CN117529341A - System and method for producing hyperpolarized material - Google Patents
System and method for producing hyperpolarized material Download PDFInfo
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- CN117529341A CN117529341A CN202280037158.9A CN202280037158A CN117529341A CN 117529341 A CN117529341 A CN 117529341A CN 202280037158 A CN202280037158 A CN 202280037158A CN 117529341 A CN117529341 A CN 117529341A
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Abstract
The present disclosure describes hyperpolarized materials for nuclear magnetic resonance, magnetic resonance imaging, or similar applications. The present disclosure describes methods for producing hyperpolarized materials for nuclear magnetic resonance, magnetic resonance imaging, or similar applications. The present disclosure describes precursor compounds for producing hyperpolarized materials for magnetic resonance imaging, magnetic resonance imaging or similar applications.
Description
Cross reference to related applications
The present application claims priority from U.S. provisional patent application No. 63/164,585, filed on 3 months 23, 2021, U.S. provisional patent application No. 63/260,631, filed on 8 months 27, 2021, and U.S. provisional patent application No. 63/266,986, filed on 21, 2022, each of which is incorporated herein by reference in its entirety for all purposes.
Technical Field
The disclosed embodiments generally relate to the generation of hyperpolarized materials for nuclear magnetic resonance, magnetic resonance imaging, or similar applications.
Background
Para-hydrogen induced polarization (PHIP) is a method of polarizing metabolites for Hyperpolarized (HP) Magnetic Resonance Imaging (MRI), with low cost and high throughput. Para-hydrogen induced polarization with side arm hydrogenation (PHIP-SAH) can be used to polarize metabolites such as acetate molecules. However, existing PHIP-SAH polarization methods may not be suitable for preclinical or clinical HP MRI applications.
Disclosure of Invention
In some embodiments, the present disclosure describes a composition comprising a compound of formula (I):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-); r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Including a bio-related contrast agent comprising non-hydrogen nuclear spins.
In some embodiments, the present disclosure describes a composition comprising a compound of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Including a bio-related contrast agent comprising non-hydrogen nuclear spins.
In some embodiments, the present disclosure describes a composition comprising: (i) A bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (III):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; r is R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; and R is 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
In some embodiments, the present disclosure describes a composition comprising: (i) A hyperpolarized bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (IV):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof, or (ii) a carbon-carbon triple bond (-c≡c-); r is R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
In some embodiments, the disclosure describes compounds of formula I, formula II, formula III, or formula IV that include a PHIP transfer moiety. In some embodiments, the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon. In some embodiments, the PHIP transfer portion comprises a CR 4 R 5 、*CR 4 Y, =c=y or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; r is R 4 And R is 5 Each independently selected from: 1 H、 2 H、 3 H. linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl; and Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl. In some embodiments, the PHIP transfer portion comprises a CR 6 R 7 –*CR 8 R 9 Or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; and is also provided with
R 6 、R 7 、R 8 And R is 9 Each independently selected from: 1 H、 2 H、 3 H. straight, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl. In some embodiments, the PHIP transfer portion comprises an ×ch 2 、*CH 2 –*CH 2 、*CHY、*C＝Y or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; and Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl. In some embodiments, the spin-1/2 atoms are selected from: 1 H、 13 C 15 N、 19 F or F 31 P. In some embodiments, the PHIP transfer moiety comprises at least one atom that is J-coupled to the non-hydrogen nuclear spin to be at least 0.1 hertz (Hz). In some embodiments, Z comprises at least one atom coupled to J of the non-hydrogen nuclear spin is at least 0.1 hertz (Hz).
In some embodiments, the disclosure describes compounds of formula I, formula II, formula III, or formula IV, wherein R 2 Including the solubilising portion. In some embodiments, R 2 Including hydrophobic and/or organophilic moieties. In some embodiments, R 2 Including organic solubilizing moieties. In some embodiments, R 2 Including hydrophilic and/or oleophobic moieties. In some embodiments, R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines. In some embodiments, R 2 Comprising or being selected from: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, hydroxyl, methanoyl, ethanoyl, n-propanoyl, isopropanol, propanoyl, n-butanoyl, sec-butanoyl, tert-butanoyl, isobutanoyl, methoxy, ethoxy, propoxy, isopropoxy, propanoyl, butoxy, tert-butoxy, sec-butoxy, ester, phenyl, substituted phenyl, primary amino, secondary amino, tertiary amino, primary amino, secondary amino and tertiary amino.
In some embodiments, the present disclosure describes compounds of formula I, formula II, formula III, or formula IV, including rawRelated contrast agents. In some embodiments, the biologically relevant contrast agent comprises formula R 10 Compounds of C (=o) X-; wherein R is 10 Selected from linear, branched or cyclic C1-C10 alkyl groups, wherein one or more C atoms are optionally substituted with c= C, CO, COH, CNH 2 、COOH、CH 2 COOH、CONH 2 OC (=o) substitution; and X is selected from NR 11 S and O; wherein R is 11 Selected from the group consisting of 1 H、 2 H、 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, benzyloxycarbonyl, t-butyl carbonate and benzyl. In some embodiments, the biologically relevant contrast agent is selected from the group consisting of: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate (zymonate), alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof. In some embodiments, the biologically relevant contrast agent comprises pyruvate. In some embodiments, the biologically relevant contrast agent comprises lactate. In some embodiments, the biologically relevant contrast agent comprises alpha-ketoglutarate.
In some embodiments, the composition of formula I, formula II, formula III, or formula IV has a solubility in water of less than 50 millimoles (mM). In some embodiments, the composition of formula I, formula II, formula III, or formula IV has a solubility in an organic solvent (e.g., acetone, ethanol, chloroform, and toluene) of less than 50 millimoles (mM).
In some embodiments, the composition reacts the composition of formula I with para-hydrogen such that the chemical yield of para-hydrogenated product is at least 30%.
In some embodiments, the compositions of the present disclosure are used in para-hydrogen induced polarization (PHIP) processes.
In some embodiments, the present disclosure describes a method for preparing a hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises: (a) Providing a composition comprising a compound of formula (I):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-); r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins; (b) Hydrogenating a double or triple bond in the compound of formula I with para-hydrogen to form a para-hydrogenated derivative of the compound of formula I, the para-hydrogenated derivative having the structure of formula (II):
Wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins; and (c) applying a polarization transfer waveform to sequentially transfer nuclear spins from at least one H in the compound of formula II to the non-hydrogen nuclear spins, thereby forming a derivative of formula II having a hyperpolarized bio-related contrast agent.
In some embodiments, the present disclosure describes a method for preparing a hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof, the method comprising: (a) Providing a composition comprising a compound of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins; and (b) applying a polarization transfer waveform to sequentially transfer nuclear spins from at least one H-x in the compound of formula II to the non-hydrogen nuclear spins, thereby forming a derivative of formula II with a hyperpolarized bio-related contrast agent.
In some embodiments, the method further comprises hydrolyzing the derivative of formula II to provide a composition comprising: (i) A hyperpolarized bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (III):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; r is R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; and R is 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines. In some embodiments, the method further comprises washing the hyperpolarized bio-related contrast agent one or more times with an organic solvent. In some embodiments, during the washing stepThereafter, the nonhydrogen nuclear spin polarization of the nonhydrogen nuclear spin is higher than 10%.
In some embodiments, the present disclosure describes a hyperpolarized bio-related contrast agent produced by the methods of the present disclosure, or a pharmaceutically acceptable salt thereof.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosed embodiments as claimed.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description, serve to explain certain principles and features of the disclosed embodiments. Drawings
Fig. 1 depicts a first exemplary process for generating polarized bio-related contrast agents, in accordance with various embodiments.
Fig. 2 depicts a second exemplary process for generating polarized bio-related contrast agents, in accordance with various embodiments.
FIG. 3A illustrates an exemplary proton corresponding to methyl 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 1 H) Nuclear Magnetic Resonance (NMR) spectroscopy.
FIG. 3B illustrates an exemplary methyl ester corresponding to 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 13 C NMR。
FIG. 4A illustrates an example of isopropyl 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 1 H NMR spectrum.
FIG. 4B illustrates an exemplary isopropyl 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 13 C NMR。
FIG. 5A illustrates an example of tert-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 1 H NMR spectrum.
FIG. 5B illustrates an example of tert-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 13 C NMR。
FIG. 6A illustrates a correspondence according to various embodimentsIn 4- ((2-oxopropionyl-1) 13 C) Exemplary of oxy) t-butyl-2-alkynoate 1 H NMR spectrum.
FIG. 6B illustrates a reaction sequence corresponding to 4- ((2-oxopropionyl-1-), according to various embodiments 13 C) Exemplary of oxy) t-butyl-2-alkynoate 13 C NMR。
FIG. 7A illustrates a reaction sequence corresponding to 4- ((2-oxopropionyl-1-), according to various embodiments 13 C) Oxy) but-2-yne 2- (methyl-d) 3 ) Propan-2-ol-1, 3-d 6 Is shown in (a) and (b) 1 H NMR spectrum.
FIG. 7B illustrates a reaction sequence corresponding to 4- ((2-oxopropionyl-1-), according to various embodiments 13 C) Oxy) but-2-yne 2- (methyl-d) 3 ) Propan-2-ol-1, 3-d 6 Is shown in (a) and (b) 13 C NMR。
FIG. 8A illustrates an exemplary butyl ester corresponding to 4- ((2-oxopropionyl) oxy) but-2-ynoic acid-4-d tert-butyl ester according to various embodiments 1 H NMR spectrum.
FIG. 8B illustrates an exemplary butyl ester corresponding to 4- ((2-oxopropionyl) oxy) but-2-ynoic acid-4-d tert-butyl ester according to various embodiments 13 C NMR。
FIG. 9A illustrates an example of a tert-butyl ester corresponding to 4- ((2-oxopropionyl) oxy) butan-2-carboxylate, according to various embodiments 1 H NMR spectrum.
FIG. 9B illustrates an example of a tert-butyl ester corresponding to 4- ((2-oxopropionyl) oxy) butan-2-carboxylate, according to various embodiments 13 C NMR。
FIG. 10A illustrates an exemplary ester of 4- ((2-oxopropionyl) oxy) -4-phenylbut-2-ynoic acid tert-butyl ester according to various embodiments 1 H NMR spectrum.
FIG. 10B illustrates an exemplary ester of 4- ((2-oxopropionyl) oxy) -4-phenylbut-2-ynoic acid tert-butyl ester according to various embodiments 13 C NMR。
FIG. 11 illustrates an exemplary embodiment of a dibenzoyl 4- ((2-oxopropionyl) oxy) but-2-ynoate according to various embodiments 1 H NMR spectrum.
FIG. 12A illustrates a 4-oxo-4-phenylbutane corresponding to 2-oxopropionic acid in accordance with various embodimentsExemplary 2-yn-1-yl esters 1 H NMR spectrum.
FIG. 12B illustrates an exemplary reaction sequence corresponding to 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate, in accordance with various embodiments 13 C NMR。
FIG. 13A illustrates a reaction sequence corresponding to 2-oxopropionic acid 4-oxo-4- (phenyl-d) in accordance with various embodiments 5 ) Exemplary but-2-yn-1-yl esters 1 H NMR spectrum.
FIG. 13B illustrates a reaction sequence corresponding to 2-oxopropionic acid 4-oxo-4- (phenyl-d) in accordance with various embodiments 5 ) Exemplary carbon-13 of but-2-yn-1-yl esters 13 C)NMR。
FIG. 14A illustrates an example of a reaction corresponding to 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate in accordance with various embodiments 1 HNMR spectrum.
FIG. 14B illustrates an example of a reaction corresponding to 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate in accordance with various embodiments 13 C NMR。
FIG. 15A illustrates an exemplary methyl 4- (2, 2-dichloroacetoxy) but-2-ynoate according to various embodiments 1 H NMR spectrum.
FIG. 15B illustrates an exemplary methyl 4- (2, 2-dichloroacetoxy) but-2-ynoate according to various embodiments 13 C NMR。
FIG. 16A illustrates an exemplary corresponding tert-butyl 4-acetoxybut-2-ynoate in accordance with various embodiments 1 H NMR spectrum.
FIG. 16B illustrates an exemplary reaction of tert-butyl 4-acetoxybut-2-ynoate in accordance with various embodiments 13 C NMR。
FIG. 17A illustrates an example of a 3-phenylallyl 2-oxopropionate corresponding to a para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate (i.e., a 2-oxopropionate having two protons H having spin order derived from para-hydrogen), according to various embodiments 1 H NMR spectrum.
FIG. 17B illustrates tert-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate (i.e., having two) s, according to various embodimentsH-4- ((2-oxopropionyl) oxy) but-2-enoic acid tert-butyl ester) 1 H NMR spectrum.
FIG. 18A illustrates an exemplary corresponding para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate (i.e., 3-phenylallyl 2-oxopropionate having two H's) according to various embodiments 1 HNMR spectrum.
FIG. 18B illustrates an example of a para-hydrogenated 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate (i.e., 4-oxo-4-phenylbut-2-en-1-yl 2-oxopropionate having two H's), according to various embodiments 1 H NMR spectrum.
FIG. 19A illustrates an exemplary corresponding to 200mM para-hydrogenated 3-phenylpropan-2-yn-1-yl 2-oxopropionate (i.e., 3-phenylallyl 2-oxopropionate having two H's), according to various embodiments 13 C NMR spectrum.
FIG. 19B illustrates an example of tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate corresponding to 200mM sec-hydrogenated tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate according to various embodiments 13 C NMR spectrum.
FIG. 20A illustrates an example of a 2-phenylpropionate corresponding to 200mM para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate (i.e., 3-phenylallyl 2-oxopropionate having two H's), according to various embodiments 13 C NMR spectrum.
FIG. 20B illustrates an exemplary embodiment of a para-hydrogenated 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate corresponding to 200mM (i.e., 4-oxo-4-phenylbut-2-en-1-yl 2-oxopropionate having two H's), according to various embodiments 13 C NMR spectrum.
FIG. 21 illustrates an example of methyl 4- ((2-oxopropionyl) oxy) but-2-enoate corresponding to 133mM para-hydrogenated methyl 4- ((2-oxopropionyl) oxy) but-2-enoate according to various embodiments 13 C NMR spectrum.
FIG. 22A illustrates a para-hydrogenated 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate (i.e., 2-oxoglutarate having two H's), in accordance with various embodimentsExemplary acid 1- (4- (tert-butoxy) -4-oxobut-2-en-1-yl) 5-ethyl ester 1 H NMR spectrum.
FIG. 22B illustrates an example of a corresponding 70mM para-hydrogenated 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate (i.e., 1- (4- (tert-butoxy) -4-oxobut-2-en-1-yl) 5-ethyl 2-oxoglutarate having two H's) according to various embodiments 13 C NMR spectrum.
Detailed Description
Reference will now be made in detail to exemplary embodiments discussed with respect to the accompanying drawings. Unless defined otherwise, technical and/or scientific terms have meanings commonly understood by one of ordinary skill in the art. The embodiments disclosed are described in sufficient detail to enable those skilled in the art to practice the embodiments disclosed. It is to be understood that other embodiments may be utilized and that changes may be made without departing from the scope of the disclosed embodiments. Accordingly, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
Recent work in the fields of Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) has demonstrated that NMR and MRI signals associated with various bio-related contrast agents can be enhanced by many orders of magnitude using various so-called hyperpolarization techniques. This signal enhancement allows for improved spectroscopic analysis of the bio-related contrast agent as it is metabolized by various tissues at different locations within the body. Analysis of metabolic information determined by such spectroscopic imaging may allow for non-invasive determination of the health status of in vivo tissues. For example, abnormal metabolism of biologically relevant contrast agents may be predictive of disease, such as cancer, at some location in the body.
The prior art for hyperpolarized bio-related contrast agents includes dissolution Dynamic Nuclear Polarization (DNP), para-hydrogen induced polarization (PHIP), PHIP sidearm hydrogenation (PHIP-SAH) and Signal Amplification By Reversible Exchange (SABRE). In PHIP-SAH, a precursor of a biologically relevant contrast agent is reacted with para-hydrogen to form a para-hydrogenated derivative of the precursor. The spin sequence is then transferred from the protons added via the para-hydrogenation reaction to the core of interest (e.g., carbon-13 core) contained within the bio-related contrast agent. The para-hydrogenated derivative of the precursor is cleaved (e.g., hydrolyzed) to produce the hyperpolarized bio-related contrast agent. The bio-related contrast agent is then purified and used in NMR or MRI procedures. In some embodiments, the precursor may include a bio-related contrast agent coupled to a side arm containing at least one unsaturated bond (e.g., at least one carbon-carbon double bond or at least one carbon-carbon triple bond) suitable for reaction with para-hydrogen. However, previous precursors have used side arms that may not allow the creation of biologically relevant contrast agents with clinically relevant polarization, concentration, volume or purity. This behavior may be related to poor solubility of the precursor in the organic solvent (where para-hydrogen is highly soluble), poor yields in the reaction between unsaturated bonds and para-hydrogen, or a variety of other factors. Thus, there is a need to generate novel PHIP-SAH precursors for hyperpolarized bio-related contrast agents with clinically relevant polarization, concentration, volume or purity.
The disclosed embodiments include systems and methods for producing biologically relevant contrast agents in clinically relevant polarization, concentration, volume, and purity. The disclosed embodiments provide a technical improvement in polarizing biologically relevant contrast agents in solution. These technical improvements support an increase in the concentration of the bio-related contrast agent and the extent of bio-related polarization.
Hyperpolarization and para-hydrogen
As used in this disclosure, hyperpolarization describes a condition in which the absolute value of the difference between the population of spin states (e.g., nuclear spin states, proton spin states, etc.) in one state (e.g., up-rotated) and the population of spin states in another state (e.g., down-rotated) exceeds the absolute value of the corresponding difference at thermal equilibrium.
Consistent with the disclosed embodiments, para-hydrogen may be used as the polarization source. As described herein, para-hydrogen is a form of molecular hydrogen in which two proton spins are in a singlet state. The disclosed embodiments are not limited to a particular method of producing para-hydrogen. Para-hydrogen may be formed in gaseous form or in liquid form. In some embodiments, para-hydrogen is produced in gaseous form by flowing hydrogen at low temperature through a chamber with a catalyst (e.g., iron oxide or another suitable catalyst). The hydrogen gas may contain both para-hydrogen and ortho-hydrogen. The low temperature can bring the hydrogen to thermodynamic equilibrium in the chamber, thereby increasing para-hydrogen population.
The disclosed embodiments are not limited to a particular para-hydrogen generation location or use location. Para-hydrogen may be produced at a first location and subsequently transported to a second location for use. In some embodiments, the first location is a chamber, which may be part of a container, bottle, rack, or other area capable of containing a gas or liquid. Such chambers may be maintained at a suitable pressure or temperature. In some embodiments, the first location is a physical location, such as a room, laboratory, particular warehouse, hospital, or other location where para-hydrogen may be generated.
The disclosed embodiments are not limited to a particular para-hydrogen transportation method. The para-hydrogen produced may be transported in a chamber, which may be different from the chamber in which the para-hydrogen is produced. The chamber in which the para-hydrogen gas is transported may be maintained at a suitable pressure or temperature, which may be transported by a vehicle or person. Transporting para-hydrogen may involve moving para-hydrogen from one vessel to a different vessel. Transporting para-hydrogen may involve moving para-hydrogen within the same location, such as from one part of a room to another part of the room. Transporting para-hydrogen may involve moving para-hydrogen from one room in a building to a different room or nearby building in the same building. Transporting para-hydrogen may involve moving the para-hydrogen to a different location in another part of the same city or to a different city. Transporting para-hydrogen may involve bringing para-hydrogen into proximity with a polarizer, NMR device, or MRI device. Transporting the para-hydrogen may involve packaging or transporting the para-hydrogen in a suitable container.
In some embodiments, the difference in population between the two spin states is the difference between the population of the two spin states divided by the total population of the two spin states. The population difference may be expressed as a fractional population difference or a percent population difference. In some embodiments, the fractional population difference is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or more, up to about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 or less, or within a range defined by any two of the foregoing values.
Hydrogen can exhibit a population difference between proton spin states that greatly exceeds the population difference between proton spin states at thermal equilibrium. Para-hydrogen may have a large population difference between the singlet spin state and any triplet spin state. In the case of Iz1Iz2, for example in spin state | +| ∈ there is a large population difference between +.i.i.i.i.i.i.between +.i.i.s. The difference in population of proton spin states may be at least about 0.1 (e.g., 10% difference in spin states—55% of the para-hydrogen molecules in the sample are in the singlet state and 45% are in the triplet state), 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or more, up to about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 or less, or within a range defined by any two of the foregoing values.
Biologically relevant contrast agents
The disclosed embodiments include systems and methods for producing and utilizing biologically relevant contrast agents in clinically relevant polarization, concentration, volume, or purity. In some embodiments, the method is used to prepare NMR materials. In some embodiments, the NMR material is suitable for use in NMR or MRI procedures. In some embodiments, the NMR material increases NMR or MRI signals and signal-to-noise ratio (SNR). In some embodiments, the NMR material is suitable for use in solution NMR spectroscopy. In some embodiments, the NMR material is a chemical compound. In some embodiments, the NMR material is a metabolite (e.g., a molecule having biological relevance, such as an amino acid, sugar, derivative thereof, etc.), such as a metabolite suitable for use in NMR metabolomics applications. In some embodiments, the NMR material is suitable for in vitro detection of the metabolism of a cell culture or other biological tissue. In some embodiments, NMR materials are used in NMR probes to study transient effects where high signal enhancement due to hyperpolarization, such as proton exchange between water and biomolecules, is required. In some embodiments, the NMR material is a small molecule or metabolite suitable for injection into a cell, tissue or organism for detection in an MRI scan. In some embodiments, NMR material is introduced into the chamber for further analysis by NMR or MRI procedures. In some embodiments, the NMR material is enriched in one or more deuterium 2 H) Or C-13% 13 C) An atom.
Consistent with the disclosed embodiments, the NMR material may contain a biologically relevant contrast agent. In some embodiments, the bio-related contrast agent may be suitable for NMR or MRI procedures. In some embodiments, the bio-related contrast agent may increase NMR or MRI signals or signal-to-noise ratio (SNR). In some embodiments, the bio-related contrast agent may be suitable for use in solution NMR spectroscopy. In some embodiments, the biologically relevant contrast agent may be a metabolite (e.g., a molecule having biological relevance, such as an amino acid, sugar, derivative thereof, etc.), such as a metabolite suitable for use in NMR metabolomics applications. In some embodiments, the bio-related contrast agent is used for perfusion imaging or contrast enhanced imaging in MRI scanning. In some embodiments, the biologically relevant contrast agent is suitable for in vitro detection of the metabolism of a cell culture or other biological tissue. In some embodiments, the bio-related contrast agent is used for in vitro detection of metabolism of a cell culture or other biological tissue. In some embodiments, bio-related contrast agents are used in NMR probes to study transient effects where high signal enhancement due to hyperpolarization, such as proton exchange between water and biomolecules, is required. In some embodiments, the biologically relevant contrast agent is a small molecule or metabolite suitable for injection into a cell, tissue or organism for detection in an MRI scan. In some embodiments, a biologically relevant contrast agent is introduced into the chamber for further analysis by NMR or MRI procedures. In some embodiments, the biologically relevant contrast agent is enriched in one or more of 2 H or 13 And C atom.
In some embodiments, the biologically relevant contrast agent comprises pyruvate, lactate, alpha-ketoglutarate, bicarbonate, fumarate, urea, dehydroascorbate, glutamate, glutamine, acetate, dihydroxyacetone, acetoacetate, glucose, ascorbate, zymonate, alanine, fructose, imidazole, nicotinamide, nitroimidazole, pyrazinamide, isoniazid, a conjugate acid of any of the above natural and unnatural amino acids, an ester thereof, or any of the above 2 H、 13 C or nitrogen-15% 15 N) enriched version. In some embodiments, the biologically relevant contrast agent comprises acetoneAcid salts, lactic acid salts, alpha-ketoglutarate salts. In some embodiments, the biologically relevant contrast agent comprises pyruvate. In some embodiments, the biologically relevant contrast agent comprises lactate. In some embodiments, the biologically relevant contrast agent comprises an alpha-ketoglutarate (e.g., ethyl alpha-ketoglutarate).
In some embodiments, the bio-related contrast agent comprises at least one non-hydrogen nuclear spin. In some embodiments, the non-hydrogen nuclei include at least one spin-1/2 atom. In some embodiments, the non-hydrogen nuclear spins comprise 13 C or 15 N. In some embodiments, the bio-related contrast agent is at least partially isotopically labeled with non-hydrogen nuclear spins. In some embodiments, the bio-related contrast agent is at least partially enriched in non-hydrogen nuclear spins when compared to an analog of the bio-related contrast agent that characterizes the non-hydrogen nuclear spins in its natural abundance. In some embodiments, the biologically relevant contrast agent is enriched to characterize the non-hydrogen nuclear spin at an abundance of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, up to about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less or within a range defined by any two of the foregoing values.
In some embodiments, the non-hydrogen nuclear spin replaces the NMR inactive (i.e., spin-0) core of an analog of a biologically relevant contrast agent that characterizes the non-hydrogen nuclear spin in its natural abundance (e.g., 12 C or quadrupoles (i.e. spins>1/2) core) (e.g., nitrogen-14, 14 N). For example, characterised by their natural abundance 13 Analogs of pyruvate of C can be contained in Structure H 3 About 98.9% at any one C of C-C (=o) -C OOH 12 C and about 1.1% 13 C. As a living organismIn relation to contrast agents, pyruvate may alternatively be used 13 Isotopically enriched in C such that one or both C include any abundance described herein 13 C. As used herein, C and C describe what may be 12 C or 13 Carbon of the C carbon isotope. For another example, characterized by its natural abundance 15 The urea analogues of N may be contained in structure H 2 N*-C(＝O)-*NH 2 About 99.6% at any one of N% 14 N and about 0.4% 15 N. As a biologically relevant contrast agent urea may alternatively be used 15 Isotopically enriched in N such that one or both N include any abundance described herein 15 N. As used herein, N and N describe what may be 14 N or 15 Nitrogen of the N nitrogen isotope.
Biologically relevant contrast agent precursors
In some embodiments, the present disclosure describes precursors (i.e., precursor compounds) that include a bio-related contrast agent and a side arm. In some embodiments, the bio-related contrast agent is covalently attached to the side arm. In some embodiments, the bio-related contrast agent is attached to the side arm by a transfer portion, such as a PHIP transfer portion, that is part of the side arm. Para-hydrogen may be used (e.g., by mixing the precursor and para-hydrogen) to conduct para-hydrogenation of the side arms. In some embodiments, the hydrogenation produces Iz1Iz2 stages, |ε >, or lower energy states between singlet spin sequences on two hydrogen spines, depending on whether the hydrogenation is carried out in a low or high magnetic field.
In some embodiments, the precursors are selected such that after hydrogenation and other optional chemical reactions, the bio-related contrast agent is suitable for hyperpolarized NMR or MRI applications. In some embodiments, additional chemical reactions after hydrogenation may be used to separate the biologically relevant contrast agent from the precursor. Such additional chemical reactions may comprise cleavage of the side arms of the precursor, for example by hydrolysis. For example, the biologically relevant contrast agent may be a metabolite molecule such that the precursor may be a derivative of the metabolite molecule, wherein the derivative has the general chemical structure of formula I. The bio-related contrast agent may be polarized using the PHIP-SAH method (i.e., para-hydrogenation of the sidearm and subsequent polarization transfer to the bio-related contrast agent). After hydrogenation and polarization transfer, the linkages (e.g., ester linkages) in the precursor may be hydrolyzed to produce the polarized bio-related contrast agent and the separate side arm elements.
Hydrolysis, as used herein, is defined as cleavage of a molecule by nucleophilic substitution reactions with the addition of elemental water. The hydrolysis may also be carried out under anhydrous conditions in the presence of hydroxide ions.
Consistent with the disclosed embodiments, the precursors of the general chemical forms presented in formula I may be used as precursors for PHIP-SAH. After hydrogenation of such precursors, two showing a self-spinning order 1 H spins close (e.g., only three, four, or five bonds) to a target carbon or nitrogen on the metabolite, which may be as described herein 13 C enrichment or 15 N enrichment. In some embodiments, an implementation 13 C or 15 N-spin and para-hydrogen derived 1 High J coupling between at least one of the H spins. In some embodiments, a J-coupling of at least about 0.1 hertz (Hz), 0.2Hz, 0.3Hz, 0.4Hz, 0.5Hz, 0.6Hz, 0.7Hz, 0.8Hz, 0.9Hz, 1Hz, 2Hz, 3Hz, 4Hz, 5Hz, 6Hz, 7Hz, 8Hz, 9Hz, 10Hz or more, up to about 10Hz, 9Hz, 8Hz, 7Hz, 6Hz, 5Hz, 4Hz, 3Hz, 2Hz, 1Hz, 0.9Hz, 0.8Hz, 0.7Hz, 0.6Hz, 0.5Hz, 0.4Hz, 0.3Hz, 0.2Hz, 0.1Hz or less, or a J-coupling within a range defined by any two of the foregoing values is achieved. For example, in some embodiments, the J-coupling is between 1 and 2Hz, between 1 and 3Hz, between 1 and 4Hz, between 1 and 5Hz, between 1 and 6Hz, between 1 and 7Hz, between 1 and 8Hz, between 1 and 9Hz, between 1 and 10Hz, between 2 and 3Hz, between 2 and 4Hz, between 2 and 5Hz, between 2 and 6Hz, between 2 and 7Hz, between 2 and 8Hz, between 2 and 9Hz, between 2 and 10Hz, between 3 and 4Hz, between 3 and 5Hz, between 3 and 6Hz, between 3 and 7Hz, between 3 and 8Hz, between 3 and 9Hz, between 3 and 10Hz, Between 4 and 5Hz, between 4 and 6Hz, between 4 and 7Hz, between 4 and 8Hz, between 4 and 9Hz, between 4 and 10Hz, between 5 and 6Hz, between 5 and 7Hz, between 5 and 8Hz, between 5 and 9Hz, between 5 and 10Hz, between 6 and 7Hz, between 6 and 8Hz, between 6 and 9Hz, between 6 and 10Hz, between 7 and 8Hz, between 7 and 9Hz, between 7 and 10Hz, between 8 and 9Hz, between 8 and 10 Hz. Such J-coupling can be achieved 13 The effective polarization of the C spin.
Disclosed herein are novel precursors comprising compounds of formulas I, II, III and IV, tautomers thereof, deuterated derivatives of those compounds and tautomers thereof, salts thereof and at one or more sites within the molecule 13 C or 15 N-enriched derivatives (which may in turn undergo hyperpolarization), and the offspring of the precursors given by formulae I, II, III and IV.
Precursors of formula I
In some embodiments, the precursor comprises a compound of formula I. Formula I encompasses the following structures:
and include tautomers thereof, deuterated derivatives of those compounds and tautomers thereof, pharmaceutically acceptable salts thereof, and at one or more sites 13 C or 15 N-enriched derivatives. In some embodiments, Z describes: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or combinations thereof (e.g., -C) 1 H＝C 1 H-、-C 1 H＝C 2 H-、-C 2 H＝C 2 H-) or (ii) a carbon-carbon triple bond (-C.ident.C-). In some embodiments, R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties, as described herein. In some embodiments, R 2 Comprising optionally substituted hydrocarbons, alkoxy groups, primaryAn amine, secondary amine, or tertiary amine, as described herein. In some embodiments, R 3 Including biologically relevant contrast agents, as described herein. In formula I, R 3 -R 1 All parts to the right of the bond (i.e. -R 1 -Z-(C＝O)-R 2 ) May be collectively referred to as side arms.
In some embodiments, the solubility of the compound of formula I in water is at least about 1 millimole (mM), 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM, 550mM, 600mM, 650mM, 700mM, 750mM, 800mM, 850mM, 900mM, 950mM, 1,000mM or more, up to about 1,000mM, 950mM, 900mM, 850mM, 800mM, 750mM, 700mM, 650mM, 600mM, 550mM, 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 20mM, 10mM, 9mM, 7mM, 6mM, 4mM, 3mM, or less, and the range is defined in any two of the foregoing.
In some embodiments, the compound of formula I has a solubility in an organic solvent (e.g., acetone, ethanol, chloroform, toluene) of at least about 1 millimole (mM), 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM, 550mM, 600mM, 650mM, 700mM, 750mM, 800mM, 850mM, 900mM, 950mM, 1,000mM or more, up to about 1,000mM, 950mM, 900mM, 850mM, 800mM, 750mM, 700mM, 650mM, 600mM, 550mM, 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 10mM, 9mM, 6mM, 5mM, 4mM, 2mM, or less in the solubility range of any of the solvent.
In some embodiments, the compound of formula I comprises methyl 4- ((2-oxopropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I comprises methyl 4- ((2-hydroxypropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I includes 5- ((4-methoxy-4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I comprises isopropyl 4- ((2-oxopropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I comprises isopropyl 4- ((2-hydroxypropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I includes 5- ((4-isopropoxy-4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I includes t-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I includes t-butyl 4- ((2-hydroxypropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I includes 5- ((4- (tert-butoxy) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I comprises 4- ((2-oxopropionyl-1-) 13 C) Oxy) t-butyl-2-alkynoate. In some embodiments, the compound of formula I comprises 4- ((2-hydroxypropionyl-1-) 13 C) Oxy) t-butyl-2-alkynoate. In some embodiments, the compound of formula I comprises 5- ((4- (tert-butoxy) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxo-pent-ne 13 And C acid.
In some embodiments, the compound of formula I includes 2- (methyl-d 3) prop-2-yl-1, 3-d6 ester of 4- ((2-oxopropionyl-1-13C) oxy) but-2-ynoic acid. In some embodiments, the compound of formula I includes 2- (methyl-d 3) prop-2-yl-1, 3-d6 ester of 4- ((2-hydroxypropionyl-1-13C) oxy) but-2-ynoic acid. In some embodiments, the compound of formula I includes 5- ((4- ((2- (methyl-d 3) prop-2-yl-1, 3-d 6) oxy) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I comprises 4- ((2-oxopropionyl) oxy) but-2-ynoic acid-4-d tert-butyl ester. In some embodiments, the compound of formula I comprises 4- ((2-hydroxypropionyl) oxy) but-2-ynoic acid-4-d-tert-butyl ester. In some embodiments, the compound of formula I includes 5- ((4- (tert-butoxy) -4-oxobut-2-yn-1-yl-1-d) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I comprises tert-butyl 4- ((2-oxopropionyl) oxy) pent-2-ynoate. In some embodiments, the compound of formula I comprises tert-butyl 4- ((2-hydroxypropionyl) oxy) pent-2-ynoate. In some embodiments, the compound of formula I includes 5- ((5- (tert-butoxy) -5-oxopent-3-yn-2-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I includes tert-butyl 4- ((2-oxopropionyl) oxy) -4-phenylbut-2-ynoate. In some embodiments, the compound of formula I includes tert-butyl 4- ((2-hydroxypropionyl) oxy) -4-phenylbut-2-ynoate. In some embodiments, the compound of formula I includes 5- ((4- (tert-butoxy) -4-oxo-1-phenylbut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I comprises diphenyl methyl 4- ((2-oxopropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I comprises diphenyl 4- ((2-hydroxypropionyl) oxy) but-2-ynoic acid. In some embodiments, the compound of formula I includes 5- ((4- (benzhydryl oxy) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I includes 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate. In some embodiments, the compound of formula I includes 4-oxo-4-phenylbut-2-yn-1-yl 2-hydroxypropionate. In some embodiments, the compound of formula I includes 4, 5-dioxo-5- ((4-oxo-4-phenylbut-2-yn-1-yl) oxy) pentanoic acid.
In some embodiments, the compound of formula I comprises 2-oxopropionic acid 4-oxo-4- (phenyl-d) 5 ) But-2-yn-1-yl ester. In some embodiments, the compound of formula I comprises 2-hydroxypropionic acid 4-oxo-4- (phenyl-d) 5 ) But-2-yn-1-yl ester. In some embodiments, the compound of formula I comprises 4, 5-dioxo-5- ((4-oxo-4- (phenyl-d) 5 ) But-2-yn-1-yl) oxy) pentanoic acid.
In some embodiments, the compound of formula I comprises t-butyl 4-acetoxybut-2-ynoate. In some embodiments, the compound of formula I comprises 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate.
In some embodiments, the compound of formula I comprises methyl 4- (2, 2-dichloroacetoxy) but-2-ynoate.
In some embodiments, the compound of formula I comprises trityl 4- ((2-oxopropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I comprises trityl 4- ((2-hydroxypropionyl) oxy) but-2-ynoate. In some embodiments, the compound of formula I includes 4, 5-dioxo-5- ((4-oxo-4- (trityloxy) but-2-yn-1-yl) oxy) pentanoic acid.
In some embodiments, the compound of formula I includes 4- (diphenylamine) -4-oxobut-2-yn-1-yl 2-oxopropionate. In some embodiments, the compound of formula I includes 4- (diphenylamine) -4-oxobut-2-yn-1-yl 2-hydroxypropionate. In some embodiments, the compound of formula I includes 5- ((4- (diphenylamine) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I includes 4- (diisopropylamine) -4-oxobut-2-yn-1-yl 2-oxopropionate. In some embodiments, the compound of formula I includes 4- (diisopropylamine) -4-oxobut-2-yn-1-yl 2-hydroxypropionate. In some embodiments, the compound of formula I includes 5- ((4- (diisopropylamine) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
In some embodiments, the compound of formula I includes 4-oxopent-2-yn-1-yl 2-oxopropionate. In some embodiments, the compound of formula I includes 4-oxopent-2-yn-1-yl 2-hydroxypropionate. In some embodiments, the compound of formula I includes 4, 5-dioxo-5- ((4-oxopent-2-yn-1-yl) oxy) pentanoic acid.
In some embodiments, the compound of formula I includes 4-oxo-4- (pyridin-2-yl) but-2-yn-1-yl 2-oxopropionate. In some embodiments, the compound of formula I includes 4-oxo-4- (pyridin-2-yl) but-2-yn-1-yl 2-hydroxypropionate. In some embodiments, the compound of formula I includes 4, 5-dioxo-5- ((4-oxo-4- (pyridin-2-yl) but-2-yn-1-yl) oxy) pentanoic acid.
In some embodiments, the compound of formula I includes 4- (1-methyl-1H-imidazol-2-yl) -4-oxobut-2-yn-1-yl 2-oxopropionate. In some embodiments, the compound of formula I includes 4- (1-methyl-1H-imidazol-2-yl) -4-oxobut-2-yn-1-yl 2-hydroxypropionate. In some embodiments, the compound of formula I includes 5- ((4- (1-methyl-1H-imidazol-2-yl) -4-oxobut-2-yn-1-yl) oxy) -4, 5-dioxopentanoic acid.
Para-hydrogenated precursor of formula II
In some embodiments, the compound of formula I is para-hydrogenated (i.e., modified by adding a para-hydrogen proton at Z through a hydrogenation reaction between formula I and para-hydrogen), as described herein. In some embodiments, para-hydrogenation of the compound of formula I yields the compound of formula II. Formula II encompasses the following structures:
and include tautomers thereof, deuterated derivatives of those compounds and tautomers thereof, pharmaceutically acceptable salts thereof, and at one or more sites 13 C or 15 N-enriched derivatives. In some embodiments, Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof (e.g., -CH 2 H*-CH 2 H*-、-CHDH*-CH 2 H*-、-CD 2 H*-CH 2 H-); or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof. In some embodiments, H represents hydrogen having a spin order derived from para-hydrogen (i.e., a hydrogen atom or proton added on a carbon-carbon double bond or carbon-carbon triple bond Z by hydrogenation reaction between a compound of formula I and para-hydrogen, as described herein). In some embodiments, H represents hydrogen with spin order derived from para-hydrogen (e.g., prior to polarization transfer). In some embodiments, R 1 Including the PHIP transfer portion, as described herein. In some embodiments, R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines, as described herein. In some embodiments of the present invention, in some embodiments,R 3 including biologically relevant contrast agents, as described herein. In formula II, R 3 -R 1 All parts to the right of the bond (i.e., -R 1 -Z'-(C＝O)-R 2 ) May be collectively referred to as para-hydrogenated side arms.
In some embodiments, the solubility of the compound of formula II in water is at least about 1 millimole (mM), 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM, 550mM, 600mM, 650mM, 700mM, 750mM, 800mM, 850mM, 900mM, 950mM, 1,000mM or more, up to about 1,000mM, 950mM, 900mM, 850mM, 800mM, 750mM, 700mM, 650mM, 600mM, 550mM, 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 20mM, 10mM, 9mM, 7mM, 6mM, 4mM, 3mM, or less, and the range is defined in any two of the foregoing.
In some embodiments, the compound of formula II has a solubility in an organic solvent (e.g., acetone, ethanol, chloroform, toluene) of at least about 1 millimole (mM), 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM, 550mM, 600mM, 650mM, 700mM, 750mM, 800mM, 850mM, 900mM, 950mM, 1,000mM or more, up to about 1,000mM, 950mM, 900mM, 850mM, 800mM, 750mM, 700mM, 650mM, 600mM, 550mM, 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 10mM, 9mM, 6mM, 5mM, 4mM, 2mM, or less in the solubility range of any of the solvent.
In some embodiments, when the composition of formula I is reacted with para-hydrogen, the chemical yield (e.g., the chemical yield of the compound of formula II) is at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, up to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30% or less, or within a range defined by any two of the foregoing values. For example, in some embodiments, when the composition of formula I is reacted with para-hydrogen, the chemical yield is between 30% and 35%, between 30% and 40%, between 30% and 45%, between 30% and 50%, between 30% and 55%, between 30% and 60%, between 30% and 65%, between 30% and 70%, between 30% and 75%, between 30% and 80%, between 30% and 85%, between 30% and 90%, between 30% and 95%, between 35% and 40%, between 35% and 45%, between 35% and 50%, between 35% and 55%, between 35% and 60%, between 35% and 65%, between 35% and 70%, between 35% and 75%, between 35% and 80%, between 35% and 85%, between 35% and 90%, between between 35% and 95%, between 40% and 45%, between 40% and 50%, between 40% and 55%, between 40% and 60%, between 40% and 65%, between 40% and 70%, between 40% and 75%, between 40% and 80%, between 40% and 85%, between 40% and 90%, between 40% and 95%, between 45% and 50%, between between 45% and 55%, between 45% and 60%, between 45% and 65%, between 45% and 70%, between 45% and 75%, between 45% and 80%, between 45% and 85%, between 45% and 90%, between 45% and 95%, between 50% and 55%, between 50% and 60%, between 50% and 65%, between 50% and 70%, between 50% and 75%, between 50% and 80%, between 50% and 85%, between 50% and 90%, between 50% and 95%, between 55% and 60%, between 55% and 65%, between 55% and 70%, between 55% and 75%, between 55% and 80%, between 55% and 85%, between 55% and 90%, between 55% and 95%, between 60% and 65%, between 60% and 70%, between 60% and 75%, between 60% and 80%, between 60% and 85%, between 60% and 90%, between 60% and 95%, between 55% and 85%, between 55% and 90%, between 60% and 95%, between between 65% and 70%, between 65% and 75%, between 65% and 80%, between 65% and 85%, between 65% and 90%, between 65% and 95%, between 70% and 75%, between 70% and 80%, between 70% and 85%, between 70% and 90%, between 70% and 95%, between 75% and 80%, between 75% and 85%, between 75% and 90%, between 75% and 95%, between 80% and 85%, between 80% and 90%, between 80% and 95%, between 85% and 90%, or between 85% and 95%.
Cleavage precursor of formula III
In some embodiments, the compound of formula II is cleaved (e.g., hydrolyzed), as described herein. In some embodiments, the compound of formula II is cleaved (e.g., hydrolyzed), as described herein, to provide the side arm compound and the corresponding biologically relevant contrast agent. In some embodiments, cleavage of a compound of formula II results in a compound of formula III and a corresponding biologically relevant contrast agent, as described herein. Formula III encompasses the following structures:
and include tautomers thereof, deuterated derivatives of those compounds and tautomers thereof, pharmaceutically acceptable salts thereof, and at one or more sites 13 C or 15 N-enriched derivatives. In some embodiments, Z "is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof.In some embodiments, R 1 ' including the PHIP transfer portion, as described herein. In some embodiments, R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines, as described herein. In formula III, all moieties R 1 -Z”-(C＝O)-R 2 May be collectively referred to as cleavage side arms or hydrolysis side arms.
In some embodiments, the solubility of the compound of formula III in water is at least about 1 millimole (mM), 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM, 550mM, 600mM, 650mM, 700mM, 750mM, 800mM, 850mM, 900mM, 950mM, 1,000mM or more, up to about 1,000mM, 950mM, 900mM, 850mM, 800mM, 750mM, 700mM, 650mM, 600mM, 550mM, 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 20mM, 10mM, 9mM, 7mM, 6mM, 4mM, 3mM, or less, and the range of any of the preceding two or more.
In some embodiments, the compound of formula III has a solubility in an organic solvent (e.g., acetone, ethanol, chloroform, toluene) of at least about 1 millimole (mM), 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM, 550mM, 600mM, 650mM, 700mM, 750mM, 800mM, 850mM, 900mM, 950mM, 1,000mM or more, up to about 1,000mM, 950mM, 900mM, 850mM, 800mM, 750mM, 700mM, 650mM, 600mM, 550mM, 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 10mM, 9mM, 6mM, 5mM, 4mM, 2mM, or less in the solubility range of any of the solvent.
Side arm of IV
In some embodiments, a biologically relevant contrast agent and a sidearm, such as a sidearm compound of formula IV, are conjugated to form a precursor compound, such as a compound of formula I, as described herein. Formula IV encompasses the following structures:
and include tautomers thereof, deuterated derivatives of those compounds and tautomers thereof, pharmaceutically acceptable salts thereof, and at one or more sites 13 C or 15 N-enriched derivatives. In some embodiments, Z describes: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or combinations thereof (e.g., -C) 1 H＝C 1 H-、-C 1 H＝C 2 H-、-C 2 H＝C 2 H-) or (ii) a carbon-carbon triple bond (-C.ident.C-). In some embodiments, R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties, as described herein. In some embodiments, R 2 Including a solubilizing moiety, as described herein. In some embodiments, R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines. In some embodiments, conjugation of a compound of formula IV with a biologically relevant contrast agent results in a compound of formula I, as described herein.
PHIP transfer part
In some embodiments, the PHIP transfer moieties described herein comprise a chemical moiety configured to allow or enhance one or more non-hydrogen nuclear spins (e.g., one or more of the bio-related contrast agents) from one or more para-hydrogenated protons H (e.g., H in a sidearm) to the bio-related contrast agents 13 C or 15 N atoms as described herein). In some embodiments, the PHIP transfer moiety allows or enhances the polarization transfer of para-hydrogen protons H in the sidearm of the compound of formula II to the non-hydrogen nuclear spin of the corresponding bio-related contrast agent of the compound of formula II. In some embodiments, PHIP transfer follows a para-hydrogenation reaction between formula I and para-hydrogenIn part, allowing or enhancing the polarization transfer from para-hydrogen protons H in the side arms of the compound of formula II to the non-hydrogen nuclear spins of the corresponding bio-related contrast agent of said compound of formula II.
In some embodiments, the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.
In some embodiments, the PHIP transition portion comprises the form CR 4 R 5 、*CR 4 Y, =c=y or any deuterated version thereof. In some embodiments, C is 12 C or 13 C carbon isotopes. In some embodiments, R 4 And R is 5 Each independently selected from: 1 H、 2 H、 3 H. straight, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl. In some embodiments, Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl. In some embodiments, the spin-1/2 atoms are selected from: 1 H、 13 C、 15 N、 19 F and F 31 P. In some embodiments of the present invention, in some embodiments, 15 n may be substituted with nitro, amino, amido or imino groups. In some embodiments of the present invention, in some embodiments, 31 p may be substituted with one or more keto groups, one or more nitro groups, one or more amine groups, one or more amide groups, or one or more imide groups.
In some embodiments, the PHIP transition portion comprises the form CR 6 R 7 –*CR 8 R 9 Or any deuterated version thereof. In some embodiments, C is 12 C or 13 C carbon isotopes. In some embodiments, R 6 、R 7 、R 8 And R is 9 Each independently selected from: 1 H、 2 H、 3 H. straight chain, branched orCyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, and haloalkyl.
In some embodiments, the PHIP transition portion comprises the form of CH 2 、*CH 2 –*CH 2 Che, =y, or any deuterated version thereof. In some embodiments, C is 12 C or 13 C carbon isotopes. In some embodiments, Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl. In some embodiments, the spin-1/2 atoms are selected from: 1 H、 13 C、 15 N、 19 F and F 31 P。
In some embodiments, the compositions described herein include a first J-coupling J between the spin-1/2 atoms described herein and the non-hydrogen nuclear spins described herein 12 . In some embodiments, the compositions described herein include a second J-coupling J between the spin-1/2 atom described herein and the para-hydrogen proton H described herein 13 . In some embodiments, the compositions described herein include a third J-coupling J between the non-hydrogen nuclear spins described herein and the para-hydrogen protons H described herein 23 . In some embodiments, J 12 And/or J 13 Greater than J 23 . In this case, the PHIP transfer portion may allow or enhance polarization transfer.
In some embodiments, the PHIP transfer portion induces a J-coupling between one or both of the nuclear spins and at least about 0.1Hz, 0.2Hz, 0.3Hz, 0.4Hz, 0.5Hz, 0.6Hz, 0.7Hz, 0.8Hz, 0.9Hz, 1Hz, 2Hz, 3Hz, 4Hz, 5Hz, 6Hz, 7Hz, 8Hz, 9Hz, 10Hz or more, up to about 10Hz, 9Hz, 8Hz, 7Hz, 6Hz, 5Hz, 4Hz, 3Hz, 2Hz, 1Hz, 0.9Hz, 0.8Hz, 0.7Hz, 0.6Hz, 0.5Hz, 0.4Hz, 0.3Hz, 0.2Hz, 0.1Hz or less, or a non-hydrogen nuclear spin within a range defined by any two of the foregoing values. For example, in some embodiments, the J-coupling is between 1Hz and 2Hz, between 1Hz and 3Hz, between 1Hz and 4Hz, between 1Hz and 5Hz, between 1Hz and 6Hz, between 1Hz and 7Hz, between 1Hz and 8Hz, between 1Hz and 9Hz, between 1Hz and 10Hz, between 2Hz and 3Hz, between 2Hz and 4Hz, between 2Hz and 5Hz, between 2Hz and 6Hz, between 2Hz and 7Hz, between 2Hz and 8Hz, between 2Hz and 9Hz, between 2Hz and 10Hz, between 3Hz and 4Hz, between 3Hz and 5Hz, between 3Hz and 6Hz, between 3Hz and 8Hz, between 3Hz and 9Hz, between 4Hz and 5Hz, between 4Hz and 6Hz, between 4Hz and 7Hz, between 4Hz and 8Hz, between 2Hz and 9Hz, between 2Hz and 10Hz, between 3Hz and 6Hz, between 5Hz and 10Hz, between 3Hz and 7Hz, between 5Hz and 8Hz, between 5Hz and 10Hz, between 5Hz, between 10Hz and 9 Hz.
2 R group
In some embodiments, R as described herein 2 The group includes optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines. In some embodiments, R as described herein 2 The group includes optionally substituted hydrocarbons, alkoxy groups, primary amines, secondary amines, or tertiary amines that function as solubilizing moieties. In some embodiments, R as described herein 2 The group includes a solubilizing moiety. In some embodiments, the solubilizing moiety comprises any chemical moiety configured to allow or enhance the solubility of a compound, such as any of the compounds of formulas I, II, III, and/or IV, in a solution in which a para-hydrogenation reaction or cleavage (e.g., hydrolysis) reaction occurs. In some embodiments, the measurement pertains to using a surrogate R 2 Variation of compounds of formula I, II, III or IV of one or more protons of a groupEnhancement of body solubility. In some embodiments, the measurement pertains to using methyl as R 2 Enhancement of solubility of variants of compounds of formula I, II, III or IV of the group.
In some embodiments, the solubilizing moiety comprises a hydrophobic moiety or an organophilic moiety. In some embodiments, the solubilizing moiety comprises an organic solubilizing moiety. For example, in some embodiments, the solubilizing moiety comprises a hydrophobic moiety, an organophilic moiety, or an organic solubilizing moiety. In some embodiments, the solubilizing moiety comprises a hydrophilic moiety or an organophobic moiety.
In some embodiments, R 2 The group comprises or is selected from: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, hydroxyl, methanoyl, ethanoyl, n-propanoyl, isopropanol, propanoyl, n-butanoyl, sec-butanoyl, tert-butanoyl, isobutanoyl, methoxy, ethoxy, propoxy, isopropoxy, propanoyl, butoxy, tert-butoxy, sec-butoxy, ester, phenyl, substituted phenyl, primary amino, secondary amino, tertiary amino, primary amino, secondary amino and tertiary amino. In some embodiments, the substituted phenyl is selected from fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, toluene, cumene, ethylbenzene, styrene, ortho-xylene, meta-xylene, para-xylene, phenol, benzoic acid, benzaldehyde, acetophenone, methyl benzoate, anisole, aniline, nitrobenzene, benzonitrile, benzamide, benzenesulfonic acid, naphthalene, and anthracene.
3 R group
In some embodiments, R as described herein 3 The group includes a biologically relevant contrast agent. In some embodiments, the biologically relevant contrast agent has formula R 4 C (=o) X-. In some embodiments, R 4 Selected from linear, branched or cyclic C1-C10 alkyl groups, wherein one or more C atoms are optionally interrupted by CO, COOH, CH 2 COOH、CONH 2 OH, amino (NR 'R'), one or more halogen atoms, one or more haloalkyl groups, or one or more carbocycles, wherein the carbocycle is optionally taken by one or more aliphatic or aromatic ringsInstead, the one or more aliphatic or aromatic rings are optionally substituted with one or more functional groups. In some embodiments, X is selected from NR' "and O. In some embodiments, each of R ', R ", and R'" is independently selected from 1 H、 2 H、 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, benzyloxycarbonyl, t-butyl carbonate and benzyl. In some embodiments, R 3 The group includes any of the biologically relevant contrast agents described herein.
In some embodiments, R 3 The group includes at least one non-hydrogen nuclear spin. In some embodiments, the non-hydrogen nuclei include at least one spin-1/2 atom. In some embodiments, the non-hydrogen nuclear spins comprise 13 C or 15 N. In some embodiments, R 3 The groups are at least partially isotopically labeled with non-hydrogen nuclear spins. In some embodiments, when and as characterized by its natural abundance, the R of the non-hydrogen nuclear spin 3 R when compared with analogues of the radicals 3 The groups are at least partially enriched in non-hydrogen nuclear spins. In some embodiments, R 3 The groups are enriched to characterize the nonhydrogen nuclear spin at an abundance of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, up to about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less or an abundance within a range defined by any two of the foregoing values.
In some embodiments, the nonhydrogen nuclear spin replaces the R that characterizes the nonhydrogen nuclear spin in its natural abundance 3 The NMR inactive (i.e., spin-0) core of the analog of the group (e.g., 12 c or quadrupoles (i.e. spins>1/2) core) the core (e.g., 14 n), as described herein. In some embodiments, the non-hydrogen nuclear spins are located at a distance R 3 The carbonyl (c=o) carbon in the group does not exceed about 1 or 2 chemical bonds.
Para-hydrogenation
Consistent with the disclosed embodiments, precursors of biologically relevant contrast agents (e.g., compounds of formula I, as described herein) may be subjected to para-hydrogenation by combining the precursors, para-hydrogen, and a hydrogenation catalyst. The disclosed embodiments are not limited to a particular method of producing a para-hydrogenated precursor. In some embodiments, the precursor is added to a mixture containing para-hydrogen. In some embodiments, zhong Qingqi is added to a solution containing a precursor (e.g., the Zhong Qingqi may be bubbled into such a solution). During hydrogenation of the precursor, para-hydrogen may produce stage Iz1Iz2, two hydrogen atoms in the precursor screwed +| |ε > or preferential population of lower energy states between singlet spin orders.
The precursor may have an unsaturated bond (e.g., an unsaturated carbon-carbon double bond or an unsaturated carbon-carbon triple bond) that may be hydrogenated by Zhong Qingqi. After the combination of precursor and para-hydrogen, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the precursor, up to about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or less of the precursor, or a percentage of the precursor within a range defined by any two of the foregoing values, may be hydrogenated.
In some embodiments, the population difference of the para-hydrogenated precursor in the para-hydrogenated proton spin state is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or within a range defined by any two of the foregoing values. For example, in some embodiments, the first and second processing elements, the difference in population is between 10% and 15%, between 10% and 20%, between 10% and 25%, between 10% and 30%, between 10% and 35%, between 10% and 40%, between 10% and 45%, between 10% and 50%, between 15% and 20%, between 15% and 25%, between 15% and 30%, between 15% and 35%, between 15% and 40%, between 15% and 45%, between 15% and 50%, between 20% and 25%, between 20% and 30%, between 20% and 35%, between between 20% and 40%, between 20% and 45%, between 20% and 50%, between 25% and 30%, between 25% and 35%, between 25% and 40%, between 25% and 45%, between 25% and 50%, between 30% and 35%, between 30% and 40%, between 30% and 45%, between 30% and 50%, between 35% and 40%, between 35% and 45%, between 35% and 50%, between 40% and 45%, between 40% and 50% or between 45% and 50%. In some embodiments, the population difference is between spin states comprising para-hydrogenated protons and other nuclear spins, such as additional protons on the compound. In some embodiments, the para-hydrogenated precursor comprises a sidearm, and the para-hydrogenated spin may be located on the sidearm.
In some embodiments, the concentration of the hydrogenation catalyst during hydrogenation is at least about 0.1mM, 0.2mM, 0.3mM, 0.4mM, 0.5mM, 0.6mM, 0.7mM, 0.8mM, 0.9mM, 1mM, 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM or more, up to about 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 20mM, 10mM, 9mM, 8mM, 7mM, 6mM, 5mM, 4mM, 3mM, 2mM, 1mM, 0.9mM, 0.8mM, 0.7mM, 0.6mM, 0.5mM, 0.4mM, 0.3mM, 0.2mM, 0.1mM or less, or within a range defined by any two of the foregoing.
The disclosed embodiments may include a method implemented by the disclosed system for producing a hyperpolarized bio-related contrast agent. The disclosed methods may comprise mixing (e.g., by a mixing mechanism) a solution comprising a precursor of a biologically relevant contrast agent and a hydrogenation catalyst. The mixing mechanism may be a device for introducing, holding and promoting a blend, mixture or solution of two or more materials. In some embodiments, the mixing mechanism is disposed in the chamber, and mixing occurs inside the chamber. In some embodiments, the solution is mixed at a location remote from the chamber. The volume of the solution may be at least about 1 milliliter (ml), 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 20ml, 30ml, 40ml, 50ml, 60ml, 70ml, 80ml, 90ml, 100ml or more, up to about 100ml, 90ml, 80ml, 70ml, 60ml, 50ml, 40ml, 30ml, 20ml, 10ml, 9ml, 8ml, 7ml, 6ml, 5ml, 4ml, 3ml, 2ml, 1ml or less, or within a volume range defined by any two of the foregoing values.
In some embodiments, the mixing mechanism is 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 comprises a membrane adapted to allow molecular hydrogen diffusion. In some embodiments, mixing may be performed using a spray chamber, wherein the solution is sprayed into the chamber filled with pressurized para-hydrogen.
In some embodiments, the catalyst is a molecule, complex, or particulate system that catalyzes hydrogenation. In some embodiments, the catalyst comprises a homogeneous metal catalyst, such as a rhodium complex or ruthenium complex. Rhodium complexes can be used for coordination and activation of precursor molecules and para-hydrogen. In some embodiments, a heterogeneous metal catalyst is attached to the nanoparticle.
Various embodiments of the present disclosure describe introducing a solution comprising a precursor of a biologically relevant contrast agent and a hydrogenation catalyst into a chamber configured to hold the solution during polarization transfer. In some embodiments, the solutions are mixed in a chamber. In some embodiments, the solution is hydrogenated in the chamber. In some embodiments, the chamber is within a magnetic shield (e.g., a mu metal shield). Magnetic shielding can reduce the effects of the earth's magnetic field (or other extraneous magnetic fields) allowing the amplitude of the low level magnetic field applied to the solution to be modulated. Thus, placing the solution within the chamber may comprise placing the solution within a magnetic shield.
As described herein, in some embodiments, para-hydrogenation occurs prior to polarization transfer (e.g., prior to modulating the magnitude of a magnetic field applied to a solution, etc.). In some embodiments, para-hydrogenation occurs during polarization transfer. For example, para-hydrogen may be combined with the solution (e.g., flowed or bubbled through the solution) during the modulation of the amplitude of the magnetic field.
In some embodiments, zhong Qingqi is combined under pressure with the solution in the hydrogenation chamber. The pressure may be at least about 10 bar, 15 bar, 20 bar, 30 bar, 50 bar or more, up to about 50 bar, 30 bar, 20 bar, 15 bar, 10 bar or less, or within a range defined by any two of the foregoing values. In some embodiments, para-hydrogen is combined with the solution in a metal chamber capable of withstanding pressure. Para-hydrogen may be combined with the solution at intervals (or dissolution of para-hydrogen may occur in less than a period of time). The time interval may be up to about 90 seconds, 60 seconds, 30 seconds, 20 seconds, 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second or less, at least about 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 20 seconds, 30 seconds, 60 seconds, 90 seconds or more, or within a range defined by any two of the foregoing values. In some embodiments, the hydrogenation is performed or occurs within a time interval.
Polarization transfer using radio frequency waveforms
In some embodiments, the concentration of the precursor in the solution prior to polarization transfer is at least about 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 200mM, 300mM, 400mM, 500mM, 600mM, 700mM, 800mM, 900mM, 1,000mM or more, at most about 1,000mM, 900mM, 800mM, 700mM, 600mM, 500mM, 400mM, 300mM, 200mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM20 mM, 10mM or less, or within a range defined by any two of the foregoing values. The volume of the solution may be at least about 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 20ml, 30ml, 40ml, 50ml, 60ml, 70ml, 80ml, 90ml, 100ml, 200ml, 300ml, 400ml, 500ml, 600ml, 700ml, 800ml, 900ml, 1000ml, 2000ml or more, up to about 2000ml, 1000ml, 900ml, 800ml, 700ml, 600ml, 500ml, 400ml, 300ml, 200ml, 100ml, 90ml, 80ml, 70ml, 60ml, 50ml, 40ml, 30ml, 20ml, 10ml, 9ml, 8ml, 7ml, 6ml, 5ml, 4ml, 3ml, 2ml, 1ml or less, or within a range defined by any two of the foregoing values.
Various embodiments of the present disclosure describe the application of polarization-transferring magnetic perturbations that aim to generate a magnetic field around a solution (e.g., around a solution containing formula II as described herein). In some embodiments of the present invention, in some embodiments, the magnetic field has a strength of at least about 0.1 gauss (G), 0.2G, 0.3G, 0.4G, 0.5G, 0.6G, 0.7G, 0.8G, 0.9G, 1G, 2G, 3G, 4G, 5G, 6G, 7G, 8G, 9G, 10G, 20G, 30G, 40G, 50G, 60G, 70G, 80G, 90G, 100G, 200G, 300G, 400G, 500G, 600G, 700G, 800G, 900G, 1,000G, 2,000G, 3,000G, 4,000G, 5,000G, 6,000G, 7,000G, 8,000G, 9,000G, 10,000G, 20,000G, 30,000G, 40,000G, 50,000G, 100,000G 50,000G or more, up to about 50,000G, 100,000G, 50,000G, 30,000G, 50,000G, 5,000G, 50,000G, 2,000G, 1,000G, 900G, 800G, 700G, 600G, 500G.400G, 300G.200G, 100G, 90G, 80G, 70G, 60G, 50G, 40G, 30G, 20G, 10G, 9G, 8G, 7G, 6G, 5G, 4G, 3G, 2G, 1G, 0.9G, 0.8G, 0.7G, 0.6G, 0.5G, 0.4G, 0.3G, 0.2G, 0.1G or less, or within a range defined by any two of the foregoing values. In some embodiments, the strength of the magnetic field around the solution is 0.1G to 200,000G. The magnetic disturbance may be generated by an electromagnet or a permanent magnet. The magnetic field may be applied to the sample in pulses or in Continuous Waves (CW). The magnetic disturbance may be static or time-varying.
The signal generator may be configured to generate one or more Radio Frequency (RF) waveforms that may be applied to the sample to transfer polarization. The signal generator may comprise one or more computing units, processors, controllers, associated memory, PCs, computer services, or any device capable of performing computing operations using inputs and producing outputs. In some embodiments, the RF coil may radiate or 'apply' a pulse train, comprising a first RF waveform. In some embodiments, the RF coil may have one or more channels. The channel may be a path for an RF signal. At least one channel may be provided for each different type of NMR spectrum. In some embodiments, at least one channel is used for 1 H, and at least one channel is used for 2 H、 13 C、 15 N、 19 F and F 31 P. For example, the first RF waveform may be applied to one or more radio frequency coils (RF coils) disposed about the sample 1 H channel. In some embodiments, the second RF waveform is applied to the RF coil 13 And C channel. In some embodiments of the present invention, in some embodiments, 1 h channel 13 The RF waveform on the C-channel is configured to apply a polarization transfer sequence, such as PH-INEPT, goldman' S sequence, S2M, S2hM, SLIC, ADAPT, or esotereic.
In some embodiments, the RF waveform is configured to support polarization transfer even in the presence of a large proton Full Width Half Maximum (FWHM). Such RF waveforms may include pulse sequences, which may include tens to hundreds of RF pulses. The sequence may be configured such that the pulses prevent adverse effects of magnetic field inhomogeneities on the polarization transfer.
In some embodiments, the pulse sequence for polarization is configured from two that are not equivalent 1 H hydrogenated spin transfer spin order, for example, when the chemical shift difference is greater than the J coupling between them. For example, esoteric may be a pulse sequence suitable for polarization transfer in this state.
In some embodiments, the pulse train is configured to be from equivalent 1 H hydrogen spin transfer spin order, for example, when the chemical shift difference is less than the J coupling between them. Such pulse sequences can be used in magnetic fields having the following strengths: at least about 0.01 milli-tesla (mT), 0.02mT, 0.03mT, 0.04mT, 0.05mT, 0.06mT, 0.07mT, 0.08mT, 0.09mT, 0.1mT, 0.2mT, 0.3mT, 0.4mT, 0.5mT, 0.6mT, 0.7mT, 0.8mT, 0.9mT, 1mT, 2mT, 3mT, 4mT, 5mT, 6mT, 7mT, 8mT, 9mT, 10mT, 20mT, 30mT, 40mT, 50mT, 60mT, 70mT, 80mT, 90mT, 100mT, 200mT, 300mT, 400mT, 500mT, 600mT, 700mT, 900, 1,000mT, 2,000mT, 3,000mT, 4,000mT, 0,000 mT 00mT, 6,000mT or more, up to about 6,000mT, 5,000mT, 4,000mT, 3,000mT, 2,000mT, 1,000mT, 900mT, 800mT, 700mT, 600mT, 500mT, 400mT, 300mT, 200mT, 100mT, 90mT, 80mT, 70mT, 60mT, 50mT, 40mT, 30mT, 20mT, 10mT, 9mT, 8mT, 7mT, 6mT, 5mT, 4mT, 3mT, 2mT, 1mT, 0.9mT, 0.8mT, 0.7mT, 0.6mT, 0.5mT, 0.4mT, 0.3mT, 0.2, 0.1, 0.09mT, 0.08, 0.07, 0.06, 0.05mT, 0.04, or less, is defined by any of the foregoing values. Examples of such sequences may be goldman sequences (m.goldman, h.j. Hannesson, physical report (c.r. Phys.)) 2005,6,575-581, incorporated herein by reference for pulse sequence configuration transferring spin order, singlet to heteronuclear magnetization (S2 hM) sequences, or other sequences used in singlet NMR (e.g., ADAPT, SLIC, etc.).
In some embodiments, the magnetic shield is configured to maintain a magnetic field applied to the solution at least about 0mG, 0.1mG, 0.2mG, 0.3mG, 0.4mG, 0.5mG, 0.6mG, 0.7mG, 0.8mG, 0.9mG, 1mG, 2mG, 3mG, 4mG, 5mG, 6mG, 7mG, 8mG, 9mG, 10mG, 20mG, 30mG, 40mG, 50mG, 60mG, 70mG, 80mG, 90mG, 100mG or more, at most about 100mG, 90mG, 80mG, 70mG, 60mG, 50mG, 40mG, 30mG, 20mG, 10mG, 9mG, 8mG, 7mG, 6mG, 5mG, 4mG, 3mG, 2mG, 1mG, 9mG, 7mG, 6mG, 5mG, 4mG, 0.0.0 mG, 0.0 mG, or more at any one of the two values defined by the values 0.0.0.0, 0.0 mG, 0mG, or more. The magnetic shielding may maintain the magnetic field strength within the polarized chamber at such an amplitude during the application of the polarized waveform to the one or more radio frequency coils.
Consistent with the disclosed embodiments, an RF waveform may be applied to a solution containing a para-hydrogenated precursor.
Transferring polarization using magnetic field modulation
In some embodiments, the polarization transferring magnetic perturbation is performed in a magnetic shield (e.g., a μshield, etc.) to achieve a uniform low magnetic field. Magnetic shielding is capable of transferring polarization to the earth under microtesla (μt) magnetic fields below the earth's magnetic field 13 And C nuclear spin.The low magnetic field may be at least about 0mG, 0.1mG, 0.2mG, 0.3mG, 0.4mG, 0.5mG, 0.6mG, 0.7mG, 0.8mG, 0.9mG, 1mG, 2mG, 3mG, 4mG, 5mG, 6mG, 7mG, 8mG, 9mG, 10mG, 20mG, 30mG, 40mG, 50mG, 60mG, 70mG, 80mG, 90mG, 100mG or more, at most about 100mG, 90mG, 80mG, 70mG, 60mG, 50mG, 40mG, 30mG, 20mG, 10mG, 9mG, 8mG, 7mG, 6mG, 5mG, 4mG, 3mG, 2mG, 1mG, 0.9mG, 0.8mG, 0.7mG, 0.4mG, or any of the preceding values of 0.0.0.4 mG, 0.3mG, or less.
In such fields, by using proton spins with other spin species of interest (including 2 H、 13 C、 15 N、 19 F and F 31 P) avoids crossing (LAC) to transfer polarization. In some embodiments, the magnetic field may be tuned to a particular magnetic field strength of the LAC. In various embodiments, the magnetic field strength may be time modulated in order to achieve robust polarization transfer in a large volume of sample. For example, the magnetic field strength may be swept through the LAC condition. Alternatively or additionally, the sample may be physically moved inside the magnetic field. Such modulation may relax constraints on magnetic field uniformity and on magnetic field offset. Thus, robust polarization transfer can be performed with greater volume and higher efficiency. Furthermore, relaxing constraints on magnetic field uniformity and on magnetic field offset may allow for the use of less complex, less accurate, or less expensive polarization systems.
The lower limit of the magnetic field modulation may be at least about-10 μT, -9 μT, -8 μT, -7 μT, -6 μT, -5 μT, -4 μT, -3 μT, -2 μT, -1 μT, -0.9 μT, -0.8 μT, -0.7 μT, -0.6 μT, -0.5 μT, -0.4 μT, -0.3 μT, -0.2 μT, -0.1 μT or more, up to about-0.1 μT, -0.2 μT, -0.3 μT, -0.4 μT, -0.5 μT, -0.6 μT, -0.7 μT, -0.8 μT, -0.9 μT, -1 μT, -2 μT, -3 μT, -4 μT, -5 μT, -6 μT, -7 μT, -8 μT, -9 μT, -10 μT or less, or within a range defined by any two of the foregoing values. The upper limit of modulation may be at least about 0.1 μT, 0.2 μT, 0.3 μT, 0.4 μT, 0.5 μT, 0.6 μT, 0.7 μT, 0.8 μT, 0.9 μT, 1 μT, 2 μT, 3 μT, 4 μT, 5 μT, 6 μT, 7 μT, 8 μT, 9 μT, 10 μT or more, up to about 10 μT, 9 μT, 8 μT, 7 μT, 6 μT, 5 μT, 4 μT, 3 μT, 2 μT, 1 μT, 0.9 μT, 0.8 μT, 0.7 μT, 0.6 μT, 0.5 μT, 0.4 μT, 0.3 μT, 0.2 μT, 0.1 μT or less, or within a range defined by any two of the foregoing values.
The magnetic field may have such an amplitude over the following volumes: at least about 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 20ml, 30ml, 40ml, 50ml, 60ml, 70ml, 80ml, 90ml, 100ml, 200ml, 300ml, 400ml, 500ml, 600ml, 700ml, 800ml, 900ml, 1,000ml, 2,000ml or more, up to about 2,000ml, 1,000ml, 900ml, 800ml, 700ml, 600ml, 500ml, 400ml, 300ml, 200ml, 100ml, 90ml, 80ml, 70ml, 60ml, 50ml, 40ml, 30ml, 20ml, 10ml, 9ml, 8ml, 7ml, 6ml, 5ml, 4ml, 3ml, 2ml, 1ml or less, or a volume within a range defined by any two of the foregoing values. The modulation may be performed for a duration of time. The duration may be at least about 100 milliseconds (ms), 200ms, 300ms, 400ms, 500ms, 600ms, 700ms, 800ms, 900ms, 1,000ms, 2,000ms, 3,000ms, 4,000ms, 5,000ms, 6,000ms, 7,000ms, 8,000ms, 9,000ms, 10,000ms, 20,000ms, 30,000ms, 40,000ms, 50,000ms or more, up to about 50,000ms, 40,000ms, 30,000ms, 20,000ms, 10,000ms, 9,000ms, 8,000ms, 7,000ms, 6,000ms, 5,000ms, 4,000ms, 3,000ms, 2,000ms, 1,000ms, 900ms, 800ms, 700ms, 600ms, 500ms, 400ms, 300ms, 200ms, 100ms or less, or within a range defined by any two of the foregoing values.
Thus, the rate of change of the amplitude of the magnetic field may be at least about 0.01 μT per second, 0.02 μT per second, 0.03 μT per second, 0.04 μT per second, 0.05 μT per second, 0.06 μT per second, 0.07 μT per second, 0.08 μT per second, 0.09 μT per second, 0.1 μT per second, 0.2 μT per second, 0.03 μT per second, 0.4 μT per second, 0.5 μT per second, 0.6 μT per second, 0.7 μT per second, 0.8 μT per second, 0.9 μT per second, 1 μT per second or more, up to about 1 μT per second, 0.9 μT per second, 0.8 μT per second, 0.7 μT per second, 0.6 μT per second, 0.5 μT per second, 0.4 μT per second, 0.3 μT per second, 0.2 μT per second, 0.1 μT per second, or less, within any of the preceding ranges. The upper limit of the rate of change of the amplitude of the magnetic field may be determined by the capabilities of the device used to make the sweep.
In some embodiments, the spatial deviation of the magnetic field in volume during modulation is less than about half (or one quarter, or one eighth or one tenth) of the magnitude of the magnetic field when the magnetic field is within the upper and lower limits disclosed above. For example, when the magnetic field strength is less than 2 μT (or greater than-2 μT), then the spatial deviation of the magnetic field in volume during modulation may be less than 1 μT. As a further example, when the magnetic field strength is less than 10 μt (or greater than-10 μt), then the spatial deviation of the magnetic field in volume during modulation may be less than 5 μt. For example, the spatial deviation may be measured by spatially randomly sampling or spatially uniformly distributing the measurements at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500 or more times the magnetic field within the volume and calculating the standard deviation of the sampled magnetic field measurements. Such uniformity may be achieved, for example, in a large uniform magnetic shield by having a large penetrating solenoid through the magnetic shield or by using a large Helmholtz coil (Helmholtz coil) with a large uniform area for generating the magnetic field amplitude modulation. In some embodiments, the modulation is a sweep of the magnetic field. In some embodiments, the magnetic field amplitude modulation comprises non-adiabatic hopping, monotonic amplitude variation, or a combination thereof.
In some embodiments, after the polarization transfer step, the non-hydrogen nuclear spins of the bio-related contrast agent (e.g., the bio-related contrast agent 13 C or 15 N) has a nuclear spin polarization of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or a polarization within a range defined by any two of the foregoing values. For example, in some embodiments, after the polarization transfer step, the non-hydrogen nuclear spin of the bio-related contrast agent has a nuclear spin polarization of between 10% and 15%, between 10% and 20%Between 25%, between 10% and 30%, between 10% and 35%, between 10% and 40%, between 10% and 45%, between 10% and 50%, between 15% and 20%, between 15% and 25%, between 15% and 30%, between 15% and 35%, between 15% and 40%, between 15% and 45%, between 15% and 50%, between 20% and 25%, between 20% and 30%, between 20% and 35%, between 20% and 40%, between 20% and 45%, between 20% and 50%, between 25% and 30%, between 25% and 35%, between 25% and 40%, between 25% and 45%, between 25% and 50%, between 30% and 35%, between 30% and 40%, between 30% and 45%, between 30% and 50%, between 35% and 40%, between 35% and 45%, between 45% and 50%, or between 45% and 50%.
In some embodiments, the following solution volumes are used: at least about 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 20ml, 30ml, 40ml, 50ml, 60ml, 70ml, 80ml, 90ml, 100ml, 200ml, 300ml, 400ml, 500ml or more, up to about 500ml, 400ml, 300ml, 200ml, 100ml, 90ml, 80ml, 70ml, 60ml, 50ml, 40ml, 30ml, 20ml, 10ml, 9ml, 8ml, 7ml, 6ml, 5ml, 4ml, 3ml, 2ml, 1ml or less, or a volume within a range defined by any two of the foregoing values.
In some embodiments, after polarization transfer, a portion of the poor population of para-hydrogenated proton spin states has been transferred to the target of the bio-related contrast agent (e.g., 13 c or 15 N) polarization of nuclear spins. This moiety may be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or at a range consisting of any two of the foregoing valuesWithin a defined range. For example, in some embodiments, the first and second processing elements, this fraction is between 10% and 15%, between 10% and 20%, between 10% and 25%, between 10% and 30%, between 10% and 35%, between 10% and 40%, between 10% and 45%, between 10% and 50%, between 15% and 20%, between 15% and 25%, between 15% and 30%, between 15% and 35%, between 15% and 40%, between 15% and 45%, between 15% and 50%, between 20% and 25%, between 20% and 30%, between 20% and 35%, between between 20% and 40%, between 20% and 45%, between 20% and 50%, between 25% and 30%, between 25% and 35%, between 25% and 40%, between 25% and 45%, between 25% and 50%, between 30% and 35%, between 30% and 40%, between 30% and 45%, between 30% and 50%, between 35% and 40%, between 35% and 45%, between 35% and 50%, between 40% and 45%, between 40% and 50% or between 45% and 50%.
In some embodiments, the magnetic field modulation includes non-adiabatic hopping of the magnetic field. Non-adiabatic hopping can be performed to a magnetic field in which energy levels including proton spins and aprotic spins avoid crossing. This value can be determined by analytical calculation, or by plotting the energy levels of the hamiltonians of the different magnetic fields and identifying the LAC, given the J-coupling between the nuclear spins in the system. In some embodiments, the magnetic field amplitude is at most about 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second, 0.9 seconds, 0.8 seconds, 0.7 seconds, 0.6 seconds, 0.5 seconds, 0.4 seconds, 0.3 seconds, 0.2 seconds, 0.1 seconds or less, at least about 0.1 seconds, 0.2 seconds, 0.3 seconds, 0.4 seconds, 0.5 seconds, 0.6 seconds, 0.7 seconds, 0.8 seconds, 0.9 seconds, 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds or more, or within a range defined by any two of the foregoing values, in a LAC condition.
In some embodiments, the modulation of the amplitude of the magnetic field comprises changing the magnetic field amplitude monotonically (or over a limited number of intervals, such as one to ten increasing intervals and/or one to ten decreasing intervals each). In some embodiments, the modulating of the amplitude of the magnetic field comprises linearly varying the amplitude of the magnetic field. The initial magnetic field amplitude of the sweep, the ending magnetic field amplitude, and the total duration of the sweep may be optimized for the target molecule. In some embodiments, the magnetic field amplitude during the sweep is within a lower limit and an upper limit. The lower limit may be at least about-2 μT, -1 μT, -0.9 μT, -0.8 μT, -0.7 μT, -0.6 μT, -0.5 μT, -0.4 μT, -0.3 μT, -0.2 μT, -0.1 μT or more, up to about-0.1 μT, -0.2 μT, -0.3 μT, -0.4 μT, -0.5 μT, -0.6 μT, -0.7 μT, -0.8 μT, -0.9 μT, -1 μT, -2 μT or less, or within a range defined by any two of the foregoing values. The upper limit may be at least about 0.1 μT, 0.2 μT, 0.3 μT, 0.4 μT, 0.5 μT, 0.6 μT, 0.7 μT, 0.8 μT, 0.9 μT, 1 μT, 2 μT or more, up to about 2 μT, 1 μT, 0.9 μT, 0.8 μT, 0.7 μT, 0.6 μT, 0.5 μT, 0.4 μT, 0.3 μT, 0.2 μT, 0.1 μT or less, or within a range defined by any two of the foregoing values. In some embodiments, the duration of the modulation may be at least about 100ms, 200ms, 300ms, 400ms, 500ms, 600ms, 700ms, 800ms, 900ms, 1,000ms, 2,000ms, 3,000ms, 4,000ms, 5,000ms, 6,000ms, 7,000ms, 8,000ms, 9,000ms, 10,000ms or more, up to about 10,000ms, 9,000ms, 8,000ms, 7,000ms, 6,000ms, 5,000ms, 4,000ms, 3,000ms, 2,000ms, 1,000ms, 900ms, 800ms, 700ms, 600ms, 500ms, 400ms, 300ms, 200ms, 100ms or less, or within a range defined by any two of the foregoing values. In some embodiments, the rate of amplitude change varies along the amplitude profile. In some embodiments, the constant adiabatic sweep is calculated by selecting a certain subset of the energy level avoidance crossings of the spin system. In some embodiments, the magnetic amplitude modulation comprises a combination of non-adiabatic hopping, monotonic amplitude modulation, and rate of change variation.
Purification and isolation
In some embodiments, the precursors may be selected or designed such that after hydrogenation and other potential chemical reactions, one of the products is a biologically relevant contrast agent that can be used in hyperpolarized NMR or MRI applications. In some embodiments, the bio-related contrast agent is produced by an additional chemical reaction after hydrogenation. Such additional chemical reactions may comprise cleaving a side arm of the molecule (e.g., cleaving a compound of formula II, as described herein) to form a biologically relevant contrast agent and a side arm (e.g., a compound of formula III, as described herein), for example, by hydrolysis. After hydrogenation and polarization transfer, the para-hydrogenated precursor (e.g., a compound of formula II, as described herein) may be cleaved to produce a hyperpolarized bio-related contrast agent.
The volume of solution containing the bio-related contrast agent after lysing (and the concentration of the bio-related contrast agent produced) may depend on the volume of solution used for polarization transfer and the concentration of the precursor in the solution. Exemplary ranges of solution volumes and precursor concentrations are described herein. As further specific examples, at least about 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, or more of a solution comprising at least about 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 200mM, 300mM, 400mM, 500mM, or more of a biologically relevant contrast agent may be produced.
Consistent with the disclosed embodiments, after polarization transfer and cleavage of the precursor to produce the hyperpolarized bio-related contrast agent, the properties of the solution containing the hyperpolarized bio-related contrast agent may be altered to induce precipitation of the hyperpolarized bio-related contrast agent.
Such precipitation may enable separation of the hyperpolarized bio-related contrast agent from other substances in the solution (e.g., sidearm fragments). The precipitate may form crystals, amorphous solid particles, polycrystalline material, and the like. After precipitation, at least a fraction of the solid hyperpolarized bio-related contrast agent (or hyperpolarized precursor) may be separated from the solution and other substances in the solution. For example, a mixture of precipitate and solution may be filtered to remove particulates. The filtered precipitate may be washed with a second solvent. The second solvent may be selected to remove residues of the original solvent and other substances in the solution without completely dissolving the filtered precipitate. In some embodiments, the washing step occurs within up to about 300 seconds, 200 seconds, 100 seconds, 90 seconds, 80 seconds, 70 seconds, 60 seconds, 50 seconds, 30 seconds, 20 seconds, 10 seconds, at least about 10 seconds, 20 seconds, 30 seconds, 50 seconds, 60 seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds, 200 seconds, 300 seconds, or more, or within a period of time within a range defined by any two of the foregoing values.
The precipitation may be performed using an aqueous solution or a solution containing an organic solvent such as acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanone, t-butanol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1, 2-dichloroethane, diethylene glycol, diethyl ether, diethylene glycol dimethyl ether (diglyme), 1, 2-dimethoxyethane (glyme, DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 4-dioxane, ethanol, ethyl acetate, ethylene glycol, glycerol, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphoric triamide (HMPT), hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyrrolidone (NMP), nitromethane, pentane, petroleum ether (volatile oil), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, water, heavy water, o-xylene, m-xylene, p-xylene. In some embodiments, an organic solvent is used for the polarizing and precipitating steps. For example, para-hydrogen may be more soluble in a range of organic solvents than in aqueous solutions. Thus, hydrogenation can be performed more efficiently in such solvents. Thus, PHIP may appear in solutions formed with organic solvents. In some embodiments, aqueous solutions are used for hydrogenation and polarization transfer. In some embodiments, the aqueous solution may be mixed with a miscible organic solvent prior to precipitation of the hyperpolarized bio-related contrast agent.
In some embodiments, precipitation of the biologically relevant contrast agent is induced by changing the pH of the solvent. In organic solvents, certain biologically relevant contrast agents (e.g., carboxylic acids, pyridines, etc.) may be soluble at concentrations suitable for polarization using PHIP. However, salts of these biologically relevant contrast agents may be very insoluble. For example, such salts may be present at a concentration within any one or more of the preceding ranges of up to about 10mM, 9mM, 8mM, 7mM, 6mM, 5mM, 4mM, 3mM, 2mM, 1mM, 0.9mM, 0.8mM, 0.7mM, 0.6mM, 0.5mM, 0.4mM, 0.3mM, 0.2mM, 0.1mM, 0.09mM, 0.08mM, 0.07mM, 0.06mM, 0.05mM, 0.04mM, 0.03mM, 0.02mM, 0.01mM or less, at least about 0.01mM, 0.02mM, 0.03mM, 0.04mM, 0.05mM, 0.06mM, 0.07mM, 0.08mM, 0.09mM, 0.1mM, 0.2mM, 0.3mM, 0.04mM, 0.05mM, 0.6mM, 0.7mM, 0.8mM, 0.9mM, 1mM, 2mM, 4mM, 7mM, 10mM, or more of any one or more of these. The organic solution may contain a concentration of a biologically relevant contrast agent suitable for hyperpolarization using PHIP. After polarization, the pH of the organic solution may be changed to induce precipitation of salts of the bio-related contrast agent. In aqueous solution, salts of certain biologically relevant contrast agents (e.g., fumarate, glutamate, etc.) are more soluble than the acidic forms. Thus, the aqueous solution may contain a concentration of a biologically relevant contrast agent suitable for hyperpolarization using PHIP. After polarization, the pH of the aqueous solution may be lowered to induce precipitation of the biologically relevant contrast agent in acidic form.
Consistent with the disclosed embodiments, the change in pH may be induced by adding acidic or basic molecules (such as sodium chloride or sodium hydroxide) to the solution. In some embodiments, the change in pH may be induced by mixing the solution with another solution having a substantially different pH. In some embodiments, precipitation due to a pH change occurs in a period of time up to about 100 seconds, 90 seconds, 80 seconds, 70 seconds, 60 seconds, 50 seconds, 40 seconds, 30 seconds, 20 seconds, 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second or less, at least about 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 60 seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds or more, or within a range defined by any two of the foregoing values.
In some embodiments, precipitation of the bio-related contrast agent is induced without changing the pH of the solution that induces the hyperpolarized bio-related contrast agent to change between salt and acid forms.
In some embodiments, the hydrogenation and polarization transfer occurs in a first solution having a first solvent. The biologically relevant contrast agent may have a high solubility in the first solvent. Precipitation may be induced by mixing the first solution with a second solvent to form a second solution. The second solvent may be selected such that the solubility of the biologically relevant contrast agent in the second solution is low enough to initiate precipitation.
In some embodiments, the temperature of the solution changes, thereby reducing the solubility of the hyperpolarized molecule and initiating precipitation. In most solvents, solubility decreases with decreasing temperature. The temperature change to a desired temperature with lower solubility may be performed in a period of time up to about 100 seconds, 90 seconds, 80 seconds, 70 seconds, 60 seconds, 50 seconds, 40 seconds, 30 seconds, 20 seconds, 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second or less, at least about 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 60 seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds or more, or within a range defined by any two of the foregoing values. For example, the maximum mole fraction of acetic acid in n-heptane is 0.935 at 14.8 ℃, is only 0.02 at-29.2 ℃, and is lower at even lower temperatures. The precipitation temperature selected may be selected to be a temperature above the freezing point of the solvent.
In some embodiments, the surface area of the solution is increased to induce nucleation of the precipitate. This can be achieved by spraying the solution, for example through a nozzle, to produce very small droplets with a high surface area. In some embodiments, a microcrystalline seed (which may be a biologically relevant contrast agent or another biocompatible compound) is added to the solution to induce precipitation.
In some embodiments, the pressure of the solution changes, thereby reducing the solubility of the hyperpolarized compound and initiating precipitation.
In some embodiments, the concentration of the hyperpolarized bio-related contrast agent is raised above its solubility limit, thereby inducing precipitation without reducing the level of compound solubility in the solvent. This may be achieved, for example, by adding non-polarized molecules of the bio-related contrast agent or by evaporating a certain volume of solvent, thereby increasing the concentration of the bio-related contrast agent above its solubility limit.
In some embodiments, the parameters of the PHIP polarization are optimized for high concentrations, such as above the solubility limit of the biologically relevant contrast agent in its acid or salt form, even at the cost of achieving lower polarization. This can be achieved, for example, by starting from a high concentration of the precursor for hydrogenation and selecting a long hydrogenation time, which can lead to a decrease of the polarization due to relaxation, to achieve a high bio-related contrast agent concentration.
In some embodiments, precipitation is accelerated by adding mechanical energy or improving the mixing of the mixture for a certain duration. This may be performed by applying ultrasound to the mixture, for example by an ultrasound convener, or by mechanical or magnetic mixing of the samples. In some embodiments, additional mixing or introduction of mechanical energy occurs for at least about 0.1 seconds, 0.2 seconds, 0.3 seconds, 0.4 seconds, 0.5 seconds, 0.6 seconds, 0.7 seconds, 0.8 seconds, 0.9 seconds, 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds or more, up to about 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second, 0.9 seconds, 0.8 seconds, 0.7 seconds, 0.6 seconds, 0.5 seconds, 0.4 seconds, 0.3 seconds, 0.2 seconds, 0.1 seconds or less, or for a period of time within a range defined by any two of the foregoing values.
In some embodiments, precipitation is induced by a chemical reaction involving hyperpolarized bio-related contrast agent. The hyperpolarized bio-related contrast agent may react with another compound or in response to an external stimulus, such as electromagnetic radiation (e.g., ultraviolet radiation). The solubility of the product of this reaction may be reduced compared to hyperpolarized bio-related contrast agents, thereby inducing precipitation. For example, the external stimulus may alter the structure of the hyperpolarized bio-related contrast agent, thereby reducing the solubility of the hyperpolarized bio-related contrast agent. After the precipitate is redissolved, additional reactions may be performed to produce the desired end product (e.g., bio-related contrast agent, NMR material, etc.).
In some embodiments, hydrolysis of the precursor induces precipitation. In some embodiments, the solvent is selected such that the precursor is more soluble than the biologically relevant contrast agent. The concentration of the precursor in the solution may be selected such that the bio-related contrast agent precipitates out of solution after cleavage of the sidearm and generation of the bio-related contrast agent. In some such embodiments, cleavage is initiated by changing the pH of the solution. For example, the cleavage may be initiated by the addition of a base (e.g., sodium hydroxide or another suitable base). In some embodiments, the solution is formed with an organic solvent, and the cleavage may be performed under alkaline conditions. After lysis, the less soluble biologically relevant contrast agent is subjected to rapid precipitation while maintaining its polarization. The same solution may be used for hydrogenation, polarization transfer and precipitation, or another solvent may be mixed into the solution for hydrogenation and polarization transfer.
In some embodiments, precipitation of the precursor occurs prior to cleavage. Such embodiments may be suitable when the precursor is more stable than the biologically relevant contrast agent. Precipitation of the precursor may be induced by changing the pH of the solution to reduce the solubility of the precursor, or by mixing in a solution or compound that reduces the solubility of the precursor. In such embodiments, cleavage of the precursor may be performed after re-dissolution of the precursor in the solvent. The precursor may be filtered and washed as described herein to remove other materials present in the original solution, such as the hydrogenation catalyst. The precursors may then be reacted (e.g., by cleaving the side arms) to form the bio-related contrast agent. The biologically relevant contrast agent may be separated from other reaction products by liquid-liquid extraction or by an additional precipitation step consistent with the precipitation methods described herein. In some embodiments, precipitation may occur after the generation of the biologically relevant contrast agent from the precursor. Such precipitation may be performed according to the methods described herein.
In some embodiments, the conversion of spin order to polarization occurs before solidifying and precipitating the compound. In other embodiments, the transformation occurs after resolubilization of the crystals with a biologically relevant contrast agent.
In some embodiments, several steps of precipitation, washing, and redissolution are performed. This may be advantageous for further purification of the biologically relevant contrast agent, thereby increasing the relaxation time of the precipitate or for further separation of the polarization and cleavage steps. For example, the first precipitate may be used to wash out the catalyst, while the second precipitate is in crystalline form with a longer relaxation time, and it may be used for transport. In some embodiments, the first precipitate is a compound of formula II after hydrogenation and polarization transfer, and the second precipitate is performed after cleavage.
Consistent with the disclosed embodiments, the precipitation (and optionally washing) step may separate the hyperpolarized bio-related contrast agent from other substances in the original solution (e.g., catalyst, original solvent, reaction product, etc.). For example, most of the hydrogenation catalyst present in the original solution may remain in the original solution after precipitation of the biologically relevant contrast agent. In some embodiments, the precipitate (optionally after washing) may be maintained up to about 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001% or less of the hydrogenation catalyst, at least about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8% or more of the hydrogenation catalyst within the hydrogenation range defined by any two or more of the hydrogenation values described above. Similarly, the precipitate may remain up to about 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001% or less of the cleavage by-product (e.g., side arm or other residue of cleavage), at least about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.7%, 0.8%, 0.9% or more of the amount of the cleavage by-product being within any two of the cleavage by-product or more than the cleavage by-product.
In some embodiments, after precipitation and separation from the original solvent (and potential transport of the hyperpolarized precipitate), the precipitate is resolubilized in the solvent (e.g., for use as a pharmaceutical agent in hyperpolarized NMR or MRI). The solvent may be a biocompatible solvent, such as an aqueous solution. In some embodiments, the redissolution is performed at up to about 60 seconds, 50 seconds, 40 seconds, 30 seconds, 20 seconds, 10 seconds, 9 seconds, 8 seconds, 7 seconds, 6 seconds, 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second or less, at least about 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 60 seconds or more, or within a time period within a range defined by any two of the foregoing values.
In some embodiments, after resolubilization, the biologically relevant contrast agent is present at a higher concentration than that used during PHIP polarization. In some embodiments, the concentration of the hyperpolarized bio-related contrast agent after resolubilization is at least about 100mM, 150mM, 200mM, 250mM, 300mM, 350mM, 400mM, 450mM, 500mM or more, up to about 500mM, 450mM, 400mM, 350mM, 300mM, 250mM, 200mM, 150mM, 100mM or less, or within a range defined by any two of the foregoing values. Thus, the concentration of the precursor or biologically relevant contrast agent during polarization may be independent of the concentration of the molecules in the injection solution. The concentration of the precursor or biologically relevant contrast agent during polarization may be selected for efficient polarization transfer. In some embodiments, the concentration of this polarization is less than the concentration of the hyperpolarized bio-related contrast agent after resolubilization. For example, the polarization concentration may be at least about 300mM, 200mM, 150mM, 140mM, 130mM, 120mM, 110mM, 100mM, 90mM, 80mM, 70mM, 60mM, 50mM, 40mM, 30mM, 20mM, 10mM or less, or up to about 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM, 80mM, 90mM, 100mM, 110mM, 120mM, 130mM, 140mM, 150mM, 200mM, 300mM or more, or within a range defined by any two of the foregoing values.
In some embodiments, the sample of the precipitate exhibits a polarization of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50% more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or a polarization within a range defined by any two of the foregoing values. For example, in some embodiments, the first and second processing elements, samples of the precipitate exhibited between 10% and 15%, between 10% and 20%, between 10% and 25%, between 10% and 30%, between 10% and 35%, between 10% and 40%, between 10% and 45%, between 10% and 50%, between 15% and 20%, between 15% and 25%, between 15% and 30%, between 15% and 35%, between 15% and 40%, between 15% and 45%, between 15% and 50%, between 20% and 25%, between 20% and 30%, between 20% and 35%, between polarization between 20% and 40%, between 20% and 45%, between 20% and 50%, between 25% and 30%, between 25% and 35%, between 25% and 40%, between 25% and 45%, between 25% and 50%, between 30% and 35%, between 30% and 40%, between 30% and 45%, between 30% and 50%, between 35% and 40%, between 35% and 45%, between 35% and 50%, between 40% and 45%, between 40% and 50% or between 45% and 50%.
The concentration of catalyst, precursor, or cleavage by-product after particle resolubilization may each be up to about 1. Mu.M, 900 nanomolar (nM), 800nM, 700nM, 600nM, 500nM, 400nM, 300nM, 200nM, 100nM, 90nM, 80nM, 70nM, 60nM, 50nM, 40nM, 30nM, 20nM, 10nM, 9nM, 8nM, 7nM, 6nM, 5nM, 4nM, 3nM, 2nM, 1nM or less, at least about 1nM, 2nM, 3nM, 4nM, 5nM, 6nM, 7nM, 8nM, 9nM, 10nM, 20nM, 30nM, 40nM, 50nM, 60nM, 70nM, 80nM, 90nM, 100nM, 200nM, 300nM, 400nM, 500nM, 600nM, 700nM, 800nM, 900nM, 1nM or more, or within a range defined by any two of the foregoing values. In some embodiments, the purity of the hyperpolarized bio-related contrast agent after resolubilization is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, at most about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90% or less, or within a range defined by any two of the foregoing values. In some embodiments, at least a portion of the hyperpolarized compound is separated from the cleaved side arms or other reaction byproducts, if present.
Transportation of
Consistent with the disclosed embodiments, polarization transfer and use of biologically relevant contrast agents may occur at different locations. In some embodiments, the precursor (in solution for polarization transfer or as a precipitate) is transported to another location after precipitation. In some embodiments, the biologically relevant contrast agent (in solution for polarization transfer, as a precipitate or resolubilization) is transported to another location. The disclosed embodiments are not necessarily limited to any particular shipping distance or duration. Instead, the maximum distance or duration may be determined based on the target molecule, the degree of origin or polarization, the desired final degree of polarization, and the transport conditions. In some embodiments, the sediment is transported in a suitable transport means for at least one meter.
Consistent with the disclosed embodiments, the transport device may be configured to transport a sample of a precursor or biologically relevant contrast agent. The transport device may be arranged and configured for transporting one or more samples simultaneously. The transport device may include a transport chamber configured to receive one or more samples. The transport device may be configured to maintain the transport chamber within a predetermined temperature range and a predetermined magnetic field strength. The transport device may be configured to maintain the one or more samples in a magnetic field of at least about 10G, 20G, 30G, 40G, 50G, 60G, 70G, 80G, 90G, 100G, 200G, 300G, 400G, 500G, 600G, 700G, 800G, 900G, 1,000G or more, at most about 1,000G, 900G, 800G, 700G, 600G, 500G, 400G, 300G, 200G, 100G, 90G, 80G, 70G, 60G, 50G, 40G, 30G, 20G, 10G or less, or in a range defined by any two of the foregoing values.
A permanent magnet or an electromagnet contained in the transport device may provide the magnetic field. In some embodiments, the permanent magnet or electromagnet is shielded to reduce the magnetic field strength outside the transport device. The transport device may also comprise a cooling system. The cooling system may be configured to maintain the sample at a predetermined temperature or within a predetermined temperature range during transportation. For example, the cooling system may be configured to maintain the sample at a temperature below 270K, below 80K, or below 4K. In some embodiments, the transport device is configured to maintain the sample at a temperature of about liquid nitrogen. The transport device may contain an insulation layer between the cooling system and the outside of the transport device to minimize heat exchange with the outside environment. In some embodiments, the cooling system is configured to maintain the temperature of the sample using a flow of cold gas. In some embodiments, the cooling system is configured to maintain the temperature of the sample using a liquid coolant. In some embodiments, the transport device comprises a Dewar (Dewar) to provide cooling of the sample. In order to distribute hyperpolarized samples also over large distances, the containers may be transported by standard transportation means, such as aircraft, trains, trucks, automobiles and boats.
In some embodiments, the hyperpolarized precipitated particles are transported in a transport device. In some embodiments, the relaxation time of the hyperpolarized precipitated particles in the transport device is at least about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours or more, up to about 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute or less, or a relaxation time within a range defined by any two of the foregoing values.
Generation of polarized bio-related contrast agents
FIG. 1 depicts a first exemplary process 1 for generating polarized bio-related contrast agents in accordance with various embodiments00. In the example shown, process 100 includes providing a composition including a compound of formula I at step 110. In some embodiments, the compound of formula (I) comprises: a Z group comprising: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-c≡c-), as described herein; r is R 1 A group comprising a PHIP transfer moiety as described herein; r is R 2 A group comprising an optionally substituted hydrocarbon, alkoxy, primary, secondary or tertiary amine or solubilizing moiety, as described herein; r is as follows 3 A group comprising a biologically relevant contrast agent, as described herein.
At step 120, the double or triple bond in the compound of formula I is hydrogenated with para-hydrogen to form a para-hydrogenated derivative of the compound of formula I, wherein the para-hydrogenated derivative is a compound having the structure of formula II. In some embodiments, the compound of formula II comprises: z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof, wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 A group comprising a PHIP transfer moiety, as described herein; r is R 2 A group comprising an optionally substituted hydrocarbon, alkoxy, primary, secondary or tertiary amine or solubilizing moiety, as described herein; r is as follows 3 A group comprising a biologically relevant contrast agent, as described herein. In some embodiments, the compound of formula I is hydrogenated with para-hydrogen using the hydrogenation methods described herein.
At step 130, a polarization transfer waveform is applied to transfer nuclear spin order from at least one H in the sidearm of the compound of formula II to any non-hydrogen nuclear spins in the bio-related contrast agent of the compound of formula II, as described herein, thereby forming a derivative of the compound of formula II having a hyperpolarized bio-related contrast agent. In some embodiments, the nuclear spin order is transferred using any of the polarization transfer methods described herein.
Fig. 2 depicts a second exemplary process 200 for generating polarized bio-related contrast agents in accordance with various embodiments of the present disclosure. In the example shown, process 200 includes providing a composition including a compound of formula II at step 210. In some embodiments, formula II comprises: z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof, as described herein, wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 A group comprising a PHIP transfer moiety, as described herein; r is R 2 A group comprising an optionally substituted hydrocarbon, alkoxy, primary, secondary or tertiary amine or solubilizing moiety, as described herein; r is as follows 3 A group comprising a biologically relevant contrast agent, as described herein.
At step 220, a polarization transfer waveform is applied to transfer nuclear spin order from at least one H in the sidearm of the compound of formula II to any non-hydrogen nuclear spins in the bio-related contrast agent of the compound of formula II, as described herein, thereby forming a derivative of the compound of formula II having a hyperpolarized bio-related contrast agent.
At step 230, the derivative compound of formula II is hydrolyzed to form a composition comprising the hyperpolarized bio-related contrast agent and the single side arm compound of formula III. In some embodiments, the compound of formula III comprises: z ", which is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof, as described herein; r is R 1 A' group comprising a para-hydrogen induced polarization (PHIP) transfer moiety, as described herein; r is as follows 2 A group comprising an optionally substituted hydrocarbon, alkoxy, primary, secondary or tertiary amine or solubilizing moiety, as described herein.
At step 240, the hyperpolarized bio-related contrast agent is washed one or more times with an organic solvent. In some embodiments, the non-hydrogen nuclear spins in the biologically relevant contrast agent after the washing step have a non-hydrogen spin polarization of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more, up to about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less, or within a range defined by any two of the foregoing values.
In some embodiments, process 100 or process 200 includes one or more additional steps or operations. In some embodiments, process 100 or process 200 omits one or more steps or operations. In some embodiments, one or more steps or operations of process 100 are combined with one or more steps or operations of process 200. In some embodiments, all steps or operations of process 100 and process 200 are combined to produce a complete process for generating a hyperpolarized contrast agent from a precursor having the structure of formula I.
Examples are given
The foregoing non-limiting embodiments disclosed herein comprise:
example 1 a composition comprising a compound of formula (I):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-); r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Including a bio-related contrast agent comprising non-hydrogen nuclear spins.
Example 2 a composition comprising a compound of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Including a bio-related contrast agent comprising non-hydrogen nuclear spins.
Example 3. A composition comprising: (i) A bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (III):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; r is R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; and R is 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
Example 4. A composition comprising: (i) A hyperpolarized bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (IV):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof, or (ii) a carbon-carbon triple bond (-c≡c-); r is R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
Embodiment 5 the composition of any one of embodiments 1-4, wherein the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.
Embodiment 6. The composition of any one of embodiments 1 to 5, wherein the PHIP transfer moiety comprises a CR 4 R 5 、*CR 4 Y, =c=y or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; r is R 4 And R is 5 Each independently selected from: 1 H、 2 H、 3 H. linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl; and Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
Embodiment 7. The composition of any one of embodiments 1 to 5, wherein the PHIP transfer moiety comprises a CR 6 R 7 –*CR 8 R 9 Or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; and R is 6 、R 7 、R 8 And R is 9 Each independently selected from: 1 H、 2 H、 3 H. straight, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl.
Embodiment 8 the composition of any one of embodiments 1-5, wherein the PHIP transfer moiety comprises an ACH 2 、*CH 2 –*CH 2 Che, =y, or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; and Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
Embodiment 9. The composition of embodiment 6 or embodiment 8, wherein the spin-1/2 atoms are selected from the group consisting of: 1 H、 13 C、 15 N、 19 f or F 31 P。
Embodiment 10. The composition of any one of embodiments 1 to 9, wherein the PHIP transfer moiety comprises at least one atom that is coupled to the J of the non-hydrogen nuclear spin to at least 0.1 hertz (Hz).
Embodiment 11. The composition of any of embodiments 1-10, wherein Z comprises at least one atom that is coupled to the J of the non-hydrogen nuclear spin at least 0.1 hertz (Hz).
Embodiment 12. The composition of any one of embodiments 1 to 11, wherein R 2 Including the solubilising portion.
Embodiment 13 the composition of any one of embodiments 1 through 12, wherein R 2 Including hydrophobic and/or organophilic moieties.
Example 14 the composition of example 13 wherein R 2 Including organic solubilizing moieties.
Embodiment 15 the composition of any one of embodiments 1 through 12, wherein R 2 Including hydrophilic and/or oleophobic moieties.
Embodiment 16. The composition of any of embodiments 1 to 15, wherein R 2 Comprising or being selected from: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl,Hydroxyl, methanol, ethanol, n-propanol, isopropanol, propanol, n-butanol, sec-butanol, tert-butanol, isobutanol, methoxy, ethoxy, propoxy, isopropoxy, propanoic, butoxy, tert-butoxy, sec-butoxy, ester, phenyl, substituted phenyl, primary amino, secondary amino, tertiary amino, primary amino, secondary amino and tertiary amino.
Embodiment 17 the composition of any one of embodiments 1 through 16, wherein the biologically relevant contrast agent comprises formula R 10 Compounds of C (=o) X-; wherein R is 10 Selected from linear, branched or cyclic C1-C10 alkyl groups, wherein one or more C atoms are optionally substituted with c= C, CO, COH, CNH 2 、COOH、CH 2 COOH、CONH 2 OC (=o) substitution; and X is selected from NR 11 S and O; wherein R is 11 Selected from the group consisting of 1 H、 2 H、 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, benzyloxycarbonyl, t-butyl carbonate and benzyl.
Embodiment 18 the composition of any one of embodiments 1 to 17, wherein the bio-related contrast agent is selected from the group consisting of: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.
Embodiment 19. The composition of any of embodiments 1 to 18, wherein the composition has a solubility in water of less than 50 millimoles (mM).
Embodiment 19a. The composition of any of embodiments 1-18, wherein the composition has a solubility in an organic solvent (e.g., acetone, ethanol, chloroform, toluene) of less than 50 millimoles (mM).
Embodiment 20. The composition of any of embodiments 1 to 19a, wherein the composition is reacted with para-hydrogen such that the chemical yield of para-hydrogenated product is at least 30%.
Embodiment 21. The composition of any one of embodiments 1 to 20 for use in a para-hydrogen induced polarization (PHIP) process.
Example 22. A method for preparing a hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof, the method comprising: (a) Providing a composition comprising a compound of formula (I):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-); r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins; (b) Hydrogenating a double or triple bond in the compound of formula I with para-hydrogen to form a para-hydrogenated derivative of the compound of formula I, the para-hydrogenated derivative having the structure of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins; and (c) applying a polarization transfer waveform to sequentially transfer nuclear spins from at least one H in the compound of formula II to the non-hydrogen nuclear spins,thereby forming a derivative of formula II having a hyperpolarized bio-related contrast agent.
Example 23 a method for preparing a hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof, the method comprising: (a) Providing a composition comprising a compound of formula (II):
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wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; wherein H is hydrogen having a spin order derived from para-hydrogen; r is R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties; r is R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and R is 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins; and (b) applying a polarization transfer waveform to sequentially transfer nuclear spins from at least one H-x in the compound of formula II to the non-hydrogen nuclear spins, thereby forming a derivative of formula II with a hyperpolarized bio-related contrast agent.
Embodiment 24. The method of embodiment 22 or embodiment 23, further comprising hydrolyzing the derivative of formula II to provide a composition comprising: (i) A hyperpolarized bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (III):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; r is R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; and R is 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
Embodiment 25. The method of embodiment 24, further comprising washing the hyperpolarized bio-related contrast agent one or more times with an organic solvent.
Embodiment 26. The method of embodiment 25, wherein after the washing step, the non-hydrogen nuclear spin polarization of the non-hydrogen nuclear spin is greater than 10%.
Embodiment 27. The method of any of embodiments 22 to 26, wherein the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.
Embodiment 28. The method of any one of embodiments 22 to 26, wherein the PHIP transfer portion comprises a CR 4 R 5 、*CR 4 Y, =c=y or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; r is R 4 And R is 5 Each independently selected from: 1 H、 2 H、 3 H. linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl; and Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
Embodiment 29. The method of any one of embodiments 22 to 26, wherein the PHIP transfer portion comprises a CR 6 R 7 –*CR 8 R 9 Or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; and R is 6 、R 7 、R 8 And R is 9 Each independently selected from: 1 H、 2 H、 3 H. straight chain, branched chainOr cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl.
Embodiment 30. The method of any one of embodiments 22 to 26, wherein the PHIP transfer portion comprises an ACH 2 、*CH 2 –*CH 2 Che, =y, or any deuterated version thereof, wherein: * C is 12 C or 13 A C carbon isotope; and Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
Embodiment 31. The method of embodiment 28 or embodiment 30, wherein the spin-1/2 atoms are selected from the group consisting of: 1 H、 13 C、 15 N、 19 f or F 31 P。
Embodiment 32. The method of any of embodiments 22-31, wherein the PHIP transfer moiety comprises at least one atom that is coupled to the J of the non-hydrogen nuclear spin to be at least 0.1 hertz (Hz).
Embodiment 33. The method of any of embodiments 22 to 32, wherein Z or Z' comprises at least one atom that is coupled to the J of the non-hydrogen nuclear spin at least 0.1 hertz (Hz).
Embodiment 34. The method of any one of embodiments 22 to 33, wherein R 2 Including the solubilising portion.
Embodiment 35 the method of any one of embodiments 22 to 34, wherein R 2 Including hydrophobic and/or organophilic moieties.
Example 36 the method of example 35 wherein R 2 Including organic solubilizing moieties.
Embodiment 37 the method of any one of embodiments 22-33, wherein R 2 Including hydrophilic and/or oleophobic moieties.
Embodiment 38. The method of any one of embodiments 22 to 37, wherein R 2 Comprising or being selected from: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, hydroxyl, methanoyl, ethanoyl, n-propanoyl, isopropanol, propanoyl, n-butanoyl, sec-butanoyl, tert-butanoyl, isobutanoyl, methoxy, ethoxy, propoxy, isopropoxy, propanoyl, butoxy, tert-butoxy, sec-butoxy, ester, phenyl, substituted phenyl, primary amino, secondary amino, tertiary amino, primary amino, secondary amino and tertiary amino.
Embodiment 39. The method of any of embodiments 22 to 38, wherein the biologically relevant contrast agent comprises formula R 10 Compounds of C (=o) X-; wherein R is 10 Selected from linear, branched or cyclic C1-C10 alkyl groups, wherein one or more C atoms are optionally substituted with c= C, CO, COH, CNH 2 、COOH、CH 2 COOH、CONH 2 OC (=o) substitution; and X is selected from NR 11 S and O; wherein R is 11 Selected from the group consisting of 1 H、 2 H、 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, benzyloxycarbonyl, t-butyl carbonate and benzyl.
Embodiment 40. The method of any one of embodiments 22 to 39, wherein the bio-related contrast agent is selected from the group consisting of: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.
Embodiment 41 a hyperpolarized bio-related contrast agent or pharmaceutically acceptable salt thereof produced by the method according to any one of embodiments 22-40.
Examples
EXAMPLE 1 NMR procedure
In the case of 1 H operates at 400.13MHzAnd for the following 13 C NMR spectra were recorded on a Bruker Avance Neo 400MHz spectrometer operating at 100.61 MHz. Trichloromethane (CHCl) 3 ) Is used as 1 Solvent for H NMR experiments, while deuterated chloroform (CDCl) 3 ) Is used as 13 Solvents for C NMR experiments. NMR chemical shifts (δ) are reported in ppm. For the following 1 H and 13 c spectrum, use of solvent signal for internal calibration [ 1 H NMR：δ(CHCl 3 )7.26； 13 C NMR：δ(CDCl 3 )77.16]. Recording in proton decoupling mode 13 C NMR spectrum. UsingHC Duo column as solid phase and mixture of cyclohexane and ethyl acetate as mobile phase with +.>The Selekt flash purification system performs flash chromatography. Column chromatography was performed on silica gel (silica 60, 63-200 μm, ma Xieli-Nagel (Macherey-Nagel)) using a mixture of cyclohexane and ethyl acetate as the mobile phase.
EXAMPLE 2 general Synthesis procedure
Synthesis of esters with a, b-unsaturated side arms
Synthesis of side arms 1a-g
Alcohols 1a, 1c, 1d, and 1g (1 a: T. Yoshinao, K. Masanari, T. Shuji, K. Sigeru, Y. Zenichi, & Japanese society of chemistry publication (Bull. Chem. Soc. Jpn.) & 1994,67,2838-2849;1c: B.R. blank, I.P. Andrews, O.Kwon, & catalysis chemistry (chemCatchem) 2020,12,4352-4372;1d: G.C. Tsui, K. Villeneuve, E. Carlson, W.Tam, & organometallic (Organometallics) 2014,33,3847-3856;1g: L. Pauli, R.Tannet, R.Scheil, A.Pfaltz, & European journal of chemistry (chem. Eur. J2015,21,1482.). 1487) were prepared according to published proceduresThe methods used to synthesize 1a, 1c, 1d, and 1g are incorporated herein by reference). Alcohol 1b was prepared starting from tetrahydro-2- (2-propynyloxy) -2H-pyran and isopropyl chloroformate by performing the procedure for synthesis 1a, followed by deprotection of the THP group with pyridinium p-toluenesulfonate. According to the use of di-tert-butyl decarbonated-d 18 Synthesis of substituted di-tert-butyl dicarbonate 1c-d by Selective deuteration of tert-butyl 9 . 1c-d by the following reaction scheme 1 Is optionally mono-deuterated:
alcohol 1e (A.Kondoh, R.Ozawa, M.Terada, chem. Lett.) 2019,48,1164-1167, incorporated herein by reference with respect to the method used to synthesize alcohol 1e, was prepared according to the disclosed one-step synthesis from t-butyl propiolate and benzaldehyde. By using CO 2 Carboxylation followed by esterification with diphenylmethanol under casting conditions and THP-cleavage according to 1c, starting from tetrahydro-2- (2-propynyloxy) -2H-pyran, produces alcohol 1f (as described in O.Mitsunobu, Y.Yamada, japanese society of chemistry publication (Bulletin chem. Soc. Japan) (1967,40 (1), 2380-2382), incorporated herein by reference for a method for synthesizing alcohol 1 f). Alcohols 1g-d 5 According to 1g using benzoyl chloride-d 5 Rather than benzoyl chloride.
Synthesis of esters 2-4 from a, b-unsaturated side arms
General procedure a:
the target carboxylic acid (1.0-2.0 eq.) was dissolved in anhydrous tetrahydrofuran (THF, 200-350 mmol), the corresponding alcohol 1a-g was added, and the solution was cooled to 0 ℃ with an ice/water bath. At this temperature, pyridine (4.0-5.0 equivalents) was added dropwise over a period of 5 minutes, followed by methanesulfonyl chloride (1.2-2.0 equivalents) (or p-toluenesulfonyl chloride dissolved in THF) dropwise over a period of 10 minutes. The mixture is stirred until all the corresponding alcohols 1a-g have been consumed (via 1 HNMR monitoring if methanesulfonyl chloride and pyruvic acidIf used in high excess, at 0℃for 2-5 hours, at ambient temperature up to 18 hours if only small amounts of methanesulfonyl chloride or p-toluenesulfonyl chloride are used. During the reaction, a colourless precipitate formed in each case. After the reaction was completed, the reaction mixture was poured into a stirred mixture of 0.5N aqueous HCl (same volume as the solvent for the reaction) and diethyl ether (same volume as the solvent for the reaction). The phases were separated, the organic phase was collected and the aqueous phase was washed with diethyl ether (2 x200 ml). The combined organic phases were treated with saturated NaHCO 3 Aqueous (100 mL) and then brine (100 mL). The organic phase was taken up in Na 2 SO 4 Dried and volatile components were removed under reduced pressure (800.fwdarw.1 mbar,40 ℃ water bath). The crude product was purified by flash chromatography or by column chromatography.
General procedure B:
the corresponding alcohols 1a-g (1.0 eq.) were dissolved in anhydrous THF (200 mmol) and cooled to-78 ℃ with an acetone/dry ice bath. To the clear mixture was added anhydrous triethylamine (NEt 3 1.0 equivalent) and then acid chloride of the target carboxylic acid (1.0 equivalent) was added dropwise over a period of 3 minutes. After complete addition of acid chloride, the cooling bath was removed and the mixture was warmed to ambient temperature. The reaction was quenched by pouring the suspension into a stirred mixture of 0.5N aqueous HCl (same volume as solvent for reaction) and diethyl ether (same volume as solvent for reaction). The phases were separated, the organic phase was collected and the aqueous phase was washed with diethyl ether (2 x200 mL). The combined organic phases were treated with saturated NaHCO 3 Aqueous (100 mL) and then brine (100 mL). The organic phase was taken up in Na 2 SO 4 Dried and volatile components were removed under reduced pressure (800.fwdarw.1 mbar,40 ℃ water bath). The crude product was purified by flash chromatography if necessary.
Example 3-4- ((2-oxopropionyl) oxy) but-2-ynoic acid methyl ester (2 a)
Structure 2a was prepared according to general procedure A from alcohol 1a (7.08 g, 62.1 mmol) in THF (300 mL), pyruvic acid (10.9 g,124mmol,2.0 eq.)), pyridine (25 mL,310mmol,5.0 eq.)) and methanesulfonyl chloride (9.6 mL,124mmol,2.0 eq.)) at 0deg.C for 4 hours (h). Purification by column chromatography gave 2a (7.1 g,38mmol,61% yield) as a colorless, slightly viscous liquid.
FIG. 3A shows an example corresponding to structure 2a 1 H NMR(400MHz，CDCl 3 ) Spectra. The spectrum shows d=2.52 (singlet, integrated signal: 3H, corresponding to CH) 3 )、3.80(s，3H，OCH 3 ) And 4.96 (s, 2H, OCH) 2 ) Peak at.
FIG. 3B shows an example corresponding to structure 2a 13 C NMR(101MHz，CDCl 3 ) Spectra. The spectrum shows d=26.78 (CH 3 )、52.84(OCH 3 )、53.05(OCH 2 )、78.61(C≡C)、79.52(C≡C)、153.00(COOCH 3 ) Peaks at 159.36 (COO) and 190.23 (c=o).
Example 4-4- ((2-oxopropionyl) oxy) but-2-ynoic acid isopropyl ester (2 b)
Structure 2b was prepared according to general procedure A from alcohol 1b (6.36 g,40.7 mmol), pyruvic acid (7.16 g,81.4mmol,2.0 eq.) in THF (200 mL), pyridine (16.4 mL,203mmol,5.0 eq.) and tosyl chloride (15.5 g,81.4mmol,2.0 eq.) at 0deg.C for 2 hours and at ambient temperature for 15 hours. Purification by flash chromatography gave 2b (5.7 g,25mmol,62% yield) as a pale yellow slightly viscous liquid.
FIG. 4A shows an example corresponding to structure 2b 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=1.28 (dual state (d), 3 J H,H ＝6.29Hz，6H，2xCH 3 )、2.50(s，3H，CH 3 )、4.94(s，2H，OCH 2 ) And 5.09 (seven states (seven), 3 J H,H ＝6.26Hz，1H，OCH)peak at.
FIG. 4B shows an example corresponding to structure 2B 13 C NMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=21.61 (2 xCH 3 )、26.79(OCH 3 )、52.93(OCH 2 )、70.64(OCH)、78.62(C≡C)、79.33(C≡C)、152.15(COO t Bu), 159.43 (COO), and 190.25 (c=o).
Example 5-4- ((2-oxopropionyl) oxy) but-2-ynoic acid tert-butyl ester (2 c)
Structure 2c was prepared according to general procedure A from alcohol 1c (30.0 g,192 mmol), pyruvic acid (33.8 g, 284 mmol,2.0 eq.) pyridine (77.0 mL,954mmol,5.0 eq.) and methanesulfonyl chloride (30.0 mL, 3838 mmol,2.0 eq.) in THF (500 mL) at 0deg.C for 3 hours. Purification by flash chromatography gave 2c (33 g,146mmol,76% yield) as a pale yellow slightly viscous liquid.
FIG. 5A shows an example corresponding to structure 2c 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed that d=1.49 (s, 9H, t Bu)、2.50(s，3H，CH 3 ) And 4.93 (s, 2H, OCH) 2 ) Peak at.
FIG. 5B shows an example corresponding to structure 2c 13 C NMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=26.81 (CH 3 )、27.97(3x CH 3 )、53.02(OCH 2 )、76.78(C≡C)、80.21(C≡C)、84.36(OC- t Bu)、151.59(COO t Bu), 159.47 (COO), and 190.32 (c=o).
13 13 Example 6-4- ((2-oxopropionyl-1-C) oxy) but-2-ynoic acid tert-butyl ester (2C-C)
Structure 2c- 13 C( 13 C labelled 2C) according to general procedure A from alcohol 1C (4.40 g,28.1 mmol), pyruvic acid-1- 13 C (5.00 g,56.1mmol,2.0 eq.) pyridine (11.3 mL,140mmol,5.0 eq.) and methanesulfonyl chloride (4.34 mL,56.1mmol,2.0 eq.) were prepared at 0deg.C for 4 hours. Purification by flash chromatography gave 2 c-a colorless, slightly viscous liquid 13 C (4.50 g,19.8mmol,70% yield).
FIG. 6A shows a structure corresponding to structure 2c- 13 Exemplary of C 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed that d=1.49 (s, 9H, t Bu)、2.50(d， 3 J C,H ＝1.58Hz，CH 3 ) And 4.93 (d, 3 J C,H ＝3.54Hz，2H，OCH 2 ) Peak at.
FIG. 6B shows a structure corresponding to structure 2c- 13 Exemplary of C 13 CNMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=26.91 (d, 2 J C,C ＝17.08Hz，CH 3 )、28.07(3xCH 3 )、53.12(d， 2 J C,C ＝2.58Hz，OCH 2 )、76.76(d， 3 J C,C ＝2.51Hz，C≡C)、80.35(C≡C)、84.49(OC- t Bu)、151.69(COO t bu), 159.56 (COO) and 190.39 (d, 1 J C,C =67.07, c=o).
13 3 Example 7-4- ((2-oxopropionyl-1-C) oxy) but-2-ynoic acid 2- (methyl-d) prop-2-yl-1, 6 3,3-d ester (2 c)d 9 13 -C)
Structures 2c-d 9 - 13 C (9 times deuteration and) 13 C labeled Structure 2C) according to general procedure A from alcohols 1C-d in THF (130 mL) 9 (5.50 g,33.2 mmol) pyruvic acid-1- 13 C (5.00 g,56.1mmol,1.7 eq.) pyridine (11.3 mL,140mmol,4.2 eq.) and methanesulfonyl chloride (4.3 mL,56.1mmol,1.7 eq.) were prepared at 0deg.CPrepared for 5 hours. Purification by flash chromatography gave 2c-d as a colorless, slightly viscous liquid 9 -13 C (5.08 g,21.6mmol,65% yield).
FIG. 7A shows the corresponding structures 2c-d 9 - 13 Exemplary of C 1 HNMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=2.48 (d, 3 J C,H ＝1.56Hz，CH 3 ) And 4.91 (d, 3 J C,H ＝3.55Hz，2H，OCH 2 ) Peak at.
FIG. 7B shows a graph corresponding to 2c-d 9 - 13 Exemplary of C 13 C NMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=26.62-27.41 (multiple state (m), 3 xCD) 3 )、26.84(d， 2 J C,C ＝17.06Hz，CH 3 )、53.06(d， 2 J C,C ＝2.68Hz，OCH 2 )、76.76(d， 3 J C,C ＝2.45Hz，C≡C)、80.27(C≡C)、83.99(OC- t Bu)、151.64(COO t Bu), 159.50 (COO) and 190.35 (d, 1 J C,C =67.13, c=o).
1 Example 8-4- ((2-oxopropionyl) oxy) but-2-ynoic acid-4-d tert-butyl ester (2 c-d)
Structures 2c-d 1 (1-fold deuterated Structure 2 c) according to general procedure A from alcohols 1c-d in THF (400 mL) 1 (14.0 g,89.0 mmol), pyruvic acid (15.8 g,178mmol,2.0 eq.) pyridine (36.0 mL, 4475 mmol,5.0 eq.) and methanesulfonyl chloride (13.8 mL,178mmol,2.0 eq.) were prepared at 0deg.C for 1 hour and at ambient temperature for 3 hours. Purification by flash chromatography gave 2c-d as a pale yellow, slightly viscous liquid 1 (13.2 g,58.1mmol,65% yield).
FIG. 8A shows the corresponding structures 2c-d 1 Is shown in (a) and (b) 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed that d=1.49 (s, 9H, t Bu)、2.51(s，3H，CH 3 ) And 4.92 (triplet (t), 2 J H,D ＝2.34Hz，2H，OCH 2 ) Peak at.
FIG. 8B shows the corresponding structures 2c-d 1 Is shown in (a) and (b) 13 C NMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=26.66 (CH 3 )、27.84(3xCH 3 )、52.66(t， 1 J C,D ＝23.56Hz，OCHD)、76.78(C≡C)、80.00(C≡C)、84.19(OC- t Bu)、151.46(COO t Bu), 159.36 (COO), and 190.24 (c=o).
Example 9-4- ((2-oxopropionyl) oxy) pent-2-ynoic acid tert-butyl ester (2 d)
Structure 2d was prepared according to general procedure A from alcohol 1d (4.83 g,28.4 mmol), pyruvic acid (5.00 g,56.8mmol,2.0 eq.) in THF (80 mL), pyridine (11.5 mL,142mmol,5.0 eq.) and methanesulfonyl chloride (4.40 mL,56.8mmol,2.0 eq.) at 0deg.C for 3 hours and at ambient temperature for 1 hour. Purification by flash chromatography gave 2d (4.85 g,20.2mmol,71% yield) as a pale yellow slightly viscous liquid.
FIG. 9A shows an example corresponding to structure 2d 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed that d=1.48 (s, 9H, t Bu)、1.64(d， 3 J H,H ＝6.80Hz，OCHC 3 H)、2.49(s，3H，CH 3 ) And 5.58 (quadruple state (q), 3 J H,H ＝6.79Hz，1H，OCHCH 3 ) Peak at.
FIG. 9B shows an example corresponding to structure 2d 13 C NMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=20.35 (OCH)CH 3 )、26.77(CH 3 )、27.97(3xCH 3 )、61.87(OCHCH 3 )、78.58(C≡C)、80.62(C≡C)、84.21(OC- t Bu)、151.82(COO t Bu), 159.26 (COO), and 190.75 (c=o).
Example 9-4- ((2-oxopropionyl) oxy) -4-phenylbut-2-ynoic acid tert-butyl ester (2 e)
Structure 2e was prepared according to general procedure A from alcohol 1e (5.81 g,25.0 mmol), pyruvic acid (4.40 g,50.0mmol,2.0 eq.) in THF (100 mL), pyridine (10.7 mL,125mmol,5.0 eq.) and methanesulfonyl chloride (3.87 mL,50.0mmol,2.0 eq.) at 0deg.C for 1.5 hours and at ambient temperature for 2.5 hours. Purification by flash chromatography gave 2e (5.00 g,16.5mmol,66% yield) as a pale yellow viscous liquid.
FIG. 10A shows an example corresponding to structure 2e 1 HNMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed that d=1.50 (s, 9H, t Bu)、2.48(s，3H，CH 3 )、6.57(s，1H，OCHPh)、7.40–7.43(m，3H，H Ph ) And 7.53-7.56 (m, 2H, H) Ph ) Peak at.
FIG. 10B shows an example corresponding to structure 2e 13 CNMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=26.98 (CH 3 )、28.09(3x CH 3 )、67.23(OCHPh)、78.88(C≡C)、80.69(C≡C)、84.51(OC- t Bu)、128.26(C Ph )、129.18(C Ph )、130.09(C Ph )、134.23(C Ph )、151.86(COO t Bu), 159.16 (COO), and 190.56 (c=o).
Example 10-4- ((2-oxopropionyl) oxy) but-2-ynoic acid diphenyl methyl ester (2 f)
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Structure 2f was prepared according to general procedure B from 1f (1.60 g,6.00 mmol) to afford 2f (1.92 g,5.70mmol,95% yield) as a colorless viscous oil.
FIG. 11 shows a diagram corresponding toExemplary Structure 2f 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=2.51 (s, 3h, ch 3 )、4.97(s，2H，OCH 2 ) 6.94 (s, 1H, OCH) and 7.28-7.38 (m, 10H, H) Ph ) Peak at.
EXAMPLE 11 2-oxo-4-phenyl-but-2-yn-1-yl 2-oxopropanoate (2 g)
Structure 2g was prepared from 1g (2.49 g,15.5 mmol) according to general method B and purified by flash chromatography to give 2g-d as a pale orange solid 5 (1.86 g,8.06mmol,52% yield).
FIG. 12A shows an example corresponding to structure 2g 1 HNMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=2.54 (s, 3h, ch 3 )、5.11(s，2H)、OCH 2 )、7.48–7.52(m，2H，H Ph )、7.61–7.66(m，1H，H Ph ) And 8.09-8.11 (m, 2H, H) Ph ) Peak at.
FIG. 12B shows an example corresponding to structure 2g 13 CNMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=26.81 (CH 3 )、53.24(OCH 2 )、84.65(C≡C)、85.56(C≡C)、128.78(C Ph )、129.65(C Ph )、134.65(C Ph )、136.03(C Ph ) Peaks at 159.59 (COO), 176.91 (C (O) Ph) and 190.34 (c=o).
5 5 Example 12-4-oxo-4- (phenyl-d) but-2-yn-1-yl 2-oxopropionate (2 g-d)
Structure 2g-d 5 According to general procedure B from 1g-d 5 (4.66 g,28.2 mmol) to give 2g-d as a pale brown solid 5 (6.1g，25.9mmol，92％)。
FIG. 13A shows the corresponding structure 2g-d 5 Is shown in (a) and (b) 1 H NMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=2.49 (s, 3h, ch 3 ) And 5.09 (s, 2H, OCH) 2 ) Peak at.
FIG. 13B shows the corresponding structure 2g-d 5 Is shown in (a) and (b) 13 C NMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d= 26.79 (CH 3 )、53.23(OCH 2 )、84.62(C≡C)、85.55(C≡C)、128.24(t， 1 J C,D ＝24.58Hz，C Ph )、129.23(t， 1 J C,D ＝24.58Hz，C Ph )、134.14(t， 1 J C,D ＝22.45Hz，C Ph )、135.83(C Ph ) Peaks at 159.54 (COO), 176.91 (C (O) Ph) and 190.35 (c=o).
Example 13-2-oxoglutarate 1- (4- (t-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl ester (3 c)
Structure 3c was prepared according to general procedure A from alcohol 1c (0.92 g,5.9 mmol), monoethyl a-ketoglutarate (1.02 g,5.85mmol,1.0 eq.) in THF (40 mL), pyridine (1.88 mL,23.3mmol,4.0 eq.) and methanesulfonyl chloride (543. Mu.L, 7.02mmol,1.2 eq.) at 0deg.C for 5 hours and at 7deg.C for 40 hours. Purification by flash chromatography gave 3c (1.40 g,4.48mmol,77% yield) as a colorless viscous liquid containing 20% 1c, since esterification was not quantified and 3c had similar retention times as 1 c.
FIG. 14A shows an example corresponding to structure 3c 1 HNMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=1.25 (t, 3 J H,H ＝7.14Hz，3H，OCH 2 CH 3 )、1.49(s，9H， t Bu)、2.68(t， 3 J H,H ＝6.49Hz，2H，CH 2 CH 2 )、3.17(t， 3 J H,H ＝6.36Hz，2H，CH 2 CH 2 )、4.14(q， 3 J H,H ＝7.14Hz，2H，OCH 2 CH 3 ) And 4.94 (s, 2H, OCH) 2 ) Peak at.
FIG. 14B shows an example corresponding to structure 3c 13 CNMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=14.26 (OCH) 2 CH 3 )、27.87(CH 2 CH 2 )、28.06(3xCH 3 )、28.10(CH 2 CH 2 )、53.16(OCH 2 )、61.15(OCH 2 CH 3 )、76.74(C≡C)、80.37(C≡C)、84.46(OC- t Bu)、151.69(COO t Bu), 159.33 (COO), 171.95 (COOEt), and 191.27 (c=o).
Example 14 methyl 4- (2, 2-dichloroacetoxy) but-2-ynoate (4 a)
Structure 4a was prepared according to general procedure B from 1a (4.00 g,35.0 mmol) to afford 4a (7.72 g,34.3mmol,98% yield) as a colorless liquid.
FIG. 15A shows an example corresponding to structure 4a 1 HNMR(400MHz，CDCl 3 ) Spectra. NMR spectra showed d=3.80 (s, 3h, och 3 )、4.97(s，2H，OCH 2 ) And 5.99 (s, 1H, CHCl) 2 ) Peak at.
FIG. 15B shows an example corresponding to structure 4a 13 CNMR(101MHz，CDCl 3 ) Spectra. NMR spectra showed d=53.19 (OCH) 2 )、54.07(OCH 3 )、63.60(CHCl 2 )、79.05(C≡C)、79.11(C≡C)、153.08(COOCH 3 ) And a peak at 163.75 (COO).
Example 15-tert-butyl 4- ((acetoxy) but-2-ynoate (5 c)
Structure 5c was prepared according to general procedure B from 1c (5.50 g,35.2 mmol) and purified by flash chromatography to give 5c (5.72 g,28.8mmol,82% yield) as a colorless liquid.
Fig. 16A shows an exemplary 1HNMR (400 mhz, cdcl 3) spectrum corresponding to structure 5 c. NMR spectra showed peaks at δ=1.49 (s, 9h, tbu), 2.10 (s, 3h, ch 3) and 4.76 (s, 2h, och 2).
Fig. 16B shows an exemplary 13C NMR (101 mhz, cdcl 3) spectrum according to structure 5C. NMR spectra showed peaks at δ=20.68 (CH3), 28.08 (3 x CH3), 51.50 (OCH 2), 78.59 (c≡c), 79.32 (c≡c), 84.16 (OC-tBu), 151.96 (COOtBu) and 170.03 (COO).
EXAMPLE 16 improved hydrogenation efficiency
FIG. 17A shows an exemplary corresponding para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate (i.e., 3-phenylallyl 2-oxopropionate having two H) 1 H NMR(400MHz，CDCl 3 ) Spectra. The para-hydrogenation reaction between 3-phenylprop-2-yn-1-yl 2-oxopropionate and para-hydrogen is 1mol% [ Rh (dppb) (COD) ]]BF 4 Is carried out at 60℃and a para-hydrogen pressure of 10 bar for 10 seconds. The reaction forms the previously known 3-phenylallyl 2-oxopropionate having two H-symbols, wherein the symbols indicate molecules containing protons derived from para-hydrogen. In the example shown, the NMR signal marked with a symbol corresponds to a para-hydrogen molecule added across the carbon-carbon triple bond of 3-phenylprop-2-yn-1-yl 2-oxopropionate. Based on 1 H NMR spectra determined a yield of about 29% for the para-hydrogenation reaction.
FIG. 17B shows an example of tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate corresponding to para-hydrogenated tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate 1 HNMR(400MHz，CDCl 3 ) Spectra. The para-hydrogenation reaction between the novel molecule and para-hydrogen is 1mol% [ Rh (dppb) (COD) ]]BF 4 Is carried out at 60℃and a para-hydrogen pressure of 10 bar for 10 seconds. Reaction to form tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate having two H's, where the symbols indicate that the compound contains a group derived from para-hydrogenProton molecules of (a). In the example shown, the NMR signal marked with a symbol corresponds to a para-hydrogen molecule added across the carbon-carbon triple bond of t-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate. Based on 1 H NMR spectra determined a yield of about 85% for the para-hydrogenation reaction.
As shown in fig. 17A and 17B, the para-hydrogenation reaction between tert-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate and para-hydrogen resulted in significantly higher yields than the para-hydrogenation reaction between 3-phenylprop-2-yn-1-yl 2-oxopropionate and para-hydrogen.
FIG. 18A shows an exemplary corresponding para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate (i.e., 3-phenylallyl 2-oxopropionate having two H) 1 H NMR(400MHz，CDCl 3 ) Spectra. The para-hydrogenation reaction between 3-phenylprop-2-yn-1-yl 2-oxopropionate and para-hydrogen is 1mol% [ Rh (dppb) (COD) ]]BF 4 Is carried out at 45℃and a para-hydrogen pressure of 10 bar for 5 seconds. The reaction forms the previously known 3-phenylallyl 2-oxopropionate having two H-symbols, wherein the symbols indicate molecules containing protons derived from para-hydrogen. In the example shown, the NMR signal marked with a symbol corresponds to a para-hydrogen molecule added across the carbon-carbon triple bond of 3-phenylpropyl pyruvate. Based on 1 H NMR spectra confirm a yield of about 21% for the para-hydrogenation reaction.
FIG. 18B shows an exemplary reaction scheme corresponding to para-hydrogenated 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate (i.e., 4-oxo-4-phenylbut-2-en-1-yl 2-oxopropionate having two H's) 1 HNMR(400MHz，CDCl 3 ) Spectra. The para-hydrogenation reaction between 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate and para-hydrogen was 1mol% [ Rh (dppb) (COD) ]]BF 4 Is carried out at 45℃and a para-hydrogen pressure of 10 bar for 5 seconds. The reaction forms 4-oxo-4-phenylbut-2-en-1-yl 2-oxopropionate having two H-symbols, wherein the symbols indicate molecules containing protons derived from para-hydrogen. In the example shown, the NMR signal marked with a symbol corresponds to a para-hydrogen molecule added across the carbon-carbon triple bond of 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate. Based on 1 Determination of para-hydrogen by H NMR SpectroscopyThe yield of the chemical reaction was about 44%.
As shown in fig. 18A and 18B, the parahydrogenation reaction between 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate and parahydrogen resulted in significantly higher yields than the known parahydrogenation reaction between pyruvate derivatives, 2-oxopropionic acid-phenylallyl ester and parahydrogen.
13 EXAMPLE 17 improved C polarization
FIG. 19A shows an exemplary representation of 3-phenylprop-2-yn-1-yl 2-oxopropionate corresponding to 200mM para-hydrogenated 2-oxopropionate in acetone-d 6 (i.e., 3-phenylallyl 2-oxopropionate having two H) 13 C NMR(101MHz，CDCl 3 ) Spectra. The para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate was formed using the procedure described herein with respect to fig. 17A. In the example shown, the para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate was determined to have about 9.8% 13 And C polarization.
FIG. 19B shows an exemplary of tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate corresponding to 200mM sec-hydrogenated tert-butyl 4- ((2-oxopropionyl) oxy) but-2-enoate in acetone-d 6 13 C NMR(101MHz，CDCl 3 ) Spectra. Tert-butyl para-hydrogenated 4- ((2-oxopropionyl) oxy) but-2-ynoate was formed using the procedure described herein with respect to fig. 17B. In the example shown, the para-hydrogenated tert-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate was determined to have about 17.5% 13 And C polarization.
As in fig. 19A and 19B, the para-hydrogenated tert-butyl 4- ((2-oxopropionyl) oxy) but-2-ynoate produced significantly higher polarization than the para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate. It should be noted that 3-phenylpropargyl ester of para-hydrogenated pyruvic acid represents one of the current gold standard precursors for the production of hyperpolarized pyruvate via PHIP-SAH. Thus, the compositions described herein may allow for the production of pyruvate and other biologically relevant contrast agents with significantly enhanced polarization compared to known precursors.
FIG. 20A shows that in acetone-d 6, corresponding to 200mM para-hydrogenated 2-oxopropionic acidExemplary 3-phenylpropan-2-yn-1-yl esters (i.e., 3-phenylallyl 2-oxopropionate having two H's) 13 C NMR(101MHz，CDCl 3 ) Spectra. The para-hydrogenated 3-phenylprop-2-yn-1-yl 2-oxopropionate was formed using the procedure described herein with respect to fig. 18A. In the example shown, the para-hydrogenated 3-phenylpropan-2-yn-1-yl 2-oxopropionate was determined to have about 13.9% 13 And C polarization.
FIG. 20B shows an exemplary sample of 2-oxopropionic acid 4-oxo-4-phenylbut-2-en-1-yl ester corresponding to 200mM para-hydrogenated 2-oxopropionic acid 4-oxo-4-phenylbut-2-en-1-yl ester having two H' s 13 C NMR(101MHz，CDCl 3 ) Spectra. Para-hydrogenated 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate was formed using the procedure described herein with respect to fig. 18B. In the example shown, the para-hydrogenated 4-oxo-4-phenylbut-2-yn-1-yl 2-oxopropionate was determined to have about 10.3% 13 And C polarization.
FIG. 21 shows an exemplary form of methyl 4- ((2-oxopropionyl) oxy) but-2-enoate corresponding to 133mM para-hydrogenated methyl 4- ((2-oxopropionyl) oxy) but-2-enoate 13 CNMR(101MHz，CDCl 3 ) Spectra. The para-hydrogenation reaction between the novel molecule and para-hydrogen is 1mol% [ Rh (dppb) (COD) ] ]BF 4 Is carried out at 60℃and a para-hydrogen pressure of 10 bar for 10 seconds. The reaction forms methyl 4- ((2-oxopropionyl) oxy) but-2-enoate having two H, where the symbols indicate molecules containing protons derived from para-hydrogen. In the example shown, the para-hydrogenated methyl 4- ((2-oxopropionyl) oxy) but-2-ynoate was determined to have about 17.2% 13 And C polarization.
EXAMPLE 18 hyperpolarized alpha-ketoglutarate
FIG. 22A shows an exemplary corresponding para-hydrogenated 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate (i.e., 1- (4- (tert-butoxy) -4-oxobut-2-en-1-yl) 5-ethyl 2-oxoglutarate having two H's) 1 H NMR(400MHz，CDCl 3 ) Spectra. 2-oxoglutarate 1- (4- (t-butoxy) -4-oxobut-2-yn-1-yl) 5-ethylThe para-hydrogenation reaction between the ester and para-hydrogen was 1mol% [ Rh (dppb) (COD) ]]BF 4 Is carried out at 60℃and a para-hydrogen pressure of 10 bar for 10 seconds. The reaction forms 1- (4- (tert-butoxy) -4-oxobut-2-en-1-yl) 5-ethyl 2-oxoglutarate having two H-symbols, wherein the symbols indicate molecules containing protons derived from para-hydrogen. In the example shown, the NMR signal marked with a symbol corresponds to a para-hydrogen molecule added across the carbon-carbon triple bond of 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate.
FIG. 22B shows an exemplary 1- (4- (tert-butoxy) -4-oxobut-2-en-1-yl) 5-ethyl 2-oxoglutarate with two H-x corresponding to 70mM sec-hydrogenated 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate in acetone-d 6 13 C NMR(101MHz，CDCl 3 ) Spectra. Para-hydrogenated 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate was formed using the procedure described herein with respect to fig. 22A. In the example shown, the para-hydrogenated 1- (4- (tert-butoxy) -4-oxobut-2-yn-1-yl) 5-ethyl 2-oxoglutarate was determined to have about 12.8% 13 And C polarization.
The foregoing description has been presented for purposes of illustration. It is not intended to be exhaustive and is not limited to the precise form or embodiment disclosed. Modifications and adaptations to the embodiments will be apparent from a consideration of the specification and practice of the disclosed embodiments. For example, the described embodiments include hardware, but systems and methods consistent with the present disclosure may be implemented in hardware and software. Additionally, while certain components have been described as being coupled to one another, such components may be integrated with one another or distributed in any suitable manner.
Furthermore, although illustrative embodiments have been described herein, the scope includes any and all embodiments having equivalent elements, modifications, omissions, combinations (e.g., of aspects across various embodiments), adaptations or alterations as per the present disclosure. The elements in the claims will be construed broadly based on the language employed in the claims and are not limited to examples described in the present specification or during the practice of the application, which examples are to be construed as non-exclusive. Further, the steps of the disclosed methods may be modified in any manner, including a reordering step or an inserting or deleting step.
The features and advantages of the present disclosure are apparent from the detailed description, and thus, the appended claims are intended to cover all such systems and methods that fall within the true spirit and scope of the present disclosure. As used herein, the indefinite articles "a" and "an" mean "one or more". Similarly, unless the use of plural terms is clear in a given context, it does not necessarily represent plural. Further, since numerous modifications and variations will readily occur upon study of the present disclosure, it is not desired to limit the disclosure to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the disclosure.
As used herein, unless specifically stated otherwise, the term "or" encompasses all possible combinations unless otherwise not possible. For example, if a component is stated to contain a or B, the component may contain a or B, or a and B, unless specifically stated or not possible otherwise. As a second example, if a component is stated to contain A, B or C, the component may contain a, or B, or C, or a and B, or a and C, or B and C, or a and B and C, unless otherwise specifically stated or not possible.
Embodiments may be further described using the following clauses:
other embodiments will be apparent from consideration of the specification and practice of the embodiments disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosed embodiments being indicated by the following claims.
Claims (42)
1. A composition comprising a compound of formula (I):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-);
R 1 including para-hydrogen induced polarization (PHIP) transfer moieties;
R 2 including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and is also provided with
R 3 Including a bio-related contrast agent comprising non-hydrogen nuclear spins.
2. A composition comprising a compound of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof;
wherein H is hydrogen having a spin order derived from para-hydrogen;
R 1 including para-hydrogen induced polarization (PHIP) transfer moieties;
R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and is also provided with
R 3 Including a bio-related contrast agent comprising non-hydrogen nuclear spins.
3. A composition, comprising: (i) A bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (III):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof;
R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; and is also provided with
R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
4. A composition, comprising: (i) A hyperpolarized bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (IV):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-);
R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety;
R 2 including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
5. The composition of any one of claims 1 to 4, wherein the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.
6. The composition according to any one of claims 1 to 5, wherein the PHIP transfer moiety comprises a CR 4 R 5 、*CR 4 Y, =c=y or any deuterated version thereof, wherein:
* C is 12 C or 13 A C carbon isotope;
R 4 and R is 5 Each independently of the otherSelected from: 1 H、 2 H、 3 H. linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl; and is also provided with
Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
7. The composition according to any one of claims 1 to 5, wherein the PHIP transfer moiety comprises a CR 6 R 7 –*CR 8 R 9 Or any deuterated version thereof, wherein:
* C is 12 C or 13 A C carbon isotope; and is also provided with
R 6 、R 7 、R 8 And R is 9 Each independently selected from: 1 H、 2 H、 3 H. Straight, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl.
8. The composition according to any one of claims 1 to 5, wherein the PHIP transfer moiety comprises CH 2 、*CH 2 –*CH 2 Che, =y, or any deuterated version thereof, wherein:
* C is 12 C or 13 A C carbon isotope; and is also provided with
Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
9. The composition of claim 6 or claim 8, wherein the spin-1/2 atoms are selected from the group consisting of: 1 H、 13 C、 15 N、 19 f or F 31 P。
10. The composition of any one of claims 1 to 9, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled to the non-hydrogen nuclear spin to be at least 0.1 hertz (Hz).
11. The composition of any one of claims 1 to 10, wherein Z comprises at least one atom coupled to J of the non-hydrogen nuclear spin is at least 0.1 hertz (Hz).
12. The composition according to any one of claims 1 to 11, wherein R 2 Including the solubilising portion.
13. The composition according to any one of claims 1 to 12, wherein R 2 Including hydrophobic and/or organophilic moieties.
14. The composition of claim 13, wherein R 2 Including organic solubilizing moieties.
15. The composition according to any one of claims 1 to 12, wherein R 2 Including hydrophilic and/or oleophobic moieties.
16. The composition of any one of claims 1 to 15, wherein R 2 Comprising the following steps: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, hydroxyl, methanoyl, ethanoyl, n-propanoyl, isopropanol, propanoyl, n-butanoyl, sec-butanoyl, tert-butanoyl, isobutanoyl, methoxy, ethoxy, propoxy, isopropoxy, propanoyl, butoxy, tert-butoxy, sec-butoxyAn ester group, a phenyl group, a substituted phenyl group, a primary amine group, a secondary amine group, a tertiary amine group, a primary amide group, a secondary amide group, and a tertiary amide group.
17. The composition of any one of claims 1 to 16, wherein the biologically relevant contrast agent comprises formula R 10 Compounds of C (=o) X-; wherein R is 10 Selected from linear, branched or cyclic C1-C10 alkyl groups, wherein one or more C atoms are optionally substituted with c= C, CO, COH, CNH 2 、COOH、CH 2 COOH、CONH 2 OC (=o) substitution; and X is selected from NR 11 S and O; wherein R is 11 Selected from the group consisting of 1 H、 2 H、 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, benzyloxycarbonyl, t-butyl carbonate and benzyl.
18. The composition of any one of claims 1 to 17, wherein the bio-related contrast agent is selected from the group consisting of: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate (zymonate), alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.
19. The composition of any one of claims 1 to 18, wherein the solubility of the composition in water is less than 50 millimoles (mM).
20. The composition of any one of claims 1 to 18, wherein the solubility of the composition in an organic solvent is less than 50 millimoles (mM); optionally wherein the organic solvent is acetone, ethanol, chloroform or toluene.
21. The composition of any one of claims 1 to 20, wherein reacting the composition with para-hydrogen results in a chemical yield of para-hydrogenated product of at least 30%.
22. The composition of any one of claims 1 to 21 for use in a para-hydrogen induced polarization (PHIP) process.
23. A method for preparing a hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof, the method comprising:
(a) Providing a composition comprising a compound of formula (I):
wherein Z comprises: (i) A carbon-carbon double bond (-c=c-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a carbon-carbon triple bond (-C≡C-);
R 1 including para-hydrogen induced polarization (PHIP) transfer moieties;
R 2 including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and is also provided with
R 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins;
(b) Hydrogenating a double or triple bond in the compound of formula I with para-hydrogen to form a para-hydrogenated derivative of the compound of formula I, the para-hydrogenated derivative having the structure of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof;
wherein H is hydrogen having a spin order derived from para-hydrogen;
R 1 including para-hydrogen induced polarization (PHIP) transfer moieties;
R 2 including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and is also provided with
R 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins;
and
(c) Applying a polarization transfer waveform to sequentially transfer nuclear spins from at least one H-x in the compound of formula II to the non-hydrogen nuclear spins,
thereby forming a derivative of formula II having a hyperpolarized bio-related contrast agent.
24. A method for preparing a hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof, the method comprising:
(a) Providing a composition comprising a compound of formula (II):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof;
wherein H is hydrogen having a spin order derived from para-hydrogen;
R 1 Including para-hydrogen induced polarization (PHIP) transfer moieties;
R 2 including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines; and is also provided with
R 3 Comprising a bio-related contrast agent comprising non-hydrogen nuclear spins;
and
(b) Applying a polarization transfer waveform to transfer nuclear spins sequentially from at least one H-x in the compound of formula II to the non-hydrogen nuclear spins,
thereby forming a derivative of formula II having a hyperpolarized bio-related contrast agent.
25. The method of claim 23 or 24, further comprising hydrolyzing the derivative of formula II to provide a composition comprising: (i) A hyperpolarized bio-related contrast agent comprising non-hydrogen nuclear spins; and (ii) a compound of formula (III):
wherein Z' is: (i) A para-hydrogenated carbon-carbon single bond (-CH-) substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof; or (ii) a para-hydrogenated carbon-carbon double bond (-ch=ch-), which is substituted to contain 1 H (proton), 2 H (deuterium) or a combination thereof;
R 1 ' comprising a para-hydrogen induced polarization (PHIP) transfer moiety; and is also provided with
R 2 Including optionally substituted hydrocarbons, alkoxy groups, primary, secondary or tertiary amines.
26. The method of claim 25, further comprising washing the hyperpolarized bio-related contrast agent one or more times with an organic solvent.
27. The method of claim 26, wherein after the washing step, the non-hydrogen nuclear spin polarization of the non-hydrogen nuclear spin is greater than 10%.
28. The method of any one of claims 23 to 27, wherein the PHIP transfer moiety comprises an optionally substituted C1 hydrocarbon or an optionally substituted C2 hydrocarbon.
29. The method according to any one of claims 23 to 27, wherein the PHIP transfer portion comprises a CR 4 R 5 、*CR 4 Y, =c=y or any deuterated version thereof, wherein:
* C is 12 C or 13 A C carbon isotope;
R 4 and R is 5 Each independently selected from: 1 H、 2 H、 3 H. linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl; and is also provided with
Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
30. The method according to any one of claims 23 to 27, wherein the PHIP transfer portion comprises a CR 6 R 7 –*CR 8 R 9 Or any deuterated version thereof, wherein:
* C is 12 C or 13 A C carbon isotope; and is also provided with
R 6 、R 7 、R 8 And R is 9 Each independently selected from: 1 H、 2 H、 3 H. straight, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl and haloalkyl.
31. The method according to any one of claims 23 to 27, wherein the PHIP transfer portion comprises a CH 2 、*CH 2 –*CH 2 Che, =y, or any deuterated version thereof, wherein:
* C is 12 C or 13 A C carbon isotope; and is also provided with
Y is selected from: spin-1/2 atoms, spin-1/2 atoms covalently bonded to one or more chemical moieties selected from the group consisting of: linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl, or heteroatoms such as N, O, S optionally substituted with linear, branched or cyclic C1-C10 alkyl hydrocarbons, C6 aryl, benzyl, phenyl, heteroaryl, halogen or haloalkyl.
32. The method of claim 29 or 31, wherein the spin-1/2 atoms are selected from the group consisting of: 1 H、 13 C、 15 N、 19 f or F 31 P。
33. The method of any one of claims 23 to 32, wherein the PHIP transfer moiety comprises at least one atom that is J-coupled to the non-hydrogen nuclear spin to be at least 0.1 hertz (Hz).
34. The method of any one of claims 23 to 33, wherein Z or Z' comprises at least one atom coupled to J of the non-hydrogen nuclear spin is at least 0.1 hertz (Hz).
35. The method of any one of claims 23 to 34, wherein R 2 Including the solubilising portion.
36. The method of any one of claims 23 to 35, wherein R 2 Including hydrophobic and/or organophilic moieties.
37. The method of claim 36, wherein R 2 Including organic solubilizing moieties.
38. The method of any one of claims 23 to 34, wherein R 2 Including hydrophilic and/or oleophobic moieties.
39. The method of any one of claims 23 to 38, wherein R 2 Comprising the following steps: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, hydroxy, methylAlcohol group, ethanol group, n-propanol group, isopropanol group, propionic acid alcohol group, n-butanol group, sec-butanol group, tert-butanol group, isobutanol group, methoxy group, ethoxy group, propoxy group, isopropoxy group, propoxy group, butoxy group, tert-butoxy group, sec-butoxy group, ester group, phenyl group, substituted phenyl group, primary amino group, secondary amino group, tertiary amino group, primary amino group, secondary amino group and tertiary amino group.
40. The method of any one of claims 23 to 39, wherein the biologically relevant contrast agent comprises formula R 10 Compounds of C (=o) X-; wherein R is 10 Selected from linear, branched or cyclic C1-C10 alkyl groups, wherein one or more C atoms are optionally substituted with c= C, CO, COH, CNH 2 、COOH、CH 2 COOH、CONH 2 OC (=o) substitution; and X is selected from NR 11 S and O; wherein R is 11 Selected from the group consisting of 1 H、 2 H、 3 H and an amino protecting group optionally selected from trifluoroacetyl, acetyl, benzoyl, benzyloxycarbonyl, t-butyl carbonate and benzyl.
41. The method of any one of claims 23 to 40, wherein the bio-related contrast agent is selected from the group consisting of: pyruvate, glutamate, glutamine, lactate, acetate, acetoacetate, zymonate, alanine, fructose, fumarate, bicarbonate, urea, dehydroascorbate, alpha-ketoglutarate, dihydroxyacetone, glucose, ascorbate, and conjugate acids thereof.
42. A hyperpolarized bio-related contrast agent or a pharmaceutically acceptable salt thereof produced by the method of any one of claims 23 to 41.
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| US63/164585 | 2021-03-23 | ||
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| US202263266986P | 2022-01-21 | 2022-01-21 | |
| US63/266986 | 2022-01-21 | ||
| PCT/IB2022/000160 WO2022200859A1 (en) | 2021-03-23 | 2022-03-23 | Systems and method for generation of hyperpolarized materials |
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