A gadolinium complex, its preparation method and application

Abstract

The present invention belongs to the technical field of coordination chemistry, and particularly relates to a gadolinium complex and its preparation method and application. The gadolinium complex provided by the present invention has the structure shown in Formula I and is composed of a central metal ion (Gd 3+ ), a ligand of diethylenetriaminepentaacetic acid derivative, and coordinated water molecules, and has a relatively high relaxation efficiency. Under the condition of a 1.5T magnetic field, the longitudinal relaxation rate (r 1 ) is 7.98 mM ‑1 s ‑1 . Moreover, in a 4.5% BSA solution, the relaxation rate of this gadolinium complex can reach 26.49 mM ‑1 s ‑1 .

Description

[0001] This application claims the priority of a Chinese patent application titled "A Gadolinium Complex and Its Preparation Method and Application", with the application number CN202211155891.9, filed with the Chinese Patent Office on September 22, 2022. The entire content thereof is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the technical field of coordination chemistry, and particularly relates to a gadolinium complex and its preparation method and application. Background Art

[0003] Magnetic resonance imaging (MRI) is a medical imaging technique for visualizing the structure and function of the human body. Clinically, some diseases can be clearly diagnosed by plain scan. However, there are still some lesions that cannot be detected and clearly diagnosed by plain scan and must undergo enhanced scanning, that is, by injecting an MRI contrast agent to improve the image contrast between normal tissues and diseased tissues, display organ function or blood flow conditions, and provide important references for the early diagnosis of diseases and the evaluation of the curative effect before surgery. The development of new MRI nuclear magnetic resonance imaging is still an active research field, and many new MRI contrast agents are currently in preclinical research or have entered clinical trials (Chem. Rev. 2019, 119, 957 - 1057).

[0004] Currently, the clinically approved T 1 -type MRI contrast agents are mainly gadolinium complex-based contrast agents. According to their structures, they are mainly divided into two categories: (1) gadolinium complex contrast agents with diethylenetriaminepentaacetic acid (DTPA) and its derivatives as the backbone, such as Gd-DTPA (Magnevist), Gd-DTPA-BMA (Omniscan), Gd-BOPTA (MultiHance), etc.; (2) gadolinium complex contrast agents with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives as the backbone, such as Gd-DOTA (Dotarem), Gd-BTDO3A (Gadovist). Although these contrast agents have been clinically used for many years and have provided great help for the diagnosis of diseases, most of the contrast agents currently used clinically have insufficient relaxation efficiency (3 - 5 mM -1 s -1 ). Summary of the Invention

[0005] In view of this, the present invention provides a gadolinium complex and its preparation method and application, and the gadolinium complex provided by the present invention has a high relaxation efficiency.

[0006] To achieve the above-mentioned invention object, the present invention provides a gadolinium complex having the structure shown in Formula I:

[0007]

[0008] The present invention also provides a preparation method of the above-mentioned gadolinium complex, comprising the following steps:

[0009] Performing an amidation reaction on 5-amino-phenanthroline and diethylenetriaminepentaacetic dianhydride in a polar aprotic solvent to obtain a diethylenetriaminepentaacetic acid derivative having the structure shown in Formula II;

[0010] Mixing the diethylenetriaminepentaacetic acid derivative, an inorganic gadolinium salt and an aqueous methanol solution, and performing a coordination reaction to obtain the gadolinium complex;

[0011]

[0012] Preferably, the polar aprotic solvent includes N,N-dimethylformamide and / or acetonitrile.

[0013] Preferably, the molar ratio of 5-amino-phenanthroline to the sum of the molar amounts of 5-amino-phenanthroline and diethylenetriaminepentaacetic dianhydride is 0.3 to 0.8:1.

[0014] Preferably, the temperature of the amidation reaction is 50 to 70 °C and the time is 12 to 24 h.

[0015] Preferably, the molar ratio of the diethylenetriaminepentaacetic acid derivative to the sum of the molar amounts of the diethylenetriaminepentaacetic acid derivative and the gadolinium element in the inorganic gadolinium salt is 0.3 to 0.8:1.

[0016] Preferably, the inorganic gadolinium salt includes one or more of gadolinium nitrate, gadolinium chloride and gadolinium perchlorate.

[0017] Preferably, the temperature of the coordination reaction is 50 to 60 °C and the time is 12 to 24 h.

[0018] The present invention also provides an application of the above-mentioned gadolinium complex or the gadolinium complex prepared by the above-mentioned preparation method in the preparation of a contrast agent.

[0019] The present invention provides a gadolinium complex having the structure shown in Formula I. The gadolinium complex provided by the present invention is composed of a central metal ion (Gd 3+ ), a diethylenetriaminepentaacetic acid derivative ligand and coordinated water molecules, and has a relatively high relaxation efficiency. Under the condition of a 1.5 T magnetic field, the longitudinal relaxation rate (r 1 ) is 7.98 mM -1 s -1Moreover, in a 4.5% BSA solution, the relaxation rate of this gadolinium complex can reach 26.49 mM -1 s -1 。 BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the mass spectrum of the diethylenetriaminepentaacetic acid derivative of Example 1;

[0021] Figure 2 is the hydrogen spectrum of the diethylenetriaminepentaacetic acid derivative of Example 1;

[0022] Figure 3 is the carbon spectrum of the diethylenetriaminepentaacetic acid derivative of Example 1;

[0023] Figure 4 is the mass spectrum of the gadolinium complex of Example 1;

[0024] Figure 5 is a plot of the reciprocal of the longitudinal relaxation time (1 / T 1 ) measured for different Gd concentrations of the gadolinium complex of Example 1 in aqueous solution under a 1.5 T magnetic field condition (37 °C);

[0025] Figure 6 is a plot of the reciprocal of the longitudinal relaxation time (1 / T 1 ) measured for different Gd concentrations of the gadolinium complex of Example 1 in a 4.5% BSA solution under a 1.5 T magnetic field condition (37 °C);

[0026] Figure 7 is an in vitro contrast image of the gadolinium complex of Example 1 in water and a 4.5% BSA solution. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention provides a gadolinium complex having the structure shown in Formula I:

[0028]

[0029] The present invention also provides a method for preparing the above-mentioned gadolinium complex, comprising the following steps: subjecting 5-amino-phenanthroline and diethylenetriaminepentaacetic anhydride to an amidation reaction in a polar aprotic solvent to obtain a diethylenetriaminepentaacetic acid derivative having the structure shown in Formula II;

[0030] mixing the diethylenetriaminepentaacetic acid derivative, an inorganic gadolinium salt, and an aqueous methanol solution to carry out a coordination reaction to obtain the gadolinium complex;

[0031]

[0032] In the present invention, the polar aprotic solvent preferably includes N,N-dimethylformamide and / or acetonitrile, more preferably N,N-dimethylformamide.

[0033] In the present invention, 5-amino-1,10-phenanthroline and diethylenetriaminepentaacetic dianhydride are subjected to an amidation reaction in a polar aprotic solvent to obtain the diethylenetriaminepentaacetic acid derivative.

[0034] In the present invention, the ratio of the number of moles of 5-amino-1,10-phenanthroline to the sum of the number of moles of 5-amino-1,10-phenanthroline and diethylenetriaminepentaacetic dianhydride is 0.3 to 0.8:1, more preferably 0.6 to 0.7:1.

[0035] In the present invention, the mass ratio of 5-amino-1,10-phenanthroline to the volume of the amide organic solvent is preferably 380 to 400 mg:30 mL, more preferably 390 g:30 mL.

[0036] In the present invention, the temperature of the amidation reaction is preferably 50 to 70 °C, more preferably 55 to 65 °C, and the time is preferably 12 to 24 h, more preferably 20 to 23 h. In the present invention, the amidation reaction is preferably carried out under a protective atmosphere, and the protective atmosphere is preferably nitrogen or helium, more preferably nitrogen.

[0037] In the present invention, the equation of the amidation reaction is:

[0038]

[0039] After the amidation reaction, the present invention preferably further includes filtering, washing, and drying the product obtained from the amidation reaction in sequence. The present invention does not make specific limitations on the filtration, and the operations well-known to those skilled in the art can be adopted. In the present invention, the washing reagent is preferably N,N-dimethylformamide, the number of washing times is preferably ≥1, more preferably 2. In the present invention, the drying is preferably vacuum drying.

[0040] After obtaining the diethylenetriaminepentaacetic acid derivative, the present invention mixes the diethylenetriaminepentaacetic acid derivative, an inorganic gadolinium salt, and an aqueous methanol solution, and conducts a coordination reaction to obtain the gadolinium complex.

[0041] In the present invention, the ratio of the number of moles of the diethylenetriaminepentaacetic acid derivative to the sum of the number of moles of the diethylenetriaminepentaacetic acid derivative and the gadolinium element in the inorganic gadolinium salt is preferably 0.3 to 0.8:1, more preferably 0.5:1. In the present invention, the mass ratio of the diethylenetriaminepentaacetic acid derivative to the volume of the aqueous methanol solution is preferably 0.2 to 0.7 g:30 to 80 mL, more preferably 0.2 to 0.65 g:30 to 50 mL.

[0042] In the present invention, the temperature of the coordination reaction is preferably 50 - 60 °C, more preferably 55 - 58 °C, and the time is preferably 12 - 24 h, more preferably 20 - 22 h.

[0043] In the present invention, taking rare earth nitrate as an example, the equation of the coordination reaction is:

[0044]

[0045] In the present invention, after the coordination reaction, it preferably further includes filtering, washing, and drying the product obtained from the coordination reaction in sequence. In the present invention, no specific limitation is imposed on the filtration, and the operations well-known to those skilled in the art can be adopted. In the present invention, the washing reagent preferably includes N,N-dimethylformamide (DMF). In the present invention, the drying is preferably vacuum drying.

[0046] The present invention also provides the use of the gadolinium complex described above or the gadolinium complex prepared by the preparation method described above in the preparation of a magnetic resonance imaging contrast agent.

[0047] Next, the technical solutions in the present invention will be clearly and completely described in conjunction with the examples in the present invention. Obviously, the described examples are only a part of the examples of the present invention, rather than all the examples. All other examples obtained by those of ordinary skill in the art based on the examples in the present invention without making creative efforts shall fall within the protection scope of the present invention.

[0048] Example 1

[0049] Dissolve 3.6474 g of 5-amino-phenanthroline and 3.3385 g of diethylenetriaminepentaacetic dianhydride in 110 mL of DMF, and then carry out an amidation reaction at 60 °C for 24 h under a nitrogen atmosphere. After the amidation reaction, filter the product obtained from the amidation reaction in sequence, collect the precipitate, wash it with a small amount of DMF, and vacuum dry it to obtain 6.4 g of the diethylenetriaminepentaacetic acid derivative.

[0050] Take 200 mg of the above diethylenetriaminepentaacetic acid derivative and 122 mg of Gd(NO 3 ) 3 ·6H 2 O and mix with 30 mL of a methanol aqueous solution. Under nitrogen protection, carry out constant-temperature stirring (coordination reaction) at 50 °C for 24 h. After the coordination reaction, filter the product obtained from the coordination reaction in sequence, collect the precipitate, and vacuum dry it to obtain 232 mg of a light yellow solid (gadolinium complex).

[0051] Figure 1 、 Figure 2 and Figure 3The mass spectrum (ESIMS), proton NMR spectrum ( 1 1H NMR), and carbon NMR spectrum ( 13 13C NMR) of the diethylenetriaminepentaacetic acid derivative obtained in Example 1, respectively. It can be seen from Figures 2 - 3 that the obtained diethylenetriaminepentaacetic acid derivative has a high purity and its structure is consistent with the theoretical prediction.

[0052] Figure 4 The mass spectrum of the gadolinium complex prepared in Example 1. The target molecular weight is 902.18, while the experimentally measured MS(ESI+) m / z: 903.1219, which is the + [M+H]+ peak, consistent with the theoretical expectation.

[0053] In the present invention, the relaxation rate of the gadolinium complex prepared in Example 1 in pure water was measured. The test method is as follows: The gadolinium complex was prepared with ultrapure water to form a solution with a total volume of 1.5 mL and concentrations of 0.5; 0.3; 0.2; 0.1; 0 mM, respectively. Then, the above solutions were subjected to T 1 -weighted imaging using a benchtop nuclear magnetic resonance imaging relaxation measurement system (produced by Shanghai Huantong Science and Education Equipment Co., Ltd.). The resonance frequency was 23.314 MHz, the magnet strength was 1.5 T, the coil diameter was 60 mm, and the magnet temperature was 37.00 °C. The reciprocal of the measured longitudinal relaxation time (1 / T 1 ) was plotted against different Gd concentrations to obtain the results shown in Figure 5 . According to the above results, the longitudinal relaxation rate (r 1 ) of the gadolinium complex can be calculated to be 7.98 mM -1 -1 -1 , and the transverse relaxation rate (r 2 ) was 8.39 mM -1 -1 -1 , and the ratio of r 2 / r 1 was 1.05. The results show that the gadolinium complex has a high relaxation efficiency. Under the condition of a 1.5 T magnetic field, the longitudinal relaxation rate (r 1 ) is 2.4 times that of clinically used Gd-DTPA (3.3 mM -1 -1 -1 ).

[0054] In the present invention, the relaxation rate of the gadolinium complex prepared in Example 1 in a 4.5% BSA solution was measured. The test method is as follows: The gadolinium complex was prepared with 4.5% BSA to form a solution with a total volume of 1.5 mL and concentrations of 0.4; 0.24; 0.16; 0.08; 0 mM, respectively. The above samples were subjected to T 1Weighted imaging, resonance frequency 23.314 MHz, magnet strength 1.5 T, coil diameter 60 mm, magnet temperature 37.00 °C. The reciprocal of the measured longitudinal relaxation time (1 / T 1 ) is plotted against different Gd concentrations to obtain the Figure 6 results shown. According to the above results, the longitudinal relaxation rate (r 1 ) of this gadolinium complex can be calculated to be 26.49 mM -1 s -1 , and the transverse relaxation rate (r 2 ) is 46.69 mM -1 s -1 , and r 2 / r 1 is 1.76. The results show that: under the condition of a 1.5 T magnetic field, in a 4.5% BSA solution, the relaxation rate of this gadolinium complex increases to 26.49 mM -1 s -1 , which is 8.0 times that of Gd-DTPA. This significantly increased relaxation rate will provide higher imaging contrast for magnetic resonance imaging, and by reducing the dosage of the contrast agent, it can also further help reduce the toxic and side effects of the gadolinium complex contrast agent.

[0055] In vitro magnetic resonance imaging of the gadolinium complex prepared in Example 1 was tested in water and 4.5% BSA solution, as shown in Figure 7 . According to the contrast images, whether in water or in a 4.5% BSA solution, the higher the concentration of the gadolinium complex, the brighter the image, showing typical T 1 contrast agent characteristics. Moreover, under the same concentration conditions, the brightness of the image in the 4.5% BSA solution is higher than that in the aqueous solution, indicating that the gadolinium complex has a better imaging effect in the 4.5% BSA solution.

[0056] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A gadolinium complex, characterized in that it has the structure shown in Formula I:

2. A method for preparing the gadolinium complex according to Claim 1, characterized in that it comprises the following steps: Performing an amidation reaction on 5 - aminophenanthroline and diethylenetriaminepentaacetic dianhydride in a polar aprotic solvent to obtain a diethylenetriaminepentaacetic acid derivative having the structure shown in Formula II; Mixing the diethylenetriaminepentaacetic acid derivative, an inorganic gadolinium salt, and an aqueous methanol solution, and performing a coordination reaction to obtain the gadolinium complex; 3. According to the preparation method described in Claim 2, characterized in that the polar aprotic solvent includes N,N - dimethylformamide and / or acetonitrile.

4. According to the preparation method described in Claim 2, characterized in that the ratio of the molar amount of 5 - aminophenanthroline to the sum of the molar amounts of 5 - aminophenanthroline and diethylenetriaminepentaacetic dianhydride is 0.3 - 0.8:

1.

5. According to the preparation method described in Claim 2 or 4, characterized in that the temperature of the amidation reaction is 50 - 70 °C, and the time is 12 - 24 h.

6. According to the preparation method described in Claim 2, characterized in that the ratio of the molar amount of the diethylenetriaminepentaacetic acid derivative to the sum of the molar amounts of the diethylenetriaminepentaacetic acid derivative and the gadolinium element in the inorganic gadolinium salt is 0.3 - 0.8:

1.

7. According to the preparation method described in Claim 2 or 6, characterized in that the inorganic gadolinium salt includes one or more of gadolinium nitrate, gadolinium chloride, and gadolinium perchlorate.

8. According to the preparation method described in Claim 2 or 6, characterized in that the temperature of the coordination reaction is 50 - 60 °C, and the time is 12 - 24 h.

9. Use of the gadolinium complex according to Claim 1 or the gadolinium complex prepared by the preparation method described in any one of Claims 2 - 8 in the preparation of a magnetic resonance imaging contrast agent.

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