JP2864448B2 - Stable radiotechnetium-labeled diagnostic compositions - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a radioactive technetium-labeled diagnostic composition containing a radioactive technetium-labeled chelating compound, and more particularly, it can be used for imaging of various organs including renal kinetic functional imaging. The present invention relates to a radioactive technetium-labeled diagnostic composition that stably holds a radioactive technetium-labeled chelate compound.

[0002]

2. Description of the Related Art Conventionally, a substance labeled with a radioisotope is administered into a living body, and radiation emitted by the substance is detected by a scintillation camera to determine the distribution and behavior of the substance in a living body in a non-invasive manner. It is represented as an image, and is used for early detection of various diseases and elucidation of disease states. This substance labeled with a radioisotope is called an imaging agent, and a substance suitable for each purpose has been developed.

For example, the imaging agent utilized in the inspection of renal function, dimercaptosuccinic acid technetium ^(99m Tc-DMSA) renal static imaging agent and diethylenetriaminepentaacetic acid technetium such as ^(99m Tc-
DTPA), sodium orthoiodated sodium hippurate ( ¹³¹ I
−, ¹²³ I-OIH) and Fritzber.
g) et al reported, ^99m Tc and mercapto glycyl glycidyl consisting sill glycine (MAG3) mercaptoacetyl glycylglycylglycine technetium ^(99m T
c-MAG3; Fritzberg AR et al: J Nucl Med, 27, 1
11,1986) are known.
These are widely used in clinical applications.

[0004] Included in many of the above imaging agents
^99m Tc, the gamma ray energy is ideal for imaging, low absorbed dose for a short half-life nuclides, it enables large doses, crisp, detailed dynamic image is obtained from the other radionuclides such as ¹³¹ I There is an advantage that it can be.
Furthermore, this ^99m Tc has the advantage that it can be taken out more freely than a commercial technetium generator, so that it can be supplied stably.

As described above, although ^99m Tc has many advantages, it still has problems in practical use, and it has been difficult to say that ^99m Tc is sufficiently satisfactory in practical use.

That is, since ^99m Tc has a half-life of 6 hours, it is common to use a technetium generator in hospitals, inspection laboratories, and the like.
It is necessary to prepare a radioactive technetium-labeled chelate compound by reacting a chelating agent such as 3. And ^99m T
At the time of c-chelate compound preparation, adjustment of radioactivity concentration and, in some cases, heating and air oxidation are necessary,
Since the operation is complicated, there is a problem that the worker is likely to be exposed to the radiation of ^99m Tc.

To solve such a problem, ^99m
It is desirable to supply the Tc chelate compound as a labeled preparation, but in order to supply it as a labeled preparation, the radioactivity at the time of use (20
(0-800 MBq), it is necessary to label with 10 to 20 times higher radioactivity and ship it.

However, technetium labeled with such a high radioactivity cleaves the bond itself between the technetium and the chelate compound by the emitted radiation, and as a result, free ^99m Tc is generated, which becomes the background. Has caused a new problem that the image is deteriorated.

[0009]

Accordingly, there has been a demand for the development of a technique that does not decompose a radioactive technetium-labeled chelate compound even when labeled with a high radioactivity.

[0010]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for preventing the decomposition of a technetium compound labeled with a high radioactivity, and as a result, if thiosulfuric acid or a salt thereof is added to the compound, The present inventors have found that the stability can be improved, decomposition can be prevented, and there is no change in pH during storage, and the present invention has been completed.

That is, the present invention provides a radioactive technetium-labeled diagnostic composition containing a radioactive technetium-labeled chelate compound and thiosulfate or a salt thereof.

The radioactive technetium-labeled chelate compound of the present invention is produced by reacting radioactive technetium with a chelate compound according to a known method.

[0013] Radioactive technetium pertechnetate salts such as sodium pertechnetate, ⁹⁹ M
Obtained from an o- ^99m Tc generator.

Examples of the chelating compound for radioactive technetium include chelating agents usable in the field of imaging agents, such as mercaptoacetylglycylglycylglycine, diethylenetriaminepentaacetic acid, dimercaptosuccinic acid, methylenediphosphonic acid and the like. Salts.

Among the radioactive technetium-labeled compounds, particularly preferred are the following formulas:

Embedded image And radioactive technetium-mercaptoacetylglycylglycylglycine (MAG3).

On the other hand, examples of thiosulfuric acid or a salt thereof include, in addition to thiosulfuric acid, sodium thiosulfate, potassium thiosulfate, ammonium thiosulfate and the like.

In the diagnostic composition of the present invention, the mixing ratio (molar ratio) of thiosulfuric acid and its salt to the chelate compound is
Since it differs depending on the chelate compound used, it can be appropriately selected according to the chelate compound. For example, when mercaptoacetylglycylglycylglycine is used as the chelate compound, the mixing ratio is preferably 3: 1 or more, particularly preferably about 20: 1. When diethylenetriaminepentaacetic acid is used, 0.001: 1. ~
The ratio is preferably about 1: 1, particularly about 0.04: 1 to 0.16: 1, and when methylene diphosphonic acid is used, about 0.001: 1 to 1: 1 and particularly about 0.023. :
It is preferable that the ratio be about 1 to 0.376: 1.

In addition, various optional components can be added to the diagnostic composition of the present invention as long as the effects of the present invention are not impaired.

The diagnostic composition of the present invention obtained as described above is used as an imaging agent for early detection of various diseases of organs such as kidney, liver, bone and the like and elucidation of pathological conditions. It can be used advantageously.

[0020]

According to the diagnostic reagent of the present invention, even if a technetium chelate compound is labeled with a high radioactivity, the degradation of the compound is prevented, so that a radioactive technetium-labeled compound having excellent properties has been labeled. It can be provided in the form. Therefore, since complicated labeling operation at the clinical site is not required, exposure of the operator due to the labeling operation is reduced, and a clinical examination such as imaging can be performed more easily.

[0021]

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Production of a chelate composition for producing a ^99m Tc-labeled ^{radiodiagnostic} agent (1): Dissolved oxygen was removed by blowing an inert gas such as nitrogen or argon into sterile water containing no pyrogen. .
After adding 20 g of sodium tartrate and 40 ml of stannous chloride solution (25 mg / ml) to 75 ml of this water,
The pH was adjusted to 7.3 using sodium hydroxide solution. Dissolve 50 mg of benzoylmercaptoacetylglycylglycylglycine (MAG3) in this solution,
The total volume was adjusted to 100 ml with water from which dissolved oxygen had been removed to obtain a chelate composition liquid.

The chelate composition solution thus obtained may be stored as an aqueous solution or in a frozen state, but may be freeze-dried and stored as a freeze-dried product. The operations in this example and the following examples were all performed aseptically under a flow of an inert gas such as nitrogen or argon.

Example 2 Preparation of ^99m Tc labeled ^{radiodiagnostic} agent (1): 0.1 ml of the chelate composition solution obtained in Example 1 and ^99m Tc (5
The mixture was mixed with 0.85 ml of a physiological saline solution containing GBq) in the form of sodium pertechnetate, stirred, and then heated at 100 ° C. for 10 minutes using a heater (heating block; manufactured by Yamato Scientific). After heating, the mixture was cooled to room temperature, was added sodium thiosulfate solution 0.05 ml, technetium-labeled MAG3 solution (hereinafter, abbreviated as ^"99m Tc-MAG3") was obtained.

Example 3 Radiochemical Purity Assay of ^99m Tc-MAG3: ^99m Tc-MAG3 obtained in Example 2 was subjected to reverse phase chromatography (reverse phase plate RP-18 manufactured by Merck; physiological saline / methanol). / acetic acid = 60/40/1) to give the examined material compound and a deployed position object of ^99m Tc-MAG3.

As a result, unreacted unbound ^99m Tc sodium pertechnetate is located at Rf 0.8 to 0.9.
It was found that the ^99m Tc tin colloid and the reduced insoluble technetium (TcO ₂ ) dehydrated remained at the origin. On the other hand, the target substance, ^99m Tc-MAG3, has a Rf
It was developed around 0.4.

Thus, the prepared ^99m Tc-MAG
The radiochemical purity of No. 3 is obtained from the following equation. Radiochemical purity (%) = A / B x 100 A: Radioactivity at peak near Rf 0.4 B: Total radioactivity on thin plate

Example 4 Influence of the stability of ^99m Tc-MAG3 and the concentration of sodium thiosulfate: According to the method shown in Example 2, ^99m Tc-MAG3 having only a different concentration of sodium thiosulfate was produced.
Sodium thiosulfate concentration of 0, 5, 50, 100, 25
The radiochemical purity of 0, 750, 1500, and 7500 μg / mg was analyzed by the method of Example 3 immediately after production and after 28 hours of storage at room temperature, and the decomposition rate was calculated from this value. Table 1 shows the results.

[0029] * Decomposition rate = (XY) / X x 100 X: Purity immediately after production (%) Y: Purity after 28 hours (%)

From the results in Table 1, sodium thiosulfate was added to 1
It was found that under the condition of the presence of 00 μg / ml or more, the radiochemical purity did not deteriorate for a long time immediately after the production.

EXAMPLE 5 Storage test of ^99m Tc-MAG3: Obtained in Example 2.
^{Of the 99m} Tc-MAG3 preparations, sodium thiosulfate to which a concentration of 750 μg / ml was added was allowed to stand at room temperature for 28 hours, and then was subjected to reverse phase chromatography (Reverse phase plate RP-18, manufactured by Merck). NaCl / methanol / acetic acid = ^60/40/1 ), ^99m Tc
The degree of decomposition was examined. In addition, as a control, the degree of decomposition was similarly examined for ^99m Tc-MAG3 to which sodium thiosulfate was not added. These results are shown in FIG. 1 and FIG. As is clear from the results, the ^99m Tc-MAG3 preparation of the present invention hardly decomposed, but the control product decomposed, and the ^99m TcO ₄ peak was clearly observed.

Example 6 Biodistribution of ^99m Tc-MAG3: ^99m Tc obtained in Example 2
-Among MAG3, the sodium thiosulfate concentration is 750 μm.
g / ml 24 hours after production
tar) rats were intravenously administered in an amount of 0.2 ml each,
One minute later and one hour later, the organs were dissected out and the radioactivity in each organ was measured. Also, ^99m produced from prepared preparation time for not containing sodium thiosulfate as compared Tc-
MAG3 was also manufactured immediately after production. Table 2 shows the results.

[0033]

As is clear from the table, there is no significant difference in the distribution in the body depending on whether sodium thiosulfate is added or not, and excellent properties as a renal function diagnostic agent excreted into urine via the kidney immediately after administration. It is understood that it holds.

Example 7 Production of a chelate composition for producing a ^99m Tc-labeled radiological diagnostic agent (2): Dissolved oxygen was removed by blowing an inert gas such as nitrogen or argon into sterile water containing no pyrogen. .
To 350 ml of this water was added diethylenetriaminepentaacetic acid (DT
PA) 10 g, 1 N sodium hydroxide solution 80 ml and stannous chloride hydrochloric acid solution (110 mg / ml) 10 ml
Is added, the pH is adjusted to 4.15 with a sodium hydroxide solution, and the total amount is adjusted to 50 with water from which dissolved oxygen has been removed.
It was 0 ml. After dispensing 1 ml of this solution into vials,
Lyophilized to obtain a chelate composition.

Example 8 Production of ^99m Tc labeled radiodiagnostic agent (2): 1 m of physiological saline containing ^99m Tc (5 GBq) in the form of sodium pertechnetate in the chelate composition obtained in Example 7
After mixing and stirring, sodium thiosulfate solution (50 mg
/ Ml) was added to obtain a technetium-labeled DTPA solution (hereinafter abbreviated as " ^99m Tc-DTPA").

Example 9 Radiochemical Purity Assay of ^99m Tc-DTPA: ^99m Tc-DTPA obtained in Example 8 was subjected to paper chromatography (acetone: water = 1: 1) to obtain the desired ^99m Tc. −
The deployment position of DTPA was examined.

As a result, the unreacted unbound sodium pertechnetate contains ^99m Tc tin colloid and reduced hydrolyzed insoluble technetium (TcO ₂ ) at the Rf 1.0 position.
Turned out to be at the origin. In contrast, the target substance, ^99m Tc-DTPA, was developed near Rf 0.7.

Thus, the prepared ^99m Tc-DTP
The radiochemical purity of A is determined from the following equation. Radiochemical purity (%) = A / B x 100 A: Radioactivity at peak near Rf 0.7 B: Total radioactivity on filter paper

EXAMPLE 10 Storage Degradability Test of ^99m Tc-DTPA: Obtained in Example 8
Of ^99m Tc-DTPA formulation, those of sodium thiosulfate concentration was added to a 2 mM, after standing at room temperature for 28 hours, by subjecting the paper chromatography in the same manner as in Example 9, ^99m Tc-D
The degree of degradation of TPA was examined. In addition, as a control, the degree of decomposition was similarly examined for ^99m Tc-DTPA to which sodium thiosulfate was not added. Table 3 shows the results.
Shown in

[0041] * Decomposition rate = (XY) / X x 100 X: Purity immediately after production (%) Y: Purity after 28 hours (%)

From the results shown in Table 3, it was clarified that the addition of sodium thiosulfate suppressed the deterioration of the radiochemical purity of ^99m Tc-DTPA and significantly increased the stability.

Example 11 Production of a chelate composition for producing a ^99m Tc-labeled radiological diagnostic agent (3): Dissolved oxygen was blown into a sterile physiological saline solution containing no pyrogen by blowing an inert gas such as nitrogen or argon. Removed. 150 mg of methylene diphosphonic acid (MDP), 0.8 and 3.2 ml of sodium thiosulfate solution (4 mg / ml), and 0.5 ml of stannous chloride solution (15 mg / ml) were added to 14 ml of the physiological saline. Thereafter, the pH was adjusted to 5.
4 and a total volume of 2 with physiological saline from which dissolved oxygen has been removed.
The volume was adjusted to 0 ml to obtain a chelate composition liquid.

Example 12 Production of ^99m Tc Labeled ^{Radiodiagnostic} Agent (3): Example 11
A chelate composition solution 1ml obtained in, ^99m Tc (1
4.8 GBq) in the form of sodium pertechnetate in the form of 1 ml of physiological saline was mixed and stirred to obtain a technetium-labeled MDP solution (hereinafter abbreviated as " ^99mTc -MDP").

Example 13 Radiochemical Purity Assay of ^99m Tc-MDP: ^99m Tc-MDP obtained in Example 12 was subjected to thin layer chromatography (Merck TLC plastic sheet silica gel 60: methyl ethyl ketone). The deployment position of the target ^99m Tc-MDP was examined.

As a result, it was found that unreacted unbound sodium pertechnetate was developed at the position of Rf 1.0, and the target substance, ^99m Tc-MDP, remained at the origin. Therefore, the radiochemical purity of the prepared ^99m Tc-MDP can be obtained from the following equation. Radiochemical purity (%) = A / B x 100 A: Radioactivity at peak near origin B: Total radioactivity on thin plate

EXAMPLE 14 Storage Degradability Test of ^99m Tc-MDP: Obtained in Example 12
^{A 99m} Tc-MDP preparation to which sodium thiosulfate has been added to a concentration of 0.5 mM is left at room temperature for 24 hours, and then subjected to thin-layer chromatography in the same manner as in Example 13. ^{Gives 99m} Tc-M
The degree of DP degradation was determined. Further, as a control, the degree of decomposition was similarly examined for ^99m Tc-MDP to which sodium thiosulfate was not added. Table 4 shows the results.

[0048] * Decomposition rate = (XY) / X x 100 X: Purity (%) immediately after production Y: Purity (%) after 24 hours

From Table 4, it was found that the addition of sodium thiosulfate suppressed the deterioration of the radiochemical purity of ^99m Tc-MDP and significantly increased the stability.

[Brief description of the drawings]

FIG. 1 is a radiochromatograph showing the degradation state of a ^99m Tc-MAG3 preparation of the present invention after storage for 28 hours.

FIG. 2 is a radiochromatograph showing the degradation state of a control ^99m Tc-MAG3 after storage for 28 hours. that's all

Continuation of the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 51/00 C07K 5/08 CA (STN)

Claims (4)

(57) [Claims] 1. A radioactive technetium-labeled diagnostic composition comprising a radioactive technetium-labeled chelate compound and thiosulfate or a salt thereof. 2. The radioactive technetium-labeled chelate compound according to claim 1, which is obtained by reacting a radioactive technetium label with a compound selected from mercaptoacetylglycylglycylglycine, diethylenetriaminepentaacetic acid and methylenediphosphonic acid. A radioactive technetium-labeled diagnostic composition. 3. The radioactive technetium-labeled chelate compound has the following formula: The radioactive technetium-labeled diagnostic composition according to claim 1, which is a compound represented by the formula: 4. The radioactive technetium-labeled diagnostic composition according to claim 1, which is an imaging agent.