KR100448100B1 - Paramagnetic metal-phthalocyanine complex compounds and contrast agent using the same - Google Patents

Abstract

The present invention provides a novel paramagnetic metal-phthalocyanine complex of formula (I) which can be used as a contrast agent in diagnostic magnetic resonance imaging (MRI) technology, X-ray imaging, computed tomography (CT), etc. To pharmaceutically acceptable salts thereof.

Preferred paramagnetic metals M in the formula are Gd (III) and Mn (II and III); R and R ₁ are each OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ .

The present invention also relates to imaging contrast agents containing the novel compounds. The novel imaging contrast agent according to the present invention can exhibit enhanced clarity in lesser amounts than conventional commercialized contrast agents, and can be used more safely in the human body.

Description

Paramagnetic metal-phthalocyanine complex compounds and imaging contrast agents using the same {Paramagnetic metal-phthalocyanine complex compounds and contrast agent using the same}

The present invention relates to a contrast agent used in diagnostic nuclear magnetic resonance imaging (MRI) technology, X-ray imaging, and computed tomography (CT). The present invention relates to novel paramagnetic metal-phthalocyanine complexes, pharmaceutically acceptable salts thereof, and imaging contrast containing the same, which make the imaging of organs or tissues of a patient more clear.

Contrast agents are commonly used to obtain images of tissues such as blood vessels or tumors and surrounding organ tissues, and to observe the location, size, and condition of the tumors with similar composition of the tissues to ensure more contrast. . In order to distinguish between tumor tissue and surrounding tissue, nuclear magnetic resonance imaging technology (MRI) shows excellent excellence and safety.

Various methods for observing the inside of the body are currently developed, and MRI technology is the most recently developed technology, but the application and utilization of MRI is increasing rapidly. This is because MRI is safer than other imaging techniques. X-ray, CT, PET and other methods have to be administered to the human body, which can never be considered harmless to the human body, so there is a drawback that it is not applicable to patients who are concerned about genetic variation, especially cancer patients or pregnant women. However, MRI is a new technology that is not bound by these shortcomings such as radioactivity and the limitation of application. The main advantage of MRI is that it is not only sensitive to tissues, but also does not expose the patient to ion radiation. Currently, MRI is widely used in the fields of chemistry, biochemistry, and medical science, and the cost of diagnostic MRI tends to decrease gradually due to the spread of technology, and is expected to become more common due to the short diagnosis time. At present, MRI contrast agents have been developed and commercialized and exported to the world, while contrast agents have not been developed in Korea. There is a lack of awareness of MRI contrast agents in Korea, and all the products used are imported. Therefore, considering the MRI penetration rate and the speed of advancement of imaging technology in the domestic medical community, domestic development of MRI contrast agent is urgent. The ramifications of domestic production of contrast agents are that it will increase the likelihood of accurate and early diagnosis of disease through better imaging, and the level of domestic medical technology will be further enhanced.

Magnetic Resonance Imaging (MRI) is a very advanced technology that can image brain and body detailed tissues using magnetic resonance phenomenon. It is a technology that applies the concept that the spin of hydrogen nucleus in water and fat in the human body changes according to the magnetic field and transfers the signal measured according to the change to the image. The distribution of hydrogen nuclei in water and fat depends on the type of tissue in the body and also on the clinical condition of the tissue, which is used to excite the hydrogen in the region of interest, causing a nuclear spin and measuring the signal. To make a diagnosis. The brightness of the image is affected by several variables, including the density of the hydrogen and the time (T ₁ , T ₂ ) the excited hydrogen relaxes. In particular, the relaxation time, T ₁ and T ₂ , refers to the time from when the hydrogen absorbs the energy until it reaches its original equilibrium due to energy dissipation. This is a very important variable for contrast. As the values of T ₁ and T ₂ become shorter, the contrast of contrast increases, and the internal tissues and organs are identified and diagnosed through the contrast of the contrast.

Such MRI imaging can be improved through the use of contrast agents. MRI contrast agents are agents that increase the contrast of the image by shortening the relaxation time of T ₁ and T _2, etc. of human tissues. Paramagnetic or superparamagnetic Products that use (superparamagnetic) are mainstream. Contrast may be used to amplify the signal of the entire or partial tissue of the desired organ or to attenuate the signal of surrounding tissue to maximize contrast. However, because of the acute toxicity of most paramagnetic metals, inorganic salts of common paramagnetic metals are undesirable as contrast agents. To solve this problem, organic chelate ligands or metal-binding agents are used. Organic chelate ligands and the like form complexes with metals, preventing free release of paramagnetic metals, and acting as nontoxic paramagnetic carriers to improve hydrogen relaxation.

To use paramagnetic metal-ligand composites as contrast agents, several requirements must be met. Form stable and hard chelates so that no toxic metals are released. It must be sufficiently water soluble to be conveniently administered to the patient. It should be possible to efficiently improve the relaxation rate of hydrogen ions. Efficacy is generally measured in “relaxation (increase in relaxation rate per paramagnetic complex mM concentration)”.

Grees et al. Described a complex used as a diagnostic reagent in US Pat. No. 4,647,447. The active paramagnetic component of the FDA-approved MRI contrast agent Magnevist is a complex of diethylenetriaminepentaacetic acid (DTPA) and gadolinium (III) (Gadolinium: Gd). However, since DTPA-Gd has a very short half-life of about 14 minutes, it is rapidly excreted in the urine after administration (Hiroki Yoshikawa et al., Gazoshindan, 6,959-969 (1986)). Blood vessel distribution, blood flow distribution, distribution, penetration, etc.) is difficult to diagnose. In addition, since the distribution of tissue cells within the blood vessels is not specified, sometimes there is no clear difference in the concentration between the normal tissue and the injured site, and no obvious contrast can be obtained. In addition, in the diagnostic method using nuclear magnetic resonance, the imaging time depends on the magnetic field strength of the MRI spectrometer to be used. Therefore, the imaging time should be long in the case of the widely used low-field MRI spectrometer. Therefore, the use of DTPA-Gd in the blood within a short period of time does not allow a detailed understanding of the condition of the damaged area, so the diagnosis using DTPA-Gd has limitations depending on the specific type of diagnostic site or diagnostic device.

Lauffer and Brady in US Pat. No. 4,899,755 describe the synthesis of paramagnetic metal-ligand complexes for MRI enhancement with tissue specificity for targeting tissue. Such tissue-specific methods show an improved effect over conventional nonspecific methods. Qualitatively, tissue-specific contrast agents confer better MR images for targeting tissues such as liver and bile. Quantitatively, tissue-specific contrast agents impart an image similar to that observed with the use of high doses of nonspecific reagents even with smaller amounts. As such, dysfunction of liver cancer or bile system that was previously unrecognizable (difficult to recognize) can be observed by using reagents specific to the liver-gallbladder.

However, the paramagnetic metal-ligand complex for improving the existing MRI has a low water solubility, there was a problem that can not be properly formulated as a contrast agent.

Human blood, on the other hand, has an osmotic pressure of 0.3 Osmol / kg-water. NMR reagents based on conventional gadolinium have an overall negative charge, whereby their aqueous formulation solutions have a high insertion force. For example, when Gd (DTPA) ^2- (where DTPA stands for diethylenetriaminepentaacetic acid) is formulated for use as 0.5M N-methylglucamine salt in water, the osmotic pressure of the solution is 1.6-2.0 Osmol / kg-water. The contrast agent injected at high osmotic pressure is known to cause side effects in the patient.

In order to solve these problems with existing MRI contrast agents, there has been an increasing need for excellent contrast agents with medium or long half-life in blood and with desirable stability, adequate solubility and osmotic pressure.

On the other hand, X-ray contrast agents currently used in the clinic include various water-soluble iodide aromatic compounds containing 3 or 6 iodine atoms per molecule. This compound may be charged or nonionic (in the form of a physiologically acceptable salt). Today's most popular contrast agents are nonionics, because in-depth studies have shown that nonionic preparations are much more stable than ionic preparations. This should handle the osmotic load of the patient. In addition to water-soluble iodide preparations, barium sulfate is often used for X-ray examination of the gastrointestinal system. Several water insoluble or particulate preparations have been proposed as parenteral X-ray contrast agents primarily for liver or lymphatic system imaging. Typical particle X-ray contrast agents for parenteral administration include, for example, suspensions of solid iodide particles, suspensions of liposomes containing aqueous iodinating agents, or emulsions of iodide oil. The development of X-ray contrast agents has a history of nearly 100 years, but there is a continuing need for X-ray contrast agents that are safer and have better light absorption.

Accordingly, an object of the present invention is to improve the clarity of the image by using as a contrast agent for MRI imaging technique, X-ray imaging, computed tomography (CT), etc., gadolinium-phthalocyanine, a novel compound that is safe for human body, and its pharmaceuticals. To provide an acceptable salt.

It is yet another object of the present invention to provide novel MRI contrast agents and X-ray contrast agents containing the novel gadolinium-phthalocyanine compounds, which exhibit enhanced clarity in lesser amounts than existing commercially available contrast agents.

1 is a ¹ H NMR-spectrum of octa (1,4,7,10-tetraoxoundecyl) Gd-phthalocyanine,

2 is a UV-spectrum of octa (1,4,7,10-tetraoxoundecyl) Gd-phthalocyanine,

3 is the ¹ H NMR-spectrum of octa (1,4,7,10-tetraoxoundecyl) Mn-phthalocyanine,

4 is a UV-spectrum of octa (1,4,7,10-tetraoxoundecyl) Mn-phthalocyanine,

5 is a result of obtaining a weighted image for the spin echo T after administering a contrast agent, a conventional contrast agent and a blank according to an embodiment of the present invention in the abdominal cavity of the mouse.

6 is a result of comparing and measuring the absorbance of light of the contrast agent and the conventional contrast agent according to an embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

The novel compounds of the present invention are combinations of paramagnetic metal ions and organic ligands, and more specifically, combinations of paramagnetic metals and substituted phthalocyanine ligands (referred to herein as "paramagnetic metal-phthalocyanine complexes"). .

That is, the present invention relates to a paramagnetic metal-phthalocyanine complex of the following structural formula (I) (also represented by compound (I)) and a pharmaceutically acceptable salt thereof.

Preferred paramagnetic metals M in the above structure are Gd (III), Fe (III), Mn (II and III), Cr (III), Cu (II), Dy (III), Tb (III), Ho (III), Selected from the group consisting of Br (III) and Eu (III), the most preferred paramagnetic metals M being Gd (III) and Mn (II and III); R and R ₁ are each OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ .

Complexes of formula (I) of the present invention and their pharmaceutically acceptable salts can be used as contrast agents for MRI. Contrast agent of the present invention is administered to a mammalian host (eg, a human), and then distributed in various concentrations to other tissues and absorbs magnetic frequency energy from a nuclear magnetic resonance imager to activate protons (in tissue) Catalyzes relaxation of). Increasing the relaxation rate of the activated protons provides a different contrast and provides the best contrast when scanning using a nuclear magnetic resonance imager. The nuclear magnetic resonance imager is generally used to record images before and after administration of the agent over a variety of times, and use the difference in the image produced by the presence of the agent in tissue to diagnose. In proton nuclear magnetic resonance imaging, paramagnetic metal ions such as Gd (III) and octahedrons Mn (II), Cr (III) and Fe (III) are preferable as M of the structural formula (I), and particularly Gd ( III) is most preferred because it has high paramagnetism, low toxicity and high instability with the water involved.

Complexes of formula (I) of the present invention can be synthesized in a homogeneous phase through a synthesis method well known in the field of organic chemistry, the synthesis of phthalocyanine is carried out by tetramerization of phthalonitrile having the formula (II).

R and R ₁ here each represent the functional group mentioned above. Synthesis of phthalocyanine using phthalonitrile is described in "Pthalocyanine-Properties and Applications, Vol. 1-4, CCLeznoff and ABP Lever VCH Ed. ".

The present invention also includes a compound conjugated with a macromolecular carrier for improving pharmaceutical properties to the complex of formula (I). The carrier is generally selected from the group consisting of amino acids, polypeptides, proteins and polysaccharides. Phthalocyanine (I) / carrier linkages can be generated between carbonyl or amine groups, or using other known functional groups or reactors, such as homo- or hetero-both functional groups.

The present invention includes pharmaceutically acceptable salts of the complexes of formula (I) and includes those derived from inorganic or organic acids and bases. The acid salt may be, for example, acetate, adipate, alginate, aspartate, benzoate, benzene-sulfonate, bisulfate, butyrate butyrate, citrate, camphorate, camphor-sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate and crown Crown ethers and the like.

The present invention also relates to a contrast agent composition comprising a complex of formula (I) and a pharmaceutically acceptable carrier, excipient or carrier. The pharmaceutically acceptable carriers, excipients or carriers include, but are not limited to, ion exchanger, alumina, aluminum stearate, lecithin, human serum albumin family Buffer materials such as serum proteins, phosphates, glycine, sorbic acid, potassium sorbate. It may also further comprise free organic ligands or pharmaceutically acceptable salts thereof, and may further comprise free organic ligands or calcium, sodium meglumine or complex salts thereof.

The complex of the formula (I) of the present invention or a contrast agent composition comprising the same can be used as a contrast agent for MRI, as well as contrast agents for X-ray imaging and computed tomography (CT).

In another aspect, the present invention provides a method for improving tissue-specific contrast of MR images of organs and tissues of a mammal, comprising administering a diagnostically effective amount of the complex of formula (I) or a contrast agent composition comprising the same. A method, comprising tissue-specific X-ray imaging and computed tomography of organs and tissues of a mammal comprising administering a diagnostically effective amount of a complex of Formula (I) or a contrast agent composition comprising the same It relates to a photography (CT) method.

When the compound according to the invention is used as a contrast agent, the dosage is selected according to the specific use of the contrast diagnosis. A sterile aqueous solution of the complex of formula (I), the contrast agent of the present invention, may be administered to mammals (eg, humans) at a concentration of 0.0001 to 10 m mo / kg, for example, when used for MRI glucose. It may also be administered at a concentration of 0.01-20 m mo / kg for X-ray diagnostics. In general, contrast agents are administered intravenously, but may be administered by oral, intraarterial or other routes as appropriate.

The residence time in the blood of the complex of formula (I) according to the present invention is within a clinically effective range. While the conventional contrast agent DTPA-Gd is washed out from the tissue for about 30 minutes, the discharge time from the tissue of the compound of formula (I) of the present invention is about 1 hour 30 minutes. As described above, since the compound of the present invention exhibits an appropriate blood retention period, the vascular distribution contrast (vascular histology) can be measured. Therefore, the diagnostic contrast agent of the present invention can contrast blood vessels without a pulse sequence which is particularly necessary for the recent remarkably advanced MR angiography, and is also useful as a diagnostic contrast agent for intravenous infusion.

Since the compound of the present invention also has a good solubility in water, it can be prepared into a liquid formulation containing a high concentration of the compound by itself. Therefore, solubilizers are not necessary for the preparation of the solution.

In addition, since the compound of the present invention is a nonionic complex, unlike DTPA-Gd, it is not ionized, so that the total morality in the preparation of the solution may be reduced, resulting in a decrease in osmotic pressure. The gadolinium complex according to the present invention almost appeared with the body fluid when prepared in 0.5 molar aqueous solution, and shows an excellent contrast agent effect even at a lower concentration. As described above, the compound according to the present invention, after administration to a living body, relieves the load on the volume and body equilibrium of the circulatory system, resulting in an advantageous result in safety.

The pH of the contrast agent composition according to the present invention is about 6.0 to 8.0, preferably 6.5 to 7.5. The contrast agent compositions according to the invention also contain physiologically applicable buffers (eg 0.08% NaCl saline solution or tris (hydroxymethyl) -aminomethane) and physiologically applicable adducts (eg stabilizers such as parabens). can do.

MRI contrast agent prepared by the method of the present invention has the following advantages over conventional contrast agents.

1. Safety

Conventional MRI contrast agent is a compound of gadolinium and DTPA, the binding force of paramagnetic metal ions and ligands is not strong and unstable. However, the phthalocyanine ligand of the present invention has a high molecular weight and a high binding force with metal ions, so that the metal ions are not easily separated from the compound, thereby reducing the toxicity by heavy metal ions.

2. Residence time in the organization

Conventional MRI contrast agents, due to their low molecular weight or short half-life, continue to be discharged through the blood even when absorbed into the tissue, so that the residual amount in the tissue decreases rapidly with time. This causes the excessive administration of contrast agent and has a disadvantage that MRI imaging time should proceed in a short time according to the residence time. The contrast agent of the present invention has a long time to stay in the cell tissue as a macromolecule and a long time to be discharged to the outside of the blood in the blood, there is an advantage that the MRI imaging time can be longer. And since the time to wash-out from the tissue is extended than the conventional contrast agent, even a small amount of administration can obtain the desired contrast effect.

3. good solubility

Conventional MRI contrast agents containing paramagnetic metal-ligand complexes have low water solubility and thus cannot be adequately formulated as contrast agents. However, the complex compound of structural formula (I) according to the present invention has good water solubility, so it is usually intravenous. More safe and simple formulation is possible with the contrast agent administered.

4. Economics

Since a smaller amount can be administered than conventional contrast agents, the probability of exposure to heavy metal ions is low and the production cost is low. In addition, the effect of import substitution of MRI contrast agent, which is imported in Korea.

As such, by using the novel contrast agent according to the present invention, imaging diagnosis such as MRI diagnosis, X-ray diagnosis, and the like can be performed more safely and efficiently.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1

Synthesis of Octa (1,4,7,10-tetraoxoundecyl) Gd-phthalocyanine

After dissolving 0.972 g (2.15 mmol) of 1,2-di (1,4,7,10-tetraoxoundecyl) -4,5-dicyanobenzene in 10 ml of DMF, 0.779 g of gadolinium (III) oxide (III) 2.15 mmol) was added and reacted with stirring at 150 ° C. for 12 hours. After the reaction, the solution was filtered, and then the solvent was evaporated to give a crude product. The obtained crude product was purified by column chromatography to give 0.74 g of octa (1,4,7,10-tetraoxoundecyl) Gd-phthalocyanine (yield 69.7%). At this time, a mixed solvent of methanol and CH ₂ CH ₂ 1: 5 was used as the elution solvent.

¹ H NMR-spectrum and UV-spectrum of the obtained material are shown in FIGS. 1 and 2, respectively.

Example 2

Synthesis of Octa (1,4,7,10-tetraoxoundecyl) Mn-phthalocyanine

1.15 g (2.55 mmol) of 1,2-di (1,4,7,10-tetraoxoundecyl) -4,5-dicyanobenzene was dissolved in 10 ml of DMF, followed by Mn (OAc)₂0.44 g (2.55 mmol) was added and the mixture was stirred at 150 ° C. for 4 days. After the reaction, the solution was filtered, and then the solvent was evaporated to give a crude product. The obtained crude product was purified by column chromatography to give octa (1,4,7,10-tetraoxoundecyl) Mn-phthalocyanine 0.303 g was obtained (yield 25.5%). At this time, elution solvents are methanol and CH₂CH₂The mixed solvent mixed with 1: 5 was used.

¹ H NMR-spectrum and UV-spectrum of the obtained material are shown in FIGS. 3 and 4, respectively.

Experimental Example 1

Contrast T _One & T ₂ Measure

Gd-DTPA (commercial contrast agent, Magnevist, Schering Co.), octa (1,4,7,10-tetraoxundecyl) Gd-phthalocyanine (hereinafter referred to as GdPC-Fux1-6) and octa (1,4,7, 10-tetraoxoundecyl) Mn-phthalocyanine (hereinafter referred to as MnPC-Fux1-18) was dissolved in 0.08% physiological saline, respectively, to prepare samples of 0.005M concentration. This included 10% of heavy water to obtain the lock signal. As a blank, 0.08% saline was prepared.

For each of these samples and blanks, the relaxation times (T ₁ and T ₂ values, units: seconds) of both were measured at 80 MHz NMR (Bruker, AC80) and 300 MHz NMR (Bruker, DRX300), respectively. Each RD value was sufficiently large so as not to affect the experimental results, and a d2 value of about 1 msec to 2 msec was used. Each of the vd values and vc values used enough values for parameter-fitting.

The relaxation time of each measured sample is shown in Table 1 below.

table. 1 T ₁ and T ₂ value in seconds

sample 80 MHz 300 MHz T ₁ T ₂ T ₁ T ₂ 0.08% NaCl 3.4 2.78 0.669 2.68 Gd-DTPA 0.0484 0.0441 0.0370 0.261 GdPC-Fux1-6 0.0243 0.0174 0.0488 0.0234 MnPC-Fux1-18 0.191 0.0335 0.317 0.0207

As can be seen from the results shown in the above table, the compounds according to the present invention GdPC-Fux1-6 and MnPC-Fux1-18 are 24.3 ms / 17.4 ms and respectively compared to the conventional paramagnetic metal-containing contrast agent Gd-DTPA and High relaxation of 191 ms / 33.5 ms (80 MHz NMR, T ₁ / T ₂ , respectively).

Experimental Example 2; Comparison of Imaging Using Mice After Contrast Agents

Samples for obtaining magnetic resonance images are referred to as Gd-DTPA (commercial contrast agent, Magnevist, Schering Co.), octa (1,4,7,10-tetraoxoundecyl) Gd-phthalocyanine (hereinafter referred to as GdPC-Fux1-6). ) And octa (1,4,7,10-tetraoxoundecyl) Mn-phthalocyanine (hereinafter referred to as MnPC-Fux1-18) were dissolved in 0.08% physiological saline each to 0.01M concentration. This is a reference to the commercialized Gd-DTPA can be administered to the human body in a condition of 0.2ml to 0.4ml / kg at 0.5M concentration.

The contrast medium of 0.01M concentration thus prepared was administered to mice (female ICR, 27-30g, n = 6) under the condition of 0.2ml / 10g. In this experiment, a 0.4 ml / kg contrast agent was injected, which is the maximum in the contrast dose range, to confirm the effect more clearly. A blank for control was administered with 0.08% NaCl solution. First, a contrast agent was injected intraperitoneally, and after 30 minutes, an anesthetic (rompum, ketamin, distilled water mixed with a solution of 1.5: 1.5: 7) was injected into the abdominal cavity so that the contrast agent sufficiently penetrated the organs of the abdominal cavity for which the image was to be seen. A tube was placed upright in the anesthetized mice so that the measuring coil of the imaging probe could later come into the abdominal cavity. The data obtained in this experiment were images scanned 40 minutes after contrast medium was administered. The experimental results of the spin echo T-weighted images after each contrast agent administration are shown in FIG. 5.

As shown in FIG. 5, the contrast effect is clearly seen in the TE = 6.46 ms condition in which the effect of T ₂ is minimized rather than in TE = 20 ms. In particular, the T _1- weighted image obtained under the conditions of set 1 and set 2 is shown. In comparison, GdPC-Fuxl-6 and MnPC-Fuxl-18 show good contrasting effects.

Experimental Example 3; Safety Experiment of Contrast Agents in Saline

Safety test in saline solution

After each 0.08% physiological saline was added to two 25 ml beakers, 0.196 g of GdPC-Fuxl-6 was dissolved in one beaker, and 0.186 g of MnPC-Fuxl-18 was dissolved in another beaker. Was prepared. The stopper was closed so as not to evaporate the steam, and heated in a hot water bath at 50 ℃ 24 hours. The UV-spectrum of GdPC-Fuxl-6 and MnPC-Fuxl-18 (FIG. 2, 3) was compared with the UV-spectrum of H ₂ -phthalocyanine to investigate the separation of Gd and Mn ions. As a result, GdPC-Fuxl-6 and MnPC-Fuxl-18 were stable for 24 hours in 0.08% saline solution (0.01M) at 50 ℃.

Gd-DTPA, a conventional commercial contrast agent, was unstable because the binding force between paramagnetic metal ions and a ligand was not strong. However, the ligand of the novel paramagnetic metal-phthalocyanine complex compound according to the present invention has a high molecular weight and a high binding strength with metal ions, and thus the metal ions are not easily separated from the compound as can be seen from the above experimental results. Toxicity by heavy metal ions is much reduced.

Experimental Example 4; Light Absorption Experiment of GdPC-Fuxl-6

Compound GdPC-Fuxl-6 of the present invention obtained in Example 1, conventional X-ray contrast agents, Ion and Super-Iron, respectively, were applied to the rods at 2.45 molar concentrations, and then X-rays. Was investigated to compare and measure the absorbance of light. The results are shown in FIG. Figure 6 shows the absorbance of light of Aion, Superion and GdPC-Fuxl-6 from the left, respectively. As can be seen from the experimental results, the compound of the present invention showed superior properties in light absorption than the conventional X-ray contrast agents Aion and Superion.

As can be seen from the above, the novel paramagnetic metal which can be used as a contrast agent in diagnostic nuclear magnetic resonance imaging (MRI) technology, X-ray imaging, computed tomography (CT), etc. Phthalocyanine complexes can be provided, and imaging contrast agents containing the novel compounds can exhibit enhanced clarity in lesser amounts than conventional commercialized contrast agents and can be used more safely in the human body.

Claims (9)

A compound of formula (I) and a pharmaceutically acceptable salt thereof: Wherein M is Gd (III) or Mn (II and III); R and R ₁ are each OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ . A compound having a macromolecule selected from the group consisting of amino acids, polypeptides, proteins and polysaccharides in combination with the compound of claim 1. Contrast agent for MRI comprising the compound of claim 1 or 2. A contrast agent for X-ray imaging and computed tomography (CT) comprising the compound of claim 1 or 2. A contrast agent composition comprising the compound of claim 1 or 2 and a pharmaceutically acceptable carrier, excipient or carrier. 6. The contrast agent composition according to claim 5, further comprising a free organic ligand or a pharmaceutically acceptable salt thereof. 6. The contrast agent composition according to claim 5, further comprising a free organic ligand or calcium, sodium meglumine or a complex salt thereof. A method of enhancing tissue-specific control of MR images of organs and tissues of a mammal, except humans, comprising administering a compound of claim 1 or 2 in a diagnostically effective amount. Tissue-specific X-ray imaging and computed tomography (CT) methods of organs and tissues of mammals, except humans, comprising administering a compound of claim 1 or 2 in a diagnostically effective amount.