Gadolinium-based contrast agent formed by covalently connecting maltotriose and chelating group as well as preparation method and application of gadolinium-based contrast agent
By using gadolinium-based contrast agents covalently linked to maltotriose and chelating groups, the problems of kinetic instability and insufficient imaging of existing gadolinium-based contrast agents have been solved, achieving higher imaging quality and targeted diagnostic effects.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-08
- Publication Date
- 2026-04-14
AI Technical Summary
Existing gadolinium-based contrast agents have low kinetic stability, easily release free Gd3+, leading to adverse reactions, and have insufficient imaging sensitivity and contrast.
A gadolinium-based contrast agent covalently linked to maltotriose and a chelating group is used. By modifying the cyclic polydentate ligand, a closed-loop structure is formed and covalently linked to maltotriose, thereby improving thermodynamic stability and targeting ability.
It effectively reduces Gd3+ release, improves the targeting ability of MRI imaging and the differentiation of bacterial infection diagnosis, and enhances image quality.
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Figure CN121851085A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of medical imaging technology, and in particular to a gadolinium-based contrast agent covalently linked to maltotriose and a chelating group, its preparation method, and its application. Background Technology
[0002] Magnetic resonance imaging (MRI) is a clinically relied-upon modern medical imaging diagnostic technique (Li H., Meade TJ Molecular Magnetic Resonance Imaging with Gd(III)-Based Contrast Agents: Challenges and Key Advances [J]. J. Am. Chem. Soc. 2019, 141, 17025-17041.). It images biological targets non-invasively and has high resolution. MRI works by applying an external magnetic field, causing water protons to generate nuclear magnetic resonance signals. Differences in water content and relaxation time between tissues produce different signals, which are then processed by a computer to form an image. Currently, MRI equipment used clinically has poor sensitivity to some diseased tissues, resulting in low imaging contrast. To improve image quality, contrast agents are used clinically.
[0003] Due to Gd 3+ The 4f orbital has 7 unpaired electrons, which can provide a long electron relaxation time and generate a high magnetic moment (μ). 2 =63BM 2 Gadolinium, with its high paramagnetic properties and strong water coordination ability, is the most widely used MRI contrast agent in clinical applications (Hermann P., Kotek J., Kubí). ek V., Luke I. Gadolinium(III) Complexes as MRI Contrast Agents: Ligand Design and Properties of the Complexes [J]. Dalton. Trans. 2008, 23, 3027-3047.). However, commercially available linear gadolinium contrast agents have relatively low kinetic stability and are prone to releasing free Gd. 3+ There is already evidence indicating the presence of free Gd. 3+It can cause adverse reactions such as renal fibrosis (Le Fur M., Caravan P. The Biological Fate of Gadolinium-based MRIContrast Agents: a Call to Action for Bioinorganic Chemists [J]. Metallomics 2019, 11, 240-254.).
[0004] Therefore, developing a novel gadolinium-based contrast agent is an urgent problem to be solved. Summary of the Invention
[0005] The purpose of this invention is to provide a gadolinium-based contrast agent covalently linked to maltotriose and a chelating group, its preparation method, and its application, thereby solving the aforementioned problems of existing gadolinium-based contrast agents.
[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a gadolinium-based contrast agent covalently linked to maltotriose and a chelating group, having the following structure: .
[0007] This invention also provides a method for preparing a gadolinium-based contrast agent covalently linked to maltotriose and a chelating group, comprising the following steps: 6-Amino-1-hexanol, benzyl chloroformate, base, and first solvent were mixed and subjected to a first reaction to obtain long-chain L1. Long-chain L1, triphenylphosphine, carbon tetrabromide, and the first solvent are mixed and a second reaction is carried out to obtain linker L2. Linker L2, base, polydentate ligand, and second solvent are mixed and a third reaction is carried out to obtain t-Bu-DOTA-L2; t-Bu-DOTA-L2, palladium on carbon, and a third solvent were mixed and a fourth reaction was carried out under a hydrogen atmosphere to obtain t-Bu-DOTA-L3; t-Bu-DOTA-L3, maltotriose, and the fourth solvent were mixed and reacted in the fifth reaction; then sodium cyanoborohydride was added and reacted in the sixth reaction to obtain t-Bu-DOTA-Mal. A mixture of t-Bu-DOTA-Mal, trifluoroacetic acid, and water was mixed and subjected to the seventh reaction to obtain DOTA-Mal; After adjusting the pH of the aqueous solution of DOTA-Mal to 8-10, an aqueous solution of gadolinium chloride hexahydrate is added to carry out the eighth reaction to obtain Gd-DOTA-Mal, which is the gadolinium-based contrast agent covalently linked to maltotriose and chelating groups.
[0008] Preferably, the molar ratio of 6-amino-1-hexanol, benzyl chloroformate, and base is 4~6:4~6:0.5~1; the conditions for the first reaction are: temperature 0℃ and time 3~5h.
[0009] Preferably, the molar ratio of the long-chain L1, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7; the conditions for the second reaction are: temperature 0℃ and time 10~12h.
[0010] Preferably, the molar ratio of linker L2, base, and polydentate ligand is 1~3:4~7:1~3; the polydentate ligand is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester; the conditions for the third reaction are: temperature 80~100℃, time 8~10h.
[0011] Preferably, the ratio of t-Bu-DOTA-L2 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the fourth reaction are: temperature 25℃, time 18~24 h, and pressure 0.1 MPa.
[0012] Preferably, the molar ratio of t-Bu-DOTA-L3, maltotriose, and sodium cyanoborohydride is 0.1~2:0.1~2:3~5; the conditions for the fifth reaction are: temperature 25℃ and time 4~6h; the conditions for the sixth reaction are: temperature 25℃ and time 8~10h.
[0013] Preferably, the volume ratio of the mixed solution of t-Bu-DOTA-Mal, trifluoroacetic acid, and water is 0.1~2 mmol:10 mL; the volume ratio of trifluoroacetic acid to water is 98:1; and the conditions for the seventh reaction are: temperature 25℃ and time 10~12 h.
[0014] Preferably, the molar ratio of DOTA-Mal to gadolinium chloride hexahydrate is 1~1.2:1; the conditions for the eighth reaction are: temperature 25℃ and time 4~8h.
[0015] The present invention also provides an application of a gadolinium contrast agent covalently linked to maltotriose and a chelating group, or a gadolinium contrast agent covalently linked to maltotriose and a chelating group prepared by the above preparation method, in magnetic resonance imaging.
[0016] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: This invention first modifies the cyclic polydentate ligand by nucleophilic substitution and then attaches a flexible long chain. Next, a primary amine on the linker terminal group is reductively aminationd with the aldehyde group of maltotriose to form a single unit. Then, trifluoroacetic acid is added to remove the protecting groups from the polydentate ligand. Finally, Gd is added... 3+ The final product is obtained through chelation. This invention uses cyclic gadolinium chelates for modification instead of linear gadolinium chelates, as cyclic gadolinium chelates exhibit higher thermodynamic stability and kinetic inertness compared to linear gadolinium chelates. The closed-ring structure effectively reduces Gd. 3+ The release of gadolinium and maltotriose, through covalent linkage, enhances targeting ability. Maltotriose, as a directing group, exhibits stronger bacterial specificity and permeability, resulting in higher differentiation in the diagnosis of bacterial infections. Attached Figure Description
[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below.
[0018] Figure 1 This is a synthetic route diagram of a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to the present invention; Figure 2 The 1H NMR spectrum of the long-chain L1 in Example 1; Figure 3 The hydrogen NMR spectrum of linker L2 in Example 1; Figure 4 The hydrogen NMR spectrum of t-Bu-DOTA-L2 in Example 1; Figure 5 The mass spectrum of t-Bu-DOTA-L3 in Example 1; Figure 6 The mass spectrum of -Bu-DOTA-Mal in Example 1; Figure 7 The hydrogen NMR spectrum of DOTA-Mal in Example 1; Figure 8 The mass spectrum of DOTA-Mal in Example 1; Figure 9 The mass spectrum of Gd-DOTA-Mal in Example 1; Figure 10 Images of Gd-DOTA-Mal from Example 1, Gd-DOTA from Comparative Example 1, and gadopentetate meglumine from Comparative Example 2 after co-incubation with Staphylococcus aureus; Figure 11The results of nuclear magnetic resonance imaging (NMR) examinations of Gd-DOTA-Mal (Example 1), Gd-DOTA (Comparative Example 1), and gadopentetate meglumine (Comparative Example 2) after co-incubation with Staphylococcus aureus are shown. Detailed Implementation
[0019] This invention provides a gadolinium-based contrast agent covalently linked to maltotriose and a chelating group, having the following structure: .
[0020] This invention also provides a method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group, the synthetic route of which is shown in the figure. Figure 1 As shown, it includes the following steps: 6-amino-1-hexanol, benzyl chloroformate, base, and first solvent were mixed and subjected to a first reaction to obtain long-chain L1 with the following structure;
[0021] Long-chain L1, triphenylphosphine, carbon tetrabromide, and the first solvent are mixed and a second reaction is carried out to obtain linker L2, whose structure is as follows:
[0022] Linker L2, base, polydentate ligand, and second solvent are mixed and subjected to a third reaction to obtain t-Bu-DOTA-L2, whose structure is as follows:
[0023] t-Bu-DOTA-L2, palladium on carbon, and a third solvent were mixed and subjected to a fourth reaction under a hydrogen atmosphere to obtain t-Bu-DOTA-L3, the structure of which is as follows;
[0024] t-Bu-DOTA-L3, maltotriose, and the fourth solvent were mixed and subjected to the fifth reaction; then sodium cyanoborohydride was added and subjected to the sixth reaction to obtain t-Bu-DOTA-Mal, whose structure is as follows;
[0025] A mixed solution of t-Bu-DOTA-Mal, trifluoroacetic acid, and water was mixed and subjected to the seventh reaction to obtain DOTA-Mal, whose structure is as follows: ; After adjusting the pH of the aqueous solution of DOTA-Mal to 8-10, an aqueous solution of gadolinium chloride hexahydrate is added to carry out the eighth reaction to obtain Gd-DOTA-Mal, which is the gadolinium-based contrast agent covalently linked to maltotriose and chelating groups.
[0026] In this invention, the molar ratio of 6-amino-1-hexanol, benzyl chloroformate, and base is preferably 4~6:4~6:0.5~1, more preferably 5~5.5:5~5.5:0.6~0.8, and even more preferably 5.12:5.12:0.71; the base is preferably triethylamine and / or potassium carbonate, more preferably triethylamine or potassium carbonate, and even more preferably triethylamine; the first solvent is preferably dichloromethane; the conditions for the first reaction are: the temperature is preferably 0°C, the time is preferably 3~5h, more preferably 3.5~4.5h, and even more preferably 4h.
[0027] Preferably, the molar ratio of the long-chain L1, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7, more preferably 5~5.5:6~6.5:6~6.5, and even more preferably 5.12:6.14:6.14; the conditions for the second reaction are: the temperature is preferably 0℃, the time is preferably 10~12h, more preferably 10.5~12h, and even more preferably 11h.
[0028] Preferably, the molar ratio of linker L2, base, and polydentate ligand is 1~3:4~7:1~3, more preferably 2~2.4:4.5~6:1~2, and even more preferably 2.35:4.9:1.96; the polydentate ligand is preferably 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester (DOTA); the base is preferably triethylamine and / or potassium carbonate, more preferably triethylamine or potassium carbonate, and even more preferably potassium carbonate; the second solvent is preferably acetonitrile; the conditions for the third reaction are: the temperature is preferably 80~100℃, more preferably 85~95℃, and even more preferably 90℃, and the time is preferably 8~10h, more preferably 8.5~9.5h, and even more preferably 9h.
[0029] Preferably, the ratio of t-Bu-DOTA-L2 to palladium on carbon is 1~5 mmol: 200~300 mg, more preferably 2~3 mmol: 230~260 mg, and even more preferably 2.35 mmol: 249 mg; the mass fraction of palladium on carbon is preferably 10%; the third solvent is preferably ethanol; and the conditions for the fourth reaction are: a temperature preferably of 25°C, a time preferably of 18~24 h, more preferably 19~22 h, and even more preferably 20 h, and a pressure preferably of 0.1 MPa.
[0030] Preferably, the molar ratio of t-Bu-DOTA-L3, maltotriose, and sodium cyanoborohydride is 0.1~2:0.1~2:3~5, more preferably 0.5~1:0.5~1:3.2~4, and even more preferably 0.7:0.7:3.48; the fourth solvent is preferably methanol; the conditions for the fifth reaction are: a temperature preferably of 25°C and a time preferably of 4~6 h, more preferably 4.5~5.5 h, and even more preferably 5 h; the conditions for the sixth reaction are: a temperature preferably of 25°C and a time preferably of 8~10 h, more preferably 9~10 h, and even more preferably 10 h.
[0031] Preferably, the volume ratio of the mixed solution of t-Bu-DOTA-Mal, trifluoroacetic acid, and water is 0.1~2 mmol:10 mL, more preferably 0.5~1 mmol:10 mL, and even more preferably 0.6 mmol:10 mL; the volume ratio of trifluoroacetic acid to water is preferably 98:1; the conditions for the seventh reaction are: a temperature of 25°C and a time of 10~12 h, more preferably 11~12 h, and even more preferably 12 h.
[0032] Preferably, the molar ratio of DOTA-Mal to gadolinium chloride hexahydrate is 1~1.2:1, more preferably 1~1.1:1, and even more preferably 1.02:1; the conditions for the eighth reaction are: the temperature is preferably 25℃, the time is preferably 4~8h, more preferably 5~7h, and even more preferably 6h.
[0033] The present invention also provides an application of a gadolinium contrast agent covalently linked to maltotriose and a chelating group, or a gadolinium contrast agent covalently linked to maltotriose and a chelating group prepared by the above preparation method, in magnetic resonance imaging.
[0034] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0035] Example 1
[0036] This embodiment provides a method for preparing a gadolinium-based contrast agent covalently linked to maltotriose and a chelating group, comprising the following steps: (1) Preparation of long-chain L1: In a 50 mL round-bottom flask, 600 mg of 6-amino-1-hexanol (5.12 mmol), 0.71 mL of benzyl chloroformate (5.12 mmol), and 0.1 mL of triethylamine (0.71 mmol) were added and dissolved in 10 mL of dichloromethane. The mixture was reacted at 0 °C for 5 h. After the reaction, the mixture was extracted with brine and ethyl acetate in a separatory funnel. The resulting organic phase was dried in anhydrous sodium sulfate and then distilled under reduced pressure to obtain a colorless oil. The colorless oily long-chain L1 was further purified on a chromatographic column with a yield of 86%. Its 1H NMR spectrum is shown below. Figure 2 As shown.
[0037] (2) Preparation of linker L2: 1.28 g of long-chain L1 (5.12 mmol), 2.03 g of carbon tetrabromide (6.14 mmol), and 1.61 g of triphenylphosphine (6.14 mmol) were added to a 50 mL round-bottom flask and dissolved in dichloromethane (10 mL). The mixture was reacted at 0 °C for 12 h. After the reaction, the mixture was extracted with brine and ethyl acetate in a separatory funnel. The resulting organic phase was dried in anhydrous sodium sulfate and then distilled under reduced pressure to obtain a colorless oil. Further purification on a chromatographic column yielded a pale yellow oil linker L2 with a yield of 79%. Its 1H NMR spectrum is shown below. Figure 3 As shown.
[0038] (3) Preparation of t-Bu-DOTA-L2: In a 50 mL round-bottom flask, 736 mg of linker L2 (2.35 mmol), 686 mg of potassium carbonate (4.9 mmol), and 1000 mg of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester (1.96 mmol) dissolved in acetonitrile (6 mL) were added. The mixture was refluxed and stirred at 80 °C for 8 h. After the reaction was completed, the solid potassium carbonate was filtered through a Buchner funnel, and the excess acetonitrile was removed by vacuum distillation. The resulting yellow oil was further purified on a chromatographic column to obtain the yellow oil t-Bu-DOTA-L2 with a yield of 75%. Its 1H NMR spectrum is shown below. Figure 4 As shown.
[0039] (4) Preparation of t-Bu-DOTA-L3: In a 50 mL round-bottom flask, 1440 mg of t-Bu-DOTA-L2 (2.35 mmol) and 249 mg of 10% wt palladium on carbon (0.23 mmol) dissolved in ethanol (10 mL) were added. Hydrogen gas was added and the mixture was stirred at room temperature and 0.1 MPa for 20 h. After the reaction was completed, the palladium on carbon solid was filtered through a Buchner funnel, and excess ethanol was removed by vacuum distillation to obtain a yellow oily substance t-Bu-DOTA-L3 with a yield of 89%. Its mass spectrum is shown in the figure. Figure 5 As shown.
[0040] (5) Preparation of t-Bu-DOTA-Mal: In a 100 mL round-bottom flask, 427 mg of t-Bu-DOTA-L3 (0.70 mmol) was dissolved in methanol (25 mL), and 351 mg of maltotriose (0.70 mmol) was dissolved in water (5 mL) to form an aqueous solution, which was then added to the above methanol solution system. After stirring at room temperature for 6 h, 218 mg of sodium cyanoborohydride (3.48 mmol) was added, and the reaction was stirred at room temperature for 10 h. After mass spectrometry monitoring of the reaction, the solvent was distilled under reduced pressure to obtain a white solid. The white solid was purified by reversed-phase silica gel column chromatography to obtain the product t-Bu-DOTA-Mal with a yield of 40%. Its mass spectrum is shown in the figure. Figure 6 As shown.
[0041] (6) Preparation of DOTA-Mal: In a 50 mL round-bottom flask, add 652 mg of t-Bu-DOTA-Mal (0.6 mmol) and 10 mL of a mixed solution of trifluoroacetic acid and water (volume ratio 98:1). Stir overnight at room temperature. After the reaction is complete as monitored by NMR, distill under reduced pressure to 1-2 mL, add methyl tert-butyl ether, and a white solid precipitates. Filter using a Buchner funnel to obtain a white solid that dissolves in water. Separate and purify the white solid using reversed-phase silica gel column chromatography to obtain DOTA-Mal with a yield of 90%. Its 1H NMR spectrum is shown below. Figure 7 As shown, its mass spectrum is as follows: Figure 8 As shown.
[0042] (7) Preparation of Gd-DOTA-Mal: In a 100 mL round-bottom flask, 459 mg of DOTA-Mal (0.49 mmol) was dissolved in 15 mL of water. The pH of the system was adjusted to 8-10 using 2 M sodium hydroxide aqueous solution. At the same time, 178 mg of gadolinium chloride hexahydrate (0.48 mmol) was dissolved in 10 mL of water. The gadolinium chloride aqueous solution was slowly added dropwise to the DOTA-Mal solution. The mixture was stirred at room temperature for 8 h. After the reaction was complete as monitored by mass spectrometry, the solvent was distilled under reduced pressure and purified by reversed-phase silica gel column chromatography to obtain a white solid as the final product Gd-DOTA-Mal, with a yield of 71%. Its mass spectrum is shown below. Figure 9 As shown.
[0043] Comparative Example 1
[0044] This comparative example provides a gadolinium-based contrast agent, Gd-DOTA, specifically the commercially available product gadoteric acid.
[0045] Comparative Example 2
[0046] This comparative example provides a gadolinium-based contrast agent, specifically the commercially available product gadopentetate meglumine (gadopentetate).
[0047] Staphylococcus aureus was grown in TSB medium at 37°C, and the bacterial concentration was determined using a bacterial turbidimeter. Gd-DOTA-Mal from Example 1, Gd-DOTA from Comparative Example 1, and gadopentetate meglumine from Comparative Example 2 were co-incubated with Staphylococcus aureus for 2 hours (images after co-incubation are shown below). Figure 10 (As shown), then centrifuged, washed, and subjected to MRI examination. The results are as follows. Figure 11 As shown, the Gd-DOTA-Mal group can produce clear imaging, while the Gd-DOTA imaging effect is weaker, and the imaging effect of commercially available gadopentetate dimeglumine is generally poor, indicating that the Gd-DOTA-Mal prepared in this invention has a stronger ability to target bacteria for imaging.
[0048] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A gadolinyl contrast agent covalently linked to maltotriose and a chelating group, characterized in that, It has the following structure: 。 2. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group as described in claim 1, characterized in that, Includes the following steps: 6-Amino-1-hexanol, benzyl chloroformate, base, and first solvent were mixed and subjected to a first reaction to obtain long-chain L1. Long-chain L1, triphenylphosphine, carbon tetrabromide, and the first solvent are mixed and a second reaction is carried out to obtain linker L2. Linker L2, base, polydentate ligand, and second solvent are mixed and a third reaction is carried out to obtain t-Bu-DOTA-L2; t-Bu-DOTA-L2, palladium on carbon, and a third solvent were mixed and a fourth reaction was carried out under a hydrogen atmosphere to obtain t-Bu-DOTA-L3; t-Bu-DOTA-L3, maltotriose, and the fourth solvent were mixed and reacted in the fifth reaction; then sodium cyanoborohydride was added and reacted in the sixth reaction to obtain t-Bu-DOTA-Mal. A mixture of t-Bu-DOTA-Mal, trifluoroacetic acid, and water was mixed and subjected to the seventh reaction to obtain DOTA-Mal; After adjusting the pH of the aqueous solution of DOTA-Mal to 8-10, an aqueous solution of gadolinium chloride hexahydrate is added to carry out the eighth reaction to obtain Gd-DOTA-Mal, which is the gadolinium-based contrast agent covalently linked to maltotriose and chelating groups.
3. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 2, characterized in that, The molar ratio of 6-amino-1-hexanol, benzyl chloroformate, and base is 4~6:4~6:0.5~1; the conditions for the first reaction are: temperature 0℃ and time 3~5h.
4. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 3, characterized in that, The molar ratio of the long-chain L1, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7; the conditions for the second reaction are: temperature 0℃ and time 10~12h.
5. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 4, characterized in that, The molar ratio of linker L2, base, and polydentate ligand is 1~3:4~7:1~3; the polydentate ligand is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester; the conditions for the third reaction are: temperature 80~100℃, time 8~10h.
6. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 5, characterized in that, The ratio of t-Bu-DOTA-L2 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the fourth reaction are: temperature 25℃, time 18~24 h, and pressure 0.1 MPa.
7. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 6, characterized in that, The molar ratio of t-Bu-DOTA-L3, maltotriose, and sodium cyanoborohydride is 0.1~2:0.1~2:3~5; the conditions for the fifth reaction are: temperature 25℃ and time 4~6h; the conditions for the sixth reaction are: temperature 25℃ and time 8~10h.
8. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 7, characterized in that, The volume ratio of the t-Bu-DOTA-Mal, trifluoroacetic acid and water mixture is 0.1~2 mmol:10 mL; the volume ratio of trifluoroacetic acid and water is 98:1; the conditions for the seventh reaction are: temperature 25℃ and time 10~12 h.
9. The method for preparing a gadolinyl contrast agent covalently linked to maltotriose and a chelating group according to claim 8, characterized in that, The molar ratio of DOTA-Mal to gadolinium chloride hexahydrate is 1~1.2:1; the conditions for the eighth reaction are: temperature 25℃ and time 4~8h.
10. The application of a gadolinium-based contrast agent covalently linked to a maltotriose and a chelating group as described in claim 1, or a gadolinium-based contrast agent covalently linked to a maltotriose and a chelating group prepared by any one of claims 2 to 9, in magnetic resonance imaging.