Gadolinium chelates and their preparation and use

Abstract

The present invention discloses a gadolinium chelate, which is a complex formed by gadolinium ion and a polymer through chelation, and its preparation method and use, and the polymer includes any one or more copolymers or mixtures of carboxylic acid-containing polymers, amino group-containing polymers, hydroxyl group-containing polymers, polyester polymers, polyether polymers, polyamide polymers, proteins, polypeptides, and polysaccharides. The present invention forms a gadolinium chelate, which is a water-soluble polymer drug, by chelation between gadolinium ion and a polymer, and improves the longitudinal relaxation rate r1, reduces the r2 / r1 ratio, has good water solubility, high stability, and at the same time, can present good imaging effect in a short time and shorten the MRI time.

Description

[Technical Field]

[0001] The present invention relates to the field of biomedical materials technology, and in particular to gadolinium chelates and their preparation and use. [Background technology]

[0002] Magnetic resonance imaging (MRI) can detect minute or specific lesions with high sensitivity, reducing the rate of missed or misdiagnosed lesions. MRI contrast agents, as chemical agents that can improve the quality of MRI images, have become an important supplement to MRI examinations. T1 (longitudinal relaxation time) and T2 (transverse relaxation time) are important tissue characteristic parameters in MRI. When paramagnetic substances (e.g., gadolinium, iron, manganese, etc.) in a sample are close to hydrogen atoms in resonance, they can effectively change the magnetic field in which protons are located, shortening the tissue relaxation times T1 and T2. This enhances the signal in the image enhancement region and improves the tissue signal-to-noise ratio (ΔSNR). Using contrast agents to enhance MRI tissue contrast is an exploitation of this property. The clinical application of MRI technology has been greatly expanded by the addition of MRI contrast agents, making them of great value in the field of clinical diagnosis.

[0003] Clinically, T1-weighted imaging, T2-weighted imaging and T2 *Weighted imaging is the most commonly used imaging sequence for tissue imaging. MRI contrast agents are divided into two types: positive contrast agents (T1 contrast agents) and negative contrast agents (T2 contrast agents) according to their enhancement characteristics. T2 contrast agents tend to produce dark images and are prone to magnetic susceptibility artifacts, while T1 contrast agents have a more pronounced effect of enhancing the brightness of image lesions, making them significantly advantageous for soft tissue examinations. Relaxivity is one of the important evaluation indices for evaluating the performance of MRI contrast agents (longitudinal relaxivity r1, transverse relaxivity r2). Generally, a larger r1 value and a smaller r2 / r1 value are more favorable for T1-weighted imaging, resulting in a higher signal-to-noise ratio for the same dose. Conversely, a larger r2 value and a larger r2 / r1 value are more favorable for T2-weighted imaging. Currently available T1 contrast agents are primarily gadolinium-based contrast agents, including cyclic and linear chelates. Cyclic chelates include: TIFF0007735413000001.tif54166

[0004] Both linear and macrocyclic gadolinium-based contrast agents cause trace amounts of gadolinium to deposit in the brain and other tissues. In clinical scans, large doses of gadolinium-based contrast agents are used to enhance the contrast between normal and diseased tissues, which may pose potential risks such as nephrotoxicity in certain patient groups. To achieve more sensitive lesion detection and to consider dose limitations, the amount of contrast agent currently used in clinical diagnosis is typically in the gram range. Reducing the amount of contrast agent used is a highly desirable method for improving the image signal-to-noise ratio, since high-relaxity compounds can be detected at lower doses or form greater contrast with low-relaxity compounds at equivalent doses, resulting in better imaging effects. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention aims to solve at least one of the technical problems in the prior art by providing a gadolinium chelate that has an extremely high longitudinal relaxation rate r1 and an extremely low r2 / r1 ratio, is water-soluble, highly stable, and exhibits excellent imaging effects in a short time, thereby shortening the MRI time.

[0006] The present invention also provides methods for preparing and using said gadolinium chelates. [Means for solving the problem]

[0007] Specifically, the technical solutions adopted by the present invention are as follows: According to a first aspect of the present invention, there is provided a gadolinium chelate, which is a complex formed by chelation between a gadolinium ion and a polymer, wherein the polymer comprises a copolymer or mixture of one or more of a carboxylic acid-containing polymer, an amino group-containing polymer, a hydroxyl group-containing polymer, a polyester-based polymer, a polyether-based polymer, a polyamide-based polymer, a protein, a polypeptide, and a polysaccharide.

[0008] The gadolinium chelate according to the first aspect of the present invention has at least the following beneficial effects:

[0009] The present invention uses the chelating action of gadolinium ions and polymers to form a water-soluble polymer drug, gadolinium chelate. Compared with the prior art, the network crosslinked structure or core-shell structure formed by coating gadolinium ions or gadolinium oxide with polymers improves the longitudinal relaxation rate r1, reduces the r2 / r1 ratio, has good water solubility, and is highly stable. At the same time, it can provide good imaging effects in a short time and shorten the MRI time.

[0010] In some embodiments of the present invention, the molecular weight of the polymer is 1,000 to 1,000,000, and an appropriate polymer can be selected according to specific circumstances.

[0011] In some embodiments of the present invention, the carboxylic acid-containing polymer comprises one or more of polyacrylic acid, polymaleic acid, polymethacrylic acid, poly(2-ethylacrylic acid), polyglutamic acid, and polyaspartic acid.

[0012] In some embodiments of the present invention, the amino group-containing polymer comprises one or more of polylysine, polyarginine, polyhistidine, and polyethyleneimine.

[0013] In some embodiments of the present invention, the hydroxyl group-containing polymer includes one or more of polyserine, polythreonine, polytyrosine, and polyvinyl alcohol.

[0014] In some embodiments of the present invention, the polyester-based polymer comprises one or more of polylactic acid, polyglycolic acid, polycaprolactone, and poly2-hydroxyethyl methacrylate.

[0015] In some embodiments of the present invention, the polyether-based polymer comprises any one or more of polyethylene glycol, polypropylene glycol, and polytetramethylene glycol.

[0016] In some embodiments of the present invention, the polyamide-based polymer includes any one or more of polyglutamine, polyasparagine, polyacrylamide, and polymethacrylamide.

[0017] In some embodiments of the present invention, the protein comprises any one or more of a human-derived protein, an animal protein, a plant protein, and a recombinant protein.

[0018] In some embodiments of the invention, the polypeptide comprises any one or more of an RGD peptide, a β-amyloid polypeptide.

[0019] In some embodiments of the invention, the polysaccharide comprises any one or more of chitosan, sodium alginate.

[0020] In some embodiments of the invention, the gadolinium ions are trivalent gadolinium ions.

[0021] According to a second aspect of the present invention, A method for preparing the gadolinium chelate is provided, which comprises the step of chelating gadolinium ions with a polymer to obtain the gadolinium chelate.

[0022] More specifically, a gadolinium ion solution is mixed with a polymer solution to cause a chelate reaction, thereby obtaining a gadolinium chelate.

[0023] In some embodiments of the present invention, the concentration of the gadolinium ion solution is 10 to 1000 mM, preferably 50 to 250 mM.

[0024] In some embodiments of the present invention, the concentration of the polymer solution is 0.1 to 50 mg / mL, preferably 2.0 to 10 mg / mL.

[0025] In some embodiments of the present invention, the volume ratio of the polymer solution to the gadolinium ion solution is 1 to 1000:1, preferably 25 to 50:1.

[0026] In some embodiments of the present invention, the gadolinium ion solution and the polymer solution are both aqueous solutions.

[0027] In some embodiments of the present invention, the gadolinium ion solution comprises a mixed solution of any one or more of gadolinium nitrate, gadolinium fluoride, gadolinium chloride, gadolinium bromide, and gadolinium iodide, and is preferably a gadolinium nitrate or gadolinium chloride solution.

[0028] In some embodiments of the present invention, the pH of the reaction solution after mixing the gadolinium ion solution and the polymer solution is 2.0 to 12.0, and preferably about 10.

[0029] In some embodiments of the present invention, the reaction temperature is 25 to 100°C, preferably 100°C.

[0030] In some embodiments of the present invention, the reaction time is >10 min, preferably 30 to 120 min.

[0031] According to a third aspect of the present invention there is provided the use of the gadolinium chelate as defined above in the preparation of a magnetic resonance imaging contrast agent (MRI contrast agent).

[0032] Compared with the prior art, the present invention has the following beneficial effects: The gadolinium chelates of the present invention have extremely high r1 values ​​(>80 mM -1 s -1 ,1.5T;≧ 29mM -1 s -1 , 3.0T) and is a commonly used MRI contrast agent in clinical practice (r1 = 4-7 mM -1 s -1 , 1.5T), and in related technology, MRI contrast agents coated with gadolinium oxide using high molecular weight polymers (>50 mM -1 s -1 , 1.5T) and a polymer network microsphere contrast agent (14mM -1 s -1 ,3.0T) and has an extremely low r2 / r1 ratio (r2 / r1<2.0, 1.5T). As a novel MRI contrast agent, the gadolinium chelate of the present invention not only significantly improves the signal-to-noise ratio of MRI images, but also has the advantages of excellent water solubility, extremely low gadolinium (Ψ) ion release rate within 7 days, stability and effectiveness, etc., and can achieve rapid imaging with low doses and shorten imaging times, making it highly practical. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 is an MRI relaxation rate diagram of Gd-PAA in Example 1. [Figure 2] 1 shows the gadolinium ion release rate of Gd-PAA in Example 1 for 1 to 7 days under the condition of pH=7.4. [Figure 3] 1 shows T1-weighted MRI images of Gd-PAA, the commercially available contrast agent Gadavist, and pure water in Example 1, along with their corresponding MRI signal intensities. [Figure 4] 1 is an infrared absorption spectrum of Gd-PAA prepared in Example 1. [Figure 5] FIG. 1 is an MRI image of a tumor-bearing mouse injected with Gd-PAA in Example 1. [Figure 6] FIG. 10 is a diagram showing the relaxation rate of Gd-PASP in Example 2. [Figure 7] 1 shows the gadolinium ion release rate of Gd-PASP in Example 2 for 1 to 7 days under the condition of pH=7.4. [Figure 8] 1 shows T1-weighted MRI images of Gd-PASP, the commercially available contrast agent Gadavist, and pure water in Example 2, along with their corresponding MRI signal intensities. [Figure 9] FIG. 10 is a relaxation rate diagram of Gd-HPMA in Example 3. [Figure 10] FIG. 10 is a diagram showing the relaxation rate of Gd-PMAA in Example 4. [Figure 11] FIG. 10 is a diagram showing the relaxation rate of Gd-PEAA in Example 5. [Figure 12] FIG. 10 is a graph showing the relaxation rate of Gd-γ-PGA in Example 6. [Figure 13] FIG. 10 is a diagram showing the relaxation rate of Gd-ε-PL in Example 7. [Figure 14] FIG. 10 is a relaxation rate diagram of Gd-PLR in Example 8. [Figure 15] FIG. 10 is a diagram showing the relaxation rate of Gd-PLH in Example 9. [Figure 16] FIG. 10 is a diagram showing the relaxation rate of Gd-PEI in Example 10. [Figure 17] FIG. 11 is a diagram showing the relaxation rate of Gd-PSer in Example 11. [Figure 18] FIG. 10 is a diagram showing the relaxation rate of Gd-PThr in Example 12. [Figure 19] FIG. 13 is a diagram showing the relaxation rate of Gd-PTyr in Example 13. [Figure 20] FIG. 10 is a relaxation rate diagram of Gd-PVA in Example 14. [Figure 21] FIG. 10 is a diagram showing the relaxation rate of Gd-PLA in Example 15. [Figure 22] FIG. 10 is a diagram showing the relaxation rate of Gd-PGA in Example 16. [Figure 23] FIG. 10 is a diagram showing the relaxation rate of Gd-PCL in Example 17. [Figure 24] FIG. 10 is a relaxation rate diagram of Gd-PHEMA in Example 18. [Figure 25] FIG. 10 is a diagram showing the relaxation rate of Gd-PEG in Example 19. [Figure 26] FIG. 10 is a diagram showing the relaxation rate of Gd-PPG in Example 20. [Figure 27] FIG. 10 is a relaxation rate diagram of Gd-PTMG in Example 21. [Figure 28] FIG. 10 is a relaxation rate diagram of Gd-PolyQ in Example 22. [Figure 29] FIG. 10 is a diagram showing the relaxivity of Gd-PHEA in Example 23. [Figure 30] FIG. 10 is a relaxation rate diagram of Gd-PAM in Example 24. [Figure 31] FIG. 10 is a relaxation rate diagram of Gd-PMAM in Example 25. [Figure 32] FIG. 10 is a diagram showing the relaxation rate of Gd-HSA in Example 26. [Figure 33] FIG. 10 is a relaxation rate diagram of Gd-BSA in Example 27. [Figure 34] FIG. 10 is a diagram showing the relaxation rate of Gd-RGD in Example 28. [Figure 35] FIG. 10 is a graph showing the relaxation rate of Gd-Aβ in Example 29. [Figure 36] FIG. 10 is a relaxation rate diagram of Gd-CS in Example 30. [Figure 37] FIG. 10 is a relaxation rate diagram of Gd-SA in Example 31. [Figure 38] FIG. 10 is a relaxation rate diagram of Gd-PAA-PLA in Example 32. [Figure 39] FIG. 10 is a relaxation rate diagram of Gd-PGA-PEG in Example 33. [Figure 40] FIG. 10 is a relaxation rate diagram of Gd-PAA / PASP in Example 34. [Figure 41] FIG. 10 is a relaxation rate diagram of Gd-γ-PGA / PASP in Example 35. DETAILED DESCRIPTION OF THE INVENTION

[0034] The technical solution of the present invention will be further described below with reference to specific examples.

[0035] Example 1 Preparation of gadolinium chelate (Gd-PAA) Polyacrylic acid (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PAA.

[0036] The samples prepared in Example 1 were characterized and tested for performance. The gadolinium recovery rate was calculated for the samples prepared in Example 1. A rate higher than 90% indicates good chelating effect and high raw material utilization. The samples prepared in Example 1, the commercially available contrast agents Magnevist and Gadavist, and gadolinium nitrate solution were each prepared into aqueous solutions of at least five different concentrations. In vitro imaging was performed using 1.5T, 3.0T clinical MRI systems, and a 7.0T small animal MRI system, and the longitudinal and transverse relaxation times (T1, T2) were measured. The longitudinal and transverse relaxation rates (r1, r2) were calculated using the following formula (where c is the concentration of the magnetic substance in the contrast agent, T is the relaxation time, and i = 1 or 2), and the results are shown in Table 1.

[0037] [Number 1] TIFF0007735413000002.tif13166

[0038] [Table 1]

[0039] Specifically, FIG. 1 shows a relaxation rate diagram when the sample Gd-PAA in Example 1 is used as an MRI contrast agent (three parallel tests were performed using three samples, Gd-PAA-1, Gd-PAA-2, and Gd-PAA-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The longitudinal relaxivity of the gadolinium chelate Gd-PAA was 56.23 ± 1.69 mM in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and was clearly higher than the extremely toxic free gadolinium ion solution. In addition, a 1.5T MRI scan system test showed that the r1 value of Gd-PAA was 82.76 ± 0.81 mM -1 s-1 The MRI contrast effect was particularly remarkable, as it had an extremely low r2 / r1 ratio (1.12±0.00). Figure 2 shows the release of gadolinium (Ψ) ions from sample Gd-PAA at pH 7.4 for 1 to 7 days. Sample Gd-PAA was hardly released (<0.2%), demonstrating the high stability of the sample from Example 1 when used as an MRI contrast agent.

[0040] Integrating the r1 value, r2 / r1 ratio, and gadolinium ion release rate in Table 1, and using the sample Gd-PAA as a representative example, the T1-weighted MRI images of Gd-PAA-a, the commercial contrast agent Gadavist, and pure water under a 7.0 T magnetic field are shown in Figure 3. (a) TR = 300 ms, TE = 6.5 ms; (b) TR = 100 ms, TE = 6.5 ms; (c) Relative MRI signal intensities of Gd-PAA, Gadavist, and pure water, ****p<0.0001. The results showed that the MRI signal intensity of Gd-PAA was significantly higher than that of the commercial contrast agent Gadavist.

[0041] Referring to Figure 4, the infrared absorption spectrum of a representative sample, Gd-PAA, is shown. -1 The strong and broad absorption peak of polyacrylic acid at 3432 cm is the OH stretching vibration peak, while the OH stretching vibration peak of the sample Gd-PAA is at 3432 cm. -1 The absorption peak narrows and becomes weaker, and the OH and hydrogen bonds at this point are broken and the Gd 3+ Polyacrylic acid reacts with 1571 cm -1 and 1409cm -1 The antisymmetric and symmetric stretching vibration absorption peaks of the carboxyl group appeared at 1717 cm. -1 A new C=O stretching vibration absorption peak appeared, indicating that the oxygen in the carboxyl group of polyacrylic acid was coordinated with a gadolinium ion, proving the formation of the gadolinium chelate Gd-PAA.

[0042] Figure 5 shows MRI images taken at different time points after tail vein injection of Gd-PAA chelate (5 mg / kg) into tumor-bearing mice. (a) MRI image before tail vein injection, (b) MRI image 15 minutes after tail vein injection, (c) MRI image 30 minutes after tail vein injection, and (d) MRI image 45 minutes after Gd-PAA chelate injection. The results showed that the MRI signal at the tumor site was strongest 30 minutes after intravenous injection. This indicates that this polymeric chelate not only significantly improved the imaging contrast of tumor tissue, but also allowed for relatively short imaging times, making it suitable for clinical use.

[0043] Example 2 Preparation of gadolinium chelate (Gd-PASP) Polyaspartic acid (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PASP.

[0044] The sample prepared in Example 2 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 2 was higher than 90%, and the utilization rate of the raw material was high. The sample prepared in Example 2 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system and a 7.0T MRI system, respectively, to measure the longitudinal relaxation time and transverse relaxation time (T1, T2). The calculated longitudinal relaxation rate and transverse relaxation rate (r 1、 r2) The results are shown in Table 2.

[0045] [Table 2]

[0046] Specifically, Figure 6 shows the relaxation rate diagram for the sample Gd-PASP in Example 2 used as an MRI contrast agent (three parallel experiments were performed using three samples, Gd-PASP-1, Gd-PASP-2, and Gd-PASP-3), and shows the relaxation rate diagram for the MRI contrast agent (1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 56.70 ± 1.34 mM for the gadolinium chelate Gd-PASP in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0047] Figure 7 shows the gadolinium ion release profile of the Gd-PASP sample at pH 7.4 for 1 to 7 days. The Gd-PASP sample showed almost no release (<0.1%), demonstrating its excellent stability when used as an MRI contrast agent.

[0048] Figure 8 shows T1-weighted MRI images and corresponding MRI relative signal intensities of Gd-PASP, the commercially available contrast agent Gadavist, and pure water. The measurement magnetic field was 7.0 T (Bruker, PharmaScan 70 / 16US). Here, (a) TR = 300 ms, TE = 6.5 ms, (b) TR = 100 ms, TE = 6.5 ms, and (c) relative MRI signal intensities of Gd-PASP, Gadavist, and pure water. ****p<0.0001. The results showed that the MRI signal intensity of Gd-PASP was significantly higher than that of Gadavist.

[0049] Example 3 Preparation of gadolinium chelate (Gd-HPMA) Polymaleic acid (M wA 40 mL solution (H = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-HPMA.

[0050] The sample prepared in Example 3 was subjected to characterization and performance testing. The sample prepared in Example 3 had a high gadolinium recovery rate and a high utilization rate of the raw material. The sample prepared in Example 3 was dissolved in at least five different concentrations of aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2). The calculated longitudinal and transverse relaxation rates (r1, r2) are shown in Table 3.

[0051] [Table 3]

[0052] Specifically, FIG. 9 shows a relaxation rate diagram for the sample Gd-HPMA in Example 3 used as an MRI contrast agent (three parallel tests were performed using three samples, Gd-HPMA-1, Gd-HPMA-2, and Gd-HPMA-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 60.86 ± 1.65 mM for the gadolinium chelate Gd-HPMA in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0053] Example 4 Preparation of gadolinium chelate (Gd-PMAA) Polymethacrylic acid (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PMAA.

[0054] The sample prepared in Example 4 was subjected to characterization and performance testing. The sample prepared in Example 4 had a high gadolinium recovery rate and a high utilization rate of the raw material. The sample prepared in Example 4 was dissolved in at least five different concentrations of aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2). The calculated longitudinal and transverse relaxation rates (r1, r2) are shown in Table 4.

[0055] [Table 4]

[0056] Specifically, FIG. 10 shows a relaxation rate diagram when the sample Gd-PMAA in Example 4 is used as an MRI contrast agent (three parallel tests were performed using three samples Gd-PMAA-1, Gd-PMAA-2, and Gd-PMAA-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 54.63 ± 1.11 mM for the gadolinium chelate Gd-PMAPA in a 3.0T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0057] Example 5 Preparation of gadolinium chelate (Gd-PEAA) Poly(2-ethyl acrylic acid) (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PEAA.

[0058] The sample prepared in Example 5 was subjected to characterization and performance testing. The sample prepared in Example 5 had a high gadolinium recovery rate and a high utilization rate of the raw material. The sample prepared in Example 5 was prepared in aqueous solution at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal relaxation time (T1, T2). The calculated longitudinal relaxation rate and transverse relaxation rate (r1, r2) are shown in Table 5.

[0059] [Table 5]

[0060] Specifically, FIG. 11 shows a relaxation rate diagram when the sample Gd-PEAA in Example 5 was used as an MRI contrast agent (three parallel tests were performed using three portions of the samples Gd-PEAA-1, Gd-PEAA-2, and Gd-PEAA-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 53.13 ± 0.64 mM for the gadolinium chelate Gd-PEAA in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s-1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0061] Example 6 Preparation of gadolinium chelate (Gd-γ-PGA) Polyglutamic acid (M w A 40 mL solution (γ = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-γ-PGA.

[0062] The sample prepared in Example 6 was subjected to characterization and performance testing. The sample prepared in Example 6 had a high gadolinium recovery rate and a high utilization rate of the raw material. The sample prepared in Example 6 was dissolved in at least five different concentrations in aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2). The calculated longitudinal and transverse relaxation rates (r1, r2) are shown in Table 6.

[0063] [Table 6]

[0064] Specifically, FIG. 12 shows a relaxation rate diagram when the sample Gd-γ-PGA in Example 6 is used as an MRI contrast agent (three parallel tests were performed using three samples, Gd-γ-PGA-1, Gd-γ-PGA-2, and Gd-γ-PGA-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T iThe relaxation rate (i = 1 or 2) was 45.59 ± 1.23 mM for the gadolinium chelate Gd-γ-PGA in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0065] Example 7 Preparation of gadolinium chelate (Gd-ε-PL) Polylysine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was named Gd-ε-PL.

[0066] The sample prepared in Example 7 was subjected to characterization and performance testing. The sample prepared in Example 7 had a high gadolinium recovery rate and a high utilization rate of the raw material. The sample prepared in Example 7 was dissolved in at least five different concentrations of aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2). The longitudinal and transverse relaxation rates (r1, r2) calculated as the results are shown in Table 7.

[0067] [Table 7]

[0068] Specifically, Figure 13 shows the relaxation rate diagram when the sample Gd-ε-PL in Example 7 was used as an MRI contrast agent (three parallel tests were performed using three samples Gd-ε-PL-1, Gd-ε-PL-2, and Gd-ε-PL-3), and shows the relaxation rate diagram of 1 / Ti The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 41.61 ± 1.20 mM for the gadolinium chelate Gd-ε-PL in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0069] Example 8 Preparation of gadolinium chelate (Gd-PLR) Polyarginine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PLR.

[0070] The sample prepared in Example 8 was subjected to characterization and performance testing. The sample prepared in Example 8 had a high gadolinium recovery rate and a high utilization rate of raw materials. The sample prepared in Example 8 was dissolved in at least five different concentrations of aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal relaxation time and transverse relaxation time (T1, T2). The longitudinal relaxation rate and transverse relaxation rate (r1, r2) were finally calculated and the results are shown in Table 8.

[0071] [Table 8]

[0072] Specifically, FIG. 14 shows a relaxation rate diagram when the sample Gd-PLR in Example 8 was used as an MRI contrast agent (three parallel tests were performed using three samples Gd-PLR-1, Gd-PLR-2, and Gd-PLR-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 38.90 ± 0.78 mM for the gadolinium chelate Gd-PLR in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0073] Example 9 Preparation of gadolinium chelate (Gd-PLH) Polyhistidine (M) at a concentration of 4.0 mg / mL w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PLH.

[0074] The sample prepared in Example 9 was subjected to characterization and performance testing. The sample prepared in Example 9 had a high gadolinium recovery rate and a high utilization rate of raw materials. The sample prepared in Example 9 was dissolved in at least five different aqueous solutions of different concentrations and subjected to in vitro imaging using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2). The longitudinal and transverse relaxation rates (r1, r2) calculated as the results are shown in Table 9.

[0075] [Table 9]

[0076] Specifically, Figure 15 shows the relaxation rate diagram when the sample Gd-PLH in Example 9 was used as an MRI contrast agent (three parallel tests were performed using three samples Gd-PLH-1, Gd-PLH-2, and Gd-PLH-3), and shows the relaxation rate diagram of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 45.46 ± 0.95 mM for the gadolinium chelate Gd-PLH on a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, it was found that the MRI contrast effect was superior.

[0077] Example 10 Preparation of gadolinium chelate (Gd-PEI) Polyethyleneimine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PEI.

[0078] The sample according to Example 10 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 10 was higher than 90%, and the utilization rate of the raw material was high. The sample prepared in Example 10 was dissolved in at least five different concentrations of aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal relaxation time and transverse relaxation time (T1, T2). The calculated longitudinal relaxation rate and transverse relaxation rate (r1, r2) results are shown in Table 10.

[0079] [Table 10]

[0080] Specifically, FIG. 16 shows a relaxation rate diagram when the sample Gd-PEI in Example 10 was used as an MRI contrast agent (three parallel tests were performed using three samples, Gd-PEI-1, Gd-PEI-2, and Gd-PEI-3), and shows the relaxation rate of 1 / T i The slope of the fitted line for the relationship that changes with gadolinium concentration is T i The relaxation rate (i = 1 or 2) was 41.09 ± 0.77 mM for the gadolinium chelate Gd-PEI in a 3.0 T clinical MRI scanning system (Philips, Ingenia). -1 s -1 The r1 value of commercially available gadolinium-based contrast agents (r1 = 4 to 7 mM) -1 s -1 ) and significantly higher than the highly toxic free gadolinium ion solution, while the r2 / r1 ratio was relatively low, demonstrating a superior MRI contrast effect.

[0081] Example 11 Preparation of gadolinium chelate (Gd-PSer) Polyserine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was named Gd-PSer.

[0082] The sample prepared in Example 11 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 11 was 88.3%, indicating high utilization of the raw material. The sample prepared in Example 11 was prepared in aqueous solution at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PSer-1, Gd-PSer-2, and Gd-PSer-3). As shown in Figure 17, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PSer was 50.45 ± 1.28 mM. -1 s -1 , r2 value is 85.90±1.80mM -1 s -1 The r2 / r1 ratio was found to be 1.70 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0083] Example 12 Preparation of gadolinium chelate (Gd-PThr) Polythreonine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was named Gd-PThr.

[0084] The sample prepared in Example 12 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 12 was 88.3%, indicating high utilization of the raw material. The sample prepared in Example 12 was prepared in at least five different concentrations in aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PThr-1, Gd-PThr-2, and Gd-PThr-3). As shown in Figure 18, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PThr in a 3.0T MRI scanning system, which is 48.21 ± 0.96 mM. -1 s -1 , r2 value is 81.42±1.68mM -1 s -1 The r2 / r1 ratio was found to be 1.69 ± 0.00. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0085] Example 13 Preparation of gadolinium chelate (Gd-PTyr) Polytyrosine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was named Gd-PTyr.

[0086] The sample prepared in Example 13 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 13 was 88.3%, indicating high utilization of the raw material. The sample prepared in Example 13 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PTyr-1, Gd-PTyr-2, and Gd-PTyr-3). As shown in Figure 19, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PTyr in a 3.0T MRI scanning system, which is 45.31 ± 1.42 mM. -1 s -1 , r2 value is 78.51±1.61mM -1 s -1 The r2 / r1 ratio was found to be 1.73 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0087] Example 14 Preparation of gadolinium chelate (Gd-PVA) Polyvinyl alcohol (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was named Gd-PVA.

[0088] The sample prepared in Example 14 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 14 was 88.3%, indicating high utilization of the raw material. The sample prepared in Example 14 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PVA-1, Gd-PVA-2, and Gd-PVA-3). As shown in Figure 20, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PVA was 45.05 ± 1.21 mM. -1 s -1 , r2 value is 76.01±1.41mM -1 s -1 The r2 / r1 ratio was found to be 1.69 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0089] Example 15 Preparation of gadolinium chelate (Gd-PLA) Polylactic acid (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PLA.

[0090] The sample prepared in Example 15 was characterized and tested for performance. The gadolinium recovery rate of the sample prepared in Example 15 was 89.3%, indicating high utilization of the raw material. The sample prepared in Example 15 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PLA-1, Gd-PLA-2, and Gd-PLA-3). As shown in Figure 21, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PLA was 40.41 ± 0.90 mM. -1 s -1 , r2 value is 66.25±1.12mM -1 s -1 The r2 / r1 ratio was found to be 1.64 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0091] Example 16 Preparation of gadolinium chelate (Gd-PGA) Polyglycolic acid (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PGA.

[0092] The sample prepared in Example 16 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 16 was 90.9%, indicating high utilization of the raw material. The sample prepared in Example 16 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PGA-1, Gd-PGA-2, and Gd-PGA-3). As shown in Figure 22, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PGA was 43.81 ± 0.98 mM. -1 s -1 , r2 value is 71.22±0.26mM -1 s -1 The r2 / r1 ratio was found to be 1.63 ± 0.03. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0093] Example 17 Preparation of gadolinium chelate (Gd-PCL) Polycaprolactone (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PCL.

[0094] The sample prepared in Example 17 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 17 was 86.6%, indicating high utilization of the raw material. The sample prepared in Example 17 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PCL-1, Gd-PCL-2, and Gd-PCL-3). As shown in Figure 23, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PCL was 42.10 ± 0.65 mM. -1 s -1 , r2 value is 69.42±0.81mM -1 s -1 The r2 / r1 ratio was found to be 1.65 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0095] Example 18 Preparation of gadolinium chelate (Gd-PHEMA) Poly(2-hydroxyethyl methacrylate) (M) at a concentration of 4.0 mg / mL w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PHEMA.

[0096] The sample prepared in Example 18 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 18 was 87.2%, indicating high utilization of the raw material. The sample prepared in Example 18 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PHEMA-1, Gd-PHEMA-2, and Gd-PHEMA-3). As shown in Figure 24, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PHEMA in a 3.0T MRI scanning system. -1 s -1 , r2 value is 67.93±0.83mM -1 s -1 The r2 / r1 ratio was found to be 1.68 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0097] Example 19 Preparation of gadolinium chelate (Gd-PEG) Polyethylene glycol (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PEG.

[0098] The sample prepared in Example 19 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 19 was 94.5%, indicating high utilization of the raw material. The sample prepared in Example 19 was prepared in at least five different concentrations in aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PEG-1, Gd-PEG-2, and Gd-PEG-3). As shown in Figure 25, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the following equation: In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PEG was 34.93 ± 0.50 mM. -1 s -1 , r2 value is 55.53±0.77mM -1 s -1 The r2 / r1 ratio was found to be 1.59 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0099] Example 20 Preparation of gadolinium chelate (Gd-PPG) Polypropylene glycol (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PPG.

[0100] The sample prepared in Example 20 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 20 was 89.2%, indicating high utilization of the raw material. The sample prepared in Example 20 was prepared in aqueous solution at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PPG-1, Gd-PPG-2, and Gd-PPG-3). As shown in Figure 26, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PPG in a 3.0T MRI scanning system. -1 s -1 , r2 value is 57.52±0.90mM -1 s -1 The r2 / r1 ratio was found to be 1.60 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0101] Example 21 Preparation of gadolinium chelate (Gd-PTMG) Polytetramethylene glycol (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PTMG.

[0102] The sample prepared in Example 21 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 21 was 86.4%, indicating high utilization of the raw material. The sample prepared in Example 21 was prepared in aqueous solution at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PTMG-1, Gd-PTMG-2, and Gd-PTMG-3). As shown in Figure 27, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PTMG was 34.47 ± 0.65 mM. -1 s -1 , r2 value is 55.34±0.92mM -1 s -1 The r2 / r1 ratio was found to be 1.61 ± 0.00. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0103] Example 22 Preparation of gadolinium chelate (Gd-PolyQ) Polyglutamine PolyQ (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PolyQ.

[0104] The sample prepared in Example 22 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 22 was 88.7%, indicating high utilization of the raw material. The sample prepared in Example 22 was prepared in aqueous solution at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PolyQ-1, Gd-PolyQ-2, and Gd-PolyQ-3). As shown in Figure 28, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PolyQ in a 3.0T MRI scanning system. -1 s -1 , r2 value is 60.79±0.82mM -1 s -1 The r2 / r1 ratio was found to be 1.56 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0105] Example 23 Preparation of gadolinium chelate (Gd-PHEA) Polyasparagine (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PHEA.

[0106] The sample prepared in Example 23 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 23 was 91.2%, indicating high utilization of the raw material. The sample prepared in Example 23 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PHEA-1, Gd-PHEA-2, and Gd-PHEA-3). As shown in Figure 29, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PHEA in a 3.0T MRI scanning system. -1 s -1 , r2 value is 69.72±0.83mM -1 s -1 The r2 / r1 ratio was found to be 1.50 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0107] Example 24 Preparation of gadolinium chelate (Gd-PAM) Polyacrylamide (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PAM.

[0108] The sample prepared in Example 24 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 24 was 90.6%, demonstrating high raw material utilization. The sample prepared in Example 24 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PAM-1, Gd-PAM-2, and Gd-PAM-3). As shown in Figure 30, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-PAM in a 3.0T MRI scanning system, which is 49.40 ± 0.61 mM. -1 s -1 , r2 value is 78.21±0.63mM -1 s -1 The r2 / r1 ratio was found to be 1.58 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0109] Example 25 Preparation of gadolinium chelate (Gd-PMAM) Polymethacrylamide (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PMAM.

[0110] The sample prepared in Example 25 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 25 was 87.7%, indicating high utilization of the raw material. The sample prepared in Example 25 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PMAM-1, Gd-PMAM-2, and Gd-PMAM-3). As shown in Figure 31, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-PMAM was 42.81 ± 1.19 mM. -1 s -1 , r2 value is 65.14±1.21mM -1 s -1 The r2 / r1 ratio was found to be 1.52 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0111] Example 26 Preparation of gadolinium chelate (Gd-HSA) Human serum albumin (M) at a concentration of 4.0 mg / mL w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-HSA.

[0112] The sample prepared in Example 26 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 26 was 90.2%, indicating high utilization of the raw material. The sample prepared in Example 26 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-HSA-1, Gd-HSA-2, and Gd-HSA-3). As shown in Figure 32, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-HSA in a 3.0T MRI scanning system. -1 s -1 , r2 value is 59.92±1.57mM -1 s -1 The r2 / r1 ratio was found to be 1.74 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0113] Example 27 Preparation of gadolinium chelate (Gd-BSA) Bovine serum albumin (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-BSA.

[0114] The sample prepared in Example 27 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 27 was 85.6%, demonstrating high raw material utilization. The sample prepared in Example 27 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-BSA-1, Gd-BSA-2, and Gd-BSA-3). As shown in Figure 33, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-HSA in a 3.0T MRI scanning system. -1 s -1 , r2 value is 59.92±1.57mM -1 s -1 The r2 / r1 ratio was found to be 1.72 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0115] Example 28 Preparation of gadolinium chelate (Gd-RGD) RGD peptide (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-RGD.

[0116] The sample prepared in Example 28 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 28 was 82.0%, indicating high utilization of the raw material. The sample prepared in Example 28 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-RGD-1, Gd-RGD-2, and Gd-RGD-3). As shown in Figure 34, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the r1 value of the gadolinium chelate Gd-RGD in a 3.0T MRI scanning system, which is 38.81 ± 0.34 mM. -1 s -1 , r2 value is 61.61±0.35mM -1 s -1 The r2 / r1 ratio was found to be 1.59 ± 0.01. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0117] Example 29 Preparation of gadolinium chelate (Gd-Aβ) β-amyloid polypeptide (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-Aβ.

[0118] The sample prepared in Example 29 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 29 was 84.4%, demonstrating high raw material utilization. The sample prepared in Example 29 was prepared in at least five different concentrations in aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-Aβ-1, Gd-Aβ-2, and Gd-Aβ-3). As shown in Figure 35, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is shown in Fig. 1. In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-Aβ was 41.47 ± 1.01 mM. -1 s -1 , r2 value is 64.85±0.64mM -1 s -1 The r2 / r1 ratio was found to be 1.56 ± 0.03. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0119] Example 30 Preparation of gadolinium chelate (Gd-CS) Chitosan (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was named Gd-CS.

[0120] The sample prepared in Example 30 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 30 was 83.6%, indicating high utilization of the raw material. The sample prepared in Example 30 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-CS-1, Gd-CS-2, and Gd-CS-3). As shown in Figure 36, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the following equation: In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-CS was 35.75 ± 1.10 mM. -1 s -1 , r2 value is 60.30±0.72mM -1 s -1 The r2 / r1 ratio was found to be 1.69 ± 0.03. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0121] Example 31 Preparation of gadolinium chelate (Gd-SA) Sodium alginate (M w A 40 mL solution (Gd = 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-SA.

[0122] The sample prepared in Example 31 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 31 was 82.5%, indicating high utilization of the raw material. The sample prepared in Example 31 was prepared in aqueous solution at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-SA-1, Gd-SA-2, and Gd-SA-3). As shown in Figure 37, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) is given by the following equation: In a 3.0T MRI scanning system, the r1 value of the gadolinium chelate Gd-SA was 36.65 ± 0.92 mM. -1 s -1 , r2 value is 60.84±0.66mM -1 s -1 The r2 / r1 ratio was found to be 1.67 ± 0.03. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0123] Example 32 Preparation of gadolinium chelate (Gd-PAA-PLA) Polyacrylic acid-polylactic acid (M w A 40 mL copolymer solution (Gd = 2000) was prepared and heated to reflux at 100°C. 0.8 mL of 125 mM gadolinium nitrate solution was then added to the reaction system, and the reaction was continued at 100°C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PAA-PLA.

[0124] The sample prepared in Example 32 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 32 was 88.6%, indicating high utilization of the raw material. The sample prepared in Example 32 was prepared in at least five different concentrations in aqueous solution, and in vitro imaging was performed using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PAA-PLA-1, Gd-PAA-PLA-2, and Gd-PAA-PLA-3). As shown in Figure 38, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) was 40.63 ± 1.17 mM for the gadolinium chelate Gd-PAA-PLA in a 3.0T MRI scanning system (Philips, Ingenia). -1 s -1 , r2 value is 62.67±0.91mM -1 s -1 The r2 / r1 ratio was found to be 1.54 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0125] Example 33 Preparation of gadolinium chelate (Gd-PGA-PEG) Polyglycolic acid-polyethylene glycol (M w A 40 mL copolymer solution (Gd = 2000) was prepared and heated to reflux at 100°C. 0.8 mL of 125 mM gadolinium nitrate solution was then added to the reaction system, and the reaction was continued at 100°C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PGA-PEG.

[0126] The sample prepared in Example 33 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 33 was 92.3%, indicating high utilization of the raw material. The sample prepared in Example 33 was prepared in at least five different aqueous solutions and subjected to in vitro imaging using a 3.0T clinical MRI system to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PGA-PEG-1, Gd-PGA-PEG-2, and Gd-PGA-PEG-3). As shown in Figure 39, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) was 42.13 ± 1.19 mM for the gadolinium chelate Gd-PGA-PEG in a 3.0T MRI scanning system (Philips, Ingenia). -1 s -1 , r2 value is 63.67±0.56mM -1 s -1 The r2 / r1 ratio was found to be 1.51 ± 0.03. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0127] Example 34 Preparation of gadolinium chelate (Gd-PAA / PASP) Polyacrylic acid / polyaspartic acid (M w A 40 mL mixture (1:1) of the polymers (both 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was designated Gd-PAA / PASP.

[0128] The sample prepared in Example 34 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 34 was 92.9%, indicating high utilization of the raw material. The sample prepared in Example 34 was prepared into aqueous solutions of at least five different concentrations, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-PAA / PASP-1, Gd-PAA / PASP-2, and Gd-PAA / PASP-3). As shown in Figure 40, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) was 45.47 ± 0.82 mM for the gadolinium chelate Gd-PAA / PASP in a 3.0T MRI scanning system (Philips, Ingenia). -1 s -1 , r2 value is 68.18±0.65mM -1 s -1 The r2 / r1 ratio was found to be 1.50 ± 0.02. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0129] Example 35 Preparation of gadolinium chelate (Gd-γ-PGA / PASP) Polyglutamic acid / polyaspartic acid (M w A 40 mL mixture (1:1) of the two polymers (both 2000) was prepared, and the polymer solution was heated to reflux at 100 °C. Next, 0.8 mL of a 125 mM gadolinium nitrate solution was added to the reaction system, and the reaction was continued at 100 °C for 60 minutes under magnetic stirring. After cooling to room temperature, the solution was purified by membrane dialysis, and the final product was Gd-γ-PGA / PASP.

[0130] The sample prepared in Example 35 was subjected to characterization and performance testing. The gadolinium recovery rate of the sample prepared in Example 35 was 82.8%, indicating high utilization of the raw material. The sample prepared in Example 35 was prepared into at least five different aqueous solutions, and in vitro imaging was performed using a 3.0T clinical MRI system (Philips, Ingenia) to measure the longitudinal and transverse relaxation times (T1, T2) (three parallel experiments were performed using three samples, Gd-γ-PGA / PASP-1, Gd-γ-PGA / PASP-2, and Gd-γ-PGA / PASP-3). As shown in Figure 41, the 1 / T i When the relationship between gadolinium concentration and T is plotted, the slope of the fitted line is i The relaxation rate (i = 1 or 2) was 29.47 ± 1.65 mM for the gadolinium chelate Gd-γ-PGA / PASP in a 3.0T MRI scanning system (Philips, Ingenia). -1 s -1 , r2 value is 54.55±2.32mM -1 s -1 The r2 / r1 ratio was found to be 1.85 ± 0.03. The r1 value is comparable to the r1 value of commercially available gadolinium-based contrast agents (r1 = 4-7 mM). -1 s -1 ) and significantly higher than the extremely toxic free gadolinium ion solution, while at the same time having a relatively low r2 / r1 ratio, the MRI contrast effect is superior.

[0131] The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples. Any other changes, modifications, substitutions, combinations and simplifications made without departing from the spirit and principles of the present invention should be considered as equivalent substitution methods, and all fall within the protection scope of the present invention.

Claims

1. A gadolinium chelate is a complex formed by chelation between a gadolinium ion and a polymer, the polymer including a carboxylic acid-containing polymer, or a copolymer or mixture of a carboxylic acid-containing polymer and one or more of an amino group-containing polymer, a hydroxyl group-containing polymer, a polyester-based polymer, a polyether-based polymer, a polyamide-based polymer, a protein, a polypeptide, and a polysaccharide; The gadolinium chelate is r in a 1.5T MRI system １ >80mM －１ s －１ and r in a 3.0T MRI system １ ≧29 mM －１ s －１ and r in a 1.5T MRI system ２ / r １ <2.0 (where r 1 is the longitudinal relaxation rate and r 2 is the transverse relaxation rate). A gadolinium chelate characterized by:

2. 2. The gadolinium chelate according to claim 1, wherein the molecular weight of the polymer is 1,000 to 1,000,000.

3. The gadolinium chelate according to claim 1, wherein the carboxylic acid-containing polymer comprises one or more of polyacrylic acid, polymaleic acid, polymethacrylic acid, poly(2-ethylacrylic acid), polyglutamic acid, and polyaspartic acid.

4. 2. The gadolinium chelate according to claim 1, wherein the amino group-containing polymer comprises one or more of polylysine, polyarginine, polyhistidine, and polyethyleneimine.

5. 2. The gadolinium chelate according to claim 1, wherein the hydroxyl group-containing polymer comprises one or more of polyserine, polythreonine, polytyrosine, and polyvinyl alcohol.

6. 2. The gadolinium chelate according to claim 1, wherein the polyester polymer comprises one or more of polylactic acid, polyglycolic acid, polycaprolactone, and poly2-hydroxyethyl methacrylate.

7. 2. The gadolinium chelate according to claim 1, wherein the polyether-based polymer comprises one or more of polyethylene glycol, polypropylene glycol, and polytetramethylene glycol.

8. The gadolinium chelate according to claim 1, wherein the polyamide-based polymer comprises one or more of polyglutamine, polyasparagine, polyacrylamide, and polymethacrylamide.

9. 2. The gadolinium chelate according to claim 1, wherein the protein comprises one or more of a human-derived protein, an animal protein, a plant protein, and a recombinant protein.

10. 2. The gadolinium chelate according to claim 1, wherein the polypeptide comprises one or more of an RGD peptide and a β-amyloid polypeptide.

11. 2. The gadolinium chelate according to claim 1, wherein the polysaccharide comprises one or more of chitosan and sodium alginate.

12. 12. The method for preparing the gadolinium chelate according to claim 1, further comprising the step of subjecting gadolinium ions to a chelate reaction with a polymer to obtain the gadolinium chelate.

13. Use of a gadolinium chelate according to any one of claims 1 to 11 in the preparation of a magnetic resonance imaging contrast agent.

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