JPWO2011096374A1 - Novel iodobenzyl-bleomycin compounds - Google Patents

Abstract

Novel iodobenzyl-bleomycin compounds are provided. In addition, a metal complex of an iodobenzyl-bleomycin compound and various metal atoms, for example, a metal complex capable of accumulating in malignant tumors, which has superior biological properties related to malignant tumor accumulation of iodobenzyl-Co-bleomycin compounds. provide. Furthermore, the present invention provides a method for synthesizing the iodobenzyl-bleomycin compound and a metal complex of the iodobenzyl-bleomycin compound and various metal atoms. According to a new iodobenzyl-bleomycin compound synthesized by adding iodobenzyl iodide synthesized using iodobenzyl alcohol and iodine as starting materials to the terminal amino group of bleomycin.

Description

  The present invention relates to novel iodobenzyl-bleomycin compounds. The present invention also relates to a metal complex of an iodobenzyl-bleomycin compound and various metal atoms, for example, a novel iodobenzyl-cobalt-bleomycin compound (hereinafter sometimes referred to as “iodobenzyl-Co-bleomycin compound”). Furthermore, it is related with the test | inspection agent of a malignant tumor etc. containing the said novel metal complex, the malignant tumor therapeutic agent, and the test | inspection method of a malignant tumor.

  This application claims the Japanese application and Japanese Patent Application No. 2010-024628 priority which are used here by reference.

Diagnostic imaging is a device that uses X-rays, ultrasound, electromagnetic waves (including electromagnetic waves emitted from radioisotopes), etc., and images and observes lesions throughout the body including the head, chest, and abdomen. An inspection to be performed. Examples of diagnostic agents for malignant tumors for SPECT (Single Photon Emission CT) include gallium citrate ( ⁶⁷ Ga) and thallium chloride ( ²⁰¹ Tl). Examples of diagnostic imaging agents for inflammatory lesions include gallium citrate ( ⁶⁷ Ga) and indium ( ¹¹¹ In) labeled leukocytes. Sodium iodide ( ¹³¹ I) is a radiopharmaceutical that treats thyroid cancer and its metastases, and Ibritumoma boutiuxetane- ⁹⁰ Y is used to treat low-grade non-Hodgkin lymphoma and mantle cell lymphoma. And radiopharmaceuticals that treat a limited number of malignant tumors. However, there are still no radiopharmaceuticals to treat common malignant tumors. As image diagnostic agents that may be a radiopharmaceutical of diagnosing general malignancies, bleomycin (non-patent document 1) is an anticancer agent, ⁵⁷ Co- bleomycin conjugated with radioactive cobalt ⁽⁵⁷ Co) is synthesized The possibility of a positive drawing agent for malignant tumor tissue was reported (Non-patent Documents 2-4).

The following are examples of problems in the prior art.
i) when using conventional gallium citrate ⁽⁶⁷ Ga), in addition to malignant tumor foci liver, kidney, most integrated well as to the bone and an obstacle in the detection of malignant tumors (Non-Patent Document 5) . ⁶⁷ Ga has three types of gamma rays, 296 keV, 184 keV, and 93 keV, and measurement for image creation was not easy, but the point ¹²³ I (one type of 160 keV gamma rays) is easy to measure and good quality Images can be created. ⁶⁷ Ga has a long physical half-life of 78 hours, which increases patient exposure, while ¹²³ I has a physical half-life of 13 hours, which reduces patient exposure and is beneficial to the patient.

ii) When thallium chloride ( ²⁰¹ Tl) is used, it is difficult to draw a malignant tumor lesion because many normal organs accumulate more than the accumulation in the malignant tumor lesion. In addition, thallium chloride ( ²⁰¹ Tl) measures 69-80 keV mercury KX-rays, so the energy is weak and the image becomes unclear when drawing with SPECT. The physical half-life of ²⁰¹ Tl is as long as 74 hours, but ¹²³ I can produce high-quality images as described above, and the physical half-life is short, which reduces patient exposure and is beneficial to patients. is there.

iii) ⁵⁷ Co- bleomycin bleomycin is an anticancer agent to bind the radioactive cobalt ⁽⁵⁷ Co), compared to normal organs (except kidney), it was reported in conjunction that a large amount accumulate in malignant tissue (Nonpatent literature 2-4). Therefore, it was experimentally used as a positive drawing agent for malignant tumor tissue, but because of the long physical half-life of ⁵⁷ Co, which is 270 days, it was radioactively released by the Ministry of Health at that time in terms of radioactive contamination of the environment and human exposure. Not allowed as a medicine.

When conventional gallium citrate ( ⁶⁷ Ga) is used, it accumulates in the liver, kidneys, bones and the like in addition to inflamed tissues, which hinders detection of inflamed tissues. As described above, ⁶⁷ Ga is more difficult to measure for image drawing than ¹²³ I, and at the same time has the disadvantage of increasing patient exposure. To draw the inflammatory site by indium ⁽¹¹¹ an In) labeled leukocytes indium leukocytes obtained from the patient ⁽¹¹¹ In) - labeled with oxine is intended to be administered to the patient, used in complex is very limited The

As described above, it is a well-known fact that bleomycin bound to cobalt has a strong ability to accumulate malignant tumors. As mentioned above, ^57- Co has a long physical half-life of 270 days, so it does not change the biological properties of Co-bleomycin on malignant tumor accumulation, and does not change the radioisotope (RI) to Co-bleomycin. Studies have been conducted on the diagnosis and treatment of malignant tumors by binding them to malignant tumors.

The following two methods can be considered as a method for labeling Co-bleomycin with RI. The first method is a method of synthesizing RI-labeled bleomycin in which RI (or a reagent thereof) is bound to bleomycin, and then binding cobalt to synthesize RI-labeled Co-bleomycin. In the second method, Co-bleomycin is synthesized in advance, and then RI (or its reagent) is bound to synthesize RI-labeled Co-bleomycin. As a first method, first of all radioactive iodine ions ¹³¹ bleomycin I ^{-, 125} I- Bolton Hunter (Bolton-Hunter) reagents, ¹²⁵ were each labeled with I-PIB reagent, this three RI together in a high yield RI-labeled bleomycin can be produced by binding to bleomycin. Cobalt chloride (CoCl ₂ ) was allowed to act on the RI-labeled bleomycin to produce RI-labeled Co-bleomycin, but cobalt was not bound to any of the three types. As a second method, the Co- bleomycin produced by the conventional method, was tried labeling the above three RI, ¹³¹ I ^- In can not be labeled, ¹²⁵ I- Bolton Hunter reagent, the ¹²⁵ I-PIB reagent Co-bleomycin can be labeled with low yield. Co-bleomycin labeled with ¹²⁵ I-Bolton Hunter reagent obtained in a small amount was examined for malignant tumor accumulation in Erlich cancer subcutaneously transplanted mice, but strong malignant tumor accumulation was not observed.

Natural and artificial bleomycins: Chemistry and antitumour activities.Pure Appl. Chem. 28 665-680 (1971) Malignant Tumor-Affinity RI Compound-About RI-labeled Bleomycin-Nuclear Medicine Vol.8, No.4, 296 (1971) The Tumor Specific Localizing Agents for Radioisotope Image-The Preparation o f Labeled Bleomycin and Their Distributions in the Tumor Bearing Mice, Radioisotopes 21 118-120 (1972) Tumor Scanning with 57Co-Bleomycin, Radioisotopes 21 436-438 (1972) Tumour affinity of 203Pb-chloride: comparison with 67Ga-citrate and 201T1-chloride, Nuclear Medicine Communications 15 39-46 (1994)

  An object of the present invention is to provide a novel iodobenzyl-bleomycin compound. In addition, the present invention is capable of accumulating in a malignant tumor in which the biological properties relating to the malignant tumor accumulation property of a metal complex of an iodobenzyl-bleomycin compound and various metal atoms, for example, an iodobenzyl-Co-bleomycin compound, are superior to those of conventional ones. It is an object to provide a metal complex. Furthermore, this invention makes it a subject to provide the synthesis method of the metal complex of the said iodobenzyl-bleomycin compound and the iodobenzyl-bleomycin compound and various metal atoms. It is another object of the present invention to provide a test agent and test method for malignant tumors or inflamed tissues, and a malignant tumor therapeutic agent, characterized by using the novel iodobenzyl-Co-bleomycin compound.

  As a result of repeated research, the inventors of the present invention added iodobenzyl iodide synthesized from iodobenzyl alcohol and iodine as starting materials to the terminal amino group of bleomycin, whereby iodobenzyl-Co having malignant tumor accumulation ability. The present invention was completed by successfully synthesizing a new iodobenzyl-bleomycin compound for producing a metal complex such as bleomycin.

That is, this invention consists of the following.
1. An iodobenzyl-bleomycin compound comprising a benzyl group substituted with an iodine atom in R of bleomycin represented by the general formula (I).
2. 2. The iodobenzyl-bleomycin compound according to item 1, wherein R in the general formula (I) has a structure represented by formula (II).
3. 3. The iodobenzyl-bleomycin compound according to item 2, wherein the iodine atom of the benzyl group represented by formula (II) is located at the meta position.
4). 4. The iodobenzyl-bleomycin compound according to any one of 1 to 3 above, wherein the substituted iodine atom is any one selected from ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I.
5. 5. An iodobenzyl-Co-bleomycin compound obtained by binding cobalt to the iodobenzyl-bleomycin compound according to any one of 1 to 4 above.
6). 6. The method for synthesizing an iodobenzyl-Co-bleomycin compound according to item 5 above, comprising a step of adding iodobenzyl iodide to a terminal amino group of bleomycin.
7). The method for synthesizing the iodobenzyl-Co-bleomycin compound according to item 6, comprising the following steps:
1) a step of synthesizing iodobenzyl iodide;
2) adding cobalt to bleomycin to synthesize Co-bleomycin;
3) A step of adding iodobenzyl-Co-bleomycin compound by adding Co-bleomycin dissolved in methanol to the iodobenzyl iodide prepared above.
8). The method for synthesizing the iodobenzyl-Co-bleomycin compound according to item 6, comprising the following steps:
1) step of synthesizing 'iodobenzyl iodide;
2) 'A step of adding bleomycin dissolved in methanol to the iodobenzyl iodide prepared above to synthesize an iodobenzyl-bleomycin compound;
3) 'A step of adding cobalt to the iodobenzyl-bleomycin compound prepared above to synthesize an iodobenzyl-Co-bleomycin compound.
9. 9. The method for synthesizing an iodobenzyl-Co-bleomycin compound according to any one of items 6 to 8, wherein the bleomycin is bleomycin demethyl A ₂ .
10. A test for malignant tumors or inflamed tissues, comprising the iodobenzyl-Co-bleomycin compound according to item 5 above.
11. 6. A malignant tumor therapeutic agent comprising the iodobenzyl-Co-bleomycin compound according to item 5 as an active ingredient.
12 6. A method for examining a malignant tumor or an inflamed tissue, comprising using the iodobenzyl-Co-bleomycin compound according to item 5 above.

According to the novel iodobenzyl-bleomycin compound of the present invention, the iodobenzyl-Co-bleomycin compound of the present invention can be easily synthesized. The iodobenzyl-bleomycin compounds of the present invention can be complexed with various metal atoms, and these complexes may have medical applications. Possible metal atoms that can form useful complexes include cobalt, iron, rhodium, ruthenium, tin, manganese, nickel, palladium, chromium, antimony, vanadium, and the like. The novel iodobenzyl-Co-bleomycin compound of the present invention has the ability to accumulate malignant tumors by conventional Co-bleomycin, and if labeled with ¹²³ I or ¹²⁴ I, can be drawn clearly with the labeled iodine. Also, ¹²³ I has a physical half-life of 13 hours and ¹²⁴ I has a physical half-life of 4.2 days, compared to ⁵⁷ Co-bleomycin where the physical half-life of radioactive cobalt ( ⁵⁷ Co) was 270 days. The novel iodobenzyl-Co-bleomycin compound of the present invention can reduce patient exposure and reduce radioactive contamination of the environment.

By drawing (by SPECT) malignant tumor lesions and inflamed tissues with the iodobenzyl-Co-bleomycin compound of the present invention, it is far more than using conventional gallium citrate ( ⁶⁷ Ga) or thallium chloride ( ²⁰¹ Tl). It is possible to draw clearly, and the patient's exposure dose can be reduced. Since the physical half-life of ¹⁸ F currently used for PET (positron emission tomography) inspection is 110 minutes, a compound for PET inspection using ¹⁸ F as a labeling substance can be synthesized as needed. Needed. In the case of the novel iodobenzyl-Co-bleomycin compound of the present invention, for example, the physical half-life length of ¹²⁴ I is 4.2 days, so it can be synthesized before the date of use and transported over a long distance. There are medical economic advantages.

Moreover, if the iodobenzyl-Co-bleomycin compound labeled with ¹³¹ I that emits beta rays is accumulated in the malignant tumor tissue and the malignant tumor cells are irradiated with the beta rays, a therapeutic effect on the malignant tumor is expected. This is the first discovery of a compound labeled with a nuclide that emits beta rays and can accumulate in large amounts in general malignant tumors.

It is a figure which shows the synthetic scheme of iodobenzyl iodide. FIG. 3 shows a synthetic scheme for adding iodobenzyl iodide to the terminal amino group site of bleomycin demethyl A ₂ or cobalt-bleomycin demethyl A ₂ . Is a diagram illustrating a 3- ¹²⁵ I- autoradiogram and Akuchiguramu thin layer chromatography iodobenzyl -Co- bleomycin compound. Example 1 Is a diagram illustrating a 3- ¹²⁵ I- Akuchiguramu of iodobenzyl iodide and Co- thin layer chromatography after reaction bleomycin demethyl A _2. Example 1 Is a diagram illustrating a 3- ¹²⁵ I- autoradiogram and Akuchiguramu of iodobenzyl -Co- bleomycin 3A thin layer chromatography. Example 1 3- ¹²⁵ I- iodobenzyl - shows the autoradiogram and Akuchiguramu tlc bleomycin. (Example 2)

  The present invention relates to novel iodobenzyl-bleomycin compounds. The present invention also relates to metal complexes of iodobenzyl-bleomycin compounds such as iodobenzyl-Co-bleomycin compounds with various metal atoms.

  First, an iodobenzyl-bleomycin compound, which is a conjugate of bleomycin and an iodo compound, will be described. Bleomycin has a structure represented by the following general formula (I). Here, various bleomycins are specified by the structure of R shown in Table 1. In the present specification, the case where the structure of R shown in Table 1 is modified, for example, by binding an iodo compound, is referred to as “bleomycin compound”, and is simply distinguished from the case of “bleomycin”.

The iodobenzyl-bleomycin compound of the present invention is characterized by containing a benzyl group substituted with an iodine atom in R (terminal amino group) of bleomycin represented by the general formula (I). Specifically, the iodobenzyl-bleomycin compound has a structure in which R in the general formula (I) is represented by the formula (II). In the formula (II), the position of the iodine atom is not particularly limited and may be any of the meta position, the para position, and the ortho position, but is most preferably located at the meta position. In the above, the substituted iodine atom may be radioactive or non-radioactive. In the case of a radioactive iodine atom, it may be any one selected from ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I, ¹²³ I and ¹²⁴ I are suitable for diagnostic imaging, and malignant tumor treatment. ¹³¹ I is preferred, and ¹²⁵ I is preferred for basic research.

  The present invention relates to the above-mentioned iodobenzyl-bleomycin compound, a metal with any metal atom selected from cobalt, copper, iron, rhodium, ruthenium, tin, manganese, nickel, palladium, chromium, antimony, vanadium, etc. It extends to complexes. The iodobenzyl- (metal atom) -bleomycin compound of the present invention is synthesized by binding a metal atom, for example, cobalt, to the iodobenzyl-bleomycin compound synthesized as described above according to the conventional method for synthesizing (metal atom) -bleomycin. You can also The iodobenzyl- (metal atom) -bleomycin compound of the present invention is synthesized by adding iodobenzyl iodide to the terminal amino group of (metal atom) -bleomycin synthesized by a method known per se and reacting. You can also As the metal complex of the iodobenzyl-bleomycin compound of the present invention and a metal atom, an iodobenzyl-Co-bleomycin compound is most preferable.

  The iodobenzyl-Co-bleomycin compound can also be synthesized by binding cobalt to the iodobenzyl-bleomycin compound synthesized as described above in accordance with a conventional Co-bleomycin synthesis method. The iodobenzyl-Co-bleomycin compound of the present invention can also be synthesized by adding iodobenzyl iodide to the terminal amino group of Co-bleomycin synthesized by a method known per se and reacting it.

Hereinafter, a method for synthesizing the iodobenzyl-Co-bleomycin compound of the present invention will be described in detail. The iodobenzyl-Co-bleomycin compound of the present invention can be synthesized by a method including a step of adding iodobenzyl iodide to the terminal amino group of bleomycin or Co-bleomycin. To synthesize iodobenzyl -Co- bleomycin compounds of the present invention have the general formula (I) and among the various bleomycin shown in Table 1, it is particularly preferable to use bleomycin demethyl A _2. Specifically, it can be synthesized by adding iodobenzyl iodide to bleomycin demethyl A ₂ or Co-bleomycin demethyl A ₂ . In the case of adding iodobenzyl iodide, cobalt may be bonded to bleomycin in advance or may not be bonded.

Specifically, the iodobenzyl-Co-bleomycin compound of the present invention can be synthesized by a method including the following steps 1) to 3). In the following, either step 1) or 2) may be performed first.
1) A step of synthesizing iodobenzyl iodide.
2) A step of adding cobalt to bleomycin to synthesize Co-bleomycin.
3) A step of adding an iodobenzyl-Co-bleomycin compound by adding Co-bleomycin dissolved in methanol to the synthesized iodobenzyl iodide.

The iodobenzyl-Co-bleomycin compound of the present invention can also be produced by a synthesis method including the following steps 1) ′ to 3) ′.
1) A step of synthesizing iodobenzyl iodide.
2) 'A step of adding an odomycin dissolved in methanol to the iodobenzyl iodide prepared above to synthesize an iodobenzyl-bleomycin compound.
3) 'A step of adding cobalt to the iodobenzyl-bleomycin compound prepared above to synthesize an iodobenzyl-Co-bleomycin compound.

Iodobenzyl iodide can be synthesized using iodobenzyl alcohol and iodine ions as starting materials based on the synthesis scheme of FIG. In FIG. 1, ¹²⁵ I ⁻ is illustrated as an iodine ion added to iodobenzyl alcohol. However, ¹²³ I ⁻ , ¹²⁴ I ^−, or ¹³¹ I ⁻ may be a radioactive iodine ion, or non-radioactive. The iodine ion may be used. Moreover, although the iodine atom of the benzene ring of the synthesized iodobenzyl iodide is located at the meta position in FIG. 1, it may be located at the para position or the ortho position. Such iodobenzyl iodide was synthesized in, for example, a iodobenzyl ^{iodide 125} I is located in the meta position 3 ¹²⁵ I- iodobenzyl iodide (3- ¹²⁵ I-iodobenzyliodide: hereinafter ^"3-125 I-BZI ") and it can be shown, those located in the ortho position 2- ¹²⁵ I-BzI, those located at the para position can be shown as 4- ¹²⁵ I-BzI.

  The method of adding iodobenzyl iodide to the above-mentioned 3) Co-bleomycin or the above 2) ′ bleomycin, ie, the step of adding iodobenzyl iodide to the terminal amino group of Co-bleomycin or bleomycin is shown in FIG. Can be based on the synthesis scheme shown in FIG.

The method of adding cobalt to the bleomycin of the above 2) or the iodobenzyl bleomycin compound of the above 3) ′, for example, the method of adding CoCl ₂ can be a method known per se. Specifically, for example, it can be based on the description of Non-Patent Document 2-4.

The novel iodobenzyl-Co-bleomycin compound of the present invention retains the malignant tumor accumulation property of conventional Co-bleomycin and can be drawn clearly with labeled iodine. Of the radioactive iodine atoms, ¹²³ I has a physical half-life of 13 hours and ¹²⁴ I has a physical half-life of 4.2 days, so that the physical half-life of radioactive cobalt ( ⁵⁷ Co) is 270 days. Compared to ⁵⁷ Co-bleomycin, the novel iodobenzyl-Co-bleomycin compound of the present invention can reduce patient dose and ambient radioactive contamination.

When drawing malignant tumor foci and inflamed tissues with the ¹²³ I-labeled iodobenzyl-Co-bleomycin compound of the present invention (by SPECT), conventional gallium citrate ( ⁶⁷ Ga) or thallium chloride ( ²⁰¹ Tl) is used. It is possible to draw much more clearly than the case, and the exposure dose of the patient can be reduced. In addition, since the physical half-life of ¹⁸ F used for PET inspection is 110 minutes, when ¹⁸ F is used as a labeling substance, it must be prepared at the time of use and used within a limited time. However, in the case of the novel iodobenzyl-Co-bleomycin compound labeled with ¹²⁴ I of the present invention, it can be synthesized before the date of use and transported over long distances due to its physical half-life. Yes, there are medical economic advantages.

If the iodobenzyl-Co-bleomycin compound labeled with ¹³¹ I that emits beta rays is accumulated in malignant tumor tissue and irradiated with malignant tumor cells with beta rays, a therapeutic effect on the malignant tumor is expected. This compound is the first to discover a compound labeled with a nuclide that emits beta rays and accumulates in large amounts in general malignant tumors.

  The present invention relates to a method for producing an iodobenzyl-Co-bleomycin compound, a diagnostic agent for a malignant tumor or inflammatory tissue containing the iodobenzyl-Co-bleomycin compound, a therapeutic agent for a malignant tumor containing the compound as an active ingredient, It extends to a method for examining malignant tumors or inflamed tissues using a compound.

  In the case of a malignant tumor therapeutic agent containing the iodobenzyl-Co-bleomycin compound of the present invention as an active ingredient, the dosage is not particularly limited. For example, when a therapeutic agent for malignant tumor containing the compound as an active ingredient is used in combination with a therapeutic agent known per se, or when the therapeutic agent for malignant tumor of the present invention is administered without using a therapeutic agent known per se In any administration method, the appropriate dose can be easily selected. The dose is appropriately set depending on the disease, weight, age, sex, etc. of the patient. For example, in the case of intravenous injection, the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day.

  In the case of a malignant tumor therapeutic agent and a malignant tumor or inflamed tissue test agent comprising the iodobenzyl-Co-bleomycin compound of the present invention as an active ingredient, the compound and a pharmaceutically and pharmaceutically acceptable carrier Or it can be used with an additive. Examples of such carriers or additives include appropriate buffers such as phosphate buffer, isotonic agents such as physiological saline, etc., for example, solubilizers or solubilizers, isotonic agents, pH adjusters, Examples of the stabilizer include ascorbic acid, and examples of the pH adjuster include hydrochloric acid and sodium hydroxide.

  By using the diagnostic agent containing the iodobenzyl-Co-bleomycin compound of the present invention as an imaging diagnostic agent, a malignant tumor or an inflamed tissue can be examined. Since the compound has the property of being specifically taken up by malignant tumors, it is possible to image malignant tumors by detecting the radiation emitted from the compound using nuclear medicine inspection techniques such as PET and SPECT. . The malignant tumor that can be examined with the compound of the present invention is not particularly limited as long as the compound can specifically accumulate, and for example, esophagus, stomach, pancreas, large intestine, lung, brain, ovary, breast, skin, Examples include malignant tumors existing in the uterus. Similarly, since the compound has a property of being specifically taken into the inflamed tissue, an image diagnosis can also be performed for the inflamed tissue.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the scope of the following examples.

In the synthesis 1) Outline of embodiment of the synthesis of Example 1 iodobenzyl -Co- bleomycin compound of bleomycin shown in general formula (I) Bleomycin-demethyl A ₂ (bleomycin demethyl A _2, hereinafter "BLM-dA ₂ "), cobalt was coupled cobalt - bleomycin demethyl _{a 2 (Co-bleomycin demethyl a} 2, were prepared following" Co-BLM-dA ₂ "). Then the terminal amino group of Co-BLM-dA _2, as shown in FIGS. 1 and 2, 3-iodobenzyl alcohol (3-iodobenzyl alcohol) and radioactive iodine ion ¹²⁵ I ^- 3 ¹²⁵ produced as a starting material I- iodobenzyl iodide and (3- ¹²⁵ I-BzI) was added, was synthesized 3- ¹²⁵ I- iodobenzyl -Co- bleomycin compound ^{(3- 125 I-Bz-Co} -BLM). R of general formula (I), the following is shown in formula ^{(III) 3- 125 I-Bz} -Co-BLM is proposed structure.

The 3- ¹²⁵ I-BzI (3.3μM / starting 20μl of 3-iodobenzyl alcohol) and was produced by the reaction of ^{_{Co-BLM-dA 2 3- 125}} I-Bz-Co-BLM, silica gel thin layer chromatography Separated (Rf 0.34-0.41). The autoradiogram and actigram of thin-layer chromatography of this isolate are shown in FIG. A fluoro image analyzer ^TM FLA-7000 (manufactured by Fuji Photo Film Co., Ltd.) was used for producing these autoradiograms and actigrams.

3-iodobenzyl alcohol starting material is reduced to 0.33MyuM, the ratio at which radioactivity was the reaction product of the combined ^3-125 I-BZI and Co-BLM-dA ₂ further detail observed to increase, in FIG. 4 the resulting ^{3- 125 I-Bz-Co-} BLM as shown in, 3A (Rf 0.39~0.48), was found to split into two as in 3B (Rf 0.35~0.43). Therefore 3A, 3B was separated by silica gel thin layer chromatography separately, to obtain a single ^{3- 125 I-Bz-Co-} BLM 3A and ^{3- 125 I-Bz-Co-} BLM 3B.

  FIG. 5 shows an example of the actogram and autoradiogram of the separated 3A silica gel thin layer chromatography.

In place of 3-iodobenzyl alcohol starting material, 2-iodobenzyl alcohol, 4-iodobenzyl alcohol in the same manner as described above using, respectively ^{2- 125 I-Bz-Co-} BLM 2A (Rf 0.42~ 0.47), 2B (Rf 0.36~0.42) , 4- 125 I-Bz-Co-BLM 4A (Rf 0.43~0.50), was obtained 4B (Rf 0.34~0.45). These 3A, 3B, 2A, 2B, 4A and 4B were used for animal experiments.

2) Synthesis method
(i) BLM-dA ₂ : Bleomycin A ₂ sulfate was produced by heating at 100 ° C. for about 80 hours under reduced pressure.

(ii) Co-BLM-dA ₂ : About 3 times the amount of CoCl ₂ is added to the aqueous solution of BLM-dA ₂ to prepare three types of pH 6.0, 6.5 and 7.0, followed by freeze-drying. did.

(iii) 3- ¹²⁵ I- iodobenzyl iodide (3- ¹²⁵ I-iodobenzyliodide, hereinafter "3- ¹²⁵ I-BzI"), ^2-125 I- iodobenzyl iodide (2- ¹²⁵ I-iodobenzyliodide, hereinafter " 2- ¹²⁵ I-BzI ") and ^4-125 I- iodobenzyl iodide (4- ¹²⁵ I-iodobenzyliodide, the synthesis of the" 4- ¹²⁵ I-BzI ")
3-iodobenzyl alcohol (3.3 μM / 20 μl), Na ¹²⁵ I solution (5 MBq / 100 μl), copper sulfate solution (100 mg / ml) 30 μl, 2,5-dihydroxybenzoic acid solution (0.25 mM / ml) 80 μl, and A solution obtained by dissolving 4 mg of stannous chloride dihydrate in 20 μl of citric acid solution (1 mM / ml) was added to a test tube and stirred for 60 minutes in a boiling water bath.

Next, a 3- ¹²⁵ I- iodobenzyl alcohol produced by the reaction (3- ¹²⁵ I-iodobenzylalcohol) and extracted with dichloromethane, dehydrated over sodium sulfate and the 3- ¹²⁵ I-BzI in tetraiodide diphosphorus (Iwata R., Pascali C., Bogni A., Horvath G., Kovacs Z., Yanai K., Ido T .: A new convenient method for the preparation of 4- [ ¹⁸ F] fluorobenzyl halides.
Applied Radiation and Isotopes 52 87-92 (2000)). Washed with water The dichloromethane solution containing 3- ¹²⁵ I-BzI, after preparative dichloromethane layer was separated and dried over sodium sulfate. The solvent fractionated dichloromethane layer was obtained evaporated to 3- ¹²⁵ I-BzI.

To increase the specific activity, it reduced the 3-iodobenzyl alcohol 0.33MyuM, others above the conducted just as to obtain a high specific radioactivity 3- ¹²⁵ I-BzI. In place of 3-iodobenzyl alcohol, likewise performed using 2-iodobenzyl alcohol and 4-iodobenzyl alcohol to give the respective ^2-125 I-BZI and 4- ¹²⁵ I-BzI.

(iv) 3- ¹²⁵ to I-Bz-Co-BLM synthesis method test tube add aforementioned 3- ¹²⁵ I-BzI of, any of the above _{Co-BLM-dA 2 1.5 mg} (pH 6.0,6.5,7.0 1 ml of methanol was added and dissolved, and heated at about 80 ° C. for 30 minutes. The reaction resulting ^{3- 125 I-Bz-Co-} BLM 10% ammonium acetate: methanol (1: 1) was separated on silica gel thin layer chromatography as a developing solvent.

Instead of 3- ¹²⁵ I-BzI, using 2- ¹²⁵ I-BzI and 4- ¹²⁵ I-BzI, it was measured in the same manner as in the 3- ¹²⁵ I-BzI.

^{3) 3- 125 I-Bz-} Co-BLM synthesis results after expansion by a silica gel thin layer chromatography, unseparated to ^{3- 125 I-Bz-Co-} BLM (3A and 3B from the silica gel layer of the plate, Rf 0.34 -0.41) were extracted and collected with a solvent (methanol: saline = 1: 1) (FIG. 3). When using Na ¹²⁵ I of 5 MBq 0.5MBq～0.75MBq of ^{3- 125 I-Bz-Co-} BLM ( unresolved in 3A and 3B) was obtained. Radiochemically very stable, with a radiochemical purity of 98% or higher, and almost no impurities were observed even after 3 weeks.

The high specific radioactivity 3- ¹²⁵ I-BzI was synthesized from ^{3- 125 I-Bz-Co-} BLM of Akuchiguramu of silica gel thin layer chromatography are shown in FIG. As shown in FIG. ^{3- 125 I-Bz-Co-} BLM showed two peaks of 3A (Rf 0.39~0.48), 3B ( Rf 0.35~0.43). 3A and 3B were extracted separately with the same solvent (methanol: saline = 1: 1). 5 when using MBq of ^{Na 125 I, 3A (3- 125} I-Bz-Co-BLM peak 3A) about 55 kBq, 3B (peak ^{3B 3- 125 I-Bz-Co} -BLM) about 70 kBq Got. When the obtained 3A was developed by silica gel thin layer chromatography using 10% ammonium acetate: methanol (1: 1) as a developing solvent, 3A having a radiochemical purity of 98% or more was obtained as shown in FIG. Similarly, 3B having a purity of 98% or more was obtained. These 3A and 3B were radiochemically stable and almost no degradation products were observed after 3 weeks, but it was estimated that there was a transition from 3A to 3B or vice versa.

In the same way, from 2- ¹²⁵ I-BzI give the ^{2- 125 I-Bz-Co-} BLM 2A (Rf 0.42~0.47) about 85kBq and 2B (Rf 0.36~0.42) about 75KBq. From 4- ¹²⁵ I-BzI give the ^{4- 125 I-Bz-Co-} BLM 4A (Rf 0.43~0.50) and 4B (Rf 0.34~0.45) together about 60KBq. These compounds were also obtained with a radiochemical purity of 98% or more, were stable radiochemically, and almost no degradation products were observed even after 3 weeks. It was estimated that 2A and 2B and 4A and 4B have the same relationship as in 3A and 3B.

4) Summary
When started synthesized using 3.3μM 3-iodobenzyl alcohol, radiochemical yield of ^3-125 I-BZI for usage of Na ¹²⁵ I is at least 50%, 3- ¹²⁵ I-Bz The yield of -Co-BLM was 10-15%. To increase the specific activity, 3-iodobenzyl alcohol when used 0.33μM 3- ¹²⁵ I- iodobenzyl alcohol yield is low, even lower yields of the order of ^3-125 I-BZI, 3- The yields of ¹²⁵ I-Bz-Co-BLM 3A (1.1%) and 3B (1.4%) were also low. ^{2- 125 I-Bz-Co-} BLM 2A (1.7%), 2B (1.5%) and ^{4- 125 I-Bz-Co-} BLM 4A (1.2%), were the same for 4B (1.2%). These compounds were very stable radiochemically.

(Experimental example 1-1) Tumor accumulation property of various ¹²⁵ I-Bz-Co-BLM In this experimental example, the malignant tumor accumulation property of various ¹²⁵ I-Bz-Co-BLM by cancer-bearing animals was confirmed.

1) Various ¹²⁵ I-Bz-Co-BLM injection solutions and tumor-bearing mice Various ¹²⁵ I-Bz-Co-BLM obtained in Example 1 were dissolved in physiological saline, and the following 7 types of physiological saline solutions for injection were used. Was prepared.
^{3- 125 I-Bz-Co-} BLM (3A and 3B in unseparated) saline solution (content 20μg~60μg in 0.3 ml, approximately 10KBq)
^{3- 125 I-Bz-Co-} BLM 3A saline solution (same 20Myuji～30myug, about 5KBq)
^{3- 125 I-Bz-Co-} BLM 3B saline solution (same 20Myuji～30myug, about 5KBq)
^{2- 125 I-Bz-Co-} BLM 2A saline solution (same 40Myuji～60myug, about 5KBq)
^{2- 125 I-Bz-Co-} BLM 2B saline solution (same 40Myuji～60myug, about 5KBq)
^{4- 125 I-Bz-Co-} BLM 4A saline solution (same 20Myuji～30myug, about 5KBq)
^{4- 125 I-Bz-Co-} BLM 4B saline solution (same 20Myuji～30myug, about 5KBq)

Tumor-bearing mice: Male scid mice (8 weeks old) purchased from Clea Japan Co., Ltd. were transplanted with Ehrlich ascites tumor cells (approximately 4 × 10 ⁷ cells) subcutaneously in the thigh. It used for experiment when it became the magnitude | size of cm.

Experimental Method the cancer-bearing mice in 2) tumor-bearing mice, the tail vein of the ^{3- 125 I-Bz-Co-} BLM (3A and 3B saline solution containing unseparated) (approximately 10 kBq, the 0.3 ml) After injection, 5 animals were sacrificed under ether anesthesia after 1 hour, 3 hours, 6 hours, 12 hours, and 24 hours, respectively, and malignant tumor tissues and main organ tissues were removed. Immediately after excision, the weight of a part of these tissues was measured, and then the radioactivity was measured with a well-type scintillation counter. Uptake rate of each ^{3- 125 I-Bz-Co-} BLM of each tissue was expressed in uptake rate for each tissue 1 g in the case where the injection amount is 100% (% / g). Since there was variation in the body weight of the mice, in order to make the results easier to compare, the body weight was standardized to 100 g in the calculation (uptake rate (% / g) × mouse body weight (g) ÷ 100 was calculated).
^{3- 125 I-Bz-Co-} BLM 3A and ^{3B, 2- 125 I-Bz-} Co-BLM 2A and 2B, for each saline solution ^{4- 125 I-Bz-Co-} BLM 4A and 4B, the tumor-bearing mice were sacrificed on under ether anesthesia by 5 animals after 1 hour and 3 hours after intravenous injection, thereafter was treated in the same manner as in the ^{3- 125 I-Bz-Co-} BLM.

3) administration 1 hour ^{3- 125 I-Bz-Co-} BLM Results Table 2 Biodistribution of various ¹²⁵ I-Bz-Co-BLM in tumor-bearing mice in tumor-bearing mice (3A and 3B unseparated), 3 The uptake rate per 1 g of each tissue after 6 hours, 12 hours and 24 hours (when the body weight is unified to 100 g) is shown. It was not shown in Table 2 because the uptake into the brain and bone was very low and difficult to measure accurately.
The rate of uptake into malignant tumor tissue was 0.35% / g after 1 hour and decreased with time. The uptake rate into normal organ tissues also decreased over time in most tissues after 1 hour.

  Table 3 shows the malignant tumor tissue / organ tissue-uptake ratio per unit weight. At 1 hour after administration, the organs of 1.0 or less (more concentrated than the malignant tumor tissue) were blood, liver, and kidney, but after 3 hours it became two organs, liver and kidney.

The results of the biodistribution of ^{3- 125 I-Bz-Co-} BLM 3A and 3B in tumor-bearing mice are shown in Tables 4 and 5.
Table 4 shows the uptake rate per 1 g of each tissue (when weight is unified to 100 g) 1 hour and 3 hours after administration. The uptake rates of malignant tumor tissues were 0.319% / g, 0.280% / g, 3 hours after 3A, and 0.331% / g, 0.259% / g after 1 hour, 3 hours, respectively. there were. Accumulation in the kidney was very large, and accumulation in the liver was also large. There was no significant difference between 3A and 3B, but all organs were smaller after 3 hours than after 1 hour.

  Table 5 shows the malignant tumor tissue / organ tissue-uptake ratio per unit weight. In 3A and 3B, the organs of 1.0 or less (more concentrated than the malignant tumor tissue) were blood, liver, kidney, and lung at 1 hour after administration, but after 3 hours, they became two organs, liver and kidney. It was. From this result, it was found that 3 hours after administration, 3A and 3B, except for the kidney and liver, were sufficiently accumulated in malignant tumor tissues compared to normal organ tissues.

The results of the biodistribution of ^{4- 125 I-Bz-Co-} BLM 4A and 4B in tumor-bearing mice are shown in Tables 6 and 7. Overall ^{3- 125 I-Bz-Co-} BLM 3A, is similar in the case of 3B, malignancies positive rendering agent (if used clinically change the ¹²⁵ I to ¹²³ I or ¹²⁴ I as in the case of considering the) it was inferior ^{3- 125 I-Bz-Co-} BLM.

The ^{4- 125 I-Bz-Co-} BLM 4A and 4B as well as ^{2- 125 I-Bz-Co-} BLM of 2A and 2B results are shown in Tables 8 and 9. In addition inferior results than the ^{4- 125 I-Bz-Co-} BLM When this compound was considered as malignancies positive rendering agent (if used clinically change the ¹²⁵ I to ¹²³ I or ¹²⁴ I) there were.

4) Evaluation as a malignant tumor positive drawing agent ¹²⁵ I-Bz-Co-BLM with a radioiodine atom attached to the second, third, or fourth carbon of the benzyl group benzene ring ( In clinical use, the possibility of changing ¹²⁵ I to ¹²³ I for SPECT and ¹²⁴ I for PET) was tested in cancer-bearing mice. It was. Among them, 3- ¹²⁵ I-Bz-Co-BLM 3A, 3B, in which a radioactive iodine atom is bonded to the 3rd carbon, was considered more suitable in this animal experiment. 3A and 3B were considered to exhibit essentially the same properties, and 4A and 4B and 2A and 2B were considered to be the same.

(Experimental Example 1-2) Inflammatory Tissue Accumulation of Various ¹²⁵ I-Bz-Co-BLM In this experimental example, confirmation of the inflamed tissue accumulation of various ¹²⁵ I-Bz-Co-BLM was performed using an inflammation-initiating substance.

1) Various ¹²⁵ I-Bz-Co-BLM injection solutions and inflammation-inducing mice Various ¹²⁵ I-Bz-Co-BLM obtained in Example 1 were dissolved in physiological saline, and the following 6 types of physiological saline solutions for injection were used. did.
^{3- 125 I-Bz-Co-} BLM 3A saline solution (content 20μg~30μg in 0.3 ml, about 5 kBq)
^{3- 125 I-Bz-Co-} BLM 3B saline solution (same 20Myuji～30myug, about 5 kBq)
^{2- 125 I-Bz-Co-} BLM 2A saline solution (same 40Myuji～60myug, about 5 kBq)
^{2- 125 I-Bz-Co-} BLM 2B saline solution (same 40Myuji～60myug, about 5 kBq)
^{4- 125 I-Bz-Co-} BLM 4A saline solution (same 20Myuji～30myug, about 5 kBq)
^{4- 125 I-Bz-Co-} BLM 4B saline solution (same 20Myuji～30myug, about 5 kBq)

  Inflammation-inducing mice: 0.2 ml of turpentine oil was injected subcutaneously into the back of male ddY mice (5 weeks old) purchased from Japan SLC Co., and used for experiments 5 days later.

2) Experimental methods above in inducing inflammation mouse ^{3- 125 I-Bz-Co-} BLM 3A saline solution (about 5 kBq, the 0.3 ml) were injected through the tail vein to the inducing inflammation 5 mice, ether after 3 hours The animals were sacrificed under anesthesia and the inflamed tissues and major organ tissues were removed. Thereafter, the tumor-bearing mouse described in 2) of Experimental Example 1-1 was treated in the same manner, and the uptake rate (% / g) into 1 g of tissue was determined. ^{3- 125 I-Bz-Co-} BLM 3B, 2- 125 I-Bz-Co-BLM 2A and 2B, was carried out in the same manner on ^{4- 125 I-Bz-Co-} BLM 4A and 4B.

3) Results of biodistribution of various ¹²⁵ I-Bz-Co-BLM in inflammation-induced mice The results are shown in Table 10, Table 11, and Table 12. After 3 hours of intravenous injection, the rate of uptake into inflamed tissues was large. The value was smaller than the kidney uptake rate, but 3A and 3B were comparable to the liver uptake rate, and the same was true for 4A and 4B. In 2A and 2B, kidney uptake rate and liver uptake rate were large.

4) Evaluation as an inflammatory tissue positive drawing agent
Each of ¹²⁵ I-Bz-Co-BLM 3A, 3B, 4A, 4B, 2A and 2B was also taken up by inflamed tissues, and the uptake rate was larger than that of malignant tumor tissues. The large amount taken into the inflamed tissue indicates that if it is labeled with ¹²³ I or ¹²⁴ I instead of ¹²⁵ I, it may be used as a drawing agent for the inflamed tissue.

In the synthesis 1) Outline of embodiment of the synthesis of bleomycin compound, 3- ¹²⁵ I- iodobenzyl - - (Example 2) iodobenzyl explaining bleomycin compound ^{(3- 125 I-Bz-BLM} ) Synthesis about. In the bleomycin represented by the general formula (I), the terminal amino group of BLM-dA ₂ is treated with 3-iodobenzyl alcohol and radioactive iodine ion ¹²⁵ I- as shown in FIG. 1 and FIG. producing the 3- ¹²⁵ I- by adding iodobenzyl iodide (3- ¹²⁵ I-BzI) as, 3- ¹²⁵ I- iodobenzyl - bleomycin compound ^{(3- 125 I-Bz-BLM} ) were synthesized. R in the general formula (I) are, 3- ¹²⁵ I-Bz-BLM as shown in formula (III) is the estimated structure.

3 ¹²⁵ I-BzI (3.3μM / starting 20μl of 3-iodobenzyl alcohol) and was produced by the reaction of ^{_{BLM-dA 2 3- 125 I-}} Bz-BLM, and separated by silica gel thin layer chromatography (Rf 0.40-0.44). A thin layer chromatogram autoradiogram and actigram of this isolate is shown in FIG. A fluoro image analyzer ^TM FLA-7000 (manufactured by Fuji Photo Film Co., Ltd.) was used to prepare the autoradiogram and actogram.

2) Synthesis method
(i) BLM-dA ₂ : Bleomycin A ₂ sulfate was produced by heating at 100 ° C. for about 80 hours under reduced pressure.

Synthesis of (ii) 3- ¹²⁵ I- iodobenzyl iodide (hereinafter "3- ¹²⁵ I-BzI")
3-iodobenzyl alcohol (3.3 μM / 20 μl), Na ¹²⁵ I solution (2 MBq / 100 μl), copper sulfate solution (100 mg / ml) 30 μl, 2,5-dihydroxybenzoic acid solution (0.25 mM / ml) 80 μl, and A solution obtained by dissolving 4 mg of stannous chloride dihydrate in 20 μl of citric acid solution (1 mM / ml) was added to a test tube and stirred for 60 minutes in a boiling water bath.

Next, a 3- ¹²⁵ I- iodobenzyl alcohol produced by the reaction (3- ¹²⁵ I-iodobenzylalcohol) and extracted with dichloromethane, dehydrated over sodium sulfate and the 3- ¹²⁵ I-BzI in tetraiodide diphosphorus (Iwata R., Pascali C., Bogni A., Horvath G., Kovacs Z., Yanai K., Ido T .: A new convenient method for the preparation of 4- [ ¹⁸ F] fluorobenzyl halides. Applied Radiation and Isotopes 52 87-92 (2000)). Washed with water The dichloromethane solution containing 3- ¹²⁵ I-BzI, after preparative dichloromethane layer was separated and dried over sodium sulfate. The solvent fractionated dichloromethane layer was obtained evaporated to 3- ¹²⁵ I-BzI.

(iii) the 3- ¹²⁵ I-Bz-BLM synthesis method test tube add aforementioned 3- ¹²⁵ I-BzI of was dissolved by addition of BLM-dA ₂ 2.1 mg and methanol 1 ml of the above, at about 80 ° C. Heated for 30 minutes. 3- ¹²⁵ I-Bz-BLM obtained by this reaction was separated by silica gel thin layer chromatography using 10% ammonium acetate: methanol (1: 1) as a developing solvent.

^{3) 3- 125 I-Bz-} BLM synthesis results after expansion by a silica gel thin layer chromatography, the silica gel layer of the plate ^{3- 125 I-Bz-BLM (} Rf 0.40~0.44) and the solvent (methanol: saline = 1: 1). 2 MBq of Na ¹²⁵ of about 0.2 MBq when using I 3- ¹²⁵ I-Bz-BLM were obtained. The radiochemical purity was about 95%, but it was stable radiochemically.

^{4) 3- 125 I-Bz-} Co-BLM producing approximately half of the above 3- ¹²⁵ I-Bz-BLM to the added CoCl ₂ a (0.71μM), adjusted to about pH 7, stirred for 30 minutes at room temperature And produced.

In (Experimental Example ^{2) 3- 125 I-Bz-} BLM and 3 ¹²⁵ tumor accumulation property this experiment of I-Bz-Co-BLM, 3- 125 by tumor-bearing animals I-Bz-BLM and 3 ¹²⁵ I -The accumulation of malignant tumors of Bz-Co-BLM was confirmed.

^{1) 3- 125 I-Bz-} BLM injection solutions and ^{3- 125 I-Bz-Co-} BLM was obtained by injection solutions and bearing mice Example 2 3- ¹²⁵ I-Bz-BLM and 3- ¹²⁵ I-Bz -Co-BLM was dissolved in physiological saline to prepare the following two types of physiological saline solutions for injection.
3- ¹²⁵ I-Bz-BLM saline solution (0.3 ml content in 20Myuji～30myug, about 10KBq)
^{3- 125 I-Bz-Co-} BLM saline solution (content 20μg~30μg in 0.3 ml, approximately 10KBq)

Tumor-bearing mice: Male scid mice (8 weeks old) purchased from Clea Japan Co., Ltd. were transplanted with Ehrlich ascites tumor cells (approximately 4 × 10 ⁷ cells) subcutaneously in the thigh. It used for experiment when it became the magnitude | size of cm.

Experimental Method the cancer-bearing mice in 2) tumor-bearing mice were injected with the tail vein of the 3- ¹²⁵ I-Bz-BLM saline solution (0.3 ml), and five were sacrificed under ether anesthesia after 3 hours Then, malignant tumor tissues and major organ tissues were removed. Immediately after excision, the weight of a part of these tissues was measured, and then the radioactivity was measured with a well-type scintillation counter. Uptake rate of 3- ¹²⁵ I-Bz-BLM of each tissue was expressed in uptake rate for each tissue 1 g in the case where the injection amount is 100% (% / g). Since there was variation in the body weight of the mice, in order to make the results easier to compare, the body weight was standardized to 100 g in the calculation (uptake rate (% / g) × mouse body weight (g) ÷ 100 was calculated).
^{3- 125 I-Bz-Co-} BLM were injected with 0.3 ml to mice similarly to the case of 3- ¹²⁵ I-Bz-BLM saline solution for physiological saline solution was similarly treated.

3) in tumor-bearing mice 3 ¹²⁵ I-Bz-BLM and 3 ¹²⁵ 3 ¹²⁵ cancer-bearing mice results in Table 13 Biodistribution of I-Bz-Co-BLM I -Bz-BLM and 3 ¹²⁵ I The accumulation (uptake rate) per 1 g of each tissue (when the body weight was unified to 100 g) 3 hours after administration of -Bz-Co-BLM was examined.
Uptake rate of malignant tumor tissue was ^3-125 In I-Bz-BLM 0.123% / g , but a ^{3- 125 I-Bz-Co-} BLM in 0.242% / g. 3 ¹²⁵ added CoCl ₂ to I-Bz-BLM, adjusted to about pH 7, good to malignant tumor tissue also ^{3- 125 I-Bz-Co-} BLM prepared by stirring at room temperature for 30 minutes Accumulated. Meanwhile, 3- ¹²⁵ I-Bz-BLM containing no Co is was observed accumulation of things significantly less uptake rate of malignant tumors than those containing Co. Moreover, the uptake rate into normal organ tissues was not significantly different between the two compounds.

As described above in detail, according to the novel iodobenzyl-bleomycin compound of the present invention, it is possible to form complexes with various metal atoms, and these complexes may be used for medical purposes. Possible metal atoms that can form useful complexes include cobalt, iron, rhodium, ruthenium, tin, manganese, nickel, palladium, chromium, antimony, vanadium, and the like. The novel iodobenzyl-Co-bleomycin compound of the present invention has the ability to accumulate malignant tumors by conventional Co-bleomycin, and if labeled with ¹²³ I or ¹²⁴ I, can be drawn clearly with the labeled iodine. Also, ¹²³ I has a physical half-life of 13 hours and ¹²⁴ I has a physical half-life of 4.2 days, compared to ⁵⁷ Co-bleomycin where the physical half-life of radioactive cobalt ( ⁵⁷ Co) was 270 days. The novel iodobenzyl-Co-bleomycin compound of the present invention can reduce patient exposure and reduce radioactive contamination of the environment.

If a malignant tumor lesion or inflammatory tissue is drawn (by SPECT) with the ¹²³ I-labeled iodobenzyl-Co-bleomycin compound of the present invention, conventional gallium citrate ( ⁶⁷ Ga) or thallium chloride ( ²⁰¹ Tl) is used. It is possible to draw much more clearly than the case, and the exposure dose of the patient can be reduced. Further, since the physical half-life of ¹⁸ F used in PET examination is 110 minutes, to the ¹⁸ F and labeling substance, it is necessary to prepare time needed, the present invention ¹²⁴ In the case of a novel iodobenzyl-Co-bleomycin compound labeled with I, it can be manufactured before the date of use due to its long physical half-life and can be transported over a long distance, which is advantageous in terms of medical economy.

If the iodobenzyl-Co-bleomycin compound labeled with ¹³¹ I that emits beta rays is accumulated in malignant tumor tissue and irradiated with malignant tumor cells with beta rays, a therapeutic effect on the malignant tumor is expected.

Claims (12)

An iodobenzyl-bleomycin compound comprising a benzyl group substituted with an iodine atom in R of bleomycin represented by the general formula (I).
The iodobenzyl-bleomycin compound according to claim 1, wherein R in the general formula (I) has a structure represented by the formula (II).
The iodobenzyl-bleomycin compound according to claim 2, wherein the iodine atom of the benzyl group represented by formula (II) is located at the meta position. The iodobenzyl-bleomycin compound according to any one of claims 1 to 3, wherein the substituted iodine atom is any one selected from ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. An iodobenzyl-cobalt-bleomycin compound obtained by binding cobalt to the iodobenzyl-bleomycin compound according to any one of claims 1 to 4. A method of synthesizing an iodobenzyl-cobalt-bleomycin compound comprising the step of adding iodobenzyl iodide to a terminal amino group of bleomycin. The method for synthesizing an iodobenzyl-cobalt-bleomycin compound according to claim 6, comprising the following steps:
1) a step of synthesizing iodobenzyl iodide;
2) adding cobalt to bleomycin to synthesize cobalt-bleomycin;
3) A step of adding cobalt-bleomycin dissolved in methanol to the iodobenzyl iodide prepared above to synthesize an iodobenzyl-cobalt-bleomycin compound. The method for synthesizing an iodobenzyl-cobalt-bleomycin compound according to claim 6, comprising the following steps:
1) step of synthesizing 'iodobenzyl iodide;
2) 'A step of adding bleomycin dissolved in methanol to the iodobenzyl iodide prepared above to synthesize an iodobenzyl-bleomycin compound;
3) 'A step of adding cobalt to the iodobenzyl-bleomycin compound prepared above to synthesize an iodobenzyl-cobalt-bleomycin compound. Bleomycin, bleomycin-demethyl A _2, iodobenzyl according to any one of claims 6-8 - cobalt - method of synthesizing bleomycin compound. A test for malignant tumors or inflamed tissues, comprising the iodobenzyl-cobalt-bleomycin compound according to claim 5. A therapeutic agent for malignant tumor comprising the iodobenzyl-cobalt-bleomycin compound according to claim 5 as an active ingredient. A method for examining a malignant tumor or an inflamed tissue, wherein the iodobenzyl-cobalt-bleomycin compound according to claim 5 is used.