JPH08295639A - Diagnostic for arteriosclerosis - Google Patents

Abstract

PURPOSE: To obtain the subject diagnostic capable of causing a clear contrast of the lesion of arteriosclerosis by X-ray irradiation from the outside of the body, containing a complex of an X-ray blocking metal and a porphyrin. CONSTITUTION: This diagnostic for arteriosclerosis contains a complex of an X-ray blocking metal such as gold or platinum and a porphyrin such as coproporphyrin III, coproporphyrin I, uroporphyrin III, uroporphyrin I or protoporphyrin IX. The complex is prepared by the following process: a halide (e.g. chloride) of a metal such as gold or platinum and a porphyrin and dissolved in a solvent followed by conducting a reaction, as necessary, under heating, and the reaction product is purified and then isolated from the solvent by e.g. isoelectric point precipitation method. The diagnostic is obtained by dissolving or suspending the above metal complex in an aqueous medium (e.g. physiological saline solution), and is administered pref. by intravenous injection at 0.01-50mg/kg body weight in each diagnosis.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention uses X-rays,
The present invention relates to a drug used for detecting arteriosclerosis in animals, particularly humans, and particularly atherosclerosis. The detection agent of the present invention easily accumulates in the affected area of arteriosclerosis, and enables easy detection of the affected area by X-ray.

[0002]

2. Description of the Related Art Arteriosclerosis is a serious condition that causes fatal diseases such as myocardial infarction, angina and stroke. For the detection of arteriosclerosis, conventional agents for detecting arteriosclerosis, which are sensitive to visible light, such as hematoporphyrins, chlorins, pheophorbides, and phthalocyanines are known (Junichi Hayashi, Hide Sato). Akira, Katsuo Aizawa,
Photodynamic treatment of atherosclerosis. Diagnosis and treatment, 81
(4), 106-108 (1993)), the depth of penetration to the tissue is at most 3 mm even with the use of a laser beam, and there is a drawback that irradiation from outside the body does not reach the lesion site.

An example is the Journal of the American Heart Society, Volume 56,
667-671, 1985, "Effects of hematoporphyrin derivatives and phototherapy on atherosclerotic rabbits" (Litvack, F., Grundfest, WS, Lee,
and Forrester JS, et al, Effects of hematoporph
yrin derivative and phtodynamic therapy on atheros
clerotic rabbits. THE AMERICAN JOURNAL OF CARDIOLO
GY, 56, 667-671 (1985)). Furthermore, a drug that clearly contrasts a lesion site when directly detecting arteriosclerosis in a body tissue using X-ray has not been known yet.

[0004]

Therefore, the present invention is intended to provide a contrast medium capable of vividly contrasting an arteriosclerotic lesion by irradiation from outside the body.

[0005]

In order to solve the above-mentioned problems, the present invention provides an arteriosclerosis diagnostic agent comprising a complex of an X-ray blocking metal and porphyrin.

[0006]

[Specific description] It is known that certain porphyrin compounds are likely to accumulate in affected areas of arteriosclerosis (Spear
s, JR., Serur, J., Shropshire, D., Paulin, S., Flu
orescenceof experimental atheromatous plaqueswith
hematoporphyrin derivative. J. Clin. Invest., 71, 3
95-399, 1983.), but they are not sensitive to X-rays, and their accumulation is difficult to detect by external irradiation. On the other hand, although it is known that certain metals block X-rays, it is completely unknown whether or not the complexes of these metals and porphyrin can be concentrated in the affected area of arteriosclerosis and accumulate there. there were. The present invention has been completed by confirming that the complex of porphyrin and X-ray blocking metal is actually accumulated in the affected area of arteriosclerosis and the accumulation can be detected by X-ray.

As a porphyrin, a single compound is easily accumulated in the affected area of arteriosclerosis, its cytotoxicity is low, and if possible, it is detected in the living body, and excretion is suitable sooner or later later. For example, coproporphyrin III. ,
Coproporphyrin I, uroporphyrin III, uroporphyrin I, protoporphyrin IX and the like are preferred.
Alternatively, these salts are also preferable. As a general rule, anything having a porphyrin skeleton and accumulating in the affected area of arteriosclerosis may be used.

The metal to be coordinated is preferably a metal which is X-ray sensitive and has no toxicity to the living body, such as gold or platinum. Therefore, the present invention, in its preferred embodiment, comprises coproporphyrin III, coproporphyrin I,
There is provided a diagnostic agent for arteriosclerosis comprising a complex comprising uroporphyrin III, uroporphyrin I or protoporphyrin IX and gold or platinum.

The complex used in the present invention can be formed according to a conventional method for forming a complex. That is, a halide of a metal such as gold or platinum, for example, chloride and porphyrin are dissolved in a suitable solvent, and these are reacted by heating if desired, and purified by column chromatography or the like, followed by isoelectric focusing. It can be isolated from the solvent by a method or the like.

The diagnostic agent for arteriosclerosis of the present invention can be obtained by dissolving or suspending the above-mentioned metal complex in an aqueous medium such as physiological saline or phosphate buffered saline. The diagnostic agent is preferably administered by intravenous injection, for example, 0.01 to 50 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight per diagnosis.

[0011]

EXAMPLES Next, the present invention will be described more specifically by way of examples. Example 1. Preparation of Complex To prepare platinum coproporphyrin III, first, platinum dichloride is dissolved in boiling benzonitrile, and coproporphyrin III tetramethyl ester is added to this solution and refluxed. Then, a vacuum is applied to remove the solvent. The formed platinum coproporphyrin III tetramethyl ester was adsorbed on a silica gel column, washed with dichloromethane, and then eluted with dichloromethane mixed with ethyl acetate.

Platinum coproporphyrin III tetramethyl ester was dissolved in tetrahydrofuran, caustic soda was added, and the mixture was allowed to stand overnight to change to platinum coproporphyrin III. The precipitate was collected, dissolved in water and adjusted to pH 3 to obtain an isoelectric point precipitate. The precipitate was washed with water having the same pH and dried. To make the sodium salt, platinum coproporphyrin III was suspended in a small amount of water and the pH was adjusted to 9.5 to 1 with 0.1N caustic soda.
The platinum coproporphyrin III was dissolved while adjusting to 0.0, and then freeze-dried to obtain powdery platinum coproporphyrin III tetrasodium salt. Thin layer chromatography (developing solvent; methanol / 0.01NpH)
6.85 phosphate buffer = 7/3).

Example 2. Of complex to arteriosclerotic lesions
Confirmation of Accumulation Coproporphyrin III platinum complex (8 mg) was administered via an ear vein to a hypercholesterolemic rabbit having a body weight of about 4 kg.
At 3 hours after administration, the abdominal aorta was exposed under Nembutal anesthesia to expose the abdominal aorta, and it was confirmed by fluorescence due to ultraviolet irradiation in the dark that the porphyrin complex was accumulated in the site of the arteriosclerotic lesion on the inner wall of the blood vessel. Furthermore, when that portion was collected and the content of platinum was measured by the tin (II) chloride coloring method,
An amount of 4.9 μg / g was detected.

Example 3. X-ray of accumulated porphyrin complex
According to the detection in Example 2, the rabbit anesthetized 3 hours after the administration of the porphyrin complex was not subjected to laparotomy, and the X-ray was used at a wavelength (0.158 angstrom) adjusted to the K-shell electron absorption of platinum, which is the metal of the porphyrin complex. When irradiated and imaged, the lesion site could be easily detected.

[0015]

INDUSTRIAL APPLICABILITY The porphyrin complex of the present invention, when administered to rabbits with hypercholesterolemia, accumulated specifically in the lesion site of arteriosclerosis. As a result of observing this rabbit by X-ray, it was confirmed that the lesion site was accurately detected.

Claims (2)

[Claims] 1. A diagnostic agent for arteriosclerosis comprising a complex of an X-ray blocking metal and porphyrin. 2. Gold or platinum and coproporphyrin III
An agent for diagnosing arteriosclerosis, which comprises a complex with coproporphyrin I, uroporphyrin III, uroporphyrin I or protoporphyrin IX.