WO2006054466A1 - Novel radioactive technetium/bisphosphinoamine complex and radioactive imaging diagnostic agent containing the complex - Google Patents

Abstract

A radioactive technetium complex that realizes enhancing of in a single photon discharge type tomogram, cardiac contrast and initial circulation extraction ratio; and a radioactive imaging diagnostic agent comprising the complex. The complex is a compound of the formula (1) (wherein 99mTc(CO)3 is a technetium-99m tricarbonyl compound and L is a bisphosphinoamine compound). As the bisphosphinoamine compound (L), there can be mentioned, for example, bis(dimethoxypropylphosphinoethyl)methoxyethylamine, bis(dimethoxypropylphosphinoethyl)ethoxyethylamine or bis(diethoxypropylphosphinoethyl)ethoxyethylamine.

Description

 Specification

 Novel radioactive technetium monobisphosphinoamine complex and radioactive diagnostic imaging agent containing the complex

 Technical field

 [0001] The present invention relates to a novel radioactive technetium-bisphosphinoamine complex useful for nuclear medicine diagnosis, particularly for nuclear medicine diagnosis in the field of tumor diagnosis and myocardial perfusion diagnosis, and a radioactive diagnostic imaging agent containing the complex.

 Background art

 [0002] Heart disease such as ischemic heart disease such as myocardial infarction occupies the top causes of death, and since death rate is high when discovery is delayed, early diagnosis is important. In addition to invasive left ventricular imaging and coronary angiography, diagnostic imaging methods in the heart region include echocardiography, X-ray computed tomography (X-ray CT), and magnetic resonance. Imaging (MRI) and nuclear medicine diagnosis such as positron emission tomography (PET) and single photon emission tomography (SPECT) are mainly used. Of these, various compounds have been developed as diagnostic agents for use in nuclear medicine in the heart region, and some of them have been clinically applied.

[0003] One of the clinically applied myocardial perfusion diagnostic agents, sodium chloride thallium 201, dissociates in aqueous solution to become a monovalent cation ( ^2Q1 TI ⁺ ) and behaves like potassium ion This is considered to be actively taken into the myocardial cells by the sodium-potassium pump. For this reason, it has the feature of providing SPECT images that reflect the distribution of blood flow in the myocardium, which is highly absorbed into the myocardium. In addition, because of the high initial circulation extraction rate (hereinafter referred to as FPEF), it also has the excellent feature of high blood flow linearity and high diagnostic accuracy.

[0004] However, thallium 201 has properties that are undesirable for use as a radiopharmaceutical because it has a low energy half of about 70 keV and a long half-life of about 73 hours, making it impossible to administer large doses. Therefore, there is a drawback that the obtained image tends to be unclear. Thallium-201 is a nuclide produced by the cyclotron. There is also the disadvantage of being inferior. Therefore, technetium 99m, which is more favorable as a nuclide for use in radiopharmaceuticals because it has a relatively short half-life of about 140 hours with an energy of about 140 keV, is cheaper and more convenient. Compounds have been developed.

 [0005] As a radiopharmaceutical for diagnosing myocardial perfusion using technetium-99m, technetium-99m-hexakis-1-methoxy-2-isobutylmonoisonitryl (hereinafter referred to as MIBI) (cardiolite) , Registered trademark, manufactured by Daiichi Radioisotope Laboratories) and technetium-99m-tetrofosmin (hereinafter referred to as tetrofosmin) (Myobiu, registered trademark, manufactured by Nippon Mediphysics Co., Ltd.) It has been applied clinically. Among these, although MIBI is suppressed in the lung, it accumulates in the liver due to slow clearance from the liver, and the heart / liver ratio calculated from the radioactivity count in the SPECT image is not sufficient. . Since the lungs and liver are present at a location close to the heart, accumulation of the administered diagnostic imaging agent in the lungs, Z, or liver hinders diagnosis in heart disease. For this reason, development of new myocardial perfusion diagnostic agents that suppress accumulation in the lungs and liver is underway. Tetrofosmin is less accumulated in the liver than MIBI, but it is desirable to use a myocardial blood flow agent with less accumulation in the liver in order to further improve the diagnostic ability.

[0006] Technetium-99m nitride bis (dimethoxypropylphosphinoethyl) ethoxyethylamine-Jetki Shetilditi talented rubamate complex (hereinafter referred to as “technetium-99m nitride”) is a compound that suppresses accumulation in the liver and improves the heart / liver ratio. ^99m TcN_PNP5) and the like, various tenetium-99m-nitride-bisphosphinoamine complexes have been developed (see, for example, Patent Documents 2 and 3). Although this compound is characterized by accumulation in the heart and low accumulation in the lungs and liver, it has the disadvantage that FPEF is low compared to MIBI, which is the preceding agent.

 [0007] Patent Document 1: JP-A-9-328495

 Patent Document 2: Pamphlet of International Publication No. 98/27100

 Patent Document 3: Japanese Translation of Special Publication 2004-505064

 Disclosure of the invention

Problems to be solved by the invention [0008] As described above, the development of ^m TcN-PNP5 has improved the heart / liver ratio, but this compound has a problem that the FPEF is not sufficient. Compounds that can be used as diagnostic agents for myocardial perfusion include compounds that have improved FPEF while retaining the excellent performance of ⁹⁹ " ¹ TcN-PNP5, which accumulates in the heart and has low accumulation in the liver and lungs. Although desirable to use, no such compound has been developed so far.

 [0009] The present invention has been made in view of the above problems, and provides a radioactive technetium complex having a high heart / liver ratio and a heart / lung ratio in a SPECT image and a higher FPEF. And means for solving the problems aimed at providing diagnostic imaging agents using the complex

[0010] As a result of intensive studies, the present inventors have found that the above-mentioned problems can be overcome by a compound in which a bis-phosphinoamine compound is coordinated to a technetium 99m tricarbonyl compound. The invention has been completed.

[0011] That is, the present invention relates to the following formula (1) in which a bisphosphinoamine compound is coordinated to a technetium-99m tricarbonyl compound:

[0012] [Chemical 12]

〖"MTc (CO) 3 (L)] (1)

(In the formula (1), ^99m Tc (CO) is technetium-99m tricarbonyl, L is bisphosphine.

 Three

 A technetium 99m tricarbonyl complex represented by the following formula: and a radioactive diagnostic imaging agent comprising the complex.

[0013] The above L is not particularly limited as long as it is a bisphosphinoamine compound capable of forming a complex with technetium-99m tricarbonyl compound, but two or more functional groups bonded to phosphorus have a primary hydroxyl group. It is preferable to use a compound other than the compound which is a lower linear alkyl group or a hydroxyl group to be contained, for example, a compound other than a bishydroxymethylphosphino compound or a bishydroxyphosphino compound.

For example, the following formula (2): [0014] [Chemical 13]

PCH ₂ CH ₂ NCH ₂ CH ₂ P (2)

Ri,

(In Formula (2),

R ¹ ″ and R ¹ ′ ″ may be the same or different and each independently represents an alkyl group, a phenyl group, or the following formula (3):

[0015] [Chemical 14]

(In formula (3), 1 is an integer of 0≤1≤4, is an integer of 0≤1'≤3) or the following formula (4):

 [0016] [Chemical 15]

In Equation (4), m is 0≤m≤4, m 'is 0≤m'≤4, m' is an integer of 0≤m ', ≤3), R ² Is a compound represented by hydrogen, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an amino group, a group represented by the above formula (3) or a group represented by the above formula (4)) Can be preferably used. Here, the alkyl group that can be selected as R ″, R ¹ ″ or R ¹ ′ ″, and the alkyl group and the substituted alkyl group that can be selected as R ² may be linear or branched. Is preferably a lower alkyl group, more preferably one having 1 to 4 carbon atoms.

[0017] Specific examples of the bisphosphinoamine compound used in the present invention include bis (diphenylphosphine). Finoethyl) amine, bis (diphenylphosphinoethyleno) methylamine, bis (diphenylphosphinoethyl) ethylamine, bis (diphenylphosphinoethyl) propylamine, bis (diphenylphosphinoethyleno) methoxyethyla Bis (diphenylphosphinoethyl) butyramine, bis (diphenylphosphinoethyl) acetonylamine, bis (dimethoxyphosphinoethyl) amine, bis (dimethoxyphosphinoethyl) methylamine, bis (dimethoxyphosphinoethyl) Ethylamine, bis (dimethoxyphosphinoethyl) propylamine, bis (dimethoxymethylphosphinoethyl) amine, bis (dimethoxymethylphosphinoethyl) methylamine, bis (dimethoxymethylphosphinoethyl) Ethylamine, bis (dimethoxymethybis (dimethoxyethylphosphinoethyl) amine, bis (dimethoxyethylphosphinoethyl) methylolamine, bis (dimethoxyethylphosphinoethyl) ethylamine, bis (dimethyoxysethylphosphinoethyl) Propylamine, bis (dimethoxypropylphosphinoethyl) ethylamine, bis (dimethoxypropylphosphinoethyleno) propylamine, bis (dimethoxypropylphosphinoethyl) methoxyethylamine, bis (dimethoxypropylphosphinoethyleno) ethoxyethyl / leamine Bis (diethoxypropy / rephosphinotech / le) ethoxyethylamine, bis (diethoxyethylphosphinotechnoethyl) ethylamine, bis (diethoxyethylphosphinotechnole) And a compound selected from propylamine, bis (diethoxyethylphosphinoethyl) methoxylamylamine, bis (dimethylphosphinoethyl) methylamine, and bis (dipropoxymethylphosphinoethyl) ethoxyethylamine. Most preferably, bis (dimethoxypropylphosphinoethyl) methoxyethylamine, bis (dimethoxypropylphosphinoethyl) ethoxyethylamine, and bis (diethoxypropylphosphinoethyl) ethoxyethylamine are A compound selected from the group consisting of:

 The diagnostic imaging agent according to the present invention can be used for diagnosis of various diseases, but can be suitably used particularly as a tumor diagnostic agent and a myocardial blood flow diagnostic agent.

 According to another aspect of the present invention, there is provided a radioactive diagnostic imaging agent preparation kit for preparing the diagnostic imaging agent.

The kit includes a first container containing a carbon monoxide source, a reducing agent and a base, and a bisphosphine. A second container containing an inoamine compound is included. The first container may contain a stabilizer if necessary.

 The bisphosphinoamine compound to be blended in the second container is not particularly limited as long as it can form a complex with technetium 99m tricarbonyl. The same phosphinoamine compound can be used.

[0019] The base is preferably an inorganic salt such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium hydroxide, or

It is more preferable to use magnesium hydroxide.

[0020] As the reducing agent, a boron borohydride or a substituted boron hydride in which at least three of the hydrogen atoms constituting the borohydride can be substituted with an inert substituent can be used. . Here, the inert substituent refers to a substituent that does not participate in the reaction, and specifically refers to an alkyl group, a phenyl group, or the like.

 The amount of reducing agent is preferably between 0.1 and 2 molar ratio of base to reducing agent, more preferably between 0.15 and 2, more preferably between 0.25 and 2. . As the stabilizer, tartrate, citrate, formate, etc. can be used, preferably tartrate, more preferably sodium L-tartrate.

[0021] In the kit according to the present invention, the compound blended in each container may be in a state of being dissolved in water or physiological saline (0.9% sodium chloride sodium chloride solution). The dried product may be dried by means such as spray drying. The invention's effect

[0022] The compound according to the present invention exhibits sufficient accumulation in the heart to obtain SPECT images, and in addition to accumulation in the lung and liver, FPEF is ^{99 m} TcN-PNP5. High performance. Therefore, by using the compound according to the present invention as a diagnostic agent for myocardial perfusion, it is possible to obtain a good SPECT image with a high heart / lung ratio and heart Z liver ratio.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0023] The compound according to the present invention provides a condition necessary for complex formation by mixing a solution containing a technetium 99m tricarbonyl compound with a solution containing a bisphosphinoamine compound. You can get power S by doing S. Hereinafter, the method for synthesizing the complex according to the present invention will be described.

In the synthesis of the complex according to the present invention, first, a solution containing a technetium-99m tricarbonyl product is prepared. As a method for preparing this solution, a known method, for example, a method described in the literature (Japanese Translation of PCT International Publication No. 2002-512616) can be used. Specifically, a solution in which pertechnetium-99111 acid ( ⁹⁹¹¹¹ 1 ^ ^〇- ) is dissolved in a solution in which a base, a reducing agent, carbon monoxide, and optionally a stabilizer are dissolved, is reacted. Can get by

 Four

 it can. The reaction can be carried out between 20 ° C. and 100 ° C. A temperature between 75 ° C. and 100 ° C. is preferred because the reaction proceeds more quickly.

 [0025] As the base, an inorganic salt can be used, and sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium hydroxide, or magnesium hydroxide is preferable. Can be used.

 [0026] The reducing agent is a borohydride or a borohydride, a substituted borohydride that is substituted with an inert substituent in up to three of the hydrogen atoms constituting the anion. Can be used. More preferably, an anion derived from a salt selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride can be used.

 The amount of the reducing agent is adjusted so that the molar ratio with respect to the sum of technetium-99m and technetium-99 is 3 or more, preferably 100 or more, more preferably 1000 or more, and most preferably 10000 or more. If the amount of the reducing agent is small, the reduction of technetium becomes insufficient.

 [0027] As the stabilizer, tartrate, citrate, formate, or the like can be used, preferably tartrate, more preferably sodium L-tartrate. The amount of stabilizer should be greater than the total amount of technetium-99m and technetium-99, and the molar ratio to the total amount of technetium-99m and technetium-99 is preferably between 100 and 1000000. More preferably between 1000 and 1000000. In this case, the amount of the stabilizer is small, and sufficient stability cannot be obtained, which is preferable.

[0028] Carbon monoxide may be introduced directly into the solution using a cylinder or the like. You may introduce | transduce using the compound which can produce | generate carbon. For example, in combination with the reducing agent, borano disodium carbonate (Na BH 2 CO 3) is dissolved in the solution.

 2 3 2 Carbon monoxide and reducing agent can be introduced simultaneously.

[0029] The amount of the base is such that the molar ratio to the reducing agent is between 0.1 and 2, preferably between 0.15 and 2, and more preferably between 0.25 and 2. At this time, if the amount of the base is small, the pH of the solution becomes low, and the reaction does not proceed sufficiently. If the amount is too large, the solute concentration becomes too high.

 Each solution used in the above reaction may be a solution using water as a solvent, but it is preferable to use a physiological saline solution as a solvent for preparing an injection.

 [0030] Bisphosphinoamine compounds are described in the literature (Claudio Bianchini et al., Organometallics, 1995, 14, p. 1489-1502 and L. Sacconi & R. Morassi, J. Chem. Soc. (A), 1969, p.2904-29 10) and can be synthesized according to the method described. For example, when synthesizing bis (dimethoxypropylphosphinoethyl) ethoxyethylamine, N, N-di (2-chloroethyl) -N-ethoxyethylamine and di (3-methoxypropyl) phosphine It can be obtained by reacting n-butyllithium with tetrahydrofuran.

 [0031] Using the synthesized bisphosphinoamine compound, a bisphosphinoamine compound solution is prepared. As a solvent for dissolving the bisphosphinoamine compound, water can be used, but a physiological saline solution may be used. In the case where the solubility of the bisphosphinoamine compound in water is low, a solution obtained by appropriately mixing an amphipathic solvent such as ethanol with water or physiological saline may be used.

It is desirable to adjust the pH by adding a pH adjuster to the bisphosphinoamine compound solution. The type and amount of the pH adjusting agent are appropriately selected so that the pH is suitable for complexing the bisphosphinoamine compound with the technetium tricarbonyl compound. For example, if the bisphosphinoamine amine compound is bis (dimethoxy propyl phosphino ethyl) Etoki Shechiruamin, since the preferred _P H in the complex formed is about 7, bis O. lmg (dimethoxypropyl phosphino ethyl) Etokishe Add 0.08 mL of 0.5 mol / L hydrochloric acid to tyramine dissolved in 0.92 mL of physiological saline.

As long as the concentration of the bisphosphinoamine compound is such that it is completely soluble in the solvent used, Although there is no particular limitation, it is preferable in consideration of operability in the complex formation reaction after the force of 0.1 force 3 mmol / L.

[0032] Next, the prepared technetium-99m tricarbonyl compound solution and the bisphosphinoamine compound solution were mixed and given conditions suitable for the reaction, and technetium-99m tricarbonate bisphosphino was mixed. An amine compound complex is synthesized.

 The amount of technetium-99m tricarbonyl compound solution and bisphosphinoamine compound solution to be mixed is appropriately adjusted according to the amount of technetium-99m tricarbonyl compound bisphosphinoamine compound complex and the concentration of each solution. Is done. For example, in the case of synthesizing 1850 MBq of technetium-99m tricarbonyl monobis (dimethoxypropylphosphinochinole) ethoxyethylamine complex, the concentration of technetium-99m tricarbonyl solution is 3700 MBq / When the concentration of mL, bis (dimethoxypropylphosphinoethyl) ethoxyethylamine solution is 0.2 mmol / L (0.2 mg / mL), 1 mL of each solution may be used.

 [0033] The ratio of the total amount of bisphosphinoamine compounds used in the reaction to the total amount of technetium tricarbonyl compounds (the total amount of technetium-99m tricarbonyl compounds and the total amount of technetium-99 tricarbonyl compounds) is used. As long as all of the technetium tricarbonyl compounds are in a sufficient amount ratio to form a complex, there is no need to specifically limit them. For example, when synthesizing technetium-99m tricarbonyl compound-bis (dimethoxypropylphosphinoethyl) ethoxyethylamine complex, the amount of bisphosphinoamine compound is 100 or more in molar ratio to technetium tricarbonyl compound. If there is enough.

 [0034] The complex formation reaction can be performed at room temperature, but it is desirable to increase the reaction temperature from the viewpoint of shortening the reaction time. For example, in the case of synthesizing technetium-99m tricarbonyl compound-bis (dimethoxypropylphosphinoethyl) ethoxyethylamine complex, it may be heated at 100 ° C. for 15 minutes.

 Next, the kit for preparing a diagnostic imaging agent for radioactivity according to the present invention will be described.

The kit according to the present invention essentially comprises a first container containing a carbon monoxide source, a reducing agent, a base, and optionally a stabilizer, and a second container containing a bisphosphinoamine compound. Including it as an element. The bisphosphinoamine compound blended in the second container is As long as it can form a complex with technetium-99m tricarbonyl compound, the ability to use the same compound as the bisphosphinoamine compound constituting the complex according to the present invention is practical. S can.

 [0036] As the reducing agent, base, and stabilizer blended in the first container, the same ones used for the preparation of the compound according to the present invention can be used. As the carbon monoxide source, it is preferable to use a compound capable of generating carbon monoxide in a solution. For example, boranonitrate carbonate can be used. By using borano disodium carbonate, the carbon monoxide source and the reducing agent can be blended in the first container at the same time.

 In addition, it is desirable to use sealed containers as the first container and the second container, and it is desirable to use lyophilized compounds for each compound in each container.

[0037] The amount of each compound blended in the first container is adjusted according to the amount of technetium-99 to be processed at one time. Specifically, it is used in the same amount ratio as in the synthesis of the complex according to the present invention. In addition, the amount of the bisphosphinoamine compound blended in the second container is such that all of the technetium-99m tricarbonyl compound and technetium-99 tricarbonyl compound produced in the first container are coordinated. A sufficient amount is sufficient.

Hereafter, 1 milliliter of technetium 99m tricarbonyl compound bis (dimethoxypropylphosphinoethyl) ethoxyethylamine using 1 mL of pertechnetium 99m acid solution (total technetium equivalent to ^10-1Q mol) eluted from the generator Taking the case of synthesizing a complex as an example, the kit for preparing a diagnostic imaging agent according to the present invention will be described.

[0038] First, borano disodium carbonate 1.5 mg, sodium tetraborate decahydrate 0.7 mg, sodium tartrate dihydrate 2.1 mg and sodium carbonate 1.8 mg are mixed in the first container. Add 1 mL of the pertechnetium-99m acid solution eluted from the generator (total technetium containing ^10-1Q mol equivalent) and react. This reaction can be performed between 20 ° C. and 100 ° C., and 75 ° C. to 100 ° C. is preferred because the reaction proceeds more quickly.

In the second container, 0.15 mg of bis (dimethoxypropylphosphinoethyl) ethoxyethylamine and 120 μL of 0.5 mol / L hydrochloric acid are blended and freeze-dried. To this was added 1.5 mL of physiological saline solution, 1 mL of which was dispensed and added to the first container, and a complex formation reaction was performed. Technetium 99m tricarbonyl compound bis (dimethoxypropylphosphinoethyl) ethoxetylamine complex is obtained. At this time, the complex formation reaction can be performed at room temperature, but it is preferable to increase the reaction temperature from the viewpoint of shortening the reaction time. For example, when synthesizing tenetium-99m-tricarbonyl-monobis (dimethoxypropylphosphinoethyl) ethoxystilamine complex, it is preferable to heat at 100 ° C. for 15 minutes. Example

 [0040] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these contents.

[0041] [Reference Example]

 Synthesis of bis (dimethoxypropylphosphinoethyl) ethoxyethylamine

[0042] Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine was synthesized according to the following procedure.

 First, 3-methoxy-1-propanol was synthesized according to the synthesis scheme described in the following formula (5).

 In a 12 L flask that had been oven dried and purged with argon, 78 g (2.1 mol) of lithium aluminum hydride (Aldrich) and 3 L of jetyl ether (Columbus Chem. Co., hereinafter referred to as “ether”) were placed. . To this, 424 g (3.59 mol) of methyl _3-methoxypropionate (manufactured by Aldric h) was added little by little over 4 hours. After the addition was complete, the mixture was stirred for 30 minutes and cooled to 0 ° C. The reaction was terminated by carefully adding 78 mL of water little by little, and 78 mL of a 15% sodium hydroxide (Vopak, USA, In) solution and 234 mL of water were added. 200 g of Celite was added as a filter remover, and the mixture was further stirred at room temperature for 30 minutes.

[0044] The obtained brown suspension was filtered, and the filtrate was further washed with 500 mL of ether, and the eluted ether was combined with the filtrate in the filtration. The filtrate was transferred to a separatory funnel and allowed to stand still, then the aqueous layer was discarded, and the organic layer was transferred to a 4 L Erlenmeyer flask. 100 g of anhydrous magnesium sulfate (manufactured by Vopak, USA, In) was added to the flask and stirred for 30 minutes. Inorganic salts were removed using a filter, and the filtrate was concentrated using a rotary evaporator to obtain 285 g of a colorless transparent oil. This was concentrated under reduced pressure at room temperature to obtain 196 g of 3-methoxy-1-propanol. [0045] [Chemical 16]

Next, synthesis of 3-methoxy-1-chloropropane was performed according to the synthesis scheme described in the following formula (6).

 196 g (2.17 mol) of 3-methoxy-1-propanol synthesized in the above step and 176 mL (2.17 mol) of anhydrous pyridine (manufactured by Aldrich) were placed in a 2 L flask that had been dried and purged with argon. In the flask, add 388 g (3.36 mol) of thionyl chloride (from Bayer Co.) over 4 hours under ice-cooling, taking care that the temperature of the reaction solution is kept at 10 to 30 ° C. Small portions were added. After the addition was complete, the mixture was heated at 70 ° C for 4 hours and then returned to room temperature.

 [0047] To this reaction solution, a mixture (suspension) of 600 g of ice and 110 mL of concentrated hydrochloric acid (manufactured by Vopak USA, Inc.) was stirred and stirred. The resulting bilayer liquid was transferred to a separatory funnel, and the organic layer was collected in a flask. The aqueous layer was extracted with 300 mL of ether, and the ether layer was combined with the organic layer. This organic layer was washed with 300 mL of 5% potassium carbonate (Aldrich) solution, further dried with 100 g of potassium carbonate, and then filtered. The filtrate was concentrated using a rotary evaporator to obtain 400 mL of a yellow liquid.

 This was distilled under normal pressure at 105 to 108 ° C. to obtain 16-6.5 g of a colorless transparent oily product, 3-methoxy-1-chloropropane.

[0048] [Chemical 17]

Next, tetra- (1-methoxypropyl) diphosphane disulfide was synthesized according to the synthesis scheme described in the following formula (7).

Into a 3 L flask purged with argon, add 66 g of 3-methoxy_1_chloropump pan synthesized in the above step and 37.2 g (1.53 mol) of shore IJ-like magnesium (manufactured by Aldrich). 1L was added. This was stirred at room temperature for 10 minutes and then allowed to stand at room temperature for 10 minutes. this An amount of iodine crystals (Aldrich) was added to the flask to cover the magnesium surface. After the ether began to boil (after about 15 minutes), 100 g of 3-methoxy-1-chloropropane synthesized in the above step was added. In this step, a Grignard reagent was generated.

[0050] Separately, under argon, thiophosphoryl chloride (manufactured by Aldrich) 54 mL (0.54 mol) was dissolved in 363 mL of ethanol to prepare a thiophosphoryl chloride solution. After completion of boiling of the Grignard reagent, the Grignard reagent was cooled to 0 ° C., and the thiophosphoryl chloride solution was added little by little over 1 hour. At this time, the reaction solution was cooled so that the temperature of the mixed solution was kept between 0 and 5 ° C. When the addition was complete, the reaction vessel was allowed to warm to room temperature with stirring and the reaction was refluxed for 2 hours. Thereafter, the reaction solution was cooled to 0 ° C.

 To this reaction solution, a mixture (suspension) of 3.3 L of ice and 134 mL of sulfuric acid (Fisher Scientific) was stirred and stirred. The resulting biphasic liquid was stirred overnight at room temperature and then transferred to a separatory funnel under argon. The organic layer was separated and concentrated with a rotary evaporator to obtain 48 g of tetra (1-methoxypropyl) diphosphane disulfide as a colorless and transparent oily substance.

[0051] [Chemical 18]

Next, g (3-methoxypropyl) phosphine was synthesized according to the synthesis scheme described in the following formula (8).

In a 2 L flask that had been dried and purged with argon, 168 mL (168 mmol) of 1 M lithium aluminum hydride / tetrahydrofuran solution was placed. Combine tetra- (1-methoxypropyl) diphosphane disulfide synthesized in the above step with tetra- (1-methoxypropyl) diphosphane disulfide separately synthesized in the same manner as in the above step, The total amount was 64 g (153 mmol), which was dissolved in 375 mL of degassed tetrahydrofuran and added to the above flask in portions over 4 hours with stirring. This solution was refluxed at 60 ° C. for 3 hours. The reaction solution was cooled to 0 ° C, and 6.4 mL of degassed water was added little by little with vigorous stirring. To this reaction solution, 6.4 mL of degassed 15% sodium hydroxide solution was added, and 19.2 mL of degassed water was further added. Stirring was stopped and the reaction solution was allowed to stand at room temperature under argon. To this reaction solution, 500 mL of degassed ether and 500 mL of degassed water were added and stirred for 30 minutes. Thereafter, stirring was stopped and the mixture was allowed to stand to separate the layers. The upper organic layer was transferred to a 3 L flask. The aqueous layer was extracted with 500 mL of ether, and the ether layer was added to the organic layer in the flask. The organic layer was dried with sodium sulfate (manufactured by Fisher Science) (300 g) and then concentrated under reduced pressure while cooling with a dry ice / isopropanol filling cooler. The reaction product was transferred to a 100 mL flask and dried under reduced pressure under conditions of 0.4 mmHg and 55-60 ° C. to obtain 9.55 g of a colorless transparent oily product, di- (3-methoxypropyl) phosphine.

[0053] [Chemical 19]

 Next, according to the synthesis scheme described in the following formula (9), N_ethoxyethyl-Ν, Ν-diethanolamine was synthesized.

 In a 3 L flask that had been dried and purged with argon, 240 mL of absolute ethanol (manufactured by Tarr), 276 g (1.97 mol) of potassium carbonate, and 120 mL (1.14 mol) of diethanolamine were placed. To this, 304 g (1.97 mol) of bromoethyl ether (Aldrich) was added little by little over 3 hours. The solution was then refluxed for 2 days under argon. The solution was cooled to 0 ° C and filtered. The filtrate was washed with ethanol, and the filtrate ethanol was mixed with the previous filtrate. This was concentrated with a rotary evaporator to obtain 800 g of a yellow oily substance.

 Further, distillation under reduced pressure was performed under conditions of 0.5 mmHg and 125 to 127 ° C. to obtain 121 g of a yellow oily substance. This product was applied to a column packed with 1 kg of silica gel and purified using methanol / dichloromethane (1: 9) 10 L to obtain 60 g of N-etochetyl ー, Ν-diethanolamine.

[0055] [Chemical 20] OEt

N

HO OH K ₂ C0 ₃ / EtOH HO OH (9)

Next, according to the synthesis scheme described in the following formula (10), N, N_di- (2_chloroethyl) 1 N-ethoxyethylamine was synthesized.

 In a 1 L-volume flask that had been dried and purged with argon, 25 mL (304 mmol) of anhydrous pyridine and 27 g (152 mmol) of N-ethoxyethyl_N, N_diethanolamine synthesized in the above steps were placed. The flask was cooled to 0 ° C., and 108.5 g (912 mmol) of thionyl chloride was added in small portions over 6 hours while maintaining the temperature at 0 to 10 ° C. The resulting viscous solution was stirred overnight under argon at room temperature under light shielding conditions.

 Unreacted salt and thioneyl were removed by distillation under reduced pressure, and then the reaction solution was cooled to 0 ° C. To the reaction solution, 200 mL of water was added little by little with vigorous stirring, and further stirred for 1 hour while maintaining at 10 ° C. Thereafter, the temperature was lowered to −5 ° C., and 40 g of sodium carbonate (Fisher Scientific) was added little by little with vigorous stirring. Stirring was continued for 1 hour until it returned to room temperature. 400 mL of etherol was added to stop stirring, and the resulting bilayered liquid was transferred to a separatory funnel. The organic layer was separated from this two-layered solution, and the aqueous layer was extracted with 200 mL of ether. The ether used for extraction was added to the separated organic layer and dried using 100 g of magnesium sulfate (manufactured by Vopak USA, In). The organic layer was filtered, and the filtrate was concentrated with a rotary evaporator in the presence of 20 mL of toluene to obtain 37 g of a yellow oil.

 The reaction mixture was chromatographed with 400 g of silica gel and 3 L of hexane / ether (5: 1). Fractions with a yellow or slightly yellow color were collected and concentrated using a rotary evaporator. This was concentrated under reduced pressure at room temperature to obtain 19 g of N, N_di- (2_chloroethyl) -N-ethoxyethylamine as a yellow transparent oil.

[0057] [Chemical 21]

( Ten ) [0058] Finally, bis (dimethoxypropylphosphinoethyl) ethoxyethylamine was synthesized according to the synthesis scheme described in the following formula (11).

 A 500 mL flask was purged with argon, and 9.5 g (53.3 mmol) of di- (3-methoxypropyl) phosphine synthesized in the above step and 115 mL of anhydrous tetrahydrofuran were calorieated. 23.4 mL (58.6 mmol) of a solution obtained by dissolving n-butyllithium in hexane to 2.5 M was added in portions over 4 hours. The reaction vessel was cooled to 0 ° C, and 5.7 g (26.7 mmol) of N, N-di (2-chloroethyl) mono-N-ethoxyethylamine synthesized in the above step was dissolved in 10 mL of anhydrous tetrahydrofuran. The solution was added in small portions over 3 hours. The reaction solution was stirred overnight at room temperature.

[0059] 40 mL of degassed cold water was added to the reaction solution little by little. Further, 100 mL of degassed ether was added, and the resulting bilayer liquid was transferred to a separatory funnel. The aqueous layer and organic layer were separated under argon. The aqueous layer was extracted with 30 mL of ether, and the ether layer was added to the organic layer. The combined organic layer was dried over 20 g sodium sulfate and filtered under argon. The filtrate was concentrated on a rotary evaporator and further depressurized overnight with stirring to obtain 12.17 g of a pale yellow oil. This compound was subjected to HPLC analysis under the following conditions, and area% was determined as HPLC purity. The HPLC purity was 90%.

 The synthesized product was applied to a silica gel chromatograph (bed volume 150 mL), and nonpolar impurities were washed out with 2 L of hexane / ether (1: 1). Thereafter, the desired product was eluted with a 5% methanol / dichloromethane solution. The eluate was concentrated to obtain 10 g of a pale yellow oil. This compound was further purified by silica gel chromatography under the same conditions to obtain 5 g of bis (dimethoxypropylphosphinoethyl) ethoxyethylamine having a HPLC purity of 95.3%. This compound was stored under argon (one 30 ° C) until use.

[0060] [Chemical 22]

[0061] HPLC analysis conditions

 Column used Kaseisorb LC ODS 300-5 (product name, manufactured by Tokyo Chemical Industry Co., Ltd.), 4.6 mm x 15 cm

 Flow rate l.OmL / min

 Detection UV-Vis spectrophotometer (Detection wavelength: 210nm)

 [0062] The synthesized bis (dimethoxypropylphosphinoethyl) ethoxyethylamine is subjected to N MR measurement, mass spectrometry, and elemental analysis (C, H, N, P, 0: each% order). It was confirmed that it was synthesized. The results of each measurement are shown below.

 [0063] H—NMR ^ OOMHz, CDC1, δ)

 Three

 [0064] 1 · 19 (3Η, s, 1), 3.48 (4H, m, 2,3), 2.65 (6H, m, 4,5), 1.56 (4H, m, 6), 1.45 (8H, m 7), 1.68 (8H, m, 8), 3.41 (8H, t, 9), 3.33 (12H, s, 10).

In the ¹ H-NMR analysis of bis (dimethoxypropylphosphinoethyl) ethoxyethylamine, carbon was numbered as shown in the following formula (12).

[0065] [Chemical 23]

[0066] Mass spectrometry

 Measurement method: ESI (+) — TOF

Theoretical value: [M + H] ⁺ 498

 Experimental value: m / z 498, 306, 205, 177 (fragment as shown in the following formula (13))

[0067] [Chemical 24]

( 13 )

 [0068] Elemental analysis:? (Each% order)

[0069] [Table 1] Results of elemental analysis of bis (dimethoxypropylphosphinoethyl) ethoxyethylamine

[0070] [Comparative Example 1]

Technetium 99m nitride Bis (dimethoxypropylphosphinoethyl) ethoxy

[0071] ⁹⁹ " ¹ TcN-PNP5 was prepared in the following manner for the purpose of obtaining a comparative example in pharmacokinetic measurement and FPEF measurement.

Tin chloride (anhydrous) O. lmg (Nacalai Testa Lot. VIP5014), succinic acid dihydrazide (SDH) recrystallized product lmg (Aldrich Lot.00229EQ) and ethylenediammine tetraacetate disohydrate lmg (Dojindo: Lot. KK078) is dissolved in physiological saline O. lmL, and pertechnetium _99m acid (" ^m TcO-) solution is 1.5 mL for measuring pharmacokinetics (radioactivity concentration: 3754 MBq / mL ), 3.2 mL (radioactive concentration: 2945 MBq / mL) was added for FPEF measurement and allowed to stand at room temperature for 15 minutes. At this time, 0.1 mol / L sodium hydroxide 20 was added to adjust the pH to about 6.5. (This solution was designated as “ ^m TcN intermediate solution”). In this ^{99 m} TcN intermediate solution, bis (dimethoxypropylphosphinoethyl) ethoxyethylamine 4 mg / mL solution (as a solubilizer, gammacyclodextrin (Lumitsu DK1242) at a concentration of 4 mg / mL And 0.5 mg each of 4 mg / mL solution of diethoxyethyl dithiocarbamate (DBODC) and 20 μL of 0.1 mol / L sodium hydroxide was added to adjust the pH to about 9. This solution was heated at 100 ° C. for 15 minutes to prepare a ^{99 m} TcN-PNP5 solution. This ^{99 m} TcN-PNP5 solution was passed through an S-Pak (registered trademark, Waters' Investment Limited) C18 cartridge (trade name, manufactured by Nippon Waters Co., Ltd.), and " ^m TcN_PNP5 was adsorbed onto the column. After washing with water and 80% ethanol solution, elute with 0.1 mol / L tetraptylammonium bromide solution Z ethanol (10/90), add physiological saline to the eluate and adjust the ethanol concentration to 10%. The final solution had a radioactivity concentration of 350 MBq / mL for pharmacokinetic measurements and 493 MBq / mL for FPEF measurements.

The prepared ^{99 m} TcN_PNP5 was subjected to TLC analysis under the following conditions, and the area% of the peak was determined to obtain the radiochemical purity. The radiochemical purity was 94.4% for pharmacokinetic measurements and 95.2% for FPEF measurements.

[0072] TLC conditions:

 TLC plate: Silica gel 60 (Product name, Merck)

 Deployment phase: Ethanol / Black mouth form / Toluene / 0.5M ammonium acetate = 5/3/3 / 0.5 Deployment length: 10 cm

 Detector: Radiochromatogram scanner (manufactured by Aroka, PS-201)

 [0073] [Comparative Example 2]

 Synthesis of In_DTPA_HSA

[0074] 10 mg of diethylenetriaminepentaacetic acid-conjugated human serum albumin was dissolved in 0.5 mL of a 0.1 mol / L citrate solution (pH 5.9). 0.2 mL of this solution was mixed with 0.15 mL of indium chloride salt 111 (activity concentration at the time of preparation: 354 · 4 to 563 · 7 MBq / mL) to prepare ^m In-DTPA_HSA.

[0075] [Example 1] Synthesis of technetium tricarbonyl-bis (dimethoxypropylphosphinoethyl) ethoxyethylamine complex (for FPEF measurement)

[0076] Sodium tetraborate decahydrate 2.8 mg, sodium tartrate dihydrate 8.5 mg, and sodium carbonate 7.3 mg dissolved in 2 mL of physiological saline (0.9% sodium chloride aqueous solution) Boranoic disodium carbonate was added to 2.3 mg. To this solution, pertechnetium mono-99m acid (" ^m Tc ○ ―

 Four

) Solution (radioactive concentration: 2334 MBq / mL) 2 mL was added and heated at 100 ° C. for 22 minutes (this solution was referred to as “technetium-99m tricarbonyl solution”).

[0077] Separately, a bis (dimethoxypropylphosphinoethyl) ethoxyethylamine 4 mg / mL solution

A solution was prepared by adding 0.79 mL of physiological saline and 0.16 mL of 0.5 mol / L hydrochloric acid to 05 mL. Add 0.5 mL of the technetium-99m tricarbonyl solution prepared above to 100 mL of this solution to 100 mL. Heat at C for 15 minutes and combine technetium-99m tricarbonyl monobis (dimethoxypropylphosphinoethyl) ethoxyethylamine complex (hereinafter referred to as “ ^99m Tc (CO) PNP5”).

 Three

Made. The radioactivity concentration of the obtained ^{99 m} Tc (CO) PNP5 was 1060 MBq / mL.

 Three

[0078] The obtained technetium 99m tricarbonyl compound solution and ^{99 m} Tc (C0) PNP5 were washed.

 Three

TLC analysis was performed under the following conditions. As a result, the Rf value changed from 0.38 in technetium-99m tricarbonyl solution to 0.50 for ^{99 m} Tc (CO) PNP5, and technetium- 99

 Three

It was confirmed that the m-tricarbonyl compound formed a complex with bis (dimethoxypropylphosphinoethyl) ethoxyethylamine. ^{99 m} Tc (CO) PN from the result of TLC analysis

 Three

The area percentage of the P5 peak was determined and used as the radiochemical purity. The resulting ^{99 m} Tc (CO) PNP5 radiation

 Three

 The chemical purity was 88.7%. The pH of the solution was 7.17.

[0079] TLC analysis conditions:

 TLC plate: Silica gel 60 (Product name, Merck)

 Developing phase: Methanol / concentrated hydrochloric acid = 99/1

 Deployment length: 10 cm

 Detector: Radiochromatogram scanner (manufactured by Aroka, model: PS-201 type)

[0080] [Example 2]

Technetium tricarbonyl monobis (dimethoxypropylphosphinoethyl) ethoxyethylamine complex [0081] Sodium tetraborate decahydrate 2.8 mg, sodium tartrate dihydrate 8.5 mg, and sodium carbonate 7.2 mg dissolved in 3 mL of physiological saline (0.9% sodium chloride aqueous solution) 1.5 mL Was added to 2.3 mg of disodium boranocarbonate. To this solution, 0.5 mL of a pertechnetium mono-99m acid (" ^m Tc 0-) solution (radioactive concentration: 2162MBq / mL) was added and heated at 100 ° C for 20 minutes. Tricarbonyl compound solution ”).

Separately, a solution obtained by adding 0.87 mL of physiological saline and 0.08 mL of 0.5 mol / L hydrochloric acid to 0.025 mL of a bis (dimethoxypropylphosphinoethyl) ethoxyethylamine 4 mg / mL solution was prepared. To this solution was added 1 mL of the technetium-99m tricarbonyl compound solution prepared above and heated at 100 ° C. for 15 minutes to synthesize “ ^m Tc (CO) PNP5. The resulting ⁹⁹ ” ¹ Tc (CO) PNP5 The radioactivity concentration of

It was 243.5 MBq / mL.

[0082] The obtained technetium-99m tricarbonyl compound solution and ^{99 m} Tc (CO) PNP5 were subjected to TLC analysis under the same conditions as in Example 1, and the technetium-99m tricarbonyl compound was bis (dimethoxy). It was confirmed that a complex was formed with propylphosphinoethyl) ethoxyethylamine. In addition, from the results of TLC analysis, the value of the area% of the peak in ^m Tc (CO) PNP5 was obtained and defined as radiochemical purity. The radiochemical purity of the obtained ^{99 m} Tc (CO) PNP5 was 90.1 The pH value of the solution was 6.56.

[0083] [Example 3, Comparative Examples 3 to 6]

 Rat body distribution

[0084] Rats (SD system, female, 9 weeks old) were administered intraperitoneally with ketamine and xylazine at 80 mg / kg and 19 mg / kg of the body weight of the rats, respectively, and anesthetized. Introduced. 45 minutes after the introduction of anesthesia, 0.1 mL of ^m Tc (CO) PNP5 (activity concentration during use: 217.2MBq / mL) was administered from the tail vein of the rat. 2 and 60 minutes after administration, the rat abdominal aorta Blood was collected and euthanized, and the organs were removed, and the weight and radioactivity of each organ were measured after removal, using a single channel analyzer (Applied Koken Kogyo Co., Ltd., model: 701_1C). Using the measured radioactivity, the accumulation rate (% 10) of each organ was calculated according to the following formula (I), and the accumulation rate value obtained for each organ was used to calculate the accumulation rate of the heart / lung. Ratio and heart / liver ratio were calculated (Example 3) Measurements were repeated four times.

[0085] [Equation 1] ^ ^ _t , Radioactivity of each organ (Time correction value) Zcpm Background / cpm, Concentration rate of each organ (% ID / _g ) = (I) Total radioactivity of each organ (Time correction value) X (Weight of each organ Zg)

[0086] Further, as a comparison, at the same conditions, ^"m TcN- PNP5 (when using concentration 287.1MBq / mL), MIBI (Daiichirajioaisotopukenkyujo Ltd., Lot No. 214, test time 300MBq / mL ) (Concentration at use: 385.2 MBq / mL), tetrofosmin (manufactured by Mediphysix of Japan, lot number TMV_C2085, 592MBq / mL at test) (concentration at use 851.3MBq / mL) and Thallium chloride 201 injection ( (Product name, manufactured by Nippon Physics Co., Ltd., lot number 2104, 74MBq / mL at the time of test) (concentration 76MBq / mL at the time of use) was administered from the rat tail vein, and the accumulation rate (% ID / g) of each organ was determined. (Comparative Examples 3, 4, 5, and 6 respectively) The dosage of each formulation was 0.1 mL for ^99m TcN_PNP5, 0.05 mL for MIBI and Thallium Chloride-201 Injection, and 0.025 mL for Tetrofosmin. The measurement was repeated 5 times for each preparation.

[0087] The results are shown in Table 2. " ^m Tc (CO) PNP5 myocardial accumulation rate (% ID / g) (Example 3) is 2 minutes

 Three

Both the score and the 60-minute score were equal to or higher than those of other technetium preparations (Comparative Examples 3 to 5). From this result, “ ^m Tc (CO) PNP5 is highly concentrated in the myocardium, like other technetium preparations.

 Three

It was confirmed to show a product. " ^m Tc (CO) PNP5 accumulation rate heart / lung ratio and heart

 Three

The value of the viscera / liver ratio was the highest, especially at 60 minutes, compared with other myocardial blood flow products (Comparative Examples 3 to 6). From this result, ^99m Tc (C〇) PNP5 is

 Three

 It was shown that the clearance was early.

[0088] [Table 2]

^ »Myocardial accumulation rate of Tc (CO) sPNP5 and other myocardial perfusion products, heart Z lung ratio and heart / liver ratio of accumulation rate

[0089] [Example 4, Comparative Examples 7 to 10] Measurement of FPEF using isolated perfused rat heart

Anesthesia was introduced into rats (SD system, male, 13-15 weeks old) by intraperitoneally administering 0.5 mL heparin and then intraperitoneally 2 mL / kg thiopental. After that, the chest was opened and the heart was removed and attached to a self-made perfusion device (see Fig. 1).

Separately, the blood of a rat different from the above was collected, and 5 mL of heparin was added to 10 mL of blood to obtain blood for preparing a perfusate. In addition, the hematocrit value is increased by mixing the blood for perfusate preparation with 5 mmol / L 2_ [4_ (2-hydroxyschetil) -1-piperajuryl] ethanesulfonic acid buffer (hereinafter referred to as HEPES buffer). A solution adjusted to 20% was prepared and used as blood for perfusion. In addition, to the above blood for perfusion, " ^m Tc (CO) PNP5, ^m In_DTPA- HSA and thallium chloride-2

 Three

01, the radioactivity concentration each 110~120 MBq / mL, 18~19 MBq / mL, the mixed liquid so that 110 to 120 MBq / mL was prepared and the ^"m Tc (CO) PNP5 dosing solution .

 Three

 As shown in FIG. 1, the perfusion apparatus is configured to supply perfusate to the aorta of the perfusion heart 9 and to sample coronary circulation blood of the perfusion heart 9 from the pulmonary artery. More specifically, the perfusate is supplied from an oxygen tank (not shown) via a conduit 1 through a conduit 1 from a perfusate container 13 through a pump 3 to a perfusion heart 9 via a delivery line 2. To be supplied. The liquid feed line 2 is provided with a filter 4 and an air trap 5 between the pump 3 and the perfusion heart 9 so as to remove foreign substances and air in the perfusion liquid. In addition, a perfusion pressure measuring device 7 is connected to the liquid supply line 2 between the air trap 5 and the perfusion heart 9 so that the perfusion pressure during the experiment can be monitored. In addition, the liquid feeding line 2 is provided with an administration liquid injection port 8 between the perfusion pressure measuring device 7 and the perfusion heart 9, from which the administration liquid can be injected into the liquid feeding line 2. In addition, a pacing device 6 for the heart is connected to the perfusion heart 9 for the purpose of keeping the heart rate constant. Then, by connecting the catheter 10 to the pulmonary artery of the perfused heart 9, the force S for sampling the coronary blood into the Sampnore vessel 11 can be obtained. In order to prevent the backflow of the perfusate, a hole was made in the apex of the perfused heart 9 with a needle (21 gauge), and a waste reservoir 12 was placed below the heart.

[0091] The perfusate was perfused with a 5 mmol / L HEPES buffer at a flow rate of 2 mL / min, and fragments of other organs (lungs, etc.) attached to the heart were removed. Thereafter, the flow rate was set to 4 mL / min, and a catheter 10 for collecting coronary blood was inserted into the pulmonary artery to remove blood. Then the pulmonary vein After ligating and replacing the perfusate with the blood for perfusion, the flow rate was set to 1 mL / min. Thereafter, the flow rate of the perfusion apparatus was adjusted so that the coronary blood flow rate was about 1 mL / min / g. About 30 minutes after replacing the perfusate with the blood for perfusion, ^{99 m} Tc (CO) PNP5 administration solution 0.1 m

 Three

L was administered directly from the administration liquid injection port 8 to the liquid delivery line 2, and about 10 to 50 seconds after administration, coronary circulation blood was collected drop by drop in the Sampnore container 11. Thereafter, coronary blood was collected every 5 seconds until 1 minute, every 10 seconds from 1 minute to 2 minutes, and every 15 seconds from 3 minutes to 5 minutes. The collected coronary blood was simultaneously measured for radioactivity of indium 111, thallium 201 and technetium 99m using a gamma ray spectrometer (EG & G ORTEC, model: GMX-10180-P). Using the following formulas (II) and (III), " ^m Tc (CO) PNP5

3 and the extraction rate E (t) of thallium-201 were determined. ^99m Tc (C〇) PNP5 and thallium—

 Three

For each of 201, the highest level, E (t), was obtained before the time at which h (t) of ^m In-DTPA-HSA reached its peak, and was designated as FPEF (Example 4 and Comparative Example 10). The measurement was repeated 6 times. [Equation 2] ft (r) = ^ (II)

 ? 0

C {t): Measured value of sample radioactivity at time point t q ₀ : Measured value of radioactivity in 0.1 mL of administration solution h _HSA (t): Α () in min-DTPA-HSA

E {t): Extraction rate at time point t [0093] Also, instead of Tc (CO) PNP5, TcN_PNP5 (concentration in use: 409. lMBq / mL), MIBI

 Three

(Prepared and prepared using a lyophilization kit manufactured by Daiichi Radioisotope Laboratories (Lot No. 304): 1160Bq / mL) (" ^m TcO—elution concentration: 1242.6MBq / mL, use concentration 955.4MBq /

 Four

mL), Tetrofosmin (manufactured by Mediphysix of Japan, lot number TMV_C4253, 592MBq / mL at the time of test) (concentration 733.9MBq / mL at the time of use), " ^m Tc (CO) PNP5 administration solution (actual

 Three

An administration solution was prepared in the same manner as in Example 4), and a ^{99 m} TcN_PNP5 administration solution (Comparative Example 7), a MIBI administration solution (Comparative Example 8) and a tetrofosmin administration solution (Comparative Example 9) were used. The radioactivity concentration of the radioactive technetium compound in each administration solution was 110 to 120 MBq / mL for ⁹⁹ " ¹ TcN_PNP5 administration solution and MIBI administration solution, and 89 to 97 MBq / mL for tetrofosmin administration solution. Experiments were carried out in the same manner as in Example 4 using 0.1 mL of each administered solution, and the radioactivity of the coronary blood was measured to determine FPEF (Comparative Examples 7 to 9). The measurement was repeated 4 times for ^m TcN -PNP5 administration solution and 5 times for other administration solutions.

The results are shown in Table 3. " ^m Tc (CO) PNP5 FPEF is" ^m TcN_PNP5 and Tetrofosmi

 Three

 (P> 0.05), equivalent to or better than MIBI.

The above results indicate that “ ^m Tc (CO) PNP5 has a high FPEF similar to MIBI.

 Three

 It was.

 [0095] [Table 3]

FPEF measurement results for 99 ^m Tc (CO) ₃ PNP5 and other myocardial perfusion products

 Industrial applicability

The technetium 99m tricarbonyl complex according to the present invention and the kit according to the present invention can be used as diagnostic imaging agents for various diseases, and in particular, have a high heart / liver ratio and heart / lung ratio in SPECT images. Since FPEF is high, it can be suitably used as a tumor diagnostic agent and a cardiac muscle blood flow diagnostic agent. Brief Description of Drawings

 FIG. 1 is a diagram showing an apparatus for measuring an initial circulation extraction rate.

 Explanation of symbols

[0098] 1 conduit

 2 Liquid feed line

 3 Pump

 4 Huino Letter

 5 Air trap

 6 Heart pacing device

 7 Perfusion pressure measuring device

 8 Injection port

 9 Perfused heart

 10 Power Tetenor

 11 Sample container

 12 Waste liquid reservoir

 13 Perfusate container

Claims

Claims Bisphosphinoamine compound is coordinated to technetium-99m tricarbonyl compound, the following formula (1):

(In the formula (1), 99mTc (C〇) is technetium-99m tricarbonyl, L is bisphosphine.

 Three

A technetium-99m tricarbonyl complex represented by a finoamine compound. The bisphosphinoamine compound L is represented by the following formula (2):

[Chemical 2]

PCH ₂ CH ₂ NCH ₂ CH ₂ P

 Ri, Ri '"

(In Formula (2),

R ¹ 'R ¹ ''and R ¹ ''' may be the same or different, and each is an alkyl group having 1 to 4 carbon atoms, a phenyl group, the following formula (3):

[Chemical 3]

• (CH ₂ ) iO (CH ₂ ) i'CH ₃ (3)

(In formula (3), 1 is an integer of 0≤1≤4, is an integer of 0≤1'≤3) or the following formula (4):

[Chemical 4] ■

(In Equation (4), m is 0≤m≤4, m 'is 0≤m'≤4, m', is an integer of 0≤m ', ≤3) and R ² represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted alkyl group having 1 to 4 carbon atoms, an aryl group, a substituted aryl group, an amino group, a group represented by the above formula (3), or the formula (4 2. The technetium-99m tricarbonyl complex according to claim 1, which is a group represented by

 [3] The bisphosphinoamine compound L is

 Bis (diphenylphosphinoethyl) amine,

 Bis (diphenylphosphinochinole) methylamine,

 Bis (diphenylphosphinoetinole) ethylamine,

 Bis (diphenylphosphinochinole) propylamine,

 Bis (diphenylphosphinoetinole) methoxyethylamine,

 Bis (diphenylphosphinochinole) butyramine,

 Bis (diphenylphosphinoetinole) acetonylamine,

 Bis (dimethoxyphosphinoethyl) amine,

 Bis (dimethoxyphosphinoethyl) methylolamine,

 Bis (dimethoxyphosphinoethyl) ethylamine,

 Bis (dimethoxyphosphinoethyl) propylamine,

 Bis (dimethoxymethylphosphinoethyl) amine,

 Bis (dimethoxymethylphosphinoethyl) methylamine,

 Bis (dimethoxymethylphosphinoethyl) ethylamine,

 Bis (dimethoxymethylphosphinoethyl) propylamine,

 Bis (dimethoxyethylphosphinoethyl) amine,

 Bis (dimethoxyethylphosphinoethyl) methylamine,

Bis (dimethoxyethylphosphinoethyl) ethylamine, Bis (dimethoxyethylphosphinoetinole) propylamine,

 Bis (dimethoxypropylphosphinoethyl) ethylamine,

 Bis (dimethoxypropylphosphinoethyl) propylamine,

 Bis (dimethoxypropylphosphinoethyl) methoxyethylamine,

 Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine,

 Bis (diethoxypropylphosphinoethyl) ethoxyethylamine,

 Bis (diethoxyethylenophosphosinoetinole) ethenoreamine,

 Bis (diethoxyethylphosphinoethyl) propylamine,

 Bis (diethoxyethylphosphinoethyl) methoxyethylamine,

 Bis (dimethylphosphinoethyl) methylamine,

 3. The technetium-99m tricarbonyl complex according to claim 1, which is selected from the group consisting of bis (dipropoxymethylphosphinoethyl) ethoxyethylamine.

 [4] The bisphosphinoamine compound L is

 Bis (dimethoxypropylphosphinoethyl) methoxyethylamine,

 Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine,

 The technetium 99m tricarbonyl complex according to claim 3, selected from the group consisting of bis (diethoxypropylphosphinoethyl) ethoxyethylamine.

 [5] Bisphosphinoamine compound coordinated to technetium-99m tricarbonyl compound, the following formula (1):

 [Chemical 5]

〖"MTc (CO) 3 (L)] (1)

(In the formula (1), 99mTc (C〇) is technetium-99m tricarbonyl, L is bisphosphine.

 Three

 A radioactive diagnostic imaging agent comprising a technetium 99m tricarbonyl complex represented by the formula:

[6] The bisphosphinoamine compound L is represented by the following formula (2):

[Chemical 6]

(In the formula (2), R ¹ R ¹ 'R ¹ ''and R ¹ ''' may be the same or different, and each represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, Following formula (3):

[Chemical 7]

• (CH ₂ ) iO (CH ₂ ) i'CH ₃ (3)

(In formula (3), 1 is an integer of 0≤1≤4, is an integer of 0≤1'≤3) or the following formula (4):

[Chemical 8]

(In formula (4), m is 0≤m≤4, m 'is 0≤m'≤4, m', is an integer of 0≤m ', ≤3) and R ² represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted alkyl group having 1 to 4 carbon atoms, an aryl group, a substituted aryl group, an amino group, a group represented by the above formula (3), or the formula (4 6. The radiodiagnostic agent according to claim 5, which comprises a technetium 99m tricarbonyl complex represented by 1).

The bisphosphinoamine compound L is

Bis (diphenylphosphinoetinole) amine,

Bis (diphenylphosphinochinole) methylamine,

Bis (diphenylphosphinoetinole) ethylamine, Bis (diphenylphosphinochinole) propylamine,

Bis (diphenylphosphinochinole) methoxyethylamine,

Bis (diphenylphosphinochinole) butyramine,

Bis (diphenylphosphinoethyl) acetonylamine,

Bis (dimethoxyphosphinoethyl) amine,

Bis (dimethoxyphosphinoethyl) methylamine,

Bis (dimethoxyphosphinoethyl) ethylamine,

Bis (dimethoxyphosphinoethyl) propylamine,

Bis (dimethoxymethylphosphinoethyl) amine,

Bis (dimethoxymethylphosphinoethyl) methylamine,

Bis (dimethoxymethylphosphinoethyl) ethylamine,

Bis (dimethoxymethylphosphinoethyl) propylamine,

Bis (dimethoxyethylphosphinoethyl) amine,

Bis (dimethoxyethylphosphinoethyl) methylolamine,

Bis (dimethoxyethylphosphinoetinole) ethylamine,

Bis (dimethoxyethylphosphinoetinole) propylamine,

Bis (dimethoxypropylphosphinoethyl) ethylamine,

Bis (dimethoxypropylphosphinoethyl) propylamine,

Bis (dimethoxypropylphosphinoethyl) methoxyethylamine,

Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine,

Bis (diethoxypropinorephosphinoetinore) ethoxyethoxyreamine,

Bis (diethoxyethinorephosphinoetinole) ethenoreamine,

Bis (diethoxyethylphosphinoethyl) propylamine,

Bis (diethoxyethylphosphinoethyl) methoxyethylamine,

Bis (dimethylphosphinoethyl) methylamine,

The radiodiagnostic agent according to claim 5 or 6, comprising a technetium-99m tricarbonyl complex selected from the group consisting of bis (dipropoxymethylphosphinoethyl) ethoxyethylamine. [8] The bisphosphinoamine compound L is

 Bis (dimethoxypropylphosphinoethyl) methoxyethylamine,

 Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine,

 The radioactive diagnostic imaging agent according to claim 7, comprising a technetium-99m tricarbonyl complex selected from the group consisting of bis (diethoxypropylphosphinoethyl) ethoxyethylamine.

 [9] A kit for preparing a diagnostic imaging agent comprising a first container containing a carbon monoxide source, a reducing agent and a base, and a second container containing a bisphosphinoamine compound.

 [10] The radioactive diagnostic imaging agent preparation kit according to claim 9, wherein the first container further contains a stabilizer.

 [11] The kit for preparing a radioactive diagnostic imaging agent according to claim 9 or 10, wherein the base is an inorganic salt.

[12] The base according to claim 11, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium hydroxide and magnesium hydroxide. A kit for preparing a diagnostic imaging agent for radioactive imaging.

 [13] The reducing agent is a group consisting of a borohydride anion, and a substituted borohydride anion in which up to three of the hydrogen atoms constituting the anion are substituted with an inert substituent. The kit for preparing a diagnostic imaging agent for radiodiagnostics according to any one of claims 9 and 12, which is selected from the above.

 [14] The borohydride anion force is derived from a salt selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, and zinc borohydride. A kit for preparing a diagnostic imaging agent for radioactive imaging.

 [15] The kit for preparing a diagnostic radiodiagnostic agent according to any one of [9] to [14], wherein the molar ratio of the base to the reducing agent is between 0.1 and 2.

 [16] Bisphosphinoamine compound power Formula (2):

[Chemical 7]

(In the formula (2), R ¹ R ¹ 'R ¹ ''and R ¹ ''' may be the same or different, and each has an alkyl group having 1 to 4 carbon atoms, a phenyl group, Following formula (3):

[Chemical 10]

• (CH ₂ ) iO (CH ₂ ) i'CH ₃ (3)

(In formula (3), 1 is an integer of 0≤1≤4, is an integer of 0≤1'≤3) or the following formula (4):

[Chemical 11]

(In formula (4), m is 0≤m≤4, m 'is 0≤m'≤4, m', is an integer of 0≤m ', ≤3) and R ² represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a substituted alkyl group having 1 to 4 carbon atoms, an aryl group, a substituted aryl group, an amino group, a group represented by the above formula (3), or the formula (4 The kit for preparing a diagnostic radiodiagnostic agent according to any one of claims 9 to 15, wherein the kit is a compound represented by

The bisphosphinoamine compound is

Bis (diphenylphosphinoetinole) amine,

Bis (diphenylphosphinochinole) methylamine,

Bis (diphenylphosphinoetinole) ethylamine, Bis (diphenylphosphinochinole) propylamine,

Bis (diphenylphosphinoetinole) methoxyethylamine,

Bis (diphenylphosphinochinole) butyramine,

Bis (diphenylphosphinoethyl) acetonylamine,

Bis (dimethoxyphosphinoethyl) amine,

Bis (dimethoxyphosphinoethyl) methylamine,

Bis (dimethoxyphosphinoethyl) ethylamine,

Bis (dimethoxyphosphinoethyl) propylamine,

Bis (dimethoxymethylphosphinoethyl) amine,

Bis (dimethoxymethylphosphinoethyl) methylamine,

Bis (dimethoxymethylphosphinoethyl) ethylamine,

Bis (dimethoxymethylphosphinoethyl) propylamine,

Bis (dimethoxyethylphosphinoethyl) amine,

Bis (dimethoxyethylphosphinoethyl) methylolamine,

Bis (dimethoxyethylphosphinoetinole) ethylamine,

Bis (dimethoxyethylphosphinoetinole) propylamine,

Bis (dimethoxypropylphosphinoethyl) ethylamine,

Bis (dimethoxypropylphosphinoethyl) propylamine,

Bis (dimethoxypropylphosphinoethyl) methoxyethylamine,

Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine,

Bis (diethoxypropinorephosphinoetinore) ethoxyethoxyreamine,

Bis (diethoxyethinorephosphinoetinole) ethenoreamine,

Bis (diethoxyethylphosphinoethyl) propylamine,

Bis (diethoxyethylphosphinoethyl) methoxyethylamine,

Bis (dimethylphosphinoethyl) methylamine,

The kit for preparing a diagnostic imaging agent according to claim 16, wherein the kit is selected from the group consisting of bis (dipropoxymethylphosphinoethyl) ethoxyethylamine.

[18] A bisphosphinoamine compound is

 Bis (dimethoxypropylphosphinoethyl) methoxyethylamine,

 Bis (dimethoxypropylphosphinoethyl) ethoxyethylamine,

 The kit for preparing a diagnostic imaging agent according to claim 17, wherein the kit is selected from the group consisting of bis (diethoxypropylphosphinoethyl) ethoxyethylamine.

 [19] The diagnostic imaging agent preparation kit according to any one of [9] to [18], wherein the contents of the container are freeze-dried.