JP5172188B2 - Glyceride compound having a fluorine-substituted alkyl group - Google Patents

Description

  The present invention relates to a glyceride compound having a fluorine-substituted alkyl group. This compound can be used as a membrane component of the liposome, and the liposome can be used as a contrast agent.

  As a non-invasive method for diagnosing arteriosclerosis, X-ray angiography is mainly used. However, since this method is a method of imaging a blood flow with a water-soluble iodine contrast medium, it is difficult to distinguish between a diseased tissue and a normal tissue. Therefore, only lesions with stenosis of 50% or more can be detected, and it is difficult to detect lesions before the onset of an ischemic disease.

  As a diagnostic method other than the above, in recent years, a method for detecting a disease by nuclear magnetic resonance tomography (MRI) using a contrast agent that is dynamically distributed in atherosclerotic plaque has been reported. However, any of the compounds reported as the contrast agent has a problem when used in diagnostic methods. For example, a hematoporphyrin derivative (see Patent Document 1) has been pointed out to have defects in deposition and coloring on the skin, and a gadolinium complex having a perfluoro side chain that has been reported to accumulate in lipid rich plaques (non- Patent Document 1) is concerned about accumulation in lipid-rich tissues and organs such as fatty liver, kidney epithelium, and muscle tissue tendons.

From the viewpoint of a compound, a compound in which a carboxylic acid having a polyaminoethylene side chain is ester-bonded to a diglyceride of a fatty acid whose alkyl group is fluorine-substituted (for example, see Patent Document 2), a compound having a polyamine is known. Is likely to have a positive charge, and there is a concern that it may develop toxicity due to interaction with cell membranes and DNA in vivo.
U.S. Patent No. 4577636 WO9834910 Circulation, 109, 2890 (2004)

  An object of the present invention is to provide a compound suitable for a liposome contrast agent for imaging a lesion selectively.

  As a result of studies conducted by the present inventors to solve the above-mentioned problems, it has been found that the glyceride compound having a fluorine-substituted alkyl group of the present invention has excellent properties as a component of a liposome as a contrast agent. I found it. The present invention has been completed based on the above findings.

［式中、ｌ及びｎは、それぞれ独立に１〜１０の整数を表し；ｍ及びｏは、それぞれ独立に２〜１０の整数を表し；Ｘは、炭素原子、酸素原子、窒素原子、硫黄原子及び水素原子からなる群から選択される原子により構成される基を表す、ただし、Ｘにおいて、炭素原子、酸素原子、窒素原子及び硫黄原子の総原子数は３〜４０個であり、炭素原子数は１〜３８個であり、酸素原子、窒素原子、及び硫黄原子の総原子数は２〜１３個であり、窒素原子数は０〜３個であり、かつ硫黄原子数は０〜３個である］で表される化合物又はその塩を提供するものである。 That is, the present invention provides the following general formula (I):

[Wherein, l and n each independently represents an integer of 1 to 10; m and o each independently represents an integer of 2 to 10; X represents a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. And a group constituted by an atom selected from the group consisting of hydrogen atoms, provided that in X, the total number of carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms is 3 to 40, and the number of carbon atoms 1 to 38, the total number of oxygen atoms, nitrogen atoms, and sulfur atoms is 2 to 13, the number of nitrogen atoms is 0 to 3, and the number of sulfur atoms is 0 to 3 Or a salt thereof.

［式中、ｌ及びｎは、それぞれ独立に１〜１０の整数を表し；ｍ及びｏは、それぞれ独立に２〜１０の整数を表し；Ｘは、炭素原子、酸素原子、窒素原子、硫黄原子及び水素原子からなる群から選択される原子により構成される基を表す、ただし、Ｘにおいて、炭素原子、酸素原子、窒素原子及び硫黄原子の総原子数は３〜４０個であり、炭素原子数は１〜３８個であり、酸素原子、窒素原子、及び硫黄原子の総原子数は２〜１３個であり、窒素原子数は０〜３個であり、かつ硫黄原子数は０〜３個である］で表される化合物、又はその塩が提供される。 As another aspect of the present invention, the following general formula (II):

[Wherein, l and n each independently represents an integer of 1 to 10; m and o each independently represents an integer of 2 to 10; X represents a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. And a group constituted by an atom selected from the group consisting of hydrogen atoms, provided that in X, the total number of carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms is 3 to 40, and the number of carbon atoms 1 to 38, the total number of oxygen atoms, nitrogen atoms, and sulfur atoms is 2 to 13, the number of nitrogen atoms is 0 to 3, and the number of sulfur atoms is 0 to 3 Or a salt thereof.

［式中、Ｘ^Aは炭素原子、酸素原子、窒素原子、硫黄原子及び水素原子からなる群から選択される原子により構成される基を表す、ただし、Ｘ^Aにおいて、炭素原子、酸素原子、窒素原子及び硫黄原子の総原子数は１〜３８個であり、このうち炭素原子数は０〜３７個であり、酸素原子、窒素原子、及び硫黄原子の総原子数は１〜１２個であり、窒素原子数は０〜３個であり、かつ硫黄原子数は０〜３個である］で表される上記式（Ｉ）又は（ＩＩ）で表される化合物又はその塩が提供される。 According to a preferred embodiment of the present invention, X is represented by the following general formula (III):

[Wherein, X ^A represents a group composed of an atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, and a hydrogen atom, provided that in X ^A , a carbon atom, an oxygen atom, nitrogen The total number of atoms of the atoms and sulfur atoms is 1 to 38, of which the number of carbon atoms is 0 to 37, the total number of atoms of oxygen atoms, nitrogen atoms, and sulfur atoms is 1 to 12, The number of nitrogen atoms is 0 to 3 and the number of sulfur atoms is 0 to 3], or a compound represented by the above formula (I) or (II) or a salt thereof is provided.

Furthermore, preferred embodiments of the present invention include any of the above compounds or salts thereof in which the atomic group constituting X ^A does not contain a sulfur atom, and from another viewpoint, in X ^A , a carbon atom, oxygen atom, a nitrogen atom and any one of the above-mentioned compounds or salts thereof total atom is 1-28 sulfur atoms, and further, the X ^a, carbon atoms, an oxygen atom, the total number of atoms of nitrogen atom and sulfur atom The compound or its salt as described in the above which is 1-18. From another viewpoint, the above-mentioned compound or a salt thereof, in which at least one of fluorine atoms constituting the compound is ¹⁸ F (radioisotope), is provided.

［式中、Ｘ^Bは、炭素原子、酸素原子、窒素原子、硫黄原子及び水素原子からなる群から選択される原子により構成される基を表す、ただし、Ｘ^Bにおいて炭素原子、酸素原子、窒素原子及び硫黄原子の総原子数は２〜３９個であり、このうち炭素原子数は０〜３７個であり、酸素原子、窒素原子、及び硫黄原子の総原子数は２〜１３個であり、窒素原子数は０〜３個であり、かつ硫黄原子数は０〜３個である］ で表される上記式（Ｉ）又は（ＩＩ）で表される化合物又はその塩が提供される。 In another embodiment of the present invention, X is represented by the following general formula (IV):

[Wherein, X ^B represents a group composed of an atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom and a hydrogen atom, provided that in X ^B a carbon atom, an oxygen atom, a nitrogen atom The total number of atoms of the atoms and sulfur atoms is 2 to 39, of which the number of carbon atoms is 0 to 37, the total number of oxygen atoms, nitrogen atoms, and sulfur atoms is 2 to 13, The number of nitrogen atoms is 0 to 3 and the number of sulfur atoms is 0 to 3.] A compound represented by the above formula (I) or (II) represented by the following formula or a salt thereof is provided.

Furthermore, preferred embodiments of the present invention include any of the above compounds or salts thereof in which the atomic group constituting X ^B does not contain a sulfur atom, and from another viewpoint, in X ^B , a carbon atom, oxygen atom, a nitrogen atom and any one of the above-mentioned compounds or salts thereof total atom is 3 to 29 sulfur atoms, and further, the X ^B, a carbon atom, an oxygen atom, the total number of atoms of nitrogen atom and sulfur atom Is any one of the above compounds or a salt thereof. From another viewpoint, the above-mentioned compound or a salt thereof, in which at least one of fluorine atoms constituting the compound is ¹⁸ F (radioisotope), is provided.

From another aspect, the present invention provides a liposome containing the above-mentioned compound or a salt thereof as a membrane constituent, and according to a preferred embodiment thereof, the above-mentioned liposome containing phosphatidylcholine and phosphatidylserine as membrane constituents is provided. .
The present invention also provides an MRI contrast agent containing the above-mentioned liposome. According to a preferred aspect of the present invention, the MRI contrast agent used for imaging of vascular diseases; the MRI contrast agent used for imaging of vascular smooth muscle cells abnormally proliferated under the influence of foamed macrophages; a tissue in which macrophages are localized or The above-mentioned MRI contrast medium used for imaging of a disease site; the above-mentioned MRI contrast medium wherein the tissue in which macrophages are localized is selected from the group consisting of liver, spleen, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium; The MRI contrast agent is provided, wherein the localized disease site is selected from the group consisting of a tumor, an inflammation site, and an infection site.

  Similarly, the present invention provides a PET contrast agent comprising the above-described liposome. According to a preferred aspect of the present invention, the PET contrast agent used for imaging of vascular diseases; the PET contrast agent used for imaging of vascular smooth muscle cells abnormally proliferated under the influence of foamed macrophages; The PET contrast agent used for imaging of a diseased site; the PET contrast agent selected from the group consisting of liver, spleen, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium; The PET contrast agent is provided, wherein the localized disease site is selected from the group consisting of a tumor, an inflammation site, and an infection site.

  Further, the use of the above-mentioned compound or a salt thereof for the production of the above-mentioned MRI contrast agent / PET contrast agent; MRI contrast / PET contrast method, comprising the above-mentioned compound or a salt thereof as a membrane constituent A method comprising the steps of MRI imaging / PET imaging after administration to a mammal including humans; a method for imaging a lesion of a vascular disease, comprising the above-mentioned compound or a liposome containing a salt as a membrane component, including humans A method is provided by the present invention comprising the step of MRI / PET imaging after administration to a mammal.

  The compound of the present invention or a salt thereof has excellent properties in the amount of liposome encapsulated as a constituent lipid of a liposome for MRI / PET contrast agent, and MRI contrast / PET contrast using a liposome containing this compound. By doing so, the contrast of the blood vessel can be selectively imaged.

  In this specification, when “substituted or unsubstituted” or “may have a substituent” for a certain functional group, the functional group may have one or more substituents. Although shown, the number of substituents to be bonded, the position of substitution, and the type are not particularly limited unless otherwise specified. When a certain functional group has two or more substituents, they may be the same or different. In this specification, when a certain functional group has a substituent, examples of the substituent include a halogen atom (in the present specification, “halogen atom” may be any of fluorine, chlorine, bromine, or iodine). An alkyl group (in this specification, the term “alkyl group” may be linear, branched, cyclic, or a combination thereof, and the cyclic alkyl group may be a polycyclic alkyl such as a bicycloalkyl group. The same applies to the alkyl moiety of other substituents including an alkyl moiety), alkenyl groups (including cycloalkenyl groups and bicycloalkenyl groups), alkynyl groups, aryl groups, heterocyclic groups, cyano groups, hydroxyl groups Group, nitro group, carboxyl group, alkoxy group, aryloxy group, silyloxy group, heterocyclic oxy group, acyloxy Carbamoyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, amino group (including anilino group), acylamino group, aminocarbonylamino group, alkoxycarbonylamino group, aryloxycarbonylamino group, sulfamoylamino group, Alkyl and arylsulfonylamino groups, mercapto groups, alkylthio groups, arylthio groups, heterocyclic thio groups, sulfamoyl groups, sulfo groups, alkyl and arylsulfinyl groups, alkyl and arylsulfonyl groups, acyl groups, aryloxycarbonyl groups, alkoxycarbonyl groups Carbamoyl group, aryl and heterocyclic azo group, imide group, phosphino group, phosphinyl group, phosphinyloxy group, phosphinylamino group and silyl group.

  l and n each independently represent an integer of 1 to 10. l and n are each independently preferably an integer of 3 to 10, more preferably an integer of 5 to 10. m and o each independently represents an integer of 2 to 10. m and o are each independently preferably an integer of 2 to 8, and more preferably an integer of 2 to 6.

X represents a group composed of an atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom and a hydrogen atom, and the total of carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms constituting X The number of atoms is 3-40. In the range of the compound represented by the general formula (I) or (II) having a group having such a size as X, the liposome-forming ability of the compound and the performance of the liposome as a contrast agent are almost the same. .
The monovalent group represented by X may be any of linear, branched, cyclic, or any combination thereof. “Total number of hetero atoms (oxygen atom, nitrogen atom, and sulfur atom) / total number of carbon atoms” in the atomic group constituting X is preferably 0.4 or more, more preferably 0.4 or more and 1.0 or less. 0.5 to 1.0 is most preferable.

  It is preferable that the monovalent group represented by X does not contain a sulfur atom, that is, the hetero atoms contained in X are only an oxygen atom and a nitrogen atom. Moreover, the number of nitrogen atoms contained in X is 0 to 3, preferably 0 to 2, and more preferably 0 to 1.

［式中、Ｘ^Aは炭素原子、酸素原子、窒素原子、硫黄原子及び水素原子からなる群から選択される原子により構成される基を表す、ただし、Ｘ^Aを構成する炭素原子、酸素原子、窒素原子及び硫黄原子の総原子数は１〜３８個であり、このうち炭素原子数は０〜３７個であり、酸素原子、窒素原子、及び硫黄原子の総原子数は１〜１２個であり、窒素原子数は０〜３個であり；硫黄原子数は０〜３個である］で表される基であることが好ましい。 Furthermore, X preferably contains at least one of a morpholine structure, an oligoethylene glycol structure, or a polyol structure. In this case, the position, number, repeating unit, and number of repetitions are not particularly limited. X is also represented by the following general formula (III):

Wherein, X ^A is a carbon atom, an oxygen atom, a nitrogen atom, by atoms selected from the group consisting of sulfur and hydrogen atoms represents a group composed, provided that the carbon atoms constituting the X ^A, an oxygen atom, The total number of nitrogen atoms and sulfur atoms is 1 to 38, of which the number of carbon atoms is 0 to 37, and the total number of oxygen atoms, nitrogen atoms, and sulfur atoms is 1 to 12. The number of nitrogen atoms is 0 to 3; the number of sulfur atoms is 0 to 3].

Monovalent group represented by X ^A is a linear, branched, cyclic, or may be any of any combination thereof. “(Total number of heteroatoms + 1) / (Total number of carbon atoms + 1)” in the atomic group constituting X ^A is preferably 0.4 or more, more preferably 0.4 or more and 1.0 or less, and 0.5 or more. 1.0 or less is most preferable. The number of nitrogen atoms contained in X ^A is usually 0-3, preferably 0-2, 0-1 is more preferable.

［式中、Ｘ^Bは、炭素原子、酸素原子、窒素原子、硫黄原子及び水素原子からなる群から選択される原子により構成される基を表す、ただし、Ｘ^Bを構成する炭素原子、酸素原子、窒素原子及び硫黄原子の総原子数は２〜３９個であり、このうち炭素原子数は０〜３７個であり、酸素原子、窒素原子、及び硫黄原子の総原子数は２〜１３個であり、窒素原子数は０〜３個であり；硫黄原子数は０〜３個である］で表される基であることが好ましい。 Furthermore, X ^A preferably contains at least one of a morpholine structure, an oligoethylene glycol structure, or a polyol structure. In this case, the position, number, repeating unit, and number of repetitions are not particularly limited.
X is also the following general formula (IV):

[Wherein, X ^B represents a group composed of an atom selected from the group consisting of a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom and a hydrogen atom, provided that the carbon atom or oxygen atom constituting X ^B The total number of nitrogen atoms and sulfur atoms is 2 to 39, of which the number of carbon atoms is 0 to 37, and the total number of oxygen atoms, nitrogen atoms, and sulfur atoms is 2 to 13. And the number of nitrogen atoms is 0 to 3; the number of sulfur atoms is 0 to 3].

Monovalent group represented by X ^B is a linear, branched, cyclic, or may be any of any combination thereof. “Total number of heteroatoms / (total number of carbon atoms + 1)” in the atomic group constituting X ^B is preferably 0.4 or more, more preferably 0.4 or more and 1.0 or less, and 0.5 or more and 1.0. The following are most preferred. The number of nitrogen atoms contained in X ^B is 0-3, preferably 0-2, 0-1 is more preferable.

Furthermore, X ^B preferably contains at least one of a morpholine structure, an oligoethylene glycol structure, or a polyol structure. In this case, the position, number, repeating unit, and number of repetitions are not particularly limited.

  The compound of the present invention may have one or more asymmetric centers. In this case, stereoisomers such as optically active substances or diastereoisomers based on the asymmetric centers exist. Any stereoisomers in pure form, mixtures of any stereoisomers, racemates, and the like are all encompassed within the scope of the present invention. In addition, the compound of the present invention may have one or more olefinic double bonds, but the arrangement may be either E or Z, and may exist as a mixture of both. . The compounds of the invention may exist as tautomers, but any tautomer, or mixture thereof, is included within the scope of the invention. Furthermore, the compound of the present invention may form a salt, and the free form compound or the salt form compound may form a hydrate or a solvate. Is included. The kind of salt is not particularly limited, and may be either an acid addition salt or a base addition salt.

Although the preferable example of the compound of this invention is shown below, the compound of this invention is not limited to these examples.

Of the fluorine atoms in the compound represented by the above general formula (I) or (II), at least one of the compounds represented by ¹⁸ F is a compound represented by any formula, wherein 1 or more and 10 or less A compound having ¹⁸ F is preferred, a compound having 1 to 5 ¹⁸ F is more preferred, and a compound having 1 to 3 ¹⁸ F is most preferred. Further, the position of substitution of ¹⁸ F is not particularly defined, but it is more preferably at the CF ₃ terminal of the fluorine-substituted fatty acid.

  Hereinafter, a general method for synthesizing the compound of the present invention will be described, but the method for synthesizing the compound of the present invention is not limited thereto. As the alkyl fatty acid having fluorine at the terminal, which is a partial structure of the compound of the present invention, a commercially available one may be used, or may be appropriately synthesized according to the application. When obtained by synthesis, the corresponding alcohol, alkyl halide, or the like can be used as a raw material by the method described in, for example, Richard C. Larock, Comprehensive organic transformations (VCH).

  The carboxylic acid is condensed with a glycerin derivative such as protected glycerin or 1,3-dihydroxyacetone to lead to a glyceride. In this case, if necessary, a protecting group can be used. In this case, the protecting group is described in, for example, Protecting groups in organic synthesis (John Wiley & sonc, inc.) By TW Green & PGM Wuts. Can be appropriately selected and used.

  The above glycerides are appropriately deprotected using the method described in the above-mentioned Protecting groups in organic synthesis (John Wiley & sonc, inc.), And then suitable carboxylic acids, carboxylic acid halides, alkyl halides, etc. By reacting, it can lead to the target compound. In this case, for example, it can be performed in accordance with the method described in the above-mentioned Richard C. Larock, Comprehensive organic transformations (VCH).

In addition, a compound in which at least one of the fluorine atoms in the compound represented by the general formula (I) or (II) is ¹⁸ F is, for example, J. Labelled Compd. Radiopharm., 40, 11-13 (1997). ) Can be synthesized in accordance with the method described in).

The compound of the present invention or a salt thereof can be used as a membrane constituent of a liposome. When preparing a liposome using the compound of the present invention or a salt thereof, the amount of the compound of the present invention or a salt thereof used is about 5 to 90% by mass, preferably 5 to 80% by mass with respect to the total mass of the membrane constituent components. %. Although the compound of this invention may use 1 type as a film | membrane structural component, you may use it in combination of 2 or more types.
As other membrane constituent components of the liposome, any lipid compound usually used in the production of liposomes can be used. For example, Biochim. Biophys. Acta 150 (4), 44 (1982), Adv. In Lipid. Res. 16 (1), 1 (1978), _RESEARCH IN LIPOSOMES_ (P. Machy, L. Leserman, John Libbey EUROTEXT Co., Ltd.), “Liposome” (Nojima, Sunamoto, Inoue Hen, Nankodo) and the like. As the lipid compound, phospholipid is preferable, and phosphatidylcholine (PC) is particularly preferable. Preferred examples of phosphatidylcholines include eggPC (egg-derived PC), dimyristoyl PC (DMPC), dipalmitoyl PC (DPPC), distearoyl PC (DSPC), dioleyl PC (DOPC), and the like. It is not limited.

In a preferred embodiment of the present invention, phosphatidylcholine and phosphatidylserine (PS) can be used in combination as membrane constituents of the liposome. Examples of phosphatidylserine include compounds having the same lipid moiety as the phospholipids listed as preferred examples of phosphatidylcholine. When phosphatidylcholine and phosphatidylserine are used in combination, the preferred molar ratio of PC and PS is between PC: PS = 90: 10 and 10:90, more preferably between 30:70 and 70:30. .
According to another preferred embodiment of the liposome of the present invention, a liposome containing phosphatidylcholine and phosphatidylserine as a membrane component and further containing a dialkyl phosphate is mentioned. The two alkyl groups constituting the dialkyl ester of the phosphoric acid dialkyl ester are preferably the same, and the carbon number of each alkyl group is 6 or more, preferably 10 or more, and more preferably 12 or more. Examples of preferred dialkyl phosphates include, but are not limited to, dilauryl phosphate, dimyristyl phosphate, dicetyl phosphate, and the like. In this embodiment, the preferred amount of dialkyl phosphate used relative to the total weight of phosphatidylcholine and phosphatidylserine is 1 to 50% by weight, preferably 1 to 30% by weight, more preferably 1 to 20% by weight. .

In the liposome containing phosphatidylcholine, phosphatidylserine, dialkyl ester phosphate and the compound of the present invention as membrane constituents, the preferred mass ratio of the above components is PC: PS: dialkyl phosphate ester: 5-50% by mass of the compound of the present invention: It can be selected between 5-50% by mass: 1-10% by mass: 1-80% by mass.
The constituent components of the liposome of the present invention are not limited to the above four, and other components can be added. Examples thereof include cholesterol, cholesterol ester, sphingoemilin, FEBS Lett. 223, 42 (1987); Proc. Natl. Acad. Sci., USA 85, 6949 (1988) and the like, Chem. Lett. 2145 (1989); Biochim. Biophys. Acta 1148, 77 (1992) and other glucuronic acid derivatives, Biochim. Biophys. Acta 1029, 91 (1990); FEBS Lett. 268, 235 (1990), etc. However, the present invention is not limited to this.

  The liposome of the present invention may be produced by any method available to those skilled in the art. Examples of production methods include, in addition to the above-listed liposome documentation, Ann. Rev. Biophys. Bioeng. 9, 467 (1980), "Liposomes" (MJ Ostro, MARCELL DEKKER, INC.), Etc. Have been described. Specific examples include sonication, ethanol injection, French press method, ether injection method, cholic acid method, calcium fusion method, freeze-thaw method, reverse phase evaporation method, etc. Absent. The size of the liposome of the present invention may be any size that can be prepared by the above method, but the average is usually 400 nm or less, preferably 200 nm or less. The structure of the liposome is not particularly limited, and may be any form such as unilamellar or multilamellar. Moreover, it is also possible to mix | blend the 1 type (s) or 2 or more types of a suitable drug and another contrast agent in the inside of a liposome.

  When the liposome of the present invention is used as a contrast agent, it can be preferably administered parenterally, more preferably intravenously administered. For example, a preparation in the form of an injection or infusion is provided as a powdered composition in a lyophilized form, and is dissolved in water or other appropriate medium (for example, physiological saline, infusion of grapes, buffer, etc.) Or it can be resuspended. When the liposome of the present invention is used as a contrast agent, the dose can be appropriately determined so that the compound content in the liposome is comparable to the compound content of a conventional contrast agent.

  Without being bound to any particular theory, in vascular diseases such as arteriosclerosis or restenosis after PTCA (percutaneous coronary angioplasty), vascular smooth muscle cells that form the media of the blood vessels grow abnormally At the same time, it is known to migrate to the intima and narrow the blood flow path. Although the triggers for normal vascular smooth muscle cells to begin to grow abnormally have not yet been fully clarified, macrophage migration and foaming are known to be important factors, followed by vascular smoothness. It has been reported that myocytes undergo phenotype conversion (from contraction to synthesis).

  When the liposome of the present invention is used, a compound that serves as a defined contrast agent can be selectively taken into vascular smooth muscles that have abnormally grown under the influence of foamed macrophages. As a result, it is possible to contrast the lesion and the non-disease site with contrast. Therefore, the contrast agent of the present invention can be suitably used particularly for imaging of vascular diseases. For example, imaging of arteriosclerotic lesions and restenosis after PTCA can be performed.

  In addition, as described in, for example, J. Biol. Chem., 265, 5226 (1990), liposomes composed of phospholipids, particularly liposomes formed from PC and PS, accumulate in macrophages via scavenger receptors. It is known to be easy. Therefore, by using the liposome of the present invention, the compound of the present invention can be accumulated in a tissue or a disease site where macrophages are localized. When the liposome of the present invention is used, more defined compounds can be accumulated in macrophages than when a suspension or oil emulsion, which is a known technique, is used.

  Examples of the tissue in which macrophage localization is recognized and which can be suitably imaged by the method of the present invention include blood vessels, liver, alveoli, lymph nodes, lymph vessels, and kidney epithelium. Further, in certain diseases, it is known that macrophages are accumulated at the disease site. Examples of such diseases include tumors, arteriosclerosis, inflammation, infection and the like. Therefore, these disease sites can be identified by using the liposome of the present invention. In particular, it is known that foamed macrophages that have incorporated a large amount of denatured LDL via a scavenger receptor accumulate in the early stage of atherosclerotic lesions [Am. J. Pathol., 103, 181 ( 1981), Annu. Rev. Biochem., 52, 223 (1983)], and by positioning the liposomes of the present invention in these macrophages and imaging them, the location of early arteriosclerotic lesions, which is difficult by other means, is specified. Is possible.

The imaging method using the liposome of the present invention is not particularly limited. For example, an imaging method used as an MRI contrast agent can be performed by measuring the nuclear spin of fluorine. Moreover, it is also possible to use it as a PET contrast agent by using a radioisotope such as ¹⁸ F.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In addition, the compound number in the following Example respond | corresponds to the number of the compound example shown above. Moreover, the structure of the compound in an Example was confirmed by the NMR spectrum.

Synthesis of Compound 1-6
6.32 g of 6- (perfluorohexyl) hexanol was dissolved in 60 mL of dichloromethane, 3.15 mL of triethylamine was added, and the mixture was stirred at 0 ° C. Further, 1.28 mL of methanesulfonyl chloride was added dropwise, and the mixture was warmed to room temperature and stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The obtained organic layer was washed with a 1N aqueous hydrochloric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was removed to obtain 7.31 g (98%) of the corresponding sulfonate ester.

  To 0.71 g of sodium hydride (oil dispersion, 60%), 25 mL of dimethylformamide (DMF) was added and stirred at 0 ° C. A solution prepared by dissolving 2.82 g of diethyl malonate in 3 mL of DMF was added dropwise, and the temperature was raised to room temperature. A solution prepared by dissolving 7.31 g of the sulfonic acid ester in 10 mL of DMF was added dropwise, and the mixture was stirred at room temperature for 2 hours and at 80 ° C. for 2 hours. A 1N aqueous hydrochloric acid solution was added to the reaction solution, followed by extraction twice with dichloromethane, and the resulting organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, removed, and purified by silica gel column chromatography to obtain 4.83 g (58%) of the corresponding malonic acid derivative.

  4.83 g of the malonic acid derivative described above was dissolved in 70 mL of 95% ethanol, 0.62 g of lithium hydroxide was added, and the mixture was stirred at room temperature. The reaction was quenched by adding 1.2 mL of 3N hydrochloric acid to the reaction solution. Dichloromethane and 1N aqueous hydrochloric acid were added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then removed. The obtained residue was dissolved in 20 mL of pyridine, 2 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 130 ° C. for 3 hours. Purification by silica gel column chromatography gave 4.83 g (58%) of the corresponding malonic acid derivative. Dichloromethane and 1N aqueous hydrochloric acid were added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, removed, and purified by silica gel column chromatography to obtain 3.55 g (89%) of 8- (perfluorohexyl) octanoic acid.

  To 0.8 g of sodium hydride were added 5 mL of DMF and 20 mL of tetrahydrofuran (THF), and the mixture was stirred at 0 ° C. (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol 2.4 g of a mixed solution of DMF (3 mL) and THF (3 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. 2.8 mL of 4-methoxybenzyl chloride was added and stirred at room temperature for 3 hours. Saturated ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed 4 times with water and once with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed, and 4.1 g of a crude product of (S)-(+)-4- (4-methoxybenzyloxymethyl) -2,2-dimethyl-1,3-dioxolane was obtained. (89%) obtained.

  4.1 g of a crude product of (S)-(+)-4- (4-methoxybenzyloxymethyl) -2,2-dimethyl-1,3-dioxolane was dissolved in 10 mL of methanol, and 1N hydrochloric acid was added to room temperature. For 1 day. Saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 6, and the mixture was extracted 4 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the residue was purified by silica gel column chromatography to obtain 2.4 g of (R)-(+)-3- (4-methoxybenzyloxy) -1,2-propanediol ( Yield 69%).

  (R)-(+)-3- (4-Methoxybenzyloxy) -1,2-propanediol 0.54 g was dissolved in dichloromethane 3.5 mL, and 8- (perfluorohexyl) octanoic acid 2.32 g, dimethylaminopyridine 28 mg and 1.10 g of ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC · HCl) were added, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed, and the residue was purified by silica gel column chromatography to obtain 2.19 g of 1,2-diglyceride. (78%) obtained.

  Add 2.40 g of dichloromethane and 4 mL of water to 2.19 g of the above 1,2-diglyceride, add 0.69 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and stir vigorously at room temperature for 2 hours and 30 minutes did. 1N Sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated ammonium chloride solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, removed, and purified by silica gel column chromatography to obtain 1.51 g (77%) of deprotected 1,2-diglyceride.

0.42 g of the above 1,2-diglyceride compound was dissolved in 3 ml of dichloromethane, and 75 mg of morpholinoacetic acid synthesized according to the method described in J. Mol. Struct., 560 (1-2), 261 (2001) 5 mg of dimethylaminopyridine was added. Furthermore, 0.13 g of hydrochloride of ethyl-3-dimethylaminopropylcarbodiimide was added and stirred at room temperature for 3 days. Water was added to the reaction solution, extracted twice with dichloromethane, and the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, then removed, and purified by silica gel column chromatography to obtain 0.40 g (84%) of compound 1-6.
Compound 1-6:
¹ H-NMR (300MHz, CDCl ₃ ) δ: 5.29 (1H, ddt), 4.38 (1H, dd), 4.31 (1H, dd), 4.19 (1H, dd), 4.13 (1H, dd), 3.78-3.72 (4H, m), 3.23 (2H, s), 2.51-2.54 (4H, m), 2.47-2.38 (4H, m), 2.16-1.95 (4H, m), 1.70-1.46 (4H, m), 1.46 -1.22 (12H, m).
¹⁹ F-NMR (300 MHz, CDCl ₃ ) δ: -81, -114, -122, -123, -124, -126.

Synthesis of Compound 2-1 Morpholine and succinic anhydride are dissolved in ethyl acetate and refluxed, and then the solvent is distilled off to obtain a crude product of monomorpholinosuccinic acid. Compound 2-1 can be obtained in the same manner as Compound 1-6 except that this crude product is used in place of morpholinoacetic acid.

Synthesis of Compound 2-2 The 1,2-diglyceride compound used for the synthesis of succinic anhydride and Compound 1-6 is dissolved in dichloromethane, and pyridine and dimethylaminopyridine are added to perform reflux. The reaction solution is concentrated and then purified by silica gel column chromatography to obtain compound 2-2.

Synthesis of Compound 2-3-3 Compound 2-3-3 can be obtained by a condensation reaction using EDC · HCl similar to Compound 1-6 using Compound 2-2 and triethylene glycol monoethyl ether. .

Synthesis of Compound 2-5 Compound 2-5 can be obtained in the same manner as Compound 2-3-3 using Compound 2-2 and 25% aqueous ammonia.

Synthesis of Compound 2-6 Using compound 2-2, compound 2-6 can be obtained according to the method described in J. Med. Chem., 40, 3381 (1997).

Synthesis of compounds 2-7-2 to 2-7-5
3-morpholinopropanoic acid, 4-morpholinobutanoic acid, 5-morpholinopentanoic acid, or 6-morpholino synthesized according to the method described in J. Mol. Struct., 560 (1-2), 261 (2001) Compounds 2-7-2 to 2-7-5 can be obtained in the same manner as Compound 1-6 except that hexanoic acid is used instead of morpholinoacetic acid.

Synthesis of Compound 2-9 Compound 2-9 can be obtained in the same manner as Compound 1-6 except that N, N-dimethylglycine is used instead of morpholinoacetic acid.

Synthesis of Compound 2-18
2,2-dimethyl-1,3-dioxolane-4-methanol is dissolved in tetrahydrofuran and stirred at 0 ° C. Slowly add 60% sodium hydride, warm to room temperature with stirring and continue stirring. Cool again to 0 ° C., add chloroacetylmorpholine dissolved in tetrahydrofuran, and stir at room temperature. Water is added, extraction is performed with ethyl acetate, and the resulting organic layer is washed with saturated brine. When the organic layer is dried over anhydrous magnesium sulfate and then the solvent is removed, a morpholine-substituted glycerin derivative is obtained.

When a dioxane hydrochloric acid solution (˜4 mol / L) is added to the glycerin derivative and stirred, and the solvent is removed after completion of the reaction, the desired diol can be obtained as a crude product.
Using 8- (perfluorohexyl) octanoic acid synthesized with the above diol, compound 2-18 can be obtained according to the method described in J. Med. Chem., 29 (12), 2457 (1986). it can.

Synthesis of Compound 2-16 The t-butyl protector of Compound 2-16 is obtained in the same manner as Compound 2-18 except that tbutyl bromoacetate is used in place of chloroacetylmorpholine. The above protector is dissolved in dichloromethane, trifluoroacetic acid is added, and the mixture is stirred at room temperature. Water and chloroform are added to the reaction solution for extraction, and the organic layer obtained is dried over sodium sulfate and then the solvent is removed. If purified by silica gel column chromatography, compound 2-16 can be obtained.

Synthesis of Compound 2-10 Cis-1,3-O-benzylideneglycerol is dissolved in tetrahydrofuran and stirred at 0 ° C. Add 60% sodium hydride slowly, warm to room temperature with stirring and continue stirring. Cool again to 0 ° C., add ethyl bromoacetate dissolved in tetrahydrofuran, and stir at room temperature. After adding a saturated ammonium chloride solution and extracting with ethyl acetate, the obtained organic layer is washed with saturated brine. The organic layer is dried over anhydrous magnesium sulfate, then removed, and purified by silica gel column chromatography to obtain a glycerol-substituted acetic acid derivative.

The glycerin-substituted acetic acid derivative is dissolved in ethanol, water and sodium hydroxide are added, and the mixture is heated to reflux. After cooling to room temperature, the mixture is adjusted to pH 1-2 with 1N hydrochloric acid and extracted with chloroform. When the solvent is removed after drying over anhydrous magnesium sulfate, the desired carboxylic acid is obtained.
The acetal protector of compound 2-10 is obtained in the same manner as compound 1-6 using the above carboxylic acid. Furthermore, the deprotection reaction using the same acid as compound 2-16 can be carried out to obtain compound 2-10.

Synthesis of Compound 2-11 Compound 2-11 can be obtained in the same manner as Compound 1-6 except that tetrahydro-2-furancarboxylic acid is used in place of morpholinoacetic acid.
Synthesis of Compound 2-12 Compound 2-12 can be obtained in the same manner as Compound 1-6 except that tetrahydro-3-furancarboxylic acid is used instead of morpholinoacetic acid.
Synthesis of Compound 2-13 Compound 2-13 can be obtained in the same manner as Compound 1-6 except that 2-furancarboxylic acid is used in place of morpholinoacetic acid.

Synthesis of Compound 2-17 Compound 2-17 can be obtained in the same manner as compound 2-5 using compound 2-16.
Synthesis of Compound 2-20-3 Triethylene glycol monoethyl ether is dissolved in tetrahydrofuran and tosyl chloride is added. Cool to 0 ° C., add triethylamine and stir at 0 ° C. and room temperature. 1N Hydrochloric acid and ethyl acetate are added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed. Purification by silica gel column chromatography provides the desired tosyl form.
Compound 2-20-3 can be obtained in the same manner as compound 2-18 using the above tosyl form.

Synthesis of Compound 2-22 The 1,2-diglyceride compound used for the synthesis of Compound 1-6 is dissolved in N, N-dimethylformamide and stirred at 0 ° C. After adding sodium hydride, warm to room temperature, add 1,3-propane sultone and continue stirring. Add 1N hydrochloric acid to the reaction solution and extract with dichloromethane. The resulting organic layer is dried over anhydrous magnesium sulfate and then removed to give compound 2-22.
Synthesis of Compound 3-6
Dissolve 1,3-dihydroxyacetone (dimer) in dichloromethane, add 8- (perfluorohexyl) octanoic acid, dimethylaminopyridine, and ethyl-3-dimethylaminopropylcarbodiimide hydrochloride, and stir at room temperature. . The reaction solution can be concentrated and then purified by silica gel column chromatography to obtain a 1,3-diester.

The above 1,3-diester is dissolved in tetrahydrofuran, water is added, and the mixture is stirred at 0 ° C. Add sodium borohydride in small portions and continue stirring at 0 ° C. After adding a saturated ammonium chloride solution, extraction is performed with dichloromethane, and the obtained organic layer is washed with saturated brine. After drying with sodium sulfate, the solvent is distilled off and purified by silica gel column chromatography to obtain 1,3-diglyceride.
Using the above 1,3-diglyceride compound, compound 3-6 can be obtained in the same manner as compound 1-6.

Synthesis of Compound 4-1
Compound 4-1 can be obtained in the same manner as Compound 2-1, except that the above 1,3-diglyceride is used instead of the 1,2-diglyceride.
Synthesis of Compound 4-2
Compound 4-2 can be obtained in the same manner as compound 2-2 except that the above 1,3-diglyceride is used instead of the 1,2-diglyceride.
Synthesis of Compound 4-3-3
Compound 4-3-3 can be obtained in the same manner as Compound 2-3-3 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of Compound 4-5
Compound 4-5 can be obtained in the same manner as compound 2-5 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.

Synthesis of Compound 4-6
Compound 4-6 can be obtained in the same manner as compound 2-6 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of compounds 4-7-2 to 4-7-5
Compounds 4-7-2 to 4-7- are prepared in the same manner as compounds 2-7-2 to 2-7-5, except that the above 1,3-diglycerides are used in place of the 1,2-diglycerides. 5 can be obtained respectively.
Synthesis of Compound 4-9
Compound 4-9 can be obtained in the same manner as compound 2-9 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of Compound 4-10
Compound 4-10 can be obtained in the same manner as compound 2-10 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.

Synthesis of Compound 4-11
Compound 4-11 can be obtained in the same manner as compound 2-11 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of Compound 4-12
Compound 4-12 can be obtained in the same manner as compound 2-12 except that the above 1,3-diglyceride is used instead of the 1,2-diglyceride.
Synthesis of Compound 4-13
Compound 4-13 can be obtained in the same manner as compound 2-13 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.

Synthesis of Compound 4-16
Compound 4-16 can be obtained in the same manner as compound 2-16 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of Compound 4-17
Compound 4-17 can be obtained in the same manner as compound 2-17 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.

Synthesis of Compound 4-18
Compound 4-18 can be obtained in the same manner as compound 2-18 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of Compound 4-20-3
Compound 4-20-3 can be obtained in the same manner as compound 2-20-3 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.
Synthesis of Compound 4-22
Compound 4-22 can be obtained in the same manner as compound 2-22 except that the above 1,3-diglyceride is used in place of the 1,2-diglyceride.

Synthesis of Compound 4-21-1
2- (cis-1,3-O-benzylideneglyceroyl) ethanol is obtained by the method described in Arch. Pharm. (Weinheim), 328, 271 (1995). In accordance with the method described in Protecting groups in organic synthesis (John Wiley & sonc, inc.) By TW Green & PGM Wuts, the t-butyldimethylsilyl (TBS) protecting group was protected, and compound 2- The TBS protector of compound 4-21-1 is obtained using the same method as 18. Furthermore, in accordance with the method described in the above Protecting groups in organic synthesis, the TBS group can be deprotected to obtain compound 4-21-1.

Test Example 1: Liposome formation
According to the method described in J. Med. Chem., 25 (12), 1500 (1982), the following proportions of di-palmitoyl PC (Funakoshi, No. 1201-41-0225), di-palmitoyl PS (Funakoshi Co., Ltd., No. 1201-42-0237) was dissolved in chloroform together with the compound 1-6 in an eggplant-shaped flask to form a homogeneous solution, and then the solvent was distilled off under reduced pressure to form a thin film on the bottom of the flask. Formed. This thin film is dried in vacuum, 0.9% physiological saline (manufactured by Hikari Pharmaceutical Co., Ltd., No512) is added in an appropriate amount, and ultrasonic irradiation (Branson Co., No.3542 probe type oscillator, 0.1 mW) is applied for 5 minutes under ice cooling By carrying out, a uniform liposome dispersion was obtained. As a result of measuring the particle size of the obtained dispersion with a WBC analyzer (manufactured by Nihon Kohden Co., Ltd., A-1042), the particle size was 85 to 110 nm. It is clear that the compound 1-6 has the following composition and can be efficiently encapsulated in liposomes and has excellent properties as a constituent lipid of liposomes for contrast agents.

Maximum amount of liposome formation
PC 50 nmol + PS 50 nmol + the above compound 1-6 40 nmol

Test Example 2: Mice 3-day continuous toxicity study ICR mouse male 6-week-old (Nippon Charles River) was purchased, and after a quarantine period of 1 week, in a clean animal house (air conditioning: Hepafilter class 1000, room temperature: 20 C. to 24.degree. C. Humidity: 35% to 60%) for one week. Thereafter, in order to determine the MTD value, a mouse serum suspension was administered from the tail vein. The mouse serum suspension was administered using either physiological saline (manufactured by Hikari Pharmaceutical Co., Ltd.) or glucose solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) as a solvent. Next, based on the determined MTD value, 1/2 of that amount was administered for 3 days from the tail vein for 3 consecutive days (n = 3). Symptoms were observed up to 6 hours after each administration. After observing neurotoxicity, autopsy was performed and findings were taken on major organs. It is clear that the compound of the present invention has low toxicity and does not show neurotoxicity, and has excellent properties as a constituent lipid of liposomes for MRI contrast agents.
Compound: MTD (mg / kg); neurotoxicity (“-” indicates negative neurotoxicity, “+” indicates positive neurotoxicity)
Compound 1-6: 400 mg / kg;

Test Example 3: MRI Imaging According to a standard method, PC (dipalmitoylphosphatidylcholine Funakoshi No.850355C), PS (dipalmitoylphosphatidylserine Funakoshi No.840037C), a chloroform solution of any one of the above compounds 1 Thus, a liposome preparation of PC: PS: compound = 50: 50: 40 (nmol) can be prepared.
Water for injection (Otsuka Pharmaceutical Co., Ltd.) can be used for the preparation.
A 12-month-old WHHL rabbit (Kitayama Labes Co., Ltd.) with a lesion in the aortic arch was obtained, bred for 1 week, and administered the above liposome preparation from the parotid vein (80 mg / kg in terms of compound) Fifteen minutes later, a focus imaging experiment can be performed by focusing on the focus of the arch and performing a fluoro MRI imaging.

Claims (17)

The following general formula (I):

[Wherein, l and n each independently represents an integer of 1 to 10; m and o each independently represents an integer of 2 to 10; and R represents a group selected from the following. Or a salt thereof.

The following general formula (II):

[Wherein, l and n each independently represents an integer of 1 to 10; m and o each independently represents an integer of 2 to 10; and R represents a group selected from the following. Or a salt thereof.

Of the fluorine atoms constituting the compound, compound, or a salt thereof according to claim 1 or 2 in which at least one ¹⁸ F. The liposome which contains the compound or its salt as described in any one of Claims 1-3 as a membrane component. The liposome according to claim 4 , comprising phosphatidylcholine and phosphatidylserine as membrane constituents. An MRI contrast agent comprising the liposome according to claim 4 or 5 . The MRI contrast agent according to claim 6 for use in imaging of vascular diseases. The MRI contrast agent according to claim 6 , which is used for imaging of vascular smooth muscle cells abnormally proliferated under the influence of foamed macrophages. The MRI contrast agent according to claim 6 for imaging a tissue or a diseased site where macrophages are localized. The MRI contrast medium according to claim 9 , wherein the tissue in which macrophages are localized is selected from the group consisting of liver, spleen, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium. The MRI contrast agent according to claim 9 , wherein the disease site where the macrophages are localized is selected from the group consisting of a tumor, an inflammation site, and an infection site. A PET contrast agent comprising the liposome according to claim 4 or 5 . The PET contrast agent according to claim 12 for use in imaging of vascular diseases. The PET contrast agent according to claim 12 , which is used for imaging of vascular smooth muscle cells abnormally proliferated under the influence of foamed macrophages. The PET contrast agent according to claim 12 for imaging a tissue or a diseased site where macrophages are localized. 16. The PET contrast agent according to claim 15 , wherein the tissue in which macrophages are localized is selected from the group consisting of liver, spleen, alveoli, lymph nodes, lymphatic vessels, and kidney epithelium. The PET contrast agent according to claim 15 , wherein the disease site where the macrophages are localized is selected from the group consisting of a tumor, an inflammation site, and an infection site.