Gallium-based radioactive contrast agent with glycosylation-modified maltotriose covalently linked with chelating group as well as preparation method and application of gallium-based radioactive contrast agent

Abstract

The invention belongs to the technical field of medical imaging, and discloses a gallium-based radioactive contrast agent with glycosylation-modified maltotriose covalently linked with a chelating group as well as a preparation method and application of the gallium-based radioactive contrast agent. The preparation method comprises the following steps: firstly, modifying a cyclic polydentate ligand, carrying out nucleophilic substitution, then connecting an upper half flexible chain or loop chain, and then carrying out glycosylation on acetyl protected maltotriose to connect a sugar part half flexible chain or loop chain; the preparation method comprises the following steps: preparing a polydentate ligand, carrying out reductive amination or urea condensation connection on aldehyde groups or aldehyde groups on half-chain end groups on two sides to form a whole, adding methanol and a sodium methoxide solution, removing acetyl of sugar, adding trifluoroacetic acid to remove protective groups on the polydentate ligand, and finally adding 68Ga for chelation to obtain a final product. And maltotriose is adopted as a guiding group, so that higher bacterial specificity and permeability are achieved, and the distinguishing degree in diagnosis of bacterial infection is higher.

Description

Technical Field

[0001] This invention relates to the field of medical imaging technology, and in particular to gallium-based radioactive contrast agents covalently linked to glycosylated maltotriose and chelating groups, their preparation methods, and applications. Background Technology

[0002] Radionuclide imaging combines nuclear technology and medicine by administering radiopharmaceuticals into living organisms and then imaging them with specialized instruments (Xu S, Liu G, Wei Q, Liu H, Wu J, Liu Y and He ZX. Recent advances in radionuclide medical imaging techniques. Front. Med. (2025) 12:1662020). The precise deposition of high-energy radionuclides into target cells directly induces cell killing through single- or double-strand DNA breaks. Compared to radiotherapy involving external radiation sources, radiopharmaceutical therapy (RPT) confines radiation within target cells and has minimal toxicity to non-target cells, thus reducing damage to normal organs (Zhang, S., Wang, X., Gao, X. et al. Radiopharmaceuticals and their applications in medicine. Sig Transduct Target Ther (2025) 10, 1).

[0003] Maltodextrin is a major glucose source for bacteria and can be absorbed in millimolecular amounts (JACC Cardiovase. Imaging 2019, 12, 875-886). Furthermore, maltodextrin transporters are absent in mammalian cells, thus allowing bacterial infections to be distinguished from other diseases (cancer, inflammation, etc.). Due to the uptake of maltodextrin transporters in Gram-negative and Gram-positive bacteria, 6″-[ 18 F]Fluorotriose appears to be specific for bacterial infections; however, [ 18 [F] Fluorides are produced by cyclotrons, which is a limitation in developing countries most affected by infectious diseases. Radioactive nuclides that emit positrons, such as gallium produced by generators (… 68 (Ga), which is widely used clinically. Structurally, for nuclear medicine imaging, a radioactive isotope must be incorporated into or attached to the biomolecule responsible for targeting. A convenient and readily established method is to complex the radioactive isotope with a chelating component, preferably without affecting the function of the tracer or compromising its integrity. 68Ga-NOTA-UBI detected Staphylococcus aureus infection and may become a PET solution for low-income countries (Mdlophane, AH, Ebenhan, T., Marjanovic-Painter, B. et al. Comparison of DOTA and NODAGA as chelates for 68 Ga-labelled CDP1 as novelinfection PET imaging agents. J Radioanal Nucl Chem (2019) 322, 629-638.). Summary of the Invention

[0004] The purpose of this invention is to provide a gallium-based radioactive contrast agent with glycosylation-modified maltotriose covalently linked to a chelating group, its preparation method, and its application, thereby solving the aforementioned problems of existing radioactive contrast agents.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a gallium-based radioactive contrast agent covalently linked to a glycosylated maltotriose and a chelating group, having the structure shown in Formula I or Formula II:

[0006] Formula I;

[0007] Formula II.

[0008] This invention also provides a method for preparing a gallium-based radioactive contrast agent covalently linked to a glycosylated maltotriose and a chelating group. When the structure is as shown in Equation I, its synthesis route diagram is as follows: Figure 1 As shown, the preparation method includes the following steps: Maltotriose, acetic anhydride, and a first solvent were mixed and subjected to the first reaction of the sugar moiety to obtain Mal-Ac, whose structure is as follows: ; Mal-Ac, hydrazine acetate, and a second solvent were mixed to carry out the second reaction of the sugar moiety, yielding Mal-Ac-OH with the following structure: ; A mixture of Mal-Ac-OH, trichloroacetonitrile, a base, and a third solvent is used to carry out the third reaction of the sugar moiety, yielding Mal-Ac-Tca, whose structure is as follows: ; Mal-Ac-Tca, triethylene glycol monobenzyl ether, TBSOTf, and a third solvent were mixed and subjected to a fourth reaction of the sugar moiety to obtain Mal-Ac-F1, whose structure is as follows: ; Mal-Ac-F1, palladium on carbon, and a fourth solvent were mixed and subjected to a fifth reaction of the sugar moiety under a hydrogen atmosphere to yield Mal-Ac-F2, whose structure is as follows: ; Mal-Ac-F2, DMSO, oxalyl chloride, a base, and a third solvent were mixed and subjected to the sixth reaction of the sugar moiety to obtain Mal-Ac-F3, whose structure is as follows: ; A mixture of tetraethylene glycol monoamine, benzyl chloroformate, a base, and a third solvent was subjected to the first reaction of the polydentate ligand moiety to yield a half-chain F4, the structure of which is as follows: ; Half-chain F4, triphenylphosphine, carbon tetrabromide, and a third solvent were mixed and subjected to a second reaction of the polydentate ligand moiety to obtain half-chain F5, the structure of which is as follows: ; Half-chain F5, a base, a polydentate ligand, and a fifth solvent were mixed and subjected to the third reaction of the polydentate ligand portion to obtain t-Bu-DOTA-F5, whose structure is as follows: ; t-Bu-DOTA-F5, palladium on carbon, and a fourth solvent were mixed and subjected to a fourth reaction of the polydentate ligand moiety under a hydrogen atmosphere to yield t-Bu-DOTA-F6, the structure of which is as follows: ; t-Bu-DOTA-F6, Mal-Ac-F3, and a sixth solvent were mixed, and then sodium cyanoborohydride was added to carry out the first overall reaction, yielding t-Bu-DOTA-F-Mal-Ac, whose structure is as follows: ; t-Bu-DOTA-F-Mal-Ac, sodium methoxide methanol solution, and a sixth solvent were mixed and subjected to a second overall reaction to obtain t-Bu-DOTA-F-Mal, whose structure is as follows: ; A mixed solution of t-Bu-DOTA-F-Mal, trifluoroacetic acid, and water was mixed and subjected to a third overall reaction to obtain DOTA-F-Mal, whose structure is as follows: ; DOTA-F-Mal, 68GaCl3 and hydrochloric acid solution were mixed and chelated to obtain the structure shown in Formula I. When the structure is as shown in Equation II, its synthesis route diagram is as follows: Figure 16 As shown, the preparation method includes the following steps: N-Cbz-4-piperidinemethanol, triphenylphosphine, carbon tetrabromide, and a third solvent were mixed and subjected to the fifth reaction of the polydentate ligand moiety to obtain a cyclic chain C1 with the following structure: ; The ring-chain C1, base, polydentate ligand, and fifth solvent were mixed, and the sixth reaction of the polydentate ligand portion was carried out to obtain t-Bu-DOTA-C1, whose structure is as follows: ; t-Bu-DOTA-C1, palladium on carbon, and a fourth solvent were mixed and subjected to a seventh reaction of the polydentate ligand moiety under a hydrogen atmosphere to obtain t-Bu-DOTA-C2, the structure of which is as follows: ; Mal-Ac-Tca, N-Cbz-4-piperidinemethanol, TBSOTf, and a third solvent were mixed and subjected to the seventh reaction of the sugar moiety to obtain Mal-Ac-C3, whose structure is as follows: ; Mal-Ac-C3, palladium hydroxide, and a fourth solvent were mixed and subjected to the eighth reaction of the sugar moiety under a hydrogen atmosphere to yield Mal-Ac-C4, with the following structure: ; Mal-Ac-C4, triphosgene, t-Bu-DOTA-C2, a base, and a third solvent are mixed and subjected to a fourth overall reaction to obtain t-Bu-DOTA-Urea-Mal-Ac, the structure of which is as follows: ; t-Bu-DOTA-Urea-Mal-Ac, sodium methoxide methanol solution, and a sixth solvent were mixed and subjected to a fifth overall reaction to obtain t-Bu-DOTA-Urea-Mal, whose structure is as follows: ; A mixed solution of t-Bu-DOTA-Urea-Mal, trifluoroacetic acid, and water was subjected to a sixth overall reaction to obtain DOTA-Urea-Mal, whose structure is as follows: ; DOTA-Urea-Mal, 68 When GaCl3 and hydrochloric acid solution are mixed, a chelation reaction is carried out to obtain the structure shown in Formula II.

[0009] Preferably, the molar ratio of maltotriose to acetic anhydride is 0.5~1:15~20; the conditions for the first reaction of the sugar fraction are: temperature 90℃ and time 2~3h.

[0010] Preferably, the molar ratio of Mal-Ac to hydrazine acetate is 0.5~1:1.5~2; the conditions for the second reaction of the sugar fraction are: temperature 50℃ and time 1~2h.

[0011] Preferably, the molar ratio of Mal-Ac-OH, trichloroacetonitrile, and alkali is 1~2:5~10:1~5; the conditions for the third reaction of the sugar portion are: temperature 25℃ and time 10~16h.

[0012] Preferably, the molar ratio of Mal-Ac-Tca, triethylene glycol monobenzyl ether, and TBSOTf is 0.5~2:0.5~3:0.1~0.3; the conditions for the fourth reaction of the sugar fraction are: temperature 0℃ and time 3~5h.

[0013] Preferably, the ratio of Mal-Ac-F1 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the fifth reaction of the sugar fraction are: temperature 25℃, time 10~20 h, and pressure 0.1 MPa.

[0014] Preferably, the molar ratio of Mal-Ac-F2, DMSO, oxalyl chloride, and alkali is 1~1.2:8~10:5~6:5~6; the conditions for the sixth reaction of the sugar fraction are: temperature -78℃ and time 2~3h.

[0015] Preferably, the molar ratio of the tetraethylene glycol monoamine, benzyl chloroformate, and base is 1~6:1~6:0.5~1; the conditions for the first reaction of the polydentate ligand portion are: temperature 0℃ and time 3~5h.

[0016] Preferably, the molar ratio of the half-chain F4, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7; the conditions for the second reaction of the polydentate ligand portion are: temperature 0℃ and time 10~12h.

[0017] Preferably, the molar ratio of F5, 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 of the polydentate ligand portion are: temperature 80~100℃, time 8~10h.

[0018] Preferably, the ratio of t-Bu-DOTA-F5 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the fourth reaction of the polydentate ligand are: temperature 25℃, time 18~24 h, and pressure 0.1 MPa.

[0019] Preferably, the molar ratio of t-Bu-DOTA-F6, Mal-Ac-F3, and sodium cyanoborohydride is 0.1~2:0.1~2:3~5; the conditions for the overall first reaction are: temperature of 25℃ and time of 8~10h.

[0020] Preferably, the ratio of t-Bu-DOTA-F-Mal-Ac to sodium methoxide methanol solution is 0.1~2 mmol:0.1 mL; the conditions for the overall second reaction are: temperature 25℃ and time 8~10 h.

[0021] Preferably, the volume ratio of the mixed solution of t-Bu-DOTA-F-Mal, trifluoroacetic acid, and water is 0.1~2 mmol:10 mL; the volume ratio of trifluoroacetic acid to water in the mixed solution of trifluoroacetic acid and water is 98:1; and the conditions for the overall third reaction are: temperature 25℃ and time 10~12 h.

[0022] Preferably, the DOTA-F-Mal, 68 The molar ratio of GaCl3 is 1~1.2:1; the temperature of the chelation reaction is 80~90℃; and the time of the chelation reaction is 10~30min.

[0023] Preferably, the molar ratio of N-Cbz-4-piperidinemethanol, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7; the conditions for the fifth reaction of the polydentate ligand part are: temperature 0℃ and time 10~12h.

[0024] Preferably, the molar ratio of the cyclic chain C1, the base, and the polydentate ligand is 1~3:3~7:1~3; the polydentate ligand is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester; the conditions for the sixth reaction of the polydentate ligand portion are: temperature 80~100℃, time 8~10h.

[0025] Preferably, the ratio of t-Bu-DOTA-C1 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the seventh reaction of the polydentate ligand are: temperature 25℃, time 18~24 h, and pressure 0.1 MPa.

[0026] Preferably, the molar ratio of Mal-Ac-Tca, N-Cbz-4-piperidinemethanol, and TBSOTf is 1~2:1~3:0.1~0.5; the conditions for the seventh reaction of the sugar fraction are: temperature 0℃ and time 3~5h.

[0027] Preferably, the ratio of Mal-Ac-C3 to palladium hydroxide is 1~5 mmol: 200~300 mg; the conditions for the eighth reaction of the sugar fraction are: temperature 25℃, time 10~12 h, and pressure 0.1 MPa.

[0028] Preferably, the molar ratio of Mal-Ac-C4, triphosgene, t-Bu-DOTA-C2, and base is 1~2:0.3~0.7:1~2:2~3.0; the conditions for the overall fourth reaction are: temperature 0℃ and time 4~6h.

[0029] Preferably, the ratio of t-Bu-DOTA-Urea-Mal-Ac to sodium methoxide methanol solution is 0.1~2 mmol:0.1 mL; the conditions for the overall fifth reaction are: temperature 25℃ and time 8~10 h.

[0030] Preferably, the volume ratio of the t-Bu-DOTA-Urea-Mal, trifluoroacetic acid and water mixture is 0.1~2 mmol:10 mL; the volume ratio of trifluoroacetic acid to water in the trifluoroacetic acid and water mixture is 98:1; the conditions for the overall sixth reaction are: temperature 25℃ and time 10~12 h.

[0031] Preferably, the DOTA-Urea-Mal, 68 The molar ratio of GaCl3 is 1~1.2:1; the temperature of the chelation reaction is 80~90℃; and the time of the chelation reaction is 10~30min.

[0032] Preferably, the first solvent is pyridine; the second solvent is tetrahydrofuran; the third solvent is dichloromethane; the fourth solvent is ethanol; the fifth solvent is acetonitrile; and the sixth solvent is methanol.

[0033] This invention also provides the application of gallium-based radiocontrast agents covalently linked to glycosylated maltotriose and chelating groups, or gallium-based radiocontrast agents covalently linked to glycosylated maltotriose and chelating groups prepared by the above preparation method, in radionuclide medical imaging.

[0034] 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, then attaches the upper flexible chain or cyclic chain. Next, acetyl-protected maltotriose is glycosylated to attach the sugar portion of the flexible chain or cyclic chain. Then, a reductive amination or urea condensation is performed on the end groups of the two half-chains to form a single unit. Following this, methanol and sodium methoxide solution are added to remove the acetyl group of the sugar. Trifluoroacetic acid is then added to remove the protecting group on the polydentate ligand. Finally, [the process is repeated]. 68 Ga is chelated to obtain the final product. This invention uses cyclic gallium chelates for modification instead of linear gallium chelates, as cyclic gallium chelates possess higher thermodynamic stability and kinetic inertness compared to linear gallium chelates. The closed-loop structure effectively reduces... 68 The release of Ga, along with the covalent connection between the cyclic gallium chelate and maltotriose, enhances the targeting ability. As a directing group, maltotriose exhibits stronger bacterial specificity and permeability, resulting in higher differentiation in the diagnosis of bacterial infections. Attached Figure Description

[0035] 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.

[0036] Figure 1 This is a synthetic route diagram for a gallium-based radioactive contrast agent covalently linked to maltotriose and a chelating group as shown in Formula I of this invention. Figure 2 The 1H NMR spectrum of Mal-Ac in Example 1; Figure 3 The 1H NMR spectrum of Mal-Ac-OH in Example 1; Figure 4 The hydrogen NMR spectrum of Mal-Ac-Tca in Example 1; Figure 5 The 1H NMR spectrum of Mal-Ac-F1 in Example 1; Figure 6 The 1H NMR spectrum of Mal-Ac-F2 in Example 1; Figure 7 The 1H NMR spectrum of Mal-Ac-F3 in Example 1; Figure 8 The hydrogen NMR spectrum of half-chain F4 in Example 1; Figure 9 The 1H NMR spectrum of half-chain F5 in Example 1; Figure 10 The hydrogen NMR spectrum of t-Bu-DOTA-F5 in Example 1; Figure 11 The hydrogen NMR spectrum of t-Bu-DOTA-F6 in Example 1; Figure 12 The 1H NMR spectrum of t-Bu-DOTA-F-Mal-Ac in Example 1; Figure 13 The mass spectrum of t-Bu-DOTA-F-Mal in Example 1; Figure 14 The hydrogen NMR spectrum of DOTA-F-Mal in Example 1; Figure 15 The mass spectrum of DOTA-F-Mal in Example 1; Figure 16 This is a synthetic route diagram for a gallium-based radioactive contrast agent covalently linked to maltotriose and a chelating group, as shown in Formula II of this invention. Figure 17 The 1H NMR spectrum of the cyclic chain C1 in Example 2; Figure 18 The hydrogen NMR spectrum of t-Bu-DOTA-C1 in Example 2; Figure 19 The hydrogen NMR spectrum of t-Bu-DOTA-C2 in Example 2; Figure 20 The hydrogen NMR spectrum of Mal-Ac-C3 in Example 2; Figure 21 The hydrogen NMR spectrum of Mal-Ac-C4 in Example 2; Figure 22 The 1H NMR spectrum of t-Bu-DOTA-Urea-Mal-Ac in Example 2; Figure 23 The mass spectrum of t-Bu-DOTA-Urea-Mal in Example 2; Figure 24 The hydrogen NMR spectrum of DOTA-Urea-Mal in Example 2; Figure 25 The mass spectrum of DOTA-Urea-Mal in Example 2; Figure 26 Gallium-based radioactive contrast agent of open-ring maltotriose, as described in Comparative Example 1 68 Synthetic route diagram of Ga-DOTA-PEG3-Mal; Figure 27 For Comparative Example 1 68 Imaging effects of Ga-DOTA-PEG3-Mal on Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa in mice; Figure 28 Example 2 68 Imaging effects of Ga-DOTA-Urea-Mal on Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa in mice. Detailed Implementation

[0037] 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.

[0038] Example 1

[0039] This embodiment provides a gallium-based radioactive contrast agent with a glycosylated maltotriose covalently linked to a chelating group, having the structure shown in Formula I:

[0040] Formula I.

[0041] Its preparation method includes the following steps: (1) Preparation of acetylated maltotriose (Mal-Ac): In a 50 mL round-bottom flask, 1381 mg of maltotriose (2.738 mmol) and 4.63 mL of acetic anhydride (49.2 mmol) were added and dissolved in pyridine (10 mL). The mixture was reacted at 90 °C for 4 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 white solid. The white solid acetylated maltotriose was further purified on a chromatographic column with a yield of 95%. Its 1H NMR spectrum is shown below. Figure 2 As shown.

[0042] (2) Preparation of Mal-Ac-OH: 2610 mg of Mal-Ac (2.7 mmol) and 373 mg of hydrazine acetate (4.05 mmol) were added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (10 mL). The mixture was reacted at 50 °C for 1.5 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 white solid. The white solid was further purified on a chromatographic column to obtain Mal-Ac-OH with a yield of 70%. Its 1H NMR spectrum is shown below. Figure 3 As shown.

[0043] (3) Preparation of Mal-Ac-Tca: In a 50 mL round-bottom flask, 1701 mg of Mal-Ac-OH (1.84 mmol), 774 mg of potassium carbonate (5.52 mmol), and 1.84 mL of trichloroacetonitrile (18.4 mmol) were dissolved in dichloromethane (6 mL). The mixture was stirred at 25 °C for 16 h. After the reaction was completed, the solid potassium carbonate was filtered through a Buchner funnel, and excess dichloromethane was removed by vacuum distillation. The resulting white solid was further purified on a chromatographic column to obtain the white solid as Mal-Ac-Tca, with a yield of 68%. Its 1H NMR spectrum is shown below. Figure 4 As shown.

[0044] (4) Preparation of Mal-Ac-F1: In a 50 mL reaction flask, 2000 mg of 5A molecular sieve, 868 mg of Mal-Ac-Tca (0.813 mmol), and 214 mg of triethylene glycol monobenzyl ether (0.89 mmol) were added and dissolved in 10 mL of dichloromethane. After stirring at room temperature for 15 min, the mixture was transferred to a low-temperature reactor. The system was kept below 0 °C, and 0.04 mL of TBSOTf (0.16 mmol) was slowly added dropwise. The reaction was carried out for 4 h. After the reaction was completed, the molecular sieve solid was filtered using a Buchner funnel, and excess dichloromethane was removed by vacuum distillation. The resulting white solid was further purified on a chromatographic column to obtain the white solid as Mal-Ac-F1, with a yield of 40%. Its 1H NMR spectrum is shown below. Figure 5 As shown.

[0045] (5) Preparation of Mal-Ac-F2: In a 50 mL round-bottom flask, 436 mg of Mal-Ac-F1 (0.38 mmol) and 40 mg of 10% wt palladium on carbon (0.04 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 using a Buchner funnel. Excess ethanol was removed by vacuum distillation to obtain a white solid. Further purification on a chromatographic column yielded a white solid as Mal-Ac-F2, with a yield of 44%. Its 1H NMR spectrum is shown below. Figure 6 As shown.

[0046] (6) Preparation of Mal-Ac-F3: In a 50 mL reaction flask placed in a low-temperature reactor at -78 °C, 211 mg of DMSO diluted with dichloromethane was added, and 198 mg of oxalyl chloride diluted with dichloromethane was slowly added dropwise. After stirring for 30 min, 300 mg of Mal-Ac-F2 (0.284 mmol) was added, and after stirring for 3 h, 0.4 mL of triethylamine (1.42 mmol) was added and the mixture was gradually brought to room temperature. After the reaction was completed, the mixture was extracted with brine and ethyl acetate in a separatory funnel. The resulting organic phase was dried in anhydrous sodium sulfate, and the organic phase was distilled under reduced pressure to obtain a white solid. Further purification on a chromatographic column yielded a white solid as Mal-Ac-F3, with a yield of 36%. Its 1H NMR spectrum is shown below. Figure 7 As shown.

[0047] (7) Preparation of half-chain F4: In a 50 mL round-bottom flask, 200 mg of tetraethylene glycol monoamine (1.04 mmol), 0.145 mL of benzyl chloroformate (1.04 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 half-chain F4 was further purified on a chromatographic column with a yield of 70%. Its 1H NMR spectrum is shown below. Figure 8 As shown.

[0048] (8) Preparation of half-chain F5: 416 mg of half-chain F4 (1.27 mmol), 436 mg of carbon tetrabromide (1.4 mmol), and 367 mg of triphenylphosphine (1.4 mmol) were added to a 50 mL round-bottom flask and dissolved in 10 mL of dichloromethane. 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 oily half-chain F5 with a yield of 35%. Its 1H NMR spectrum is shown below. Figure 9 As shown.

[0049] (9) Preparation of t-Bu-DOTA-F5: In a 50 mL round-bottom flask, 136 mg of half-chain F5 (0.35 mmol), 111 mg of potassium carbonate (0.8 mmol), and 163 mg of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester (0.32 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 by chromatographic column chromatography to obtain the yellow oil t-Bu-DOTA-F5 with a yield of 69%. Its 1H NMR spectrum is shown below. Figure 10 As shown.

[0050] (10) Preparation of t-Bu-DOTA-F6: In a 50 mL round-bottom flask, 694 mg of t-Bu-DOTA-F5 (0.84 mmol) and 90 mg of 10% wt palladium on carbon (0.08 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 using a Buchner funnel, and excess ethanol was removed by vacuum distillation to obtain a yellow oily substance, t-Bu-DOTA-F6, with a yield of 85%. Its 1H NMR spectrum is shown below. Figure 11 As shown.

[0051] (11) Preparation of t-Bu-DOTA-F-Mal-Ac: In a 100 mL round-bottom flask, 475 mg of t-Bu-DOTA-F6 (0.45 mmol) and 310 mg of Mal-Ac-F3 (0.45 mmol) were dissolved in methanol (25 mL). After stirring at room temperature for 6 h, 283 mg of sodium cyanoborohydride (4.5 mmol) was added and the mixture 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-F-Mal-Ac, with a yield of 44%. Its 1H NMR spectrum is shown below. Figure 12 As shown.

[0052] (12) Preparation of t-Bu-DOTA-F-Mal: In a 100 mL round-bottom flask, add 465 mg of t-Bu-DOTA-F-Mal-Ac (0.28 mmol) and 0.1 mL of sodium methoxide methanol solution dissolved in methanol (25 mL). Stir the reaction at room temperature for 10 h. After mass spectrometry monitoring, distill the solvent under reduced pressure to obtain a white solid. Purify the white solid by reversed-phase silica gel column chromatography to obtain the product t-Bu-DOTA-F-Mal with a yield of 83%. Its mass spectrum is shown below. Figure 13 As shown.

[0053] (13) Preparation of DOTA-F-Mal: In a 50 mL round-bottom flask, add 392 mg of t-Bu-DOTA-F-Mal (0.3 mmol) and 10 mL of a mixed solution of trifluoroacetic acid and water (volume ratio 98:1). Stir at room temperature for 12 h. After the reaction is complete as monitored by NMR, distill under reduced pressure to 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-F-Mal with a yield of 80%. Its 1H NMR spectrum is shown below. Figure 14 As shown, its mass spectrum is as follows: Figure 15 As shown.

[0054] (14) Preparation 68 Ga-DOTA-F-Mal: eluted directly from the germanium-gallium generator using 0.05 mol / L HCl. 68 GaCl3 solution, according to DOTA-F-Mal and 68 GaCl3 was added to DOTA-F-Mal at a molar ratio of 1.1:1, and the mixture was incubated at 85℃ for 15 min. The solution was then filtered through a 0.22 μm microporous membrane to obtain... 68 Ga-DOTA-F-Mal, with a yield of 95%, is the gallium-based radioactive contrast agent covalently linked to the maltotriose and chelating groups.

[0055] Example 2

[0056] This embodiment provides a gallium-based radioactive contrast agent with a glycosylated maltotriose covalently linked to a chelating group, having the structure shown in Formula II:

[0057] Formula II.

[0058] Its preparation method includes the following steps: (1) Preparation of cyclic C1: 500 mg of N-Cbz-4-piperidinemethanol (2.00 mmol), 796 mg of carbon tetrabromide (2.4 mmol), and 630 mg of triphenylphosphine (2.4 mmol) were added to a 50 mL round-bottom flask and dissolved in 10 mL of dichloromethane. 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 oily cyclic C1 with a yield of 78%. Its 1H NMR spectrum is shown below. Figure 17 As shown.

[0059] (2) Preparation of t-Bu-DOTA-C1: In a 50 mL round-bottom flask, 572 mg of cyclic C1 (2.35 mmol), 427 mg of potassium carbonate (3.05 mmol), and 630 mg of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester (1.22 mmol) dissolved in acetonitrile (8 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 by chromatographic column chromatography to obtain the yellow oil t-Bu-DOTA-C1 with a yield of 76%. Its 1H NMR spectrum is shown below. Figure 18 As shown.

[0060] (3) Preparation of t-Bu-DOTA-C2: In a 50 mL round-bottom flask, 789 mg of t-Bu-DOTA-C1 (1.06 mmol) and 112 mg of 10% wt palladium on carbon (0.11 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 using a Buchner funnel, and excess ethanol was removed by vacuum distillation to obtain a yellow oily substance, t-Bu-DOTA-C2, with a yield of 89%. Its 1H NMR spectrum is shown below. Figure 19 As shown.

[0061] (4) Preparation of Mal-Ac-C3: In a 100 mL reaction flask, 2000 mg of 5A molecular sieve, 1720 mg of Mal-Ac-Tca (1.61 mmol) prepared in Example 1, 422 mg of N-Cbz-4-piperidinemethanol (1.70 mmol), and 10 mL of dichloromethane were added. After stirring at room temperature for 15 min, the mixture was transferred to a low-temperature reactor. The system was kept below 0 °C, and 0.1 mL of TBSOTf (0.4 mmol) was slowly added dropwise. The reaction was carried out for 4 h. After the reaction was completed, the molecular sieve solid was filtered using a Buchner funnel, and excess dichloromethane was removed by vacuum distillation. The resulting white solid was further purified on a chromatographic column to obtain the white solid as Mal-Ac-C3, with a yield of 43%. Its 1H NMR spectrum is shown below. Figure 20 As shown.

[0062] (5) Preparation of Mal-Ac-C4: In a 50 mL round-bottom flask, 2854 mg of Mal-Ac-C3 (2.47 mmol) and 173 mg of 20% wt palladium hydroxide (0.25 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 carbon solid was filtered using a Buchner funnel. Excess ethanol was removed by vacuum distillation to obtain a white solid. Further purification on a chromatographic column yielded a white solid as Mal-Ac-C4, with a yield of 84%. Its 1H NMR spectrum is shown below. Figure 21 As shown.

[0063] (6) Preparation of t-Bu-DOTA-Urea-Mal-Ac: In a 100 mL round-bottom flask, 244 mg of t-Bu-DOTA-C2 (0.4 mmol) and triphosgene (0.16 mmol) were added in dichloromethane (10 mL), and 0.1 mL of triethylamine (0.52 mmol) was added dropwise. After stirring at 0 °C for 2 h, 400 mg of Mal-Ac-C4 (0.38 mmol) and 0.12 mL of triethylamine (0.85 mmol) were added dropwise. After stirring at 0 °C for 3 h, the reaction was completed. 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 white solid. The white solid was purified by silica gel column chromatography to obtain the product t-Bu-DOTA-Urea-Mal-Ac, with a yield of 48%. Its 1H NMR spectrum is shown below. Figure 22 As shown.

[0064] (7) Preparation of t-Bu-DOTA-Urea-Mal: In a 100 mL round-bottom flask, add 531 mg of t-Bu-DOTA-Urea-Mal-Ac (0.32 mmol) and 0.1 mL of sodium methoxide methanol solution dissolved in methanol (25 mL). Stir the reaction at room temperature for 10 h. After mass spectrometry monitoring, distill the solvent under reduced pressure to obtain a white solid. Purify the white solid by reversed-phase silica gel column chromatography to obtain the product t-Bu-DOTA-Urea-Mal with a yield of 79%. Its mass spectrum is shown below. Figure 23 As shown.

[0065] (8) Preparation of DOTA-Urea-Mal: In a 50 mL round-bottom flask, add 309 mg of t-Bu-DOTA-Urea-Mal (0.25 mmol) and 10 mL of a mixed solution of trifluoroacetic acid and water (volume ratio 98:1). Stir at room temperature for 12 h. 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-Urea-Mal with a yield of 82%. Its 1H NMR spectrum is shown below. Figure 24 As shown, its mass spectrum is as follows: Figure 25 As shown.

[0066] (9) Preparation 68 Ga-DOTA-Urea-Mal: eluted directly from the germanium-gallium generator using 0.05 mol / L HCl. 68 GaCl3 solution, according to DOTA-Urea-Mal and 68GaCl3 was added to DOTA-Urea-Mal at a molar ratio of 1.1:1, and the mixture was incubated at 85℃ for 15 min. The solution was then filtered through a 0.22 μm microporous membrane to obtain... 68 Ga-DOTA-Urea-Mal, with a yield of 93%, is the gallium-based radioactive contrast agent covalently linked to the maltotriose and chelating groups.

[0067] Comparative Example 1

[0068] This comparative example provides a gallium-based radioactive contrast agent based on an open-ring maltotriose. 68 Ga-DOTA-PEG3-Mal has the following structure:

[0069] Its synthetic route diagram is as follows Figure 26 As shown, the process includes the following steps: First, the cyclic polydentate ligand is modified by nucleophilic substitution and then linked with a flexible PEG3 long chain. Next, a reductive amination is performed between the primary amine at the linker end group and the aldehyde group of maltotriose to form a single unit. Then, trifluoroacetic acid is added to remove the protecting groups on the polydentate ligand. Finally, [the process is described in the original text]. 68 Ga was chelated to obtain the final product.

[0070] Establishment of rat infection model: 1×10⁻⁶ mmol / L was injected intramuscularly into the thigh. 8 A bacterial myositis model was established in rats by injecting Staphylococcus aureus and Escherichia coli into the left and right hind legs, respectively. An aseptic inflammation model was established by injecting silica nanoparticles (SiO2NPs, 100 nm, 20 mg / mL). -1 The virus was introduced into the leg muscles of rats. After 24 hours, images of these models were acquired, and tissue sections were prepared to assess the success of the infection model.

[0071] Gallium-based radioactive contrast agents are used for targeted detection of bacterial infections in vivo. After establishing a rat model of bacterial myositis, rats were anesthetized by intraperitoneal injection of 0.1 mL of chloral hydrate (10 wt%). 68 To observe and estimate the bacterial targeting ability of the contrast agent, Ga-DOTA-PEG3-Mal was injected into the leg muscles of three mice with similar physical signs, specifically Staphylococcus aureus cells, Escherichia coli cells, and Pseudomonas aeruginosa cells. PET scans were performed, and images were collected at the desired time points (30, 60, and 120 min). Then... 68 To observe and estimate the bacterial targeting ability of the contrast agent, Staphylococcus aureus cells, Escherichia coli cells, and Pseudomonas aeruginosa cells of Ga-DOTA-Urea-Mal were injected into the leg muscles of three mice with similar physical signs. PET scans were performed, and images were collected at the required time points (30, 60, and 120 min).

[0072] Experiments have found that, 68 Ga-DOTA-PEG3-Mal imaging retention is relatively weak (e.g.) Figure 27 (as shown) 68 The Ga-DOTA-Urea-Mal group can be clearly imaged. (e.g.) Figure 28 (As shown) This invention prepares... 68 Ga-DOTA-Urea-Mal has a stronger ability to target bacterial imaging.

[0073] 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 gallium-based radioactive contrast agent covalently linked to a chelating group and a glycosylated maltotriose, characterized in that, It has the structure shown in Equation I or Equation II: Formula I; Formula II.

2. The method for preparing the gallium-based radioactive contrast agent covalently linked to the glycosylated maltotriose and chelating group as described in claim 1, characterized in that, When the structure is as shown in Formula I, the preparation method includes the following steps: Maltotriose, acetic anhydride, and the first solvent were mixed and subjected to the first reaction of the sugar fraction to obtain Mal-Ac. Mal-Ac, hydrazine acetate, and a second solvent are mixed to carry out the second reaction of the sugar moiety, yielding Mal-Ac-OH; Mal-Ac-OH, trichloroacetonitrile, alkali, and a third solvent are mixed to carry out the third reaction of the sugar moiety, yielding Mal-Ac-Tca. Mal-Ac-Tca, triethylene glycol monobenzyl ether, TBSOTf, and a third solvent were mixed and subjected to the fourth reaction of the sugar moiety to obtain Mal-Ac-F1. Mal-Ac-F1, palladium on carbon, and the fourth solvent were mixed and subjected to the fifth reaction of the sugar moiety under a hydrogen atmosphere to obtain Mal-Ac-F2. Mal-Ac-F2, DMSO, oxalyl chloride, base, and third solvent were mixed and subjected to the sixth reaction of the sugar moiety to obtain Mal-Ac-F3. Tetraethylene glycol monoamine, benzyl chloroformate, base, and a third solvent were mixed and subjected to the first reaction of the polydentate ligand to obtain half-chain F4. Half-chain F4, triphenylphosphine, carbon tetrabromide, and a third solvent are mixed and subjected to a second reaction of the polydentate ligand portion to obtain half-chain F5; Half-chain F5, base, polydentate ligand, and fifth solvent are mixed and subjected to the third reaction of the polydentate ligand portion to obtain t-Bu-DOTA-F5; t-Bu-DOTA-F5, palladium on carbon, and a fourth solvent were mixed and subjected to a fourth reaction of the polydentate ligand in a hydrogen atmosphere to obtain t-Bu-DOTA-F6. t-Bu-DOTA-F6, Mal-Ac-F3, and the sixth solvent were mixed, and then sodium cyanoborohydride was added to carry out the first overall reaction to obtain t-Bu-DOTA-F-Mal-Ac; t-Bu-DOTA-F-Mal-Ac, sodium methoxide methanol solution, and the sixth solvent were mixed and subjected to the overall second reaction to obtain t-Bu-DOTA-F-Mal; A mixed solution of t-Bu-DOTA-F-Mal, trifluoroacetic acid, and water was mixed to carry out the overall third reaction to obtain DOTA-F-Mal; DOTA-F-Mal, 68 GaCl3 and hydrochloric acid solution were mixed and chelated to obtain the structure shown in Formula I. When the structure is as shown in Formula II, the preparation method includes the following steps: N-Cbz-4-piperidinemethanol, triphenylphosphine, carbon tetrabromide, and a third solvent were mixed and subjected to the fifth reaction of the polydentate ligand moiety to obtain the cyclic chain C1. The ring chain C1, the base, the polydentate ligand, and the fifth solvent were mixed and the sixth reaction of the polydentate ligand part was carried out to obtain t-Bu-DOTA-C1; t-Bu-DOTA-C1, palladium on carbon, and the fourth solvent were mixed and subjected to the seventh reaction of the polydentate ligand part under a hydrogen atmosphere to obtain t-Bu-DOTA-C2. Mal-Ac-Tca, N-Cbz-4-piperidinemethanol, TBSOTf, and a third solvent were mixed and subjected to the seventh reaction of the sugar moiety to obtain Mal-Ac-C3. Mal-Ac-C3, palladium hydroxide, and the fourth solvent were mixed and subjected to the eighth reaction of the sugar moiety under a hydrogen atmosphere to obtain Mal-Ac-C4. Mal-Ac-C4, triphosgene, t-Bu-DOTA-C2, base, and third solvent are mixed and subjected to an overall fourth reaction to obtain t-Bu-DOTA-Urea-Mal-Ac; t-Bu-DOTA-Urea-Mal-Ac, sodium methoxide methanol solution, and the sixth solvent are mixed and subjected to the overall fifth reaction to obtain t-Bu-DOTA-Urea-Mal; A mixed solution of t-Bu-DOTA-Urea-Mal, trifluoroacetic acid, and water was mixed and subjected to the sixth overall reaction to obtain DOTA-Urea-Mal; DOTA-Urea-Mal, 68 When GaCl3 and hydrochloric acid solution are mixed, a chelation reaction is carried out to obtain the structure shown in Formula II.

3. The method for preparing a gallium-based radioactive contrast agent covalently linked to a chelating group by glycosylation-modified maltotriose according to claim 2, characterized in that, The molar ratio of maltotriose to acetic anhydride is 0.5~1:15~20; the conditions for the first reaction of the sugar fraction are: temperature 90℃, time 2~3h; The molar ratio of Mal-Ac to hydrazine acetate is 0.5~1:1.5~2; the conditions for the second reaction of the sugar fraction are: temperature 50℃, time 1~2h; The molar ratio of Mal-Ac-OH, trichloroacetonitrile, and alkali is 1~2:5~10:1~5; the conditions for the third reaction of the sugar part are: temperature 25℃, time 10~16h; The molar ratio of Mal-Ac-Tca, triethylene glycol monobenzyl ether, and TBSOTf is 0.5~2:0.5~3:0.1~0.3; the conditions for the fourth reaction of the sugar fraction are: temperature 0℃, time 3~5h; The ratio of Mal-Ac-F1 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the fifth reaction of the sugar part are: temperature 25℃, time 10~20 h, and pressure 0.1 MPa. The molar ratio of Mal-Ac-F2, DMSO, oxaloyl chloride, and alkali is 1~1.2:8~10:5~6:5~6; the conditions for the sixth reaction of the sugar part are: temperature -78℃ and time 2~3h.

4. The method for preparing the gallium-based radioactive contrast agent covalently linked to the glycosylated maltotriose and chelating group according to claim 3, characterized in that, The molar ratio of the tetraethylene glycol monoamine, benzyl chloroformate, and base is 1~6:1~6:0.5~1; the conditions for the first reaction of the polydentate ligand are: temperature 0℃, time 3~5h; The molar ratio of the half-chain F4, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7; the conditions for the second reaction of the polydentate ligand are: temperature 0℃ and time 10~12h. The molar ratio of F5, 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 of the polydentate ligand are: temperature 80~100℃, time 8~10h; The ratio of t-Bu-DOTA-F5 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the fourth reaction of the polydentate ligand are: temperature 25℃, time 18~24 h, and pressure 0.1 MPa.

5. The method for preparing a gallium-based radioactive contrast agent covalently linked to a chelating group by glycosylation-modified maltotriose according to claim 4, characterized in that, The molar ratio of t-Bu-DOTA-F6, Mal-Ac-F3, and sodium cyanoborohydride is 0.1~2:0.1~2:3~5; the conditions for the overall first reaction are: temperature 25℃ and time 8~10h. The ratio of t-Bu-DOTA-F-Mal-Ac to sodium methoxide methanol solution is 0.1~2 mmol:0.1 mL; the conditions for the overall second reaction are: temperature 25℃, time 8~10 h; The volume ratio of the t-Bu-DOTA-F-Mal, trifluoroacetic acid and water mixture is 0.1~2 mmol:10 mL; the volume ratio of trifluoroacetic acid to water in the trifluoroacetic acid and water mixture is 98:1; the conditions for the overall third reaction are: temperature 25℃ and time 10~12 h.

6. The method for preparing a gallium-based radioactive contrast agent covalently linked to a chelating group by glycosylation-modified maltotriose according to claim 5, characterized in that, The molar ratio of N-Cbz-4-piperidinemethanol, triphenylphosphine, and carbon tetrabromide is 4~6:5~7:5~7; the conditions for the fifth reaction of the polydentate ligand part are: temperature 0℃ and time 10~12h. The molar ratio of the cyclic chain C1, the base, and the polydentate ligand is 1~3:3~7:1~3; the polydentate ligand is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tritert-butyl ester; the conditions for the sixth reaction of the polydentate ligand part are: temperature 80~100℃, time 8~10h; The ratio of t-Bu-DOTA-C1 to palladium on carbon is 1~5 mmol: 200~300 mg; the conditions for the seventh reaction of the polydentate ligand are: temperature 25℃, time 18~24 h, and pressure 0.1 MPa.

7. The method for preparing a gallium-based radioactive contrast agent covalently linked to a chelating group by glycosylation-modified maltotriose according to claim 6, characterized in that, The molar ratio of Mal-Ac-Tca, N-Cbz-4-piperidinemethanol, and TBSOTf is 1~2:1~3:0.1~0.5; the conditions for the seventh reaction of the sugar part are: temperature 0℃, time 3~5h; The ratio of Mal-Ac-C3 to palladium hydroxide is 1~5 mmol: 200~300 mg; the conditions for the eighth reaction of the sugar part are: temperature 25℃, time 10~12 h, and pressure 0.1 MPa.

8. The method for preparing a gallium-based radioactive contrast agent covalently linked to a chelating group by glycosylation-modified maltotriose according to claim 7, characterized in that, The molar ratio of Mal-Ac-C4, triphosgene, t-Bu-DOTA-C2, and base is 1~2:0.3~0.7:1~2:2~3.0; the conditions for the overall fourth reaction are: temperature 0℃, time 4~6h; The ratio of t-Bu-DOTA-Urea-Mal-Ac to sodium methoxide methanol solution is 0.1~2 mmol:0.1 mL; the conditions for the overall fifth reaction are: temperature 25℃, time 8~10 h; The volume ratio of the t-Bu-DOTA-Urea-Mal, trifluoroacetic acid and water mixture is 0.1~2 mmol:10 mL; the volume ratio of trifluoroacetic acid to water in the trifluoroacetic acid and water mixture is 98:1; the conditions for the overall sixth reaction are: temperature 25℃ and time 10~12 h.

9. The method for preparing a gallium-based radioactive contrast agent covalently linked to a chelating group by glycosylation-modified maltotriose according to claim 8, characterized in that, The DOTA-F-Mal, 68 The molar ratio of GaCl3 is 1~1.2:1; the DOTA-Urea-Mal, 68 The molar ratio of GaCl3 is 1~1.2:1; the temperature of the chelation reaction is 80~90℃; and the time of the chelation reaction is 10~30min.

10. The application of the gallium-based radiocontrast agent covalently linked to the glycosylated maltotriose and chelating group as described in claim 1, or the gallium-based radiocontrast agent covalently linked to the glycosylated maltotriose and chelating group prepared by any one of claims 2 to 9, in radionuclide medical imaging.

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