JPH05186372A - Fat emulsion and contrast medium for mri diagnosis - Google Patents

Abstract

PURPOSE:To provide a fat emulsion containing a paramagnetic metal atom and useful for a nuclear magnetic resonance diagnosis method used for clinical diagnosis. CONSTITUTION:The contrast medium for MRI diagnosis contains a compound of the formula (m is 1-3; R1, R2 are H, lower alkyl; R3 to R6 are OH, etc.,) capable of forming a chelate bond with a paramagnetic metal atom (e.g. Gd, Tb, Ho). The preferable composition comprises 0.01-15% of the paramagnetic metal atom, the compound of the formula in a molar rate of approximately 1-5 based on the paramagnetic metal atom, 0.5-50%W/V of a fat or oil (e.g. soybean oil), an emulsifier (e.g. phospholipid, synthetic surfactant) in an amount of 1-100 pts.wt. per 100 pts.wt. of the fat or oil, and a suitable amount of water. When used as a contrast medium for MRI diagnosis, the fat emulsion gives images having excellent contrasts and has an effect to transfer to various organ tissues such as reticuloendothelial system organs, inflammatory sites and arteriosclerotic sites.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to fat emulsions and their uses. More specifically, the present invention relates to magnetic resonance imaging (hereinafter,
The present invention relates to a fat emulsion containing a paramagnetic metal atom useful as a diagnostic contrast agent (referred to as MRI).

[0002]

2. Description of the Related Art MRI is an image diagnostic method capable of obtaining a tomographic image of an arbitrary direction of a living body by using a static magnetic field and a varying magnetic field (gradient magnetic field or radio frequency wave). The application has started. Initially, a normal-conducting magnet was used to create a static magnetic field, but in the 1980s, a superconducting magnet that could accommodate the human body was developed, which made it possible to significantly improve image quality and further spread MRI. I got higher. In addition, the introduction of a superconducting magnet that can create a static magnetic field of 1.5 Tesla (T) or higher will cause protons (hydrogen nuclei).
Other than nuclides, namely phosphorus ( ³¹ P) and sodium ( ²³ Na)
It became possible not only to visualize the anatomical structure of the living body but also to diagnose the function of many tissues or organs. For MRI, the above-mentioned nuclear magnetic resonance (n
In addition to uclear magnetic resonance (NMR), electron spin resonance (ESR) is included.

MRI has been introduced into the medical field in recent years, and since then, it has rapidly progressed and spread. Unlike conventional X-ray CT, MRI is characterized in that it does not require radiation and thus does not pose a problem of being exposed to radiation, that it can visualize an arbitrary cross section, and that it does not interfere with bones. Currently, a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) complex compound is used as a contrast agent (contrast enhancer) for MRI diagnosis. This utilizes the fact that gadolinium, which is a paramagnetic metal atom, has the action of shortening the relaxation time of surrounding hydrogen atoms and enhancing the contrast.
In addition, the above complex compound chelates gadolinium to reduce toxicity due to gadolinium.

[0004]

Since Gd-DTPA is carried to each tissue along with the bloodstream and exists in extracellular fluid, Gd-DTPA shortens the relaxation time at the site where the brain barrier is broken or the site where blood flow is large, but It does not sufficiently migrate to system organs, inflammatory sites, arteriosclerotic sites, etc., and the contrast medium itself has no ability to identify tissues. Therefore, development of a contrast agent for MRI diagnosis targeting a specific tissue is desired. The present invention was devised to solve the above-mentioned problems of the prior art, and is for MRI diagnosis having sufficient contrast enhancing ability, which is sufficiently transferred to reticuloendothelial organs, inflammatory sites, arteriosclerotic sites, etc. An object is to provide a contrast agent and a fat emulsion therefor.

[0005]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have conducted various studies on contrast agents, and as a result, it has been found that a fat emulsion containing a paramagnetic metal atom was used as a contrast agent for MRI diagnosis. The present invention has been completed by finding that an image having a contrast can be obtained and that the fat emulsion can be transferred to each organ / tissue such as the reticuloendothelial organ, the inflammatory site, and the arteriosclerotic site. That is, the present invention is a fat emulsion containing a paramagnetic metal atom, and an MRI diagnostic contrast agent comprising the same.

The contrast agent of the present invention is a fat emulsion containing paramagnetic metal atoms. The composition of the fat emulsion can be appropriately adjusted depending on the purpose and method of use of the fat emulsion.
When used as a contrast agent for I diagnosis, its preferable composition is about 0.01 to 15% (W / V) of a paramagnetic metal atom, preferably about 0.1.
About 1 to 10% (W / V), a compound capable of forming a chelate bond with a paramagnetic metal atom (hereinafter referred to as a chelating compound) in a molar ratio of about 1 to 5 with respect to the paramagnetic metal atom, preferably 0.5 to 1.5 Degree, fat (preferably soybean oil) about 0.5 to 50% (W / V), preferably about 2 to 30% (W / V), weight ratio to fat 100 of 1 to 1
An emulsifier in an amount of 00, preferably 5-60 (e.g. phospholipids,
It is a fat emulsion consisting of synthetic surfactants, etc.) and an appropriate amount of water.

As the paramagnetic metal atom, various paramagnetic metal atoms can be used.
I When used as a diagnostic contrast agent, paramagnetic metal atoms include chromium (Cr), gadolinium (Gd), manganese (M
n), iron (Fe), cobalt (Co), nickel (Ni), praseodymium (Pr), neodymium (Nd), samarium (Sm), ytterbium (Yb), terbium (Tb), dysprosium (Dy), holmium ( Examples thereof include divalent or trivalent ions such as Ho), erbium (Er), and copper (Cu). In particular, ions such as gadolinium, terbium, dysprosium, holmium, erbium, and iron are preferably used.

The preparation of fat emulsions containing paramagnetic metal atoms comprises
For example, it is carried out by preparing a fat emulsion of a chelating compound by emulsifying the chelating compound and fats and oils with an emulsifier, and making a chelate bond between the fat emulsion and a paramagnetic metal atom (preferably gadolinium). It can also be carried out by preparing a fat emulsion using a paramagnetic metal atom previously chelated with a chelating compound. The fat emulsion at this time can be carried out by a means known per se.

The above-mentioned chelating compound is not particularly limited as long as it can form a complex with a paramagnetic metal atom and has a suitable fat-solubility so as to be suitable for fat emulsion formation. Examples include DTPA (diethylenetriaminepentaacetic acid) derivatives and salts thereof, and examples thereof include monoalkylamide DTPA, monoarylamide DTPA, monoalkyl ester DTPA, monoaryl ester DTPA,
Dialkylamide DTPA, Diarylamide DTPA
A, dialkyl ester DTPA, diaryl ester DTPA, alkylated DTPA and the like are exemplified. Of these compounds, alkyl is exemplified by alkyl having 1 to 20 carbon atoms, and aryl is exemplified by phenyl, naphthyl and the like. Further, the aryl may be alkyl, aryl substituted with a halogen atom or the like. Other examples of chelating compounds include: TTHA: triethylenetetraaminehexaacetic acid EDTA: ethylenediaminetetraacetic acid DOTA: 1,4,7,10-tetraazacyclododecanetetraacetic acid EHPG: N, N'-ethylenebis [2 -(2-Hydroxyphenyl) glycine] cyclam: fat-soluble derivatives such as 1,4,8,11-tetraazacyclotetradecane.

Preferred chelating compounds include compounds represented by the following general formula [I] and salts thereof. [Wherein, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different and each is a hydrogen atom or a lower alkyl group, R ₃ , R ₄ and R 2
₅ and R ₆ are the same or different and are a hydroxyl group or a group: (In the formula, n is 0 or 1, X is —NH— or —O—, Y is an alkylene group, A is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group,
B represents an alkyl group or an alkenyl group). However, among R ₃ , R ₄ , R ₅ and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R ₃ and R ₅ are both hydroxyl groups and R ₄ and R ₆ Except those in which both are hydroxyl groups. ]

In the compound represented by the above general formula [I], the lower alkyl group may be linear or branched and has 1 to 4 carbon atoms, specifically methyl, ethyl,
Examples include propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. The alkylene group is
It may be linear or branched and may be methylene, ethylene, propylene, tetramethylene, pentamethylene, 1
-Methylethylene, 1-methyltetramethylene, hexamethylene, octamethylene, decamethylene and the like are exemplified.

The lower alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy and the like. The alkyl group may be linear or branched and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl and the like. The alkenyl group may be linear or branched, and the position and number of double bonds are not particularly limited, but preferably hexenyl, octenyl, 3,7-dimethyl-2,6-dioctadienyl, 9-octadecenyl. Etc. Examples of the halogen atom include chlorine atom and bromine atom.

In the compound represented by the general formula [I],
A compound in which the sum of carbon numbers of Y and B is 5 or more is preferable. More preferably, a compound in which the sum of carbon numbers of Y and B is 8 to 12 is preferable. The bonding positions of the substituents A and B on the phenyl group are not particularly limited, but B is preferably Y
On the other hand, meta or para position is preferable. As the salt of the compound represented by the general formula [I], a pharmaceutically acceptable salt is preferably used, and such a salt includes a salt with a metal (for example, sodium, potassium, etc.), an organic base [for example, ethanolamine, Morpholine, meglumine (N-methylglucamine) and the like], and salts with amino acids (eg arginine, ornithine and the like) are exemplified.

The compound represented by the general formula [I] is a novel compound. The said compound can be manufactured by various methods, for example, can be obtained by the method shown by the following reaction scheme-1.

Reaction formula-1 (In the formula, m, n, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y,
A and B are the same as above, and X ₁ is —NH ₂ or —OH. )

In the above reaction step, the compound [III], which is an acid anhydride, is the known dehydration reaction of the compound [II] with, for example, acetic anhydride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, etc. It can be obtained by attaching to. This reaction can be carried out by reacting in a solvent that does not adversely affect the reaction at about 50 to 100 ° C. for about 3 hours to 3 days. Compound [I] is a compound
It can be obtained by reacting [III] with a compound [IV]. The reaction between the compound [III] and the compound [IV] can be carried out according to a conventional method of reacting an acid anhydride with an amino compound or a hydroxy compound.
To a solution dissolved in an organic solvent such as N, N-dimethylformamide (DMF), compound [IV] is dissolved in an organic solvent such as methylene chloride or chloroform, if necessary, and added, and then at room temperature to about 90 ° C for 30 minutes It can be carried out by reacting for about 5 days. In this reaction, a basic compound such as pyridine, triethylamine, N, N-dimethylaniline or the like may be added. In this reaction, R _{3 of} compound [I]
In the case of preparing a compound having two hydroxyl groups in R _{6 to} R ₆ , compound [IV] is used in an amount of 2.0 to 2.3 equivalents based on compound [III].
When preparing a compound having three hydroxyl groups, the compound [I
V] is used in 1.0 to 1.3 equivalents relative to compound [III]. When the number of the hydroxyl groups is 3, after the reaction, about 1.0 equivalent of water is added and the reaction is carried out under the above reaction conditions to add water to the unreacted carboxylic acid anhydride moiety, leading to the compound [I]. The addition reaction of water to the carboxylic acid anhydride moiety is performed by the compound [II
The compound [III] may be performed prior to the reaction of [I] and [IV]. The salt of compound [I] can be prepared according to a conventional method. The compound [I] and its salt thus obtained can be isolated and purified by a conventional method such as recrystallization, reprecipitation, column chromatography and the like.

In the compound represented by the general formula [I], a suitable chelating compound is specifically shown as N- (4-
Octylphenylcarbamoylmethyl) diethylenetriamine-N, N ', N ", N" -tetraacetic acid; N- (4-hexylphenylcarbamoylmethyl) diethylenetriamine-N, N', N ",
N "-tetraacetic acid; N- (4-decylphenylcarbamoylmethyl) diethylenetriamine-N, N ', N", N "-tetraacetic acid; N-
(4-dodecylphenylcarbamoylmethyl) diethylenetriamine-N, N ', N ", N" -tetraacetic acid; N, N "-bis (4-octadecaphenylcarbamoylmethyl) diethylenetriamine-N, N', N" -tri Acetic acid; N, N "-bis (4-tetradecaphenylcarbamoylmethyl) diethylenetriamine-N, N ', N"-
Triacetic acid; N, N "-bis (4-dodecylphenylcarbamoylmethyl) diethylenetriamine-N, N ', N" -triacetic acid; N, N "
-Bis (4-octylphenylcarbamoylmethyl) diethylenetriamine-N, N ', N "-triacetic acid; N, N" -bis (4-hexylphenylcarbamoylmethyl) diethylenetriamine-N, N', N "-triacetic acid; N- (4-hexylphenylcarbamoylmethyl) triethylenetetraamine-N, N ', N ", N'",
N '"-pentaacetic acid; N, N'"-bis (4-octadecaphenylcarbamoylmethyl) triethylenetetraamine-N, N ', N ",
N '"-tetraacetic acid; N, N'"-bis (4-octylphenylcarbamoylmethyl) triethylenetetraamine-N, N ', N ",
N '"-tetraacetic acid; N- (4-octylphenylcarbamoylmethyl) triethylenetetraamine-N, N', N", N '", N'"-pentaacetic acid; N, N "-bis (4- Butylphenylmethoxycarbonylmethyl) diethylenetriamine-N, N ', N "-triacetic acid;
N, N "-bis (4-tridecylphenylmethoxycarbonylmethyl) diethylenetriamine-N, N ', N" -triacetic acid; N- (4-
Tridecylphenylmethoxycarbonylmethyl) diethylenetriamine-N, N ', N ", N" -tetraacetic acid; and the like.

Other preferred chelating compounds include compounds represented by the following general formula [V] and salts thereof. [Wherein, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different and each is a hydrogen atom or a lower alkyl group, R ₃ , R ₄ and R 2
₅ and R ₆ are the same or different and are a hydroxyl group or a group: (In the formula, Q and T are the same or different, -NH- or -O-, D and E are the same or different, and a fatty acid residue having 6 or more carbon atoms or an alkyl group having 6 or more carbon atoms, p Is 0
Represents an integer from 6 to 6, and when p is 0, T is not present). However, among R ₃ , R ₄ , R ₅ and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R ₃ and R ₅ are both hydroxyl groups and R ₄ and R ₆ Except those in which both are hydroxyl groups. ]

In the compound represented by the above general formula [V], examples of the lower alkyl group include those defined in the compound represented by the above general formula [I]. In the fatty acid residue (acyl group) having 6 or more carbon atoms of D and E,
Examples of the fatty acid include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, elaidic acid, erucic acid, linoleic acid, linoleic acid, arachidone. Examples include saturated or unsaturated higher fatty acids such as acids. Further, the alkyl group having 6 or more carbon atoms of D and E may be linear or branched, and examples of the alkyl group include hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and the like. Is exemplified. Examples of the salt of the compound represented by the general formula [V] are the same as the salts of the compound represented by the general formula [I]. The compound represented by the general formula [V] is a novel compound, and the compound can be produced by various methods. For example, the compound represented by the general formula [III] is represented by the method shown in the reaction scheme 1. After the compound described above is prepared, it can be produced by the method represented by the following reaction process formula-2.

Reaction process formula-2 (In the formula, m, p, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , T,
D and E are the same as above, and Q ₁ is —NH ₂ or —OH. )

As shown in the above reaction scheme, the compound [V] can be obtained by reacting the compound [III] with the compound [VI]. Compound [VI] used in this reaction can be prepared by a conventional method. For example, the compound with p = 0 is described by LD Bergelson, "Lipid Bi
ochemical Preparations "(1980, ELSEVIER / NORTH-HO
It can be prepared according to the method described in LLAND BIOMEDICAL PRESS, p115-122). The compound having p of 1 to 6 can be prepared by reacting the compound obtained above with an alkylating agent having a hydroxyl group or an amino group at the terminal. The reaction between the compound [III] and the compound [VI], and the isolation and purification of the obtained compound [V] are
This can be performed according to the method for producing the compound [I] represented by the reaction process formula-1.

Other preferred chelating compounds are:
Examples thereof include compounds represented by the following general formula [VII] and salts thereof. [Wherein, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different and each is a hydrogen atom or a lower alkyl group, R ₃ , R ₄ and R 2
₅ and R ₆ are the same or different, and are a hydroxyl group or a group: -Q- (CH ₂ ) _p- T-sterol (in the formula, Q and T are the same or different and are -NH- or -O-, p Is an integer from 0 to 6, and when p is 0, T
And the sterol binding position is the 3-position). However, among R ₃ , R ₄ , R ₅ and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R ₃ and R ₅ are both hydroxyl groups and R ₄ and R ₆ Except those in which both are hydroxyl groups. ]

In the compound represented by the above general formula [VII], examples of the lower alkyl group include those defined in the compound represented by the above general formula [I]. Sterol is a kind of steroid, is a steroid alcohol widely distributed in the animal and plant kingdom, and has a hydroxyl group at the 3-position. There are saturated compounds, but most are unsaturated compounds having a double bond between the 5th and 6th positions or at other positions. The 17-position has a chain side chain having 8 to 10 carbon atoms. Representative examples of sterols include cholesterol, cholestanol, cerebrosterol, ergosterol, fucosterol and the like. General formula [VI
The salt of the compound represented by the formula [I] includes the above general formula [I]
Examples of the salts of the compound represented by The compound represented by the general formula [VII] is a novel compound, and the compound can be produced by various methods.
According to the method shown in the reaction process formula-1, the general formula [II
I] is prepared, the following reaction process formula-
It can be manufactured by the method shown in 3.

Reaction formula-3 (In the formula, m, p, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and T
Is the same as above, and Q ₁ is —NH ₂ or —OH. )

As shown in the above reaction scheme, compound [VII] is compound [III] and compound [VIII].
It is obtained by reacting with. Compound [VIII] used in this reaction can be prepared by a conventional method. For example, for a compound with p = 0 and Q ₁ = NH ₂ , there is a method in which the hydroxyl group at the 3-position of the sterol is converted into a leaving group such as a sulfonic acid ester and then reacted with ammonia to substitute an amino group (RD Howarth et al, J. Chem.
Soc., 1953, p1110). The compound having p of 1 to 6 can be prepared by reacting the compound or sterol compound obtained above with an alkylating agent having a hydroxyl group or an amino group at the terminal. Compound [II
The reaction of I] with the compound [VIII], and the isolation and purification of the obtained compound [VII] can be carried out according to the production method of the compound [I] represented by the reaction scheme-1. ..

Other preferred chelating compounds are:
Examples thereof include compounds represented by the following general formula [IX] and salts thereof. (In the formula, R ₇ represents an alkyl group having 6 or more carbon atoms, and m represents an integer of 1 to 3.)

In the compound represented by the above general formula [IX], examples of the alkyl group having 6 or more carbon atoms include those defined in the compound represented by the above general formula [V]. Examples of the salt of the compound represented by the general formula [IX] include the same salts as those of the compound represented by the general formula [I]. The compound represented by the general formula [IX] is a novel compound, and the compound can be produced by various methods. One of the methods is Toshio Takeshita, Shigeru Maeda, Vol. No. 984-993 (1
970).

Preferred chelating compounds for preparing a fat emulsion capable of containing and retaining a sufficient amount of contrast agent include compounds represented by the following general formula [X] and salts thereof. [Wherein, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different and each is a hydrogen atom or a lower alkyl group, R ₃ , R ₄ and R 2
₅ and R ₆ are the same or different and are a hydroxyl group or a group: (In the formula, R ₈ and R ₉ , which are the same or different, each represents a fatty acid residue). However, among R ₃ , R ₄ , R _5, and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R ₃
And those in which R ₅ and R ₅ are both hydroxyl groups and those in which R ₄ and R ₆ are both hydroxyl groups. ]

In the compound represented by the above general formula [X], examples of the lower alkyl group include those defined in the compound represented by the above general formula [I]. The fatty acid residue (acyl group) of R ₈ and R ₉ is not particularly limited, and examples of the fatty acid include palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, elaidic acid, and erucic acid. And saturated or unsaturated higher fatty acids such as linoleic acid, linoleic acid, and arachidonic acid. Examples of the salt of the compound represented by the general formula [X] include the same salts as the salts of the compound represented by the general formula [I]. The compound represented by the general formula [X] is a novel compound, and the compound can be produced by various methods. For example, the compound represented by the general formula [III] can be produced according to the method shown in the reaction scheme-1. After the compound described above is prepared, it can be produced by the method represented by the following reaction scheme-4.

Reaction formula-4 (In the formula, m, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as above.)

As shown in the above reaction scheme, compound [X] is obtained by reacting compound [III] with phosphatidylethanolamine. Phosphatidylethanolamine (hereinafter referred to as PE) is a kind of phospholipid represented by the following general formula, is widely distributed in the living world, and is contained in animal and plant cells and bacterial cells. (In the formula, R ₈ and R ₉ are the same as above.)

The PE used in the present invention is not particularly limited as long as it is purified to the extent that it can be used as a medicine. It may be isolated and purified from animal or plant cells, bacterial cells, etc., or may be chemically synthesized. Reaction of compound [III] with PE,
And, the isolation, purification and the like of the obtained compound [X] can be carried out according to the method for producing the compound [I] represented by the reaction scheme 1. Further, as a simpler preparation method, there is a method of preparing a fat emulsion containing PE in advance and then reacting it with the compound [III]. PE is an emulsifier for preparing a fat emulsion, either alone or mixed with other phospholipids,
It is used in a weight ratio of 100 to 100, preferably 5 to 60. For the reaction, the compound [III] may be added to the aqueous solution containing the emulsion. A reaction time of about 30 minutes to 1 day, a reaction temperature of room temperature to about 50 ° C., and a pH of about 7 to 9 are suitable.

As the fat and oil used in the fat emulsion of the present invention, any fat and oil can be used as long as it is an edible oil, and examples thereof include vegetable oils (eg, soybean oil, cottonseed oil, safflower oil, corn oil, coconut oil, perilla oil, Perilla oil, etc.), fish oil (eg, cod liver oil, etc.), medium-chain fatty acid triglycerides [eg, panacetate (trade name), ODO (trade name), etc.] and chemically synthesized triglycerides [eg, 2-linoleoyl.
Chemic such as -1,3-dioctanoylglycerol (8L8), 2-linoleoyl-1,3-didecanoylglycerol (10L10)
1 or 2 selected from "ally defined triglycerides"
One or more kinds of fats and oils are preferably used. More preferable fats and oils include vegetable oils, particularly soybean oil (preferably containing 99.9% or more of triglyceride, diglyceride and monoglyceride). Further, as the emulsifier, any emulsifier can be used as long as it is an emulsifier used in pharmaceutical formulations, for example, phospholipids (eg, egg yolk phospholipids,
Hydrogenated egg yolk phospholipids, soybean phospholipids, hydrogenated soybean phospholipids, etc., synthetic surfactants [eg Pluronic F6
8, HCO-60 (both are trade names, etc.)] and the like. If necessary, positively charged lipids such as oleylamine and stearylamine, and negatively charged lipids such as oleic acid, phosphatidic acid and phosphatidylserine can be used. You may use the said emulsifier individually or in combination of 2 or more types.

The fat emulsion of the present invention further comprises a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or a physiologically acceptable salt thereof in an amount of up to 0.3% (W / V). Are already known as emulsification aids of (1), and such known ones may be used) as emulsification aids. Further, 0.5% (W / V) or less, preferably 0.1% (W / V) or less amount of cholesterol, or 5% (W / V) or less, preferably 1% (W / V)
The following amounts of phosphatidic acid may be included as stabilizers. Further, if necessary, a buffering agent, a pH adjusting agent, etc. may be added within a range that does not affect the emulsification system. Also,
To make the emulsion isotonic, it is also possible to add isotonic agents such as commonly used glycerin and glucose.

As described above, in the fat emulsion of the present invention, a chelating compound fat emulsion is prepared and then the fat emulsion and the paramagnetic metal atom are chelated, or the paramagnetic metal atom and the chelating compound are combined. It is obtained by emulsifying with a fat that has been previously chelated. Whether the chelate bond between the paramagnetic metal atom and the chelating compound is carried out before or after the preparation of the fat emulsion itself does not affect the preparation of the fat emulsion itself. Hereinafter, the method for preparing the fat emulsion of the present invention will be described in detail, but for convenience, an example prepared according to the former method will be described here.

In preparing the fat emulsion of the present invention, first, a chelating compound fat emulsion is prepared. The chelating compound fat emulsion can be prepared by using a conventional homogenizer such as a pressure jet homogenizer and an ultrasonic homogenizer. For example, each required amount of fats and oils (preferably soybean oil), emulsifier, chelating compound can be prepared. And, if necessary, other additives (for example, an emulsification aid, a stabilizer, a pH adjusting agent, an isotonicity agent, etc.) are mixed with water, and after homogenization treatment,
Then, a required amount of water is added to this, and homogenization is performed again using a homogenizer, whereby it can be easily prepared. Usually, by these operations, a chelating compound fat emulsion having an average particle size of 3 μm or less can be prepared. In addition, stabilizers and tonicity agents may be added to the prepared fat emulsion.

The chelating compound fat emulsion thus obtained is then chelated with a paramagnetic metal atom (preferably gadolinium). The chelate bond can be formed according to a conventional method. For example, a paramagnetic metal oxide or halide compound may be added to the chelating compound fat emulsion for treatment. It is preferable that the chelating compound and the paramagnetic metal atom in the fat emulsion form equimolar amounts to form a complex compound. In order to neutralize the charge of the complex compound of the paramagnetic metal atom and the chelating compound, it can be used medicinally with an acid (eg organic acid, inorganic acid etc.) or base (eg alkali metal hydroxide, basic amino acid etc.). Acceptable salts may be formed.

The contrast agent for MRI diagnosis of the present invention comprises the fat emulsion containing the paramagnetic metal atom obtained above. The contrast agent for MRI diagnosis of the present invention may be directly used as a liquid preparation after sterilizing the fat emulsion according to a conventional method.
It may also be prepared as a freeze-dried preparation. Freeze-drying can be performed by a method known per se. The freeze-dried preparation is generally diluted or dispersed with a physiologically acceptable aqueous solution before use.

The administration of the contrast agent for MRI diagnosis of the present invention is preferably parenteral, particularly intravenous administration. The dose varies depending on the administration route, administration site, etc., but when administered to an adult for the purpose of MRI diagnosis, it is generally 1
~ 500 ml / dose is preferred.

The contrast agent for MRI diagnosis of the present invention can be used in the same manner as a conventional contrast agent. For example, in the computer tomography method using the contrast agent for MRI diagnosis of the present invention, the number of doses of the drug is several minutes. After that, scanning is performed using an MRI diagnostic contrast apparatus, and display is performed by, for example, a dot drawing method. INDUSTRIAL APPLICABILITY The contrast agent for MRI diagnosis of the present invention has the property that small fat particles migrate to reticuloendothelial organs, sites of inflammation, etc., and exhibit excellent contrast enhancing ability. Therefore, various organs such as liver and spleen, arthritis, tumor Suitable for imaging areas such as areas and blood vessels. Therefore, arteriosclerosis,
It is useful for diagnosis of diabetes, rheumatoid arthritis, cancer and the like.
In particular, it is useful for diagnosis of atherosclerosis and liver tumor.

[0041]

EXAMPLES The present invention will now be described in more detail with reference to production examples, reference examples, examples and experimental examples, but the present invention is not limited thereto. Production Example 1 Synthesis of 1,3 -O-distearoylglycerol 1,3-di (stearoyloxy) acetone 1,3-dihydroxyacetone dimer 4.64 g (25 mmol),
A solution of 28.4 g (100 mmol) of stearic acid dissolved in 150 ml of pyridine and 25.0 g (120 mmol) of dicyclohexylcarbodiimide dissolved in 150 ml of chloroform was added, and the solution was added at room temperature to 91
Stir for hours. Target compound 15.6 by recrystallization from acetone
Obtained in g (yield 50%). 1,3-O-distearoyl glycerol 1,3-di (stearoyloxy) acetone 12.5 g (20 mmol)
Was suspended in 200 ml of tetrahydrofuran, and 25.5 ml (26 mmol) of a 1M tetrahydrofuran solution of BH ₃ was added dropwise under ice cooling, followed by stirring at room temperature for 22 hours. By acetone recrystallization,
The target compound was obtained as colorless needle crystals (8.5 g, yield 67%).

Production Example 2 2-O- (2-aminoethyl) -1,3-O-dilauri
Synthesis of Luglycerol 1,3-O-dilaurylglycerol 27.0 ml (118.8 mmol) of lauryl alcohol and 5.27 g (131.6 mmol) of sodium hydride were added to 60 ml of anhydrous dioxane.
After stirring at 90 ° C for 30 minutes, under ice cooling, epichlorohydrin
3.1 ml (39.6 mmol) was added and the mixture was heated under reflux for 4 hours to give 1,3-O-
A mixture of dilauryl glycerol and 1,2-O-dilauryl glycerol was obtained. 2-O-carbamoylmethyl-1,3-O-dilauryl glycerol 0.79 g (6.9 mmol) of potassium hydride was suspended in 50 ml of anhydrous tetrahydrofuran to prepare 1,3-O- and 1,2-O-dilauryl glycerol. A solution prepared by dissolving 2.15 g (5.0 mmol) of the mixture in 12 ml of anhydrous tetrahydrofuran was added, and the mixture was heated under reflux for 1 hour. Then, at room temperature, a solution of 2.82 g (15.3 mmol) of iodoacetic acid amide in 10 ml of anhydrous tetrahydrofuran was added and refluxed under heating for 2 hours. I went. Purification was performed by a column chromatogram method (eluent: hexane-ethyl acetate) to obtain white crystals of 2-O-carbamoylmethyl-1,3-O-dilaurylglycerol. 2-O- (2-aminoethyl) -1,3-O-dilaurylglycerol 2-O-carbamoylmethyl-1,3-O-dilaurylglycerol 3.34 g (7.0 mmol) was dissolved in anhydrous tetrahydrofuran 14 ml, Under ice cooling, 3.5 ml of 10M BH ₃ · Me ₂ S complex (35.0
mmol) was added and the mixture was heated under reflux for 3 hours. Purification was performed by column chromatogram method (eluent: dichloromethane-methanol) to obtain 2.16 g of the target compound as a colorless oil (yield: 64.3
%)Obtained.

Reference Example 1 Synthesis of diethylenetriaminepentaacetic acid diamides
1 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = R 4 =} p-C 8 H 17 C 6 H 4 NH-, R 5 = R 6 = O
Compound of H, DTPA-DIOA) Diethylenetriamine pentaacetic acid dianhydride 2.05 g (5.7 mmol) anhydrous DMF 100m
dissolves in l. In this solution, 2.36 g of 4-octylaniline (1
A solution of 1.4 mmol) dissolved in 10 ml of methylene chloride is added, and the mixture is stirred at room temperature for 15 hours. The crystals obtained are collected by filtration, washed with ether and recrystallized (solvent; ethanol: methanol: benzene = 6: 1: 1) to give the desired compound (white amorphous,
mp 207.0-208.5 ° C) was obtained in 3.64 g (82.7% yield). ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.88
(6H, t, J = 6.4Hz), 1.2 ~ 1.4 (20H, m), 1.5 ~ 1.7 (4H,
m), 2.57 (4H, t, J = 7.6Hz), 3.2 ~ 3.4 (4H, m), 3.6 ~
3.9 (6H, m), 4.33 (4H, s), 4.43 (4H, s), 7.16 (8H,
s) IR (KBr): 3350, 1680, 1620 cm ^-1

Reference Example 2 Synthesis of diethylenetriaminepentaacetic acid diamides
2 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = R 4 =} p-C 6 H 13 C 6 H 4 NH-, R 5 = R 6 = O
Compound of H, DTPA-DIHA) Diethylenetriamine pentaacetic acid dianhydride 2.02g (5.7mmol) anhydrous DMF 100m
dissolves in l. To this solution, 2.02 g of 4-hexylaniline (1
A solution of 1.4 mmol) dissolved in 10 ml of methylene chloride is added, and the mixture is stirred at room temperature for 15 hours. The solvent was distilled off, and the residue was crystallized using ether and recrystallized (solvent; THF: methanol = 3:
1) and the target compound (white amorphous, mp 207.5-2
09.0 ° C.) was obtained in 3.36 g (yield 82.8%). ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.88
(6H, t, J = 6.2Hz), 1.2 ~ 1.4 (12H, m), 1.5 ~ 1.7 (4H,
m), 2.58 (4H, t, J = 7.7Hz), 3.2 ~ 3.4 (4H, m), 3.7 ~
3.9 (6H, m), 4.34 (4H, s), 4.44 (4H, s), 7.17 (8H,
s) IR (KBr): 3330, 1680, 1620 cm ^-1

Reference Example 3 Synthesis of triethylenetetraaminehexaacetic acid diamides (in the compound of general formula [I], m = 2, R ₁ = R ₂ =
_{H, R 3 = R 4 =} p-C 8 H 17 C 6 H 4 NH-, R 5 = R 6 = O
Compound of H, TTHA-DIOA) triethylenetetraaminehexaacetic acid dianhydride (obtained from triethylenetetraaminehexaacetic acid by a conventional dehydration reaction using acetic anhydride and pyridine) 1.20 g (2.6 mmol) Anhydrous DM
Dissolve in 120 ml of F. Add 4-octylaniline to this solution.
A solution prepared by dissolving 1.04 g (5.1 mmol) in 10 ml of methylene chloride is added, and the mixture is stirred at room temperature for 4 days. The obtained crystals are collected by filtration, washed with ether and then with ethanol, and recrystallized (solvent; THF: methanol = 3: 1) to give 1.55 g of the desired compound (white amorphous, mp 212.5-214.0 ° C) (yield 68.0
%). ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.88
(6H, t, J = 6.4Hz), 1.2 ~ 1.4 (20H, m), 1.5 ~ 1.7 (4H,
m), 2.59 (4H, t, J = 7.7Hz), 3.4 ~ 3.8 (8H, m), 3.8 ~
4.1 (8H, m), 4.36 (4H, m), 4.50 (4H, m), 7.19 (8H, m
s) IR (KBr): 3600-3200, 1720, 1670 cm ^-1

Reference Example 4 Synthesis of diethylenetriaminepentaacetic acid monoamides
1 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = p-C} 8 H 17 C 6 H 4 NH-, R 4 = R 5 = R 6 = O
Compound of H, DTPA-OA) 3.00 g (8.4 mmol) of diethylenetriaminepentaacetic acid dianhydride in anhydrous DMF at 75 ° C.
After dissolving in 45 ml and adding 0.15 ml (8.3 mmol) of water dropwise, the mixture is stirred at the above temperature for 1 hour to produce diethylenetriaminepentaacetic acid monoanhydride. To this solution, 1.75 g (8.3 mmol) of 4-octylaniline is added dropwise, and the mixture is further stirred for 1 hour at the above temperature. Purification was performed by the column chromatogram method (eluent: 40% water-containing methanol) to obtain 1.48 g (yield 30.0%) of the target compound (white amorphous, mp 164.0-167.0 ° C). ¹ H-NMR (CD ₃ OD + CF ₃ COOD) δ: 0.89
(3H, t, J = 6.4Hz), 1.1 ~ 1.5 (10H, m), 1.5 ~ 1.7 (2H,
m), 2.56 (2H, t, J = 7.5Hz), 3.1 ~ 3.4 (4H, m), 3.4 ~
3.6 (4H, m), 3.6 ~ 3.9 (8H, m), 4.36 (2H, s), 7.13
(2H, d, J = 8.4Hz), 7.49 (2H, d, J = 8.4Hz) IR (KBr): 3400 to 3000, 1680, 1610 cm ^-1

Reference Example 5 Synthesis of diethylenetriaminepentaacetic acid monoamides
2 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = p-C} 6 H 13 C 6 H 4 NH-, R 4 = R 5 = R 6 = O
Compound of H, DTPA-HA) At 75 ° C., 3.00 g (8.4 mmol) of diethylenetriaminepentaacetic acid dianhydride was added to anhydrous DMF.
After dissolving in 45 ml and adding 0.15 ml (8.3 mmol) of water dropwise, the mixture is stirred at the above temperature for 1 hour to produce diethylenetriaminepentaacetic acid monoanhydride. To this solution, 1.47 g (8.3 mmol) of 4-hexylaniline was added dropwise, and the mixture was further stirred for 1 hour at the above temperature. Purification was carried out by a column chromatogram method (eluent: 20% water-containing methanol) to obtain 1.74 g (yield 38.0%) of the target compound (slightly yellow amorphous, mp 159.0-160.0 ° C). ¹ H-NMR (CD ₃ OD) δ: 0.89 (3H, t, J = 6.5H
z), 1.2 to 1.5 (6H, m), 1.5 to 1.8 (2H, m), 2.55 (2H, t,
J = 7.5Hz), 3.1 to 3.5 (8H, m), 3.60 (2H, brs), 3.68
(6H, brs), 3.79 (2H, brs), 7.11 (2H, d, J = 8.4Hz),
7.53 (2H, d, J = 8.4Hz) IR (KBr): 3380 to 3000, 1680, 1610 cm ^-1

Reference Example 6 Synthesis of diethylenetriaminepentaacetic acid monoamides
3 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = p-C} 10 H 21 C 6 H 4 NH-, R 4 = R 5 = R 6 =
Compound of OH, DTPA-DeA) 3.75 g (11.1 mmol) of diethylenetriaminepentaacetic acid dianhydride was dissolved in 60 ml of anhydrous DMF at 75 ° C., 0.20 ml (11.1 mmol) of water was added dropwise, and the mixture was stirred at the temperature for 1 hour. Then, diethylenetriaminepentaacetic acid monoanhydride is produced. To this solution, a solution of 2.59 g (11.1 mmol) of 4-decylaniline dissolved in 5 ml of anhydrous methylene chloride is added dropwise, and the mixture is further stirred for 1 hour at the above temperature.
Column chromatogram method (eluent: 40% hydrous methanol)
The target compound (white amorphous, mp 16
9.0-172.0 ° C) was obtained in 3.06 g (yield 45.3%). ¹ H-NMR (CD ₃ OD) δ: 0.89 (3H, t, J = 6.3H
z), 1.2 to 1.4 (14H, m), 1.5 to 1.7 (2H, m), 2.56 (2H,
t, J = 7.5Hz), 3.1 to 3.4 (8H, m), 3.59 (2H, s), 3.63
(4H, s), 3.71 (2H, s), 3.73 (2H, s), 7.12 (2H, d, J
= 8.3Hz), 7.53 (2H, d, J = 8.3Hz) IR (KBr): 3500 to 3000, 1680, 1620 cm ^-1

Reference Example 7 Synthesis of diethylenetriaminepentaacetic acid monoamides
4 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = p-C} 12 H 25 C 6 H 4 NH-, R 4 = R 5 = R 6 =
Compound of OH, DTPA-DoA) 3.75 g (11.1 mmol) of diethylenetriaminepentaacetic acid dianhydride was dissolved in 60 ml of anhydrous DMF at 75 ° C., 0.20 ml (11.1 mmol) of water was added dropwise, and the mixture was stirred at the temperature for 1 hour. Then, diethylenetriaminepentaacetic acid monoanhydride is produced. To this solution, a solution prepared by dissolving 2.91 g (11.1 mmol) of 4-dodecylaniline in 5 ml of anhydrous methylene chloride is added dropwise, and the mixture is further stirred for 1 hour at the above temperature. Purification by column chromatogram method (eluent: 40% hydrous methanol) gave the target compound (white amorphous,
mp 171.0-173.5 ° C) was obtained in 2.60 g (yield 36.7%). ¹ H-NMR (CD ₃ OD) δ: 0.89 (3H, t, J = 6.4H
z), 1.2 to 1.4 (16H, m), 1.5 to 1.7 (2H, m), 2.56 (2H,
t, J = 7.5Hz), 3.1 to 3.4 (8H, m), 3.50 (2H, s), 3.61
(2H, s), 3.66 (4H, s), 3.71 (2H, s), 7.11 (2H, d, J
= 8.4Hz), 7.54 (2H, d, J = 8.4Hz) IR (KBr): 3500 to 3000, 1680, 1620 cm ^-1

Reference Example 8 Combination of triethylene tetraamine hexaacetic acid monoamides
Synthesis 1 (in the compound of the general formula [I], m = 2, R ₁ = R ₂ =
_{H, R 3 = p-C} 8 H 17 C 6 H 4 NH-, R 4 = R 5 = R 6 = O
Compound H, TTHA-OA) At 80 ° C., 4.63 g (10.1 mmol) of triethylenetetraaminehexaacetic acid dianhydride was dissolved in 55 ml of anhydrous DMF, and 0.18 ml (10 mmol) of water was added dropwise.
Stir for 30 minutes at the above temperature to generate triethylenetetraaminehexaacetic acid monoanhydride. 2.3 ml (10.1 mmol) of 4-octylaniline was added dropwise to this solution, and the mixture was further stirred for 1 hour at the above temperature. Purification was carried out by the HPLC method (eluent: 35% water-containing methanol) to obtain 2.28 g (yield 33%) of the target compound (brown amorphous, mp 182 to 184 ° C). ¹ H-NMR (CD ₃ OD) δ: 0.89 (3H, t, J = 6.4H
z), 1.1 to 1.45 (10H, m), 1.45 to 1.7 (2H, m), 2.56 (2H,
t, J = 7.5Hz), 2.9 to 3.25 (6H, m), 3.25 to 3.55 (10H,
m), 3.57 (2H, s), 3.65 ~ 3.9 (6H, m), 7.11 (2H, d, J
= 8.4Hz), 7.55 (2H, d, J = 8.4Hz) IR (KBr): 3400, 1620 cm ^-1

Reference Example 9 Combination of triethylene tetraamine hexaacetic acid monoamides
Composition 2 (in the compound of the general formula [I], m = 2, R ₁ ═R ₂ ═
_{H, R 3 = p-C} 6 H 13 C 6 H 4 NH-, R 4 = R 5 = R 6 = O
Compound of H, TTHA-HA) 500 mg (1.1 mmol) of triethylenetetraaminehexaacetic acid dianhydride at 80 ° C
After dissolving in 10 ml of MF and adding 0.02 ml (1.1 mmol) of water dropwise,
Stir for 1 hour at the above temperature to generate triethylenetetraaminehexaacetic acid monoanhydride. To this solution, 0.18 g (1.0 mmol) of 4-hexylaniline is added dropwise, and the mixture is further stirred for 1 hour at the above temperature. Column chromatogram method (eluent:
Purification with 20% hydrous methanol), 119 mg of the target compound (colorless amorphous, mp 168.0-170.0 ° C) (yield 18.0
%). ¹ H-NMR (CD ₃ OD) δ: 0.89 (3H, t, J = 6.4H
z), 1.2 to 1.5 (6H, m), 1.5 to 1.7 (2H, m), 2.57 (2H, t,
J = 7.5Hz), 3.0 ~ 3.3 (6H, m), 3.3 ~ 3.5 (6H, m), 3.5
~ 3.6 (4H, m), 3.61 (2H, s), 3.7 ~ 3.9 (6H, m), 7.11
(2H, d, J = 8.4Hz), 7.54 (2H, d, J = 8.4Hz) IR (KBr): 3380 to 3000, 1680, 1610 cm ^-1

Reference Example 10 Synthesis of diethylenetriaminepentaacetic acid diesters
1 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = R 4 =} p-C 4 H 9 C 6 H 4 CH 2 O-, R 5 = R 6 =
Compound of OH) At 80 ° C., 1.43 g (4.00 mmol) of diethylenetriaminepentaacetic acid dianhydride is dissolved in 24 ml of anhydrous DMF. To this solution, 1.32 g of 4-butylbenzyl alcohol (8.
A solution of 00 mmol) dissolved in 12 ml of anhydrous DMF is added, and the mixture is stirred at the above temperature for 16 hours. The solvent was distilled off and recrystallization (solvent: chloroform-hexane) was performed to obtain 2.04 g (yield 74.5%) of the target compound (white amorphous, mp 61.5-63.5 ° C).
Got with. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (6H, t, J = 7.2H
z), 1.2 to 1.4 (4H, m), 1.5 to 1.6 (4H, m), 2.56 (4H,
t, J = 7.6Hz), 3.0 to 3.2 (4H, m), 3.3 to 3.7 (12H, m),
4.0 ~ 4.2 (2H, m), 5.02 (4H, s), 7.10 (4H, d, J = 8.1H
z), 7.19 (4H, d, J = 8.1Hz) IR (KBr): 3400, 1730, 1620 cm ^-1

Reference Example 11 Synthesis of diethylenetriaminepentaacetic acid diesters
2 (in the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = R 4 =} p-C 13 H 27 C 6 H 4 CH 2 O-, R 5 = R
₆ = OH compound) In Reference Example 10, 4-tridecylbenzyl alcohol (synthesized by a conventional method) was used in place of 4-butylbenzyl alcohol, and the target compound (pale yellow amorphous, mp157. 0-161.0 ° C) was obtained. ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.87 (6
H, t, J = 6.3Hz), 1.2 to 1.4 (40H, m), 1.5 to 1.7 (4
H, m), 2.56 (4H, t, J = 7.4Hz), 3.1 to 3.9 (10H,
m), 4.0 to 4.3 (8H, m), 5.12 (4H, brs), 7.15 (8
H, m) IR (KBr): 3400, 1730, 1700, 1620 cm ^-1

Reference Example 12 Synthesis of diethylenetriaminepentaacetic acid monoesters
No. 1 (In the compound of the general formula [I], m = 1, R ₁ = R ₂ =
_{H, R 3 = p-C} 13 H 37 C 6 H 4 CH 2 O-, R 4 = R 5 = R
₆ = OH compound DTPA-TBE) In Reference Example 4, 4-tridecylbenzyl alcohol was used in place of 4-octylaniline, and the target compound (pale yellow amorphous, mp 194.0-197.0 ° C) was obtained in the same manner. Obtained. ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.88 (3
H, t, J = 6.6Hz), 1.2 to 1.4 (20H, m), 1.5 to 1.7 (2
H, m), 2.61 (2H, t, J = 7.8Hz), 3.3 to 3.4 (4H,
m), 3.6 to 3.8 (4H, m), 3.80 (2H, s), 4.26 (6H,
s), 4.31 (2H, s), 5.22 (2H, s), 7.21 (4H, s) IR (KBr): 3400, 1720, 1700, 1630cm ^-1

Reference Example 13 Synthesis of diethylenetriaminepentaacetic acid monoesters
No. 2 [In the compound of the general formula [V], m = 1, R ₁ = R ₂ =
_{H, R 3 = -O-CH} (CH 2 OCOC 11 H 23) 2, R 4 =
R ₅ = compound of _{R 6 = OH, DTPA-GLE} ] diethylenetriaminepentaacetic acid dianhydride at 75 ° C. 3.00 g (8.4 mm
ol) was dissolved in 45 ml of anhydrous DMF, and 0.15 ml of water (8.3 mmol)
And then stirred at the above temperature for 1 hour to generate diethylenetriaminepentaacetic acid monoanhydride. To this solution is added 3.84 g (8.4 mmol) of 1,3-O-dilauroylglycerol (synthesized according to Production Example 1), and the mixture is further stirred for 18 hours at the above temperature. Purification by column chromatogram method (eluent: methanol) and recrystallization (chloroform-methanol) gave the desired compound (colorless amorphous, mp182.
0-184.0 ° C) was obtained in 2.47 g (yield 35.0%). ¹ H-NMR (CD ₃ OD + CF ₃ COOD) δ: 0.87 (6
H, t, J = 6.3Hz), 1.1 to 1.5 (32H, m), 1.5 to 1.8 (4
H, m), 2.38 (4H, t, J = 7.3Hz), 3.0 to 3.5 (4H,
m), 3.5-4.0 (6H, m), 4.0-4.8 (12H, m), 5.2-
5.4 (1H, m) IR (KBr): 3400, 1720, 1620cm ^-1

Reference Example 14 Synthesis of diethylenetriaminepentaacetic acid monoesters
Part 3 [In the compound of the general formula [V], m = 1, R ₁ = R ₂ =
_{H, R 3 = -O-CH} (CH 2 OCOC 17 H 35) 2, R 4 =
R ₅ = R ₆ = OH compound] At 75 ° C., 3.00 g (8.4 mmol) of diethylenetriaminepentaacetic acid dianhydride in anhydrous DMF 45
After dissolving in 0.1 ml of water and adding 0.15 ml (8.3 mmol) of water dropwise, the mixture is stirred at the above temperature for 1 hour to produce diethylenetriaminepentaacetic acid monoanhydride. To this solution, 5.25 g (8.4 mmol) of 1,3-O-distearoyl glycerol is added, and the mixture is further stirred for 16 hours at the above temperature. Purification by recrystallization (chloroform-methanol) gave 4.16 g (yield 50.0%) of the target compound (colorless amorphous, mp188.0-190.0 ° C). ¹ H-NMR (CD ₃ OD + CF ₃ COOD) δ: 0.88 (6
H, t, J = 6.7Hz), 1.1 to 1.5 (56H, m), 1.5 to 1.8 (4
H, m), 2.41 (4H, t, J = 7.6Hz), 3.2 to 3.6 (4H,
m), 3.6 to 4.0 (6H, m), 4.0 to 4.5 (10H, m), 4.5 to
4.6 (2H, m), 5.2 ~ 5.4 (1H, m) IR (KBr): 3400, 1730, 1620cm ^-1

Reference Example 15 Synthesis of diethylenetriaminepentaacetic acid monoamides
5 [in the compound of the general formula [V], m = 1, R ₁ = R ₂ =
_{H, R 3 = -NHCH 2 CH} 2 O-CH (CH 2 OC
₁₂ H ₂₅ ) ₂ , R ₄ = R ₅ = R ₆ = OH compound] Diethylenetriamine pentaacetic acid dianhydride 0.30 g (0.8 mmo
l) is dissolved in 60 ml of anhydrous DMF and 0.015 ml of water (0.8 mmol)
And then stirred at the above temperature for 1.5 hours to produce diethylenetriaminepentaacetic acid monoanhydride. To this solution, 0.40 g (0.8 mmol) of 2-O- (2-aminoethyl) -1,3-O-dilaurylglycerol (synthesized according to Production Example 2) was added, and the mixture was further stirred for 1.5 hours at the above temperature. To do. Purify by the column chromatogram method (eluent: methanol) to obtain 0.3% of the target compound (white amorphous, mp 180.0-184.0 ° C).
Obtained in 1 g (58.5% yield). ¹ H-NMR (CD ₃ OD) δ: 0.90 (6H, t, J = 6.4H
z), 1.2 to 1.4 (36H, m), 1.5 to 1.7 (4H, m), 3.10 to 3.35
(8H, m), 3.35 ~ 3.55 (12H, m), 3.55 ~ 3.75 (11H, m) IR (KBr): 3400, 1720, 1630 cm ^-1

Reference Example 16 Synthesis of diethylenetriaminepentaacetic acid diesters
3 [in the compound of the general formula [V], m = 1, R ₁ = R ₂ =
_{H, R 3 = R 4 =} -O-CH (CH 2 OCOC 11 H 23) 2,
Compound of R ₅ = R ₆ = OH] 1.00 g (2.8 mmol) of diethylenetriaminepentaacetic acid dianhydride is dissolved in 25 ml of anhydrous DMF. To this solution, add 1,3-O-dilauroyl glycerol 2.
Add 56 g (5.6 mmol) and stir at 80 ° C. for 21 hours. Flash column chromatogram method (eluent: chloroform
-Methanol) and a chromatogram method (eluent: methanol) to give the desired compound (yellow amorphous, mp 55.0-56.0 ° C) in 1.30 g (yield 36.0%). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (12H, t, J = 6.0H
z), 1.1 to 1.5 (64H, m), 1.5 to 1.9 (8H, m), 2.32
(8H, t, J = 7.0Hz), 3.0 to 3.4 (4H, m), 3.4 to 3.9 (1
2H, m), 4.0 to 4.6 (10H, m), 5.1 to 5.4 (2H, m) IR (CHCl ₃ ): 3450, 1735, 1630 cm ^-1

Reference Example 17 Synthesis of diethylenetriaminepentaacetic acid monoesters
No. 4 (In the compound of the general formula [VII], m = 1, R ₁ = R ₂ =
_{H, R 3 = -O- (3} ) _{cholesterol, R 4 = R 5 = R} 6
= OH compound, DTPA-ChE) At 75 ° C, 3.00 g (8.4 mmol) of diethylenetriaminepentaacetic acid dianhydride was dissolved in 45 ml of anhydrous DMF, and 0.15 ml (8.3 mmol) of water was added dropwise, followed by 1 hour at the above temperature. Stir to form diethylenetriaminepentaacetic acid monoanhydride. Cholesterol (3.25 g, 8.4 mmol) is added to this solution, and the mixture is further stirred for 15 hours at the temperature. Column chromatogram method (eluent: 30%
After elution of impurities with water-containing methanol, elution with methanol) followed by recrystallization (chloroform-methanol)
The target compound (colorless amorphous, mp19
8.0-200.0 ° C.) was obtained in 2.13 g (yield 33.0%). ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.69 (3
H, s), 0.8 to 0.9 (9H, m), 1.0 (3H, s), 1.1 to 1.7
(20H, m), 1.7 to 2.2 (6H, m), 2.2 to 2.5 (2H, m),
3.1 to 3.5 (4H, m), 3.5 to 4.0 (6H, m), 4.0 to 4.5 (8
H, m), 4.6 to 4.9 (1H, m), 5.3 to 5.5 (1H, m) IR (KBr): 3400, 1720, 1620 cm ^-1

Reference Example 18 Synthesis of diethylenetriaminepentaacetic acid diesters
4 (in the compound of the general formula [VII], m = 1, R ₁ = R ₂ =
_{H, R 3 = R 4 =} -O- (3) cholesterol, R ₅ = R ₆
= OH compound) 0.89 g (2.5 mmol) of diethylenetriaminepentaacetic acid dianhydride is dissolved in 15 ml of anhydrous DMF. To this solution, add 1.93 g (5.0 mmol) of cholesterol to anhydrous DM
Add a solution dissolved in F10 ml and stir at 70 ° C. for 16 hours. The precipitated crystals are collected by filtration and recrystallized (chloroform-methanol) to give the desired compound (pale yellow amorphous,
mp201.0-204.0 ° C) was obtained in 1.76 g (62.3% yield). ¹ H-NMR (CDCl ₃ + CF ₃ COOD) δ: 0.69 (6
H, s), 0.87 (12H, d, J = 6.6Hz), 0.92 (6H, d, J =
6.3Hz), 1.02 (6H, s), 1.1 to 1.7 (40H, m), 1.7 to
2.1 (12H, m), 2.2 to 2.5 (4H, m), 3.3 to 3.5 (4H,
m), 3.6 to 3.9 (6H, m), 4.23 (4H, brs), 4.31 (4
H, brs), 4.6 to 4.8 (2H, m), 5.3 to 5.4 (2H, m) IR (KBr): 3400, 1730, 1710, 1640cm ^-1

Reference Example 19 Synthesis of alkylated diethylenetriaminepentaacetic acid (in the compound of the general formula [IX], R ₇ = C ₁₄ H ₂₉ compound, DTPA-C14) diethylenetriamine (16.2 m
l, 149 mmol) in 80% water-containing ethanol solution (9 ml) at 85 ° C, α-bromohexadecanoic acid (5.0 g, 14.9 mmol) in ethanol (10 ml) and 30% aqueous sodium hydroxide solution (5 ml) are added, and the mixture is kept at the same temperature for 15 hours. Agitate, 2-tetradecyl-2- [2-
(2-Aminoethyl) aminoethyl)] aminoacetic acid (9 g) was obtained. This compound was dissolved in 30 ml of 2N sodium hydroxide aqueous solution, and a solution of α-bromoacetic acid (20.7 g, 149 mmol) dissolved in 80 ml of 2N sodium hydroxide aqueous solution was added, and the pH was maintained at 10 at 90 ° C for 6 hours. Heated and stirred. The reaction mixture was made acidic with concentrated hydrochloric acid, the precipitate was collected by filtration, and purified by column chromatogram method (eluent: 40% water-containing methanol) to obtain the target compound (colorless amorphous, mp188.0 to 190.0).
Was obtained in 2.55 g (yield 29.0%). ¹ H-NMR (D ₂ O) δ: 0.85 (3 H, t, J = 6.3 Hz), 1.
05 ~ 1.65 (24H, m), 1.65 ~ 2.0 (2H, m), 3.0 ~ 3.4
(6H, m), 3.4 to 3.65 (4H, m), 3.65 to 3.8 (3H,
m), 3.8 to 4.0 (4H, m) IR (KBr): 3400, 3200, 1620 cm ^-1

Example 1 100 g of purified soybean oil, 60 g of purified egg yolk phospholipid and DTPA-
After 40 g of OA was added and mixed, 1750 ml of distilled water and 44.2 g of glycerin were added and homogenized with a homomixer. Next, high-pressure emulsification was performed using a Menton-Gaulin type high-pressure homogenizer. This allows DTP
A homogenized extremely fine fat emulsion having an average particle size of 1 μm or less containing A-OA was obtained. This fat emulsion 100m
About 1.3 g of GdCl ₃ per liter was added, the pH was adjusted to around 7.0 with 0.1N sodium hydroxide aqueous solution, and the mixture was thoroughly shaken and mixed, and then allowed to stand at room temperature for 1 hour to give a Gd · DTPA-OA fat emulsion. Got The osmotic pressure ratio of the obtained Gd.DTPA-OA fat emulsion to physiological saline was about 2.0. The composition is as follows. (Composition) Gd / DTPA-OA 2 W / V% Soybean oil 5 W / V% Egg yolk phospholipids 3 W / V% Glycerin 2.2 W / V% Distilled water for injection Appropriate amount

Example 2 In Example 1, DTP was used instead of 40 g of DTPA-OA.
Using 40 g of A-DeA, Gd.DTP according to Example 1
An A-DeA fat emulsion was obtained.

Example 3 In Example 1, DTP was used instead of 40 g of DTPA-OA.
Using 40 g of A-DoA, Gd.DTP was prepared according to Example 1.
An A-DoA fat emulsion was obtained.

Example 4 In Example 1, DTP was used instead of 40 g of DTPA-OA.
Using 40 g of A-TBE, according to Example 1, Gd.DTP
An A-TBE fat emulsion was obtained.

Example 5 In Example 1, DTP was used instead of 40 g of DTPA-OA.
Using 40 g of A-GLE, according to Example 1, Gd.DTP
An A-GLE fat emulsion was obtained.

Example 6 In Example 1, DTP was used instead of 40 g of DTPA-OA.
Using 40 g of A-ChE, Gd.DTP was prepared according to Example 1.
An A-ChE fat emulsion was obtained.

Example 7 In Example 1, DTP was used instead of 40 g of DTPA-OA.
A-C14 40 g was used, and Gd.DT was used according to Example 1.
A PA-C14 fat emulsion was obtained.

Example 8 A desired Gd.DTPA-OA fat emulsion was obtained in the same manner as in Example 1 except that the amount of purified egg yolk phospholipid was changed to 12 g.

Example 9 A target fat emulsion was obtained in the same manner as in Example 1 except that 0.5 g of sodium oleate and 0.5 g of phosphatidic acid were further added as the raw materials of Example 1.

Example 10 To an aqueous solution in which 5.8 g of DTPA-OA was dissolved in 800 ml of distilled water, 200 ml of 0.05M GdCl ₃ solution was gradually added, and a 0.1N sodium hydroxide aqueous solution was added to maintain the pH at around 7.0. The mixture was stirred and reacted at room temperature for about 1 hour.
After the reaction, the reaction solution was freeze-dried to give 7.92 g of Gd / DTPA.
-OA was obtained. Gd DTPA-OA thus obtained
2.0 g, purified soybean oil 5.0 g, purified egg yolk phospholipid 3.0 g, glycerin 1.0 g and distilled water 92.1 ml were mixed and emulsified with an ultrasonic crusher for 15 minutes. The pH was adjusted to around 7.0 with a 0.1N sodium hydroxide aqueous solution to obtain a homogenized extremely fine fat emulsion having an average particle size of 1 μm or less.

Example 11 To 30 g of purified soybean oil, 18 g of purified egg yolk phospholipid (containing 20% of phosphatidylethanolamine) was added and mixed, and 185 ml of distilled water was added to the mixture and homogenized with a homomixer. .. Next, high-pressure emulsification was performed using a Manton-Gaulin type high-pressure homogenizer to obtain a homogenized extremely fine fat emulsion having an average particle size of 1 μm or less. 20 ml of this emulsion
250 mg of anhydrous DTPA was added thereto while adjusting the pH to 8, and the mixture was stirred for 1 hour at room temperature. Repeat this operation 3 times for a total of 1000
mg anhydrous DTPA was added. 1mM G was added to the obtained emulsion.
0.4 ml of the dCl ₃ solution was added to 1 ml of the emulsion, and the mixture was dialyzed against distilled water (for 2 days) to obtain the desired Gd.DTPA-PE fat emulsion.

Example 12 The procedure of Example 11 was repeated except that the purified egg yolk phospholipid 18 g was replaced with purified phosphatidylcholine (derived from egg yolk) 9 g and purified phosphatidylethanolamine (derived from egg yolk) 9 g. A DTPA-PE fat emulsion was obtained.

Experimental Example 1 Micelle of complex compound of chelating compound and gadolinium
Measurement of Limiting Concentration The micelle limiting concentration of the complex compound of the chelating compound prepared in Reference Examples 4, 6, 7, 12, 13, 16 and 18 and gadolinium was measured. Measured by Corrin, ML, Hark
ins, WD, J. Am. Chem. Soc., 69, 679 (1947) and Herzfeld, SH, J. Phys. Chem., 56, 953 (1952).
It was carried out according to. The results are shown below.

Micelle limit concentration (mM) Gd.DTPA-OA 4.1 Gd.DTPA-DeA 1.0 Gd.DTPA-DoA 0.4 Gd.DTPA-TBE 0.5 Gd.DTPA-GLE 0.4 Gd -DTPA-ChE 0.4 Gd-DTPA-C14 7.0

Experimental Example 2 Measurement of embedding rate The embedding rate of the fat emulsions prepared in Examples 1, 2, 3 and 7 was measured. The measurement was performed according to the following procedure. The emulsion was diluted 10-fold with water and 100-fold, and 0.5 ml each was centrifuged with an ultrafilter (5000 r
pm, 30 minutes) to obtain the filtrate. The concentration of the complex compound of the chelating compound and gadolinium in the emulsion before filtration and this filtrate is measured by a high performance liquid chromatogram method, and the embedding rate is calculated from the following formula. Embedding rate = (A−B) × 100 / A A = concentration of complex compound of chelating compound and gadolinium in emulsion before filtration B = concentration of complex compound of chelating compound and gadolinium in filtrate High performance liquid chromatography conditions Column C18 Column Solvent Methanol: 1% triethylamine (pH 8)
= 65: 35 Flow rate 1 ml / min

Embedding rate (%) 10-fold dilution 100-fold dilution Gd / DTPA-OA fat emulsion 62.2 45.2 Gd / DTPA-DeA fat emulsion 94.1 77.2 Gd / DTPA-DoA fat emulsion 99.7 89.8 Gd / DTPA-C14 fat emulsion 72.5 45.7

Experimental Example 3 Measurement of Blood Half-life The fat emulsion containing Gd.DTPA-OA obtained in Example 1 was administered to an arteriosclerosis model rabbit (atheroma rabbit) prepared by ingesting cholesterol continuously for 3 months. did. Blood was collected with time from a catheter cannulated in the femoral vein for up to 6 hours, and the blood concentration after administration was measured. For the measurement, a supernatant was obtained from the collected blood by centrifugation,
After washing with ethanol, high performance liquid chromatogram method (65%
Methanol, 1% triethylamine, pH 7.0, C18 column)
I went there. The drug should be delivered from the ear canal vein at a rate of 2 ml / min.
200 μmol / kg was continuously administered. The measurement result is shown in FIG.

Experimental Example 4 Diagnosis of Atherosclerosis Using the MRI Diagnostic Contrast Agent of the Present Invention An arteriosclerosis model rabbit was fixed in the dorsal position without anesthesia, and the fat emulsion obtained by the present invention was fed at a rate of 2 ml / min. 20 from the ear vein
0 μmol / kg was continuously administered. Five minutes, thirty minutes, and six hours after administration, the rabbit was killed by drug, the thoracic aorta was taken out, fat adhering to the outside of the aorta was carefully removed, and then the blood vessel was cut open and the arteriosclerotic region was cut out. The cut out sample is
The sample was put in an MR sample tube and MRI imaging was performed. The MRI system uses Siemens Magnetom 1.5T and the coil is Eye c
I used oil. Imaging condition is repeat time (TR) = 500m
sec, echo time (TE) = 22 msec, slice thickness = 1 mm, number of integration = 8 times, matrix = 128 × 256. In the obtained image, the arteriosclerosis part in the blood vessel was drawn very clearly, and 30 minutes after administration, the image shows a marked increase in the thickened part of the blood vessel wall where the arteriosclerosis seems to be progressing. The signal strength is shown. The maximum signal intensity ratio (maxSIR) is shown below.
Note that maxSIR means a signal intensity ratio with water in the same image.

MaxSIR Gd.DTPA -OA fat emulsion 5.9 Gd.DTPA-DoA fat emulsion 5.0 Gd.DTPA-PE fat emulsion 5.0

Experimental Example 5 Measurement of Distribution in Rat Organs The fat emulsion of the present invention was bolus administered from the tail vein. After a lapse of a predetermined time after administration, the animal was sacrificed with CO ₂ gas and then blood was removed, and each organ (liver, kidney, spleen) was taken out. After homogenizing each organ, ethanol was added, centrifugation was performed to obtain a supernatant, and measurement was performed by a high performance liquid chromatogram method (see Experimental Example 3). The results are shown in FIGS. 2 and 3. Figure 2 shows Gd DTPA-OA fat emulsion (dose:
0.2 mmol / kg) and FIG. 3 shows the case of administering a Gd.DTPA-DeA fat emulsion (dose: 0.02 mmol / kg; kidney and spleen distribution is omitted). As shown in FIGS. 2 and 3, the fat emulsion of the present invention showed excellent accumulation in the liver.

Experimental Example 6 Diagnosis of Liver Cancer Using the Contrast Agent for MRI Diagnosis of the Present Invention Male Wistar rats (body weight about 250 g) were treated with sodium pentoba.
rbital (50 mg / kg ip) under anesthesia, fix in dorsal position.
After shaving the abdomen, the abdomen is opened along the midline to expose the rectangular lobes of the liver. Walker 256 carcinosa suspended in Hank's solution
Inject rcoma (2.5 × 10 ⁷ cells / 50 μl) into the capsule of the liver (square leaf) with a stainless needle (31 G). Seven days after the tumor implantation, urethane anesthesia (1.25 g / kg, intraperitoneal administration) was performed, a contrast medium was administered through the tail vein, and allowed to stand for 30 minutes, followed by MRI imaging. The measurement conditions are the same as in Experimental Example 4 except that the slice thickness is 3 mm.

Signal strength Dose Cancer tissue Normal tissue ratio Gd · DTPA-DoA fat emulsion 0.01 mmol / kg 330.1 385.1 0.86 〃 0.02 mmol / kg 401.2 483.1 0.83 Ratio: Cancer tissue signal strength / Normal tissue signal strength

[0084]

INDUSTRIAL APPLICABILITY According to the fat emulsion containing paramagnetic metal atoms of the present invention, the paramagnetic metal atoms are uniformly dispersed in the small fat particles, so that the paramagnetic metal atoms can be stably and uniformly contained. it can. Further, the contrast agent for MRI diagnosis of the present invention is composed of a fat emulsion having the above-mentioned properties, and small fat particles migrate to the reticuloendothelial system, inflammatory site, arteriosclerotic site, etc., and exhibit an excellent contrast enhancing ability. It has properties and can advantageously perform imaging of various organs such as liver and spleen, arthritis, tumorous parts, blood vessels and the like.

[Brief description of drawings]

FIG. 1 is a graph showing a change in blood concentration when the fat emulsion of the present invention was administered to an arteriosclerotic rabbit in Experimental Example 3.

FIG. 2 Distribution of drug in rat organs in Experimental Example 5
It is a figure showing (dose: 0.2 mmol / kg).

FIG. 3 Distribution of drug in rat liver in Experimental Example 5
It is a figure showing (dose: 0.02 mmol / kg).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazuki Murakami 2-25-1 Otani, Hirakata-shi Invited by Midori Cross Central Research Institute Co., Ltd. (72) Masakazu Shindome Hyokata 2-25-1 Otani, Hirakata Company Midori Cross Central Research Institute (72) Inventor Tadashi Okano Invited Hirakata City No. 25-1 Otani Midori Co., Ltd. (72) Inventor Takako Ohashi Invited Hitakata City No. 25-1 Otani Midori Co., Ltd. CROSS CENTRAL LABORATORY (72) Inventor Fumio Mori 2-25-1 Otani, Hirakata City Midori Co., Ltd. CROSS CENTRAL LABORATORY (72) Inventor Kim Naomoto 18-1-301 Kitaoka, Kita Suita Taro Marukawa 3-1 Hiroji Honcho, Showa-ku, Nagoya pier 3C-4 (72) Inventor Kozuka ▲ Takahiro 2-Sekimori-cho, Suma-ku, Kobe -15

Claims (11)

[Claims] 1. A fat emulsion containing a paramagnetic metal atom. 2. A contrast agent for magnetic resonance imaging comprising a fat emulsion containing a paramagnetic metal atom. 3. The contrast agent for magnetic resonance imaging according to claim 2, comprising a fat emulsion containing a complex compound of a paramagnetic metal atom and a compound capable of forming a chelate bond with the metal. 4. A compound capable of forming a chelate bond with a paramagnetic metal atom has a general formula: [In the formula, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different, a hydrogen atom or a lower alkyl group, R ₃ , R ₄ , R ₅ and R ₆ are the same or different, and are a hydroxyl group. Or group: (In the formula, n is 0 or 1, X is —NH— or —O—, Y is an alkylene group, A is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group, and B is an alkyl group. Or represents an alkenyl group). However, R ₃ , R ₄ , R
Of ₅ and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, those in which both R ₃ and R ₅ are hydroxyl groups and those in which R ₄ and R ₆ are both hydroxyl groups are excluded. ] The contrast agent for magnetic resonance imaging according to claim 3, which is a compound represented by the formula or a salt thereof. 5. A compound capable of forming a chelate bond with a paramagnetic metal atom is represented by the general formula: [In the formula, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different, a hydrogen atom or a lower alkyl group, R ₃ , R ₄ , R ₅ and R ₆ are the same or different, and are a hydroxyl group. Or group: (In the formula, Q and T are the same or different, -NH- or -O-, D and E are the same or different, and a fatty acid residue having 6 or more carbon atoms or an alkyl group having 6 or more carbon atoms, p Represents an integer of 0 to 6, and when p is 0, T does not exist). However, among R ₃ , R ₄ , R ₅ and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R ₃ and R ₅ are both hydroxyl groups and R ₄ and R ₆
Except those in which both are hydroxyl groups. ] The contrast agent for magnetic resonance imaging according to claim 3, which is a compound represented by the formula or a salt thereof. 6. A compound which can form a chelate bond with a paramagnetic metal atom has a general formula: [In the formula, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different, a hydrogen atom or a lower alkyl group, R ₃ , R ₄ , R ₅ and R ₆ are the same or different, and are a hydroxyl group. or a group: -Q- (CH _{2) p} -T- sterol (wherein, Q and T are the same or different, -NH- or -O-, p represents an integer of 0 to 6, p is 0 In the case of, there is no T, and the sterol binding position is the 3-position). However, among R ₃ , R ₄ , R ₅ and R ₆ , there are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R ₃ and R ₅ are both hydroxyl groups and R ₄ and R ₆ Except those in which both are hydroxyl groups. ] The contrast agent for magnetic resonance imaging according to claim 3, which is a compound represented by the formula or a salt thereof. 7. A compound capable of forming a chelate bond with a paramagnetic metal atom has a general formula: (In the formula, m is an integer of 1 to 3, and R ₇ represents an alkyl group having 6 or more carbon atoms.) The contrast agent for magnetic resonance imaging according to claim 3, which is a compound or a salt thereof. 8. A compound capable of forming a chelate bond with a paramagnetic metal atom has a general formula: [In the formula, m is an integer of 1 to 3, R ₁ and R ₂ are the same or different, a hydrogen atom or a lower alkyl group, R ₃ , R ₄ , R ₅ and R ₆ are the same or different, and are a hydroxyl group. Or group: (In the formula, R ₈ and R ₉ are the same or different and each represents a fatty acid residue). However, among R ₃ , R ₄ , R ₅ and R ₆ ,
There are 2 or 3 hydroxyl groups, and when there are 2 hydroxyl groups, R
Excluding those in which ₃ and R ₅ are both hydroxyl groups and those in which R ₄ and R ₆ are both hydroxyl groups. ] The contrast agent for magnetic resonance imaging according to claim 3, which is a compound represented by the formula or a salt thereof. 9. A method of preparing a fat emulsion containing phosphatidylethanolamine, followed by reacting with an acid anhydride of ethylenediaminetetraacetic acid, an acid anhydride of diethylenetriaminepentaacetic acid or an acid anhydride of triethylenetetraminehexaacetic acid. The method for producing a contrast agent for magnetic resonance imaging according to claim 8. 10. A diagnostic agent for arteriosclerosis, which comprises the contrast agent for magnetic resonance imaging according to any one of claims 1 to 8. 11. A liver tumor diagnostic agent comprising the magnetic resonance imaging diagnostic contrast agent according to claim 1.