1. A stable isotope labeled PM-PBB3 compound, wherein the stable isotope labeled PM-PBB3 compound has a chemical structure general formula:

wherein R is₁、R₂Independently of one another, hydrogen or deuterium or C_1-4An alkyl group; wherein R is₃To R₁₂Independently of one another, hydrogen or deuterium; wherein R is₁₃、R₁₄、R₁₅、R₁₆And/or R₁₇Independently of one another, hydrogen or deuterium, branched or straight-chain C₁-C₁₀Alkoxy, branched or straight chain C₁-C₁₀Alkyl, substituted or unsubstituted C₆-C₁₀Monocyclic or bicyclic aryl, substituted or unsubstituted alkyl-C₆-C₁₀A monocyclic or bicyclic aryl group,Substituted or unsubstituted C₅-C₁₀Monocyclic or bicyclic heteroaryl, substituted or unsubstituted alkyl-C₆-C₁₀Monocyclic or bicyclic heteroaryl or hydroxy, wherein none or one or more hydrogen atoms are replaced by deuterium; wherein R is₁To R₁₇In which at least one hydrogen atom is deuterated.

2. The stability isotope labeled PM-PBB3 class compound according to claim 1, wherein the stability isotope labeled PM-PBB3 class compound has a chemical structure general formula:

or one of the array combinations between different deuterated positions and deuterated numbers of different substituent groups.

3. A method for using a stable isotope labeled PM-PBB3 compound, wherein the deuterated PM-PBB3 compound of any one of claims 1-2 is used as a contrast agent for magnetic resonance imaging.

4. The use of claim 3, wherein the deuterated PM-PBB3 compound is used as a DMI contrast agent for detecting Tau protein.

5. The method of use according to claim 3, wherein said contrast agent further comprises at least one pharmaceutically acceptable excipient.

6. The method of use of claim 5, wherein the excipient is one of a carrier, a bulking agent, or a solvent.

7. A preparation method of a deuterated PM-PBB3 compound is characterized by comprising the following steps:

s1 preparation of Compound I-2: under the protection of inert gas, adding 3, 3-diethoxy-1-propylene, potassium chloride, tetrabutylammonium bromide, alkali and palladium acetate into an organic solution of a compound I-1, namely 5-bromo-2-nitropyridine, heating for reaction, cooling after the reaction is finished, adding an organic solvent and acid, stirring, adding alkali liquor for neutralization, extracting with the organic solvent, drying, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound I-2;

s2: preparation of Compound I-4: under the protection of low-temperature inert gas, dropwise adding diisopropylamine into an anhydrous THF (tetrahydrofuran) solution of n-butyllithium, stirring for reaction, dropwise adding an anhydrous THF solution of 6-methoxy-2-methylbenzo [ d ] thiazole, keeping the temperature, stirring for reaction, then dropwise adding an anhydrous THF solution of diethyl chlorophosphate, keeping the temperature, stirring for reaction, heating to room temperature, stirring for reaction, quenching with an aqueous solution of ammonium chloride, extracting with an organic solvent, washing an organic layer with alkali liquor, washing with brine, drying, filtering, concentrating under reduced pressure, and carrying out silica gel column chromatography to obtain an orange oily compound I-4;

s3: preparation of Compound I-5: under the protection of inert gas, adding the compound I-4 into an organic solvent, cooling, adding sodium hydrogen, stirring for reaction, adding the compound I-2, reacting until the raw materials disappear, pouring the reaction liquid into ice water, stirring, filtering, adding a filter cake into toluene, concentrating under reduced pressure, filtering, and drying in vacuum to obtain a compound I-5;

s4: preparation of Compound I-6: adding the compound I-5 into an organic solvent, adding acetic acid, reduced iron powder and hydrochloric acid, stirring overnight, dropwise adding alkali liquor under ice bath, filtering out precipitates, adding the precipitates into the organic solvent, stirring, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography to obtain a compound I-6;

s5 preparation of Compound I-7: adding the compound I-6 into an organic solvent under the protection of inert gas, cooling, adding sodium hydrogen, stirring for reaction, dropwise adding deuterated iodomethane, introducing a reaction solution into ice water after the reaction is finished, extracting with the organic solvent, washing with brine, drying, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound I-7;

s6 preparation of Compound I-8: adding the compound I-7 into an organic solvent under the protection of inert gas, cooling, dropwise adding boron tribromide, stirring for reaction, cooling, adding alkali liquor for neutralization, filtering out precipitates, washing with water, adding into the organic solvent, stirring, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography to obtain a compound I-8;

compound I-10: adding a compound I-8, alkali and a catalytic amount of 18-crown-6 into an organic solvent, adding a compound I-9, stirring, carrying out reflux reaction, carrying out reduced pressure concentration, and carrying out silica gel column chromatography to obtain a compound I-10;

compound I-11: adding the compound I-10 into an organic solvent, adding a tetrahydrofuran solution of TBAF, stirring, refluxing, reacting, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound I-11.

8. The application method of the stable isotope labeled PM-PBB3 compound is characterized in that the stable isotope labeled PM-PBB3 compound is used as a DMI contrast agent for detecting Tau protein.

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, produces a large, albeit transient, signal enhancement four to five orders of magnitude higher than Boltzmann polarization at clinically viable MRI field strengths, enabling targeted metabolic studies by spectroscopic 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. The positron drug fluorine-18 (F-18), i.e. positron radionuclide, currently used in PET examination is prone to cause secondary damage to multiple detections of patients, and at the same time, 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 positron drug fluorine-18 (F-18) is obviously improved (109.8min), but the positron drug fluorine-18 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 defects of the prior art, the invention aims to provide a stable isotope labeled PM-PBB3 compound and a preparation and application method thereof, and aims to solve the problems that in the prior art, a positron radioactive nuclide is used as a contrast agent, secondary damage is easily caused to a patient through multiple detections, and the tracking of the whole metabolic process cannot be realized.

The technical scheme of the invention is as follows:

a stability isotope labeled PM-PBB3 compound, wherein the chemical structure general formula of the stability isotope labeled PM-PBB3 compound is as follows:

wherein R is₁、R₂Independently of one another, hydrogen or deuterium or C_1-4An alkyl group; wherein R is₃To R₁₂Independently of one another, hydrogen or deuterium; wherein R is₁₃、R₁₄、R₁₅、R₁₆And/or R₁₇Independently of one another, hydrogen or deuterium, branched or straight-chain C₁-C₁₀Alkoxy, branched or straight chain C₁-C₁₀Alkyl, substituted or unsubstituted C₆-C₁₀Monocyclic or bicyclic aryl, substituted or unsubstituted alkyl-C₆-C₁₀Monocyclic or bicyclic aryl, substituted or unsubstituted C₅-C₁₀Monocyclic or bicyclic heteroaryl, substituted or unsubstituted alkyl-C₆-C₁₀Monocyclic or bicyclic heteroaryl or hydroxy, wherein none or one or more hydrogen atoms are replaced by deuterium; wherein R is₁To R₁₇Wherein at least one hydrogen atom is deuterated;

further, the general chemical structure formula of the stable isotope labeled PM-PBB3 compound is as follows:

or one of the array combinations between different deuterated positions and deuterated numbers of different substituent groups.

A preparation method of a stable isotope labeled PM-PBB3 compound comprises the following steps:

s1 preparation of Compound I-2: under the protection of inert gas, adding 3, 3-diethoxy-1-propylene, potassium chloride, tetrabutylammonium bromide, alkali and palladium acetate into an organic solution of a compound I-1, namely 5-bromo-2-nitropyridine, heating for reaction, cooling after the reaction is finished, adding an organic solvent and acid, stirring, adding alkali liquor for neutralization, extracting with the organic solvent, drying, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound I-2;

s2: preparation of Compound I-4: under the protection of low-temperature inert gas, dropwise adding diisopropylamine into an anhydrous THF (tetrahydrofuran) solution of n-butyllithium, stirring for reaction, dropwise adding an anhydrous THF solution of 6-methoxy-2-methylbenzo [ d ] thiazole, keeping the temperature, stirring for reaction, then dropwise adding an anhydrous THF solution of diethyl chlorophosphate, keeping the temperature, stirring for reaction, heating to room temperature, stirring for reaction, quenching with an aqueous solution of ammonium chloride, extracting with an organic solvent, washing an organic layer with alkali liquor, washing with brine, drying, filtering, concentrating under reduced pressure, and carrying out silica gel column chromatography to obtain an orange oily compound I-4;

s3: preparation of Compound I-5: under the protection of inert gas, adding the compound I-4 into an organic solvent, cooling, adding sodium hydrogen, stirring for reaction, adding the compound I-2, reacting until the raw materials disappear, pouring the reaction liquid into ice water, stirring, filtering, adding a filter cake into toluene, concentrating under reduced pressure, filtering, and drying in vacuum to obtain a compound I-5;

s4: preparation of Compound I-6: adding the compound I-5 into an organic solvent, adding acetic acid, reduced iron powder and hydrochloric acid, stirring overnight, dropwise adding alkali liquor under ice bath, filtering out precipitates, adding the precipitates into the organic solvent, stirring, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography to obtain a compound I-6;

s5 preparation of Compound I-7: adding the compound I-6 into an organic solvent under the protection of inert gas, cooling, adding sodium hydrogen, stirring for reaction, dropwise adding deuterated iodomethane, introducing a reaction solution into ice water after the reaction is finished, extracting with the organic solvent, washing with brine, drying, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound I-7;

s6 preparation of Compound I-8: adding the compound I-7 into an organic solvent under the protection of inert gas, cooling, dropwise adding boron tribromide, stirring for reaction, cooling, adding alkali liquor for neutralization, filtering out precipitates, washing with water, adding into the organic solvent, stirring, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography to obtain a compound I-8;

compound I-10: adding a compound I-8, alkali and a catalytic amount of 18-crown-6 into an organic solvent, adding a compound I-9, stirring, carrying out reflux reaction, carrying out reduced pressure concentration, and carrying out silica gel column chromatography to obtain a compound I-10;

compound I-11: adding the compound I-10 into an organic solvent, adding a tetrahydrofuran solution of TBAF, stirring, refluxing, reacting, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a compound I-11;

an application method of a stable isotope labeled PM-PBB3 compound, wherein the stable isotope labeled PM-PBB3 compound is used as a DMI contrast agent for detecting Tau protein.

Has the advantages that: the invention provides a PM-PBB3 compound labeled by stable isotope, which can be used for detecting whether Tau protein exists in the interior of cerebral neuron, and the invention utilizes the compound¹The 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 compounds, the detection resolution and the sensitivity are higher, and the dynamic intersection of single metabolites can be detectedAlternatively, by measuring¹The 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 contrast agent used in the invention can be taken, so that the deuterium contrast agent cannot cause harm to a human body after being detected for many times; 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 schematic diagram of a preparation method of a stable isotope labeled PM-PBB3 compound 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.

Alzheimer's disease is a progressive disease with the initial symptoms of mild memory loss. Tau neurofibrillary tangles and amyloid deposits are considered to be hallmarks of alzheimer's disease. In alzheimer's patients, pathological forms of Tau protein occur inside neurons in the brain, forming neurofibrillary tangles. However, it is difficult to accurately detect whether Tau protein exists in the interior of cerebral neurons in the prior art.

Based on the technical scheme, the invention provides a stable isotope labeled PM-PBB3 compound, wherein the chemical structure general formula of the stable isotope labeled PM-PBB3 compound is as follows:

wherein R is₁、R₂Independently of one another, hydrogen or deuterium or C_1-4An alkyl group; wherein R is₃To R₁₂Independently of one another, hydrogen or deuterium; wherein R is₁₃、R₁₄、R₁₅、R₁₆And/or R₁₇Independently of one another, hydrogen or deuterium, branched or straight-chain C₁-C₁₀Alkoxy, branched or straight chain C₁-C₁₀Alkyl, substituted or unsubstituted C₆-C₁₀Monocyclic or bicyclic aryl, substituted or unsubstituted alkyl-C₆-C₁₀Monocyclic or bicyclic aryl, substituted or unsubstituted C₅-C₁₀Monocyclic or bicyclic heteroaryl, substituted or unsubstituted alkyl-C₆-C₁₀Monocyclic or bicyclic heteroaryl or hydroxy, wherein none or one or more hydrogen atoms are replaced by deuterium; wherein R is₁To R₁₇Wherein at least one hydrogen atom is deuterated;

in some embodiments, the general chemical structure of the stability isotope labeled PM-PBB 3-based compound is:

or one of the series combinations between different deuterated positions and deuterated numbers of different substituent groups, but not limited thereto.

The preparation method of the stable isotope labeled PM-PBB3 compound comprises the following steps:

s1 preparation of Compound I-2(E) -3- (6-nitropyridin-3-yl) acrolein: adding 3, 3-diethoxy-1-propylene (96.1g,738mmol), potassium chloride (18.3g,246mmol), tetrabutylammonium bromide (23.8g,73.8mmol), potassium carbonate (50.9g,369mmol) and palladium acetate (2.8g,12.3mmol) into a DMF (500mL) solution of the compound I-1, namely 5-bromo-2-nitropyridine (50.0g,246mmol) under the protection of nitrogen, heating to 100 ℃ for reaction, cooling after the reaction is finished, adding ethyl acetate and 1N hydrochloric acid, stirring, adding a sodium bicarbonate solution for neutralization, extracting with ethyl acetate, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out silica gel column chromatography to obtain 6.2g of the compound I-2(E) -3- (6-nitropyridine-3-yl) acrolein with the yield of 14.1%;

s2: preparation of compound I-4 (6-methoxybenzo [ d ] thiazol-2-yl) methylphosphonic acid diethyl ester: diisopropylamine (8.76mL, 62.5mmol) was added dropwise to a solution of N-butyllithium (2.5M, N-hexane, 25mL, 62.5mmol) in anhydrous THF (25mL) under nitrogen protection at 78 deg.C, stirred for 30min, 6-methoxy-2-methylbenzo [ d ] thiazole (5.00g, 27.9mmol) in anhydrous THF (40mL) was added dropwise, stirred for 30min at 78 deg.C, then diethyl chlorophosphate (4.44mL, 30.7mmol) in anhydrous THF (20mL) was added dropwise, the reaction was stirred for 10min at-78 deg.C, warmed to room temperature, stirred for 1h, quenched with 1N aqueous ammonium chloride (100mL), DCM extracted, the organic layer was washed with 2% aqueous sodium carbonate, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatographed on silica gel (dichloromethane/methanol: 50:1) to give 5.91g of orange-4 (6-methoxybenzo [ d ] methylthiazol [ 2-methyl) as an oily oil Diethyl phosphonate, yield 67%;

s3: preparation of the compound I-56-methoxy-2- (1E,3E) -4- (6-nitropyridin-3-yl) butan-1, 3-dien-1-yl) benzo [ d ] thiazole: adding compound I-4 (6-methoxybenzo [ d ] thiazol-2-yl) methyl phosphonic acid diethyl ester (10.2g,32.3 mmol) into THF (300mL) under the protection of nitrogen, cooling in ice bath, adding sodium hydrogen (content 60%, 1.3g,32.3mmol), stirring at room temperature for 30min, adding compound I-2(E) -3- (6-nitropyridin-3-yl) acrolein (5.0g,28.1 mmol), reacting until the raw materials disappear, pouring the reaction liquid into ice water, stirring, filtering, adding the filter cake into toluene, concentrating under reduced pressure, filtering, vacuum drying to obtain 6.3g compound I-56-methoxy-2- (1E,3E) -4- (6-nitropyridin-3-yl) butata-1, 3-dien-1-yl) benzo [ d ] thiazole, the yield is 66.1%;

s4: preparation of compound I-65- (1E,3E) -4- (6-methoxybenzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) pyridin-2-amine: adding compound I-56-methoxy-2- (1E,3E) -4- (6-nitropyridin-3-yl) butan-1, 3-dien-1-yl) benzo [ d ] thiazole (6.0g,17.7mmmol) into ethanol (100mL), adding acetic acid (100mL), reduced iron powder (4.5g,80.0mmol) and 12N hydrochloric acid (20mL), stirring overnight, dropwise adding sodium hydroxide aqueous solution under ice bath, filtering off precipitate, adding into methanol, stirring, filtering, concentrating the filtrate under reduced pressure, performing silica gel column chromatography to obtain 2.3g compound I-65- (1E,3E) -4- (6-methoxybenzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) pyridin-2-amine, the yield is 42.0%;

s5 preparation of Compound I-75- (1E,3E) -4- (6-methoxybenzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) -N- (methyl-d 3) pyridin-2-amine: adding compound I-65- (1E,3E) -4- (6-methoxybenzo [ d ] thiazol-2-yl) butan-1, 3-diene-1-yl) pyridin-2-amine (2.0g,6.5mmmol) into DMF (40mL) under the protection of nitrogen, cooling in an ice bath, adding sodium hydrogen (content 60%, 0.3g,7.2mmol), stirring at room temperature for 30min, dropwise adding deuterated iodomethane (0.9g,6.2mmol), introducing the reaction solution into ice water after the reaction is finished, extracting with chloroform, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out column chromatography on silica gel to obtain 1.4g of compound I-75- (1E,3E) -4- (6-methoxybenzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) -N- (methyl-d 3) pyridin-2-amine, yield 69.1%;

s6 preparation of Compound I-82- (1E,3E) -4- (6- (methyl-d 3) amino) pyridin-3-yl) butan-1, 3-dien-1-yl) benzo [ d ] thiazol-6-ol: adding compound I-75- (1E,3E) -4- (6-methoxybenzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) -N- (methyl-d 3) pyridin-2-amine (1.0g,3.1 mmol) into DCM (20mL) under the protection of nitrogen, cooling to-78 deg.C, adding boron tribromide (1.0M dichloromethane solution, 15.5mL,15.5mmol), stirring overnight at room temperature, adding 1N sodium hydroxide solution and sodium bicarbonate solution under ice bath for neutralization, filtering out precipitate, washing with water and ether, adding into methanol, stirring, filtering, concentrating the filtrate under reduced pressure, performing silica gel column chromatography to obtain 686mg of compound I-82- (1E,3E) -4- (6- (methyl-d 3) amino) pyridin-3-yl) butan-1, 3-dien-1-yl) benzo [ d ] thiazol-6-ol, yield 71.7%;

s7 preparation of Compound I-10N- (methyl-d 3) -5- (1E,3E) -4- (6- (carbonyl-2-methoxy) benzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) pyridin-2-amine: adding compound I-82- (1E,3E) -4- (6- (methyl-d 3) amino) pyridin-3-yl) butan-1, 3-dien-1-yl) benzo [ d ] thiazol-6-ol (600mg,1.9mmmol), potassium carbonate (787mg,5.7mmmol) and catalytic amount of 18-crown-6 into acetone (20mL), adding compound I-9 epichlorohydrin (268mg,2.9mmmol), stirring at 80 deg.C under reflux for 12h, concentrating under reduced pressure, performing silica gel column chromatography to obtain 122mg of compound I-10N- (methyl-d 3) -5- (1E,3E) -4- (6- (carbonyl-2-methoxy) benzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) pyridin-2-amine, yield 18.0%;

s8 preparation of compound I-111-fluoro-3- (2- (1E,3E) -4- (6- ((methyl-d 3) amino) pyridin-3-yl) butane-1, 3-dien-1-yl) benzo [ d ] thiazol-6-yl) oxopropan-2-ol: adding compound I-10N- (methyl-d 3) -5- (1E,3E) -4- (6- (carbonyl-2-methoxy) benzo [ d ] thiazol-2-yl) butan-1, 3-dien-1-yl) pyridin-2-amine (90mg,0.24mmmol) to toluene (20mL), adding a tetrahydrofuran solution of TBAF (1mL,1.0mmmol), stirring at 80 ℃ for reflux reaction for 12h, concentrating under reduced pressure, and performing silica gel column chromatography to obtain 26mg of compound I-111-fluoro-3- (2- (1E,3E) -4- (6- ((methyl-d 3) amino) pyridin-3-yl) butane-1, 3-dien-1-yl) benzo [ d ] thiazol-6-yl) oxypropane-2-ol, the yield is 27.4%;

in the present invention, the deuterated PM-PBB3 can be combined with the region where Tau protein is misfolded and accumulated in the brain after intravenous administration. Then, the imaging of the brain can help to identify whether Tau protein pathology exists in neurons of the brain, so that preliminary judgment on the Alzheimer disease is made.

Based on the above, the stable isotope labeled PM-PBB3 compound provided by the invention can be used as a DMI contrast agent for detecting Tau protein. The stable isotope labeled PM-PBB3 compound is ready for use²H-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 signals in the proton magnetic resonance spectrum generated by the H can obtain the conversion condition of the deuterated PM-PBB3 compound, thereby obtaining the metabolic condition. Is turned on in a given timeAfter the nuclear magnetic resonance spectrometer scans the part to be detected of the subject again under the same parameters and forms a deuterated PM-PBB3 compound¹The used map of H is such that the deuterated PM-PBB3 compound is fully converted in vivo, which is helpful for obtaining more accurate detection results and embodying metabolic conditions.

In some practical application scenarios, the part to be detected of a subject is scanned by a nuclear magnetic resonance spectrometer and is formed before a PM-PBB3 compound labeled by a stable isotope is used¹H pre-use profile; in particular, the nmr spectrometer may employ a standard nmr scanner, such as a 3T MRI scanner or a 7T MRI scanner, without the risk of exposure to ionizing radiation, without the need for special equipment, and with ease of use. By way of example, the sequence and imaging parameters may then 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).

Administering to the subject, after obtaining the pre-use profile, a stable isotope labeled PM-PBB3 compound that may be a single dosage unit 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 ingredients, i.e., each dose contains the same weight²The H-labeled substance can be directly or diluted for use by a subject, or the composition can be made into different specifications, such as different specifications of the PM-PBB3 compound containing the stable isotope labeling, so that the composition with different specifications can be administered for use according to the condition of the subject, the composition can be made into different forms of liquid or solid, and according to the different conditions of the subject, different doses of the PM-PBB3 compound containing the stable isotope labeling can be administered, such as the PM-PBB3 compound which is dissolved in 200 to 300ml of water according to the dosage of 0.60 to 0.75 g/kg of body weight and the maximum 60 g of body weight, the PM-PBB3 compound containing the stable isotope labeling can be used in an injection mode according to the different specifications of the PM-PBB3 compound containing the stable isotope labeling, and the PM-PBB3 compound containing the stable isotope labeling can also be used in an injection modeA 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 in the signal in the proton magnetic resonance spectrum generated by H can obtain the conversion status of the stable isotope labeled PM-PBB3 compound, thereby obtaining the metabolic status 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 a compound of the PM-PBB3 type labelled with a stable isotope within a given time¹H, a post-use map; the given time is preferably 20 to 90 minutes, so that the stable isotope labeled PM-PBB3 compound can be sufficiently converted in vivo to obtain more accurate detection results and reflect metabolic conditions, and multiple measurements can be taken at intervals within the given time, such as every five minutes or ten minutes to obtain the map data of the 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.

In conclusion, the invention provides a PM-PBB3 compound labeled by stable isotopes, and the contrast agent can be used for detecting whether Tau protein exists in neurons of the brain. By using¹The universality and the easy implementation advantage of H proton magnetic resonance spectrum detection and the excellent spectral resolution can track the metabolite transferred by the deuterated taltirelin contrast agent, the detection resolution and the sensitivity are higher, the dynamic exchange of single metabolite can be detected, and the detection is realized by measuring¹H proton magnetic resonanceThe change of the wave spectrum can be detected under high spectral resolution²The method has the advantages that metabolites 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 taltirelin contrast agent used in the method 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.