A new bismuth-based chelate ct contrast agent and its preparation method and application

Abstract

The application discloses a novel bismuth-based chelate CT contrast agent and a preparation method and application thereof. The synthesis method comprises the following steps: 2,6-pyridine dimethyl alcohol is reacted with chlorosulfoxide to obtain 2,6-bis(chloromethyl)pyridine; the 2,6-bis(chloromethyl)pyridine is reacted with N,N',N''-tris(p-tolylsulfonyl)divinyltriamine and an inorganic base in a solvent and is heated, is deprotected by concentrated sulfuric acid to obtain an intermediate pyclen; the pyclen is heated and reacted with a halogenated carboxylic acid ester under alkaline conditions in a polar organic solvent, is hydrolyzed to obtain a ligand product; and the ligand product is heated and chelated with a bismuth agent to obtain the target bismuth-based chelate. The application realizes the laboratory scale preparation of the small-molecule bismuth-based chelate CT contrast agent, and a non-ionic contrast agent is prepared, which has low osmotic pressure, high stability, high water solubility and good biological safety and is used for CT imaging of the digestive system, the urinary system and the circulatory system.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical contrast agent technology, and in particular to a novel bismuth-based chelate CT contrast agent, its preparation method, and its application. Background Technology

[0002] Computed tomography (CT) is a common medical imaging technique widely used in clinical diagnosis, especially for observing internal tissues and organs. Because the difference in X-ray attenuation between soft tissues in the human body is relatively small, contrast agents are often used to improve image contrast, thereby enhancing diagnostic accuracy and treatment efficacy assessment. Currently available CT contrast agents are primarily small organic iodine (I)-based contrast agents containing the m-triiodophenyl core structure. However, iodine has a moderate atomic number (Z = 53) and a relatively low K-margin value (33 keV), resulting in limited X-ray attenuation capabilities and low imaging sensitivity, thus requiring larger doses. Furthermore, the use of iodine-based contrast agents is extremely cautious in patients with kidney damage, iodine allergy, or hypothyroidism. Therefore, there is an urgent clinical need to develop non-iodine-based, highly sensitive CT contrast agents.

[0003] Bismuth (Bi) is the non-radioactive metallic element with the highest atomic number. Its atomic number (Z = 83) and high K edge value (91 keV) endow it with excellent X-ray attenuation capabilities, particularly demonstrating great imaging potential in energy-dispersive CT and photon-counting CT. Bismuth also boasts advantages such as high biocompatibility and low cost. Therefore, bismuth is considered an ideal substitute for iodine. Currently reported bismuth-based CT contrast agents are mainly divided into nanomaterials and small-molecule chelates. Bismuth-based nanomaterials exhibit poor reproducibility in synthesis, unclear metabolic mechanisms, and are easily absorbed by the reticuloendothelial system, resulting in non-specific retention and difficulty in metabolism; their biocompatibility requires further investigation. In contrast, small-molecule bismuth-based chelates have well-defined structures, good biocompatibility, and clear metabolic pathways, showing promising prospects for clinical translation. Currently reported small-molecule bismuth-based chelate CT contrast agents are classified according to ionization status into Bi-DTPA, Bi-DOTA, Bi-DOTAPXD ionic chelates, and Bi-HPDO3A non-ionic chelates. Ionic chelates have high osmotic pressure, which can easily lead to safety issues such as nephrotoxicity, vascular endothelial damage, and electrolyte disturbances. Nonionic chelates have an electrically neutral structure, and their osmotic pressure can be significantly reduced, making them the main direction for the development of bismuth-based chelate CT contrast agents. However, only one case of the nonionic bismuth-based chelate Bi-HPDO3A has been reported so far, which is relatively few. Moreover, Bi-HPDO3A has low water solubility, making it difficult to achieve a balance between water solubility, osmotic pressure, and stability, which limits its imaging contrast and overall imaging performance, thus restricting its clinical translation. Summary of the Invention

[0004] The purpose of this invention is to provide a novel bismuth-based chelate CT contrast agent, its preparation method, and its application, to address the aforementioned bottleneck problems. This invention enables the laboratory-scale preparation of a small-molecule bismuth-based chelate CT contrast agent. Bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid is a non-ionic contrast agent with low osmotic pressure, high stability, high water solubility, and good biocompatibility, and can be used for CT imaging of the digestive, urinary, and circulatory systems.

[0005] The embodiments of the present invention are implemented as follows:

[0006] A novel bismuth-based chelate CT contrast agent comprising bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, with the following chemical structural formula:

[0007]

[0008] A method for preparing a novel bismuth-based chelate CT contrast agent, bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, comprising:

[0009] S100, thionyl chloride is added to 2,6-pyridinediethanol, stirred, and the mixture is heated to react. After the reaction is complete, the remaining thionyl chloride is removed by vacuum evaporation, water is added to quench the excess thionyl chloride, then alkali solution is added to adjust the pH, and the mixture is filtered to collect the solid product 2,6-bis(chloromethyl)pyridine.

[0010] S200, compound N,N',N''-tris(p-toluenesulfonyl)diethylenetriamine and compound 2,6-bis(chloromethyl)pyridine are added to a polar organic solvent, an inorganic base-binding acid agent is added, the reaction is first heated, and then the product obtained from the heated reaction is filtered, the solvent is evaporated under reduced pressure, and a white solid product is obtained.

[0011] S300: Add concentrated acid to the white solid obtained in S200, heat and react. After the reaction is complete, dilute the concentrated acid with water, extract the reaction solution with an organic solvent, adjust the pH of the aqueous phase with an alkaline solution, then extract with an organic solvent and retain the organic phase. Dry the organic phase with a desiccant and filter. Evaporate the solvent under reduced pressure to obtain pyclen.

[0012] S400 involves adding compound pyclen, a halocarboxylic acid ester, and an inorganic base-binding acid agent to a polar organic solvent, first heating the reaction, and then hydrolyzing the product obtained from the heating reaction to obtain compound 3,6,9,15-tetraazabicyclo[9.3.1]pentadene-3,6,9-tricarboxylic acid.

[0013] S500, the compound 3,6,9,15-tetraazabicyclo[9.3.1]pentadene-3,6,9-tricarboxylic acid is subjected to a heating chelation reaction with a bismuth agent to obtain the compound bismuth(III)2,2',2''-(3,6,9-triaza-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid.

[0014] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in S100,

[0015] The alkaline solution includes at least one of the following: sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide aqueous solution.

[0016] The heating reaction is carried out under nitrogen atmosphere, at a temperature of 40 ℃ to 100 ℃, for a time of 2 h to 8 h.

[0017] The pH adjustment range is 7 to 12.

[0018] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S200,

[0019] The polar organic solvent includes at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, and tetrahydrofuran.

[0020] The inorganic base-binding acid agent includes at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide.

[0021] The heating reaction is carried out under nitrogen atmosphere, at a temperature of 40 ℃ to 100 ℃, for a time of 24 h to 48 h.

[0022] The molar ratio of the compound N,N',N''-tris(p-toluenesulfonyl)diethylenetriamine, the compound 2,6-bis(chloromethyl)pyridine, and the inorganic base-binding acid agent is 1:(1-2):(2-10).

[0023] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S300,

[0024] The concentrated acid includes at least one of concentrated sulfuric acid, concentrated nitric acid, concentrated hydrochloric acid, and concentrated phosphoric acid.

[0025] The heating reaction is carried out under nitrogen atmosphere, at a temperature of 80 ℃ to 160 ℃, and for a time of 0.5 h to 2 h.

[0026] The organic solvent includes at least one of dichloromethane, chloroform, ethyl acetate, and diethyl ether.

[0027] The alkaline solution includes at least one of the following: sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide aqueous solution.

[0028] The desiccant includes at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride.

[0029] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S400,

[0030] The polar organic solvent includes at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, and tetrahydrofuran.

[0031] The halocarboxylic acid esters include at least one of methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, tert-butyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, isopropyl bromoacetate, tert-butyl bromoacetate, methyl 3-chloropropionate, ethyl 3-chloropropionate, isopropyl 3-chloropropionate, tert-butyl 3-chloropropionate, methyl 3-bromopropionate, ethyl 3-bromopropionate, isopropyl 3-bromopropionate, tert-butyl 3-bromopropionate, methyl 4-chlorobutyrate, ethyl 4-chlorobutyrate, isopropyl 4-chlorobutyrate, tert-butyl 4-chlorobutyrate, methyl 4-bromobutyrate, ethyl 4-bromobutyrate, isopropyl 4-bromobutyrate, and tert-butyl 4-bromobutyrate.

[0032] The inorganic base-binding acid agent includes at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide.

[0033] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S400,

[0034] The molar ratio of the compound pyclen, the halocarboxylic acid ester, and the inorganic base-binding acid agent is 1:(3-6):(3-10).

[0035] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S400,

[0036] The heating reaction is carried out under nitrogen atmosphere, at a temperature of 40 ℃ to 100 ℃, for a time of 2 h to 8 h.

[0037] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S500,

[0038] The bismuth agent includes at least one of bismuth chloride, bismuth nitrate, bismuth acetate, basic bismuth carbonate, bismuth oxide, bismuth bromide, and bismuth sulfate.

[0039] The molar ratio of the compound 2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid and the bismuth agent is 1:(1-3).

[0040] The heating chelation reaction is carried out under nitrogen atmosphere, at a temperature of 50 ℃ to 100 ℃, for a time of 8 h to 72 h.

[0041] A formulation method based on bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, characterized in that it comprises the following components in mass percentage:

[0042] Bismuth(III) 2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid 7.46 wt%~74.6 wt%.

[0043] The metal ion scavenger is 0-0.05 wt%, and the metal scavenger includes at least one selected from diethylenetriaminepentaacetic acid, disodium ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

[0044] The pH buffer is 0.1 wt% to 1.0 wt%, and the pH buffer includes at least one of physiological saline, phosphate buffer solution, Tris buffer and Tris-HCl buffer.

[0045] Stabilizer 0-0.05 wt%, said stabilizer includes at least one of sodium bisulfite, sodium ascorbate and methionine.

[0046] Water 0–92.44 wt%.

[0047] The bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid is the bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid as described above.

[0048] Its technical advantages are as follows: by introducing metal scavengers, constructing physiological buffer systems, controlling solution pH and stability, and combining aseptic filtration and optional terminal sterilization processes, stable injection solutions suitable for intravenous administration can be prepared.

[0049] Application of a CT imaging contrast agent based on bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, wherein the CT contrast agent is used for at least one of the following purposes:

[0050] Prepare a CT contrast agent for imaging the gastrointestinal tract of rats.

[0051] Prepare a CT contrast agent for imaging a rat model of acute kidney injury.

[0052] Prepare a CT contrast agent for conventional CT angiography (CTA) of the upper and lower limbs of New Zealand white rabbits.

[0053] Prepare a CT contrast agent for conventional CTA of upper and lower limb metal artifacts in New Zealand white rabbits.

[0054] Prepare a CT contrast agent for upper and lower limb metal artifact energy-spectral CTA in New Zealand white rabbits.

[0055] Prepare a CT contrast agent for routine CTA of the upper limbs of Bama pigs.

[0056] The CT imaging contrast agent based on bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid is the CT imaging contrast agent based on bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid as described above.

[0057] The beneficial effects of the embodiments of the present invention are:

[0058] This invention prepares a novel non-ionic small-molecule bismuth-based chelate CT contrast agent. By chelating bismuth ions with specific ligands, a stable small-molecule bismuth-based complex is formed, allowing bismuth to exist in a chelated state. This fully utilizes the X-ray absorption advantage brought by bismuth's high atomic number, while avoiding the potential safety hazards of free bismuth ions, thus obtaining a CT imaging contrast agent that combines high contrast with good biocompatibility.

[0059] The bismuth-based chelate CT contrast agent of the present invention can be prepared on a laboratory scale with strong process controllability. The bismuth-based chelate CT contrast agent adopts a well-defined six-step reaction synthesis route. The reaction conditions of each step are mild and reproducible. The raw materials and intermediates used are easy to obtain and purify, making it suitable for large-scale preparation under laboratory conditions. This lays a good process foundation for subsequent process scale-up, quality control, and industrial production.

[0060] The bismuth-based chelate CT contrast agent prepared in this invention is a nonionic contrast agent with low osmotic pressure, high water solubility, and high stability. Because bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid has a nonionic small molecule structure, it produces little or no free ions in aqueous solution, significantly reducing the osmotic pressure of the solution and thus minimizing osmotic pressure stimulation to the body during injection. Simultaneously, this contrast agent has good water solubility, facilitating the preparation of high-concentration injectable formulations. Its stable chelate structure effectively prevents bismuth ion dissociation, ensuring storage stability and safety for in vivo application.

[0061] The bismuth-based chelate CT contrast agent of the present invention exhibits good biocompatibility and tolerability. By stably chelating bismuth ions into the ligand structure and combining it with a non-ionic, small molecule molecular design, it is less likely to generate ion load or release of metal ions in vivo, effectively reducing the risk of potential toxic side effects and adverse reactions, and improving the safety and patient tolerability during clinical use.

[0062] The bismuth-based chelate CT contrast agent of this invention is suitable for multi-system CT imaging diagnosis. The bismuth-based chelate CT contrast agent of this invention, bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, possesses excellent X-ray attenuation capabilities and good in vivo distribution characteristics. It can be used for CT imaging examinations of the digestive, urinary, and circulatory systems, clearly displaying relevant tissues and luminal structures, providing reliable contrast enhancement for the imaging diagnosis of systemic diseases, and has broad clinical application prospects. Attached Figure Description

[0063] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0064] Figure 1 A schematic diagram of the synthetic route for the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid of the present invention;

[0065] Figure 2 This is a schematic diagram of the proton nuclear magnetic resonance spectrum of the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)triacetic acid (Bi-PCTA) of the present invention;

[0066] Figure 3 This is a schematic diagram of the carbon NMR spectrum of Bi-PCTA, a bismuth-based chelate CT contrast agent of the present invention.

[0067] Figure 4 This is a high-resolution mass spectrometry diagram of Bi-PCTA, the bismuth-based chelate CT contrast agent of this invention;

[0068] Figure 5 Schematic diagram of osmotic pressure for Bi-DTPA, Bi-HPDO3A and Bi-PCTA;

[0069] Figure 6 Schematic diagram of UV absorption of Bi-PCTA at different pH values ​​(1-8) for 24 h;

[0070] Figure 7 Bi-PCTA at 25 times the equivalent of Zn 2+ Schematic diagram of ultraviolet absorption in the presence of light;

[0071] Figure 8A schematic diagram showing the solubility of Bi-DTPA, Bi-HPDO3A, and Bi-PCTA;

[0072] Figure 9 This is a schematic diagram of kidney imaging in normal SD rats using Bi-PCTA, a bismuth-based chelate CT contrast agent of the present invention.

[0073] Figure 10 This is a schematic diagram of the gastrointestinal tract imaging of the bismuth-based chelate CT contrast agent Bi-PCTA in normal SD rats.

[0074] Figure 11 This is a schematic diagram of the upper and lower limb CTA of the bismuth-based chelate CT contrast agent Bi-PCTA of the present invention in normal New Zealand white rabbits;

[0075] Figure 12 Schematic diagrams of conventional and energy-dispersive CTA of the bismuth-based chelate CT contrast agent Bi-PCTA and iohexol in the upper limb metal artifact model of New Zealand white rabbits;

[0076] Figure 13 This is a schematic diagram of conventional and energy-dispersive CTA images of the bismuth-based chelate CT contrast agent Bi-PCTA and iohexol in a lower limb metal artifact model of New Zealand white rabbits.

[0077] Figure 14 This is a schematic diagram of the bismuth-based chelate CT contrast agent Bi-PCTA of the present invention in the upper limb CTA of Bama pigs. Detailed Implementation

[0078] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The components of the embodiments of the present invention described and shown in the accompanying drawings can generally be arranged and designed in various different configurations.

[0079] The first embodiment of the present invention provides a bismuth-based chelate CT contrast agent, bismuth(III)2,2',2''-(3,6,9-triaza-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, with the following chemical structural formula:

[0080]

[0081] It includes bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)triacetic acid (Bi-PCTA), bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tripropionic acid, and bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tributyric acid.

[0082] The chemical structural formula of bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)triacetic acid is as follows:

[0083]

[0084] The chemical structural formula of bismuth(III)2,2',2''-(3,6,9-triaza-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tripropionic acid is:

[0085] .

[0086] The chemical structural formula of bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tributyric acid is:

[0087] .

[0088] Please refer to Figure 1The second embodiment of the present invention provides a method for preparing the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, comprising: S100, adding thionyl chloride to 2,6-pyridinediethanol, stirring, heating the mixture to react, after the reaction is completed, removing the remaining thionyl chloride by vacuum evaporation, adding alkaline solution to adjust the pH, and filtering to collect the solid product 2,6-bis(chloromethyl)pyridine; S200, adding compound N,N',N''-tris(p-toluenesulfonyl)diethylenetriamine and compound 2,6-bis(chloromethyl)pyridine to a polar organic solvent, adding an inorganic base-binding acid agent, first heating the reaction, then filtering the product obtained by the heating reaction, evaporating the solvent under vacuum to obtain a white solid product; S300, in S200... Concentrated acid was added to the obtained white solid, and the temperature was raised to react. After the reaction was completed, the concentrated acid was diluted with water, and the reaction solution was extracted with an organic solvent. The pH of the obtained aqueous phase was adjusted with an alkaline solution, and then extracted with an organic solvent while retaining the organic phase. The organic phase was dried with a desiccant and filtered. The solvent was evaporated under reduced pressure to obtain pyclen. In S400, compound pyclen, a halocarboxylic acid ester, and an inorganic base-binding acid agent were added to a polar organic solvent. The reaction was first heated, and then the product obtained from the heating reaction was hydrolyzed to obtain the ligand 2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid. In S500, the compound PCTA was heated and chelated with a bismuth agent to obtain the compound bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid.

[0089] In S100, the alkaline solution includes at least one of the following: sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide aqueous solution; the heating reaction is carried out under nitrogen atmosphere, the reaction temperature is 40 ℃ to 80 ℃, and the reaction time is 2 h to 8 h; the pH adjustment range is 7 to 14.

[0090] In S200, the polar organic solvent includes at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, and tetrahydrofuran; the inorganic base-binding acid agent includes at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide; the heating reaction is carried out under nitrogen atmosphere, the reaction temperature is 40 ℃~100 ℃, and the reaction time is 24 h~48 h; the molar ratio of the compound N,N',N''-tris(p-toluenesulfonyl)diethylenetriamine, the compound 2,6-bis(chloromethyl)pyridine, and the inorganic base-binding acid agent is 1:(1~2):(2~10).

[0091] In S300, the concentrated acid includes at least one of concentrated sulfuric acid, concentrated nitric acid, concentrated hydrochloric acid, and concentrated phosphoric acid; the heating reaction temperature is between 80 ℃ and 160 ℃, and the reaction time is between 0.5 h and 2 h; the organic solvent includes at least one of dichloromethane, chloroform, ethyl acetate, and diethyl ether; the alkaline solution includes at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide aqueous solution; and the desiccant includes at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride.

[0092] In S400, the polar organic solvent includes at least one selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, and tetrahydrofuran; the halocarboxylic acid ester includes methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, tert-butyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, isopropyl bromoacetate, tert-butyl bromoacetate, methyl 3-chloropropionate, ethyl 3-chloropropionate, isopropyl 3-chloropropionate, tert-butyl 3-chloropropionate, methyl 3-bromopropionate, ethyl 3-chloro ... At least one of the following: ethyl 4-bromopropionate, isopropyl 3-bromopropionate, tert-butyl 3-bromopropionate, methyl 4-chlorobutyrate, ethyl 4-chlorobutyrate, isopropyl 4-chlorobutyrate, tert-butyl 4-chlorobutyrate, methyl 4-bromobutyrate, ethyl 4-bromobutyrate, isopropyl 4-bromobutyrate, and tert-butyl 4-bromobutyrate; the inorganic base-binding acid agent includes at least one of the following: sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide.

[0093] In S400, the molar ratio of the compound pyclen, the haloacetic acid ester side chain group, and the inorganic base-binding acid agent is 1:(3-6):(3-10).

[0094] In S400, the heating reaction is carried out under nitrogen conditions, the reaction temperature is 40℃~100℃, and the reaction time is 2h~8h; after the heating reaction, the product is purified by adding methanol, ethanol and precipitate to the aqueous phase.

[0095] In a preferred embodiment of the present invention, in the preparation method of the above-mentioned bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, in step S500, the bismuth agent includes at least one of bismuth oxide, bismuth nitrate, bismuth chloride, and basic bismuth carbonate.

[0096] In S500, the molar ratio of the compound bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid and the bismuth agent is 1:(1-3).

[0097] In S500, the heating chelation reaction is carried out under nitrogen conditions, with a reaction temperature of 50 ℃ to 100 ℃ and a reaction time of 8 h to 24 h; the heating chelation reaction is carried out in an aqueous phase, which is deionized water; after the heating chelation reaction, the product is purified, which includes precipitation and static crystallization, and the required solvent is at least one of diethyl ether, methanol, ethanol and isopropanol.

[0098] The specific implementation of the preparation method of the bismuth-based chelate CT contrast agent Bi-PCTA is as follows: Figure 1 As shown, it includes:

[0099] (1) Synthesis of 2,6-bis(chloromethyl)pyridine

[0100] 30 g (215 mmol) of 2,6-pyridinediethanol was added to 200 mL of thionyl chloride solution in an ice bath. After stirring for 10 min, the mixture was heated to 80 °C and reacted for 4 h. After the reaction was complete, the remaining thionyl chloride was removed by evaporation under reduced pressure. 200 mL of water was added, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was then filtered to collect the solid product. The 1H NMR spectrum of 2,6-bis(chloromethyl)pyridine was as follows: 1 HNMR (500MHz, CDCl3) δ 7.70 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.8Hz, 2H), 4.60 (s, 4H).

[0101] (2) Synthesize pyclen

[0102] 45.36 g of 80 mmol N,N',N''-tris(p-toluenesulfonyl)diethylenetriamine and 22.08 g of 160 mmol anhydrous potassium carbonate were added to 1.2 L of acetonitrile solution containing 14.08 g of 80 mmol 2,6-bis(chloromethyl)pyridine. The mixture was heated to reflux. After reacting for 48 h, the mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, yielding a white solid. This solid was stirred with 100 mL concentrated sulfuric acid at 150 °C for 30 min, and then 200 mL of water was carefully and slowly added in an ice bath. The solution was washed with 3 × 300 mL dichloromethane to remove nonpolar impurities, then the pH was adjusted to 14 with 40% sodium hydroxide solution, and then extracted with 3 × 300 mL dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure to give a yellow oily substance, pyclen. The 1H NMR spectrum results are as follows: 1 HNMR(400MHz, CDCl3) δ 7.52 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6Hz, 2H), 3.96 (s,4H), 2.86 (brs, 3H), 2.69 (t, J = 5.3 Hz, 4H), 2.26(q, J = 5.3Hz, 4H).

[0103] (3) Synthesis of 3,6,9,15-tetraazabicyclo[9.3.1]pentadene-3,6,9-triacetic acid (PCTA)

[0104] 11.54 g (56 mmol) of Pyclen was dissolved in 300 mL of acetonitrile. 77.28 g (560 mmol) of potassium carbonate and 28.99 g (173.6 mmol) of ethyl bromoacetate were added, and the mixture was subjected to alkylation at 50 °C for 2 h. After the reaction, the crude product was filtered and concentrated, then dissolved in 150 mL of anhydrous methanol. Sodium hydroxide solution (173.6 mmol of sodium hydroxide dissolved in 30 mL of water) was added, and the mixture was stirred for hydrolysis for 2 h at 25 °C. After evaporating the solvent under reduced pressure, the resulting carboxylate was dissolved in 40 mL of water. The pH was adjusted to 2 with 12 M hydrochloric acid, and the solution was evaporated to dryness. The solid was added to 90 mL of water, and after dissolution, 900 mL of anhydrous ethanol was added and stirred for 2 h, resulting in a white precipitate. The target ligand PCTA was finally obtained by filtration. The NMR spectroscopy results of PCTA are as follows: 1HNMR (400MHz, D2O) δ 7.93 (t, J = 7.9Hz, 1H), 7.41 (d, J =7.9Hz, 2H), 4.74 (s, 4H), 4.02 (s, 4H), 3.55 (s, 2H), 3.43 (t, J = 5.5Hz, 4H), 2.94 (s, 4H). 13 CNMR (100MHz, D2O) δ 174.48, 170.06, 150.21, 140.37, 122.72, 59.39, 57.46, 55.53, 54.01, 51.32.

[0105] (4) Synthesis of Bi-PCTA

[0106] 14.89 g (39.2 mmol) of PCTA and 18.27 g (39.2 mmol) of bismuth oxide were added to 100 mL of water. The solution was heated to 85 °C and reacted for 24 h. After cooling to room temperature, the mixture was filtered, and the pH of the filtrate was adjusted to neutral with 0.1 M hydrochloric acid. The mixture was then concentrated, and the residue was redissolved in 65 mL of water, followed by the addition of 650 mL of anhydrous ethanol. After 2 h, a white solid precipitated, which was filtered and dried to give the final product, Bi-PCTA. Figure 2 As shown, the obtained proton NMR spectrum of Bi-PCTA is as follows: 1 HNMR (400MHz, D2O) δ 8.16 (t, J = 7.8Hz, 1H), 7.60 (d, J = 7.8Hz, 2H), 4.91 (d, J = 16.9Hz, 2H), 4.51 (d, J = 16.9Hz, 2H), 4.26 (s, 2H), 4.11 (d, J= 2.6Hz, 4H), 3.79 (d, J = 14.9Hz, 2H), 3.48-3.35 (m, 2H), 3.35-3.20 (m, 2H), 2.96 (t, J =1 1.6Hz, 2H). Such as Figure 3 As shown, the obtained carbon NMR spectrum of Bi-PCTA is as follows: 13 CNMR (100MHz, D₂O) δ 179.03, 177.63, 158.11, 142.36, 123.30, 61.92, 61.30, 59.51, 58.91, 55.71. (e.g.) Figure 4 As shown, the high-resolution mass spectrometry results for Bi-PCTA are: HRMS (ESI) m / z: [M+Na]+ calcd for C 17 H 21 BiN4NaO6 + , 609.1166; found, 609.1157.

[0107] The osmotic pressure comparison between the Bi-PCTA prepared in this invention and the existing small molecule bismuth-based chelates Bi-DTPA and Bi-HPDO3A is as follows: Figure 5 As shown.

[0108] The UV absorption of the Bi-PCTA prepared in this invention at different pH values ​​(1-8) for 24 h is as follows: Figure 6 As shown.

[0109] The Bi-PCTA prepared by this invention has a Zn equivalent of 25 times. 2+ UV absorption in the presence of such conditions is as follows Figure 7 As shown.

[0110] The solubility comparison of the Bi-PCTA prepared in this invention with the existing small molecule bismuth-based chelates Bi-DTPA and Bi-HPDO3A is as follows: Figure 8 As shown.

[0111] A third embodiment of the present invention provides a formulation method based on bismuth(III)2,2',2''-(3,6,9-triaza-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, characterized in that it comprises the following components in mass percentages: bismuth(III)2,2',2''-(3,6,9-triaza-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid 7.46 wt% to 74.6 wt%; a metal ion scavenger 0 to 0.05 wt%, wherein the metal scavenger includes at least one selected from diethylenetriaminepentaacetic acid (DTPA), disodium ethylenediaminetetraacetate (EDTA-2Na), ethylenediaminetetraacetic acid (EDTA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; and a pH buffer 0.1 wt% to 1.0 wt%. The pH buffer comprises at least one of physiological saline, phosphate-buffered saline (PBS), Tris buffer, and Tris-HCl buffer; the stabilizer comprises 0 to 0.05 wt%, which comprises at least one of sodium bisulfite, sodium ascorbate, and methionine; the water comprises 0 to 92.44 wt%; the bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid is bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid as described above.

[0112] Its technical advantages are as follows: by introducing metal scavengers, constructing physiological buffer systems, controlling solution pH and stability, and combining aseptic filtration and optional terminal sterilization processes, stable injection solutions suitable for intravenous administration can be prepared.

[0113] The formulation methods for Bi-PCTA-based CT imaging contrast agents include:

[0114] (1) Add Bi-PCTA to water for injection and dissolve it under stirring to obtain a solution of the target concentration. If necessary, ultrasound-assisted dissolution can be used.

[0115] (2) Add metal ion scavenger.

[0116] (3) Add buffer solution to adjust the pH of the solution. Adjust the pH of the system to 6.5-7.5 using any of the following components or combinations thereof: physiological saline, phosphate-buffered saline (PBS), Tris buffer, and Tris-HCl buffer. The Tris / Tris-HCl buffer system can improve pH stability and inhibit complex degradation.

[0117] (4) Adding stabilizers. To improve the stability of the formulation during storage, one or more antioxidants may be added, including: sodium bisulfite, sodium ascorbate, methionine, in an amount of 0.0005-0.05 wt%.

[0118] (5) Sterilization by filtration. The above solution is sterilized by filtration through a 0.22 μm microporous membrane (such as PVDF or PES material) to obtain sterile filtrate. The filtration process can be carried out in a closed solution preparation system or isolator to ensure sterility.

[0119] (6) Filling and sterilization. The resulting sterile solution may be processed as follows:

[0120] ① Aseptic filling: Fill into glass bottles or pre-filled syringes under aseptic conditions and store in a sealed container.

[0121] ② Terminal sterilization: Moist heat sterilization at 121 °C for 15-20 min. After sterilization, the structural stability of Bi-PCTA needs to be verified.

[0122] Please refer to Figures 9 to 14The fourth embodiment of the present invention provides an application of a method for synthesizing a novel bismuth-based chelate CT contrast agent, wherein the CT contrast agent is used for at least one of the following purposes: preparing a CT contrast agent for imaging the gastrointestinal tract of rats; preparing a CT contrast agent for imaging a rat acute kidney injury (AKI) model; preparing a CT contrast agent for conventional CT angiography (CTA) of the upper and lower limbs of New Zealand white rabbits; preparing a CT contrast agent for conventional CTA of upper and lower limb metal artifacts in New Zealand white rabbits; preparing a CT contrast agent for New Zealand white rabbits. CT contrast agent for upper and lower limb metal artifact energy spectrum CTA; preparation of CT contrast agent for conventional upper limb CTA in Bama pigs; the CT imaging contrast agent based on bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid is the CT imaging contrast agent based on bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid as described above.

[0123] Among them, in vivo imaging schemes based on Bi-PCTA CT imaging contrast agents include:

[0124] (1) Imaging of normal kidneys in Sprague Dawley (SD) rats

[0125] Bi-PCTA was administered via tail vein to SD rats, and CT scans were performed at different time points: 10 s, 30 s, 1 min, 5 min, 10 min, 30 min, 1 h, 2 h, and 24 h to acquire CT images of the kidneys. The injection dose was 0.91 mmol / kg. Imaging of the kidneys of normal SD rats with Bi-PCTA is shown below. Figure 9 As shown.

[0126] (2) Normal gastrointestinal imaging of SD rats

[0127] Bi-PCTA was orally administered to SD rats. CT scans were performed before injection and at different time points (5 min, 15 min, 30 min, 1 h, 2 h, and 24 h) after injection to acquire CT images of the gastrointestinal tract. The injection dose was 2.27 mmol / kg. Gastrointestinal imaging of normal SD rats using Bi-PCTA is shown below. Figure 10 As shown.

[0128] (3) Routine CTA of normal New Zealand white rabbits

[0129] New Zealand female rabbits were induced to anesthesia with isoflurane. A 24G indwelling needle was inserted into the marginal ear vein. After injecting 1 mL of saline to ensure patency, the indwelling needle was connected to a high-pressure injector. Following the start of contrast agent injection, a routine CTA scan was performed after a 2-second delay, with a scan time of 6 seconds. For routine upper limb CTA, the field of view (FOV) was set from the head to the lower edge of the pericardium, and the scanning direction was from the proximal to the distal end. The slice thickness was 0.5 mm, adaptive tube current was used, and the tube voltage was 120 kV. The injection rate of the high-pressure injector was 1.5 mL / s, and the injection dose was 2.22 mmol Bi / kg. For routine lower limb CTA, the scanning parameters were the same as for routine upper limb CTA, except that the field of view was set from the upper edge of the pericardium to the distal tibia, and the scan time was 8 seconds. Bi-PCTA in normal New Zealand white rabbits showed the following results: Figure 11 As shown.

[0130] (4) Conventional and energy-spectral CTA of the New Zealand White Rabbit metal artifact model

[0131] Intramedullary nails (titanium-niobium alloy) were selected to construct the upper limb metal artifact model, and artificial hip joints were selected to construct the lower limb metal artifact model. The experimental protocol and contrast agent dosage for upper and lower limb CTA were the same as above. Conventional CTA scanning parameters: After the contrast agent injection, a 2-second delay was followed by a conventional CTA scan, with a scan time of 6 s. The field of view (FOV) was set from the upper pericardium to the distal tibia. The slice thickness was 0.5 mm, using adaptive tube current and a tube voltage of 120 kV. The injection rate of the high-pressure injector was 1.5 mL / s, and the injection dose was 2.22 mmol Bi / kg. Spectroradiometric CTA scanning parameters: FOV: upper pericardium to distal tibia; slice thickness: 0.5 mm; tube voltage: 90 / 150 Sn kV. Bi-PCTA and iohexol were used in conventional and spectral CTA of the upper limb metal artifact model in New Zealand white rabbits. Figure 12 As shown, the conventional and energy-dispersive CTA images of Bi-PCTA and iohexol in the hind limb metal artifact model of New Zealand white rabbits are as follows. Figure 13 As shown.

[0132] (5) CTA of normal upper limb of Bama pig

[0133] Bama pigs were induced anesthetized with isoflurane. A 22G indwelling needle was inserted into the marginal ear vein. After injecting 1 mL of normal saline to ensure patency of the needle, it was connected to a high-pressure injector. Following the start of contrast agent injection, a routine CTA scan was performed after a 12-second delay, with a scan time of 6 seconds. The field of view (FOV) was set from the head to the lower edge of the pericardium, and the scanning direction was from the proximal to the distal end. The slice thickness was 0.5 mm, adaptive tube current was used, and the tube voltage was 120 kV. The injection rate of the high-pressure injector was 2.5 mL / s, and the injection dose was 0.8 mmol Bi / kg. Bi-PCTA in the upper limb CTA of Bama pigs... Figure 14 As shown.

[0134] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. A novel bismuth-based chelate CT contrast agent, characterized in that, Its name is bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid, and its chemical structural formula is: 。 2. A method for synthesizing a novel bismuth-based chelate CT contrast agent, characterized in that, include: S100, thionyl chloride is added to 2,6-pyridinediethanol, stirred, and the mixture is heated to react. After the reaction is completed, the remaining thionyl chloride is removed by vacuum evaporation, the pH is adjusted by adding alkaline solution, and the mixture is filtered to collect the solid product 2,6-bis(chloromethyl)pyridine. S200, a compound is added to a polar organic solvent. N,N',N'' Tris(p-toluenesulfonyl)diethylenetriamine and compound 2,6-bis(chloromethyl)pyridine were added with an inorganic base-binding acid agent, and the reaction was first carried out by heating. The product obtained by the heating reaction was then filtered, and the solvent was evaporated under reduced pressure to obtain a white solid product. S300: Add concentrated acid to the white solid obtained in S200, heat and react. After the reaction is complete, add water to dilute the concentrated acid, extract the reaction solution with an organic solvent, adjust the pH of the aqueous phase with alkaline solution, then extract with an organic solvent and retain the organic phase. After drying the organic phase with a desiccant, filter it and evaporate the solvent under reduced pressure to obtain pyclen. S400 involves adding compound pyclen, a halocarboxylic acid ester, and an inorganic base-binding acid agent to a polar organic solvent, first heating the mixture, then hydrolyzing the product obtained from the heating reaction to yield the ligand 2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid. In S400, the molar ratio of compound pyclen, the halocarboxylic acid ester, and the inorganic base-binding acid agent is 1:(3-6):(3-10). The heating reaction temperature is 40 ℃ to 100 ℃, and the reaction time is 2 h to 8 h. The inorganic base-binding acid agent is at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide. S500, the compound 2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid is subjected to a heated chelation reaction with a bismuth agent, wherein the bismuth agent is at least one selected from bismuth chloride, bismuth nitrate, bismuth acetate, basic bismuth carbonate, bismuth oxide, bismuth bromide, and bismuth sulfate. The heated chelation reaction temperature is 50 ℃ to 100 ℃, and the reaction time is 8 h to 72 h, to obtain the compound bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid.

3. The method for preparing the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid according to claim 2, characterized in that, In S100, The alkaline solution is at least one of the following: sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide aqueous solution. The heating reaction was carried out under nitrogen atmosphere, with a reaction temperature of 40 ℃ to 80 ℃ and a reaction time of 2 h to 8 h. The pH range is 7 to 14.

4. The method for preparing the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid according to claim 2, characterized in that, In S200, The polar organic solvent is at least one selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, and tetrahydrofuran; The inorganic base-binding acid agent is at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide. The heating reaction is carried out under nitrogen atmosphere, at a temperature of 40 ℃ to 100 ℃, for a time of 24 h to 48 h. The compound N,N',N'' The molar ratio of tris(p-toluenesulfonyl)diethylenetriamine, the compound 2,6-bis(chloromethyl)pyridine, and the inorganic base-binding acid agent is 1:(1-2):(2-10).

5. The method for preparing the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid according to claim 2, characterized in that, In S300, The concentrated acid is at least one of concentrated sulfuric acid, concentrated nitric acid, concentrated hydrochloric acid, and concentrated phosphoric acid; The heating reaction temperature is between 80 ℃ and 160 ℃, and the reaction time is between 0.5 h and 2 h. The organic solvent is at least one selected from dichloromethane, chloroform, ethyl acetate, and diethyl ether. The alkaline solution is at least one of the following: sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide aqueous solution. The desiccant is at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride.

6. The method for preparing the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid according to claim 2, characterized in that, In S400, The polar organic solvent is at least one selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, and tetrahydrofuran; The halocarboxylic acid ester is at least one of methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, tert-butyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, isopropyl bromoacetate, tert-butyl bromoacetate, methyl 3-chloropropionate, ethyl 3-chloropropionate, isopropyl 3-chloropropionate, tert-butyl 3-chloropropionate, methyl 3-bromopropionate, ethyl 3-bromopropionate, isopropyl 3-bromopropionate, tert-butyl 3-bromopropionate, methyl 4-chlorobutyrate, ethyl 4-chlorobutyrate, isopropyl 4-chlorobutyrate, tert-butyl 4-chlorobutyrate, methyl 4-bromobutyrate, ethyl 4-bromobutyrate, isopropyl 4-bromobutyrate, and tert-butyl 4-bromobutyrate. The inorganic base-binding acid agent is at least one of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and rubidium hydroxide.

7. The method for preparing the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid according to claim 2, characterized in that, In S500, The molar ratio of the compound 2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid and the bismuth agent is 1:(1-3).

8. A formulation based on the bismuth-based chelate CT contrast agent bismuth(III)2,2',2''-(3,6,9-triazine-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid as described in claim 1, characterized in that, The components include the following components by mass percentage: Bismuth(III) 2,2',2''-(3,6,9-triaza-1(2,6)-pyridine-cyclodecane-3,6,9-triyl)tricarboxylic acid 7.46 wt%~74.6 wt%; The metal ion scavenger is 0-0.05 wt%, and the metal scavenger is at least one selected from diethylenetriaminepentaacetic acid, disodium ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. pH buffer 0.1 wt% to 1.0 wt%, wherein the pH buffer is at least one of physiological saline, phosphate buffer solution, Tris buffer and Tris-HCl buffer; Stabilizer 0-0.05 wt%, wherein the stabilizer is at least one selected from sodium bisulfite, sodium ascorbate and methionine; Water 0–92.44 wt%.

9. The application of a novel bismuth-based chelate CT contrast agent as described in claim 1, characterized in that, The CT contrast agent is used for at least one of the following purposes: Preparation of CT contrast agents for imaging the gastrointestinal tract of rats; Preparation of CT contrast agent for imaging a rat model of acute kidney injury; Preparation of CT contrast agents for routine CT angiography of the upper and lower limbs of New Zealand white rabbits; Preparation of CT contrast agents for conventional CTA of upper and lower limb metal artifacts in New Zealand white rabbits; Preparation of CT contrast agents for upper and lower limb metal artifact spectral CTA in New Zealand white rabbits; Prepare a CT contrast agent for routine CTA of the upper limbs of Bama pigs.

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