JPH03261786A - Porphyrin metal complex and use thereof - Google Patents

Abstract

NEW MATERIAL:A complex in which nonradioactive metal manganese is linked into the porphyrin skeleton of a porphyrin compound (salt) expressed by the formula through chelate bonds. EXAMPLE:Manganese complex of 4-[1-[2-[N,N'-N'',N''-tetrakis(carboxymethyl)- diethylenetriaminoacetyloxy]ethoxy]ethyl]-2-vinyldeuteroporphyrin. USE:A carrier for radiodiagnosis, excellent in accumulating properties in cancerated tissues with low phototoxicity and providing a radiodiagnostic agent capable of safely, rapidly and clearly performing cancerous scintigraphy by complexing thereof with a radioactive metal. PREPARATION:A chelating side chain is initially removed from a compound expressed by the formula and the resultant precursor is trealed with a salt of nonradioactive metal manganese in an aqueous medium to afford a manganese chelate combination of the aforementioned precursor, which is then reacted with a reagent having the above-mentioned chelating side chain in a medium.

Description

[Detailed Description of the Invention] [Field of Industrial Application] This invention relates to a porphyrin metal complex and its uses, particularly a porphyrin metal complex useful as a carrier for a radiodiagnostic agent and a radioactive porphyrin metal complex useful as a radiodiagnostic agent. Regarding.

[Prior Art 2] It has been well known that porphyrin derivatives have selective accumulation properties in cancer tissues.

However, the selectivity of porphyrin derivatives toward cancer tissues is still far from satisfactory, and they inevitably accumulate in normal tissues to some extent. Porphyrin derivatives thus accumulated in normal tissues exhibit toxicity when exposed to light. Therefore, in order to avoid toxic effects when porphyrin derivatives are administered to the human body, the patient should remain in the dark for a long time until the porphyrin derivatives that have accumulated in normal tissues are excreted from the body. Is required.

In addition, the development of a diagnostic agent for cancer scintigraphy that positively depicts cancer is one of the long-standing themes in the field of nuclear medicine, and currently, gallium citrate (Ga-67) is used clinically.
and thallium chloride (Tl-201) are used for that purpose4.
I'm here. However, their physical properties such as half-life and gamma ray energy are not necessarily satisfactory, and they accumulate not only in cancer but also benign tumors and inflammatory foci, and bone drawings that interfere with image interpretation occur. It has the following drawbacks.

[Problems to be Solved by the Invention] The present inventors searched for a porphyrin derivative that reduced phototoxicity while maintaining good accumulation in cancer tissues, and
By using this in combination with appropriate diagnostic nuclides, we have conducted various studies with the aim of providing a radioactive diagnostic agent suitable for cancer imaging.

[Means for solving the problem] As a result, a porphyrin metal complex obtained by chelate-bonding non-radioactive metal manganese within the porphyrin skeleton of a porphyrin derivative to which a specific side chain with chelate-forming ability is bound is found to be effective against cancer. It was found that it has excellent tissue accumulation and significantly reduced phototoxicity. The porphyrin metal complex can be easily complexed with a radioactive metal due to its side chain having strong chelate-forming ability, and there is no need to worry about phototoxicity by using the radioactive porphyrin metal complex obtained here. Cancer scintigraphy can be performed safely without any cancer.

Further, as a result of detailed examination to address the demands for cancer scintigraphy in the clinical field, it was determined that Tc-99m is the best radionuclide to use.

Tc-99m is frequently used in current clinical settings,
It is inexpensive and easy to obtain, its gamma ray energy is suitable for the characteristics of gamma cameras, and its half-life is appropriately long, making it possible to keep the patient's exposure dose relatively low, making it ideal as a diagnostic nuclide. It is.

Furthermore, radioactive T is added to the side chain of the porphyrin metal complex.
The radioactive porphyrin metal complex obtained by coordinating c-99m can be used for a relatively short period of time after administration (e.g., about 3
It has been found that the pathological condition of cancer can be clearly depicted in terms of time), and there is virtually no bone accumulation, which has been a problem in the past. These features are extremely superior and not found in conventional cancer scintigraphy agents.

[Summary of the invention] The present invention has been completed based on the above findings, and includes:
The gist is: A porphyrin metal complex consisting of a porphyrin compound or a salt thereof represented by the formula: and a non-radioactive metal manganese chelate-bonded within its porphyrin skeleton; It consists of a radioactive porphyrin metal complex consisting of bound non-radioactive metal manganese and radioactive T c-99m coordinately bound to its side chain having chelate-forming ability.

The carrier for a radiodiagnostic agent of the present invention comprises a porphyrin compound (
The active ingredient is a porphyrin metal complex in which non-radioactive metal manganese is chelated to the porphyrin skeleton of 1) or a salt thereof, and the radioactive diagnostic agent of the present invention is The active ingredient is a radioactive porphyrin metal complex in which a radioactive metal Tc-99m is bound to the side chain having chelate-forming ability.

[Function] The radioactive diagnostic agent of the present invention only needs to have the radioactive porphyrin metal complex present at the time of application to the human body. That is, the radioactive diagnostic agent may be commercially available and provided with the radioactive porphyrin metal complex present, or the porphyrin metal complex and the radioactive metal may be commercially available and provided separately, and these may be used separately. The above-mentioned radioactive porphyrin metal complex may be prepared by blending the above-mentioned radioactive porphyrin metal complex.

The porphyrin metal complex used as a carrier for the diagnostic agent of the present invention is usually the porphyrin compound (1) or a salt thereof or a side chain having chelate-forming ability is excluded.
The precursor and a salt of non-radioactive metal manganese are treated in an aqueous medium to form a manganese chelate conjugate of the precursor, which is then reacted with the reagent having the side chain in an appropriate medium. obtained by The radioactive porphyrin metal complex used as the radiodiagnostic agent of the present invention is composed of the porphyrin metal complex and the radioactive metal Tc-
It is formed by treating the 99m salt in an aqueous medium.

To prepare the radioactive porphyrin metal complex at the time of use,
Although the porphyrin metal complex may be stored in the form of a dissolved or frozen solution, it is usually stored in a powder state by freeze-drying, low-temperature vacuum distillation, or the like. The porphyrin metal complex in powder or solution state may be added with a pharmaceutically acceptable solubilizing agent (for example, an organic solvent) as necessary.
, pHEIi formulations (e.g. acids, bases, buffers), stabilizers (e.g. ascorbic acid), dandruff agents (e.g. glucose), isotonic agents (e.g. sodium chloride), etc. and the valence state of Tc-99m. Reducing agent for preparing (
For example, stannous chloride) or an oxidizing agent (for example, hydrogen peroxide) may be added. The other radioactive metal Tc-99m
is commonly used as its water-soluble salt, especially sodium pertechnetate, which may be dissolved in water or an isotonic solution (eg, physiological saline). By mixing water or an isotonic solution containing sodium pertechnetate with the powdered porphyrin metal complex shown above, or the powder containing sodium pertechnetate and the porphyrin metal complex dissolution, radioactive porphyrins can be produced. Metal composites are easily prepared in a short time.

At this time, in order to make the radioactive metal T c-99 +++ act as a stable complex with the porphyrin metal complex that is its carrier, it is desirable to have a reducing agent present in the reaction system. Examples of the reducing agent include divalent tin salts (eg, tin halides, tin sulfate, tin nitrate, etc.) and hydrogen sulfite. In the above preparation, there is no particular restriction on the mixing order of each reagent, but it is usually best to avoid mixing the stannous salt and pertechnetate ion first in an aqueous medium.

In order for the T c-99m-labeled radioactive porphyrin metal body prepared in this manner to be useful as a radiodiagnostic agent, it is necessary to have a radioactivity amount and radioactivity concentration sufficient for its medical purpose. Therefore, for the nuclear medicine use of the Tc-99m labeled radioactive porphyrin metallometallic body, when prepared, f2 has a radioactivity of, for example, about 1 to 2 (IGBQ (3 to 9 F!j as solution volume)). The Tc-99m-labeled radioactive porphyrin metal may be administered immediately after preparation, but it is desirable that it has enough stability to withstand storage for an appropriate period of time after preparation. If necessary, pH adjusters (eg, acids, alkalis, buffers), stabilizers (eg, ascorbic acid), isotonic agents (eg, sodium chloride), etc. may be added.

When using Tc-99m-labeled radioactive porphyrin metal in nuclear medicine, the expected clinical dose is LDs for mice and rats. Values 1/100 and 1/4 respectively
00, and the safety as an injection is extremely high. In addition, the Tc-99m-labeled radioactive porphyrin metal has low bone accumulation, so it can prevent bone visualization, which is a problem in cancer imaging. Tumors can also be visualized early. Therefore, the Tc-99+n-labeled radioactive porphyrin metal complex is extremely useful as a radiodiagnostic agent.

[Example] Next, the present invention will be explained in more detail with reference to Examples. In addition, the manganese complex and the gallium complex for 4-11-[2-[N,N',N",N"tetrakis(calphokidimethyl)diethylenetriaminoacetyloxy]ethoxy3ethyl]-2-hinyl deuteroporphyrin The bodies are hereinafter abbreviated as ATN-10 and ATS-2, respectively.

Example 1 Synthesis of ATN-10 485 g of protoporphyrin methyl ester was mixed with 485 g of acetic acid.
After the dropwise addition, the reaction temperature was gradually raised to room temperature and stirred overnight.Then, the reaction solution was concentrated under reduced pressure to obtain a residue. Add 27 units of ethylene glycol to the oil and heat at room temperature.
The reaction was carried out by stirring day and night (introduction of ethylene glycol into the porphyrin derivative).

Addition of water produced a dark purple precipitate, which was collected by filtration (4.5 g). The entire amount of the obtained t5 precipitate was dissolved in 45 ml of methanol, and then 45 m of mankanese acetate (■) was added.
Add methanol solution (20 ml) containing 9 g of hydrate,
refluxed for an hour (introduction of manganese into the ethylene glycol porphyrin derivative). After refluxing, the reaction solution was concentrated under reduced pressure, and the remaining oil was mixed with 2N potassium hydroxide/methanol and water-cooled.
60 molecules were added dropwise (saponification of noester in porphyrin derivative).

After the dropwise addition, the reaction temperature was gradually raised to room temperature, stirred all day and night, cooled with water again, and the p)l of the solution was adjusted to 7 with IN hydrochloric acid. After neutralization, a dark reddish brown precipitate was formed by standing in a refrigerator day and night. The precipitate was collected by filtration and purified by silica gel column chromatography (eluent: ethyl acetate-methanol mixture) to obtain a manganese complex of 4=E1-C2-hydroquinethoquine)ethyl]2-vinyl deuteroporphyrin. (1.479). The entire amount of the obtained complex was dissolved in pyridine 70J112, and anhydrous DTPA was added.
(19) was added and reacted under heating and stirring (DTPA introduction into the complex). After the reaction, the precipitate was filtered off, and ethyl acetate was added to the filter to obtain crude crystals of the target product. Then, purification was performed using silica gel column chromatography (eluent: ethyl acetate-methanol mixture) to obtain ATS-10 (
089, total yield 1O%) Example 2 Mass spectrometry of ATN-10 The mass of this product was measured using ATS-10 (remaining amount: 1052) by secondary ion mass spectrometry. As a result, m/z−1
Peaks were observed at 052, 1074, and 1090, which were [M-do, [M-H+Na-do, and [M-H+KE], respectively, and were confirmed to be the target products.

Example 3 Elemental analysis of ATN-10 ATN-10-hydrate (C5[IH59N?O+sMr
++ ·H, 0, remaining amount: 1071.01), its carbon, hydrogen, and nitrogen atoms were analyzed using a CHN coder, and its manganese atoms were analyzed using an inductively coupled high-frequency plasma spectrometer. The results are shown in the table below.

Table Elemental analysis of ATN-10 Elements Theoretical value/% Actual value/% C56,155,8 H5,75,7 N 9.2 8.9Mn
51 5.1 From the table above, the measured values were in good agreement with the theoretical values.

Example 4 Rat photosensitivity caused by porphyrin compounds In order to confirm photosensitivity in rats, the following breeding environment was set up.

Fluorescent lamps that emit light closest to natural light (Solar Light,
product name), and place two of them in close contact with each long side of the polycarbonate breeding cage (the bottom of the umbrella of the fluorescent light stand equipped with the Taiyo TruLight should match the height of the bottom of the polycarbonate breeding cage). It was installed so that the light was illuminated from the side. At this time, the illuminance inside the cage is approximately 6,000 to 12,000 LLIX. In an animal breeding room where temperature and humidity were controlled (temperature: 23.5 ± 1.5°C, humidity = 70 ± 5%), breeding cages equipped with solar TruLight were placed in breeding racks, 2 cages per stage for a total of 4.
Fixed. In addition, white cardboard was appropriately attached around the rack to prevent light interference between the upper and lower rearing cages. Light irradiation time (8.00~
20:OO), solar TruLight sentinels were set on a timer.

The animals tested were SD female rats (SPF), 6 weeks old and weighing 120 to 160 g.

The test solutions were ATN-2/citrate buffer and ATN-
10/citrate buffer, and the dosage of each solution is
The body weight was about 0.5, about 1 and about 10 zg/9.

Each test solution was administered in a single dose through the tail vein of rats under non-anesthetized conditions (5 animals per administration group), and then observations and tests after administration were conducted for 6 days as follows.

(1) Weight measurement Body weight will be measured at a certain time during the observation period (8:30-9:00)
Measured daily.

(2) General condition The general condition and the presence or absence of death were observed continuously from 00 hours after administration, and several times a day during the light irradiation period from the day after administration.

(3) Rats that died during the autopsy observation period will be dissected immediately after discovery.
Organs and tissues were observed macroscopically. In addition, for rats that survived until the end of the observation period, the rats were killed by bleeding from the abdominal aorta using a syringe under Labonal anesthesia, and then the organs and tissues were macroscopically observed.

(4) Pathological examination Regardless of whether the macroscopic findings are normal or abnormal, the ear shell, where photosensitivity symptoms are most prominent, and organs and tissues that are found to be abnormal at autopsy, will be examined immediately after removal. The solution was fixed with 10% neutral formalin.

Pathological specimen preparation (HE staining) and pathological examination were performed for each specimen.

(5) Approximately 61g of the blood collected in the syringe in serological test (3)
was placed in a blood collection tube and left at room temperature. For each blood, the following three blood biochemical tests were performed.

■ Liver function test items Total protein, total bilirubin, direct bilirubin, G.

S GPT ■ Renal function test items urea nitrogen, creatinine ■ Other potassium (increased in rats with acute photosensitivity), lipid peroxide (indirect evidence of active oxygen generation) After completing the post-administration observation period, the following The results were obtained.

ATN-2: Dose IM No notable abnormalities were observed in items (1) to (5) above at M97 and body weights below 9. However, with a weight of approximately 10m and 97kg, (1)
Weight change: There was a slight decrease in weight for 1 day after administration, but it steadily increased thereafter. (2) - Membrane condition: Erythema on the ear shell on the gold side from 8 hours after administration.
Swelling was observed and continued during the observation period (pathological condition of photosensitivity). (3) Autopsy: No particular abnormality was found. (4) Pathological examination: Dilation of peripheral blood vessels in the golden side of the ear shell and in the subcutaneous tissue. Findings such as inflammatory cell infiltration and edema (pathological condition of photosensitivity) were obtained. (5) Serological tests: No particular abnormalities were found.

ATN-10: No notable abnormalities were observed in items (1) to (5) above at all doses.

For the ATS-2 test solution administration group in which an abnormality was observed,
To confirm whether this was due to the influence of light, a second test group was conducted in which light was blocked. As a result, ATN-2: The above (1
) to (5), no notable abnormalities were observed.

From this, it was confirmed that the abnormal findings observed in the light irradiation group of ATN-2: approximately 10 buttocks 97 and 9 body weight administered were photosensitivity caused by ATN-2.

From the above results, ATN-2 has a dosage of approximately lOjIg/k
G produced photosensitivity in rats, but ATN
At -10, no evidence of photosensitivity was found at t2.

Example 4 Acute toxicity test combination for intravenous administration of ATS-10 in mice and rats was prepared as follows.

Mouse: ATN-10,0,259 with acetate buffer, 1
0xj was added and dissolved, and sterile filtration was performed to obtain a test solution.

Rat: ATN-10,2,59 with acetate buffer tL251
12 was added and dissolved, followed by sterile filtration to obtain a test solution.

The animal species and strains tested are as follows.

Mouse (SPP): rcR strain (♀), 25 weeks old, body weight 35-489° Rat (SPF)/SD strain (♀), 6 weeks old, body weight 137
~1699° The dose for test animals is 35
0197 and 4 dose groups reduced by a common ratio of 1.15, and the highest dose was 700 n/ky for rats,
Five dose groups were established with a common ratio of 1.32 below.

The dose layer weight was calculated for each test animal based on the body weight measured immediately before administration using the test solution, and approximately 0.3x was added from the tail vein.
A single dose was administered at a rate of Q/min.

Thereafter, the LDso value and its 95% confidence limit value were calculated by the Spearman-Karber method from the mortality rate during the observation period (10 days) of each group of mice and rats.

The results are shown below.

In mice, death was observed in each group administered at a dose of 265m9/9 or higher, and in all cases, the onset occurred within 2 minutes immediately after administration, and no deaths were observed during the subsequent observation period. Ta. The number of deaths increased depending on the dose, with deaths occurring on the gold side in the 9 dose group at 350m9/. Furthermore, in the 230m9/9 dose group, no deaths were observed during the observation period.

Based on these results, the LD5o value and its 95% confidence limit value are estimated to be 299.8 (277,0 to 324
．． 5) Water/kg.

Rats: Deaths were observed in each group at doses of 304 m9/9 or higher. Most of them occurred within 7 minutes immediately after administration, but in the 304 m9/9 and 402 tp, 9/kq dose group, 53 cases occurred 2 days after administration.
On 011!9/, death cases were observed in each of the 9 dose groups on the first day after administration! B. The onset time decreased as the dose increased. However, no deaths were observed after 3 days after administration. The number of deaths increased depending on the dose as in mice, 53
Death of all animals was observed in the 0x9/9 dose group or higher. Furthermore, in the 231g9/9 dose group, no deaths were observed during the observation period. Based on the above results, LD
Estimating the 5o value and its 95% confidence limit value is 363
．． 1 (313°8~42000) m9/9.

Example 5 Preparation of ATN-10 for Tc-99m labeling Ascorhinic acid (AA), 35M9, was dissolved in deoxygenated water, 100 rtr (l) to prepare an AA solution. Also, anhydrous stannous chloride, 19
0m9 was dissolved in 100mQ of deoxygenated water to obtain a tin solution. Deoxygenation was performed by blowing nitrogen into 0.2M acetate buffer 1 (pH 5, 3) for 1 hour under water cooling. Under water cooling and a nitrogen stream, 18 ml of this buffer was mixed with 1 ml of AA solution, and 1 ml of tin solution, and 9 of ATN 10.33 was added and dissolved. Then, while performing sterile filtration, 0 and 5 mQ were dispensed into sterile vials to obtain an ATNIO solution for Tc-99m labeling. After further dispensing, it was stored frozen until it was used for labeling.

Example 6 Preparation of Tc-99m-ATN-10 After thawing the ATN-10 solution for Tc-99m labeling, sodium pertechnetate [Tc-99m1/physiological saline solution,
0.3x+7 (radioactivity upon labeling: 322 MBq) was added and mixed by shaking to prepare a Tc-99m-ATN-10 injection solution.

Example 7 Radiochemical purity of Tc-99m-ATN-10 injection solution An appropriate amount of the Tc-99m-ATN-10 injection solution obtained in Example 6 was placed on a silica gel thin layer plate (silica gel 6OW, layer thickness: 0.25 mm). , Merck & Co., Ltd.) from one end, and a methanol-acetic acid mixture (5 μm) was used as a developing solvent.
:3, capacity ratio), 100i11 was developed from the coating position. After development, it was air-dried and scanned with a radiochromatography scanner. As a result, a radioactivity peak was observed only around Rf: 0.5. On the other hand, sodium pertechnetate [Tc
-99m] solution, a radioactivity peak was observed near the front of the solvent. From the above results, Tc-
The radiochemical purity of 99+n-ATN-10 injection is 10
I have confirmed that it is 0%.

Example 8 In vitro stability of Tc-99m-ATN-10 injection limb The in vitro stability of the powder was evaluated by examining the radiochemical purity of Tc-99m-ATN-10 injection over time. did. Tc- prepared according to Example 6
The 99m-ATN-10 injection solution was allowed to stand at room temperature in the dark, and after preparation of the liquid solution, 0.5.3.6.12 and 24 hours later, the Tc-99m-ATN-10 injection limb was treated according to Example 7. Radiochemical purity was determined.

As a result, the radiochemical purity of the powder at each measurement point was approximately 1O
It was confirmed that the powder was stable for at least 24 hours.

Example 9 Tc-99m-ATN-10 and In-111A
Tumor-bearing animal experiment of TN-10 Tc-99m-ATN-10 or In-111-
The in vivo behavior of ATN-10 in mice transplanted with Lewis lung cancer or colon 26 (colon cancer) was investigated.

The test animals were male BDFl mice with Lewis lung carcinoma implanted on the side of the body, or CD mice with colon 26 implanted on the side of the body.
The mice were F1 female mice. Tc-99m-ATN
-10 or In-111-ATN-10 (dose 1
, 03 *9/kg) was administered through the mouse tail vein,
Images were taken 3 hours later.

As shown in the attached FIGS. 1 and 2, Tc99n-
From the imaging results of Lewis lung cancer (Fig. 1) or Colon 26 (Fig. 2) obtained by administration of ATN-10, it was revealed that tumor drawing was successful. On the other hand, as shown in the attached FIGS. 3 and 4, the imaging results for Lewis lung cancer (FIG. 3) and colon 26 (FIG. 4) after administration of In-111-ATN-10 revealed that tumors could not be drawn. Ta.

Example 1O Tc-99m-ATN-10 and In-111A
Normal animal experiment of TN-10 Tc-99m-ATN-10 or In-111
The in-vivo behavior of ATN 10 in normal rats was investigated.

Tc-99mATN from the tail vein of normal female SD rats
-10 or In-111-ATNlo (dose 1.
After administration, the rats were kept in metabolic cages for 3 and 24 hours. Afterwards, bed anesthesia was performed, and an autopsy was performed.
The main organs were removed, their wet weight was measured, and the radioactivity was measured.
They were counted and the distribution rate in the body was calculated.

The biodistribution results are shown in Tables I and 2, respectively.

Three hours after administration, the difference in the distribution rate between the two tracts was observed only in the kidney accumulation rate, with Tc-99m-ATN-10 showing approximately 3 times higher values than In-111-ATN-10. . Furthermore, 24 hours after administration, differences in distribution rates were observed except for the large intestine, muscle, blood, urine, and feces, and among the organs in which differences were observed, Tc-99m-
ATN-10 had lower accumulation. Assuming that radioactive chemical species excreted into the gastrointestinal tract are not reabsorbed from the gastrointestinal tract, the distribution rate to the liver, gastrointestinal tract, and feces at each anatomical point is summed up to r2 (liver cumulative accumulation rate, Table 3). As shown in Table 3, the total accumulation rate in the liver was found to be the same between both tracts. Although the total accumulation rate in the liver of both tracts remains unchanged,
24 hours after administration, the liver accumulation rate was Tc-99m-ATN.
-10 is lower. In addition, the accumulation in bones is Tc −
99+n-ATN-10, I
It is less than 1/2 of n-111-ATN-10.

Table 1゜Liver Small Intestine Large Warm Stomach Pancreas Lung Heart Kidney Blood/Muscle/9 Muscle/g Adrenal Skin/g Urine Feces Tc -99m-ATN -10 Normal Rat 1,
3±06 15.1±1.1 3.8±0.7 0.4±0.0 0.5±0.1 1 O±0.1 0.5±0.0 3.2±0. 3 2.9±0.2 0.4±0.0 0.1±0.0 0.1±0.0 0.2±0. l l 2.0±1.2 0.0±0.0 8.6± 21± 16.6±1 O02± 0.3± 0.3± 0.1 ± 3.9± 0.0± 0 .2± Ol± 0.0± 0.1 ± 26.4± 26.6± 0.5 0.2 1.7 0.0 0.0 0.0 0.0 0 0.0 0 0.0 0.0 0.0 2.6 7 Table 2. Normal rats for In-111-ATN-10 Table 3 Normal rats for Tc-99m ATN-10 and In 11-ATN-10 (n=3-4) Liver Small intestine Large intestine Stomach Pancreas Lung Heart Kidney Blood/j! Q Bone/9 Muscle/g Adrenal skin/g Urine/feces 118±1.2 15.8+1.0 5.3±1.8 0.5±0.1 0.6±0.0 1.1±0. 1 06±0.1 1.1±0.1 26±0.4 0.4±010 0, l±0.0 0, l±0.0 0.2±0.0 14, l±0. 7 0.0±0.0 13.0±0.4 3.0±0.1 8.3±4.4 0.3±0.0 0.8±0.1 0.7±0.1 0 2+0.0 06±0.1 O90±00 0.4±0.0 0.1″:0.0 0.1±0.0 0.2±0.0 24.0±1.0 28. 5±3.9 Tc-99m-ATN-1030,6±1.5 54
．． 0±2.5In-111-ATN-1033,4±2
．． 6 53.0±1. These values were calculated using the following formula: Liver cumulative accumulation rate (% dose) = Liver (% dose) + l Portion tube (% dose) Cow dung (%
Dose) [Effects of the Invention] The T c-99m-labeled radioporphyrin metal complex provided by the present invention is a stable complex in vitro, and it can be easily prepared in a short time at the time of use. The 'f c-99m-labeled radioactive porphyrin metal complex has a coordinate bond between a porphyrin metal complex that has cancer affinity but does not exhibit phototoxicity, and T c-99m, which is an ideal nuclide in nuclear medicine. It is possible to provide high-resolution images with low exposure doses.

In addition, the pathological condition of cancer can be clearly and quickly examined in a short time after administration, and there is almost no bone accumulation, which has been a problem in cancer diagnosis. In view of these characteristics, the T c-99
The m-labeled radioactive porphyrin metal body is useful as a radiopharmaceutical, particularly as a diagnostic agent for cancer scintigraphy.

[Brief explanation of drawings]

Figure 1 is a schematic diagram showing a negative scintigram of a Lewis lung cancer transplanted mouse 3 hours after Tc-99m-ATN-10 administration, and Figure 2 is a colon 26 transplanted mouse 3 hours after Tc-99m-ATN1010 administration. FIG. 3 is a schematic diagram showing a negative image of a scintigram of In111-ATN-10 administration 3.
A schematic diagram showing a negative scintigram of a mouse transplanted with Lewis lung cancer after hours, and FIG.
FIG. 10 is a schematic diagram showing a negative scintigram of a colon 26-implanted mouse 3 hours after administration. 1 Figure 2 Figure 3 Figure 4 ＼axis

Claims (1)

[Claims] 1. Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ A porphyrin consisting of a porphyrin compound represented by [I] or a salt thereof and a non-radioactive metal manganese chelate-bonded within the porphyrin skeleton. metal composite. 2. A carrier for a radiodiagnostic agent comprising the porphyrin metal complex according to claim 1. 3. The carrier for radioactive diagnostic agent according to claim 2 and radioactive Tc-
A radioactive diagnostic agent consisting of a combination with 99m. 4. The radioactive diagnostic agent according to claim 3, which is used for cancer imaging. 5. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The porphyrin compound or its salt represented by [I], the non-radioactive metal manganese chelate-bonded within its porphyrin skeleton, and its side chain with chelate-forming ability. A radioactive porphyrin metal complex consisting of coordinately bound radioactive Tc-99m. 6. A radioactive diagnostic agent comprising the radioactive porphyrin metal complex according to claim 5. 7. The radioactive diagnostic agent according to claim 6, which is used for cancer imaging.