Boron cluster structure-containing compounds, and boron neutron capture therapy agents containing the same

Abstract

The objective is to provide a boron cluster structure-containing compound that exhibits excellent transportability to bone and accumulation in bone, making it usable as a boron neutron capture therapy for cancerous tissue surrounding bone, and which can be used for both treatment and diagnosis as needed, as well as a boron neutron capture therapy agent containing the same. [Solution] In the boron cluster structure-containing compound, the boron cluster group is bonded to a bone-transporting and / or bone-accumulating oligopeptide group via a linker group. The agent for boron neutron capture therapy contains this boron cluster structure-containing compound.

Description

[Technical Field]

[0001] The present invention 10 This invention relates to a boron cluster structure-containing compound used in boron neutron capture therapy, which reduces or kills cancer cells by accumulating B at the site of bone metastatic lesions of cancer and causing the surrounding cancer cells to emit alpha particles and Li nuclei, and to a boron neutron capture therapy agent containing the same. [Background technology]

[0002] The three main treatments for cancer are: surgical removal of cancerous tissue such as the primary tumor, metastatic lesions, or organs affected by the tumor; drug therapy such as chemotherapy, endocrine therapy (hormone therapy), and molecular targeted therapy; and radiation therapy, which uses therapeutic radiation such as X-rays, electron beams, proton beams, heavy ion beams, alpha rays, beta rays, gamma rays, and neutron beams to reduce or kill cancer cells. Recently, nuclear medicine therapy has also become available, in which radioactive isotopes are accumulated in cancerous tissue, particularly cancer cells, such as the primary tumor, and radiation is applied only to the surrounding area to reduce or kill cancer cells.

[0003] Boron neutron capture therapy (BNCT), a treatment method distinct from such nuclear medicine therapies, is a cancer treatment method based on the uptake of boron compounds into cancer cells and irradiation with neutrons (Non-patent documents 1-3).

[0004] Boron ( 10 When thermal neutrons are irradiated onto B), alpha rays with high linear energy transfer (LET) and relative biological effectiveness (RBE) are produced. 7 It splits into Li nuclei (Non-Patent Literature 4). These have strong cytotoxic properties, and their respective ranges are 9-10 μm and 4-5 μm, which is roughly equivalent to or less than the size of a single cell, so they have almost no effect on surrounding normal cells. 10It is possible to selectively kill cancer cells by damaging the DNA of cancer cells that have incorporated B. From these perspectives, BNCT is necessary for cancer cells to 10 A high level of B integration is required (Non-Patent Document 5).

[0005] As compounds used for BNCT, 10 Boronophenylalanine containing B is known (Patent Document 1). Boronophenylalanine can improve tumor accumulation due to its phenylalanine structure and is already used as an anticancer drug called steboronine (generic name: borophalan).

[0006] 10 B is not only difficult to fission without thermal neutron irradiation, but also naturally occurring boron 10 Despite containing B, it is known to be safe for the human body, so using it in BNCT is unlikely to cause adverse effects on other organs or the blood that are not irradiated with thermal neutrons.

[0007] Incidentally, bone is rich in growth factors, making it an ideal environment for cancer to proliferate, and bone metastases from cancer are frequently seen in patients with breast cancer, prostate cancer, lung cancer, and other cancers. As bone metastases progress, fractures, pain, and spinal cord compression occur, reducing ADL and QOL. Currently, clinical treatments for bone metastases include surgery, hormone therapy, chemotherapy, and bone-modifying agents such as zoledronic acid and denosumab, but these are aimed at preventing fractures and alleviating pain, and are not first-line treatments for bone metastases. Furthermore, bone has poor blood flow, and the low affinity of drugs for hydroxyapatite, a major component of bone, limits the delivery of most anticancer drugs to the bone, leading to reduced treatment effectiveness. Therefore, selective delivery of anticancer drugs to the bone is required for the treatment of bone metastases.

[0008] On the other hand, non-collagen proteins found in bone, such as osteopontin and bone sialoprotein, are known to contain many acidic amino acid sequences such as aspartic acid (Asp) and glutamic acid (Glu). The repeating sequences of Asp and Glu have a high affinity for hydroxyapatite, and their usefulness as transport carriers to bone has been reported.

[0009] Voronophenylalanine exhibits tumor accumulation but shows little to no bone transport or accumulation. Therefore, there was a need for a compound that, unlike boronophenylalanine, has excellent transport and accumulation properties in bone, making it usable as a boron neutron capture therapy, and that can be used for both treatment and diagnosis as needed. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Heber EM, et al., Proc Natl Acad Sci US A. 2014 Nov 11;111(45):16077-81. doi: 10.1073 / pnas.1410865111. Epub 2014 Oct 27. PMID: 25349432; PMCID: PMC4234606. [Non-Patent Document 2] Nedunchezhian K et al., J Clin Diagn Res. 2016 Dec;10(12):ZE01-ZE04. doi: 10.7860 / JCDR / 2016 / 19890.9024. Epub 2016 Dec 1. PMID: 28209015; PMCID: PMC5296588. [Non-Patent Document 3] Barth RF, et al., Cancer Commun (Lond). 2018 Jun 19;38(1):35. doi: 10.1186 / s40880-018-0299-7. PMID: 29914561; PMCID: PMC6006782. [Non-Patent Document 4] Barth RF, et al., Realities and prospects. Cancer. 1992 Dec 15;70(12):2995-3007. doi: 10.1002 / 1097-0142(19921215)70:12<2995::aid-cncr2820701243>3.0.co;2-#. PMID: 1451084. [Non-Patent Document 5] Barth RF, et al., Sci Am. 1990 Oct;263(4):100-3, 106-7. doi: 10.1038 / scientificamerican1090-100. PMID: 2173134. [Patent Documents]

[0011] [Patent Document 1] Japanese Patent Publication No. 2019-1761 [Overview of the Initiative] [Problems that the invention aims to solve]

[0012] The inventors of the present invention have found a compound containing a closo-dodecaborate group, which is a boron cluster, in the same molecule using an aspartic acid peptide as a transport carrier to bone targeting hydroxyapatite, and based on this compound, peripheral compounds using oligopeptides with bone transportability and / or bone accumulation properties, and further, a derivative compound having a ligand such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) that forms a stable complex with gallium as a RI labeling site, and have found that the above problems can be solved, thereby completing the present invention.

[0013] The present invention has been made to solve the above problems, and has excellent transportability to bone and accumulation in bone, can be used for treatment as boron neutron capture therapy for cancer tissue around bone, and can be used for treatment and diagnosis as needed, and an object thereof is to provide a boron cluster structure-containing compound and a boron neutron capture therapy agent containing the same.

Means for Solving the Problems

[0014] The boron cluster structure-containing compound made to achieve the above object is characterized in that the boron cluster group is bonded to an oligopeptide group having bone transportability and / or bone accumulation through a linker group.

[0015] In this boron cluster structure-containing compound, the boron cluster group is, for example, the following chemical formula (1)

Chemical formula

[0016] In this boron cluster structure-containing compound, at least any one of the boron atoms in the boron cluster group is 10It is preferable that it consists only of B.

[0017] In this boron cluster structure-containing compound, all boron atoms in the boron cluster group are 10 It is even more preferable if it is B.

[0018] This boron cluster structure-containing compound is characterized in that the oligopeptide group is at least one dehydrogenated group selected from, for example, an acidic amino acid such as oligoaspartic acid, oligoglutamic acid, oligo(γ-carboxyglutamic acid), and a peptide obtained by mixing at least two of these acidic amino acids.

[0019] In this boron cluster structure-containing compound, a group consisting of a ligand having at least multiple oxygen atoms, nitrogen atoms, and sulfur atoms coordinated with an atom of a radioactive isotope may be bonded to the linker group.

[0020] This boron cluster structure-containing compound contains, for example, the radioactive isotope, 64 Cu, 67 Ga, 68 Ga, 99m Tc and 111 It is at least one of the options selected from In.

[0021] This boron cluster structure-containing compound is characterized in that the ligand is at least one selected from DOTA, HBED-CC, NOTA, HYNIC, MAG3, and DTPA.

[0022] This boron cluster structure-containing compound has the linker group, for example, as shown in chemical formula (2) below. [ka] (In formula (2), A 1This refers to a group consisting of a ligand having at least one of several oxygen atoms, nitrogen atoms, and sulfur atoms coordinated with a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an atom of a radioactive isotope, and A 2 This represents the oligopeptide group, and A 3 (represented by the boron cluster group) That is the case.

[0023] The boron neutron capture therapy agent developed to achieve the aforementioned objective is characterized by containing the boron cluster structure-containing compound.

[0024] This boron neutron capture therapy agent emits alpha particles and Li nuclei from the boron cluster structure-containing compound upon irradiation with thermal neutrons.

[0025] This boron neutron capture therapy agent may further contain a boron-containing compound that is decaborane. [Effects of the Invention]

[0026] The boron cluster structure-containing compound of the present invention has excellent transport and / or accumulation capabilities in bone because it possesses bone-transporting and / or bone-accumulating oligopeptides. Furthermore, because it has a boron cluster structure, it is a useful component that can be used for cancer treatment in bone cancer tissue and surrounding cancer tissue that has metastasized to the bone in the early to late stages of breast cancer, lung cancer, prostate cancer, and multiple myeloma. By irradiating these tissues with thermal neutrons, it emits alpha rays, damaging the DNA of the cancer cells and specifically and selectively reducing or killing the cancer cells.

[0027] If this boron cluster structure-containing compound has ligands that coordinate with radioactive isotope atoms as needed, it becomes possible to diagnose cancer by detecting radiation emission based on the radioactive isotope and treat cancer by emitting alpha rays based on the boron in the boron cluster structure.

[0028] Using a boron neutron capture therapy agent containing this boron cluster structure compound 10 Previously, neutron irradiation in a nuclear reactor was necessary to decay boron (B), but in recent years, thermal neutron generators, such as cyclotrons, have become smaller and are increasingly being used in medical settings to irradiate boron with thermal neutrons. As a result, boron neutron capture therapy drugs can now be used relatively easily in clinical settings using such generators to treat cancer.

[0029] Boron neutron capture therapy drugs utilize a combination of a boron cluster structure-containing compound, which exhibits excellent transport and accumulation capabilities in bone, and a boron compound without a boron cluster structure, which exhibits excellent transport and accumulation capabilities in cancer cells other than bone. This combination synergistically exhibits anticancer effects, resulting in high therapeutic efficacy. [Brief explanation of the drawing]

[0030] [Figure 1] This chart shows the purity of the boron neutron capture therapy agent to which the present invention is applied. [Figure 2] This chart shows the purity of another boron neutron capture therapy agent to which the present invention is applied. [Figure 3] This graph shows the degree of binding of two boron neutron capture therapy agents to hydroxyapatite, to which the present invention is applied. [Figure 4] This graph shows the absorption and distribution of two types of boron neutron capture therapy drugs to organs using the present invention, as indicated by their radioactivity distribution. [Figure 5] This graph shows the absorption and distribution of a boron neutron capture therapy agent to organs, as well as the boron and radioactivity distributions, according to the present invention. [Modes for carrying out the invention]

[0031] The following describes in detail embodiments for carrying out the present invention, but the scope of the present invention is not limited to these embodiments.

[0032] The boron cluster structure-containing compound of the present invention is given by the following chemical formula (1) [ka] The clotho-dodecaborate group represented by (in formula (1), ● represents BH), i.e., the following chemical formula (1') [ka] The boron cluster group is bonded to the bone-transporting and / or bone-accumulating oligopeptide group via a linker group that connects the boron cluster group to the bone-transporting and / or bone-accumulating oligopeptide group.

[0033] Natural boron also contains 20% 10 Where B is present, the boron cluster group of formula (1) has 12 boron atoms, all of which are 20%, just like in nature. 10 It may include B, but at least one of them 10 It may consist only of B, and all of them 10 It may consist only of B.

[0034] The bone-transporting and / or bone-accumulating oligopeptide groups include 2 to 14 molecules, preferably 5 to 11 molecules, and more preferably 8 to 11 molecules of oligopeptides, such as oligoaspartic acid, oligoglutamic acid, and the dehydrogenation group of an oligomer in which oligo(γ-carboxyglutamic acid) is directly bonded, with oligo(γ-carboxyglutamic acid) being particularly preferred. The aspartic acid (Asp), glutamic acid (Glu), and γ-carboxyglutamic acid (Gla) constituting these may be optically active (D-isomer or L-isomer; for example, 99ee% or more) or racemic (DL-isomer), but inexpensive L-aspartic acid, L-glutamic acid (Glu), and L-γ-carboxyglutamic acid are preferred. Due to their high bone affinity, such oligopeptides can efficiently transport or accumulate boron cluster structure-containing compounds in bone.

[0035] The linker group can be of any structure as long as it does not inhibit the efficient transport or accumulation of boron cluster structure-containing compounds in bone, but among them, the following chemical formula (2) [ka] (In formula (2), A 1 This represents a hydrogen atom and a linear, branched, and / or cyclic alkyl group having 1 to 6 carbon atoms, but may also represent a group consisting of a ligand coordinated with an atom of a radioactive isotope, as described later. 2 This represents the oligopeptide group. 3 Preferably, the group is represented by the boron cluster group mentioned above.

[0036] Compounds containing such boron cluster structures have bone-transporting and / or bone-accumulating oligopeptide groups. These oligopeptide groups guide the boron cluster groups to exhibit high transport and accumulation capabilities in bone, particularly in bone metastatic lesion sites.

[0037] The detailed mechanism by which these compounds exhibit high transport and accumulation capabilities in bone, particularly in bone metastatic lesion sites, is not entirely clear, but it is speculated as follows: These oligopeptides, which make up the oligopeptide group, are known to have osteoffinity and accumulate in hydroxyapatite. Therefore, it is speculated that the high transport and accumulation capabilities of the boron cluster structure-containing compound in bone containing a considerable amount of hydroxyapatite are due to the osteoffinity of this oligopeptide group. To explain in more detail, it is strongly speculated that in bone, particularly in areas with high osteoblastic activity within bone metastatic lesion sites, bone is successively formed in an amorphous or amorphous state. Due to the amorphous state, the surface area there is large, and blood flow in the surrounding area increases. As a result, the boron cluster structure-containing compound accumulates in bone metastatic lesion sites, i.e., hydroxyapatite, due to the osteoffinity of this oligopeptide group, which can accumulate in bone metastatic lesion sites, i.e., hydroxyapatite, more than in normal bone.

[0038] Bone metastases can occur in the early to late stages of breast cancer, lung cancer, prostate cancer, and multiple myeloma. Cancer cells that have metastasized to the bone release parathyroid hormone-related protein (PTHrP), which stimulates osteoblasts to express RANK (receptor activator of NF-κB) ligand. When this ligand binds to RANK in preosteoclasts, it promotes the differentiation of preosteoclasts into osteoclasts, causing bone resorption and the elution of growth factors such as transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF) from the bone, resulting in the proliferation of cancer cells. However, since compounds containing boron cluster structures accumulate at the site of bone metastases, localized irradiation with thermal neutrons can lead to the accumulation of boron cluster structures. 10 When B decays, it emits alpha particles and lithium nuclei, which damage the DNA of cancer cells in bone cancer tissue and surrounding cancer tissue with alpha particles, making it possible to specifically and selectively reduce or kill cancer cells.

[0039] 10 A group consisting of a ligand having at least multiple oxygen atoms, nitrogen atoms, and sulfur atoms coordinated with an atom of a radioactive isotope other than B, such as an atom of a radioactive isotope metal element like copper, gallium, technetium, or indium used for diagnostics, may be bonded to the linker group.

[0040] These radioactive isotopes decay and emit positrons, making them detectable by positron detection. More specifically, 64 Copper, like Cu 68 Ga· 68 Gallium, like Ga, 99m Technetium such as Tc, and 111 This includes at least one radioactive isotopic metallic element selected from indium, such as In.

[0041] The ligand is at least one selected from DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrazcetic acid), HBED-CC (N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), HYNIC (Hydrazinonicotinic acid)), MAG3 (mercapto acetyltriglycin), and DTPA (1,4,7-triazaheptane-1,1,4,7,7-pentaacetic acid).

[0042] A radioactive isotope and the ligand that coordinates to it, 64 Cu, 67 Ga, 68 Ga or 111 In and DOTA; 67 Ga or 68 Ga and HBED-CC or NOTA; 99m Tc and HYNIC; and 99m Tc and MAG3; 111 A combination selected from In and DTPA is preferable.

[0043] Having a group consisting of such ligands allows for the sequential diagnosis of cancer, particularly bone metastases, by detecting radioactive isotope-based radiation emission using only boron cluster structure-containing compounds, and the treatment of bone metastases and surrounding cancers by alpha-ray emission based on boron in the boron cluster structure. For example, a boron cluster structure-containing compound is administered, and the radiation emission is imaged using a scintigram by capturing it with a scintillation camera or scanning it with a scintillation scanner. This allows for cancer diagnosis by detecting the extent to which the compound is absorbed, distributed, and accumulated in bone metastases, surrounding areas, or other organs. When the compound has sufficiently accumulated in the area to be treated, thermal neutrons are locally irradiated near that area to detect the boron in the boron cluster structure. 10Cancer treatment can be performed by emitting alpha rays and lithium nuclei based on B.

[0044] Within nuclear medicine practice, nuclear medicine diagnosis focuses primarily on diagnosis, while nuclear medicine therapy focuses primarily on treatment. However, in tumor treatment using nuclear medicine therapy, various tests and diagnoses must be performed before treatment begins to determine the appropriate treatment method. In particular, boron cluster structure-containing compounds with ligand groups can be used in radiotheranotics, a diagnostic and therapeutic method that combines nuclear medicine diagnosis and nuclear medicine therapy, by utilizing radionuclides with different properties to enable diagnosis and treatment using compounds with the same or similar skeletons.

[0045] Thus, when a boron cluster structure-containing compound has a group consisting of such ligands, it becomes possible to predict therapeutic effects and side effects, and set the dosage for each patient. Even if the size, extent, and stage of progression of bone metastases and surrounding cancerous tissue differ from patient to patient, it is possible to administer an appropriate dosage that is highly effective with fewer side effects, thereby reducing the burden on the patient and enabling effective treatment, and thus allowing for appropriate diagnosis and treatment, and enabling personalized medicine.

[0046] Furthermore, once the therapeutic effects of boron neutron capture therapy agents containing boron cluster structure-containing compounds having groups made up of such ligands can be sufficiently understood for treating bone metastases and surrounding cancerous tissue, it will become possible to use boron cluster structure-containing compounds that are similar except for lacking ligand groups, without requiring detection of radioactive emissions.

[0047] An example of a boron cluster structure-containing compound can be synthesized as follows, with reference to the chemical reaction equation below. [ka]

[0048] First, the DOTA group and (Gla) are obtained from derivative 16 by hydrolysis. 11A lysine derivative 17 having an oligomer is synthesized. A boron cluster group-containing derivative 13 obtained by a known method is condensed with a terephthalic acid derivative 11 to obtain a boron cluster group-containing terephthalic acid derivative, which is reacted with the lysine derivative 17 to synthesize a boron cluster structure-containing compound precursor 18, and finally 67 Ga(as needed) 68 By coordinating Ga, a desired boron cluster structure-containing compound 19 is obtained. Furthermore, DOTA is used as the ligand and the radioactive isotope element is 67 Ga(or 68 Although an example using Ga) has been shown, boron cluster structure-containing compounds with other ligands, other radioactive isotopes, or other oligopeptide groups can be synthesized in the same manner. Similarly, boron cluster structure-containing compounds without ligands can also be synthesized in the same manner.

[0049] Thus, compounds containing boron cluster structures can be used as useful components for cancer treatment using boron neutron capture therapy.

[0050] The boron neutron capture therapy agent of the present invention contains an appropriate amount of the boron cluster structure-containing compound dissolved or suspended in water, such that the DNA of cancer cells in and around bone metastatic lesion sites is damaged by alpha radiation from thermal neutron irradiation, thereby relieving pain and causing the death or reduction of cancer cells.

[0051] This boron neutron capture therapy agent can be used as a bone medicine, for example, as a pain reliever for bone metastases or as a cancer treatment drug, because its oligopeptide groups, such as the oligo(γ-carboxyglutamic acid) group, exhibit high bone affinity, bone transport, and / or bone accumulation. If this boron neutron capture therapy agent has a ligand group coordinated with an atom of a radioactive isotope element, it can be used in radiotheranostics, where the radioactive isotope element is used as a radionuclide and, for example, in bone imaging to visualize bone metastases, while also being used as a pain reliever for bone metastases or as a cancer treatment drug (anticancer drug) for treatment.

[0052] This boron neutron capture therapy agent, when administered to the body, is transported and accumulates in the bone, particularly in the site of bone metastases. Upon irradiation with thermal neutrons, the boron cluster structure-containing compound emits alpha particles and lithium nuclei, damaging the DNA of cancer cells in and around the bone metastases with alpha particles, thus providing pain relief and leading to the death or reduction of cancer cells, making it useful in cancer treatment.

[0053] This boron neutron capture therapy agent may contain a boron-containing compound that is decaborane, along with a boron cluster structure-containing compound. The decaborane-containing compound is used in boron neutron capture therapy and has a different mechanism of action than the boron cluster structure-containing compound. Therefore, by irradiating with thermal neutrons, it emits alpha rays to different cancer cells, killing or reducing them, thus producing a synergistic anticancer effect.

[0054] In recent years, relatively small cyclotrons that generate thermal neutrons have become commercially available, so boron neutron capture therapy agents containing boron cluster structure compounds can be used for treatment relatively easily and in a variety of locations. [Examples]

[0055] The following shows an example of synthesizing a boron cluster structure-containing compound to which the present invention is applied, preparing a boron neutron capture therapy agent containing it, and evaluating it.

[0056] (Reagents and equipment) [ 67Ga]Ga-citrate was purchased from Nippon Medi-Physics Co., Ltd. (Tokyo, Japan). Following the previously reported method (Ben Azzouna R, et al., EJNMMI Radiopharm Chem., 2017;2(1):3. doi: 10.1186 / s41181-016-0021-5. Epub 2017 Feb 7. PMID: 29527564; PMCID: PMC5835976), Sep-Pak® Silica Plus Light Cartridge (Waters Co., Ltd., Milford, USA) was used [ 67 It was converted to Ga[GaCl3]. 2-Chlorotrityl chloride resin and 5-Chloro-1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole 3-oxide hexafluorophosphate (HCTU) were purchased from Watanabe Chemical Industry Co., Ltd. (Hiroshima, Japan). 1-hydroxybenzotriazole monohydrate (HOBt) and N,N-diisopropylcarbodiimide (DIPCI) were purchased from Kokusan Chemical Co., Ltd. (Tokyo, Japan). dl-serine, benzyl bromide (BnBr), methanesulfonyl chloride (MsCl), di-tert-butyl malonate, sodium hydride (NaH), triisopropylsilane (TIS), N,N-diisopropylethylamine (DIPEA), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl), ethyl bromoacetate, and N,N-Dimethylacetamide (DMA) were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Tetrahydrofuran (THF) was purchased from Kanto Chemical Co., Ltd. (Tokyo, Japan). Z-chloride (CbzCl), triethylamine (TEA), sodium iodide (NaI), 10% Pd(OH)2 / C, Fmoc-OSu, tert-butyl bromoacetate, trifluoroacetic acid (TFA), sodium tetrafluoroborate (NaBF4), and N,N-dimethylformamide (DMF) were purchased from Fujifilm Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Sodium dodecahydrododecaborate was purchased from Katchem Ltd (Prague, Czech Republic). Cyclen was purchased from BLD Pharmatech (Shanghai, China). Fmoc-l-Asp(OtBu)-OH and Fmoc-l-Lys(Boc)-OH were purchased from AmBeed (Arlington Heights, IL, USA). Other reagents were purchased from Nacalai Tesque Co., Ltd. (Kyoto, Japan). Furthermore, only top-grade reagents were used. Regarding reverse-phase HPLC, Cosmosil 5C 18 -AR-II(4.6×150mm), Cosmosil 5C 18 -AR-II (10×150mm), Cosmosil 5C 18 - Each AR-II (20×250mm) column was purchased from Nakalai Tesque Co., Ltd., and Hydrosphere C 18 The (10×150 mm) was purchased from YMC Corporation (Kyoto, Japan). The LC-20AD liquid delivery unit, CTO-20A column oven, and SPD-20A absorbance detector were products of Shima Corporation, Tsu Works (Kyoto, Japan). For nuclear magnetic resonance (NMR) spectroscopy measurements, a JEOL Ltd. (Tokyo, Japan) JNM-ECS400 was used, and for mass spectrometry, a JEOL Ltd. JMS-T100TD was used. For radiation measurement, a Hitachi, Ltd. (Tokyo, Japan) ARC-7010 Autowell Gamma System was used.

[0057] First, an aspartic acid oligopeptide group is used as a transport carrier to bone targeting hydroxyapatite, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrazcetic acid (DOTA), which is known to form a stable complex with gallium, is used as the RI labeling site, and the radioisotope-containing compound clotho-Dodecaborate-l-Lys-[ contains the boron cluster clotho-dodecaborate within the same molecule. 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Ga19) and radioisotope-free compounds19 were synthesized and evaluated. Furthermore, with the aim of synthesizing compounds that accumulate more readily in bone, we considered that the density of carboxyl groups contributes to high accumulation in bone, and focused on γ-carboxyglutamic acid (Gla), an acidic amino acid in which another carboxyl group is bonded to the γ carbon of glutamic acid. Using the γ-carboxyglutamic acid oligopeptide group as a transport carrier to bone, we formulated a radioactive isotope-containing compound clotho-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67 We synthesized and evaluated a compound 24 free of radioactive isotopes [Ga]24).

[0058] In addition, 68 Ha (T 1 / 2 (68 min) is one of the positron-emitting radionuclides used in PET, and is currently a widely used PET radionuclide in clinical practice. 18 F 11A cyclotron is necessary for the production of carbon, 68 Ga teeth 68 Ge- 68 Because it can be produced using a Ga generator, it can be used even in medical facilities without expensive cyclotron equipment, and has been widely used in clinical practice in recent years. Therefore, 68 It may also be used for Ga-labeled PET, but in this example, a longer half-life and easier handling are used. 67 Ha (T 1 / 2 Synthesis and evaluation will be carried out using (3.3 days).

[0059] (Example 1: Synthesis example of a boron cluster structure-containing compound) (1-1) Synthesis of non-radiolabeled compounds and labeled precursors, and compounds such as radiolabeled Fmoc-Gla(OtBu)2-OH and DOTA-tris(tert-butyl ester) (1-10) The synthesis of functionally protected Fmoc-Gla(OtBu)2-OH and DOTA-tris(tert-butyl ester) was carried out in much the same manner as existing methods (see Jiang S, et al., J.Org.Chem., 71, p7307-7314 (2006) and Davis JS, et al., J. Chem. Soc., Perkin Trans. 1, 24, p2907-2915 (2000) for Gla; see Chabloz N, et al., Chem Eur J. 25, p10895-10906 (2019) for DOTA) (Schemes 1-2). Fmoc-Gla(O t During one of the synthesis steps of Bu)2-OH, racemization occurred, and subsequent evaluations were performed using the racemic mixture.

[0060] [ka]

[0061] [ka]

[0062] (1-2) Bis(2,5-dioxopyrrolidin-1-yl) terephthalate (11) Terephthalic acid (0.50 g, 3.0 mmol), N-hydroxysuccinimide (NHS) (0.8 g, 7.3 mmol), and EDCI·HCl (1.4 g, 7.5 mmol) were added to 30 mL of dichloromethane and stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the solvent was removed by vacuum distillation, and the compound was purified by silica gel chromatography (Hexane / Ethyl Acetate = 1 / 1, 1 / 2, 1 / 3, 0 / 1) to obtain 0.3 g of compound 11 as a white powder (yield 30%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.91 (s, 8H), 8.31 (s, 4H)

[0063] (1-3) Tetrabutylammonium-4-amino-EG2-closo-dodecaborate (13) Compounds 12 and 13 were synthesized based on an existing method (Mishiro K, et al., J Med. Chem., 2022 Dec 22;65(24), p16741-16753 (2022). doi: 10.1021 / acs.jmedchem.2c01586. Epub 2022 Dec 13. PMID: 36512639.).

[0064] (1-4) NHS-1,4-dioxane-closo-dodecaborate (14) Compound 13 (20 mg, 41 μmol) was dissolved in 3.0 mL of N,N-dimethylmethanamide (DMF), then compound 11 (74 mg, 0.21 mmol) and TEA (23 μL, 0.16 mmol) were added, and the mixture was stirred for 18 hours. MS (ESI -After confirming the completion of the reaction, the solvent was removed by reduced pressure. The solution was purified by silica gel chromatography (Ethyl Acetate / Acetonitrile = 1 / 0,0 / 1) to obtain 24 mg of 14 as a white powder (yield 80%). MS (ESI - ) m / z: [M] - calcd for C 16 H 27 B 12 N2O7 - 489.30131; found, 489.28188

[0065] [ka]

[0066] (1-5) Introduction of Fmoc-l-Asp(OtBu)-OH and Fmoc-l-Lys(Boc)-OH into 2-Chlorotrityl chloride resin (15,20) To 2-Chlorotrityl chloride resin (92.6 mg, 0.10 mmol), dichloromethane (1.8 mL), Fmoc-l-Asp(OtBu)-OH (165 mg, 0.4 mmol), and diisopropylethylamine (DIPEA) (38 μL, 0.2 mmol) were added and the mixture was stirred at room temperature for 5 minutes. Then, DIPEA (19 μL, 0.1 mmol) was added and the mixture was stirred at room temperature for 2 hours. Next, methanol (1.5 mL) was added and the mixture was reacted for 20 minutes, after which it was washed with DMF and Fmoc-l-Asp(OtBu)-OH was introduced. Similarly, introduction was also performed using Fmoc-Gla(OtBu)2-OH instead of Fmoc-l-Asp(OtBu)-OH.

[0067] (1-6) Extension of the protective peptide chain As shown below, the protected peptide was extended by repeatedly performing the deprotection of the Fmoc group and the condensation reaction of the Fmoc-l-Asp(OtBu)-OH with the side chain protected. (1-6(i)) Deprotection of the Fmoc group 20% piperidine / DMF was added and the mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the mixture was washed with DMF until the washing solution was neutral. (1-6(ii)) Side chain protection Condensation reaction of Fmoc-l-Asp(OtBu)-OH and Fmoc-l-Lys(Boc)-OH To a protected peptide resin (0.1 mmol) from which the Fmoc group had been removed, Fmoc-l-Asp(OtBu)-OH (103 mg, 0.25 mmol) with its side chains protected, DMF (1 mL), and HOBt (38.3 mg, 0.25 mmol) were added. DIPCI (39 μL, 0.25 mmol) was then added, and the mixture was stirred at room temperature for 1.5 hours. After washing with DMF, a Kaiser test was performed on a portion of the resin, and the condensation reaction was repeated until a negative result was obtained. The corresponding Gla compounds were synthesized by repeatedly condensing Fmoc-Gla(OtBu)2-OH in the same manner as above. After the synthesis of the corresponding Asp compound, a protected peptide resin (0.1 mmol) from which the Fmoc group had been removed was mixed with side-chain protected Fmoc-L-Lys(Boc)-OH (117 mg, 0.25 mmol), DMF (1 mL), and HOBt (38.3 mg, 0.25 mmol). DIPCI (39 μL, 0.25 mmol) was then added, and the mixture was stirred at room temperature for 1.5 hours. After washing with DMF, a Kaiser test was performed on a portion of the resin, and the condensation reaction was continued until a negative result was obtained. In the same manner as above, condensation of Fmoc-L-Lys(Boc)-OH was carried out to introduce Fmoc-L-Lys(Boc)-OH into the corresponding Gla compound.

[0068] (1-7) Binding of DOTA-tris(tert-butyl ester) (16,21) After constructing the protective peptide chain on the resin, the Fmoc group was removed by 20% piperidine / DMF treatment, as in the method described above. Then, DOTA-tris(tert-butyl ester) (172 mg, 0.3 mmol) and HCTU (124 mg, 0.3 mmol) were added in DMF (1 mL), followed by the addition of DIEPA (102 μl, 0.6 mmol). The mixture was stirred at room temperature for 3 days to allow conjugation.

[0069] (1-8) Release from DOTA-tris(tert-butyl ester)-bound peptide chain and removal of acid-sensitive side chain protecting group (17,22) A protective peptide resin (0.1 mmol) bound to DOTA-tris(tert-butyl ester) was sequentially mixed with TFA (950 μL), TIS (25 μL), and H2O (25 μL), and the mixture was stirred at room temperature for 5 hours. After removing the solvent with nitrogen gas, the resin was removed by suction filtration using a Kiriyama funnel with methanol. The filtrate was concentrated and purified by reverse-phase HPLC. DOTA- l-Lys-(l-Asp) 11 -OH purification is 5C 18 Using an AR-II (20 × 250 mm) transduction device, the mobile phase was converted from a 95:5 water:methanol mixture containing 0.1% TFA to an 80:20 mixture over 20 minutes using a gradient method at a flow rate of 12.0 mL / min. Purification of DOTA- l-Lys-(Gla)5-OH is performed using Hydrosphere C 18 A 10×150 mm column was used, and the mobile phase was changed from 100:0 water:methanol containing 0.1% TFA to 95:5 over 20 minutes using a gradient method at a flow rate of 4.0 mL / min. DOTA-l-Lys-(Gla)5-OH is highly polar and not easily retained in the column, so the unretained target product was recovered, and impurities were removed as much as possible. DOTA- l-Lys-(l-Asp) 11 -OH was obtained as a white powder in an amount of 14.2 mg (yield 7.9%). MS (ESI+) calcd for C66 H 95 N 17 O 42 ([M + 2H] 2+ ): 899.80 found 899.90 DOTA - l - Lys - (Gla)5 - OH was obtained as a white powder (76.8 mg, yield 54.9%). MS (ESI+) calcd for C 52 H 75 N 11 O 34 ([M + 2H] 2+ ): 699.73 found 699.84

[0070] (1 - 9) closo - Dodecaborate - l - Lys - DOTA - (l - Asp) 11 - OH (18) Compound 14 (6.2 mg, 8.4 μmol), 17 (5.0 mg, 2.8 μmol), and TEA (80 μL, 0.58 mmol) were added to 0.40 mL of DMF and stirred at room temperature for 3 hours. The completion of the reaction was confirmed by reverse - phase HPLC and purification was carried out. Purification was performed using 5C 18 AR - II (10×150 mm), with a mobile phase gradient method that changes from water:methanol = 85:15 containing 0.1% TFA to 55:45 in 20 minutes at a flow rate of 4.0 mL / min, and 2.3 mg of 18 was obtained as a white powder (yield 38%). MS (ESI - ) m / z: [M] 2- calcd for C 78 H 118 B 12 N 18 O 46 1086.43; found, 1086.39

[0071] (1 - 10) closo - Dodecaborate - l - Lys - DOTA - (Gla)5 - OH (23) Compound 14 (8.4 mg, 11 μmol), 22 (10 mg, 7.2 μmol), and TEA (100 μL, 0.73 mmol) were added to 0.30 mL of DMF and stirred at room temperature for 3 hours. The reaction was confirmed by reverse-phase HPLC and then purified. Purification was performed using 5C. 18 Using an AR-II (10 × 150 mm) microscope, the mobile phase was converted from 0.1% TFA-containing water:methanol 80:20 to 70:30 over 20 minutes using a gradient method at a flow rate of 4.0 mL / min, yielding 3.2 mg of TFA as a white powder (yield 25%). MS (ESI - ) m / z: [M] - calcd for C 64 H 98 B 12 N 12 O 38 1773.74; found, 1773.69

[0072] (1-11) closo-Dodecaborate-l-Lys-(Ga-DOTA)-(l-Asp) 11 -OH (19) Compound 18 (1.6 mg, 0.7 μmol) and Ga(NO3)3 (1.9 μg, 7.4 μmol) were added to 0.50 mL of 3 M acetate / ammonium acetate buffer (pH 5.0) and stirred at 40°C for 2 hours. The reaction was confirmed to be complete by reverse-phase HPLC, and the mixture was purified. Purification was performed using 5C. 18 Using an AR-II (4.6 × 150 mm) microscope, the mobile phase was converted from 0.1% TFA-containing water:methanol 85:15 to 45:55 over 20 minutes using a gradient method at a flow rate of 1.0 mL / min, yielding 0.45 mg of TFA as a white powder (yield 27%). MS (ESI - ) m / z: [M] 2- calcd for C 64 H 98 B 12 N 12 O 38 1119.89; found, 1119.57

[0073] (1-12) closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Ga] 19) Compound 18 (41 μg, 19 nmol) was dissolved in 40 μL of 3 M acetate / ammonium acetate buffer (pH 5.0), and then [ 67 40 μL of Ga]GaCl3 (1.1 MBq) was added, and the mixture was allowed to stand at 80°C for 15 minutes. Purification was then performed by reverse-phase HPLC. 18 Using AR-II (4.6 × 150 mm), the mobile phase was changed from 85:15 water:methanol containing 0.1% TFA to 45:55 over 20 minutes using a gradient method at a flow rate of 1.0 mL / min. 67 Ga19 was obtained (radiochemical yield 91%, radiochemical purity 95%).

[0074] (1-13) closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67 Ga]24) Compound 23 (40 μg, 23 nmol) was dissolved in 70 μL of 0.4 M HEPES (pH 5.0), and then [ 67 14 μL of Ga]GaCl3 (2.1 MBq) was added, and the mixture was allowed to stand at 80°C for 15 minutes. Purification was then performed by reverse-phase HPLC. Purification was performed in 5C. 18 Using AR-II (4.6 × 150 mm), the mobile phase was changed from 80:20 water:methanol containing 0.1% TFA to 70:30 over 20 minutes using a gradient method at a flow rate of 1.0 mL / min. 67 Ga24 was obtained (radiochemical yield 87%, radiochemical purity 98%).

[0075] [ka]

[0076] [ka]

[0077] (Example 2: Purity evaluation test example of a boron cluster structure-containing compound) (3.1) Closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Ga]19) and the radioactive isotope-free clotho-Dodecaborate-l-Lys-(Ga-DOTA)-(l-Asp) 11 -OH (19) purity [ 67 Ga]19 was obtained with a radiochemical yield of 91% and a radiochemical purity of 95% or higher. Purification [ 67 Figure 1 shows the chromatograms obtained by analyzing Ga19 and Ga19 using reverse-phase HPLC with radioactivity and UV detectors, respectively. 67 Ga]19 showed the same retention time as 19. From the above, [ 67 It was confirmed that both Ga]19 and 19 exhibit the same chemical structure. (3.2) Closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67 Purity of Ga

[24] and the radioactive isotope-free clotho-Dodecaborate-l-Lys-(Ga-DOTA)-(Gla)5-OH (24) [ 67 Ga]24 was obtained with a radiochemical yield of 87% and a radiochemical purity of 98% or higher. After purification, [ 67 Figure 2 shows the chromatograms obtained by analyzing Ga24 and Ga24 using reverse-phase HPLC. 67 Ga]24 showed the same retention time as 24. From the above, [ 67 It was confirmed that both Ga]24 and 24 exhibit the same chemical structure.

[0078] (Example 3: Affinity evaluation test example of a boron cluster structure-containing compound with hydroxyapatite) closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Ga]19), and closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67 The affinity of compounds containing boron cluster structures with Ga

[24] to hydroxyapatite was evaluated as follows: Radioactive isotope element content[ 67 Ga]19 or [ 67 A 0.4 mL test solution (n=4) was prepared by adjusting the concentration of Ga24 (0.78 pM) and radioactive isotope-free Ga24 (39 μM) in Tris / HCl-buffered saline (150 mM NaCl, 50 mM Tris-HCl) (pH 7.4) to a total of 39 μM. 0.2 mL of this solution was then mixed with 0.2 mL of hydroxyapatite solution (1 mg / mL, 2.5 mg / mL, 10 mg / mL, 25 mg / mL) prepared in Tris / HCl-buffered saline (150 mM NaCl, 50 mM Tris-HCl) (pH 7.4). The 0.4 mL test solution was stirred at 800 rpm for 1 hour at room temperature, then centrifuged at 10,000 G for 5 minutes. The supernatant was used to measure radioactivity and perform a hydroxyapatite affinity evaluation test. The results are shown in Figures 3(a) and 3(b), respectively.

[0079] As is clear from Figure 3, 67 The binding rate of the Ga-labeled compound increased in a hydroxyapatite concentration-dependent manner. This indicates that compounds containing boron cluster structures exhibit excellent bone transport and bone accumulation properties.

[0080] (Example 4: Experimental example I of evaluating the distribution of radioactivity in normal mice containing a boron cluster structure) closo-Dodecaborate-l-Lys-[ 67Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Ga]19), and closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67 The in vivo radioactivity distribution of boron cluster structure-containing compounds with [Ga]24) was evaluated in normal mice (n=4) as follows. Each of these boron cluster structure-containing compounds was prepared in physiological saline to approximately 555 kBq (1.5 mL) to prepare test solutions for boron neutron capture therapy. 0.1 mL of each test solution was intravenously injected into the tail of male ddy mice (6 weeks old; manufactured by Nippon SLC Co., Ltd.; n=4). After 10 minutes, 1 hour, and 3 hours, the mice were sacrificed, their organs were removed and their mass measured, and their radioactivity was measured in the same manner as above. closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 For Ga]19), the weight of all major organs was measured. On the other hand, closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67 For Ga[24), bone and kidney data were measured in the same manner. The results are shown in Figures 4(a) and (b), respectively.

[0081] As is clear from Figure 4(a), closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Ga19) showed high accumulation in bone and was rapidly metabolized and excreted by the kidneys, where it did not accumulate, but it was hardly distributed or absorbed by other organs. From this, it was found that it hardly accumulated in major organs and was rapidly cleared by the kidneys. On the other hand, closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(Gla)5-OH ([ 67Ga]24) indicates that the accumulation of the probe in the bone is closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH ([ 67 Compared to Ga19), similar accumulation was observed even with a smaller number of oligopeptide groups, and similar high accumulation in bone and rapid metabolism and excretion in the kidneys were observed.

[0082] (Example 5: Experimental example II of evaluating the distribution of radioactivity in the body of a boron cluster structure-containing compound using inductively coupled plasma atomic emission spectroscopy (IPC) in normal mice) Six-week-old male ddY mice (manufactured by Nippon SLC Co., Ltd.; n=4) were given 418.9 μg (25 μg as boron) of closo-Dodecaborate-l-Lys-[ 67 Ga](Ga-DOTA)-(l-Asp) 11 -OH was diluted in physiological saline and administered via tail vein. The animals were euthanized 60 minutes after administration, and each organ was removed and its weight measured. 500 μL of stock nitrate was added to each organ, and the organs were incinerated at 110°C for 48 hours. 500 μL of indium standard solution (In 1000) (Fujifilm Wako Pure Chemical Industries, Ltd.), diluted to 200 ppb, was added as an internal standard, and the solution was diluted with ultrapure water to a total volume of 5 mL. Then, the solution was diluted with 6% nitric acid and indium standard solution, diluted to 20 ppb, to a total volume of 20 mL. The boron concentration of this solution was measured using an ICP-OES iCAP Pro XP Duo (Thermo Fisher Scientific). 11 B was quantified using ICP mixed standard solution B (Kanto Chemical Co., Ltd., Tokyo, Japan). The amount of compound uptake by each organ is shown as the percentage of the amount of boron administered per unit tissue weight (%dose / g). The results, along with the radioactivity measurement results as described above, are shown in Figure 5.

[0083] As is clear from Figure 5, the amount of boron measured by IPC-OES is different from the amount measured by radioactivity (RI). 67It was shown that the distribution is equivalent to that of Ga. 10 It was found that B can be used as a boron neutron capture therapy.

[0084] In summary, the boron cluster structure-containing compound to which the present invention is applied, and the boron neutron capture therapy agent containing the same, exhibit excellent transportability and accumulation in bone, making them useful for boron neutron capture therapy at or around bone metastatic lesion sites. This makes it possible to kill or reduce cancer cells at or around bone metastatic lesion sites, and to alleviate pain associated with bone metastases. [Industrial applicability]

[0085] The boron cluster structure-containing compound of the present invention and the boron neutron capture therapy agent containing the same are useful as anticancer agents that kill or reduce cancer cells in bone metastatic lesion sites and surrounding areas, and alleviate pain associated with bone metastases.

Claims

1. A boron cluster structure-containing compound characterized in that a boron cluster group is bonded to a bone-transporting and / or bone-accumulating oligopeptide group via a linker group.

2. The boron cluster group is represented by the following chemical formula (1) 【Chemistry 1】 The boron cluster structure-containing compound according to claim 1, characterized in that it is a clothodecaborate group represented by formula (1) (wherein ● represents BH).

3. In the boron cluster group, at least one of the boron atoms is １０ The boron cluster structure-containing compound according to claim 1, characterized in that it consists only of B.

4. In the aforementioned boron cluster group, all boron atoms are １０ The boron cluster structure-containing compound according to claim 3, characterized in that it is B.

5. The boron cluster structure-containing compound according to claim 1, characterized in that the oligopeptide group is at least one dehydrogenated group selected from oligoaspartic acid, oligoglutamic acid, oligo(γ-carboxyglutamic acid), and peptides obtained by mixing at least two of these acidic amino acids.

6. The boron cluster structure-containing compound according to claim 1, characterized in that a group comprising a ligand having at least multiple oxygen atoms, nitrogen atoms, and sulfur atoms coordinated with an atom of a radioactive isotope is bonded to the linker group.

7. The aforementioned radioactive isotope is, ６４ Cd, ６７ Ga, ６８ Ga, ９９ｍ Tc and １１１ The boron cluster structure-containing compound according to claim 6, characterized in that it is at least one selected from In.

8. The boron cluster structure-containing compound according to claim 6, characterized in that the ligand is at least one selected from DOTA, HBED-CC, NOTA, HYNIC, MAG3, and DTPA.

9. The aforementioned linker group is represented by the following chemical formula (2) 【Chemistry 2】 (In formula (2), A １ represents a group composed of a ligand having a plurality of at least one of an oxygen atom, a nitrogen atom, and a sulfur atom coordinated with a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an atom of a radioisotope, and A ２ represents the oligopeptide group, and A ３ represents the boron cluster group). A group represented by The boron cluster structure-containing compound according to claim 1, characterized in that it is the same as described in claim 1.

10. A boron neutron capture therapy agent characterized by containing a boron cluster structure-containing compound according to any one of claims 1 to 9.

11. The boron neutron capture therapy agent according to claim 10, characterized in that the boron cluster structure-containing compound emits Li atomic nuclei upon irradiation with thermal neutrons.

12. The agent for boron neutron capture therapy according to claim 10, characterized by containing a boron-containing compound that is decaborane.

Images