CN116082368A - Gadolinium complex and preparation method and application thereof - Google Patents

Gadolinium complex and preparation method and application thereof Download PDF

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Publication number
CN116082368A
CN116082368A CN202310039328.3A CN202310039328A CN116082368A CN 116082368 A CN116082368 A CN 116082368A CN 202310039328 A CN202310039328 A CN 202310039328A CN 116082368 A CN116082368 A CN 116082368A
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China
Prior art keywords
gadolinium
pentaacetic acid
gadolinium complex
diethylenetriamine pentaacetic
acid derivative
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唐晓亮
茹嘉喜
陈小芬
刘伟生
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Lanzhou University
Wenzhou Medical University
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Lanzhou University
Wenzhou Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA

Abstract

The invention belongs to the technical field of coordination chemistry, and particularly relates to a gadolinium complex and a preparation method and application thereof. The gadolinium complex provided by the invention has a structure shown in a formula I, and is prepared from a central metal ion (Gd 3+ ) The diethylene triamine pentaacetic acid derivative ligand and coordinated water molecules are formed, the relaxation efficiency is high, and the longitudinal relaxation rate (r 1 ) 7.98mM ‑1 s ‑1 . Moreover, the relaxation rate of the gadolinium complex in 4.5 percent BSA solution can reach 26.49mM ‑1 s ‑1 。

Description

Gadolinium complex and preparation method and application thereof
The present application claims priority from chinese patent office, application number CN202211155891.9, entitled "gadolinium complex and method for its preparation and use", filed in month 22 of 2022, 9, the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the technical field of coordination chemistry, and particularly relates to a gadolinium complex and a preparation method and application thereof.
Background
Magnetic resonance imaging (magnetic resonance imaging, MRI) is a medical imaging technique that visualizes human structures and functions. Clinically, some diseases can be clearly diagnosed only by sweeping. However, some lesions cannot be found and clearly diagnosed during the panning, and enhanced scanning is necessary, namely, by injecting a nuclear magnetic contrast agent (MRI contrast agent), the image contrast of normal tissues and lesion tissues is improved, organ functions or blood flow conditions are displayed, and important references are provided for early diagnosis of diseases and pre-operation curative effect evaluation. The development of new MRI nmr techniques remains an active area of research and many new nuclear magnetic contrast agents are currently in preclinical studies or have entered clinical trials (chem. Rev.2019,119, 957-1057).
Currently, T is approved for clinical use 1 The nuclear magnetic contrast agent is mainly based on gadolinium complex. According to its structure, it is mainly divided into two categories: (1) Gadolinium complex contrast agents with diethylenetriamine pentaacetic acid (DTPA) and derivatives thereof as a framework, such as Gd-DTPA (Magnevist), gd-DTPA-BMA (Omniscan), gd-BOPTA (MultiHance) and the like; (2) Gadolinium complex contrast agents such as Gd-DOTA (dotrem), gd-BTDO3A (Gadovist) with 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) and derivatives thereof as a backbone. Although these contrast agents have been in clinical use for many years, providing great assistance in the diagnosis of disease, most of the contrast agents currently in clinical use have insufficient relaxation efficiency (3-5 mM -1 s -1 )。
Disclosure of Invention
In view of the above, the invention provides a gadolinium complex, a preparation method and application thereof, and the gadolinium complex provided by the invention has higher relaxation efficiency.
In order to achieve the above object, the present invention provides a gadolinium complex having a structure represented by formula I:
Figure BDA0004050489910000021
the invention also provides a preparation method of the gadolinium complex, which comprises the following steps:
carrying out amidation reaction on 5-amino phenanthroline and diethylenetriamine pentaacetic acid dianhydride in a polar aprotic solvent to obtain diethylenetriamine pentaacetic acid derivative with a structure shown in a formula II;
mixing diethylene triamine pentaacetic acid derivative, inorganic gadolinium salt and aqueous solution of methanol, and carrying out coordination reaction to obtain the gadolinium complex;
Figure BDA0004050489910000022
preferably, the polar aprotic solvent comprises N, N-dimethylformamide and/or acetonitrile.
Preferably, the ratio of the number of moles of the 5-aminophthaline to the sum of the number of moles of the 5-aminophthaline and the number of moles of the diethylenetriamine pentaacetic acid dianhydride is 0.3 to 0.8:1.
preferably, the amidation reaction is carried out at a temperature of 50-70 ℃ for 12-24 hours.
Preferably, the ratio of the number of moles of the diethylenetriamine pentaacetic acid derivative to the sum of the number of moles of gadolinium element in the diethylenetriamine pentaacetic acid derivative and the inorganic gadolinium salt is 0.3 to 0.8:1.
preferably, the inorganic gadolinium salt comprises one or more of gadolinium nitrate, gadolinium chloride and gadolinium perchlorate.
Preferably, the temperature of the coordination reaction is 50-60 ℃ and the time is 12-24 h.
The invention also provides application of the gadolinium complex or the gadolinium complex prepared by the preparation method in preparation of contrast agents.
The invention provides a gadolinium complex which has a structure shown in a formula I. The gadolinium complex provided by the invention consists of a central metal ion (Gd 3+ ) The diethylene triamine pentaacetic acid derivative ligand and coordinated water molecules are formed, the relaxation efficiency is high, and the longitudinal relaxation rate (r 1 ) 7.98mM -1 s -1 . Moreover, the relaxation rate of the gadolinium complex in 4.5 percent BSA solution can reach 26.49mM -1 s -1 。
Drawings
FIG. 1 is a mass spectrum of diethylenetriamine pentaacetic acid derivative of example 1;
FIG. 2 is a hydrogen spectrum of diethylenetriamine pentaacetic acid derivative of example 1;
FIG. 3 is a carbon spectrum of diethylenetriamine pentaacetic acid derivative of example 1;
FIG. 4 is a mass spectrum of gadolinium complex of example 1;
FIG. 5 is the inverse of the measured longitudinal relaxation time (1/T) of the gadolinium complex of example 1 in aqueous solution under a magnetic field of 1.5T (37 ℃ C.) 1 ) Different Gd concentrations were plotted;
FIG. 6 shows the reciprocal of the longitudinal relaxation time (1/T) measured for the gadolinium complex of example 1 in 4.5% BSA solution under 1.5T magnetic field conditions (37 ℃) 1 ) Different Gd concentrations were plotted;
FIG. 7 is a contrast image of gadolinium complex of example 1 in water and 4.5% BSA solution in vitro.
Detailed Description
The invention provides a gadolinium complex, which has a structure shown in a formula I:
Figure BDA0004050489910000031
the invention also provides a preparation method of the gadolinium complex, which comprises the following steps: carrying out amidation reaction on 5-amino phenanthroline and diethylenetriamine pentaacetic acid dianhydride in a polar aprotic solvent to obtain diethylenetriamine pentaacetic acid derivative with a structure shown in a formula II;
mixing diethylene triamine pentaacetic acid derivative, inorganic gadolinium salt and aqueous solution of methanol, and carrying out coordination reaction to obtain the gadolinium complex;
Figure BDA0004050489910000041
in the present invention, the polar aprotic solvent preferably includes N, N-dimethylformamide and/or acetonitrile, more preferably N, N-dimethylformamide.
The invention carries out amidation reaction on 5-amino phenanthroline and diethylenetriamine pentaacetic acid dianhydride in polar aprotic solvent to obtain the diethylenetriamine pentaacetic acid derivative.
In the present invention, the ratio of the number of moles of the 5-aminophthaline to the sum of the number of moles of the 5-aminophthaline and the number of moles of the diethylenetriamine pentaacetic acid dianhydride is 0.3 to 0.8:1, more preferably 0.6 to 0.7:1.
in the invention, the mass ratio of the 5-amino phenanthroline to the amide organic solvent is preferably 380-400 mg:30mL, more preferably 390g:30mL.
In the present invention, the temperature of the amidation reaction is preferably 50 to 70 ℃, more preferably 55 to 65 ℃, and the time is preferably 12 to 24 hours, more preferably 20 to 23 hours. In the present invention, the amidation reaction is preferably performed under a protective atmosphere, which is preferably nitrogen or helium, more preferably nitrogen.
In the present invention, the equation for the amidation reaction is:
Figure BDA0004050489910000042
after the amidation reaction, the present invention preferably further includes sequentially filtering, washing and drying the product obtained by the amidation reaction, and the present invention does not specifically limit the filtering, and may employ an operation well known to those skilled in the art. In the present invention, the washing reagent is preferably N, N-dimethylformamide, and the number of times of washing is preferably not less than 1, more preferably not less than 2. In the present invention, the drying is preferably vacuum drying.
After the diethylenetriamine pentaacetic acid derivative is obtained, the diethylenetriamine pentaacetic acid derivative, inorganic gadolinium salt and aqueous solution of methanol are mixed for coordination reaction, and the gadolinium complex is obtained.
In the present invention, the ratio of the number of moles of the diethylenetriamine pentaacetic acid derivative to the sum of the number of moles of gadolinium element in the diethylenetriamine pentaacetic acid derivative and 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 diethylenetriamine pentaacetic acid derivative to the aqueous methanol solution is preferably 0.2 to 0.7g:30 to 80mL, more preferably 0.2 to 0.65g: 30-50 mL.
In the present invention, the temperature of the coordination reaction is preferably 50 to 60 ℃, more preferably 55 to 58 ℃, and the time is preferably 12 to 24 hours, more preferably 20 to 22 hours.
In the present invention, taking rare earth nitrate as an example, the equation of the coordination reaction is:
Figure BDA0004050489910000051
in the present invention, it is preferable that the method further comprises, after the coordination reaction, sequentially filtering, washing and drying the product obtained by the coordination reaction. In the present invention, the filtration is not particularly limited, and may be performed by an operation well known to those skilled in the art. In the present invention, the washing reagent preferably includes N, N-Dimethylformamide (DMF). In the present invention, the drying is preferably vacuum drying.
The invention also provides application of the gadolinium complex or the gadolinium complex prepared by the preparation method in preparation of magnetic resonance imaging contrast agents.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
3.6474g of 5-aminophthaline and 3.3385g of diethylenetriamine pentaacetic acid dianhydride were dissolved in 110mL of DMF, and then amidation reaction was carried out under nitrogen atmosphere at 60℃for 24 hours. After the amidation reaction, the product obtained by the amidation reaction was sequentially filtered, and the precipitate was collected, washed with a small amount of DMF and dried in vacuo to give 6.4g of the diethylenetriamine pentaacetic acid derivative.
200mg of the above diethylenetriamine pentaacetic acid derivative and 122mg of Gd (NO) 3 ) 3 ·6H 2 O and 30mL of methanol aqueous solution are mixed, stirring (coordination reaction) is carried out for 24 hours at a constant temperature under the protection of nitrogen, after the coordination reaction, products obtained by the coordination reaction are sequentially filtered, sediment is collected, and vacuum drying is carried out, thus obtaining 232mg of beige solid (gadolinium complex).
FIGS. 1, 2 and 3 are respectively the mass spectrum (ESI MS) and the hydrogen spectrum of the diethylenetriamine pentaacetic acid derivative obtained in example 1 1 H NMR) and carbon spectrum [ ] 13 C NMR), as can be seen from fig. 2 to 3: the purity of the obtained diethylenetriamine pentaacetic acid derivative is higher, and the structure accords with theoretical prediction.
FIG. 4 is a mass spectrum of a gadolinium complex prepared in example 1, target molecular weight 902.18, and MS (ESI+) M/z 903.1219, which is [ M+H ]] + Peaks, consistent with theoretical expectations.
The relaxation rate of the gadolinium complex prepared in the example 1 in pure water is measured, and the measurement method comprises the following steps: preparing solution with total volume of 1.5mL and concentration of 0.5 by using ultrapure water; 0.3;0.2;0.1;0mM, the solutions were each measured using a bench-top MRI relaxation measurement system (Shanghai atlas science)Equipment limited) to T 1 Weighted imaging, resonance frequency 23.314MHz, magnet strength 1.5T, coil diameter 60mm, magnet temperature 37.00 ℃. Inverse of the measured longitudinal relaxation time (1/T 1 ) Different Gd concentrations were plotted to give the results shown in fig. 5. From the above results, the longitudinal relaxation rate (r) 1 ) 7.98mM -1 s -1 Transverse relaxation rate (r 2 ) 8.39mM -1 s -1 R is 2 /r 1 1.05. The results show that: the gadolinium complex has high relaxation efficiency, and has longitudinal relaxation rate (r 1 ) For clinical use Gd-DTPA (3.3 mM -1 s -1 ) Is 2.4 times as large as the above.
The relaxation rate of the gadolinium complex prepared in example 1 in 4.5% BSA solution was measured. The testing method comprises the following steps: preparing a solution of gadolinium complex with total volume of 1.5mL and concentration of 0.4 by using 4.5% BSA; 0.24;0.16;0.08; t was performed on the above sample with a bench-top MRI relaxation measurement system (manufactured by Shanghai atlas science device Co., ltd.) at 0mM 1 Weighted imaging, resonance frequency 23.314MHz, magnet strength 1.5T, coil diameter 60mm, magnet temperature 37.00 ℃. Inverse of the measured longitudinal relaxation time (1/T 1 ) Different Gd concentrations were plotted to give the results shown in fig. 6. From the above results, the longitudinal relaxation rate (r) 1 ) 26.49mM -1 s -1 Transverse relaxation rate (r 2 ) 46.69mM -1 s -1 R is 2 /r 1 1.76. The results show that: the gadolinium complex has a relaxation rate of 26.49mM in 4.5% BSA solution under a magnetic field of 1.5T -1 s -1 Is 8.0 times of Gd-DTPA. This significantly improved relaxation rate will provide a higher imaging contrast for magnetic resonance imaging, and may further help to reduce the toxic side effects of gadolinium complex contrast agents by reducing the contrast agent dosage.
The gadolinium complex prepared in example 1 was tested in vitro magnetic resonance imaging in water and 4.5% BSA solution, as shown in FIG. 7. According to contrastComparison of figures, the higher the gadolinium complex concentration, the brighter the image, representing a typical T, in either water or 4.5% bsa solution 1 Contrast agent characteristics. And, the brightness of the image in the 4.5% BSA solution is higher than that in the water solution under the same concentration condition, which shows that the gadolinium complex has better imaging effect in the 4.5% BSA solution.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (9)

1. A gadolinium complex characterized by having the structure of formula I:
Figure FDA0004050489900000011
2. a process for the preparation of a gadolinium complex according to claim 1, comprising the steps of:
carrying out amidation reaction on 5-amino phenanthroline and diethylenetriamine pentaacetic acid dianhydride in a polar aprotic solvent to obtain diethylenetriamine pentaacetic acid derivative with a structure shown in a formula II;
mixing the diethylenetriamine pentaacetic acid derivative, inorganic gadolinium salt and methanol aqueous solution, and carrying out coordination reaction to obtain the gadolinium complex;
Figure FDA0004050489900000012
3. the method of claim 2, wherein the polar aprotic solvent comprises N, N-dimethylformamide and/or acetonitrile.
4. The production method according to claim 2, wherein the ratio of the number of moles of the 5-aminophthaline to the sum of the number of moles of the 5-aminophthaline and the number of moles of the diethylenetriamine pentaacetic acid dianhydride is 0.3 to 0.8:1.
5. the process according to claim 2 or 4, wherein the amidation reaction is carried out at a temperature of 50 to 70℃for a period of 12 to 24 hours.
6. The production method according to claim 2, wherein the ratio of the number of moles of the diethylenetriamine pentaacetic acid derivative to the sum of the number of moles of gadolinium element in the diethylenetriamine pentaacetic acid derivative and the inorganic gadolinium salt is 0.3 to 0.8:1.
7. the method of preparation of claim 2 or 6, wherein the inorganic gadolinium salt comprises one or more of gadolinium nitrate, gadolinium chloride and gadolinium perchlorate.
8. The method according to claim 2 or 6, wherein the temperature of the coordination reaction is 50 to 60 ℃ for 12 to 24 hours.
9. Use of a gadolinium complex as claimed in claim 1 or prepared by a method as claimed in any one of claims 2 to 8 in the preparation of a magnetic resonance imaging contrast agent.
CN202310039328.3A 2022-09-22 2023-01-13 Gadolinium complex and preparation method and application thereof Pending CN116082368A (en)

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CN202211155891 2022-09-22

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