KR102659229B1 - Gadolinium-based compound, mri contrast agent comprising the same - Google Patents

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 protocatechuic acid. The MRI contrast agent may include the compound.

Description

Gadolinium-based compound, MRI contrast agent containing the same {GADOLINIUM-BASED COMPOUND, MRI CONTRAST AGENT COMPRISING THE SAME}

The present invention relates to a gadolinium-based compound and an MRI contrast agent containing the same.

Today, due to the aging of the population, the number of patients with degenerative brain diseases is increasing, and accordingly, the need for early detection of the diseases is emerging. Degenerative brain diseases include Parkinson's disease, vascular dementia, and Alzheimer's disease, and neurotoxicity caused by excessive accumulation of amyloid beta polymer (oligomeric Aβ) is considered one of the causes of the disease.

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

The amyloid beta molecule can aggregate to form a soluble polymer that can exist in various forms. The formed amyloid beta polymer (oligomeric Aβ) is toxic to nerve cells and accumulates excessively in the brain, directly contributing to the development of Alzheimer's disease. It is known to do so. Therefore, it was expected that detecting changes in the concentration of amyloid beta polymer would enable early diagnosis of degenerative brain diseases.

Meanwhile, Magnetic Resonance Image (MRI) is a method of obtaining images of anatomical, physiological, and biochemical information of the body by using the phenomenon of hydrogen atoms being relaxed in a magnetic field due to differences in the distribution of hydrogen atoms between tissues in the body. . Unlike CT or PET, MRI does not use radiation harmful to the human body, but uses magnetic field gradients and radio waves under a strong magnetic field to create images inside the body, so it is non-invasive, has high resolution, and is excellent for soft tissue examination.

In order to utilize such MRI equipment more precisely, a contrast agent is injected into the object to obtain an MRI image. The contrast between tissues on an MRI image is a phenomenon that occurs because the relaxation of the nuclear spins of water molecules within the tissue to return to an equilibrium state is different for each tissue. The contrast agent uses a paramagnetic or superparamagnetic material to affect the relaxation effect, widening the difference in relaxation between tissues and causing changes in MRI signals to make the contrast between tissues clearer.

Currently, the most commonly used contrast agent clinically is a contrast agent based on gadolinium (Gd) chelate. Currently, Gd-DTPA (Magnevist®), Gd-DOTA (Dotaram®), Gd(DTPA-BMA) (Omniscan®), Gd(DO3A-HP) (ProHance®), Gd(BOPTA) (MultiHance®), etc. It is being used. However, most of the commercially available contrast agents are non-specific contrast agents that are distributed into the extracellular space (extracellular fluid, ECF). As a specific contrast agent, a special contrast agent is used.

Recent research is promoting the development of contrast agents that have specific targeting or can show signal enhancement due to physiological activity (pH change, enzyme activity), but to date, MRI contrast agents with specific targeting, especially for degenerative brain Sufficient results have not been obtained for disease-specific MRI contrast agents.

One object of the present invention is to provide a compound that specifically binds to amyloid beta polymer.

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

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neuroinflammatory diseases containing the above compound.

In one aspect, the present invention provides a compound having the formula (1):

(One)

here,

L is *-(CH ₂ ) _x -A ¹ -(CH ₂ ) _y -A ² -(CH ₂ ) _z -*,

x, y and z are each independently selected as random integers from 0 to 5,

A ¹ and A ² are single bonds, in the group containing *-COO-*, *-CO-*, *-NH-*, *-CH ₂ -*, *-CONH-* and *-O-* Each is one or more independently selected structures,

X is a structure having the following formula (2):

(2)

* is the binding site.

In one embodiment, A ² may be *-NH-*.

In one embodiment, 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).

(3)

In one embodiment, the gadolinium (Gd) may coordinate with one or more water molecules.

In one embodiment, the compound can specifically bind to mammalian amyloid beta polymer (oligomeric Aβ).

In one embodiment, the compound may have a relaxation rate of 3.5 to 4.4 s ^-1 .

In one embodiment, the compound can pass through the blood-brain-barrier (BBB) when injected intravenously.

In another aspect, the present invention provides an MRI contrast agent containing the above compound.

In one embodiment, the MRI contrast agent can be used for diagnosis of degenerative brain disease.

In one embodiment, the MRI contrast agent can be used to diagnose Alzheimer's disease.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating neuroinflammatory diseases comprising the compound or a pharmaceutically 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.

The compound according to an embodiment of the present invention can specifically bind to amyloid beta polymer, and therefore, an MRI contrast agent containing the compound can be used in the diagnosis of degenerative brain diseases including Alzheimer's.

Meanwhile, the compound according to the embodiment of the present invention reduces oxidative stress that causes neuroinflammation and has antioxidant and anti-inflammatory functions that reduce NLRP3, ASC, etc., which are inflammatory factors expressed in pathways that cause neuroinflammation. It can be used as an active ingredient in a pharmaceutical composition for preventing or treating neuroinflammatory diseases.

Figures 1 to 9 are diagrams showing experimental results according to experimental examples of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. Since the present invention can be subject to various changes and can 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 a specific disclosed form, and should be understood to include all changes, equivalents, and substitutes included in the spirit and technical scope of the present invention. While describing each drawing, similar reference numerals are used for similar components. In the attached drawings, the dimensions of the structures are enlarged from the actual size for clarity of the present invention.

The terms used in this application are only used to describe specific embodiments and are not intended to limit the invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this application, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, or a combination thereof described in the specification, but are not intended to indicate the presence of one or more other features or numbers. It should be understood that this does not exclude in advance the possibility of the existence or addition of steps, operations, components, or combinations thereof.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the technical field to which the present invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and should not be interpreted in an ideal or excessively formal sense unless explicitly defined in the present application. No.

Compounds according to embodiments of the present invention may have the following formula (1).

(One)

In the formula (1), the gadolinium ion (Gd ³⁺ ) may form a complex by coordinating with the carboxylate (COO ^- ) group of the formula (1).

In the formula (1), L may be *-(CH ₂ ) _x -A ¹ -(CH ₂ ) _y -A ² -(CH ₂ ) _z -*, and x, y and z are any of 0 to 5. can be each independently selected as an integer, and A ¹ and A ² are a single bond, *-COO-*, *-CO-*, *-NH-*, *-CH ₂ -*, *-CONH-* and *-O-*. * is the binding site.

The L may be a linker connecting the nitrogen and the X in the cyclic structure of the compound. The A ¹ and A ² may determine the functional group determined by the method or the method by which the linker connects the nitrogen and the X in the ring-shaped structure of the compound. The x, y and z may determine the length of the chain connecting A ¹ and A ² in the linker. In one embodiment, A ² may be *-NH-*. In one embodiment, 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.

As long as the compound according to the embodiment of the present invention substantially has the structure of Formula (1), bonding or removal of bonding acceptable to those skilled in the art is not excluded from the scope of the present invention. For example, in one embodiment, the gadolinium (Gd) in the compound may coordinate with one or more water molecules.

In the above formula (1), X may have a structure having the following formula (2).

(2)

* is the binding site.

In one embodiment, the compound may have the following formula (3).

(3)

In one embodiment, the compound can specifically bind to mammalian amyloid beta polymer (oligomeric Aβ). In one embodiment, the compound may have a relaxation rate of 3.5 to 4.4 s ^-1 . In one embodiment, the compound can pass through the blood-brain-barrier (BBB) when injected intravenously.

As discussed above, the compound according to the embodiment of the present invention can specifically bind to amyloid beta polymer.

An MRI contrast agent according to an embodiment of the present invention may include the above compound. In one embodiment, the MRI contrast agent can be used for diagnosis of degenerative brain disease. In one embodiment, the MRI contrast agent can be used to diagnose Alzheimer's disease.

As discussed above, the MRI contrast agent according to an embodiment of the present invention can be used in the diagnosis of degenerative brain diseases including Alzheimer's.

A pharmaceutical composition for preventing or treating neuroinflammatory diseases according to an embodiment of the present invention may include the above compound or a pharmaceutically 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.

In one embodiment, the “pharmaceutically acceptable salt” is not limited as long as it forms an addition salt with the compound, and includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. 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 performed by a person skilled in the art based on the structure of the compound without separate explanation.

The pharmaceutical composition of the present invention may contain alone the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, but may also further contain a pharmaceutically acceptable carrier. The pharmaceutically 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 solution, purified water, etc.).

In the present invention, the term “prevention” refers to suppressing the occurrence of a disease or disease in an individual who has not been diagnosed as having a neuroinflammatory disease or disease but is prone to such disease or disease. In addition, the term "treatment" in the present invention means inhibition of the development of a neuroinflammatory disease or disease, alleviation of the disease or disease, and elimination of the disease or disease.

The pharmaceutical composition of the present invention can be prepared in various forms for parenteral or oral administration according to known methods.

Hereinafter, embodiments of the present invention will be described in detail. However, the examples described below are only some embodiments of the present invention, and the scope of the present invention is not limited to the following examples.

<Synthesis of Gd-DO3A-Pca>

The Gd-DO3A-Pca compound was prepared by step-by-step synthesis of material 1 to final material 5 .

① tri-tert-butyl 2,2',2''-(10-(2-ethoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, 1 of synthesis

Dissolve tri-tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (9.72 mmol) in 160 mL acetonitrile and add potassium bicarbonate. (29.69 mmol) was added and stirred for 30 minutes. Afterwards, ethyl bromoacetate (10.69 mmol) was added and stirred at 60°C for 24 hours. After 24 hours, the product was filtered and the solvent was removed by filtration under reduced pressure. After dissolving the product in dichloromethane, insoluble substances were removed, all solvents were removed, and the product was vacuum dried to obtain a slightly yellow solid. Yield rate: 99%

② tri-tert-butyl 2,2',2''-(10-(2-oxo-2-((2-(3,4,5-trihydroxybenzamido)ethyl)amino)ethyl)-1,4,7 Synthesis of ,10-tetraazacyclododecane-1,4,7-triyl)triacetate, 2

After dissolving 1 (5.33 mmol) in 7 mL of methanol, 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, and an oil-like solid was obtained, which was washed several times with ethyl ether. After vacuum drying, insoluble substances dissolved in methanol were removed by filtration, and then open column chromatography was performed under dichloromethane/methanol mixed solvent conditions to separate and purify a slightly yellow solid. Yield: 57%

③ tri-tert-butyl 2,2',2''-(10-(2-((2-(3,4-dihydroxybenzamido)ethyl)amino)-2-oxoethyl)-1,4,7,10- Synthesis of tetraazacyclododecane-1,4,7-triyl)triacetate, 3

Protocatechuic acid (6.97 mmol) was dissolved in dimethylformamide and stirred at 0°C. Afterwards, EDC·HCl (7.67 mmol) and HOBt hydrate (7.67 mmol) dissolved in dimethylformamide were added to the gallic acid solution and stirred for 30 minutes. Next, 2 (4.88 mmol) dissolved in dimethylformamide was added to the reaction mixture, DIPEA (13.94 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Afterwards, dimethylformamide was concentrated as much as possible by filtration under reduced pressure, extracted using dichloromethane and brine, dehydrated with sodium sulfate, and filtered under reduced pressure. Afterwards, open column chromatography was performed under dichloromethane/methanol mixed solvent conditions to separate the solid. The next reaction was carried out without additional separation and purification.

④ 2,2',2''-(10-(2-((2-(3,4-dihydroxybenzamido)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4 Synthesis of ,7-triyl)triacetic acid, 4

After adding an excess amount of trifluoroacetic acid to 3 °C at 0°C, the reaction was stirred at room temperature for 20 hours. Afterwards, dichloromethane was added and reduced pressure filtration was repeated. Next, high-performance liquid chromatography was performed using a mixed solvent of water/acetonitrile with 0.1% trifluoroacetic acid to obtain a purified solid. Yield (2 -> 4): 12%

⑤ Synthesis of Gd-DO3A-Pca, 5

4 (0.76 mmol) was dissolved in water, the pH was adjusted to 3 using 1 M sodium hydroxide, and GdCl ₃ ·6H ₂ O (0.53 mmol) dissolved in water was added. Afterwards, the pH was adjusted to 7 using 1 M sodium hydroxide and stirred at room temperature for 20 hours. The solid obtained by filtration under reduced pressure was separated and purified using high-performance liquid chromatography in a water/acetonitrile mixed solvent with 10 mM ammonium acetate added. Yield: 69%

<HR-MS and purity analysis results of Gd-DO3A-Pca>

Gd-DO3A-Pca was analyzed through HR-MS. Figure 1 is a diagram showing the results. Referring to Figure 1, it can be seen that a peak (738.1731 m/z) corresponding to the peak (738.1734 m/z) predicted for Gd-DO3A-Pca appears.

In addition, the results of analyzing the purity of Gd-DO3A-Pca using HPLC are shown in Figure 2. Referring to Figure 2, it can be seen that Gd-DO3A-Pca has a purity of about 98%.

<Gd-DO3A-Pca performance evaluation method and results>

1) Measurement of relaxation rate

The self-relaxation rate ( r ₁ , r ₂ ) of each material was measured using synthesized Gd-DO3A-Pca and cyclic commercial contrast agents Gadovist ^® and Dotarem ^® as comparison groups. Specifically, a phantom was produced by diluting the gadolinium complex in tertiary distilled water to five concentrations (0.0625, 0.125, 0.25, 0.5, 1 mM), and then T ₁ and T ₂ relaxation times were measured in 3T MRI. . Through this, R (Relaxation rate=1/ T ) of each concentration was calculated, and the self-relaxation rate ( r ₁ , r ₂ ) results of the gadolinium complex were obtained through linear regression analysis (see FIG. 3) and shown in Table 1 below.

Referring to Table 1 above, it can be seen that r ₁ of Gd-DO3A-Pca has a value of 3.6±0.1 and r ₂ has a value of 4.3±0.1, which is a self-relaxation rate value sufficient for clinical use, so Gd-DO3A- It was confirmed that Pca can be used as a contrast agent.

2) Kinetic stability evaluation

A phantom was prepared by diluting Gd-DO3A-Pca and various commercial contrast agents to a concentration of 2.5mM in PBS (pH 7.4), and then adding 1 equivalent of 250mM zinc chloride (ZnCl ₂ ) to form the DO3A ligand and Gd metal ion. Binding stability was evaluated. This can be confirmed by measuring the transmetallation of gadolinium ions by zinc ions as a change in self-relaxation rate.

Looking at Figure 4 showing the results, it can be seen that Gd-DO3A-Pca of the present invention has sufficient stability to be used as an MRI contrast agent because the R ₂ change rate maintains a large value of 0.9 or more.

3) pH stability evaluation

1 mM Gd-DO3A-Pca and commercial contrast agent Gadovist ^® as comparison group. After diluting it in a buffer solution of pH 1, 3, 5, 7, 9, 11, T ₂ -weighted images are taken at 3T MRI for 3 weeks to measure the R ₂ value. By measuring the R ₂ value over time, the change in value immediately after dilution can be confirmed, and as the value remains constant, the pH stability can be evaluated as high.

Looking at Figure 5 showing the results, Gd-DO3A-Pca of the present invention showed no change in R ₂ value for 3 weeks in the pH range of 3-9, and the value was maintained even under strong acid-base conditions of pH 1 and pH 11. The change wasn't big. The results confirmed that Gd-DO3A-Pca was stable in body pH conditions and was stable even in strong acid-base conditions.

4) Antioxidant effect analysis

The free radical scavenging ability of Gd-DO3A-Pca was evaluated through 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay. Protocatechuic acid and vitamin C (ascorbic acid), a representative antioxidant, were used as comparison groups. The DPPH radical is dark purple and turns yellow when reduced by reacting with antioxidants. The redox reaction causes a change in absorbance at a wavelength of 517 nm, and the antioxidant effect of Gd-DO3A-Pca can be verified by measuring this. In the present invention, various concentrations of Gd-DO3A-Pca (0, 5, 10, 20, 30 uM) were added to DPPH solution dissolved in ethanol (final concentration 100 uM), then reacted in the dark for 30 minutes to measure the absorbance to determine the antioxidant effect. was analyzed, and the results are shown in Figure 6.

Referring to Figure 6, Gd-DO3A-Pca showed higher radical scavenging ability than the comparison group, protocatechuic acid, and vitamin C (ascorbic acid), a representative antioxidant. These results show that Gd-DO3A-Pca has an excellent effect in inhibiting oxidative stress.

5) Evaluation of amyloid beta polymer targeting

5-1) Phantom experiment method to confirm amyloid beta polymer targeting

① 221.5 uL of HFIP was added to 1 mg of amyloid beta at a concentration of 1 mM and shaken for 1 hour at room temperature using a shaker to remove preaggregation.

② Dry the amyloid beta from which pre-aggregation was removed and add 221.5 uL of DMSO to make a 1 mM concentration. Use a mixer and sonicator to form a suspension, then add 878.5 uL of PBS (1X, pH 7.4) to make a 0.2 mM concentration. .

③ After culturing at 37°C for 4 days using a shaker, 200 uL of polymerized amyloid beta polymer was dispensed, and 20 uL of Gd-DO3A-Pca dissolved in PBS at a concentration of 2 mM and a commercial contrast agent (Gadovist ^® ) were added. Afterwards, the cells were cultured at 37°C for 24 hours using a shaker.

④ After 24 hours, centrifugation was performed to remove the supernatant, the amyloid beta polymer was washed using PBS, and 200 uL of a solution of PBS:DMSO = 9:1 was added to the pellet to prepare an MRI phantom sample. As a control, a phantom sample cultured only with amyloid beta polymer was used.

5-2) Amyloid beta polymer targeting effect analysis results

Using the phantom sample, the amyloid beta polymer targeting of Gd-DO3A-Pca and a commercial contrast agent (Gadovist ^® ) according to an example of the present invention was evaluated on a 9.4T MR equipment.

Referring to Figure 7 showing the results, there was little difference in contrast enhancement effect between the phantom cultured with only amyloid beta polymer (Aβ) and the phantom cultured with Gadovist ^® (Aβ+Gadovist), but Gd-DO3A-Pca and The phantom treated together ((Aβ+ Gd-DO3A-Pca) showed a signal intensity that increased more than twofold compared to the phantom cultured with only amyloid beta polymer. Through this, it was confirmed that the gadolinium contrast agent of the present invention has a targeting effect on amyloid beta polymer. Confirmed.

Amyloid beta polymers and fibrils, which are formed by the aggregation of overexpressed amyloid beta, accumulate in the brain, causing toxicity and destroying nerve cells, causing Alzheimer's disease, a degenerative brain disease. Gd-DO3A-Pca according to an embodiment of the present invention has the function of targeting amyloid beta polymer, a toxic protein, and may have the function of diagnosing Alzheimer's disease.

6) In vitro toxicity evaluation

An experiment was conducted to evaluate cytotoxicity against BV-2 cells, a mouse microglial cell line, and the results are shown in Figure 8.

Referring to Figure 8, when Gd-DO3A-Pca was treated at various concentrations (0, 100, 200, 400, 800 μM), the cell viability was 78% at 800 μM, and the cell viability (Cell) increased up to a high concentration of 400 μM. viability) showed a result of over 80%.

Considering that cell viability is slightly reduced at high concentrations exceeding 800 μM, it is desirable to treat Gd-DO3A-Pca up to 400 μM in in vitro experiments using BV-2 cells.

7) In vitro efficacy evaluation

BV-2 cells are activated by LPS (Lipopolysaccharides) and are therefore commonly used in neuroinflammatory cell experiments. 5x10 ⁴ BV-2 cells were seeded in 6 wells and treated with 200 ng LPS derived from Escherichia coli O127:B8 in serum free media. After 4 hours, LPS was removed, Gd-DO3A-Pca was treated at various concentrations (0, 100, 200, 400 uM), and 20 hours later, Griess assay was performed using the cell supernatant. The recovered cells were confirmed for expression levels of inflammatory factors through Western blot. In this experiment, cells not treated with LPS and normal BV-2 cells treated with Gd-DO3A-Pca were tested together to confirm the sole effect of Gd-DO3A-Pca on BV-2 cells.

Oxidative stress, protein aggregation, and several inflammatory cytokines play a role in the process of causing neuroinflammation. Looking at Figure 9, Gd-DO3A-Pca showed that it functioned to reduce oxidative stress by inhibiting free radical NO (nitric oxide) and iNOS (inducible nitric oxide synthase) induced by LPS.

Meanwhile, an increase in NO scavenging ability according to the concentration of Gd-DO3A-Pca was confirmed by quantifying expressed NO through Griess assay, and as a result of quantitative analysis of the amount of iNOS, a NO synthase enzyme, through western blot, NO In the same way as above, the result of inhibition by Gd-DO3A-Pca was confirmed.

Meanwhile, neuroinflammation is known to affect the development of neurodegenerative diseases such as dementia and Parkinson's disease. The NLRP3 inflammasome pathway, which causes neuroinflammation, is well known, and the results of Western blot (FIG. 9) show that Gd-DO3A-Pca reduces NLRP3, ASC, etc., which are inflammatory factors expressed in the pathway. You can check it through.

Although the present invention has been described above with reference to preferred embodiments, those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention as set forth in the following patent claims. You will understand that it is possible.

Claims (15)

A pharmaceutical composition for preventing or treating neuroinflammatory diseases, comprising a compound having the following formula (1) or a pharmaceutically acceptable salt thereof:
(One)
here,
L is *-(CH ₂ ) _x -A ¹ -(CH ₂ ) _y -A ² -(CH ₂ ) _z -*,
x, y and z are each independently selected as random integers from 0 to 5,
A ¹ and A ² are single bonds, in the group containing *-COO-*, *-CO-*, *-NH-*, *-CH ₂ -*, *-CONH-* and *-O-* Each is one or more independently selected structures,
X is a structure having the following formula (2):
(2)
* is the binding site. According to paragraph 1,
The A ² is *-NH-*,
Pharmaceutical composition. According to paragraph 2,
The A ¹ is *-CONH-*,
Pharmaceutical composition. According to paragraph 3,
where x is 1,
where y is 2,
where z is 0,
Pharmaceutical composition. According to paragraph 1,
A pharmaceutical composition, wherein the compound has the formula (3):
(3) According to paragraph 1,
The compound is gadolinium (Gd) coordinated with one or more water molecules,
Pharmaceutical composition. According to paragraph 1,
The compound specifically binds to mammalian amyloid beta polymer (oligomeric Aβ),
Pharmaceutical composition. According to paragraph 1,
The compound has a relaxation rate of 3.5 to 4.4 s ^-1 ,
Pharmaceutical composition. According to paragraph 1,
The compound crosses the blood-brain-barrier (BBB) when injected intravenously.
Pharmaceutical composition. delete delete delete delete According to paragraph 1,
The neuroinflammatory disease is an inflammatory neurodegenerative brain disease,
Pharmaceutical composition. According to clause 14,
The inflammatory neurodegenerative brain disease is a disease selected from Alzheimer's disease or Parkinson's disease,
Pharmaceutical composition.