CN113429307A - Preparation method and application of stable isotope labeled glutamic acid and glutamic acid derivative - Google Patents

Preparation method and application of stable isotope labeled glutamic acid and glutamic acid derivative Download PDF

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CN113429307A
CN113429307A CN202110654686.6A CN202110654686A CN113429307A CN 113429307 A CN113429307 A CN 113429307A CN 202110654686 A CN202110654686 A CN 202110654686A CN 113429307 A CN113429307 A CN 113429307A
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glutamic acid
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阮英恒
周静洋
杨晓云
杨晓军
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Shenzhen Dingbang Chemicals Co ltd
Shenzhen Dingbang Biotechnology Co ltd
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Abstract

The invention provides stable isotope labeled glutamic acid and glutamic acid derivatives, and a preparation method and application thereof. The stable isotope labeled glutamic acid and glutamic acid derivatives used in the invention can exist stably in vivo as contrast agents, and can not cause harm to human bodies after multiple detections; the method has the advantages of simple and practical method, high precision, reliable result and capability of analyzing the metabolic condition in a quantitative positioning manner.

Description

Preparation method and application of stable isotope labeled glutamic acid and glutamic acid derivative
Technical Field
The invention relates to the technical field of medicines, in particular to stable isotope labeled glutamic acid and glutamic acid derivatives, and a preparation method and application thereof.
Background
The increasing use of hydrogen and its isotopes in the pharmaceutical industry, for example, research in magnetic resonance molecular imaging has resulted in two promising methods of imaging isotopes of glucose metabolism: hyperpolarization (HP)13C Magnetic Resonance Imaging (MRI) and deuterometabolic imaging (DMI). Although it is used for13There are multiple possible pathways for C hyperpolarization, but HP13C MRI most often relies on13Dynamic nuclear polarization pre-polarization of the C-labeled substrate followed by rapid dissolution produced a large signal enhancement four to five orders of magnitude higher than Boltzmann polarization at clinically viable MRI field strengths, enabling target metabolic studies by spectral imaging. However,13c has a short magnetization lifetime and requires compact studies and fast, carefully calibrated MRI scans. In contrast, a DMI that is not hyperpolarized takes advantage of the relatively large magnetic moment provided by Boltzmann polarization.
Positron Emission Tomography (PET) is the most advanced medical imaging technology at present, can realize high-resolution imaging of cell metabolism and functions, and carry out noninvasive, three-dimensional and dynamic research on physiological and biochemical processes of a human body on a molecular level, and PET is applied to diagnosis of tumors including tumors, early diagnosis and identification of benign and malignant differentiation, staging, typing, relapse and metastasis of malignant tumors, selection of treatment schemes, monitoring of chemotherapeutic effects, observation of tumor change processes and detection of the conditions after healing. PET examination differs from other examinations in that it relies on positron drugs (PET drugs) that specifically concentrate on the target organ for diagnostic and evaluation purposes. Positron drugs currently used in PET examinations include fluorodopamine, which is a kind of positron-like radionuclide that is prone to cause secondary damage for multiple examinations of patients, and has a half-life period that is significantly improved (109.8min) compared to other imaging labeled nuclides such as oxygen-15 (O-15), nitrogen 13(N-13), and carbon 11(C-11), but still cannot be tracked as the whole metabolic process.
Glutamate is a key molecule in cellular metabolism. In humans, dietary proteins are broken down by digestion into amino acids, which act as metabolic fuels for other functional roles in the human body. One of the key processes in amino acid decomposition is the amino exchange, wherein the amino group of the amino acid is transferred to an alpha-keto acid, a process typically catalyzed by a transaminase.
Glutamine has a variety of biochemical functions including: substrates for DNA synthesis; an important role in protein synthesis, the major source of fuel for intestinal cells (cells measured in the lining small intestine); rapid division of precursor material of immune cells, thereby contributing to immune function; ammonium is produced, thereby modulating the acid-base balance in the kidney.
Cancer cells consume glucose through warburg metabolism, a process that forms the basis of tumor imaging through Positron Emission Tomography (PET). Immune cells that swell tumors are also glucose dependent, and impaired immune cell metabolism in the Tumor Microenvironment (TME) leads to immune evasion by tumor cells. However, it is not clear whether the metabolic imbalance of immune cells in TME is regulated by the intracellular processes or by nutrients that compete with cancer cells for a limited amount. Here we used PET tracers to measure glucose and glutamine acquisition and uptake by specific subsets of cells in the TME. Notably, in a series of cancer models, myeloid cells have the most capacity to take up glucose in the oral cavity, followed by T cells and cancer cells. In contrast, the cancer cells take the highest amount of glutamine. This unique nutritional partitioning is performed in a cell-intrinsic manner through mTORC1 signaling and expression of genes associated with glucose and glutamine metabolism. Inhibition of glutamine absorption enhanced glucose uptake by tumor resident cell types, indicating that glucose is absent in TME and inhibition of glucose uptake by glutamine metabolism is a limiting factor. Thus, intracellular programs drive immune and cancer cells to preferentially acquire glucose and glutamine, respectively. The cell-selective partitioning of these nutrients can be used to develop therapeutic and imaging strategies to enhance or monitor the metabolic plan and activity of specific cell populations in the TME.
A preliminary observation of cancer metabolism is that tumors consume glucose in the presence of oxygen to produce lactate. Aerobic glycolysis is widely seen in rapidly proliferating cells, including activated immune cells, to support biosynthetic demands. In vivo carbon labeling studies have demonstrated that glucose supports anabolism of transformed and T cells. Glutamine metabolism provides a resistive fuel, inhibiting glucose-dependent differentiation and macrophage and T cell function. These metabolic pathways may be interrupted in the immune cells of TME to prevent anti-tumor immunity.
The glucose can be taken up18F-Fluorodeoxyglucose (FDG) imaging to detect cancer and monitor treatment response. As a metabolic mechanism of immunosuppression, consumption of glucose in TME by cancer cells may lead to nutritional competition. High concentrations of glucose were measured in mouse and human TME, ranging from 0.2 to 2 mM. Furthermore, the metabolic phenotype of T cells persists even after these cells are removed from the TME and cultured in nutrient rich media. Intrinsic metabolic programming or nutritional competition between cancer cells and immune cells for limited nutrientsThe extent of contention is still uncertain. Here, we used PET probes to directly measure glucose and glutamine uptake in TME cell subsets.
The nutritional ingredients in TME are divided: immune cells may contribute significantly to glucose consumption in TME. We measured nutrient enrichment in interstitial fluid extracted from freshly resected human Renal Cell Carcinoma (RCC) and mouse subcutaneous tumor specimens by mass spectrometry. The concentrations of glucose, glutamine and lactate measured in the TME were all similar to those in the matched healthy kidney tissue or plasma. Next, we directly measured in vivo glucose uptake to quantify the accessibility of glucose to different cell populations in the TME. Subcutaneous MC38 tumors were visualized by FDG PET imaging and the radioactivity of 18F in each cell was measured in isolated tumor cell subsets. Magnetic microbeads for CD45+ selection separated tumor cells into an abundant population of CD45- (mainly cancer cells) and CD45+ (immune cells). FDG was more effective on unseparated tumor cells than control tissue splenocytes. Notably, tumor-infiltrating CD45+ immune cells take up more FDG per cell than CD 45-cells. FDG self-thermography and immunohistochemistry showed a uniform distribution of FDG and CD45+ cells, indicating that differential uptake was not due to a spatial distribution favoring immune cells. Immune cells also have higher FDG availability in tumors of mouse subcutaneous CT26 and kidney cancer, and orthotopic tumors show higher per-cell FDG availability in immune cells compared to CD 45-tumor cells. In both the AOM/DSS mouse model induced by methyl oxynitride and dextran sulfate and the genetically engineered mouse model of intermediate T antigen of breast cancer polyoma virus (PyMT) (GEMM), the uptake of FDG by the infiltrating immunocyte is higher than that of EPCAM + cancer cells. These results indicate that glucose is available in the TME and preferentially permeates immune cells, not cancer cells.
Recent studies have shown that18Tumors that are imaged as false negative by F-FDG may use a metabolic pathway different from sugar metabolism-glutamine glycolysis. When the proto-oncogene is activated, the major source of energy for these tumors may be converted from glucose to glutamine (tumors use glutamine for intramitochondrial use of glutamine for trioCarboxylic acid cycles to produce energy and to produce materials required for tumor cell proliferation), or some tumors may prefer to use both carbohydrate metabolism and glutamine glycolysis. To overcome this problem18F-FDG, some of which are developed for clinical studies, e.g., 4-, [ 2 ]18F]Fluoro-glutamic acid, (2S,4R) -, [ 2 ]18F]Fluoro-glutamine, (2S,4R) - [ 2 ]18F]Fluoro-glutamic acid and (4S) -4- (3-, [ 2 ]18F]Fluoropropyl) -L-glutamyl. The research on the PET imaging of the small animal shows that (2S,4R) -, (2S,4R) -, (2S-4-S18F]Fluoro-glutamine and (2S,4R) - [ 2 ]18F]The fluorine-glutamic acid can be taken up in tumor tissue cells which are proliferated rapidly, and high-efficiency tumor targeting is shown, however, both the two amino acid imaging agents are generated in a defluorination phenomenon in vivo, so that interference is caused to the PET imaging quality. Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide stable isotope labeled glutamic acid and glutamic acid derivatives, and a preparation method and application thereof, and aims to solve the problems that in the prior art, positron-type radioactive nuclide is used as a contrast agent, secondary damage is easily caused to a patient during multiple detections, and the positron-type radioactive nuclide cannot be used for tracking the whole metabolic process.
The technical scheme of the invention is as follows:
the stable isotope labeled glutamic acid and glutamic acid derivative has a chemical structure general formula as follows:
Figure RE-GDA0003226495110000061
wherein
R1Represents hydroxy, branched or straight chain C1-C5Alkoxy, branched or straight-chain hydroxy C1-C5Alkoxy, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl, N (C)1-C5Alkyl radical)2、NH2N (H) -L, O-L or O-Z, wherein none or one or more hydrogen atoms are replaced by deuterium;
R2、R3、R4and/or R5Independently of one another, hydrogen or deuterium, branched or straight-chain F-C1-C10Alkoxy, branched or straight chain F-C1-C10Alkyl, branched or straight chain F-C2-C10Alkenyl, branched or straight chain F-C2-C10Alkynyl, substituted or unsubstituted F-C6-C10Monocyclic or bicyclic aryl, substituted or unsubstituted F-alkyl-C6-C10Monocyclic or bicyclic aryl, substituted or unsubstituted F-C5-C10Monocyclic or bicyclic heteroaryl, substituted or unsubstituted F-alkyl-C6-C10Monocyclic or bicyclic heteroaryl, substituted or unsubstituted F-C3-C6Cycloalkyl, substituted or unsubstituted F-alkyl-C3-C6Cycloalkyl, hydroxy, branched or straight chain C1-C5Alkyl or branched or straight chain C1-C5Alkoxy, wherein none or one or more hydrogen atoms are replaced by deuterium;
R6represents hydrogen or deuterium;
R7and/or R8Independently of one another, hydrogen or deuterium, methoxycarbonyl, propoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 1-dimethylpropynyl, 1-methyl-1-phenylethoxycarbonyl, 1-methyl-1- (4-biphenyl) ethoxycarbonyl, cyclobutylcarbonyl, 1-methylcyclobutylcarbonyl, vinylcarbonyl, propenylcarbonyl, adamantylcarbonyl, benzhydrylcarbonyl, cinnamylcarbonyl, formyl, benzoyl, trityl, p-methoxyphenyl-benzhydryl, di (p-methoxyphenyl) phenylmethyl, tert-butoxycarbonyl or a halo thereof, wherein none or one or more of the hydrogen atoms are replaced by deuterium;
R9represents hydroxy, branched or straight chain C1-C5Alkoxy, branched or straight-chain hydroxy C1-C5Alkoxy, branched or straight chain O-C2-C5Alkenyl, branched orStraight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl, branched or straight chain O-C2-C5Alkynyl, triphenylmethoxy or O-Z, wherein none or one or more hydrogen atoms are replaced by deuterium;
wherein alkyl is optionally interrupted by O, S or N, or is replaced by it, R1～R9In which at least one hydrogen atom is deuterated, L is a branched or straight chain C1-C5Alkyl, branched or straight chain C2-C5Alkenyl, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl or branched or straight chain O-C2-C5Alkynyl, Z is a metal ion equivalent;
where n-0, 1, 2 or 3, and where possible diastereomers and/or mixtures of enantiomers are included, as well as enantiomerically pure compounds and pharmaceutical salts thereof.
Further, the chemical structural formula of the stable isotope labeled glutamic acid and glutamic acid derivative is as follows:
Figure RE-GDA0003226495110000071
Figure RE-GDA0003226495110000081
Figure RE-GDA0003226495110000091
Figure RE-GDA0003226495110000101
or one of the array combinations between different deuterated positions and deuterated numbers of different substituent groups.
A method for preparing stable isotope labeled glutamic acid and glutamic acid derivatives, which comprises the following steps:
under the protection of inert gas, dripping an organic solution of acryloyl chloride into LiAlD4The organic solvent is one or a mixture of more than two of anhydrous ether, anhydrous tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like in any proportion, preferably the anhydrous ether, the anhydrous tetrahydrofuran and the like are stirred and reacted at the temperature of-20 ℃ to 50 ℃, and the post-treated crude product is distilled under normal pressure to obtain 2-ene-1, 1-d 2-1-alcohol;
adding phosphorus tribromide into perfluorohexane, adding an organic solution of 2-ene-1, 1-d 2-1-alcohol, reacting in a dark place, and distilling a post-treatment crude product at normal pressure to obtain 3-bromo-1-ene-3, 3-d 2;
cooling to-80-0 ℃, dropwise adding a tetrahydrofuran solution of lithium bis (trimethylsilyl) amide into a tetrahydrofuran solution of Boc-dimethyl glutamate, reacting at-80-30 ℃ for 1-3 h, dropwise adding 3-bromo-1-ene-3, 3-d2, reacting for 1-3 h, and purifying the post-treated crude product by silica gel column chromatography to obtain (2s,4s) -2- (allyl-1, 1-d2) -4- (tert-butoxycarbonyl) amino) dimethyl glutarate;
under the protection of inert gas at the temperature of-30 ℃, dropwise adding borane tetrahydrofuran complex into (2s,4s) -2- (allyl-1, 1-d2) -4- (tert-butoxycarbonyl) amino) dimethyl glutarate solution, carrying out heat preservation reaction at the temperature of-30 ℃, adding alkali and hydrogen peroxide solution, stirring for reaction, and purifying a post-treated crude product by silica gel column chromatography to obtain (2s,4s) -2- (tert-butoxycarbonyl) amino) -4- (3-hydroxypropyl-1, 1-d2) dimethyl glutarate;
adding (2s,4s) -2- (tert-butoxycarbonyl) amino) -4- (3-hydroxypropyl-1, 1-d2) dimethyl glutarate into a solvent at the temperature of between 30 and 30 ℃, wherein the solvent is one or more than two of diethyl ether, tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, mixing at any ratio, adding diethylaminosulfur trifluoride, carrying out heat preservation reaction, and purifying the post-treated crude product by silica gel column chromatography to obtain (2s,4s) -2- (tert-butoxycarbonyl) amino) -4- (3-fluoropropyl-1, 1-d2) dimethyl glutarate;
adding (2s,4s) -2- (tert-butyloxycarbonyl) amino) -4- (3-fluoropropyl-1, 1-d2) glutaric acid dimethyl ester into a solvent, wherein the solvent is one or a mixture of more than two of diethyl ether, tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethylformamide, dimethylacetamide and dimethyl sulfoxide according to any proportion, adding alkali, stirring for reaction, and adding acid into the crude product after the reaction to prepare and separate (2s,4s) -2-amino-4- (3-fluoropropyl-1, 1-d2) glutaric acid;
the invention discloses application of stable isotope labeled glutamic acid and glutamic acid derivatives, wherein the stable isotope labeled glutamic acid and glutamic acid derivatives are used as contrast agents for magnetic resonance imaging.
Wherein the stable isotope labeled glutamic acid and glutamic acid derivatives are used as tumor amino acid metabolism imaging agents.
Wherein the contrast agent further comprises at least one pharmaceutically acceptable excipient.
Wherein the excipient is one of a carrier, a filler or a solvent.
Has the advantages that: the invention provides stable isotope labeled glutamic acid and glutamic acid derivatives, and a preparation method and application thereof. The stable isotope labeled glutamic acid and glutamic acid derivatives used in the invention can exist stably in vivo as contrast agents, and can not cause harm to human bodies after multiple detections; the method has the advantages of simple and practical method, high precision, reliable result and capability of analyzing the metabolic condition in a quantitative positioning manner.
Drawings
Fig. 1 is a chemical reaction diagram of a method for preparing stable isotope-labeled glutamic acid and glutamic acid derivatives according to an embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides stable isotope labeled glutamic acid and a glutamic acid derivative, wherein the stable isotope labeled glutamic acid and the glutamic acid derivative have the chemical structural general formula:
Figure RE-GDA0003226495110000131
wherein
R1Represents hydroxy, branched or straight chain C1-C5Alkoxy, branched or straight-chain hydroxy C1-C5Alkoxy, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl, N (C)1-C5Alkyl radical)2、NH2N (H) -L, O-L or O-Z, wherein none or one or more hydrogen atoms are replaced by deuterium;
R2、R3、R4and/or R5Independently of one another, hydrogen or deuterium, branched or straight-chain F-C1-C10Alkoxy, branched or straight chain F-C1-C10Alkyl, branched or straight chain F-C2-C10Alkenyl, branched or straight chain F-C2-C10Alkynyl, substituted or unsubstituted F-C6-C10Monocyclic or bicyclic aryl, substituted or unsubstituted F-alkyl-C6-C10Monocyclic or bicyclic aryl, substituted or unsubstituted F-C5-C10Monocyclic or bicyclic heteroaryl, substituted or unsubstituted F-alkyl-C6-C10Monocyclic or bicyclic heteroaryl, substituted or unsubstituted F-C3-C6Cycloalkyl, substituted or unsubstituted F-alkyl-C3-C6Cycloalkyl, hydroxy, branched or straight chain C1-C5Alkyl or branched or straight chain C1-C5Alkoxy, wherein none or one or more hydrogen atoms are replaced by deuterium;
R6represents hydrogen or deuterium;
R7and/or R8Independently of one another, hydrogen or deuterium, methoxycarbonyl, propoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 1-dimethylpropynyl, 1-methyl-1-phenylethoxycarbonyl, 1-methyl-1- (4-biphenyl) ethoxycarbonyl, cyclobutylcarbonyl, 1-methylcyclobutylcarbonyl, vinylcarbonyl, propenylcarbonyl, adamantylcarbonyl, benzhydrylcarbonyl, cinnamylcarbonyl, formyl, benzoyl, trityl, p-methoxyphenyl-benzhydryl, di (p-methoxyphenyl) phenylmethyl, tert-butoxycarbonyl or a halo thereof, wherein none or one or more of the hydrogen atoms are replaced by deuterium;
R9represents hydroxy, branched or straight chain C1-C5Alkoxy, branched or straight-chain hydroxy C1-C5Alkoxy, branched or straight chain O-C2-C5Alkenyl, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl, branched or straight chain O-C2-C5Alkynyl, triphenylmethoxy or O-Z, wherein none or one or more hydrogen atoms are replaced by deuterium;
wherein alkyl is optionally interrupted by O, S or N, or is replaced by it, R1～R9In which at least one hydrogen atom is deuterated, L is a branched or straight chain C1-C5Alkyl, branched or straight chain C2-C5Alkenyl, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl or branched or straight chain O-C2-C5Alkynyl, Z is a metal ion equivalent;
where n-0, 1, 2 or 3, and where possible diastereomers and/or mixtures of enantiomers are included, as well as enantiomerically pure compounds and pharmaceutical salts thereof.
Further, the chemical structural formula of the stable isotope labeled glutamic acid and glutamic acid derivative is as follows:
Figure RE-GDA0003226495110000141
Figure RE-GDA0003226495110000151
Figure RE-GDA0003226495110000161
or one of the array combinations between different deuterated positions and deuterated numbers of different substituent groups.
The invention also provides a preparation method of stable isotope labeled glutamic acid and glutamic acid derivatives, the reaction process is shown in figure 1, and the preparation method specifically comprises the following steps:
s10, compound B: under the protection of nitrogen at 0 ℃, dropwise adding an ether (700mL) solution of acryloyl chloride (147.2g,1.63mol) of the compound A into a stirred slurry of LiAlD4(102.4g,2.44mol) in ether (1500mL), stirring at room temperature for 2 hours, cooling to 0 ℃, sequentially adding water, a 15% sodium hydroxide aqueous solution and water, filtering, washing a filter cake with ether, concentrating a filtrate under reduced pressure, and distilling a residue under normal pressure to obtain 60.9g of a colorless oil compound B, wherein the yield is 62.3%;
s20, compound C: slowly adding phosphorus tribromide (88.6g,328mmol) into perfluorohexane, after 10min, precipitating phosphorus tribromide to the bottom of a bottle, slowly adding an ether (800mL) solution of a compound B (59.0g,982mmol) to form the uppermost layer solution, keeping out of the light, stirring at room temperature for 12h, layering, washing the ether layer with cold water, a sodium carbonate solution and water in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and distilling the residue at normal pressure to obtain 90.7g of a compound C with a yield of 75.1%;
s30, compound E: adding Boc-glutamic acid dimethyl ester (60.5g,220mmol) into tetrahydrofuran (600mL), cooling to-70 ℃, slowly dropwise adding a tetrahydrofuran solution (1M,484mL,484mmol) of lithium bis (trimethylsilyl) amide at 70 ℃, keeping the temperature for reaction for 2h, slowly dropwise adding a compound C (81.2g, 658mmol), keeping the temperature for reaction for 1h, adding 2M hydrochloric acid and ethyl acetate, carrying out layering, washing an organic layer with water to neutrality, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out chromatography purification on a residual silica gel column to obtain 19.8g of a compound E, wherein the yield is 28.4%;
s40, compound F: adding a compound E (19.2g,60.5mmol) into tetrahydrofuran (150mL), cooling to 0 ℃, slowly dropwise adding a borane tetrahydrofuran complex (1M,79mL, 79mmol) under the protection of nitrogen, keeping the temperature for reaction for 1h, stirring overnight at room temperature, slowly dropwise adding a 1N sodium hydroxide solution, then dropwise adding 18mL of a 30% hydrogen peroxide solution, stirring for 0.5h, adding water for dilution, concentrating under reduced pressure to remove tetrahydrofuran, adding ethyl acetate for extraction, layering, washing an organic layer to be neutral, drying an anhydrous sodium sulfate silica gel column, concentrating under reduced pressure, and carrying out chromatographic purification on a residue to obtain 4.1g of a compound F, wherein the yield is 20.2%;
s50, compound G: adding compound F (7.9g,11.63mmol) into dichloromethane (80mL), cooling to 0 ℃, adding diethylaminosulfur trifluoride (3.8g,23.57mmol), reacting for 1h while keeping the temperature, adding water for washing, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue with silica gel column chromatography to obtain 458mg of compound F with a yield of 11.5%;
s60, compound H: adding the compound G (410mg,1.22mmol) into tetrahydrofuran (15mL), adding 10mL of 1N aqueous sodium hydroxide solution, stirring at room temperature for reaction for 4H, concentrating under reduced pressure, dissolving the residue in 20mL of 3N ethereal hydrogen chloride solution again, stirring, evaporating and concentrating, adding ether for redistillation, and carrying out preparative separation on the crude product by using a C18 column to obtain 78mg of compound H with the yield of 30.7%;
the invention also provides application of the stable isotope labeled glutamic acid and glutamic acid derivatives, wherein the stable isotope labeled glutamic acid and glutamic acid derivatives are used as contrast agents for magnetic resonance imaging.
Further, the stable isotope labeled glutamic acid and glutamic acid derivatives are used as tumor amino acid metabolism imaging agents.
When proto-oncogenes are activated, the major source of energy from these tumors may be converted from glucose to glutamine (tumors use glutamine to produce energy in the mitochondria using the tricarboxylic acid cycle and to produce the raw material required for tumor cell proliferation), or some tumors may prefer to use both carbohydrate metabolism and glutamine glycolysis. To overcome this problem18F-FDG, some of which are developed for clinical studies, e.g., 4-, [ 2 ]18F]Fluoro-glutamic acid, (2S,4R) -, [ 2 ]18F]Fluoro-glutamine, (2S,4R) - [ 2 ]18F]Fluoro-glutamic acid and (4S) -4- (3-, [ 2 ]18F]Fluoropropyl) -L-glutamyl. The research on the PET imaging of the small animal shows that (2S,4R) -, (2S,4R) -, (2S-S, 4R) -18F]Fluoro-glutamine and (2S,4R) - [ 2 ]18F]The fluorine-glutamic acid can be taken up in tumor tissue cells which are proliferated rapidly, and high-efficiency tumor targeting is shown, however, both the two amino acid imaging agents are generated in a defluorination phenomenon in vivo, so that interference is caused to the PET imaging quality.
In the embodiment, stable isotope labeled glutamic acid and glutamic acid derivatives are used as tumor amino acid metabolism imaging agents, and tumor metabolic processes are detected through magnetic resonance imaging, so that diagnosis is made. The embodiment of the invention adopts stable isotope labeled glutamic acid and glutamic acid derivative as contrast agent, which has the following advantages: high content of deuterium atoms; accumulate in brain tissue for a reasonable period of time to a concentration sufficient for diagnosis; the toxicity is low and the intact agent is almost completely excreted from the body. This allows effective diagnosis using a dose that is not harmful to the human body.
In some embodiments, there is provided a method of using stable isotope labeled glutamic acid and glutamic acid derivatives as an imaging agent for tumor amino acid metabolism, comprising the steps of:
administering the contrast agent to a subject;
after a sufficient accumulation time after administration of the contrast agent, magnetic resonance imaging is performed at the frequency of deuterons to obtain2H-MR images;
obtained by analysis2H-MR imageAn abnormally high intensity signaling region is found and the tumor metabolic process is diagnosed based on the observed abnormal signal intensity of deuterons.
In the present embodiment, the signal intensity measured based on the contrast agent of the present embodiment may be compared with typical signal intensities observed in corresponding tissues in healthy subjects, so as to compare the judgment difference, thereby making a judgment on the condition of the subject.
The detection method provided by the present embodiment is independent of any detrimental effects of ionizing radiation (typically, for example, for CT, PET, SPECT methods), which in turn increases the safety of the study and allows the study to be repeated more frequently. The present invention aims to obtain diagnostic information similar to Positron Emission Tomography (PET), but unlike the latter, it can eliminate the risks associated with ionizing radiation of radiopharmaceuticals.
In some embodiments, the contrast agent further comprises at least one pharmaceutically acceptable excipient, such as, for example, one of a carrier, a filler, or a solvent.
In some embodiments, the contrast agent is administered to the subject orally or parenterally.
In some specific embodiments, the contrast agent is administered to the subject at 0.60-0.75 grams of contrast agent per 1kg of body weight.
In some embodiments, the stable isotope labeled glutamic acid and glutamic acid derivatives can also be used as contrast agents for tracking related metabolites, which specifically comprises the following steps:
before scanning the site to be examined by the subject by means of nuclear magnetic resonance spectroscopy and forming glutamic acid and glutamic acid derivatives labelled with stable isotopes1H pre-use profile; standard nuclear magnetic resonance apparatus, such as 3T MRI scanner or 7T MRI scanner, can be used without the risk of exposure to ionizing radiation, without the need for special equipment, and with ease of use, the sequences and imaging parameters can be selected as follows: using PRESS sequence (TR/TE 2500/16ms, spectrum width 4kHz, 90 pulse bandwidth 5400Hz, 180 pulse bandwidth 2400Hz, point 4006, vapro water suppression, average＝128)。
Administering to the subject, after obtaining the pre-use profile, a stable isotope labeled glutamic acid and glutamic acid derivative, which may be a single dosage unit form composition, i.e., the composition may be in a single dose or may contain one or more unit doses in a single container, each dose containing the same composition, i.e., each dose contains the same weight of the same composition2H-labelled substance, each dose of which may be administered to a subject directly or after dilution, or the composition may be formulated to different specifications, for example comprising stable isotope labelled glutamic acid and glutamic acid derivatives, and the compositions may be administered to subjects in different specifications for use, the composition can be made into liquid or solid, and can be administered with different dosage of stable isotope labeled glutamic acid and glutamic acid derivative according to different subjects, such as dissolving in 200-300 ml water according to 0.60-0.75 g/kg body weight and maximum 60 g, according to different specifications of the stable isotope labeled glutamic acid and glutamic acid derivatives, the stable isotope labeled glutamic acid and glutamic acid derivatives can be used in an injection mode, the deuterated FSPG also can be a composition in the form of any one of powder, tablet, pill, capsule or liquid. By using2H-mark means using2H for one or more1H atoms, thereby leading to the corresponding metabolites1Overall reduction of H MRS signal, thus through quantization2H substitution1The decrease of the signal in the proton magnetic resonance spectrum generated by H can obtain the conversion condition of stable isotope labeled glutamic acid and glutamic acid derivative, thereby obtaining the metabolic condition of the cell. After rescanning the site to be examined of the subject by means of a nuclear magnetic resonance spectrometer under the same parameters and forming glutamic acid and glutamic acid derivatives labelled with stable isotopes within a given time1H, a post-use map; the given time is preferably 20-90 min, so that the deuterated FSPG can be sufficiently converted in vivo to obtain more accurate detection result and represent metabolic condition, and the deuterated FSPG can be introduced at certain time intervals in the given timeMultiple measurements are taken, such as every five or ten minutes to obtain map data for that time point. Due to the fact that2H has a lower NMR frequency and a wider intrinsic broad peak on the NMR spectrum, so that deuterium imaging is influenced minimally by magnetic field inhomogeneity, but so that2The nmr spectrum of H contains only a few metabolite peaks,1the sensitivity of H MRS is higher, and the H MRS can be independently detected2And the H MRS can not obtain the maps of certain metabolites, so that a more accurate detection result is obtained, and the metabolic dynamic process of key metabolites can be detected in the same acquisition process while the steady-state metabolic information of several metabolites is provided.
The method obtains the concentrations of the designated metabolites before and after the stable isotope labeled glutamic acid and glutamic acid derivative is used by analyzing the data of the map before and after the stable isotope labeled glutamic acid and glutamic acid derivative is used, and obtains the metabolic condition of the tissue according to the concentration change before and after the stable isotope labeled glutamic acid and glutamic acid derivative is used. By using1The universality and the easy implementation advantage of H proton magnetic resonance spectrum detection and the excellent spectral resolution can track the metabolites transferred by stable isotope labeled glutamic acid and glutamic acid derivatives, the detection resolution and the sensitivity are higher, the dynamic exchange of single metabolites can be detected, and the measurement is carried out1The change of the H proton magnetic resonance spectrum can be detected under high spectral resolution2Metabolites which cannot be detected by H proton magnetic resonance spectrum are obtained, so that the rate of in vivo metabolic cycle is obtained, steady state information and metabolic rate of a plurality of metabolites can be provided by one-time acquisition, and meanwhile, the glutamic acid and the glutamic acid derivatives marked by the stable isotope used in the invention can be taken, so that the human body cannot be injured by multiple detections; for the1The detection of H proton magnetic resonance spectrum can also use standard nuclear magnetic resonance instrument, does not need special equipment, has lower cost, and uses standard nuclear magnetic resonance instrument1The conversion of deuterium marks can be directly monitored by H proton magnetic resonance spectrum acquisition hardware and signal processing, and the method is simple and practical, has high precision and reliable result, and can quantitatively position and analyze the metabolic condition.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (7)

1. The stable isotope labeled glutamic acid and glutamic acid derivatives are characterized in that the chemical structure general formula of the stable isotope labeled glutamic acid and glutamic acid derivatives is as follows:
Figure RE-FDA0003226495100000011
wherein R is1Represents hydroxy, branched or straight chain C1-C5Alkoxy, branched or straight-chain hydroxy C1-C5Alkoxy, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl, N (C)1-C5Alkyl radical)2、NH2N (H) -L, O-L or O-Z, wherein none or one or more hydrogen atoms are replaced by deuterium;
R2、R3、R4and/or R5Independently of one another, hydrogen or deuterium, branched or straight-chain F-C1-C10Alkoxy, branched or straight chain F-C1-C10Alkyl, branched or straight chain F-C2-C10Alkenyl, branched or straight chain F-C2-C10Alkynyl, substituted or unsubstituted F-C6-C10Monocyclic or bicyclic aryl, substituted or unsubstituted F-alkyl-C6-C10Monocyclic or bicyclic aryl, substituted or unsubstituted F-C5-C10Monocyclic or bicyclic heteroaryl, substituted or unsubstituted F-alkyl-C6-C10Monocyclic or bicyclic heteroaryl, substituted or unsubstituted F-C3-C6Cycloalkyl, substituted or unsubstituted F-alkyl-C3-C6Cycloalkyl, hydroxy, branched or straight chain C1-C5Alkyl or branched or straight chain C1-C5Alkoxy, wherein none or one or more hydrogen atoms are replaced by deuterium;
R6represents hydrogen or deuterium;
R7and/or R8Independently of one another, hydrogen or deuterium, methoxycarbonyl, propoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 1-dimethylpropynyl, 1-methyl-1-phenylethoxycarbonyl, 1-methyl-1- (4-biphenyl) ethoxycarbonyl, cyclobutylcarbonyl, 1-methylcyclobutylcarbonyl, vinylcarbonyl, propenylcarbonyl, adamantylcarbonyl, benzhydrylcarbonyl, cinnamylcarbonyl, formyl, benzoyl, trityl, p-methoxyphenyl-benzhydryl, di (p-methoxyphenyl) phenylmethyl, tert-butoxycarbonyl or a halo thereof, wherein none or one or more of the hydrogen atoms are replaced by deuterium;
R9represents hydroxy, branched or straight chain C1-C5Alkoxy, branched or straight-chain hydroxy C1-C5Alkoxy, branched or straight chain O-C2-C5Alkenyl, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl, branched or straight chain O-C2-C5Alkynyl, triphenylmethoxy or O-Z, wherein none or one or more hydrogen atoms are replaced by deuterium;
wherein alkyl is optionally interrupted by O, S or N, or is replaced by it, R1～R9In which at least one hydrogen atom is deuterated, L is a branched or straight chain C1-C5Alkyl, branched or straight chain C2-C5Alkenyl, branched or straight chain O-C1-C5Alkyl- (O-C)1-C4Alkyl) n-O-C1-C4Alkyl or branched or straight chain O-C2-C5Alkynyl, Z is a metal ion equivalent;
where n-0, 1, 2 or 3, and where possible diastereomers and/or mixtures of enantiomers are included, as well as enantiomerically pure compounds and pharmaceutical salts thereof.
2. The stable isotope labeled glutamic acid and glutamic acid derivative according to claim 1, wherein the stable isotope labeled glutamic acid and glutamic acid derivative has a chemical structural formula of:
Figure RE-FDA0003226495100000031
Figure RE-FDA0003226495100000041
Figure RE-FDA0003226495100000051
Figure RE-FDA0003226495100000052
or one of the array combinations between different deuterated positions and deuterated numbers of different substituent groups.
3. A method for preparing stable isotope labeled glutamic acid and glutamic acid derivatives is characterized by comprising the following steps:
under the protection of inert gas, dripping an organic solution of acryloyl chloride into LiAlD4The organic solvent is one or a mixture of more than two of anhydrous ether, anhydrous tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like in any proportion, preferably the anhydrous ether, the anhydrous tetrahydrofuran and the like are stirred and reacted at the temperature of-20 ℃ to 50 ℃, and the post-treated crude product is distilled under normal pressure to obtain 2-ene-1, 1-d 2-1-alcohol;
adding phosphorus tribromide into perfluorohexane, adding an organic solution of 2-ene-1, 1-d 2-1-alcohol, reacting in a dark place, and distilling a post-treatment crude product at normal pressure to obtain 3-bromo-1-ene-3, 3-d 2;
cooling to-80-0 ℃, dropwise adding a tetrahydrofuran solution of lithium bis (trimethylsilyl) amide into a tetrahydrofuran solution of Boc-dimethyl glutamate, reacting at-80-30 ℃ for 1-3 h, dropwise adding 3-bromo-1-ene-3, 3-d2, reacting for 1-3 h, and purifying the post-treated crude product by silica gel column chromatography to obtain (2s,4s) -2- (allyl-1, 1-d2) -4- (tert-butoxycarbonyl) amino) dimethyl glutarate;
under the protection of inert gas at the temperature of-30 ℃, dropwise adding borane tetrahydrofuran complex into (2s,4s) -2- (allyl-1, 1-d2) -4- (tert-butoxycarbonyl) amino) dimethyl glutarate solution, carrying out heat preservation reaction at the temperature of-30 ℃, adding alkali and hydrogen peroxide solution, stirring for reaction, and purifying a post-treated crude product by silica gel column chromatography to obtain (2s,4s) -2- (tert-butoxycarbonyl) amino) -4- (3-hydroxypropyl-1, 1-d2) dimethyl glutarate;
adding (2s,4s) -2- (tert-butoxycarbonyl) amino) -4- (3-hydroxypropyl-1, 1-d2) dimethyl glutarate into a solvent at the temperature of between 30 and 30 ℃, wherein the solvent is one or more than two of diethyl ether, tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, mixing at any ratio, adding diethylaminosulfur trifluoride, carrying out heat preservation reaction, and purifying the post-treated crude product by silica gel column chromatography to obtain (2s,4s) -2- (tert-butoxycarbonyl) amino) -4- (3-fluoropropyl-1, 1-d2) dimethyl glutarate;
adding (2s,4s) -2- (tert-butyloxycarbonyl) amino) -4- (3-fluoropropyl-1, 1-d2) glutaric acid dimethyl ester into a solvent, wherein the solvent is one or a mixture of more than two of diethyl ether, tetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethylformamide, dimethylacetamide and dimethyl sulfoxide according to any proportion, adding alkali, stirring for reaction, and adding acid into the crude product after the reaction to prepare and separate (2s,4s) -2-amino-4- (3-fluoropropyl-1, 1-d2) glutaric acid.
4. Use of stable isotope-labeled glutamic acid and a glutamic acid derivative as described in any one of claims 1 to 2 as a contrast agent for magnetic resonance imaging.
5. The use of stability isotope-labeled glutamic acid and glutamic acid derivatives according to claim 4, wherein the stability isotope-labeled glutamic acid and glutamic acid derivatives are used as an imaging agent for tumor amino acid metabolism.
6. The use of stable isotope labeled glutamic acid and glutamic acid derivatives according to claim 5, wherein the contrast agent further comprises at least one pharmaceutically acceptable excipient.
7. The use of stable isotope labeled glutamic acid and glutamic acid derivatives according to claim 6, wherein the excipient is one of a carrier, a filler or a solvent.
CN202110654686.6A 2021-06-11 2021-06-11 Preparation method and application of stable isotope labeled glutamic acid and glutamic acid derivative Pending CN113429307A (en)

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