arsenic-75, bromine-79, bromine-81, rubidium-85, rubidium-87, strontium The method according to claim 27, comprising rontium-87, zirconium-91, niobium-93, molybdenum-95, molybdenum-97, ruthenium-99, ruthenium-101, palladium-105, indium-113, indium-115, antimony-121, antimony-123, iodine-127, cesium-133, barium-135, barium-137, lanthanum-138, lanthanum-139, hafnium-177, hafnium-179, tantalum-181, rhenium-185, rhenium-187, osmium-189, iridium-191, iridium-193, gold-197, mercury-201, bismuth-209, or uranium-235.

29. The method according to claim 1, wherein the at least one source atom is present in the first solution at a source concentration of at least 0.2 M.

30. The method according to claim 1, wherein (a) imparts at least 2% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of the source compound.

31. The method according to claim 1, wherein (c) imparts at least 0.02% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound.

32. The method according to claim 1, wherein the cross-relaxation term between the source atom and the at least one target atom is at most 1 Hertz (Hz).

33. The method according to claim 1, wherein the target compound is present in the first solution at a target concentration of up to 1,000 millimoles (mM) or less.

34. The method according to claim 1, wherein the target compound is incorporated into a surface, a solid, a film, nanoparticles, or microparticles.

35. The method according to claim 1, wherein the target compound comprises a small molecule, a peptide, a polypeptide, a protein, a nucleic acid, a ribonucleic acid, a deoxyribonucleic acid, a carbohydrate, or a polymer.

36. A system for increasing the nuclear spin polarization of a target compound, A first solution receiving module configured to receive a first solution, A first solution receiving module comprising a source compound dissolved therein, wherein the source compound comprises at least one source atom, and the at least one source noncarbon atom is present in the first solution at a source concentration of at least 0.1 moles (M), A polarization module coupled to the first solution-receiving module, configured to impart at least 1% of a first non-thermal equilibrium nuclear spin polarization to at least one source atom of the source compound, A second solution receiving module configured to receive a second solution, A second solution-receiving module containing the target compound dissolved therein, A mixing module fluidly coupled to the polarization module and the second solution receiving module, the mixing module being configured to mix the first solution and the second solution, thereby allowing the first non-thermal equilibrium nuclear spin polarization to be transferred to at least one target atom of the target compound via nuclear Overhauser effect (NOE) transfer, thereby imparting at least 0.01% of a second non-thermal equilibrium nuclear spin polarization to at least one target atom of the target compound, A system that includes this.

37. The system according to claim 36, further comprising a chamber fluidly coupled to the first solution receiving module, wherein the chamber is configured to receive the source compound and the liquid, and to mix the source compound and the liquid to form the first solution.

38. The system according to claim 36, wherein the polarization module includes a parahydrogen polarization module.

39. The system according to claim 36, wherein the polarization module includes a PETS module.

40. The system according to claim 36, further configured to carry out the method described in claim 1.

41. A system for increasing the nuclear spin polarization of a target compound, It is a container, An internal volume configured to contain a source compound including at least one PETS portion, A first magnetic field source that at least partially surrounds the internal volume and is configured to generate a first magnetic field within the internal volume, At least one optical window, coupled to a light source and configured to thereby allow the optical polarization of at least one PETS portion, A container comprising at least one container port configured to allow the passage of the source compound, A solution preparation system, A dissolution vessel is configured to be connected to at least one container port, to receive the source compound after it has passed through the at least one container port, and to receive a first solution containing pressurized gas and the compound dissolved therein, A second magnetic field source is configured to at least partially surround the dissolution vessel and generate a second magnetic field within the dissolution vessel, A grinding head is located within the dissolution container and is configured to grind the source compound, thereby allowing the source compound to dissolve in the first solution, and thereby producing a second solution. A solution preparation system comprising: at least one solution port configured to allow the passage of the second solution through it; A system that includes this.

42. The system according to claim 41, wherein the source compound comprises a dopant-doped crystalline host.

43. The system according to claim 42, wherein the crystalline host comprises naphthalene, p-terphenyl, or benzoic acid.

44. The system according to claim 42, wherein the dopant comprises pentacene.

45. The system according to claim 41, wherein the first magnetic field source or the second magnetic field source includes at least one solenoid.

46. The system according to claim 41, wherein the first magnetic field or the second magnetic field has an intensity of at least about 1 mT.

47. The system according to claim 41, wherein the first magnetic field or the second magnetic field has a maximum intensity of about 5000 mT.

48. The system according to claim 41, wherein the pressurized gas includes nitrogen, argon, or any combination thereof.

49. The system according to claim 41, further comprising a shaft mechanically coupled to the grinding head and configured to allow the movement of the grinding head, thereby grinding the source compound.

50. The system according to claim 49, further comprising a rotary motor mechanically coupled to the shaft and configured to provide the movement to the grinding head via the shaft, thereby grinding the source compound.

51. The system according to claim 41, wherein the solution port is configured to be coupled to an NMR tube configured to receive the second solution therein.

52. The system according to claim 41, wherein the solution port is configured to be coupled to a flow system configured to receive the second solution and transport the second solution to an NMR tube located in an NMR spectrometer.

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