CN112079888A - Deuterated glucose and preparation method and application thereof - Google Patents

Deuterated glucose and preparation method and application thereof Download PDF

Info

Publication number
CN112079888A
CN112079888A CN202011030806.7A CN202011030806A CN112079888A CN 112079888 A CN112079888 A CN 112079888A CN 202011030806 A CN202011030806 A CN 202011030806A CN 112079888 A CN112079888 A CN 112079888A
Authority
CN
China
Prior art keywords
glucose
deuterated
deuterated glucose
deuterium
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN202011030806.7A
Other languages
Chinese (zh)
Inventor
杨晓军
阮英恒
李焕锡
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Dingbang Biotechnology Co ltd
Original Assignee
Shenzhen Dingbang Biotechnology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Dingbang Biotechnology Co ltd filed Critical Shenzhen Dingbang Biotechnology Co ltd
Priority to CN202011030806.7A priority Critical patent/CN112079888A/en
Publication of CN112079888A publication Critical patent/CN112079888A/en
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention discloses deuterated glucose and a preparation method and application thereof, wherein the deuterated glucose has a chemical structural general formula
Figure DDA0002703556060000011
Wherein R is1、R2、R3、R4、R5、X1、X2、R6a、R6b、R6c、R6d、R6eAt least one of them is deuterium, and X1、X2Simultaneously deuterium or not deuterium. The invention can track the metabolite transferred by the deuterated glucose by using the deuterated glucose as the tumor contrast agent,the detection resolution and sensitivity are higher, the dynamic exchange of single metabolites can be detected, and the detection is realized by measurement1The change of the H proton magnetic resonance spectrum can be detected under high spectral resolution2The method can provide steady state information and metabolic rate of several metabolites by one-time collection, and simultaneously, the deuterated glucose used in the method can be taken, so that the human body cannot be injured by multiple detections.

Description

Deuterated glucose and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to deuterated glucose and a preparation method and application thereof.
Background
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. The most prominent positron drug currently used in PET examinations is18F-fluorodeoxyglucose (F-fluorodeoxyglucose)18F-FDG)，18F-FDG as a tumor metabolism medicament plays a great role in the diagnosis and differential diagnosis of malignant tumors, but18Fluorine in the F-FDG is selected from fluorine-18 which belongs to positron emission type radioactive isotopes, namely positron radioactive nuclides, which easily cause secondary damage to a patient after multiple detections, and compared with other imaging labeled nuclides such as oxygen-15 (O-15), nitrogen 13(N-13) and carbon 11(C-11), the half-life period of the F-FDG is obviously improved (109.8min), but the F-FDG cannot be used for tracking the whole metabolic process.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, the present invention aims to provide a deuterated glucose, a preparation method thereof and an application thereof, and aims to solve the problem of the prior art adopting the deuterated glucose18F-fluorodeOxygen glucose is used as a contrast agent, so that secondary damage is easily caused to a patient by multiple detections, and the oxygen glucose cannot be used for tracking the whole metabolic process.
The technical scheme of the invention is as follows:
the deuterated glucose is represented by the chemical structural formula:
Figure BDA0002703556040000021
wherein R is1、R2、R3、R4、R5、X1、X2、R6a、R6b、R6c、R6d、R6eAt least one of them is deuterium, and X1、X2Simultaneously deuterium or not deuterium.
The deuterated glucose is represented by the chemical structural formula
Figure BDA0002703556040000022
Figure BDA0002703556040000031
Figure BDA0002703556040000032
One kind of (1).
A preparation method of deuterated glucose comprises the following steps:
under the protection of nitrogen, reactants are reacted
Figure BDA0002703556040000033
Dissolving in heavy water, sequentially adding samarium diiodide THF solution and triethylamine, and mixing to obtain reaction liquid;
introducing air into the reaction solution, and adding dichloromethane and hydrochloric acid for dilution;
and (3) extracting, drying, filtering, spin-drying and column-passing the diluted reaction solution to obtain the deuterated glucose.
The preparation method of the deuterated glucose is characterized in that the reactant
Figure BDA0002703556040000034
The molar ratio of the heavy water to the heavy water is as follows: 1: 18-1: 5000.
The application of the deuterated glucose is characterized in that the deuterated glucose or the deuterated glucose prepared by the preparation method is used as a tumor contrast agent.
The application of the deuterated glucose is that the tumor comprises one of breast cancer, lung cancer, hepatocellular carcinoma, prostate cancer, brain tumor, lung cancer, gastric cancer, thyroid cancer and colorectal cancer.
Has the advantages that: the invention provides deuterated glucose and a preparation method and application thereof1The universality and the easy implementation advantage of H proton magnetic resonance spectrum detection and the excellent spectral resolution can track the metabolites transferred by the deuterated glucose, the detection resolution and the sensitivity are higher, the dynamic exchange of single metabolites can be detected, and the measurement is realized1The change of the H proton magnetic resonance spectrum can be detected under high spectral resolution2Metabolites which cannot be detected by the 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 deuterated glucose 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.
Drawings
Fig. 1 is a chemical reaction diagram of a preparation method of deuterated glucose according to the invention.
FIG. 2 shows an infusion [6, 6' -2H2]Glucose measurement in the midbrain1H MRS spectrum (10 min acquisition, 256 mean).
FIG. 3 is [6, 6' -2H2]Glucose and [2,2, 2' -2H3]Schematic diagram of the metabolic pathway of acetate in vivo.
Detailed Description
To more clearly illustrate the objects, technical solutions and advantages of the embodiments of the present invention, the present invention will be further described with reference to the following embodiments, which are clearly and completely described, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without inventive step, are within the scope of the present invention.
The invention provides deuterated glucose, which has a chemical structural general formula as follows:
Figure BDA0002703556040000051
wherein R is1、R2、R3、R4、R5、X1、X2、R6a、R6b、R6c、R6d、R6eAt least one of them is deuterium, and X1、X2Simultaneously deuterium or not deuterium.
In some embodiments, the deuterated glucose has a chemical structural formula
Figure BDA0002703556040000052
Figure BDA0002703556040000053
Figure BDA0002703556040000061
Figure BDA0002703556040000062
One kind of (1).
In some embodiments, a preparation method of the deuterated glucose is further provided, wherein different preparation methods are adopted according to different deuterated positions:
when preparing
Figure BDA0002703556040000063
Wherein R is1、R3、R4、R5、X1、X2Is deuterium, and the deuterium position corresponds to R6a、R6b、R6c、R6d、R6eWhen the corresponding is hydrogen, the following preparation method is adopted, wherein the preparation method comprises the following steps:
under the protection of nitrogen, reactants are reacted
Figure BDA0002703556040000071
Dissolving in heavy water, adding a catalyst Ru/C, and heating at 80 ℃ for reaction for 24 hours to obtain a reaction solution;
filtering the reaction solution, and spin-drying to obtain deuterated glucose
Figure BDA0002703556040000072
In the embodiment, the preferential content of the catalyst Ru/C is 10 percent, and the preferential range is 1 to 200 percent; the heating temperature is preferably 80 ℃, and the temperature range is 60-250 ℃; the reaction time is preferably 24 hours, preferably in the range of more than 1 hour.
In some embodiments, when prepared
Figure BDA0002703556040000073
Wherein R is1、R2、R3、R4、R5、X1、X2、R6a、R6b、R6c、R6d、R6eIn which at least one is deuterium, X1、X2With or without deuterium, R2Deuterated alone or R2When deuterated with other sites, the preparation method is preferably adopted, wherein the preparation method comprises the following steps:
under the protection of nitrogen, reactants are reacted
Figure BDA0002703556040000081
Dissolving in heavy water, adding a catalyst Pd/C, and heating at 160 ℃ for reaction for 24 hours to obtain a reaction solution;
filtering the reaction solution, and spin-drying to obtain deuterated glucose
Figure BDA0002703556040000082
The substitution position and amount can be controlled by controlling the reaction temperature, reaction time and pressure.
In the embodiment, the amount of the catalyst Pd/C is preferably 10 percent, and the preferable range is 1 to 200 percent; the heating temperature is preferably 160 ℃, and the temperature range is preferably 50-250 ℃; the reaction time is preferably 24 hours, and the preferable time range is more than 1 hour; the reaction pressure is preferably normal pressure, and preferably within the range of normal pressure to 10 MPa.
In some embodiments, when prepared
Figure BDA0002703556040000083
Wherein, X1、X2When the deuterium is substituted, other sites are not deuterated, the following preparation method is preferably adopted:
under the protection of nitrogen, reactants are reacted
Figure BDA0002703556040000091
Dissolving in heavy water, sequentially adding samarium diiodide THF solution and triethylamine, and mixing to obtain reaction liquid;
introducing air into the reaction solution, and adding dichloromethane and hydrochloric acid for dilution;
and (3) extracting, drying, filtering, spin-drying and column-passing the diluted reaction solution to obtain the deuterated glucose.
In this example, the samarium diiodide, as an excellent single electron transfer reagent, can be used as a reducing agent to react with various substrates to generate free radicals. Triethylamine is used as an absorption base, which is beneficial to improving the activity of reaction substrate acid and promoting the reaction to be carried out smoothly.
In some embodiments, the reactant is
Figure BDA0002703556040000092
The molar ratio of the heavy water to the heavy water is as follows: 1: 18-1: 5000.
In some embodiments, as shown in fig. 1, reactant 1(100mg, 0.5155mmol, 1eq.) is dissolved in heavy water (3.4mL,185.58mmol, 360eq.) under nitrogen protection, added dropwise to a three-necked flask containing 0.1M samarium diiodide THF solution (31mL,3.1mmol,6eq.), added triethylamine (1.3mL,9.279mmol, 18eq.) and stirred at room temperature for 2 h.
Excess samarium diiodide was quenched by bubbling air for oxidation. The reaction mixture was diluted with dichloromethane (30mL) and hydrochloric acid (1M,30 mL). The aqueous phase was extracted with dichloromethane (3 × 30mL), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and spin dried to give the crude product. The crude product was purified by column chromatography (eluent: ethyl acetate/petroleum ether: 6:1 to 2:1) to yield 72mg of the desired product (yield: 77%).
In some embodiments, the invention provides a use of deuterated glucose as a tumor contrast agent, wherein the deuterated glucose has a chemical structural formula:
Figure BDA0002703556040000101
wherein R is1、R2、R3、R4、R5、X1、X2、R6a、R6b、R6c、R6d、R6eAt least one of them is deuterium, and X1、X2Simultaneously deuterium or not deuterium.
In this example, it was confirmed that deuterated glucose can be taken into cancer cells via GLUT as a result of pharmacological tests using the same. By bringing a composition containing deuterated glucose of the present invention into contact with a target cell as a reagent, the target can be imaged at a single-cell level. According to the present invention, formation can also be performed by bringing the deuterated glucose of the present invention into contact with a tissue containing target cells, thereby imaging the cells in the tissue at the single cell level. The deuterated glucose of the present invention can be administered to a living body to be imaged, whereby a tissue in which a tumor contains these cells can be detected, and this method is useful as a method for detecting a tumor. The deuterated glucose of the present invention can be applied to any form of composition, solution, gel or other form of cells, and is not particularly limited as long as it can be applied to cells.
In some embodiments, the site to be detected is scanned by NMR spectroscopy and formed before the use of deuterated glucose1H 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: a PRESS sequence is used (TR/TE 2500/16ms, spectrum width 4kHz, 90 pulse bandwidth 5400Hz, 180 pulse bandwidth 2400Hz, points 4006, vapro water suppression, average 128).
After obtaining the pre-use profile, the subject is administered deuteroglucose, which may be a composition in the form of a single dosage unit, i.e., the composition may be in a single dose or one or more unit doses contained in a single container, each dose containing the same ingredients, i.e., each dose contains the same weight2H-label substance, each dose can be directly or diluted for use by a subject, or the composition can be made into different specifications, such as different specifications containing deuterated glucose, the composition can be used by being administered to the subject according to the condition of the subject, the composition can be made into different forms of liquid or solid, and different doses of deuterated glucose can be administered according to the condition of the subject, such as the deuterated glucose is dissolved in 200-300 ml of water according to the dosage of 0.60-0.75 g/kg of body weight and the maximum dosage of 60 g for use, and according to the different specifications of the deuterated glucose, the deuterated glucose can be used in an oral non-invasive mode or an injection mode,the deuterated glucose can also 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 reduction of the signal in the proton magnetic resonance spectrum generated by H can obtain the conversion condition of the deuterated glucose, thereby obtaining the metabolic condition of the cell. After the site to be detected of the subject is scanned again by a nuclear magnetic resonance spectrometer under the same parameters within a given time and the deuterated glucose is formed1H, a post-use map; the given time is preferably 20-90 min, so that the deuterated glucose can be sufficiently converted in vivo to obtain more accurate detection results and reflect metabolic conditions, and the measurement can be performed at intervals within the given time, for example, the map data of the time point can be obtained every five or ten minutes, as shown in fig. 2, and the patient can take the composition
[6,6′-2H2]The post-glucose Glu-H4 peak decreased in amplitude with time and formed a distinct peak at 2.35ppm in the difference spectrum. While detecting1H MRS, also detect simultaneously2H MRS, and then quantitative analysis of Glx concentration by a quantitative analysis software of spectrum such as LCModel, it can be seen that1H MRS and2h MRS in [6, 6' -2H2]The initial linear increase started to plateau after 45 minutes post-glucose with good agreement between the two, indicating that1H MRS can accurately reflect the dynamic change of Glx after taking deuterated glucose. 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 detected2The profiles of some metabolites which can not be obtained by the H MRS can be obtained, so that more accurate detection results can be obtained, and the steady state metabolic information of several metabolites can be provided,the metabolic dynamic process of key metabolites can be detected in the same acquisition process.
Processing and analyzing pre-use profile and post-use profile data according to the specific metabolites1The characteristic spectrum of H obtains the concentration of the designated metabolite before and after the deuterated glucose is used, the concentration difference of the metabolite before and after the deuterated glucose is the conversion of the deuterated glucose, and the enrichment rate of the designated metabolite is obtained by the following formula:
enrichment rate ═ (pre-metabolite concentration used-metabolite concentration after use)/pre-metabolite concentration used 100%
The metabolic pathway of the deuterated glucose is obtained through the enrichment of different metabolites, and the metabolic condition of the part to be detected is obtained by comparing the measured values of the same metabolite under the functions of the subject and normal tissues. In taking [6, 6' -2H2]The concentration profiles of various metabolites before and after glucose were corrected in the figure using the following correction factors, adjusted at 1.33ppm [6, 6' -2H2]One or two after taking glucose2The amount of H group transferred from acetyl-CoA to downstream metabolites can be seen in the figure for the administration of [6, 6' -2H2]The gradual enrichment of Glx after glucose and eventually plateau, after 45 minutes of administration, increased by 0.89 + -0.23 mM (about 9% enrichment), and by quantitative analysis alone, increased by 0.68 + -0.15 mM (about 11% enrichment), increased by 0.21 + -0.12 mM (about 8% enrichment), and increased by 0.25 + -0.10 mM (about 10% enrichment) for changes in GABA. It is known that the development of some pathological tissues, especially tumors, is closely related to the metabolism of cells, and tumor cells are more dependent on glycolysis to support the growth, proliferation and survival of cells, and the Warburg effect shows that the marker of the low-efficiency metabolic process is the increase of the absorption of Glc and the subsequent conversion into Lac, and the yield of Lac is obviously increased compared with the normal physiological condition, and the metabolic condition of the tissues can be clearly and accurately obtained through the change of the concentrations of the metabolites. The value of normal tissue function can be derived from medically prescribed values or from several healthy samplesThe average value of (c) is used.
In some embodiments, the deuterated glucose has a chemical structural formula
Figure BDA0002703556040000121
Figure BDA0002703556040000131
Figure BDA0002703556040000141
One kind of (1).
The deuterated glucose is used as [6, 6' -2H2]The glucose, deuterated acetate is [2,2, 2' -2H3]Acetate salt as an example, [6, 6' -2H2]Glucose and [2,2, 2' -2H3]The metabolism of acetate in the body is shown in fig. 3, and therefore it is preferable to detect any one or more of glutamic acid, glutamine, γ -aminobutyric acid, and lactic acid as important metabolites. Glucose labeled at the sixth carbon position was superior to [1-2H]Glucose (D) because of the higher deuterium content (two)2H atom) and cost better than [1,2,3,4,5,6, 6' -2H 7]Glucose, reduced cost and minimization2The complexity of the H nuclear magnetic resonance spectrum is more beneficial to improving the detection precision and accuracy. As shown in FIG. 2, the [6, 6' -2H2]In the brain before and after 60 minutes of glucose1H MRS, in which a reduction in Glu-H4 amplitude at 2.35ppm was clearly observed, was subtracted from the spectrum before glucose administration1H MRS profile, in addition to several glutamic acid (Glu), glutamine (Gln), gamma-aminobutyric acid (GABA) and aspartic Acid (ASP) resonances, the Glu-H4 resonance at 2.35ppm was significantly increased, well above background signal, with a large reduction in the spectrum of difference between 3.3 and 3.6ppm due to the administration of [6, 6' -2H2]Resonance generation of non-deuterated protons on glucose, with a considerable increase between 3.6 and 4.0ppmPlus, which corresponds to deuterium-labeled Glc-H6 resonance (3.9ppm), Glu + Gln-H2 (Glx-H2; 3.8ppm), due to the high sensitivity of the assay, while at 1.33ppm there was a slight decrease in Lac-H3 resonance, which is due to the small amount of unlabeled Lac produced by the brain tissue as a result of the glucose administered. In taking [6, 6' -2H2]For glucose, oral administration [6, 6' -2H2]Glucose, in an amount of 0.75 g/kg body weight, dissolved in 300 ml of water of 200-2H2]Glucose was dissolved in water at a concentration of 1M, and injected in an amount of 1.95g/kg body weight, and infusion was performed through the femoral vein or the intraperitoneal vein, or [2 ], [ solution ]2H3]Acetate was dissolved in water at a concentration of 2. mu.M and injected like glucose to give 2g/kg body weight in total2H3]An acetate salt. At the same time, cells from the site to be detected can also be harvested, washed with phosphate buffered saline and cultured under standard culture conditions (37 ℃ and 5% CO)2) Lower and containing 100% [6-13C]Glucose or [6-13C，6,6′-2H2]Incubation in DMEM, 6 hours later, the medium was collected and [2-13C]Glycine as an internal standard, followed by freeze-drying of the sample (5ml) on a freeze-dryer, and addition of 600. mu.l of a mixed solution containing phosphate buffer (100mM), D and a standard for chemical shift and internal concentration to the freeze-dried sample2O (10%), sodium formate and imidazole in water. In the examples we injected the subjects intravenously [6, 6' -2H2]Glucose is injected into 250 mul in 15 seconds, then the infusion rate is reduced to 191 mul/min, the infusion rate is manually reduced once every 30s after the index is reduced until the final infusion rate of the initial 8min is 13.7 mul/min, the infusion is finished in 70min, and then the midbrain is scanned by a nuclear magnetic resonance spectrometer to obtain the injection1H MRS, brain (6.5 × 2.5 mm) in a control group using PRESS (TR/TE: 2500/16ms, spectrum width: 4kHz, 90 pulse bandwidth: 5400Hz, 180 pulse bandwidth: 2400Hz, point: 4006, vapro water suppression, average: 128)3N ═ 6) and glioblastoma (4x4x4 mm)3N is 3); the measured in vivo pairs were then tested using LCMODel software1H MRS to quantify the concentration of metabolites, when uninhibited water peaks were used as concentration standards, LCModel applied a 9.4T self-pick-up (TE ═ 16ms) basis set and contained Ala, Asp, creatine, phosphocreatine, GABA, Glc, Gln, Glu, glycerophosphocholine, choline carbonate, glutathione, inositol, NAA + Glu, glycoinositol and taurine, lipid resonances of 0.9, 1.3 and 2.0ppm, respectively, macromolecular resonances of 0.9, 1.2, 1.4, 1.7 and 2.0ppm, after which the post-infusion levels were subtracted from the pre-infusion levels and the changes in metabolite levels were divided by the pre-infusion values to calculate the enrichment of each metabolite.
The method obtains the concentrations of the designated metabolites before and after the deuterated glucose is used by analyzing the data of the before-use map and the after-use map of the deuterated glucose, and obtains the metabolic condition of the tissue according to the concentration changes before and after the deuterated glucose 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 the deuterated glucose, the detection resolution and the sensitivity are higher, the dynamic exchange of single metabolites can be detected, and the measurement is realized1The change of the H proton magnetic resonance spectrum can be detected under high spectral resolution2Metabolites which cannot be detected by the 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 deuterated glucose 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.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.

Claims (6)

1. The deuterated glucose is characterized by having a chemical structural general formula:
Figure FDA0002703556030000011
wherein R is1、R2、R3、R4、R5、X1、X2、R6a、R6b、R6c、R6d、R6eAt least one of them is deuterium, and X1、X2Simultaneously deuterium or not deuterium.
2. The deuterated glucose as recited in claim 1, wherein the deuterated glucose has a chemical structural formula
Figure FDA0002703556030000012
Figure FDA0002703556030000013
Figure FDA0002703556030000021
Figure FDA0002703556030000022
One kind of (1).
3. A method for preparing deuterated glucose as described in any one of claims 1-2, comprising the steps of:
under the protection of nitrogen, reactants are reacted
Figure FDA0002703556030000023
Dissolving in heavy water, sequentially adding samarium diiodide THF solution and triethylamine, and mixing to obtain reaction liquid;
introducing air into the reaction solution, and adding dichloromethane and hydrochloric acid for dilution;
and (3) extracting, drying, filtering, spin-drying and column-passing the diluted reaction solution to obtain the deuterated glucose.
4. The method of claim 3, wherein the reactant is selected from the group consisting of glucose, glucose
Figure FDA0002703556030000031
The molar ratio of the heavy water to the heavy water is as follows: 1: 18-1: 5000.
5. Use of deuterated glucose as described in any one of claims 1-2 or as prepared by the process of any one of claims 3-4 as a contrast agent for tumors.
6. The use of deuterated glucose as recited in claim 5 wherein the tumor comprises one of breast cancer, lung cancer, hepatocellular cancer, prostate cancer, brain tumor, lung cancer, gastric cancer, thyroid cancer, and colorectal cancer.
CN202011030806.7A 2020-09-27 2020-09-27 Deuterated glucose and preparation method and application thereof Withdrawn CN112079888A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011030806.7A CN112079888A (en) 2020-09-27 2020-09-27 Deuterated glucose and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011030806.7A CN112079888A (en) 2020-09-27 2020-09-27 Deuterated glucose and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN112079888A true CN112079888A (en) 2020-12-15

Family

ID=73738347

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011030806.7A Withdrawn CN112079888A (en) 2020-09-27 2020-09-27 Deuterated glucose and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN112079888A (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050130A2 (en) * 2004-10-29 2006-05-11 Target Discovery, Inc. Glycan analysis using deuterated glucose
US20100322865A1 (en) * 2009-06-19 2010-12-23 Duerk Jeffrey L Deuterated metabolic water precursor for detecting and treating diseased tissue

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050130A2 (en) * 2004-10-29 2006-05-11 Target Discovery, Inc. Glycan analysis using deuterated glucose
US20100322865A1 (en) * 2009-06-19 2010-12-23 Duerk Jeffrey L Deuterated metabolic water precursor for detecting and treating diseased tissue

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FELIX KREIS ET AL.: ""Measuring Tumor Glycolytic Flux in Vivo by Using Fast Deuterium MRI"", 《RADIOLOGY》 *
NURY PÉREZ-HERNÁNDEZ ET AL.: ""Deuterium-induced isotope effects on the 13C chemical shifts of a-D-glucose pentaacetate"", 《MAGN. RESON. CHEM.》 *
TESIA V. CHCIUK ET AL.: ""Proton-Coupled Electron Transfer in the Reduction of Carbonyls by Samarium Diiodide-Water Complexes"", 《J. AM. CHEM. SOC.》 *
王乐天 等: "肿瘤靶向性造影剂的研究进展", 《中国药科大学学报》 *

Similar Documents

Publication Publication Date Title
Rich et al. 1H magnetic resonance spectroscopy of 2H-to-1H exchange quantifies the dynamics of cellular metabolism in vivo
JPH05501869A (en) Perfluoro-t-butyl-containing compounds for use in fluorine-19 NMR and/or MRI
Cember et al. Integrating 1H MRS and deuterium labeled glucose for mapping the dynamics of neural metabolism in humans
US9034928B2 (en) Methods for metabolic imaging
Anemone et al. In vitro and in vivo comparison of MRI chemical exchange saturation transfer (CEST) properties between native glucose and 3‐O‐methyl‐D‐glucose in a murine tumor model
Utsumi et al. Free radical imaging using in vivo dynamic nuclear polarization-MRI
CN112079888A (en) Deuterated glucose and preparation method and application thereof
US8722420B2 (en) Method for detecting an endogenous biomolecule
CN113372348A (en) Deuterated FP-beta-CIT and preparation method and application thereof
JP2011519554A (en) Method for measuring alanine transaminase (ALT) activity by 13C-MR detection using hyperpolarized 13C-pyruvate
Zhang et al. [6, 6′‐2H2] fructose as a deuterium metabolic imaging probe in liver cancer
Zou et al. A new deuterium‐labeled compound [2, 3, 4, 6, 6’‐2H5]‐D‐glucose for deuterium magnetic resonance metabolic imaging
CN113292464A (en) Stable isotope labeled methionine compound and preparation and application methods thereof
CN108191603B (en) 3-18F-fluoro lactic acid analogue and preparation method and application thereof
CN112479911A (en) Deuterated dopamine, preparation method and application thereof
Liu et al. Study of kinetics of 19 F-MRI using a fluorinated imaging agent (19 FIT) on a 3T clinical MRI system
CN112321509A (en) Deuterated piperidone as well as preparation method and application thereof
CN117800856A (en) Preparation method and application of stable isotope-substituted choline compound
CN113209317A (en) Deuterated taltirelin contrast agent
CN113416168A (en) Stable isotope labeled nitroimidazole compound and preparation and application methods thereof
CN113491515A (en) Nuclear magnetic detection method based on deuterium substitutes for detecting metabolism
CN112933254A (en) Deuterated Tauvid contrast agent
Prior et al. Fluorine-19F NMR Spectroscopy and Imaging In-Vivo
CN113429307A (en) Preparation method and application of stable isotope labeled glutamic acid and glutamic acid derivative
CN116813673A (en) Preparation method and application of pentadeuterated glucose

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication
WW01 Invention patent application withdrawn after publication

Application publication date: 20201215