Gadolinium-based compounds and MRI contrast agents containing same

Abstract

A gadolinium-based compound and an MRI contrast agent containing the same are disclosed. The gadolinium-based compound may be a DO3A-based gadolinium compound bound to vanillic acid. The MRI contrast agent may contain the compound. Meanwhile, the present invention discloses a pharmaceutical composition for preventing or treating a neuroinflammatory disease, comprising the compound or a pharma- ceutical acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to gadolinium-based compounds and MRI contrast agents containing the same. [Background technology]

[0002] Today, the number of patients with degenerative brain diseases is increasing due to the aging of the population, and this has led to an increased need for early detection of the diseases. Degenerative brain diseases include Parkinson's disease, vascular dementia, Alzheimer's disease, etc., and neurotoxicity due to excessive accumulation of amyloid β polymers (oligomeric Aβ) is considered to be one of the causes of the onset of these diseases.

[0003] Amyloid beta (Aβ) is a 36-43 amino acid peptide that is the main component of amyloid plaques found in the brains of Alzheimer's patients and is critically involved in Alzheimer's disease. The peptide is derived from the amyloid precursor protein (APP).

[0004] The amyloid β molecules can aggregate to form soluble polymers that can exist in a variety of forms. The formed amyloid β polymers (oligomeric Aβ) are known to be toxic to neurons and to be directly involved in the pathogenesis of Alzheimer's disease when they are excessively accumulated in the brain. Therefore, it was expected that detecting changes in the concentration of amyloid β polymers could lead to early diagnosis of degenerative brain diseases.

[0005] Meanwhile, Magnetic Resonance Imaging (MRI) is a method to obtain images of anatomical, physiological and biochemical information of the body by utilizing the phenomenon that hydrogen atoms are distributed differently among the internal tissues and are relaxed in a magnetic field. Unlike CT and PET, MRI does not use radiation that is harmful to the human body, but creates images of the inside of the body using magnetic field gradients and radio frequencies under a strong magnetic field, making it non-invasive, high resolution and excellent for soft tissue examination.

[0006] To make more precise use of this MRI equipment, a contrast agent is injected into the subject to obtain an MRI image. The contrast between tissues on an MRI image is a phenomenon that occurs when the relaxation process in which the nuclear spins of water molecules in tissues return to equilibrium differs from tissue to tissue. Contrast agents use paramagnetic or superparamagnetic substances to affect this relaxation process, widening the difference in relaxation between tissues and inducing changes in the MRI signal, making the contrast between tissues clearer.

[0007] Currently, the most commonly used contrast agents in clinical practice are those based on gadolinium (Gd) chelates. Currently, DTPA (Magnevist®), Gd-DOTA (Dotaram®), Gd(DTPA-BMA) (Omniscan®), Gd(DO3A-HP) (ProHance®), Gd(BOPTA) (MultiHance®), etc. are used. However, most of the commonly used contrast agents are non-specific contrast agents distributed in the extracellular fluid (ECF). As for specific contrast agents, only liver-specific contrast agents are used.

[0008] Recent research has promoted the development of contrast agents that have specific targeting or can show signal enhancement due to physiological activity (pH change, enzymatic activity). However, to date, there have been no satisfactory results for MRI contrast agents with specific targeting, especially for MRI contrast agents specific to degenerative brain diseases. Summary of the Invention [Problem to be solved by the invention]

[0009] One object of the present invention is to provide a compound that specifically binds to amyloid β polymers.

[0010] Another object of the present invention is to provide an MRI contrast agent containing the compound.

[0011] It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating a neuroinflammatory disease, comprising the compound. [Means for solving the problem]

[0012] In one aspect, the present invention provides a compound having the following formula (1): [ka]

[0013] In the formula: L is *-(CH2) x -A 1 -(CH2) y -A 2 -(CH2) z -*, x, y, and z are each independently selected from an integer of 0 to 5; A 1 and A 2 is one or more structures independently selected from the group consisting of a single bond, *-COO-*, *-CO-*, *-NH-*, *-CH2-*, *-CONH-* and *-O-*; X is a structure having the following chemical formula (2): [ka] * denotes the binding site.

[0014] In one embodiment, the A 2 may be *-NH-*. In one embodiment, the A 1 may be *-CONH-*. In one embodiment, x may be 1. In one embodiment, y may be 2. In one embodiment, z may be 0. In one embodiment, the compound may have the following formula (3): [ka]

[0015] In one embodiment, the gadolinium (Gd) may be coordinated with one or more water molecules. In one embodiment, the compound may specifically bind to mammalian oligomeric Aβ. In one embodiment, the compound has a molecular weight of 3.7 to 4.6s. -1 may have a relaxivity of 0.05. In one embodiment, the compound is capable of crossing the blood-brain-barrier (BBB) ​​when injected intravenously.

[0016] In another aspect, the present invention provides an MRI contrast agent comprising the compound. In one embodiment, the MRI contrast agent can be used in the diagnosis of degenerative brain diseases. In one embodiment, the MRI contrast agent can be used in the diagnosis of Alzheimer's disease.

[0017] In still another aspect, the present invention provides a pharmaceutical composition for preventing or treating a neuroinflammatory disease, comprising the compound or a pharma- ceutically acceptable salt thereof. In one embodiment, the neuroinflammatory disease may be an inflammatory neurodegenerative brain disease. In one embodiment, the inflammatory neurodegenerative brain disease may be a disease selected from Alzheimer's disease or Parkinson's disease. Effect of the Invention

[0018] The compounds according to the embodiments of the present invention can specifically bind to amyloid β polymers, and thus MRI contrast agents containing the compounds can be used in the diagnosis of degenerative brain diseases including Alzheimer's.

[0019] Meanwhile, the compounds according to the embodiments of the present invention have an anti-inflammatory function of reducing factors associated with the occurrence of neuroinflammation such as NLRP3, ASC, iL-1β, etc., and reducing Aβ and Bace-1 associated with amyloid β expression, thereby suppressing amyloid β formation, and therefore can be used as an active ingredient in a pharmaceutical composition for preventing or treating neuroinflammatory diseases. [Brief description of the drawings]

[0020] [Figure 1] 1 is a diagram showing experimental results according to an example of the present invention; [Diagram 2] 1 is a diagram showing experimental results according to an example of the present invention; [Diagram 3] 1 is a diagram showing experimental results according to an example of the present invention; [Figure 4] 1 is a diagram showing experimental results according to an example of the present invention; [Diagram 5] 1 is a diagram showing experimental results according to an example of the present invention; [Figure 6] 1 is a diagram showing experimental results according to an example of the present invention; [Figure 7] 1 is a diagram showing experimental results according to an example of the present invention; [Figure 8] 1 is a diagram showing experimental results according to an example of the present invention; [Figure 9] 1 is a diagram showing experimental results according to an example of the present invention; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Hereinafter, the embodiments of the present invention will be described in detail with reference to the accompanying drawings. Since the present invention may be varied in various ways and may have various forms, specific embodiments will be illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to the specific disclosed form, but it should be understood that the present invention includes all modifications, equivalents, and alternatives within the spirit and technical scope of the present invention. In describing each drawing, similar components are given similar reference numerals. The dimensions of the structures in the accompanying drawings are exaggerated to clarify the present invention.

[0022] The terms used in this application are merely used to describe specific embodiments and are not intended to limit the present invention. A singular expression includes a plural expression unless the context clearly indicates otherwise. In this application, the terms "include" or "have" indicate the presence of features, numbers, steps, operations, components, or combinations thereof described in the specification, and should be understood not to preclude the presence or additional possibility of one or more other features, numbers, steps, operations, components, or combinations thereof.

[0023] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention pertains. Terms as defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and should not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

[0024] The compound according to the embodiment of the present invention may have the following chemical formula (1): [ka]

[0025] In the above chemical formula (1), gadolinium ion (Gd 3+The carboxylate (COO) represented by the formula (1) is - ) group to form a complex.

[0026] In the above chemical formula (1), L is *-(CH2) x -A 1 -(CH2) y -A 2 -(CH2) z -*, where x, y and z are each independently selected to be any integer from 0 to 5; A 1 and A 2 may be one or more structures independently selected from the group consisting of a single bond, *-COO-*, *-CO-*, *-NH-*, *-CH2-*, *-CONH-* and *-O-*. * is a binding site.

[0027] The L may be a linker connecting the nitrogen in the ring structure of the compound to the X. 1 and A 2 can determine the manner in which the linker connects the nitrogen in the ring structure of the compound to the X, or a functional group determined by the manner in which the x, y, and z are the A in the linker. 1 and A 2 In one embodiment, the length of the chain connecting A 2 may be -NH-. 1 may be *-CONH-*. In one embodiment, the x may be 1. In one embodiment, the y may be 2. In one embodiment, the z may be 0.

[0028] As long as the compound according to the embodiment of the present invention has substantially the structure of the formula (1), the present invention does not exclude the removal or addition of bonds that are acceptable to those skilled in the art. For example, in one embodiment, the gadolinium (Gd) in the compound can be coordinated with one or more water molecules.

[0029] In the above chemical formula (1), X may have a structure represented by the following chemical formula (2): [ka] * denotes the binding site.

[0030] In one embodiment, the compound may have the following formula (3): [ka]

[0031] In one embodiment, the compound is capable of specifically binding to mammalian amyloid β polymers (oligomeric Aβ). -1 In one embodiment, the compound can cross the blood-brain-barrier (BBB) ​​when injected intravenously.

[0032] As described above, the compounds according to the embodiments of the present invention can specifically bind to amyloid β polymers.

[0033] An MRI contrast agent according to an embodiment of the present invention may include the compound. In one embodiment, the MRI contrast agent may be used in the diagnosis of degenerative brain diseases. In one embodiment, the MRI contrast agent may be used in the diagnosis of Alzheimer's disease.

[0034] As described above, the MRI contrast agents according to embodiments of the present invention can be used in the diagnosis of degenerative brain diseases, including Alzheimer's.

[0035] A pharmaceutical composition for preventing or treating a neuroinflammatory disease according to an embodiment of the present invention may include the compound or a pharma- ceutical acceptable salt thereof. In one embodiment, the neuroinflammatory disease may be an inflammatory neurodegenerative brain disease. In one embodiment, the inflammatory neurodegenerative brain disease may be a disease selected from Alzheimer's disease or Parkinson's disease.

[0036] In one embodiment, the "pharmaceutical acceptable salt" is not limited to a salt that forms an addition salt with the compound, and includes a salt derived from a pharmaceutical acceptable inorganic acid, organic acid, or base. The compound according to the present invention can be converted into its salt by a conventional method, and the preparation of the salt can be easily carried out by a person skilled in the art based on the structure of the compound without any special description.

[0037] The pharmaceutical composition of the present invention may contain the compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof alone, or may further contain a pharma- ceutically acceptable carrier in addition to the compound. The pharma- ceutically acceptable carrier may be one commonly used in the pharmaceutical field, and may be an excipient (e.g., starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (e.g., physiological saline, purified water, etc.).

[0038] In the present invention, the term "prevention" refers to inhibiting the occurrence of a disease or condition in an individual who has not been diagnosed as having a neuroinflammatory disease or condition but is susceptible to such a disease or condition, and in the present invention, the term "treatment" refers to inhibiting the development of a neuroinflammatory disease or condition, alleviating the disease or condition, and eliminating the disease or condition.

[0039] The pharmaceutical compositions of the present invention may be prepared by known methods into a variety of parenteral or oral administration forms.

[0040] Hereinafter, embodiments of the present invention will be described. However, the embodiments described below are only some embodiments of the present invention, and the scope of the present invention is not limited to the following embodiments.

[0041] <Synthesis of Gd-DO3A-Va> [Chemical formula] Substances 1 to 5 were synthesized step by step to produce the Gd-DO3A-Va compound.

[0042] <1> Synthesis of tri-tert-butyl 2,2’,2’’-(10-(2-ethoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate After dissolving tri-tert-butyl 2,2’,2’’-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (9.72 mmol) in 160 mL of acetonitrile, potassium bicarbonate (29.69 mmol) was added and stirred for 30 minutes. Then, ethyl bromoacetate (10.69 mmol) was added and stirred at 60 °C for 24 hours. After 24 hours, the product was filtered through a filter and vacuum filtered to remove the solvent. The product was dissolved in dichloromethane, the undissolved substances were removed, and after removing all the solvent, it was dried under vacuum to obtain a slightly yellow solid. Yield: 99%

[0043] <2> Synthesis of tri-tert-butyl 2,2',2''-(10-(2-oxo-2-((2-(3,4,5-trihydroxybenzamido)ethyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, 2 1 (5.33 mmol) was dissolved in 7 mL of methanol, and then 6 mL of ethylenediamine was added and reacted at room temperature for 4 days. The solvent was removed by heating to 55°C under vacuum to obtain an oil-like solid, which was washed several times with ethyl ether. After drying under vacuum, it was dissolved in methanol and the undissolved material was removed by filtration. After that, open column chromatography was performed under dichloromethane / methanol mixed solvent conditions to separate and purify a slightly yellow solid. Yield: 57%

[0044] <3> Synthesis of tri-tert-butyl 2,2',2''-(10-(2-((2-(4-hydroxy-3-methoxybenzamido)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, 3 Vanillic acid (6.97mmol) was dissolved in dimethylformamide and stirred at 0°C. Then, EDC·HCl (7.67mmol) and HOBt hydrate (7.67mmol) dissolved in dimethylformamide were added to the gallic acid solution and stirred for 30 minutes. Next, 2 (4.88mmol) dissolved in dimethylformamide was added to the reaction mixture, DIPEA (13.94mmol) was added, and the mixture was stirred at room temperature for 24 hours. After that, the mixture was filtered under reduced pressure to concentrate the dimethylformamide to the maximum extent, and then extracted with dichloromethane and brine, dehydrated with sodium sulfate, and filtered under reduced pressure. Then, open column chromatography was performed under dichloromethane / methanol mixed solvent conditions to separate the solid. The next reaction was carried out without further separation and purification.

[0045] <4> Synthesis of 2,2',2''-(10-(2-((2-(4-hydroxy-3-methoxybenzamido)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, 4 After adding an excess amount of trifluoroacetic acid to 3 at 0°C, the reaction mixture was stirred at room temperature for 20 hours. Then, dichloromethane was added and filtration under reduced pressure was repeated. Next, a purified solid was obtained by high performance liquid chromatography in a mixed solvent of water / acetonitrile containing 0.1% trifluoroacetic acid. Yield (2→4): 44%

[0046] <5> Synthesis of Gd-DO3A-Va, 5 After dissolving 4 (0.84 mmol) in water, the pH was adjusted to 3 with 1 M sodium hydroxide, and GdCl3·6H2O (0.59 mmol) dissolved in water was added. Then, after adjusting the pH to 7 with 1 M sodium hydroxide, the mixture was stirred at room temperature for 20 hours. The solid obtained by vacuum filtration was separated and purified using high-performance liquid chromatography under the condition of a water / acetonitrile mixed solvent added with 10 mM ammonium acetate to obtain a solid. Yield: 73%

[0047] <HR-MS and Purity Analysis Results of Gd-DO3A-Va> Gd-DO3A-Va was analyzed by HR-MS. Figure 1 is a drawing showing the results. Referring to Figure 1, it can be confirmed that a peak (752.1894 m / z) corresponding to the predicted peak (752.1890 m / z) for Gd-DO3A-Va appears. Also, the results of analyzing the purity of Gd-DO3A-Va using HPLC are shown in Figure 2. Referring to Figure 2, it can be confirmed that Gd-DO3A-Va has a purity of approximately 98%.

[0048] <Gd-DO3A-Va Performance Evaluation Method and Results> 1) Relaxivity Measurement Using the synthesized Gd-DO3A-Va and the cyclic common contrast agents Gadovist® and Dotarem® as comparison groups, the relaxivities (r1, r2) of each substance were measured. Specifically, after diluting the gadolinium complex in triple-distilled water to five concentrations (0.0625, 0.125, 0.25, 0.5, 1 mM) to prepare a phantom, the T1 and T2 relaxation times were measured by 3T MRI. Thereby, the R (Relaxation rate = 1 / T) of each concentration was calculated, and the relaxivity (r1, r2) results of the gadolinium complex were obtained through linear regression analysis (see Figure 3) and shown in Table 1 below.

[0049]

Table 1

[0050] Referring to Table 1, it was found that the r1 of Gd-DO3A-Va was 3.8±0.1 and the r2 was 4.4±0.2, which are sufficient relaxivity values ​​for clinical use, and therefore it was confirmed that Gd-DO3A-Va can be used as a contrast agent.

[0051] 2) Kinetic stability evaluation Gd-DO3A-Va and various commonly used contrast agents were diluted to a concentration of 2.5 mM in PBS (pH 7.4) to prepare phantoms, and then 1 equivalent of 250 mM zinc chloride (ZnCl2) was added to evaluate the binding stability of DO3A ligand and Gd metal ion. This can be confirmed by measuring the transmetallation of gadolinium ion by zinc ion through relaxivity change. Referring to FIG. 4 showing the results, it can be seen that the Gd-DO3A-Va of the present invention has sufficient stability to be used as an MRI contrast agent, since the R2 change rate remains close to 1.

[0052] 3) pH stability evaluation 1 mM Gd-DO3A-Va and Gadovist®, a commonly used contrast agent for comparison, were diluted in buffer solutions of pH 1, 3, 5, 7, 9, and 11, and T2-weighted images were taken with a 3T MRI for three weeks to measure the R2 value. The R2 value was measured over time to confirm the change in value from immediately after dilution, and the more constant the value is maintained, the higher the stability against pH can be evaluated. 5 showing the results, the R2 value of Gd-DO3A-Va of the present invention did not change over a period of three weeks in the pH range of 3 to 11. The value changed slightly under strong acidic conditions of pH 1, but the change was not large. This result confirmed that Gd-DO3A-Va is stable under the pH conditions in the body, and is also stable under strong acid-base conditions.

[0053] 4) Evaluation of amyloid β polymer targeting 4-1) Phantom experimental method for confirming amyloid β polymer targeting <1> 221.5 uL of HFIP was added to 1 mg of 1 mM amyloid β, and the mixture was shaken at room temperature for 1 hour using a shaker to remove preaggregation. <2> The amyloid β from which preaggregation was removed was dried and 221.5uL of DMSO was added to adjust the concentration to 1mM, and then a suspension was formed using a mixer and an ultrasonic machine. Then, 878.5uL of PBS (1X, pH 7.4) was added to adjust the concentration to 0.2mM. <3> After incubation at 37°C for 4 days on a shaker, 200uL of fully polymerized amyloid beta polymers were dispensed into aliquots, and 20uL each of Gd-DO3A-Va and a commonly used contrast agent (Gadovist), both dissolved in PBS at a concentration of 2mM, were added. The cells were then incubated at 37°C for 24 hours on a shaker. <4> After 24 hours, the supernatant was removed by centrifugation, and the amyloid β polymers were washed with PBS. Then, 200uL of PBS:DMSO=9:1 solution was added to the pellet to prepare an MRI phantom sample. As a control group, a phantom sample in which only amyloid β polymers were cultured was used.

[0054] 4-2) Analysis of the effect of targeting amyloid β polymers Using the phantom sample, the amyloid β polymer targeting evaluation of Gd-DO3A-Va according to an embodiment of the present invention and a commonly used contrast agent (Gadovist®) was performed using 9.4T MR equipment. Referring to FIG. 6 showing the results, there was almost no difference in contrast enhancement effect between the phantom cultured with only amyloid β polymers (Aβ) and the phantom cultured with Gadovist® (Aβ+Gadovist), but the phantom treated with Gd-DO3A-Va (Aβ+Gd-DO3A-Va) showed increased signal intensity compared to the phantom cultured with only amyloid β polymers. This confirmed that the gadolinium contrast agent of the present invention has a targeting effect on amyloid β polymers. Overexpressed amyloid β polymers accumulate in neurons, causing toxicity and destroying neurons, resulting in Alzheimer's disease, a degenerative brain disease. Since Gd-DO3A-Va according to an embodiment of the present invention has the function of targeting amyloid β polymers, which are toxic proteins, it can be used as a drug for diagnosing Alzheimer's disease.

[0055] 5) In vitro toxicity evaluation Experiments were carried out to evaluate the cytotoxicity against C8-D1A (astrocyte cells) and SIM-A9 (microglial cells), and the results are shown in Figures 7 and 8. Referring to FIG. 7, when cells were treated with Gd-DO3A-Va at various concentrations (0, 100, 200, 400 μM), the cell viability was about 100% up to the high concentration of 400 μM. As shown in FIG. 8, the cytotoxicity evaluation on SIM-A9 (microglial cells) showed that when Gd-DO3A-Va was treated at various concentrations (0, 100, 200, 400 μM), the cell survival rate was about 100% up to the high concentration of 400 μM.

[0056] The two main types of brain cells are neurons and neuroglia (glial cells). Glia cells include astrocytes and microglia, and it is known that these glial cells perform functions such as supporting neurons and providing nutrients. Gd-DO3A-Va was confirmed to have no cytotoxicity up to a high concentration of 400μM in brain cells such as astrocytes and microglia.

[0057] 6) In vivo efficacy evaluation Gd-DO3A-Va was administered repeatedly 15 times over a period of two months to 5XFAD (6 months, male), a dementia mouse model. The control group consisted of mice of the same age that were administered saline, and WB was a non-treatment group of 6-month-old mice. After the experiment, the brains of the mice were removed, and the hippocampus and cortex were separated and analyzed by Western blot. Referring to FIG. 9 showing the results, it was confirmed that factors related to the occurrence of inflammation, such as NLRP3, ASC, and iL-1β, increased in the control group compared to WB. Meanwhile, in the Gd-DO3A-Va administration group, the factors and Aβ and Bace-1 related to amyloid β expression were all decreased. From this experiment, it can be confirmed that Gd-DO3A-Va reduces inflammatory factors, inhibits amyloid β formation, and treats Alzheimer's disease.

[0058] Although the present invention has been described above with reference to preferred embodiments, it should be understood that those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the present invention as set forth in the appended claims.

Claims

1. A compound having the following chemical formula (1): 【Chemistry 1】 In formula (1), L is *-(CH ２ ) ｘ -A １ - (CH ２ ) ｙ -A ２ - (CH ２ ) ｚ -*, x, y, and z are each independently selected from 0 to 5; A １ and A ２ is a single bond, *-COO-*, *-CO-*, *-NH-*, *-CH ２ one or more structures independently selected from the group consisting of -*, *-CONH-* and *-O-*; X is a structure having the following chemical formula (2): 【Chemistry 2】 * denotes the binding site.

2. The above A ２ The compound according to claim 1, wherein is *-NH-*.

3. The above A １ The compound according to claim 2, wherein is *-CONH-*.

4. The x is 1, The y is 2, The compound of claim 3 , wherein z is 0.

5. A compound having the following chemical formula (3): 【Chemistry 3】

6. The compound of claim 1 , wherein the gadolinium (Gd) is coordinated with one or more water molecules.

7. The compound according to claim 1 , which specifically binds to mammalian oligomeric Aβ.

8. The compound is 3.7 to 4.6 s －１ The compound of claim 1 having a relaxivity of

9. The compound of claim 1, wherein the compound crosses the blood-brain-barrier (BBB) ​​when injected intravenously.

10. 10. An MRI contrast agent comprising a compound according to any one of claims 1 to 9.

11. 11. The MRI contrast agent of claim 10, wherein the MRI contrast agent is used in the diagnosis of a degenerative brain disease.

12. 12. The MRI contrast agent of claim 11, wherein the MRI contrast agent is used in the diagnosis of Alzheimer's disease.

13. A pharmaceutical composition for preventing or treating a neuroinflammatory disease, comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 13, wherein the neuroinflammatory disease is an inflammatory neurodegenerative brain disease.

15. 15. The pharmaceutical composition of claim 14, wherein the inflammatory neurodegenerative brain disease is a disease selected from Alzheimer's disease or Parkinson's disease.

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