Targeting agent for diagnosing and treating cancer with high expression of CXCR4

Abstract

The invention relates to the technical field of medical drugs, particularly discloses a targeting agent for diagnosing and treating high-expression CXCR4 cancers, and particularly relates to a structure shown in a general formula (I): # imgabs0 # or an optical isomer, a pharmaceutically acceptable salt and / or a solvate thereof, a preparation method of the compounds and a pharmaceutical composition containing the compounds. The invention also relates to application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in treatment of CXCR4 expression cancers.

Description

Technical Field

[0001] The present invention relates to radiolabeled compounds for selective imaging or treatment of cancer, in particular to compounds targeting cancers with high expression of CXCR4. Background Art

[0002] At present, CXCR4 is a specific receptor for the chemokine stromal cell-derived factor-1 (SDF-1 / CXCL12). Its essence is a cell-expressed protein that plays an important role in the occurrence, chemotaxis and metastasis of tumor cells. CXCR4 is expressed in 75% of tumors (including pancreatic cancer, breast cancer, lung cancer, prostate cancer and colon cancer, etc.). Therefore, the use of radioactive isotope-labeled SDF-1 chelates can be used to perform in vivo CXCR4 expression. In this way, it can be used as a new form of CXCR4 expression in the diagnosis and treatment of highly expressed cancers.

[0003] In the current therapeutic applications of radiolabeled CXCR4 inhibitors, organs with physiological CXCR4 expression prove to be dose-limiting, thus minimizing the therapeutic success rate. In particular, a high renal and salivary gland uptake of the radiolabeled CXCR4 inhibitor substances is significant, which can cause considerable side effects in the case of therapeutic applications. A large accumulation of CXCR4 ligands in the salivary and lacrimal glands leads to considerable side effects. However, a reduction in salivary and lacrimal gland uptake has not yet been achieved and is still described as critical and dose-limiting in early clinical work. The salivary and lacrimal glands are severely and partly irreversibly damaged, especially when using 225 Therefore, there remains a need for improved CXCR4 ligands that provide advantageous options for the detection, treatment and management of CXCR4-expressing cancers, particularly prostate cancer.

[0004] The present invention proposes a series of novel CXCR4 marker inhibitors. Through PET imaging, new compounds are found to be used as tracers and imaging agents in nuclear medicine and for treating cancers expressing CXCR4. Summary of the invention

[0005] The purpose of the present invention is to provide a targeting agent for diagnosing and treating cancers with high CXCR4 expression, so as to achieve the application effect proposed in the above background technology.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A targeting agent for diagnosing and treating cancers with high CXCR4 expression, comprising a structure represented by general formula (I):

[0008]

[0009] in:

[0010] X1 is cyclopropane-1,4-dione, C=CNO2, C=S, 3-cyclobutene-1,2-dione or C=NH;

[0011] R1 is the nuclide;

[0012] R2 is a nuclide with a linker arm or a chelating agent capable of grabbing a nuclide;

[0013] R is H;

[0014] X2 are independently selected from substituted or unsubstituted aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl.

[0015] Preferably, the R can also be selected from

[0016] Preferably, the nuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 2. 191 Radionuclides of Pt, Fe and radionuclides of Pb.

[0017] Preferably, the nuclide with a connecting arm is selected from the following structures:

[0018]

[0019]

[0020] wherein Y4 and Y5 are independently H, alkyl or optionally substituted or unsubstituted aryl, alkylaryl, heteroaryl and alkylheteroaryl; wherein n is an integer from 0 to 5 (ie, n is 0, 1, 2, 3, 4 or 5).

[0021] Preferably, the chelating agent capable of grabbing nuclides can selectively bind to radioactive metals, and its structure is selected from (1a), (1b) and (1c):

[0022]

[0023] wherein R3, R4, R5 and R6 are independently selected from H, -CH2-COOH and -CH2-C(=O)-NH2, or wherein R3 and R5 form -(CH2) m -bridge, m is an integer of 2;

[0024] Where r, v and q are independently 0 or 1.

[0025] Preferably, the chelating agent capable of grabbing nuclides is selected from the following structures:

[0026]

[0027] etc., but not limited to.

[0028] A complex comprising: a radionuclide and any one of the above-mentioned targeting agents.

[0029] Preferably, the radionuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra,165 2. 191 Radionuclides of Pt, Fe and radionuclides of Pb.

[0030] A drug complex comprises the above-mentioned targeting agent or the above-mentioned complex.

[0031] The use of the above-mentioned targeting agent or the above-mentioned complex or the above-mentioned pharmaceutical composition in the following (1) or (2): (1) preparing a drug for treating, improving or preventing cancer expressing CXCR4 and / or its metastasis; (2) preparing a reagent for diagnosing cancer expressing CXCR4 and / or its metastasis.

[0032] The term "CXCR4-expressing cancer and / or its metastases" as used within the meaning of the present invention relates to any cancer whose cancer cells express CXCR4 and its respective metastases. Preferably, the cancer (or cancer cells) that can be treated according to the present invention is selected from pancreatic cancer, prostate cancer, neuroendocrine cancer, colon cancer, lung cancer and breast cancer. In a particularly preferred aspect of the present invention, the cancer expressing CXCR4 is prostate cancer or breast cancer, in particular prostate cancer.

[0033] It should be understood that the CXCR4 targeting agent or the CXCR4 targeting agent contained in the complex can be in the form of anions, or in the form of salts of the novel CXCR4 targeting agent of general formula (I). Therefore, the present invention also relates to salts of the CXCR4 targeting agent of general formula (I) or the CXCR4 targeting agent contained in the complex, in particular pharmaceutically acceptable salts. The present invention also relates to solvates of these CXCR4 targeting agents, including salts and active metabolites thereof, and, where appropriate, tautomers thereof, including prodrug preparations.

[0034] "Pharmaceutically acceptable salts" are pharmaceutically acceptable organic or inorganic acid or basic salts of the compounds of the present invention. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetates, carbonates, chlorides, gluconates, glutamates, lactates, laurates, malate or tartrates.

[0035] The term "aryl" as used in the context of the present invention refers to optionally substituted aromatic groups, i.e. in particular optionally substituted 5-membered aromatic rings or 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups (aryl groups), which may also contain non-aromatic rings.

[0036] The term "heteroaryl" as used in the context of the present invention refers to optionally substituted heteroaryl, i.e. in particular optionally substituted 5-membered aromatic rings or 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups, if more than one heteroatom is present in the ring system, at least two heteroatoms present may be identical or different. Suitable heteroaryl groups are known to the skilled person.

[0037] In the context of the present invention, the term "cycloalkyl" refers to optionally substituted cycloalkyl residues, wherein they may be monocyclic or polycyclic groups, and optionally substituted cyclohexyl can be mentioned as a preferred example of cycloalkyl residues; the term "heterocycloalkyl" refers to optionally substituted cycloalkyl residues having at least one heteroatom in the ring, wherein they may be monocyclic or polycyclic groups; the term "substituted cycloalkyl residue" or "cycloheteroalkyl" refers to a cycloalkyl residue or a cycloheteroalkyl residue in which at least one H is substituted by a suitable substituent.

[0038] The term "alkylaryl" or "alkylheteroaryl" used within the meaning of the present invention refers to a group in which the aryl or heteroaryl group is attached to the respective remainder of the building block via an alkyl group.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] The present inventors have discovered novel targeting agents that are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents and for the treatment of various disease states in cancers expressing CXCR4, particularly high-expressing cancers. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 is one of the PET imaging images of the compound of the present invention;

[0042] Figure 2 This is the second PET imaging image of the compound of the present invention;

[0043] Figure 3 This is the third PET imaging image of the compound of the present invention;

[0044] Figure 4 This is the fourth PET imaging image of the compound of the present invention;

[0045] Figure 5 This is the fifth PET imaging image of the compound of the present invention. DETAILED DESCRIPTION

[0046] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] Embodiment 1:

[0048] 1. According to a preferred embodiment of the present invention, it comprises a structure shown in general formula (I):

[0049]

[0050] in:

[0051] X1 is cyclopropane-1,4-dione, C=CNO2, C=S, 3-cyclobutene-1,2-dione or C=NH;

[0052] R1 is the nuclide;

[0053] R2 is a nuclide with a linker arm or a chelating agent capable of grabbing a nuclide;

[0054] R is selected from substituted or unsubstituted alkylaryl, aryl, alkylheteroaryl and heteroaryl;

[0055] X2 are independently selected from substituted or unsubstituted aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl.

[0056] Preferably, the R is

[0057] Preferably, the nuclide is selected 68 Ga, nuclide structure with linker arms:

[0058] Preferably, the chelating agent capable of grabbing nuclides can selectively bind to radioactive metals, and its structure is selected from (1a):

[0059] wherein R3, R4, R5 and R6 are independently H;

[0060] Where r is 1.

[0061] Preferably, the structure of the chelating agent capable of grabbing nuclides is:

[0062] The results showed that these compounds displayed high binding affinity to CXCR4 and were efficiently internalized.

[0063] As mentioned above, the present invention also relates to a pharmaceutical composition comprising a compound as described above or below, or a complex as described above or below. It should be understood that the pharmaceutical composition comprises a therapeutically effective amount of the compound and / or complex, respectively. The composition may also comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0064] "Patient" includes animals, such as humans, monkeys, cows, horses, cats or dogs. Animals can be mammals, such as non-primates and primates (e.g., monkeys and humans). In one embodiment, the patient is a human.

[0065] Typically, the targeting agent of general formula (I) or its pharmaceutical composition can be administered orally or by parenteral route, typically by injection or infusion. "Parenteral route" means a mode of administration other than enteral and topical administration, and is generally suitable for injection. And includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0066] Embodiment 2:

[0067] 1. Materials and Methods

[0068] All commercially available chemicals were of analytical grade and used without further purification. The in vitro experiments were performed three times, and at least three independent sets of data were obtained for each experiment.

[0069] 2. Synthesis of Chelating Agents

[0070] The chelator moiety was synthesized in high yield and characterized by LC-MS.The synthesis of the chelator bifunctional macrocyclic cyclotamine analog 4-[(1,4,8,11-tetraazacyclotetradecylamine-1-yl)-methyl]benzoic acid, cross-bridged glutaric acid is disclosed.

[0071] I. Synthesis of new CXCR4 ligands

[0072] CXCR4 was prepared by solid phase synthesis on 2-chlorotrityl resin (2CT-resin). Preparation process: Fmoc-Lys(Alloc)-OH was fixed on 2-chlorotrityl resin in equimolar amounts and aminosulfonyl imidazole of the glutamine moiety was generated using N,N'-sulfonyldiimidazole. Benzyloxycarbonyl protected lysine fixed on 2-chlorotrityl resin was added and the reaction was stirred for 20 h to produce the compound. The resin was filtered off and the benzyloxycarbonyl protecting group was cleaved to obtain the intermediate. The substances were separated by preparative HPLC using a water-acetonitrile gradient containing trifluoroacetic acid. To this end, a gradient of acetonitrile in water with a volume fraction of 20% to 50% was used to purify the compound for 15 minutes. The purified compound was analyzed by analytical HPLC, wherein the compound was treated in an acetonitrile aqueous solution containing 1% by volume trifluoroacetic acid (HPLC gradient elution of acetonitrile from 0% to 100% by volume) for 5 minutes and analyzed using a 100×3 mm Monolith RP HPLC column and LC / MS.

[0073] II. Ligands for Copper Isotope Imaging and Therapy

[0074] The product was obtained by stirring the compound with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified and the final product was analyzed by HPLC as described above.

[0075]

[0076] Chemical structure of the chelating agent CTPA-NHS-ester

[0077] III. Lead isotopes for alpha therapy ( 203 Pb / 212 Pb) CXCR4 ligand

[0078] The product was obtained by stirring the compound with 1.5 equivalents of p-SCN-Bn-TCMC chelator [TCMC = 1,4,7,10-tetraaza-1,4,7,10-tetrakis(2-carbamoylmethyl)cyclododecane] and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified and the final product was analyzed by HPLC as described above.

[0079]

[0080] Chemical structure of chelating agent p-SCN-Bn-TCMC

[0081] IV. Chelating spacer moieties that enhance the pharmacokinetic properties of CXCR4

[0082] The product was obtained by stirring the compound with 1.5 equivalents of p-NHS-Bn-DOTA chelator and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified and the final product was analyzed by HPLC as described above.

[0083]

[0084] The chemical structure of the chelating agent p-NHIS ester-Bn-DOTA. The NHS structure in p-NHIS ester-Bn-DOTA plays a catalytic role, and NHS will fall off during the reaction.

[0085] V. Synthesis of Radiolabeled Complexes

[0086] V.1 203 / 212 Radiochemical synthesis of Pb-CXCR4-ligand

[0087] 80 nanomoles of the conjugate (1 mM in water, 80 μL, 80 nanomoles) were added to 400 μL of sodium acetate buffer (0.4 M in water, pH 5), 10 μL of an aqueous solution containing 20% ​​by mass of ascorbic acid, and 140 μL of 203 The mixture was heated at 95°C for 5 minutes and the labeling was controlled by radio-HPLC.

[0088] V.2 68 Radiochemical Synthesis of Ga-CXCR4

[0089] from 68 Elution in Ge / Ga generator 68 Ga, the conjugate (1 mM in DMSO, 20 μL, 20 nmol) was added to 320 μL of sodium acetate buffer (0.4 M in water, pH 4 to 5), 10 μL of ascorbic acid (20% in water) and 400 MBq 68 The mixture was heated at 95°C for 5 min and labeled by radio-HPLC (0% to 100% MeCN in 5 min, Monolith column) with a flow rate of 2 mL / min and a retention time of 2.4 min.

[0090] VI. Used for 18 F ligands for imaging and therapy

[0091]

[0092] 18 Structure of F-labeled ligand 4-(difluoro(18F)methyl)benzoic acid

[0093]

[0094] 18 Structure of F-labeled ligand trifluoromethylphenyl-Tz-d-TCObenzoic acid

[0095] VI. In vitro competitive binding assay and internalization rate

[0096] MultiScreen was washed with 100 μl PBS containing 1% BSA per well at room temperature. HTS -DV filter plate was incubated for 30 minutes. After removing the PBS / BSA solution, 1×10 5 C4-2 cells. 0.75 nM 68 Ga-labeled CXCR4-HBED-CC dimer ( 68 Ga-CXCR4) was used as a standard to determine the inhibitory potency of the synthesized compounds. All unlabeled compounds were dissolved in Opti-MEM at the following concentrations in a volume of 300 μL: 0 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM, 10 nM, 25 nM, 50 nM, 100 nM, 500 nM, 1000 nM and 5000 nM. Then, 3 μL of radiolabeled compound was added and 50 μL of this mixture was taken to obtain a 0.75 nM concentration of radiolabeled ligand. After incubation at 37°C for 45 minutes, the cells were washed twice with PBS on a multi-screen vacuum manifold and the cell-bound radioactivity was measured using a gamma counter. 68 Ga-labeled CXCR4-HBED-CC dimer was used as a reference to determine the inhibitory potency. K was calculated using a nonlinear regression algorithm (Graph Pad Prism 5.01 software). i The experiment was performed four times.

[0097] To determine the specific internalization rate, 24-well plates were incubated with 0.1% poly-L-lysine in PBS for 20 min at room temperature and washed once with PBS. In the next step, 1 × 10 51mL RPMI medium of C4-2 cells and cultured overnight. The conditions for each compound during the experiment were: incubation at 37°C or 4°C with or without blocking the receptor by 2-(phosphonomethyl)glutaric acid (2-PMPA; Axxora) at a final concentration of 500μM. Then, the cells were incubated with 250uL of 30nM labeled compound solution. The plate was incubated in a 37°C water bath or on ice at 4°C for 45 minutes. Then, the cells were washed three times with 1mL ice-cold PBS and incubated with glycine (50mM in HCl, pH2.8) for 5 minutes. After an additional washing step with 1mL ice-cold PBS, the cells were lysed with 0.5mL of 0.3M NaOH, collected and measured for radioactivity with a gamma counter for 1 minute. By subtracting the corresponding uptake under blocking conditions, the binding to 10 cells (IA / 10 6 Specific cellular uptake was determined as a percentage of the initial added radioactivity per 100 cells. All experiments were performed in triplicate. i The determination showed the nanomolar binding affinity of the synthetic ligands to CXCR4. IC50 values ​​were calculated using GraphPad Prism software (GraphPad software, San Diego, CA, USA). Data are presented as mean ± SEM. Among them, the IC50 in Table 2 and Table 3 represents the affinity of the target probe to the corresponding cell line, and the specific calculation method is as follows:

[0098] LqCy 50 =X m -I(PP m -P n ) / 4

[0099] Among them, X m represents 1g (maximum dose), I represents 1g (highest dose / adjacent dose), P represents the sum of positive reaction rates, P m represents the maximum positive reaction rate, P n Indicates the minimum positive reaction rate. The results show that the IC50 value of the product is about 0.97 / μm, which has a good affinity.

[0100] VII. In vivo PET imaging studies

[0101] Tumor-bearing nude mice were placed in an anesthesia box and pre-anesthetized with 3% isoflurane-oxygen mixed gas for 5-10 minutes. The mice were placed on the scanning bed, their limbs were fixed with medical tape, and anesthesia was maintained with isoflurane-oxygen mixed gas. The position was adjusted so that it was in the center of the micro-PET scanner's field of view. A 1 mL insulin syringe was used to draw the diluted saline solution. 18The target probe solution labeled with F was measured for radioactivity and the measurement time was recorded. After the tail vein was injected into the tumor-bearing mouse, the injection time was recorded, and then the residual radioactivity in the insulin syringe was measured and the measurement time was recorded. Static scanning was performed for 10 minutes at 30, 90, and 180 minutes after the injection of the probe, and the acquisition mode was 3D mode. The three-dimensional ordered subset expectation maximization (3D OSEM) algorithm was used for image reconstruction. The results are shown in Figure 1 , Figure 2 , Figure 3 , Figure 4 and Figure 5 .

[0102] From the above, it can be seen that the present inventors have discovered novel targeting agents that are useful and advantageous radiopharmaceuticals and can be used as tracers, imaging agents and in nuclear medicine for treating various disease states of cancers expressing CXCR4, especially high-expressing cancers.

[0103] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples, unless they are contradictory.

[0104] In the drawings of the embodiments disclosed in the present invention, only the structures involved in the embodiments disclosed in the present invention are involved, and other structures can refer to the general design. In the absence of conflict, the same embodiment and different embodiments of the present invention can be combined with each other.

[0105] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A targeting agent for diagnosing and treating cancers that highly express CXCR4, characterized in that: Including the structure shown in general formula (I): in: X1 is cyclopropane-1,4-dione, C=CNO2, C=S, 3-cyclobutene-1,2-dione or C=NH; R1 is the nuclide; R2 is a nuclide with a linker arm or a chelating agent capable of grabbing a nuclide; R is H or -CH3; X2 are independently selected from substituted or unsubstituted aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl.

2. The targeting agent according to claim 1, characterized in that: The R can also be selected 3. The targeting agent according to claim 1, characterized in that: The nuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 2. 191 Radionuclides of Pt, Fe and radionuclides of Pb.

4. The targeting agent according to claim 1, characterized in that: The nuclide with the connecting arm is selected from the following structures: wherein Y4 and Y5 are independently H, alkyl or optionally substituted or unsubstituted aryl, alkylaryl, heteroaryl and alkylheteroaryl; and wherein n is an integer from 0 to 5.

5. The targeting agent according to claim 1, characterized in that: The chelating agent structure capable of grabbing nuclides is selected from (1a), (1b) and (1c): wherein R3, R4, R5 and R6 are independently selected from H, -CH2-COOH and -CH2-C(=O)-NH2, or wherein R3 and R5 form -(CH2) m -bridge, m is an integer of 2; Where r, v and q are independently 0 or 1.

6. The targeting agent according to claim 5, characterized in that: The chelating agent structure capable of grabbing nuclides is selected from the following structures:

7. A complex, characterized in that The complex comprises: a radionuclide and the targeting agent according to any one of claims 1 to 6.

8. The complex according to claim 7, characterized in that: The radionuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 2. 191 Radionuclides of Pt, Fe and radionuclides of Pb.

9. A drug complex, characterized in that: The drug complex comprises: the targeting agent described in any one of claims 1 to 7 or the complex described in any one of claims 7 to 8.

10. Use of the targeting agent according to any one of claims 1 to 7, the complex according to any one of claims 7 to 8, or the pharmaceutical composition according to claim 9 in the following (1) or (2): (1) preparing a drug for treating, ameliorating or preventing cancer expressing CXCR4 and / or its metastases; (2) preparing a reagent for diagnosing cancer expressing CXCR4 and / or its metastases.

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