JPH08143478A - Magnetic resonance contrast medium - Google Patents

Abstract

PURPOSE: To obtain a magnetic resonance contrast medium facilitating diagnoses of cancer or vascular lesions, by coating the surface of a metal-including fullerene as core with a polysaccharide. CONSTITUTION: The surface of core, a metal-including fullerene 5-10Å in average particle diameter expressed by formula Mm aCn (M is a paramagnetic metal element; (m) is 1-3; (n) is 30-100) is coated with a water-soluble polysaccharide bearing a functional group selected from among sulfate, ketone, amino and alkyls (e.g. chondroitintetrasulfuric acid). Specifically, 1-15wt. times of the polysaccharide based on the metal-including fullerene is used and a reaction is conducted at room temperature to 120 deg.C for 10min to 10h, thus obtaining the objective magnetic resonance contrast medium. By intravascularly administering this contrast medium, the signal intensity of vascular site(s) is enhanced with T1-emphasized image, enabling a white contrast to be manifested. This contrast medium is easy to administer, high in stability as a pharmaceutical preparation, and high in biological safety. Besides, this medium is long in the retention time in the blood vessel, therefore enabling vascular contrast and facilitating test time setting.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a magnetic resonance contrast agent (hereinafter referred to as an MR contrast agent) having improved utility for diagnosis by magnetic resonance imaging (MRI) of a living body, and particularly useful as an MR blood vessel contrast agent. It relates to MR contrast agents.

[0002]

BACKGROUND OF THE INVENTION In nuclear magnetic resonance (NMR) imaging, in order to enhance the NMR signal intensity or the contrast of the NMR image,
There is a method of using as a contrast agent a paramagnetic compound that reduces the spin-lattice relaxation time (T1) at low concentrations and the spin-spin relaxation time (T2) at high concentrations. As the paramagnetic compound, inorganic paramagnetic salts such as iron, manganese and chromium have been proposed.

However, none of these contrast agents for NMR was sufficient in terms of sharpness and accuracy of NMR images. On the other hand, other transition elements or lanthanoids (such as gadolinium), which have a larger number of unpaired electrons than iron, manganese, etc. and have a strong relaxation time shortening effect, especially the relaxation time T of hydrogen atoms present in the living body,
It is desired to use it as a so-called T1-weighted contrast agent that emphasizes 1 (spin-lattice). However, paramagnetic metals other than the essential metals of the human body cannot be used alone because they are highly toxic to living organisms and are poorly soluble in water. Therefore, for example, a gadolinium chelate complex of diethylenetriaminepentaacetic acid (Gd- It has been proposed to use it in the form of chelate complexes such as DTPA) (US Pat. No. 4,647,447).

However, since such a chelate complex contrast agent is distributed as an ionic contrast agent from the blood vessel to the extracellular fluid, there is a restriction on the diagnostic site in the body, and the blood brain barrier in the head region and the like. Not suitable for imaging at the brain capillary region due to the barrier. Further, the chelate complex is inferior in stability due to separation of ions and has a problem of side effects due to internal administration.

In addition, a conventional MR composed of Gd-DTPA
Since the I contrast medium is immediately excreted from the blood through the kidneys as urine, it cannot stay in the blood vessel for a long time, and thus it cannot be used as an MR blood vessel contrast medium. A main object of the present invention is to obtain a high contrast T1-weighted image due to the effect of reducing the relaxation time of tissue by a paramagnetic substance, which makes it possible to easily diagnose a lesion site and has high stability and safety. Is to provide.

Another object of the present invention is to provide an MR which has a long residence time in a blood vessel, does not exude from a blood vessel to a tissue unlike a Gd-DTPA contrast medium, and makes a contrast between a blood vessel portion and a tissue clear. It is to provide a contrast agent.

[0007]

Means and Actions for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that a metal having a structure in which a paramagnetic metal is confined in a cage made of carbon atoms. When the endohedral fullerene or its salt is used as an MR contrast agent, the original function of a paramagnetic metal that a T1-weighted image with an increased T1 effect in MRI is obtained is effectively exhibited, and toxicity is significantly reduced. Furthermore, they have found a surprising fact that they have excellent stability both in vivo and in vitro.

[0008] Further, the present inventors used a metal-encapsulated fullerene or a salt thereof as a core, and the surface of this core had a functional group selected from the group consisting of a sulfone group, a ketone group, an amino group and an alkyl group for formulation. By coating with a polysaccharide having a metal-encapsulated fullerene or a salt thereof, the affinity for water is increased, thereby increasing the in-vivo affinity and mitigating the harmful effects of long-term retention in blood vessels. Load is reduced, the safety is improved, and moreover, the specific functional group of the polysaccharide that serves as the outer shell reacts with the metal-encapsulated fullerene or its salt to form a strong bond,
We have also found new facts that show high stability over a long period of time.

That is, the MR contrast agent of the present invention has the general formula: M _m @C _n (where M is a paramagnetic metal element, m is an integer of 1 to 3, and n is an integer of 30 to 100). ) The average particle size is 5
A metal-encapsulated fullerene of 10 to 10 liters or a salt thereof is used as a core, and the surface of this core is coated with a polysaccharide having a functional group selected from the group consisting of a sulfone group, a ketone group, an amino group and an alkyl group.

Since the MR contrast agent of the present invention contains a paramagnetic metal, it exhibits a high paramagnetic effect, the T1 effect is increased, and it can be used as a T1-weighted contrast agent. Further, the paramagnetic metal is included in the fullerene, and the fullerene is coated with the polysaccharide, so that the problems of biological reaction and toxicity are solved, and the affinity with blood is improved.
Moreover, the MR contrast agent of the present invention has an advantage that it can stay in the blood vessel for a long time because the excretion from the kidney is delayed. Furthermore, since the metal-encapsulated fullerene used in the present invention has an extremely small average particle size of 5 to 10Å, even if it stays in a blood vessel for a long time, it is free from adverse effects such as lowering blood pressure and shock, and is highly safe for living organisms. .

The formula for the metal-encapsulated fullerene indicates that the fullerene having n carbon atoms contains m paramagnetic metal elements. That is, the symbol @ means that the fullerene composed of n carbons contains m metal atoms. Examples of the paramagnetic metal element include transition elements. The transition elements include 3A group (current 3 group) to 7A group (current 7 group), 8 group (current 8, 9 and 10 group), 1B group (current 11 group) in the periodic table.
Each element belonging to (group) is included. Specifically, for example, S
c, Y, lanthanoid element, actinide element, Ti,
Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn,
Tc, Re, Fe, Ru Os, Co. Rh, Ir, N
i, Pd, Pt, Cu, Ag, Au, etc. are included in the transition elements. Of these, in the present invention, it is preferable to use an element having a large number of unpaired electrons in 3d and 4f orbits. Mn, Fe, Co, etc. in the 3d orbital, eg G in the 4f orbital
d, Eu, Tb, Er, etc. are included. The number of metal elements contained in the fullerene is not particularly limited,
It is suitable to be an individual.

Further, fullerene is a group of cage-shaped carbon molecules.
It is a generic term and is a hollow molecule in which multiple carbon atoms are bonded.
It C for fullerene₃₂ C₅₀ C₆₀ C₇₀ C₇₆ C
₇₈ C ₈₂ C₈₄ C₉₀ C₉₆Such as C₃₀~ C₁₀₀Represented by
Included fullerene, preferably C₆₀~ C₁₀₀so
Included are the fullerenes represented. Metal in the present invention
The endohedral fullerene can be produced by a known method.
It A typical manufacturing method is laser evaporation under high temperature and high pressure.
Is. That is, the predetermined metal oxide and graphite particles
Heated at a temperature of 200-1200 ℃
To dissolve the pitch and mix evenly.
Metal oxidation by heat treatment (baking) at ~ 1800 ° C
Removes oxygen atoms from the material to form metal carbide,
Makes fullerene easier. Then, the sample is a quartz tube
High temperature in the vicinity of evaporation while accommodating inside and flowing inert gas
Keep it at a constant temperature and evaporate it with a YAG laser.
Generate a genus endohedral fullerene.

Further, as the evaporation means, arc discharge may be used instead of the laser. That is, a sample rod containing a metal carbide is set as an anode in an arc discharge device, an arc discharge is caused to occur, and the generated soot is collected. The generation and recovery of soot by arc discharge are preferably performed almost completely under anaerobic conditions. This method is particularly suitable for mass production of metal-containing fullerenes. The produced metal-encapsulated fullerene is isolated through extraction, separation and purification. As a means for separating and purifying the specific metal-encapsulated fullerene, high performance liquid chromatography capable of extracting the specific metal-encapsulated fullerene from an extract containing various sizes of the fullerene and the metal-encapsulated fullerene can be preferably used.

Further, in the present invention, the metal-encapsulated fullerene can be used by carrying a salt such as an anion salt. Examples of anion salts of metal-encapsulated fullerenes include alkali metal salts of metal-encapsulated fullerenes, alkaline earth metal salts,
Examples thereof include amine salts, and alkali metal salts are particularly preferable. The anion salt of metal-encapsulated fullerene can be produced, for example, by dropping a chlorobenzene solution of metal-encapsulated fullerene into a tetrahydrofuran solution of alkaline earth elements of tetraphenylboron. In addition,
In the following description, “metal-encapsulated fullerene” is used as a concept including its salt.

In the present invention, the obtained metal-encapsulated fullerene is used as a core, and the surface of this core is coated with the above-mentioned polysaccharide having a specific functional group. As the polysaccharide having a specific functional group, a water-soluble one is preferable, and for example, chondroitin 4-sulfate, chondroitin 6-sulfate, hyaluronic acid, dermatan sulfate, keratosulfate, chitin, heparin,
Examples thereof include polysaccharides or mucopolysaccharides such as pullulan, sialic acid, neuraminic acid, acetylhexosamine, inulin, agarose, glycomannan, triacetyl cellulose, dextran and N-acetylglycosamine derivatives. Furthermore, a sulfone group substituted, an amino group substituted, alkyl-substituted or ketone group (e.g., _{-CH 2 -CO-CH 2 CH 3} , -CH 2
-OCO-NH ₂ etc.) substituted dextrin can also be preferably used.

Examples of the alkyl group include carbon 1 such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, t-butyl group, pentyl group and hexyl group.
~ 6 alkyl groups. These polysaccharides have a number average molecular weight of about 100 to 300,000, preferably about 500 to
Suitably, it is in the range of 100,000, more preferably about 2000-50,000. In addition, the polysaccharide may be used as a mixture with various oligosaccharides (glucose, maltose, lactose, cellobiose, maltotriose, melibiose, etc.), pullulan and the like.

Further, the polysaccharide can be added with various receptors having specificity of accumulation in abnormal cells such as tumors to impart a function as a therapeutic agent. Examples of the receptor include various monoclonal antibodies, various proteins, and immune-related agents (immune cell activation and activation materials).
This helps, for example, in the diagnosis and treatment of brain tumors,
It also has a killer cell inducing effect.

The MR contrast agent of the present invention is produced by a method in which an aqueous sol of metal-encapsulated fullerene is prepared and then coated with a polysaccharide. The reaction between the metal-encapsulated fullerene and the polysaccharide is usually carried out by mixing these at a predetermined ratio and heating. The weight ratio of the metal-encapsulated fullerene to the polysaccharide may be about 1: 1 to 1: 6. The reaction may be performed at room temperature to about 120 ° C. for about 10 minutes to 10 hours, and usually about 1 hour of heating under reflux is sufficient. The concentration of the metal-encapsulated fullerene in the reaction solution is usually about 0.1 to 10% by weight / volume as a metal element, preferably about 1 to 10.
A range of 5% weight / volume is suitable.

After the reaction, a purification operation for separating unreacted polysaccharides and low molecular weight compounds is carried out by using a known means such as ultrafiltration to obtain an aqueous sol having a predetermined purity and concentration. To this, a poor solvent such as methanol, ethanol, or acetone was added to preferentially precipitate and deposit the metal-encapsulated fullerene-polysaccharide complex, and this was separated, and then the precipitate was redissolved in water and dialyzed with running water. , Concentrate under reduced pressure if necessary,
An aqueous sol of the above complex is obtained. Then, if necessary,
You may perform centrifugation, filtration, pH adjustment, etc.

The MR contrast agent of the present invention thus obtained is
The average particle diameter is about 10 to 100 nm, and the magnetic iron oxide fine particles as the core have an average particle diameter of about 5 to 10Å. These particle sizes are measured by the dynamic light scattering method. The amount of the polysaccharide used is about 1 to 15 times, preferably 3 to 10 times based on the weight of the metal-encapsulated fullerene used.

The addition and mixing of the respective aqueous solutions can be carried out with heating from room temperature to about 100 ° C. with stirring. If necessary, a base or acid is added to adjust the pH,
The reaction is carried out by heating under reflux at a temperature of about 30 to 120 ° C. for about 10 minutes to 5 hours, preferably about 1 hour. The obtained reaction liquid is purified in the same manner as in the first method, and if necessary, pH adjustment, concentration and filtration are performed.

In these methods, the particle size of the produced composite can be controlled by adjusting the reaction time and the reaction temperature. The ratio of the polysaccharide to the metal-encapsulated fullerene is not particularly limited, but generally, the polysaccharide is about 0.1 to 5 parts by weight, preferably 0.2 per 1 part by weight of the metal element in the metal-encapsulated fullerene. It can be contained within the range of 3 parts by weight.

The above-mentioned polysaccharide and the metal-encapsulated fullerene react with each other by the above-mentioned method to form a compound bonded to each other. Specifically, it has a form in which a metal-encapsulated fullerene is used as a core, and the surface thereof is strongly coated with a polysaccharide. This means that, for example, when the reaction product is fractionated on a gel column, an elution peak is observed on the polymer side of the elution position of the polysaccharide,
And it is confirmed by the analysis of the peak that both sugar and metal element are detected.

The T1 relaxation ability of the MR contrast agent of the present invention is generally about 2 to 30 (sec · mM) ⁻¹ , preferably about 5 to 15 (s).
ec · mM) ^-1 . Also, T2 mitigation capacity is generally about 5
~ 300 (sec ・ mM) ^-1 , preferably about 6 ~ 30 (sec ・ m)
M) ^-1 . The MR contrast agent of the present invention is preferably used in the form of an aqueous sol. The concentration of the metal-encapsulated fullerene-polysaccharide complex in the aqueous sol can be appropriately set in consideration of the dose to the living body and the like, but is usually about 0.05 to 3 in terms of metal element.
A mmol / l, preferably about 0.2-1 mmol / l is sufficient. Further, in the preparation of the aqueous sol, for example, inorganic salts such as sodium chloride, monosaccharides such as glucose, sugar alcohols such as mannitol and sorbitol, acetates, lactates, citrates, organic acid salts such as tartaric acid. , Phosphate buffer, Tris buffer and the like can be added as appropriate.

The MR contrast agent of the present invention uses a fullerene encapsulating a paramagnetic metal element as a core, and the polysaccharide serving as an outer shell has a specific functional group. The effect as a magnetic material is expressed,
It can be used as a T1-weighted contrast agent. In addition, according to electron microscope observation, the side chain of the outer shell polysaccharide has an elastic body structure in the form of a hairball-shaped or coiled mass, and if it is extended, it has a very long molecular structure. It is not easily decomposed in the body and can be present in blood for a long time as a drag agent. Therefore, a paramagnetic effect is exhibited even when administered in an extremely small amount, and it can be suitably used as a blood vessel contrast medium or a T1 tissue relaxation contrast medium. Therefore, it is appropriate that the MR contrast agent of the present invention is used in an amount of about 1 to 2 cc / kg by intravenous administration in the case of an aqueous sol having a metal element conversion concentration of 0.2 mmol / l. A general dose in terms of metal element is about 0.1 to 2 mmol / l / kg, preferably about 0.2 to 1 mmol / l / kg in terms of metal element.

The administration method is preferably intravenous injection, intraarterial injection, intravesical injection, intramuscular injection, infusion and the like, but oral administration and enteral administration are also possible. M of the present invention
The R contrast agent has a characteristic that it stays in the bloodstream for a long time, is less likely to be excreted in the urine through the kidney, and can stay in the vascular system, which is a characteristic of a sugar agent, for a long time. At that time, the recognition sulfone group to the polysaccharide surface with an outer shell by the presence of certain functional groups, such as (-SO ₃ H, sulphate group), a ketone group, the recognition of the biological defense mechanism and the sugar compound And delay the decomposition and absorption of the metal-encapsulated fullerenes. In addition, it is estimated that it takes a relatively long time to decompose and absorb in vivo due to the outer shell structure of the polysaccharide due to the reaction with the metal-encapsulated fullerene (for example, in the case of β-bonded polysaccharide, the side chains are enzymatically related to each other). It is hard to be cut). Therefore, MRI can be suitably performed on an organ that requires a relatively long time to reach the contrast agent, and
There is an advantage that the inspection time can be set easily. In addition,
Blood vessels are mainly targeted as an organ to be imaged. Unlike conventional Gd-chelate contrast agents, it does not penetrate through blood vessels and is suitable for contrast enhancement between blood vessels and surrounding tissues.
In addition, the liver, lymphatic vessel, brain, spleen, and digestive tract can be imaged.

At this time, the MR contrast medium of the present invention has safety such as intravenous bolus injection without lowering blood pressure or shock. In particular, the MR contrast agent of the present invention has a T1 relaxation capacity larger than the T2 relaxation capacity by making the particle size of the metal-encapsulated fullerene extremely small.
Since the presence of the metal-encapsulated fullerenes has a high signal and has an excellent characteristic that white images can be taken, the effect is considered to be great in the latest equipment such as high-speed MRI imaging. As a result, the effect of significantly facilitating the diagnosis of lesions such as cancer and blood vessel lesions can be expected.

[0028]

【Example】

 Reference example (Production of gadolinium-encapsulated fullerene) manufactured by Toyo Tanso Co., Ltd.
Graphite electrode (diameter 20 mm, length 250 mm)
Drill a hole with a diameter of 15 mm and a length of 122 mm at one end.
Gadolinium oxide Gd in₂O ₃, Graphite powder
Fill a mixture of pitch and pitch and puncture with a graphite lid.
Closed. At this time, the ratio of the number of atoms of gadolinium and carbon
Was set to 1:50. Put this in a high vacuum heat treatment furnace,
Heat at 0 ° C for 10 minutes to melt the pitch and make a uniform sample.
I got a composite rod.

In order to remove the volatile components contained in the pitch, as a pretreatment, the composite rod was placed in a quartz tube and baked at 1000 ° C. for 1 hour while evacuating to vacuum with an oil rotary pump. Then, in order to form a gadolinium carbide, baking was performed at 1600 ° C. for 3 hours in a high vacuum heat treatment furnace while evacuating to a vacuum with an oil diffusion pump.

Next, the baked composite rod is set as an anode in a carbon cluster generator (arc discharge device), the interior of the device is evacuated by an oil rotary pump, and then the anode and the cathode (carbon cathode) are brought into contact with each other. In this state, an electric current was flown so as not to blow an arc to heat it, and baking was performed again. This is to remove oxygen and impurities attached to the surface of the rod.

After completion of baking, helium gas was introduced while exhausting with an oil rotary pump, and the inside of the apparatus was 40 torr.
Adjusted so that Then, move the anode a few mm from the cathode
Separated, DC current 500A (current density about 1.6A / m
An arc discharge was generated at m ² ). Since the anode was evaporated and decreased by the arc discharge, the anode was slowly advanced toward the cathode by the manual operation panel so that the gap between the anode and the cathode became constant.

The soot produced by the arc discharge was sent from the production chamber to the recovery chamber by a helium gas stream, cooled with liquid nitrogen and trapped. After the arc discharge, nitrogen gas was introduced into the device to return it to atmospheric pressure, and the soot in the recovery chamber was recovered. The recovered soot was subjected to Soxhlet extraction for 2 days using carbon disulfide as a solvent. The residue remaining in the cylinder paper was subjected to Soxhlet extraction again using pyridine as a solvent.

Each extract was dissolved in toluene and subjected to high performance liquid chromatography (recycle preparative HPLC type LC-908 and LC-908-C60 manufactured by Nippon Analytical Industry Co., Ltd.).
Type) and separated and purified. The column used was a pyrene-based Cosmosil Buckprep Column. Detection wavelength is 3
It is 12 nm. The size of each fraction produced in this HPLC corresponds to the fullerene size, or which fraction corresponds to the gadolinium-encapsulating fullerene. Laser desorption time-of-flight mass spectrometry (Laser-DesorptionTime-of-
Flight mass spectrometry; LD-TOF-MS).

The results are shown in FIGS. FIG. 1 shows the results of time-of-flight mass spectrometry of what was extracted with carbon disulfide, and FIG. 2 shows the HPLC chart after C ₈₆ in the one extracted with carbon disulfide. In FIG. 2, * indicates a fraction containing gadolinium-encapsulating fullerenes. FIG. 3 shows the result of mass spectrometry in the fraction of (*) in FIG.

FIG. 4 shows the results of time-of-flight mass spectrometry of the pyridine-extracted product, and FIG. 5 shows the HPLC chart of the pyridine-extracted product. In FIG. 5, * indicates a fraction containing gadolinium-encapsulating fullerenes. Figure 6
Shows the result of mass spectrometry in the fraction of (*) in FIG. From these figures, it can be seen that most of the gadolinium-encapsulating fullerenes are present in the pyridine extract. Example 1 (Production of chondroitin sulfate-gadolinium-encapsulated fullerene complex) On the other hand, an aqueous solution prepared by dissolving 43 g of chondroitin sulfate in 120 ml of distilled water was heated to 80 ° C. under an Ar atmosphere, and 10 g of gadolinium-encapsulated fullerene was added.

While maintaining the temperature at 80 ± 5 ° C., 3N sodium hydroxide was added dropwise with stirring to adjust the pH to 11. Then, 6N hydrochloric acid was added dropwise to adjust the pH to 6.9. In this state, the temperature of the solution was kept at 100 ° C., heated for 1 hour, then cooled to 20 ° C., and then 3000 rpm
Centrifugation was carried out for 30 minutes, and the supernatant was collected. 262 ml of methanol was added to 414 ml of this supernatant liquid,
The precipitate of the complex was obtained by centrifugation at 3000 rpm for 11 minutes. Dissolve this precipitate in 150 ml of water,
The pH was adjusted to 8 with N sodium hydroxide, and dialysis with running water was performed for about 20 hours. The dialysate was adjusted to pH 8 with 3N sodium hydroxide and concentrated under reduced pressure to obtain an aqueous sol of a chondroitin sulfate-gadolinium-encapsulated fullerene complex in which the gadolinium-encapsulated fullerene was coated with chondroitin sulfate. The analysis results of this aqueous sol are shown below.

Gadolinium-encapsulated fullerene concentration: 46.2 mg / ml chondroitin sulfate concentration: 153.5 mg / ml pH: 7.0 Core average particle size: 8.5Å Magnetization at 10 Tesla (10 K): 17.5 emu / g T1 relaxation ability: 2.8 (sec · mM) ⁻¹ T2 relaxation ability: 3.2 (sec · mM) ⁻¹ Average particle size of the whole: 42 nm Test example (in vivo MR imaging) Rat (Wistar species, postnatal 3) After anesthesia by injecting 0.25 cc of Nembutal into the abdominal cavity of a body weight of 300 g for a week, the liver, the kidney, and the muscle site before injection of the contrast agent are axially cut using the spin echo method.
T3 weighted image (repetition time: 600 ms, echo time: 15 ms), T2 weighted image (repetition time: 2000 ms, echo time: 90 m) with a slice thickness of 3 mm in the direction
s) and proton density image (repetition time: 2
000 ms, echo time: 15 ms) was imaged and used as a control image.

Then, the complex (contrast agent) obtained in Example 1
After administration of 0.3 cc (concentration 13.0 μM) into the tail vein, within about 15 to 30 minutes, a T1-weighted image (repetition time: 600 ms, with the same cross section and the same slice thickness by the same spin echo method as described above) Echo time: 15 ms), T2-weighted image (repetition time: 2000 ms, echo time: 90)
ms) and proton density image (repetition time:
(2000 ms, echo time: 15 ms) was imaged and the change in signal intensity was compared with the control image before administration of the contrast agent. For the value of the signal strength of the image, the Roy (region of interest) on the CRT (display) screen was set, and the average value was calculated.
Table 1 shows the results.

A clinical MR device as an image pickup device (trade name "Magnetom" manufactured by Siemens, static magnetic field strength: 1.5)
T) was used.

[0040]

[Table 1]

From Table 1, it can be seen that the signal intensity was enhanced in the T1-weighted image as a whole, and the signal intensity was significantly enhanced especially in the liver having a large blood volume. That is, the signal intensity of the blood vessel portion was enhanced and the image was white. The same T1 contrast effect was obtained when 0.4 cc of the complex (contrast agent) obtained in Example 2 (concentration 8.8 μM) was administered to the tail vein of rats in the same manner as above.

[0042]

INDUSTRIAL APPLICABILITY The MR contrast agent of the present invention, when administered into a blood vessel, enhances the signal intensity of the blood vessel portion in a T1-weighted image to allow white contrast, and is easy to administer. It is highly stable and highly safe for living organisms. Furthermore, since the MR contrast agent of the present invention has a long residence time in the blood vessel, the blood vessel can be imaged and the examination time can be easily set.

[Brief description of drawings]

FIG. 1 is a graph showing the result of time-of-flight mass spectrometry of a sample extracted with carbon disulfide in a reference example.

FIG. 2 is an enlarged view of an HPLC chart of C _{86 and} after in a product extracted with carbon disulfide.

FIG. 3 is a graph showing the results of time-of-flight mass spectrometry for the fraction (*) in FIG.

FIG. 4 is a graph showing the results of time-of-flight mass spectrometry of the pyridine-extracted product.

FIG. 5 is an HPLC chart of the product extracted with pyridine.

6 is a graph showing the results of time-of-flight mass spectrometry for the fraction (*) in FIG.

Claims (3)

[Claims] 1. An average particle size represented by the general formula: M _m @C _n (where M is a paramagnetic metal element, m is an integer of 1 to 3, and n is an integer of 30 to 100). Is 5
A metal-encapsulated fullerene of 10 to 10 liters or a salt thereof is used as a core, and the surface of the core is coated with a polysaccharide having a functional group selected from the group consisting of a sulfone group, a ketone group, an amino group and an alkyl group. Magnetic resonance contrast agent. 2. The magnetic resonance contrast agent according to claim 1, wherein the metal element in the metal-encapsulated fullerene is a transition element. 3. The magnetic resonance contrast agent according to claim 2, wherein the transition element is a lanthanoid element.