CN110396122B - Nuclear magnetic resonance contrast agent, preparation method and application thereof in tumor diagnosis - Google Patents
Nuclear magnetic resonance contrast agent, preparation method and application thereof in tumor diagnosis Download PDFInfo
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Abstract
The nuclear magnetic resonance contrast agent is shown in a formula I, wherein n is an integer of 1-3; l isAthe-COOH is any one of glycyrrhetinic acid, cholic acid and folic acid, and the compound has the advantages of high relaxation rate, good targeting effect on tumors, particularly liver tumors, and small dosage, and is an effective nuclear magnetic resonance contrast agent for tumor diagnosis.
Description
Technical Field
The invention relates to a nuclear magnetic resonance contrast agent, in particular to a gadolinium metal complex contrast agent of DO3A derivative ligand modified by glycyrrhetinic acid, cholic acid or folic acid, a preparation method thereof and application thereof in nuclear magnetic resonance diagnosis of tumors.
Background
Magnetic Resonance Imaging (MRI) is a technique of generating signals by using the resonance of water molecular hydrogen nuclei in a living body in a magnetic field, and obtaining images through spatial encoding and reconstruction. Compared with conventional imaging examination methods (X-ray, CT, PET, ECT, etc.), MRI shows excellent advantages such as higher spatial resolution, good soft tissue contrast, no ionizing radiation damage, and capability of functional imaging. At present, research on a magnetic resonance imaging technology mainly focuses on two aspects, namely, research on a high-sensitivity magnetic signal molecular probe and improvement of imaging tissue resolution; but rather speeds up the imaging rate. Magnetic Resonance Imaging (MRICA) is one of the research contents of the former, namely, the relaxation time of T1 and T2 of surrounding water protons is shortened, the relaxation rate is accelerated, the image imaging ratio between tissues is improved, and the sensitivity and the specificity of MRI diagnosis are improved.
At present, the commercialized MRI contrast agents applied to clinic mainly comprise 6 kinds, all of which are micromolecular gadolinium chelate with time-sharing Gd-DTPA
Gd-DEPA-BMA as diamide derivative thereof
Gd-DTPA-BMEA
Gd-DOTA
And ligand derivative Gd-DO3A-butrol thereof
Gd-HP-DO3A
The above MRI contrast agents are all extracellular agents, which are non-specifically distributed in vivo, and rapidly leak out of blood vessels and are cleared by the kidney after intravenous injection, so that the dosage required for examination is high, and particularly, for tissue lesions such as liver, spleen and the like and tumor lack of specificity, sometimes for the purpose of diagnosis, the dosage has to be increased, thereby increasing the risk of adverse reactions of the organism.
The drug targeting is to distribute the therapeutic drug selectively to the diseased region, thereby improving the concentration of the diseased drug, increasing the utilization rate of the drug, and simultaneously reducing the toxic and side effects of the drug on normal tissues. In recent years, the research of MRI contrast agents draws on the above ideas, designs and synthesizes water-soluble paramagnetic complexes with tissue specificity, especially, the research on tumor targeting is more, and how to design and realize that the MRI contrast agents accurately reach tumor tissues and show higher relaxation efficiency according to the characteristics of tissue pathological physiology gradually becomes a research hotspot. (Radiology, 1987, vol.163, 255-258) gadolinium is chemically combined with DTPA derivatives containing two alkyl side chains, so that Gd-DTPA-SA double-membrane liposomes are finally prepared, the average particle size is 400nm, a large number of mononuclear macrophages (kupffer cells) belonging to the reticuloendothelial system exist in normal liver tissues, when the particle size of heterogeneous particles in plasma is larger than 200nm, the heterogeneous particles tend to be recognized, phagocytized and eliminated by the mononuclear macrophages, and tumor cells lack the kupffer cells and have no or little contrast agent to stay in the mononuclear macrophages. The Gd-DTPA-SA double-membrane liposome is used as a contrast agent, and the obvious enhanced imaging effect of the liver is obtained (+ 110% of the liver, 4 ℃, 180% of the liver and 37 ℃). (Radiology, 1992, vol.183, 59-64) benzene Ethoxy (EOB) is covalently linked to diethylenetriaminepentaacetic acid (DTPA) to prepare the amphiphilic small-molecule gadolinium chelate MRI contrast agent Gd-EOB-DTPA, and the small-molecule gadolinium chelate is modified by lipophilic groups containing benzene rings to be recognized by glutathione S-aryl transferase in normal liver and kidney cells, so that the phagocytosis ability of the liver cells is enhanced, the accumulation in liver tissues is achieved, and the image contrast of the liver cells and liver tumor tissues is enhanced.
With the increasing requirements of people on tumor diagnosis, especially on early cancer lesions, such as early liver lesion diagnosis, and the deep understanding of toxic and side effects of currently used MRI contrast agents, the research on the distribution rule of the MRI contrast agents in vivo and the tissue and organ specificity identification shows that the MRI contrast agents with better targeting performance, smaller dosage and smaller toxic and side effects are more important and urgent to design.
From the targets of changing the targeting action mechanism of the liver contrast agent and reducing the dosage, small molecules with very high liver targeting such as glycyrrhetinic acid, cholic acid, folic acid and the like are introduced into a contrast agent metal complex to prepare the contrast agent with high identification and relaxation rate, and no literature report exists at present.
The present invention is directed to solving the above technical problems.
Disclosure of Invention
The invention aims to provide a small molecular nuclear magnetic resonance contrast agent which has high relaxation rate, good targeting effect on tumors, particularly liver tumors, and small dosage. In order to achieve the purpose, the invention provides a metal complex contrast agent of DO3A derivative ligand of gadolinium metal modified by glycyrrhetinic acid, cholic acid or folic acid. The complex has a structure shown in formula I:
wherein n is an integer of 1 to 3; l isA-COOH is any one of glycyrrhetinic acid, cholic acid and folic acid.
The invention also aims to provide a preparation method of the nuclear magnetic resonance contrast agent, which comprises the following synthetic route:
the method comprises the following steps:
step (1): reacting the cyclen II with tert-butyl chloroacetate, adjusting the pH to 8-9, and carrying out alcohol precipitation to obtain 1,4,7, 10-tetraazacyclododecane-1, 4, 7-tert-butyl triacetate III;
step (2): dissolving a compound shown in a formula III and chloroalkyl alcohol IV in acetonitrile, adding alkali, and reacting to prepare a compound shown in a formula V;
mixing the compound shown in the formula V with glycyrrhetinic acid, cholic acid or folic acid, adding a 20% TFA aqueous solution, and carrying out esterification condensation reaction to obtain a glycyrrhetinic acid, cholic acid or folic acid modified dodecanitrogen heterocyclic ligand compound VI;
and (4): and (3) carrying out a complex reaction on the compound shown in the formula V and gadolinium chloride, and then carrying out alcohol precipitation to obtain the nuclear magnetic resonance contrast agent shown in the formula (I).
Preferably, the reaction in the step (1) is carried out under the catalysis of an acid binding agent, and the reaction is carried out for 10 to 24 hours at the temperature of between 60 and 90 ℃.
Further, the acid-binding agent is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or tert-butylamine.
Preferably, the molar ratio of the cyclen II to the acid binding agent is 1: 1.5-4.
Further, in the step (2), the base is an inorganic base or an organic base, preferably sodium hydroxide, potassium hydroxide or triethylamine; the reaction is heated and refluxed for 5 to 20 hours.
Further, the esterification condensation reaction in the step (3) is carried out at a temperature of 50-95 ℃, and the reaction time is preferably 16-32 hours.
Preferably, the molar ratio of the compound of formula V in the step (4) to gadolinium chloride is 1: 1-1.5.
More preferably, the temperature of the complexation reaction is 30-90 ℃, preferably 70-85 ℃.
The invention also aims to provide the application of the nuclear magnetic resonance contrast agent or the nuclear magnetic resonance contrast agent prepared by the method in nuclear magnetic resonance diagnosis of tumors, preferably liver cancer tumors.
Drawings
FIG. 1 shows MRI of primary liver cancer mice obtained after injecting mice with the compound I-1-a contrast agent prepared in example 2.
FIG. 2 shows MRI of mice with metastatic liver cancer obtained after injection of compound I-1-a contrast agent prepared in example 2 into mice.
Detailed Description
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art and are intended to be within the scope of the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned in this application are herein incorporated by reference.
Example 1: preparation of intermediate V-1(n ═ 2)
The preparation route is as follows:
5g of cyclen (II) was added to 20mL of deionized water, and stirred, tert-butyl chloroacetate (1.5 equiv.) was dissolved in 15mL of deionized water, and an aqueous solution of 5.0g of sodium carbonate dissolved in 10mL of deionized water was added. Heating to 75 ℃, controlling the pH value of the reaction system to be about 9, reacting for 12 hours, finishing the reaction, cooling to room temperature, slowly adding 150ml of ethanol, separating out a large amount of solid, filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain 8.6g of the compound shown in the formula III (the HPLC purity is 87%).
Dissolving 6g of the crude compound of the formula III in 35mL of acetonitrile, adding chloro-n-propanol IV-1, adding 3mL of triethylamine, heating and refluxing for 18 hours, cooling to room temperature, adding 30mL of water and 40mL of dichloromethane, separating, washing organic phases with 20mL of multiplied by 3 water, combining the organic phases, and recovering the solvent by reduced pressure distillation to obtain 7.1g of the crude compound of the formula V-1. The mixture was added to 25mL of a mixed solvent of dichloroethane and diethyl ether at a volume ratio of 1:3 to recrystallize, thereby obtaining 4.5g of pure V-1 compound (HPLC purity: 99.2%).
1H NMR(400MHz，D2O，TMS):＝4.51(s，27H)， 4.22(t，1H)，3.75(s,6H)，3.47(m，12H)，3.41(m， 4H)，3.33(t，2H)，3.28(m，2H)
Example 2: i-1-a to I-1-c (n ═ 2, L)A-COOH for glycyrrhetinic acid, cholic acid, folic acid):
the preparation route is as follows:
(1) 0.8g of the compound of formula V-1 and glycyrrhetinic acid (1.1 eq) are dissolved in ethanol, 1.2mL of 20% aqueous TFA solution is added, the mixture is heated under reflux for 20 hours, cooled to room temperature, 20mL of ethyl acetate is added, the organic phase is extracted, 20mL of 3 water is used to wash the organic phase, the organic phases are combined, and the solvent is recovered by distillation under reduced pressure to obtain intermediate VI-1-a (HPLC purity: 95%).
The compound of formula V-1 was condensed with cholic acid (1.1 equiv.) and folic acid (1.5 equiv.) by the same method as described above to give intermediates VI-1-b (HPLC purity: 92%) and VI-1-c (HPLC purity: 94%), respectively.
(2) Adding 0.5g of compound V-1-a into 5mL of deionized water, adding 0.95g of gadolinium chloride, heating to 85, reacting for 6 hours, cooling to room temperature, adjusting the pH to 8 with an aqueous solution of sodium hydroxide, dropwise adding 60mL of ethanol, heating to reflux, stirring and crystallizing for 4 hours, cooling to room temperature, filtering, and drying in vacuum to obtain 0.83g of complex I-1-a.
The complexes I-1-b and I-1-c are prepared respectively by the same method.
Example 3:
magnetic resonance imaging and relaxation rate testing: imaging effectThe fruit and relaxation rate are measured by Siemens Trio 3T magnetic resonance imaging equipment, the gadolinium complex is diluted according to concentration gradient and is placed in a centrifugal tube of 1.5ml, the nuclear magnetic resonance imaging is carried out by adopting an inversion recovery method under the field intensity of 3T, and the longitudinal relaxation time (T) of each concentration solution can be calculated through the brightness of the image1) And then, by the formula:
c.r1+1/TW＝1/T1
calculating T at each concentration1(where c is the gadolinium content, TWLongitudinal relaxation time of water molecules), and finally obtaining the relaxation rate r of the contrast agent by computer fitting1. Wherein the gadolinium content is determined by means of full-spectrum direct-reading plasma emission spectroscopy (ICP-AES).
The relaxation rates of the compounds I-1-a, I-1-b and I-1-c are respectively 12.1mM and 12.1mM as determined by a nuclear magnetic resonance imaging experiment-1s-1、11.3mM-1s-1、13.6mM-1s-1Is commercially available Gd-HP-DO3A (II)
r1＝3.7mM-1s-1) More than three times.
Example 4: the compound I-1-a is used for mouse liver tumor targeted in vitro nuclear magnetic resonance imaging:
(1) primary liver tumor animal model: mice were injected with 100mg/kg of Diethylnitrosamine (DEN) 2 weeks after birth, 2-acetamidofluorene (2-AAF, dissolved in olive oil) 20mg/kg after 2 weeks of starvation treatment, and 2-AAF was injected again 2 weeks later. All mice were then cycled 12h day/night, fed water and food, and cultured under normal conditions. The mice were observed for MRI imaging after 6-7 months of age, and then sacrificed for liver resection and pathological sectioning immediately on liquid nitrogen freezing.
(2) Tumor model establishment and contrast agent contrast evaluation method. The clinical chemical induction of liver cancer by mice is generally induced for 5-6 months, and tumor masses can be seen with naked eyes after dissection. The injection adopts the same injection mode as clinical injection, namely intravenous injection, and the intravenous injection which is easy to operate for mice is tail vein injection. The recommended dosage of the refractive index of the contrast agent is 3 mmol/kg. Considering effectiveness, at least three groups of two mice per group, one primary and one metastatic, were measured per contrast agent. The effect of the contrast agent was mainly observed: i) metabolism in the body, including organ accumulation, blood half-life, etc. According to FDA requirements, it must be completely metabolized out of the body as a diagnostic reagent. This is also an important indicator as to the safety of diagnostic reagents. 2) Effectiveness, i.e. observation of the enhancement of tumor to background contrast before and after injection.
The results of the MRI test on the MRI contrast agent of contrast agent I-a-1 are shown in FIGS. 1-2, and it can be seen that the size of the lesion ranges from 0.4 mm to 1mm, and the metastatic lesions are irregular in shape and spherical with respect to the primary lesion. Therefore, when the contrast agent is used for nuclear magnetic resonance imaging of liver cancer, the position and the size of the tumor disease can be clearly displayed by two liver cancer models.
Claims (12)
1. A compound, having the structure shown in formula I:
wherein n is an integer of 1 to 3; l isA-COOH is glycyrrhetinic acid, and the use of the compound in the preparation of a nuclear magnetic resonance contrast agent for diagnosing liver cancer tumors.
2. A process for the preparation of the compound according to claim 1, which is synthesized by the following steps:
3. the method for preparing according to claim 2, characterized in that it comprises the steps of:
step (1): reacting the cyclen II with tert-butyl chloroacetate, then adjusting the pH to 8-9, and carrying out alcohol precipitation to obtain 1,4,7, 10-tetraazacyclododecane-1, 4, 7-tert-butyl triacetate III;
step (2): dissolving a compound shown in a formula III and chloroalkyl alcohol IV in acetonitrile, adding alkali, and reacting to prepare a compound shown in a formula V;
and (3): mixing the compound shown in the formula V with glycyrrhetinic acid, adding 20% TFA aqueous solution, and carrying out esterification condensation reaction to obtain a glycyrrhetinic acid modified dodecanitrogen heterocyclic ligand compound VI;
and (4): carrying out complex reaction on the compound shown in the formula V and gadolinium chloride, and then carrying out alcohol precipitation to obtain the compound shown in the formula I.
4. The preparation method according to claim 3, wherein the reaction of the step (1) is carried out under catalysis of an acid-binding agent, and the reaction is carried out at 60-90 ℃ for 10-24 hours; the molar ratio of the cyclen II to the acid binding agent is 1: 1.5-4.
5. The method of claim 4, wherein the acid-binding agent is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or tert-butylamine.
6. The production method according to claim 4 or 5, wherein in the step (2), the base is an inorganic base or an organic base; the reaction is heated and refluxed for 5 to 20 hours.
7. The production method according to claim 6, wherein the base is selected from sodium hydroxide, potassium hydroxide, or triethylamine.
8. The method according to claim 3, wherein the esterification condensation reaction of the step (3) is carried out at a temperature of 50 to 95 ℃ for 16 to 32 hours.
9. The preparation method according to claim 3 or 8, wherein the molar ratio of the compound of formula V to gadolinium chloride in the step (4) is 1: 1-1.5.
10. The method according to claim 9, wherein the temperature of the complexation reaction is 30-90 ℃.
11. The method of manufacturing according to claim 10, wherein: the temperature of the complexation reaction is 70-85 ℃.
12. Use of a compound according to claim 1 or a compound prepared by the preparation method according to any one of claims 2 to 11 for the preparation of a nuclear magnetic resonance contrast agent for the diagnosis of hepatoma tumors.
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