JPH08245425A - Diagnostic for low hypoxia or mitochondria function disorder - Google Patents

Abstract

PURPOSE: To obtain the subject diagnostic having containing transfer to a target tissue, affinity for reduction reaction in the tissue, stability in a non-target tissue and rapid disappearance from the nontarget tissue, containing a radioactive dithiosemicarbazone copper complex, etc. CONSTITUTION: This diagnostic contains (A) a radioactive dithiosemicarbazone copper complex of formula I (R1 to R4 are each H, an alkyl or an alkoxy; Cu is radio isotope Cu-62) or (B) a radioactive diaminediol Schiff base copper complex of formula II (R5 to R7 are as shown for R1 to R4 ) or formula III (R8 is H or an alkyl). Preferably the component A is Cu-62-diacetyl-bis(N4- methylthiosemicarbazone) complex or Cu-62-pyruvaldehyde-bis(N4- dimethylthiosemicarbazone) complex and the component B is Cu-62- disalicylaldehyde-2,2-dimethyl-1,3-propanediamino complex.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a diagnostic agent for hypoxia or mitochondrial dysfunction, which comprises a copper complex of a radioactive dithiosemicarbazone derivative or a copper complex of a radioactive diaminediol Schiff base derivative, and particularly to the brain and myocardium. , A pharmaceutical useful for detecting hypoxic sites and mitochondrial dysfunction sites in tumor tissues and the like.

[0002]

2. Description of the Related Art The existence of hypoxic sites or mitochondrial dysfunction sites has been pointed out in ischemic diseases in the brain and myocardium or in certain tumors. It is considered that such sites are caused by hypoxia due to high energy requirement and decreased blood flow, or an electron excess state resulting from mitochondrial dysfunction. The detection of such a hypoxic site or mitochondrial dysfunction site can be carried out by a certain method in starting treatment for a tissue in anoxia or mitochondrial dysfunction while retaining metabolic function in ischemic diseases in the brain and myocardium. It is important to determine the use of radiosensitizers to improve the radiosensitivity of hypoxic tumors. In this field, development of many hypoxia-detecting radiopharmaceuticals having a nitroimidazole group as a skeleton has hitherto been attempted. However, conventional nitroimidazole-based radiopharmaceuticals are basically based on the viewpoint of preparing a compound developed as a radiosensitizer as a label. The greatest problem of the radiosensitizer is that it has neurotoxicity, and in order to reduce this, the radiopharmaceutical has been developed in the direction of lowering lipophilicity and cell transferability. Since the dose is very small when considered as a radiopharmaceutical, it is possible to place importance on the property of reaching the cells early, accumulating in the hypoxic site, and rapidly disappearing from the normal site. As in the past, as long as the design of a radiopharmaceutical having low membrane permeability is directly introduced into a hypoxia-detecting radiopharmaceutical, the hypoxia-detecting radiopharmaceutical is difficult to migrate into target cells and also disappears from normal cells slowly. Also, improvement in selectivity between target cells and normal cells cannot be expected.

A large number of F-18-labeled compounds have been investigated as those having good cell transferability and transferability from normal cells, but their production requires an in-hospital cyclotron, which poses a problem in versatility. Thus, the hypoxia-detecting radiopharmaceuticals that have been conventionally studied have problems in terms of selectivity and versatility, and have not been put into practical use. Further, no radiopharmaceutical for detecting mitochondrial dysfunction was known. However, in recent years, a Zn-62 / Cu-62 generator has been developed, and Cu-62, which is a positron nuclide, can be easily obtained in the form of a glycine complex, and a positron nuclide labeled substance can be prepared without the need for a hospital cyclotron. You can get it.

[0004]

SUMMARY OF THE INVENTION In view of the above situation, the present invention provides a good target tissue transferability as a hypoxia or mitochondrial dysfunction detector, affinity for reduction reaction in the target tissue, and non-target. It is an object of the present invention to provide a diagnostic agent for hypoxia or mitochondrial dysfunction, which has high stability in tissues and rapid elimination therefrom.

[0005]

Means for Solving the Problems The present inventors have found that an organic compound having a very low redox potential is basically necessary for detecting a hypoxic site or a mitochondrial dysfunction site.
As a result of earnest research from the viewpoint that it is necessary to accept and retain electrons only in cells in an electron-rich state, as a result, copper complexes of dithiosemicarbazone derivatives or diaminediol Schiff-based derivatives were found to be found in the brain and myocardium. , Etc., but it has a very low redox potential, so that it rapidly migrates to the outside without being reduced in normal mitochondria. Anoxic perfusate and oxygen-containing perfusion in rat perfused myocardial model. It was found that there is a significant difference in the retention property in the myocardium with the liquid, and the present invention has been completed.
That is, the present invention is a radioactive dithiosemicarbazone copper complex represented by the following general formula 7 (hereinafter abbreviated as Cu-62-DTS) or a radioactive diamine diol schiff base copper complex represented by the general formula 8 or 9 (Hereinafter Cu-
62-DDS) for the diagnosis of hypoxia or mitochondrial dysfunction.

[Chemical 7] (However, R1, R2, R3 and R4 are each independently
It represents a hydrogen atom, an alkyl group or an alkoxy group. Cu
Represents the radioactive isotope Cu-62. )

Embedded image (However, R5, R6, and R7 each independently represent a hydrogen atom, an alkyl group, or an alkoxy group. Cu represents the radioactive isotope Cu-62.)

[Chemical 9] (However, R8 represents a hydrogen atom or an alkyl group. Cu represents the radioactive isotope Cu-62.)

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents R1, R2, R3
The alkyl group and the alkoxy group in the definition of R4 each have usually 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms. Specifically, glyoxal-bis (N4-methylthiosemicarbazone) copper complex (hereinafter, Cu-62-GT
Abbreviated as SM), glyoxal-bis (N4-dimethylthiosemicarbazone) copper complex (hereinafter, Cu-62-GT)
SM2), ethyl glyoxal-bis (N4-
Methylthiosemicarbazone) copper complex (hereinafter Cu-62
-Abbreviated as ETSM), ethylglyoxal-bis (N
4-Ethylthiosemicarbazone) copper complex (hereinafter Cu-
62-ETSE), pyruvaldehyde-bis (N
4-methylthiosemicarbazone) copper complex (hereinafter Cu-
62-PTSM), pyruvaldehyde-bis (N
4-dimethylthiosemicarbazone) copper complex (hereinafter, Cu
-62-PTSM2), pyruvaldehyde-bis (N4-ethylthiosemicarbazone) copper complex (hereinafter, C
u-62-PTSE), diacetyl-bis (N4
-Methylthiosemicarbazone) copper complex (hereinafter Cu-6
2-ATSM), diacetyl-bis (N4-dimethylthiosemicarbazone) copper complex (hereinafter Cu-62-
ATSM2), diacetyl-bis (N4-ethylthiosemicarbazone) copper complex (hereinafter Cu-62-AT
(Abbreviated as SE) and the like are shown. Of these, a diacetyl-bis (N4-methylthiosemicarbazone) copper complex or a pyruvaldehyde-bis (N4-dimethylthiosemicarbazone) copper complex is a preferred embodiment.

The carbon number of the alkyl group and the alkoxy group in the definition of the substituents R5, R6 and R7 in the chemical formula 8 is usually 1 to 5, and preferably 1 to 3. In particular,
Disalicy aldehyde-1,3-propanediamine copper complex (hereinafter abbreviated as Cu-62-DSP), disalicylaldehyde-2,2-dimethyl-1,3-propanediamine copper complex (hereinafter, Cu-62-DSDP) Abbreviated)
4-methoxysalicylaldehyde-1,3-propanediamine copper complex (hereinafter abbreviated as Cu-62-DMSP),
Di-4-methoxysalicylaldehyde-2,2-dimethyl-1,3-propanediamine copper complex (hereinafter Cu-6
(Abbreviated as 2-DMSDP), and among them, disalicylic aldehyde-2,2-dimethyl-1,3-propanediamine copper complex is a preferred embodiment. The carbon number of the alkyl group in the definition of the substituent R8 in Chemical formula 9 is usually 1 to 5, preferably 1 to
It is 3. Specifically, diacetylacetone ethylenediamine copper complex (hereinafter abbreviated as Cu-62-DAED),
A diacetylacetone-1,2-propanediamine copper complex (hereinafter abbreviated as Cu-62-DAPD) and the like are shown.
Of these, diacetylacetone ethylenediamine copper complex is a preferred embodiment.

The copper complex of the dithiosemicarbazone derivative is synthesized as follows. For example, Petering et al.
(Cancer Res., 24 , 367-372, 1964), that is, a 1 molar aqueous solution of α-ketoaldehyde or a 50% ethanol solution is used over 30 to 40 minutes for thiosemicarbazide, N4-methylthiosemicarbazide, N4-. It is added dropwise to a 5% glacial acetic acid solution containing 2.2 mol of dimethylthiosemicarbazide or the like at 50 to 60 ° C. The reaction solution is stirred during the dropping. After the dropping is completed, the mixture is left at room temperature for several hours and then cooled to separate crystals. The crystals are dissolved in methanol and recrystallized for purification. The obtained dithiosemicarbazone derivative is Gre
Dimethyl sulfoxide (DMSO) by the method described in en et al. (Nucl. Med. Biol., 14 , 59-61, 1987).
As a solution, a copper complex is obtained by contacting with a solution of copper nitrate. In addition, Zn-62 / Cu-62 generator (Fu
jibayashi et al .: J. Nucl. Med., 30, 1838-1842, 19
89) and the Cu-62-glycine complex and dithiosemicarbazone derivative obtained by the method of Fujibayashi et al. (Fujibayashi et al .: Nucl. Med. Biol., 19 , 3).
9-44, 1992) By conducting a ligand exchange reaction, Cu
A -62-DTS derivative is obtained.

The ligand exchange reaction between Cu-62-glycine and pyruvaldehyde-bis (N4-methylthiosemicarbazone copper complex (hereinafter abbreviated as PTSM)) is specifically performed as follows: Zn-62 / Cu- The Cu-62-glycine complex was obtained as a glycine solution by elution using an aqueous solution for injection containing 200 mM glycine as the eluent with a 62 generator.
By mixing the glycine solution of the glycine complex with the ethanol or DMSO solution of PTSM at room temperature, the ligand exchange reaction is easily performed and the Cu-62-PTS is quantitatively analyzed.
M can be obtained. The obtained Cu-62-PTSM
Has a radiochemical purity of 95% or more. Copper complexes of diaminediol Schiff-based derivatives are described by Chen D. et al. (Ino
Chem., 26 , 1026-1030, 1987; Inorg. Chem. 28,
2647-2652, 1989) and conduct a ligand exchange reaction with Cu-62-glycine as described above to obtain a Cu-62-DDS derivative. In the case of Cu-ATSM, which is a non-radioactive Cu complex obtained in the same manner, the reduction state of Cu by mouse brain mitochondria was examined. In mitochondria treated with an electron transfer system inhibitor, rotenone, leading to hypoxia or an electron-excessive state similar to mitochondrial dysfunction, Cu reduction proceeds, and specific reduction of Cu-ATSM in the electron-excessive state occurs. Was shown. Such enhancement of reduction reaction is caused by other Cu-DTS.
It was similarly found in the derivative and the Cu-DDS derivative. This means that Cu-DTS derivatives and Cu-D
It is shown that the DS derivative is useful as a marker of tissue hypoxia or mitochondrial dysfunction. This behavior with respect to oxygen can be said to be the same with the labeled form of Cu-62 which is a radioisotope.

Further, in a study using a rat perfusion myocardial model, Cu-62-AT was observed in the presence of oxygen in the perfusate.
SM rapidly disappeared from the myocardium, and decreased to about 20% of the maximum value 15 minutes after administration. The perfusate of this perfused heart specimen was switched to anoxic, and after about 10 minutes, Cu-62
-When ATSM was administered, it showed high retention. Further, when Cu-62-ATSM was administered after returning the perfusate, a retention curve similar to that of the first administration was shown. That is, since the retention in the tissue changes depending on the oxygen concentration, the state of the oxygen concentration in the tissue can be known by measuring the concentration of Cu-62-ATSM in the tissue.

Each Cu-62-DTS derivative and Cu-
The biodistribution of the 62-DDS derivative shows a characteristic accumulation behavior depending on the difference in side chains. For example Cu-62-
PTSM has a relatively high retention in the brain as well as a relatively high retention, but it was expected that PTSM may have a higher retention in abnormal cases. In addition, Cu-62-ATSM, Cu-62
It was revealed that -PTSM2, Cu-62-ATSM2 and the like, once transferred to the brain, disappeared promptly and showed no retention in the normal animal brain. Similar tendency is C
u-62-ETSM, Cu-62-ETSE, Cu-6
2-PTSE, Cu-62-ATSE, Cu-62-D
SDP, Cu-62-DAED, etc. were also shown.
Thus, Cu-62-DTS derivative and Cu-62
The -DDS derivative has properties suitable for detection of hypoxia, in addition to the property of transfer to the brain and the property of being reduced only in the electron excess state described above. Furthermore, by easily obtaining the Cu-62-labeled substance which is a positron nuclide,
It became easier to detect a very small amount of transfer.

The Cu-62-DTS derivative or Cu-62-DDS derivative according to the present invention is usually prepared as a diagnostic agent as follows. For example, Cu-62 obtained by eluting Cu-62 with an aqueous solution for injection containing 0.2 M glycine from a Zn-62 / Cu-62 generator in 0.2 ml of DMSO solution containing 0.1 mg of DTS was obtained. It is obtained by aseptically adding 4 ml of a glycine aqueous solution of a Cu-62-glycine complex containing 5 to 20 mCi as a mixture and stirring several times. This corresponds to a single dose. The diagnostic agent of the present invention is useful for diagnosing hypoxia or mitochondrial dysfunction in brain, heart, tumor and other tissues, and specific diseases include cerebral infarction, ischemic heart disease, epilepsy, dementia, myocardial infarction, Examples include tumors.
Hereinafter, the present invention will be described more specifically with reference to Examples.

[0013]

【Example】

(Example 1) Effect of mitochondrial electron transfer inhibition on reduction of Cu-DTS derivative and Cu-DDS derivative Male ddY mouse brain was subjected to Potter-Elevehje.
It was homogenized with an m-type homogenizer at a concentration of 1.5 g / ml. The crude mitochondrial fraction was prepared by centrifuging at 1000 g for 5 minutes, further collecting the supernatant and centrifuging at 10,000 g for 10 minutes. To bring the obtained mitochondrial fraction into a state similar to that of hypoxia, an electron transfer system inhibitor rotenone was added to the mitochondrial fraction. By the rotenone drug treatment, an electron-rich state similar to the hypoxic state can be obtained in the mitochondrial electron transport system complex and its upstream site. The degree of reduction of the Cu-DTS derivative and the Cu-DDS derivative was quantified by an electron spin resonance device (ESR). Each derivative 0.2 mM DM
0.2 ml of SO solution was added to 1.8 ml of normal or rotenone-treated mitochondrial suspension and incubated at 37 ° C. for 15 minutes. Transfer 0.3 ml to ESR tube,
The ESR signal was measured under liquid nitrogen cooling. For ESR measurement, JOEL X-band spelltrometer JES-FE3
XG was used. Microwave output 5m
W, Modulation amplitude 6.3 Gauss,
The modulation frequency was 100 kHz, the microwave frequency was 9.25 GHz, and the magnetic field was 3300 ± 500 gauss. The quantification was performed by comparing the signal intensities. The results are shown in Table 1. In addition, Cu-ATSM and Cu-PTSM
The results for 2 are shown in FIG. In the case of Cu-ATSM, the reduction of Cu by normal mitochondria hardly occurs, but the reduction of Cu proceeded when treated with rotenone, indicating the existence of a specific reduction of Cu-ATSM in the electron excess state. . Such enhancement of reduction reaction
It was similarly found in other Cu-DTS derivatives and Cu-DDS derivatives.

Example 2 Effect of oxygen on retention of Cu-62-DTS derivative and Cu-62-DDS derivative in myocardium by perfusion myocardial model As a complex of Cu-62-DTS derivative obtained as described above. Cu-62-ATSM, Cu-62-PTSM
2 and Cu-62-PTSM, Cu-62-DED was used as a complex of the Cu-62-DDS derivative, and the experiment was conducted as follows. The rat perfused myocardial model was created according to the method of Langerdorf et al. Wistar male rats were treated with heparin 500i. u. Was intraperitoneally administered, and the heart was excised. The heart was washed with cold perfusion solution, a stainless cannula was inserted into the aorta, and perfusion was immediately started. The perfusate is Krebslinger bicarbonate solution at 37 ° C.
The perfusion rate was 6 ml / min.
The perfusate used was appropriately saturated with 95% oxygen + 5% carbon dioxide or 95% nitrogen + 5% carbon dioxide in advance. The Cu-62-DTS derivative solution was appropriately diluted with a perfusion solution and bolus-administered to a perfused heart model using a hexagonal valve injector. B shielded from the heart by lead
A GO detector was installed, and the radioactivity retained in the myocardium was continuously measured to correct the half-life, and the maximum value was set to 100 to obtain a retention curve. The experimental results in the presence of oxygen (control), in the absence of oxygen (anoxic), and in the presence of reoxygen (reoxygen supply) are shown in FIGS. 2 and 3 for Cu-62-ATSM and Cu-62-PTSM2. A comparison of accumulated amounts 10 minutes after administration is shown in Table 2 and FIG. In the presence of oxygen (control), Cu-62-ATSM rapidly disappeared from the myocardium and decreased to about 20% of the maximum value 15 minutes after administration. Switch the perfusate of this perfused heart sample to anoxic state,
When Cu-62-ATSM was administered again after 0 minutes, high retention was exhibited. Furthermore, when Cu-62-ATSM was administered after the perfusate was restored (reoxygenation), the same retention curve as that of the first administration was shown. Cu shown in FIG.
-62-PTSM2 has a disappearance rate of Cu-62-ATSM
Although it was slower than the above, a similar tendency was shown after about 15 minutes. Table 2 and FIG. 4 compare the accumulated amounts in the presence of oxygen (control), in the absence of oxygen (anoxia), and in the presence of reoxygenation (reoxygen supply) at 15 minutes after administration. In all cases, rapid disappearance from the tissue in the presence of oxygen, and high accumulation and retention in hypoxia were apparent. As a result, Cu-62-DTS derivative and Cu-62-DD
The S-derivative showed a clear difference in the retention property depending on the presence or absence of oxygen in the tissue, indicating that the S-derivative was selectively accumulated in the hypoxic site.

(Example 3) Distribution of Cu-DTS derivative and Cu-62-DDS derivative in the body Cu-62-DTS derivative or C was added to male ddY mouse.
The u-62-DDS derivative was administered through the tail vein, and sacrificed and dissected over time. After removing blood and each organ and weighing them,
The radioactivity contained in each was measured with a well-type scintillation counter, and the accumulated value in each organ was calculated.
The results are shown in Table 3 to Table 12. Each Cu-62-DTS
The derivative and the Cu-62-DDS derivative each showed characteristic accumulation behavior depending on the difference in side chains. For example, C
u-62-PTSM showed high transferability to the brain and retention. On the other hand, Cu-62-ATSM,
It was revealed that Cu-62-PTSM2, Cu-62-ATSM2, etc., disappeared promptly after once transferred to the brain, and that these Cu-62-DTS derivatives do not exhibit retention in the normal animal brain. It was Other Cu-
The same applies to the 62-DTS derivative and the Cu-62-DDS derivative. This property was considered to be suitable for detection of hypoxia, together with the property of undergoing reduction only in the electron excess state described above.

[0016]

[Table 1] Effect of mitochondrial electron transfer inhibition treatment on reduction of Cu-DTS derivative and Cu-DDS derivative ────────────────────────── ────────── Reduced copper (%) ───────────────────────── Copper complex control After rotenone treatment ──── ─────────────────────────────── Cu-PTSM 48.8 ± 3.7 77.8 ± 2.9 Cu-PTSM2 4.9 ± 2.1 15.3 ± 4.3 ─ ────────────────────────────────── Cu-ATSM 3.4 ± 2.7 14.7 ± 3.4 Cu-ATSE 10.4 ± 4.7 24.5 ± 5.6 Cu-ATSM2 4.3 ± 2.9 15.1 ± 5.4 ─────────────────────────────────── Cu-ETSE 56.5 ± 7.3 76.6 ± 4.6 ─────────────────────────────────── Cu-DAED 19.1 ± 2.7 30.8 ± 1.7 ───────────────────────────────────

[0017]

[Table 2] Effect of oxygen on retention of Cu-62-DTS derivative and Cu-62-DDS derivative in myocardium by perfusion myocardial model (10 minutes after administration) ────────────── ───────────────────── Myocardial retention (%) ───────────────────── ────── Cu-62- complex control Anoxic reoxygen supply ────────────────────────────────── ─ Cu-62-ATSM 23.77 ± 2.98 81.10 ± 3.41 22.88 ± 4.75 Cu-62-PTSM2 38.35 ± 7.51 85.23 ± 19.49 29.40 ± 7.86 Cu-62-PTSM 89.72 ± 4.01 98.88 ± 2.63 81.42 ± 14.03 Cu-DAED 55.65 ± 15.50 68.87 ± 19.12 43.37 ± 5.34 ──────────────────────────────────

[0018]

[Table 3] Distribution of Cu-62-PTSM in the body (n = 4) [Upper row:% ID / g (organization), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 5 minutes 30 minutes ─────────────────────────── Blood 4.01 2.73 1.48 ( O.27) (0.27) (0.18) Brain 8.23 7.15 7.42 (1.37) (O.56) (1.01) Heart 21.64 14.94 14.62 (7.25) (1.39) (2.69) Lung 26.21 22.26 17.54 (6.43) (2.77) (1.31) ) Liver 5.35 14.34 23.99 (2.44) (2.18) (3.40) Kidney 12.75 13.90 12.08 (3.54) (1.63) (0.79) ──────────────────────── ──── Brain / Blood 2.05 2.64 4.73 (0.29) (0.37) (0.40) Heart / Blood 5.36 5.53 8.42 (1.57) (0.99) (1.43) ──────────────── ───────────

[0019]

[Table 4] Distribution of Cu-62-ATSM in the body (n = 4) [Upper row:% ID / g (organization), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 5 minutes 30 minutes ─────────────────────────── Blood 2.94 1.42 2.13 ( O.51) (0.25) (0.29) Brain 6.01 2.37 2.81 (0.82) (O.30) (0.41) Heart 5.63 2.10 2.97 (1.19) (0.27) (0.44) Lung 36.00 34.92 13.12 (4.17) (8.11) (3.90) ) Liver 4.45 10.61 18.07 (0.47) (1.62) (3.33) Kidney 16.60 12.76 10.91 (1.37) (1.99) (1.19) ─────────────────────── ──── Brain / Blood 2.06 1.68 1.33 (0.22) (0.11) (0.15) Heart / Blood 1.91 1.49 1.41 (0.18) (0.17) (0.18) ──────────────── ───────────

[0020]

[Table 5] Distribution of Cu-62-PTSM2 in the body (n = 4) [Upper row:% ID / g (organization), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 5 minutes 30 minutes ─────────────────────────── Blood 1.99 1.50 1.42 ( O.35) (0.22) (0.37) Brain 5.16 3.35 1.58 (1.40) (O.48) (0.06) Heart 6.30 2.04 1.64 (1.56) (0.39) (0.20) Lung 26.15 17.19 11.45 (4.52) (3.36) (1.90) ) Liver 2.59 11.34 13.77 (0.50) (2.13) (2.90) Kidney 9.09 3.96 5.08 (1.31) (0.28) (0.68) ─────────────────────── ──── Brain / Blood 2.57 2.25 1.19 (0.41) (0.28) (0.36) Heart / Blood 3.14 1.36 1.25 (0.35) (0.22) (0.49) ──────────────── ───────────

[0021]

[Table 6] Distribution of Cu-62-ATSM2 in the body (n = 4) [Upper row:% ID / g (tissue), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 5 minutes 30 minutes ─────────────────────────── Blood 21.41 2.78 1.79 ( 7.15) (0.64) (0.38) Brain 1.82 1.54 0.50 (0.74) (O.39) (0.11) Heart 14.70 2.64 1.60 (7.87) (0.75) (0.27) Lung 85.75 12.23 7.37 (20.70) (5.48) (1.46) Liver 19.40 30.70 17.59 (6.41) (6.46) (1.35) Kidney 4.84 3.77 6.32 (1.36) (0.95) (1.06) ────────────────────────── --Brain / Blood 0.08 8.56 0.28 (0.01) (0.13) (0.06) Heart / Blood 0.65 0.95 0.28 (0.65) (0.95) (0.91) ────────────────── ─────────

[0022]

[Table 7] Cu-62-ETSM distribution in the body (n = 5) [Upper row:% ID / g (tissue), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 10 minutes 20 minutes ─────────────────────────── Blood 5.85 4.46 2.94 ( 0.78) (0.30) (0.31) Brain 9.63 9.79 8.50 (0.63) (O.69) (1.17) Heart 18.64 16.43 12.10 (2.00) (0.96) (2.06) Lung 27.24 28.95 23.76 (2.63) (2.79) (4.70) Liver 10.17 18.80 17.95 (1.98) (1.23) (1.84) Kidney 25.27 21.02 15.17 (1.91) (1.49) (1.73) ────────────────────────── ──

[0023]

[Table 8] Distribution of Cu-62-ETSE in the body (n = 5) [Upper row:% ID / g (tissue), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 10 minutes 20 minutes ─────────────────────────── Blood 5.90 3.92 3.21 ( 0.62) (0.41) (0.62) Brain 9.99 6.69 5.88 (0.73) (O.77) (0.65) Heart 16.13 8.43 6.96 (1.40) (1.51) (0.96) Lung 17.95 18.67 16.71 (1.50) (2.35) (0.69) Liver 10.92 21.37 19.87 (1.47) (2.40) (2.52) Kidney 21.34 15.76 12.35 (1.14) (1.60) (1.97) ────────────────────────── ──

[0024]

[Table 9] Cu-62-PTSE distribution in the body (n = 5) [Upper row:% ID / g (organization), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 10 minutes 20 minutes ─────────────────────────── Blood 4.89 3.89 2.56 ( 0.34) (0.48) (0.21) Brain 8.45 8.28 6.42 (0.77) (O.30) (O.73) Heart 13.24 11.61 8.48 (1.81) (1.58) (1.28) Lung 17.20 23.14 18.79 (1.80) (1.11) (3.36) ) Liver 8.78 18.82 16.97 (1.05) (2.63) (4.58) Kidney 19.80 17.43 13.23 (3.08) (1.93) (0.95) ─────────────────────── ────

[0025]

[Table 10] Distribution of Cu-62-ATSE in the body (n = 5) [Upper row:% ID / g (organization), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 10 minutes 20 minutes ─────────────────────────── Blood 4.51 2.78 1.73 ( 0.41) (0.49) (0.10) Brain 7.54 2.99 1.59 (0.64) (O.55) (0.18) Heart 7.32 3.42 2.20 (0.76) (0.64) (0.34) Lung 40.42 27.96 20.52 (3.33) (1.46) (2.04) Liver 8.08 16.93 13.46 (2.16) (1.05) (1.79) Kidney 20.24 12.62 7.84 (1.78) (2.07) (1.13) ───────────────────────── ──

[0026]

[Table 11] Distribution of Cu-62-DSDP in the body (n = 5) [Upper row:% ID / g (tissue), lower row: Mean ± standard deviation] ──────────────── ──────────── 1 minute 10 minutes 20 minutes ─────────────────────────── Blood 16.03 5.40 3.09 ( 2.12) (0.77) (0.53) Brain 1.50 0.69 0.53 (1.19) (0.11) (0.03) Heart 8.32 6.66 5.01 (1.37) (0.92) (0.72) Lung 17.49 21.49 16.49 (1.63) (2.56) (3.43) Liver 14.61 25.03 24.42 (1.29) (0.57) (2.90) Kidney 19.76 22.22 15.71 (1.49) (1.48) (2.84) ────────────────────────────

[0027]

[Table 12] Distribution of Cu-62-DAED in the body (n = 5) [Upper row:% ID / g (organization), lower row: Mean ± standard deviation] ───────────────── ──────────── 1 minute 10 minutes 20 minutes ─────────────────────────── Blood 16.03 4.76 3.42 ( 2.36) (0.60) (0.27) Brain 0.69 0.52 0.43 (0.11) (0.07) (0.06) Heart 7.36 6.13 4.99 (1.46) (0.46) (0.59) Lung 16.48 20.19 15.94 (2.44) (3.72) (2.25) Liver 14.78 25.55 22.48 (1.73) (3.27) (2.62) Kidney 19.64 20.13 15.36 (2.88) (2.04) (1.55) ────────────────────────────

[0028]

INDUSTRIAL APPLICABILITY The diagnostic agent for hypoxia and mitochondrial dysfunction containing the copper complex of radioactive dithiosemicarbazone derivative or the copper complex of radioactive diamine diol Schiff base derivative of the present invention is a hypoxia or mitochondrial dysfunction detector. As it has good target tissue transferability, affinity for reduction reaction at hypoxic sites, high stability in non-target tissues and rapid elimination from it, hypoxia of various organs such as brain and myocardium and tissues It is also extremely useful as a diagnostic agent for mitochondrial dysfunction.

[Brief description of drawings]

FIG. 1 shows the effect of mitochondrial electron transfer inhibition on the reduction of Cu-ATSM and Cu-PTSM2.

FIG. 2 shows the effect of oxygen on the retention of Cu-62-ATSM complex in the myocardium in a perfused myocardial model.

FIG. 3 Cu-62-PTSM2 by perfusion myocardial model.
It is a figure which shows the influence of oxygen with respect to the retention | restoration in a cardiac muscle of a complex.

FIG. 4 is a diagram showing the effect of oxygen on the accumulation of Cu-62-ATSM complex and Cu-62-PTSM2 in the myocardium in a perfused myocardial model.

Claims (7)

[Claims] 1. A hypoxia or mitochondrial dysfunction comprising a radioactive dithiosemicarbazone copper complex represented by the following general formula 1 or a radioactive diamine diol Schiff base copper complex represented by the general formula 2 or formula 3. Diagnostic agent. Embedded image (However, R1, R2, R3 and R4 are each independently
It represents a hydrogen atom, an alkyl group or an alkoxy group. Cu
Represents the radioactive isotope Cu-62. ) (However, R5, R6, and R7 each independently represent a hydrogen atom, an alkyl group, or an alkoxy group. Cu represents the radioactive isotope Cu-62.) (However, R8 represents a hydrogen atom or an alkyl group. C
u represents the radioactive isotope Cu-62. ) 2. A diagnostic agent for hypoxia or mitochondrial dysfunction, which comprises a radioactive dithiosemicarbazone copper complex represented by the following general formula 4. [Chemical 4] (However, R1, R2, R3 and R4 are each independently
It represents a hydrogen atom, an alkyl group or an alkoxy group. Cu
Represents the radioactive isotope Cu-62. ) 3. A diagnostic agent for hypoxia or mitochondrial dysfunction, which comprises a radioactive diaminediol Schiff-based copper complex represented by the following general formula 5. Embedded image (However, R5, R6, and R7 each independently represent a hydrogen atom, an alkyl group, or an alkoxy group. Cu represents the radioactive isotope Cu-62.) 4. A diagnostic agent for hypoxia or mitochondrial dysfunction, which comprises a radioactive diaminediol Schiff-based copper complex represented by the following general formula 6. [Chemical 6] (However, R8 represents a hydrogen atom or an alkyl group. C
u represents the radioactive isotope Cu-62. ) 5. The radioactive dithiosemicarbazone copper complex is C
u-62-Diacetyl-bis (N4-methylthiosemicarbazone) complex or Cu-62-pyruvaldehyde-
The diagnostic agent for hypoxia or mitochondrial dysfunction according to claim 1 or 2, which is a bis (N4-dimethylthiosemicarbazone) complex. 6. The radioactive diamine diol Schiff base copper complex is a Cu-62-disalicylic aldehyde-2,2-dimethyl-1,3-propanediamine complex.
Or the diagnostic agent for hypoxia or mitochondrial dysfunction according to 3. 7. The diagnostic agent for hypoxia or mitochondrial dysfunction according to claim 1 or 4, wherein the radioactive diaminediol Schiff-based copper complex is a diacetylacetone ethylenediamine complex.