Prostate-specific membrane antigen (PSMA) labeling inhibitor, its use as an imaging agent and drug for the treatment of prostate cancer

Abstract

To provide labeled inhibitors of prostate specific membrane antigen, and their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer.SOLUTION: The present invention provides a metal complex comprising a compound of the following formula (where R' represents a chelator such as 1,4,7,10-tetraazacyclododecane-N,N',N',N"'-tetraacetic acid (DOTA), and the chelator is complexed to 225Ac), or a salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention is generally used in the field of radiopharmaceuticals and for the treatment of various stages of prostate cancer. Regarding its use in nuclear medicine as a tracer and imaging agent. [Background technology]

[0002] Background of the Invention Prostate cancer (PCa) is the leading cancer among residents of the United States and European countries. It is less common in the Western Hemisphere. At least 1 to 2 million men suffer from prostate cancer, and the disease is found in one in six men between the ages of 55 and 85. It is estimated that in the United States, more than 300,000 new cases of prostate cancer are diagnosed each year. It is possible. The mortality rate from this disease is the second highest after lung cancer. Computed tomography (CT) Current anatomical methods such as magnetic resonance (MR) imaging and ultrasound are used for the clinical imaging of prostate cancer. It is the mainstream approach. It is currently the dominant approach globally for surgery, radiation therapy, drug therapy, and minimally invasive treatment. An estimated $2 billion is currently being used. However, currently, recurrent, metastatic, androgen-induced dysplasia is being treated. There is no effective treatment for vertical prostate cancer.

[0003] Radiation-labeled choline analog [ 18 F] Fluorodihydrotestosterone ([ 18 F]FDHT), anti-1A Mino-3-[ 18 F]fluorocyclobutyl-1-carboxylic acid (anti[18F]F-FACBC, 11 C] Acetate 1-(2-deoxy-2-[ 18 F]Fluoro-L-arabinofuranosyl)-5-methyluracil(-[ 18 F]F Various experimental low-molecular-weight PCa imaging agents such as MAU are currently being pursued clinically (non-patent literature). 1; Non-patent document 2; Non-patent document 3; Non-patent document 4; Non-patent document 5; Non-patent document 6; Non-patent Reference 7; Non-patent document 8). Each operates in a different mechanism and has specific advantages, for example [ 11 C] Phosphorus has disadvantages such as low urinary excretion and a short physical half-life for positron-emitting radionuclides. It holds.

[0004] Tumors may express specific proteins associated with their malignant phenotypes, or they may be normal. It is well known that tumor cells can overexpress more normal constituent proteins than cells do. The expression of different proteins on the surface of cells is used for phenotypic identification and biochemical composition of tumors. Exploring activity provides an opportunity to diagnose and characterize diseases. Specific tumors Radioactive molecules that selectively bind to tumor cell surface proteins are used to image tumors in non-invasive conditions. Offering attractive pathways for imaging and therapy. A promising novel series of low molecular weight imaging agents. The technology targets prostate-specific membrane antigen (PSMA) (Non-Patent Document 9; Non-Patent Document 10; Non-Patent Document) Document 11; Non-patent document 12; Patent document 1).

[0005] PSMA is abundant and limited on the surface of PCa, particularly androgen-independent progressive and metastatic diseases. It is a transmembrane 750-amino acid type II glycoprotein that exhibits expression (Non-Patent Literature 13). Since all PCa become androgen-independent over time, the latter (latter) is important. PSM A is a criterion for a promising target for treatment, namely abundant in all stages of the disease (prostate). It has limited expression and is not released into circulation, instead being presented on the cell surface and acting as an enzyme or signal. It is associated with signal transduction activity (Non-Patent Literature 13). The PSMA gene is localized on the short arm of chromosome 11. and functions as both folate hydrolase and neuropeptidase. The gene is has neuropeptidase activity equivalent to that of glutamate carboxypeptidase II (GCPII) and is referred to as "brain PSMA", which cleaves N-acetylaspartylglutamate (NAAG) into N-acetyla spartate (NAA) and glutamate, thereby regulating glutamatergic neurotransmissi on (Non-Patent Document 14). There are up to 10 6 PSMA molecules per cancer cell, which has further suggested that PSMA is an ideal target for imaging and therapy using radionuclide-based techniques (Non-Patent Document 15).

[0006] The radioimmunoconjugate of anti-PSMA monoclonal antibody (mAb) 7E11 (known as PROSTASCINT (Registered Trademar k) scan) is currently used for diagnosing metastasis and recurrence of prostate cancer . However, this agent tends to produce images that are difficult to interpret (Non-Patent Document 16; Non-Patent Document 17; Non-Patent Document 18). More recently, monoclonal antibodies that bind to the extracellular domain of PMSA have been developed, which have been radiolabeled and shown to accumulate in PMSA-positive prosta tic tumor models in animals. However, diagnosis and tumor detection using monoclonal antibodie s is limited due to the low penetration of monoclonal antibodies into solid tumors .

[0007] Selective targeting of cancer cells using radiopharmaceuticals for either imaging or therapeutic purpose is challenging. 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 123 I and​131 Various radioactive nuclei such as I The species is known to be useful for radioimaging or cancer radiotherapy. In recent years, radiation Glutamate-urea-glutamate (GUG) or glyceride-ligand conjugate bound to a radionuclide ligand conjugate Several compounds containing the glutamate-urea-lysine (GUL) recognition factor exhibit high affinity for PSMA. It was shown to exhibit harmonious properties. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] WO 2013 / 022797

[0009] [Non-Patent Document 1] Scher, B.; et al. Eur J Nucl Med Mol Imaging 2007, 34, 45-53 [Non-Patent Document 2] Rinnab, L.; et al. BJU Int 2007, 100, 786,793 [Non-Patent Document 3] Reske, SN; et al. J Nucl Med 2006, 47, 1249-1254 [Non-Patent Document 4] Zophel, K.; Kotzerke, J. Eur J Nucl Med Mol Imaging 2004, 31,756-759 [Non-Patent Document 5] Vees, H.; et al. BJU Int 2007, 99, 1415-1420 [Non-Patent Document 6] Larson, SM; et al. J Nucl Med 2004, 45, 366-373 [Non-Patent Document 7] Schuster, DM; et al. J Nucl Med 2007, 48, 56-63 [Non-licensed document 8] Tehrani, OS; et al. J Nucl Med 2007, 48, 1436-1441

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

[0010] A new approach to radiotherapy that enables rapid visualization and specific targeting of prostate cancer. A specific medication is required.

[0011] Therefore, the object of the present invention is to interact with PSMA and for the detection, treatment, and management of prostate cancer. Develop ligands with suitable radionuclides that offer promising and novel targeting options. That is what it is. [Means for solving the problem]

[0012] Summary of the Invention The above-mentioned problem is solved by providing the embodiments characterized in the claims. It will be achieved.

[0013] The inventors have developed a novel compound that is a useful radiopharmaceutical, and for various stages of prostate cancer. We discovered their use as tracers and imaging agents in nuclear medicine for therapeutic purposes.

[0014] Novel imaging agents with structural modifications in the linker region exhibit tumor targeting properties and pharmacokinetics. It improved the study. Pharmacophores interact with each side chain of PSMA. Three carboxyl groups that can be used and one as part of the zinc complex in the active center It presents two oxygen atoms. In addition to these obligatory interactions, the inventors also found that phosphorus We were able to optimize the interaction of lipophilicity in the Kerr region.

[0015] In other words, the gist of this invention is, [1] Equation (Ia) or (Ib): [ka] , during the ceremony [Table A-1] The compound, [2] A compound having an R'-linker-R structure, where R'= - DOTA, R= - Glu-Urea-L ys: [ka] And, During the ceremony, R'-Linker-R teeth, [ka] [ka] [ka] A compound selected from [1], [3] and below: [ka] [ka] [ka] [ka] [ka] A compound selected from [1] or [2], [4] Use of any of the compounds described in [1] to [3] for the preparation of radiolabeled compounds, [5] Metal composites containing radioactive nuclides and any of the compounds described in [1] to [3], [6] Radioactive nuclides, 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 2 13 Bi, 225 The metal composite described in [5] is Ac or Fe, [7] A compound described in any of [1] to [3], or a metal composite described in [5] or [6] The body, or a pharmaceutically acceptable salt or ester thereof, and pharmaceutically acceptable Pharmaceutical composition containing a carrier, [8] For use in imaging methods for patients, one of the descriptions in [1] to [3] is required. Compound or metal composite as described in [5] or [6], [9] For use in methods for diagnosing prostate cancer and / or its metastasis, [1] to [3] ) A compound described in either of the above or a metal composite described in [5] or [6],

[10] For use in methods of treating prostate cancer and / or its metastases, [1] to [ 3) Any of the compounds described in [5] or [6] or the metal composite described in [5] or [6] Regarding. [Effects of the Invention]

[0016] The present invention provides a labeling inhibitor for prostate-specific membrane antigen (PSMA) for the treatment of prostate cancer. Its use as an imaging agent and pharmaceutical agent may be offered. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1: PET imaging of MB17. Whole-body coronal microPET images of athymic male nude mice with LNCaP tumor xenografts. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB17 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. Graph A shows the time-activity curves for the kidney and bladder, respectively, and Graph B shows the time-activity curves for the heart, muscle, and tumor, respectively. Values ​​are expressed as mean SUV (standardized uptake). [Figure 2] Figure 2: Organ distribution 1 hour after injection. Organ distribution 1 hour after injection of 0.06 nmol of 68Ga-labeled PSMA inhibitor MB17. PSMA blocking by co-administration of 2 mg / kg body weight of 2-PMPA demonstrates PMSA-specific uptake in tumors and kidneys. Data are expressed as mean % ID / g tissue ± SD (n=3). [Figure 3] Figure 3: PET imaging of MB4. Whole coronal microPET images of athymic male nude mice with LNCaP tumor xenografts. [68Ga]MB4 tumor targeting efficiency and pharmacokinetic properties were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. Graph A shows the time-activity curves for the kidney and bladder, respectively, and Graph B shows the time-activity curves for the heart, muscle, and tumor, respectively. Values ​​are expressed as mean SUV (standardized uptake). [Figure 4]Figure 4: Organ distribution of 0.06 nmol of 177Lu-labeled MB17 24 hours after injection, expressed as % ID / tissue g±SD (n=5). Organ distribution using 177Lu shows that high initial renal uptake almost completely disappears after 24 hours (2.13±1.36% ID / g), while tumor uptake remains high and even increases (10.58±4.50% ID / g). Other organs, such as the liver (0.08±0.03% ID / g), lungs (0.11±0.13% ID / g), and spleen (0.13±0.05% ID / g), showed very low uptake. Favorable pharmacokinetics resulted in very high tumor-to-background ratios (tumor / blood: 1058; tumor / muscle: 529) after 24 hours. [Figure 5] Figure 5: PET imaging of MB2. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB2 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 6] Figure 6: PET imaging of MB3. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB3 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 7] Figure 7: PET imaging of MB10. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB10 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 8] Figure 8: PET imaging of MB17.D. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB17.D were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. MB17D: Stereoisomer of MB17(L): Synthesized based on Fmoc-3(2-naphthyl)-D-alanine. [Figure 9]Figure 9: PET imaging of MB22. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB22 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 10] Figure 10: PET imaging of MB24. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB 24 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 11] Figure 11: PET imaging of MB25. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB25 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 12] Figure 12: PET imaging of MB31. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB31 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 13] Figure 13: PET imaging of MB33. Whole coronal microPET image of a thymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB33 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 14] Figure 14: PET imaging of MB35. Whole coronal microPET image of athymic male nude mouse with LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB35 were evaluated by dynamic microPET scanning. Approximately 15 MBq was injected per mouse. [Figure 15]Figure 15: PET scans of mice injected with 68Ga-CHX-DTPA. Left caudal, central dorsal, and right lateral views. The images cover time progressions of 20–40 minutes (top), 40–60 minutes (middle), and 120–140 minutes (bottom). [Figure 16] Figure 16: MB-17 vs. MB-17.D. Whole coronal microPET images of athymic male nude mice with LNCaP tumor xenografts. The tumor targeting efficiency and pharmacokinetic properties of the stereoisomers MB-17 and MB-17D were directly compared 2 hours after injection. [Figure 17a] Figure 17: Human PET / CT imaging of 68Ga-labeled MB17. (a) The first clinical trial using 68Ga-labeled MB17 PET / CT shows the detection of small lymph node metastases 1 hour after injection, mainly due to high-radiation tracer uptake. Red arrows indicate representative lesions with an SUVmax of 36.5 and a tumor-to-background ratio of 52.1 1 hour after injection. MIP = maximum intensity PET radiation 1 hour after injection. [Figure 17b] (b) A significant advantage of 68Ga-labeled MB17 PET / CT is its high sensitivity in detecting lesions even at low PSA levels. [Figure 18] Figure 18: PET imaging of a patient with multiple prostate cancer metastases. (a) The first scan shows the initial PET imaging of a patient with multiple prostate cancer metastases with a blood PSA level of 14. Two months later, 3.3 GBq of 177Lu-labeled MB17 was applied. At this point, the blood PSA level reached 38. After the first cycle, the PSA level decreased to 8. Three months after the first cycle, an additional 4 GBq of 177Lu-labeled MB17 was applied. A control PET scan was performed one month after the second cycle. This treatment showed a significant effect on tumor lesions and PSA levels and resulted in a reduction in bone pain. (b) The graph shows the significant effect on the reduction in PSA levels after the first application of the therapeutic dose of 177Lu-labeled MB17. [Modes for carrying out the invention]

[0018] Detailed description of the invention This invention relates to radiopharmaceuticals and tracers for the treatment of various stages of prostate cancer. Regarding its use as an imaging agent in nuclear medicine.

[0019] Therefore, the present invention relates to general formula (Ia) or (Ib): [ka] It is expressed as, in the formula [Table 1] Regarding the compound in question.

[0020] Unless otherwise stated, the present invention refers to an alkyl group (preferably C1 ~C 10 The alkyl group can be linear or branched, unsubstituted or substituted. Preferred alkyl groups are methyl Isopropyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentanyl, n-butyl It is xanyl. Preferably, the corresponding cycloalkyl compound having 3 to 10 carbon atoms. The same applies to this as well.

[0021] "Aryl" is an aromatic compound having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. This refers to a cyclic or polycyclic ring system. The aryl group may be appropriately one or more alkyl groups. It can be substituted with a ring substituent. Preferred aryl groups are phenyl, benzyl, or naphthyl. That is the case.

[0022] The Z group is preferably -CO2H, but can also be -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, or -PO4H2. Any biosteric substituent that can be easily substituted, for example, "The Practice of Medicine See "inalChemistry" (Academic Press New York, 1996), page 203.

[0023] In the sense of the invention, unless otherwise stated in the definition of the base, all bases are They are considered combinatorial. All possible subgroups of them are considered disclosed. .

[0024] In a preferred embodiment, the motif that specifically binds to the cell membrane of neoplastic cells is cancerous cell A motif that specifically binds to the cell membrane, and here preferably, the motif is a prostate It comprises gland-specific membrane antigen (PSMA), and in particular, the PSMA conforms to the following formula in Scheme 1. Contains a glutamate-urea-lysine motif.

[0025] Therefore, the preferred molecule of the present invention is the three main components (Scheme 1): hydrophilic PSMA Binding motif (Glu-urea-Lys; =Glu-NH-CO-NH-Lys), variable linker and preferably DOTA It consists of a chelating agent.

[0026] Scheme 1: Structure of the preferred compound of the present invention [ka]

[0027] Different preferred linkers are shown below, and as above, in the formula, R = - It is Glu-urea-Lys. , R'= - DOTA (as a preferred example of a chelating agent) is one such example. [ka] [ka] [ka] [ka]

[0028] Preferred compounds of the present invention include, for example, [ka] [ka] [ka] [ka] [ka] That is the case.

[0029] The invention also relates to pharmaceutically acceptable salts of compounds of general formula (Ia) and / or (Ib). The invention also includes a solvate of the compound, comprising salts and active metabolites of the compound, Where appropriate, intermodulation of compounds of general formula (Ia) and / or (Ib), including prodrug formulations. Regarding isomers.

[0030] "Pharmacologically acceptable salt" refers to a pharmaceutically acceptable organic or non-organic salt of the compound of the invention. It is a salt of an acid or base. Typical pharmaceutically acceptable salts include, for example, an alkah. Metallic salts, alkaline earth salts, ammonia salts, water-soluble and water-insoluble salts, such as acetate salts, Carbonates, chlorides, glucons, glutamates, lactates, laurates, malates Examples include tartrates.

[0031] The term "prodrug" refers to a substance that undergoes chemical transformation through metabolic processes when administered to a patient. This refers to a drug precursor, a compound that is destined to become an active pharmaceutical agent. Formula (Ia) and / or (Ib) Exemplary prodrugs of the compounds are esters and amides, preferably fatty acid esters. It is an alkyl ester of . Here, the prodrug formulation is enzymatic, metabolic or optional. Formed by simple transformations including hydrolysis, oxidation, or reduction in any other form. Includes all substances. Suitable prodrugs include, for example, enzymatically digestible linkers (e.g., Cal). Dissolvability enhancers (e.g., via bamates, phosphates, N-glycosides, or disulfide groups) For example, general substances bonded to tetraethylene glycol, polysaccharides, formic acid or glucuronic acid, etc. The compound comprises a substance of formula (Ia) and / or (Ib). Such prodrugs of the compounds of the invention are used in patients. This prodrug can be applied to obtain the desired medicinal effect using general formula (Ia) It can be converted into the substance of (Ib).

[0032] Some compounds of formula (Ia) and / or (Ib) are racemic compounds, their enantio Mers and optionally their diastereomer forms, as well as all possible mixtures thereof. It is encompassed by the form of an object.

[0033] According to the invention, all chiral C atoms have D- and / or L-coordination, and one chemical Combinations within the compound are also possible; that is, some of the chiral C atoms may be D-coordinated. Often, other configurations can be L-coordinate.

[0034] The resulting compounds are in their enantiomers and / or diastereomers. , can be separated by any known method (e.g., Allinger, NL und Elliel EL in" Topicsin Stereochemistry, Vol. 6, Wiley Interscience, 1971). Enantiomers One possible method of separation is the use of chromatography.

[0035] The invention also includes, together with a therapeutically effective amount of the active ingredient (a compound of formula (Ia) or (Ib) of the invention), Organic compounds suitable for the intended administration and that interact with the active ingredient without causing harm. The present invention relates to a pharmaceutical formulation comprising an inorganic solid or liquid pharmaceutically acceptable carrier.

[0036] The phrase "pharmaceutically acceptable" in this specification means, within the bounds of reliable medical judgment. Without excessive toxicity, irritation, allergic reactions, or other problems or complications, and with reasonable efficacy. Compounds, substances, and compositions that are suitable for use in contact with patient tissue, balanced by the benefit / risk ratio. It is used to refer to both and / or dosage forms.

[0037] Examples of "patients" include humans, monkeys, cows, horses, cats, or dogs. The animal may be a non-primate or a mammal such as a primate (e.g., monkeys and humans). In one embodiment, the patient is a human being.

[0038] Generally, compounds of formula (Ia) or (Ib) or their pharmaceutical compositions are administered orally or parenterally. It can be administered via a route, usually by injection or infusion.

[0039] "Pareral administration routes" refer to forms of administration other than enteral and local administration, such as conventional injections. Without limitation, intravenous, intramuscular, intraarterial, intrasacral, intracapsular, intraocular, intracardiac, intradermal, and peritoneal cavities. Internal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injections One example is injection.

[0040] The dosage of the compound according to this invention is determined by patient-specific parameters such as age, weight, sex, and disease severity. The dosage is determined by a physician based on the meter reading. The dosage is preferably 0.00001 mg / kg body weight to 10 The amount is 0 mg / kg body weight, preferably 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight. .

[0041] Depending on the type of administration, the medicine is prepared, for example, according to the general galenic method. Solutions or suspensions, simple tablets or dragees, hard or soft gelatin capsules, It is appropriately formulated in the form of suppositories, ovules, and injectable preparations.

[0042] The compounds of this invention may, where appropriate, be further active substances and common excipients for pharmaceutical compositions. The agent and carrier may be formulated together, for example, talc, arabic, depending on the formulation being manufactured. Gum, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous Aqueous carriers, animal or plant-derived fats, paraffin derivatives, glycols (especially poly Ethylene glycol), various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (e.g.) It can be formulated together with air, oxygen, carbon dioxide, etc., and preservatives.

[0043] To manufacture liquid formulations, sodium chloride solution, ethanol, sorbitol, glycerin Phosphorus, olive oil, peanut oil, propylene glycol, or ethylene glycol, etc. The following additives may be used.

[0044] When using a solution for injection or injection, the solution is preferably an aqueous solution or suspension. Yes, for example, the active ingredient itself or mannitol, lactose, glucose, albumin It is possible to manufacture it before use from a freeze-dried formulation that includes carriers such as ions. The liquid is sterilized and, where appropriate, contains excipients such as preservatives, stabilizers, emulsifiers, solubilizers, and buffers. It is mixed with the agent and / or salts to adjust the osmotic pressure. Sterilization is performed on the composition if appropriate. It can be obtained by sterilization by filtration using a small-diameter filter that can be freeze-dried. To ensure maintenance, a small amount of antibiotic may also be added.

[0045] The phrase “effective dose” or “therapeutic effective dose” means, when used herein, any medical treatment Applicable reasonable benefit / risk ratios in at least some subpopulations of cells in animals A compound comprising the compound of the invention or other active ingredients that is effective in producing the desired therapeutic effect. This refers to the amount of a substance, material, or composition. The therapeutically effective amount of the compound of this invention is the amount of the disease In the treatment of prevention, the amount of a therapeutic agent alone or in combination with other therapeutic agents that provides therapeutic benefit is considered to be the amount of the therapeutic agent that provides therapeutic benefit. To taste. When used in relation to the compounds of the present invention, the term means to improve the overall treatment, To reduce or avoid the symptoms or causes of the disease, or to improve the effectiveness of other therapeutic agents. This can include quantities that enhance the synergistic effect.

[0046] As used herein, the terms “to treat” or “to treat” mean “to diagnose,” “to prevent” (prophylaxis). This is intended to include prevention, therapy, and cure.

[0047] The terms "prevent," "preventing," and "prevention" )” refers to the onset or recurrence of a disease in a patient caused by the administration of a preventive or therapeutic agent. This refers to preventing the spread of the virus.

[0048] The compounds of formula (Ia) and / or (Ib) of the present invention may be used as radioimaging agents or Depending on whether it is to be used as a radiopharmaceutical, different radionuclides are complexed with chelating agents. Examples of radioactive nuclides include, for example, 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 17 7 Lu, 99m Tc, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 15 7 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Examples include Er and Fe. In one aspect of this invention Then, radioactive nuclides 111 In, 90 Y, 68 Ga, 64 Cu, 153 Gd, 155 Gd, 213 Bi, 225Ac, Fe or 17 7 It is Lu.

[0049] As described above, complexes of compounds of formula (Ia) or (Ib) are rapidly proliferating cells, such as PS. Suitable for use as a radioimaging or therapeutic agent for the treatment of MA-expressing prostate cancer cells. It may contain one or more radionuclides. According to the present invention, the composite is a "metal composite" and It is called a "radiopharmaceutical."

[0050] Preferred imaging methods include positron emission tomography (PET) or single-photon emission computer-assisted imaging. This is a type of tomography (SPECT).

[0051] Therefore, in one embodiment, radionuclides and compounds of formula (Ia) or formula (Ib), salts thereof. This includes solvates, stereoisomers or tautomers, and pharmaceutically acceptable carriers. A pharmaceutical composition including a compound is provided.

[0052] In another aspect, a pharmaceutical composition suitable for in vivo imaging and radiotherapy is provided. A suitable pharmaceutical composition may contain the element, namely radioactive iodine, or formula (Ia) and / or (Ib) is a pharmaceutically acceptable radioactive metal chelate complex of any of the compounds of (Ib). A radioimaging agent or radiation containing radioactive nuclides in sufficient quantities for imaging together with a radioactive vehicle. May contain radiotherapy agents. Human serum albumin; aqueous buffer solution, e.g., Tris(hydromethylcellulose). (Chill) Aminomethane (and its salts), phosphates, citrates, bicarbonates, etc.; Sterilized physiological Saline solutions; as well as chloride salts and / or bicarbonates or calcium, potassium, sodium Prepared ionic solution containing normal plasma cations (cautions) such as um and magnesium Radioactive vehicles, such as liquids, should be suitable for injection or inhalation.

[0053] The concentration of imaging agents or therapeutic agents in the radioactive vehicle provides satisfactory imaging. It should be sufficient. For example, when using an aqueous solution, the dose should be about 1.0 to 100 ml. It is a syrup. However, the dose actually administered to patients for imaging or therapeutic purposes is The decision is made by the treating physician. The imaging agent or treatment agent is administered to the patient for approximately 1 hour to 10 days. It should be administered to maintain the level, but longer or shorter durations are acceptable. Therefore, a convenient ampoule containing 1 to 10 mL of aqueous solution can be prepared.

[0054] Imaging is performed, for example, by injecting a sufficient amount of imaging composition to provide appropriate imaging, Scan using an appropriate imaging or scanning machine such as a stratification scanner or gamma-ray camera. This can be carried out in a standard manner. In a specific embodiment, the patient's area is imaged. The method involves (i) administering to the patient a diagnostically effective dose of a radionuclide combined with a compound; (ii) the step of exposing a patient's area to a scanning device; and (ii) the step of obtaining an image of the patient's area. In certain embodiments, the imaged region is the head or chest. In other embodiments... Compounds and complexes of formula (Ia) and / or (Ib) target the PSMA protein.

[0055] Therefore, in some embodiments, spleen tissue, kidney tissue, or PSMA-expressing tumor tissue A method for imaging tissues such as the tissue, and the radioactive nuclide and formula (Ia) and / or A method comprising contacting a complex synthesized by contacting a compound of formula (Ib). It will be provided.

[0056] The amount of the compound of the present invention administered to the patient, or the metal and formula (Ia) and / or (Ib) A formulation containing the compound or its salt, solvate, stereoisomer, or tautomer complex The quantity depends on the imaging performed, the nature of the tissue targeted for imaging or treatment, and The physician will provide information such as the patient's weight and medical history, which will be used to image or treat them with radiopharmaceuticals. It depends on several physiological factors that are commonly used.

[0057] Therefore, in another aspect, the invention provides a patient with a therapeutically effective amount of radionuclide and complex Compounds of the modified formula (Ia) and / or (Ib), or pharmaceutically acceptable salts of the complex, Alternatively, administering a solvate to treat patients suffering from cell proliferation disorders or impairments. To provide a method for treating patients. Specifically, the compounds, pharmaceutical compositions or Cell proliferation disorders or disorders treated or imaged using radiopharmaceuticals are, for example, Cancers of the lungs, liver, kidneys, bones, brain, spinal cord, bladder, etc., such as prostate cancer and / or pre-prostate cancer. It is a metastatic case of prostate cancer.

[0058] The synthesis of the compounds of the present invention is described in detail in the section on examples. An overview of the synthesis is provided in DOTACon. This is illustrated in Scheme 2 relating to the Jugate PSMA inhibitor. However, those skilled in the art will understand this. For example, the reaction can be modified by using a different chelating agent. Therefore, this scheme is The compounds of the present invention should not be understood to be limited solely to DOTA chelating agents.

[0059] Scheme 2 [ka]

[0060] The synthesized compounds are chemically characterized by RP-HPLC, MS, and / or NMR.

[0061] Novel chelating agent conjugates with structural modifications in the linker region The imaging agent (ated) has improved tumor targeting properties and pharmacokinetics. A has three carboxyl groups that can interact with each side chain of PSMA, and in the active center It presents oxygen as part of the zinc complex. In addition to these obligatory interactions The inventors were able to optimize the lipophilic interaction in the linker region.

[0062] Preclinical evaluation is performed using in vitro assays (affinity, internalization) and in vitro assays. This includes experiments (μPET screening and organ distribution).

[0063] The compounds of the present invention are known reference compounds in terms of renal clearance and enrichment in tumors. It is also superior. The binding affinity of the PSMA inhibitor of the present invention may be affected by linker modification. Two cyclic motives and at least one aromatic part in the linker region of the substance. This is likely to result in preferred and high-affinity compounds MB4 and MB17. In this regard, MB17 is a very promising compound.

[0064] Therefore, the compounds of the present invention were also confirmed by organ distribution and small animal PET imaging. We present a novel PSMA target probe with optimal characteristics. The compound of the present invention exhibits high PSMA characteristics. It shows heterologous tumor uptake. Furthermore, they show early enrichment in the bladder and also in the kidneys. It is characterized by its maximum uptake. Regarding therapeutic use, this means that other PSMA inhibitors Compared to the present invention, the compound offers clear clinical advantages. (See PET schematic diagram) Furthermore, the compounds of the present invention, particularly MB17, exhibit rapid background clearance after 2 hours. Although it shows a substantial reduction in enrichment in the kidney, the compound accumulates further in PSMA-expressing tumors. And it remains. In addition, the first in vivo treatment using MB17 showed promising data (Figures 17 and 18). reference).

[0065] The following examples illustrate the present invention in more detail, but in no case shall the present invention be used as an example. It is not intended to be limited to the embodiments shown. [Examples]

[0066] Examples Example 1: Synthesis of DOTA conjugate inhibitor DOTA-conjugated PSMA inhibitors are synthesized via solid-phase peptide synthesis (Ski (See M2). In the first step, 3 mmol of bis(tert-butyl)-L-glutamate and Mix 3 mL of N-ethyldiisopropylamine (DIPEA) with 200 mL of dry CH2Cl2, then add 1 mmol to Adding riphosgen to a 10 mL solution of dried CH2Cl2 over 3 hours at 5°C is performed to extract the glutamyl portion. Isocyanate was generated in situ. After the reaction, 0.5 mmol of resin was fixed (2-chloro-tri Add ε-allyloxycarbonyl protected lysine (Chillesin) and stir gently until 16:00 The reaction was allowed to proceed. The resin was filtered out, and 50 mg of tetrakis-(triphenyl)para was added to 4 mL of CH2Cl2. The allyloxy protecting group was removed over 2 hours using zinc and 400 μL of morpholine.

[0067] The subsequent synthesis of the peptide-mimicking PSMA-binding motif was carried out according to the standard Fmoc protocol. The following linker coupling is performed using 2 mmol of the corresponding Fmoc protective acid in a final volume of 4 mL of DMF. The test was performed using 96 mmol of HBTU and 2 mmol of N-ethyl-diisopropylamine. 3.95 equivalents After 2 hours of activation with HBTU and DIPEA, 4 equivalents of tris(t-bu)-DO are added to the resin load. TA (Chematech) was reacted with a final volume of 3 mL of DMF. Trifluoroacetic acid, triisopropyl alcohol. The product was cleaved from the resin in a 2 mL mixture of rusilane and water (95:2.5:2.5).

[0068] Chelate using HBTU-activated DOTA-NHS ester (CheMatech) or DOTA-TFP ester. The agent was also conjugated (Mier W., Hoffend J., Kraemer S., Schuhmacher J., Hull W. E., Eisenhut M., Haberkorn U., Bioconjugate Chem. 2005, 16: 237-240).

[0069] Analysis of the synthesized molecules is performed using a linear AB gradient (0% B to 100% B, 6 mins), with a flow rate of 4 mL / min (analysis) or 6 m Reverse-phase high-performance liquid chromatography (RP-HPLC; ChromolithRP-18e, 100 L / min (purification) The procedure was performed using a 4.6 mm x 4.6 mm microscope (Merck, Darmstadt, Germany). Solvent A consisted of 0.1% aqueous TFA. Solvent B consisted of 0.1% TFA in CH3CN. HPLC system (L6200 A; Merck-Hitachi, Darmstadt, Ge The rmany (presumably a type of radar) is equipped with UV and gamma-ray detectors (Bioscan; Washington, USA). UV absorbance is 214 nm. The measurement was performed using a MALDI-MS Daltonics Microflex system (Bruker Daltonics, Bremen, Germany). Mass spectrometry was performed using this method.

[0070] Example 2: Radiation labeling Typically, 1.5 nmol of the synthesized compound from Example 1 (0.1 M HEPES buffer pH 7) is used in 100 μL. Dissolve in 5) 10 μL 2.1 M HEPES solution and 40 μL [ 68 Ga]Ga 3+ Add to the mixture of eluent (40 MBq) The pH of the labeled solution was adjusted to 4.5.

[0071] Radiolabeling of the compound yielded a radiochemical yield of >97% after 15 minutes at 95°C, and RP-HPLC was performed. Measurements were taken using TLC. Subsequent purification was performed using a Sep-Pak C18 cartridge.

[0072] Example 3: Synthesis of compounds MB4 and MB17 3 mmol of bis(tert-butyl)L-glutamate and 1.5 mL of N- in 200 mL of dry CH2Cl2 1 mmol triphosgene in 10 mL of dry CH2Cl2 of a mixture of ethyl diisopropylamine (DIPEA) The glutamyl isocyanate was added to the solution over 4 hours at 0°C, and the glutamyl moiety was analyzed in situ. Success. After stirring the reaction mixture at 25°C for 1 hour, 0.5 mmol of resin (2-chloro-tri) was added to 4 mL of DCM. Add ε-allyloxycarbonyl protected lysine (Chillesin) and stir gently for 16 The mixture was allowed to react for a set time. The resin was filtered out, and 30 mg of tetrakis(triphenyl)para was added to 4 mL of CH2Cl2. The allyloxy protecting group was removed over 3 hours using zinc(0) and 400 μL of morpholine. The following refers to 4-(Fmoc-aminomethyl)benzoic acid (in the case of MB4) or Fmoc-3-(2-naphthyl)-L-ara. Nin and trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (in the case of MB17) Each of the three couplings was performed with 2 mmol of Fmoc protective acid and 1.96 mmol of HBTU in a final volume of 4 mL of DMF. The procedure was carried out stepwise using 2 mmol of N-ethyldiisopropylamine. 3.95 equivalents of HBTU And after 2 hours of activation in DIPEA, 4 equivalents of tris(t-bu)-DOTA(Chemate) are added to the resin load. The mixture (ch) was reacted for 3 hours in a final volume of 3 mL LDMF. Trifluoroacetic acid, triisopropyl sulfate The product was cleaved from the resin in a 2 mL mixture of ranic acid and water (95:2.5:2.5). RP-HPLC The product was purified using [a specific method], and the purified product was analyzed using analytical RP-HPLC and MALDI-MS. .

[0073] To prepare MB-17D, a stereoisomer of MB17(L), the synthesis is performed using Fmoc-3(2-naphthyl)-D-A Based on ranin. Unless otherwise stated, MB17 in this description is L-stereoisinic. It means sexual body.

[0074] Example 4: Coupling to various chelating agents [ka] Chelating agents (DOTA, NOTA, NODAGA, DTPA, CHX-DTPA, PCTA, Do3A) are synthesized in solid phase via MB17. It was coupled to a linker. Generally, 13 μmol was coupled to a PSMA-binding motif. The resin was swollen with DCM in a syringe with a filter. After washing the resin five times with DMF, The N-terminus was deprotected by incubation in 20% piperidine in DMF for 5 minutes twice. I continued washing it five times.

[0075] 1.5 to 4 equivalents of chelating agent (depending on the chelating agent), 0.98 × n キレート剤 HATU (if necessary) Dissolve 10 equivalents of DIPEA in 500 μl of DMF, and draw the solution into a syringe containing resin. Then, the resin was incubated overnight. Next, the resin was mixed with DMF, methanol, DCM and d The samples were washed five times with ethyl ether and then dried under vacuum.

[0076] Test separation was used to investigate the reaction state. This involved filling a small amount of resin with DCM. Rinse the tip of the filter and add 100 μl of separation solution containing 95% TFA, 2.5% water, and 2.5% TIPS. This was achieved. After a 30-minute incubation, the solution was pipetted into ice-cold diethyl ether. The mixture was then centrifuged. The diethyl ether was discarded, and the remaining pellet was mixed with 35 μl of ACN:H2O (1:1 The samples were dissolved in () and analyzed by HPLC (0-100% ACN in water, within 5 minutes) and LC / MS.

[0077] If the desired product was obtained, the complete peptide was separated from the resin. 500 μl of the dried resin was separated. The solution (95% TFA, 2.5% H2O, 2.5% TIPS) was incubated for 2 hours. The resulting solution was then cooled on ice. Mixed with diethyl ether and centrifuged (4000 min) -1 (5 minutes). Discard the supernatant and use a new jelly. Chill ether was added, and the container was shaken vigorously to resuspend the pellet. The solution was then centrifuged again. Distance (4000min -1 (5 minutes), and the resulting supernatant was discarded. Next, the pellets were vacuum-dried, and finally It was then resuspended in 1 ml of ACN:H2O (1:1).

[0078] Purification was achieved by preliminary HPLC, and the peak was obtained by analytical HPLC (0-100% ACN in water, within 5 minutes). The samples were analyzed by LC / MS, and the products were pooled and freeze-dried.

[0079] Example 5: Radiation labeling 177 Lu label 177 Mix Lu (approximately 100 MBq) with 200 μl of 0.4 M sodium acetate buffer (pH=5) containing Chelex. The following was done: 10 μl of 1 mM compound solution in 10% DMSO water, 2 μl of saturated ascorbic acid solution and 40 μl of 177 The Lu-containing solution was mixed and heated to 95°C for 10 minutes. Radioactive HPLC (0-100% ACN in water, 5 minutes) was performed. Within the Monolith column, the labels were examined.

[0080] 68 Ga sign CHX-DTPA for PET scan 68 Labeled with Ga. 1 ml 68 Ga was tested using 0.6 M HCl. 68 Ge / 68 Elution was performed from the Ga-generating substance. 10 mM CHX-D in 298 μl NaOAc buffer and 1 μl DMSO. TPA solution was added and incubated for 5 minutes. Then, the product was generated using a SOLA cartridge. The substance was purified. Washing was performed with a 0.9% NaCl solution, and ethanol was used for elution. Next Then evaporate the ethanol, and add the remaining product to 100 μl of 0.9% NaCl solution and 10 μl of phosphoric acid. It was dissolved in the buffer.

[0081] Example 6: IC 50 Measurement of Values Filter plate MultiScreen HTS -DV in 100 μl PBS with 1% BSA added per well. Then incubated at room temperature for 30 minutes. After removing the PBS / BSA solution, 10 in 50 μl Opti-MEM 5 LNC aP cells were applied to each well. Different concentrations of the compound were added to 300 μl of Opti-MEM (in each well). Opti (producing concentrations of 0, 0.5, 1, 2.5, 5, 10, 25, 50, 100, 500, 1000 and 5000 nM) -3μl 150nM in MEM 125 The solution was mixed with I-labeled MIP-1466. 50 μl of the resulting solution was placed in each well. It was added to and each concentration was diluted fourfold by pipetting (in quadruples). Here, each well was A radioactively labeled ligand at a concentration of 0.75 nM and an unlabeled ligand at the aforementioned concentration. The plate was then incubated on a shaker at room temperature for 45 minutes.

[0082] After incubation, the cells were washed with 2 × 100 μl of ice-cold PBS and 1 × 200 μl of ice-cold PBS. Finally, the filters were retrieved and the remaining radioactivity was measured with a gamma-ray detector. The measurement was taken for 5 minutes.

[0083] The data measured with a gamma-ray detector was evaluated using Graphpad Prism, and the radioactively labeled MIP-1095 was identified. Inhibitory concentration for 50 (IC) 50 ) was achieved. [Table 2]

[0084] Example 7: μPET imaging using CHX-DTPA-MB17 Prior to injection into mice, the purified 68 solution containing Ga-CHX-DTPA-coupled PSMA inhibitor was sterilized by filtration. 100 μl of this solution was drawn into a syringe and injected into BALB / c nude mice bearing LNCaP xenografts via intravenous injection into the tail vein. PET scanning was performed for 1 40 minutes using a Siemens Inveon PET (Figure 15).

[0085] Example 8: Determination of competitive binding affinity To compare a series of novel compounds, competitive binding affinity and specific internalization were analyzed using the PSMA-expressing cell line LNCaP. To measure specific cellular uptake, cells were blocked with 2-(pho sphonomethyl)pentanedioic acid (PMPA). Inhibitory capacity was also investigated by the enzymatic NAALADase assay.

[0086] Cell culture For binding assays and in vivo experiments, LNCaP cells (metastatic lesion of human prostate cancer, ATCC C RL-1740) were cultured in RPMI medium supplemented with 10% fetal bovine serum and Glutamax (PAA, Austria) . During cell culture, cells were grown at 37°C in an incubator equilibrated with humidified air containing 5% CO 2. Cells were harvested using trypsin-ethylenediaminetetraacetic acid (trypsin EDTA; 0.25% trypsin, 0.0 2% EDTA, all from PAA, Austria), and washed with PBS.

[0087] Cell binding and internalization Competitive cell binding assays and internalization experiments were performed as described above (Eder et al. 2012). Cleanly, each cell (10 per well) 5 ) is a radioactive ligand (68Ga labeled [Glu-urea-Lys(Ahx )]2-HBED-CC (Schafer et al., 2012) and 12 samples of different concentrations (0-5000nM, 100μL / wet) Incubated in the presence of (L). After incubation, multi-screen vacuum manifold was used. Cleaning was performed using a hold (Millipore, Billerica, MA). A gamma-ray detector (PackardCob) was used. Cell-bound radioactivity was measured using raII (GMI, Minnesota, USA). The 50% inhibitory concentration (IC50) was The data was fitted and calculated using a nonlinear regression algorithm (GraphPad Software). The experiment was conducted three times.

[0088] To measure specific cell uptake and internalization, 24 hours before incubation 10 5 The cells were seeded into a poly-L-lysine coated 24-well cell culture plate. After washing, the cells The samples were incubated with a 25 nM radiolabeled compound at 37°C and 4°C for 45 minutes each. -(phosphonomethyl)pentanedioic acid (500 μM final concentration, PMPA, Axxora, Loerrach, Germany) Specific cell uptake was measured by competitive blocking. The cells were washed four times with 1 mL of ice-cold PBS and then finely divided. Cell uptake was terminated. Subsequently, the cells were placed in 0.5 mL of glycine HCl (50 mM, pH=2.8) in PBS for 5 minutes. The cells were incubated twice, and the surface-bound fraction was removed. The cells were washed with 1 mL of ice-cold PBS and 0 The compound was dissolved in 0.3NNaOH (0.5 mL). The surface-bound and internalized fractions were measured using a gamma-ray detector. 1 0 6 Cellular uptake was calculated as the percentage of the initially added radioactivity bound to each individual cell [%ID / 10 6 cell].

[0089] Naaladase assay Recombinant human PSMA (rhPSMA, R&D systems, Wiesbaden, Germany) in assay buffer (50 The substrate was diluted to 0.4 μg / mL with mMHEPES, 0.1 M NaCl, pH 7.5. (Irchen, Germany, 40 μM final concentration) was used with the natGa-labeled test sample and an assay buff with a final volume of 125 μL. The mixture was mixed at concentrations ranging from 0.05 nM to 1000 nM. The mixture was then added to 125 μL of rhPSMA solution (0.4 μg / mL). The mixture was incubated at 37°C for 1 hour. The reaction was stopped by heating at 95°C for 5 minutes. 25 0 μL of 15 mM ortho-phthaldialdehyde (Sigma, Taufkirchen, Germany) solution for all The mixture was added to the ial and incubated at ambient temperature for 10 minutes. Finally, 200 μL of the reaction mixture was collected. Filled onto an F16 Black Maxisorp plate (Nunc, Langenselbold, Germany), approximately 330nm At excitation and emission wavelengths of 450 nm, respectively, using a microplate reader (DTX-880, Beckm The data was read using GraphPad (GraphPad Software). Data was obtained using a one-site-total joint regression algorithm at (California, USA). We analyzed it.

[0090] Biodistribution 5×10 6 LNCaP cells (in 50% Matrigel; Becton Dickinson, Heidelberg, Germany) were subcutaneously inoculated into the right trunk of 7- to 8-week-old male BALB / c nu / nu mice (Charles River Laboratories) . Tumors were grown to a size of approximately 1 cm3. The radiolabeled compound was injected into the tail vein (approximately 1 MBq per mouse; 0.06 nmol). One hour after injection, the animals were sacrificed. Target organs were excised , blotted dry and weighed. Radioactivity was measured using a gamma counter and calculated as %ID / g.

[0091] MicroPET For microPET studies, 10 to 25 MBq of radiolabeled compound (approximately 0.5 nmol) in a volume of 0.15 ml was injected via the lateral tail vein into mice bearing LNCaP tumor xenografts. Anesthetized animals (2% sevoflurane , Abbott, Wiesbaden, Germany) were placed in prone position on an Inveon small-animal PET scanner (Siemens, Knoxvi lle, Tenn, USA), and dynamic microPET scanning and 20-minute static scanning were performed; see Figures 1, 3, 5 to 14. Table 3 Table 4

[0092] This example shows that the binding affinity of a PSMA inhibitor can be affected by linker modification and it is shown. Two cyclic motives in the linker region of the substance and at least one aromatic moieties are preferred, which are thought to occur in high affinity compounds MB4 and MB17. These novel variants exhibit nanomolar affinity for the LNCap cell line, 48% at 37°C ID / 10 6 were specifically internalized into the cells. According to the previous test, in addition to binding affinity, PSMA-targeted probe internalization characteristics are very important, and it has been shown that high in vivo tumor uptake and retention requires a high internalization rate. Therefore, MB17 corresponds to a novel PSMA-targeted probe with optimal characteristics that have also been confirmed by small animal PET imaging MB17 shows high PSMA-specific tumor uptake (Figure 2). In addition, dynamic PET imaging of MB17 ( Figure 2) shows initial accumulation in the bladder, and maximum kidney uptake (the highest point of the time-activity curve) occurs as early as 15 minutes after radiotracer injection, and substantially decreases already at 20 minutes after injection For therapeutic use, this demonstrates a clear clinical advantage of MB17 over other PSMA inhibitors. In the schematic PET image (Figure 1), MB17 shows rapid background clearance and a substantial reduction in kidney accumulation after 2 hours, while it further accumulates and is retained in PSMA-expressing tumors.

[0093] In addition, 177 the biodistribution of Lu (Figure 4) shows that the high initial kidney uptake is almost completely cleared after 24 hours (2.13±1.36% ID / g), while tumor uptake remains high and further increases (10.58± 4.50% ID / g). The values for liver (0.08±0.03% ID / g), lung (0.11±0.13% ID / g) and spleen ( Other organs, such as 0.13±0.05%ID / g, showed very low uptake. Favorable pharmacokinetics. This resulted in an extremely high tumor-to-background ratio after 24 hours (tumor / blood: 1058; Tumor / Muscle: 529).

[0094] Table A shows that chemical modifications in the linker region of a molecule affect its biological properties, such as affinity. And it has been clearly confirmed that it affects internalization efficiency. MB17 and MB4 affect cells It exhibits the most promising bonding properties.

[0095] Example 9: Clinical data on MB17 PET / CT imaging was performed using the Ga-68 labeled radioactive tracer MB17 (see Figure 17).

[0096] Used in radiopharmaceutical products 68 Ge / 68 The Ga-generating material is IDB-Holland BV (Baarle-Nassau, Th Purchased from eNetherlands. Disposable cassette kits and GMP- used for radiosynthesis. Chemicals containing compliant precursors are classified as ABX advanced biochemical compounds. Obtained from Radeberg, Germany. Chromolith Performance RP-18e column (100x4.6mm) Ultimate 3000 HPLC system (Dionex) (Acetolamine) equipped with Merck and NaI radiation detector (Raytest) Tonitrile (A), water + 0.1% TFA (B); gradient: 0.5 min 95% B, 10.0 min 80% A, flow rate: 2 mL / min) The radiochemical purity was measured using a 6850 Series gas chromatograph (Ag was measured using silentTechnologies. The endotoxin test was performed using Endosafe®- PTS device (Charles River).

[0097] 2 μg of MB17 was dissolved in 1.5 M acetate buffer pH 4.5 (1 mL) and 1 M ascorbic acid (10 μL) , and transferred to a reaction vessel. 68 Ge / 68 Ga generator material was diluted with 10 mL of 0.6 M HCl and 9 mL of ultrapure water eluted with eluent. The mixture was then transferred to a cation exchange cartridge (Macherey-Nagel PS-H+, SizeM), and eluted into a preheated reaction vessel (100°C) using 5 M NaCl solution (1.2 mL) . The reaction mixture was heated for 10 minutes. The crude reaction mixture was then removed from the reaction vessel and transferred to a pre-conditioned (10 mL EtOH / 10 mL ultrapure water) C18 cartridge (Waters Sep-Pak light). 9 mL of ultra- pure water was used to rinse the reaction vessel, and the rinse was passed through the C18 cartridge. The C18 cartridge was further washed with 5 mL of ultrapure water. The final product was eluted from the C18 cartridge with 2 mL of EtOH / H2O (v:v 1:1) , filtered for sterilization (Millipore Cathivex-GV, 0.22 μm), and diluted with 10 mL of phosphate buffered saline (PBS ) solution pH 7.4 (in accordance with Eur. Ph. 8.0 (4005000)). 68 The Ga-MB17 complex solution was intravenously administered to the patient as a bolus.

[0098] Example 10: 177 Human Therapy Using Lu-labeled MB17 For therapy, the PSMA ligand MB17 was radiolabeled with Lu-177. 177 LuCl3 was obtained from Perkin Elmer Obtained from (4 GBq, NEZ307D, 0.04 M HCl). 80 nmol of MB17 in 5 μL of 20% ascorbic acid. The solution was dissolved in 400 μL of sodium acetate buffer (0.4 M, pH 5) to which the solution had been supplemented. 177 LuCl3 Transferred and incubated at 95°C for 10 minutes. Finally, 2 mL of 0.9% NaCl was added. Quality control ITLC and radiation HPLC were performed for this purpose.

[0099] 177 Lu-labeled MB17 was administered to the patient as an intravenous bolus (5 mL, slowly within 30 seconds). Intravenous administration was achieved by starting 0.5 hours prior and administering 0.9% NaCl for 4.5 hours. See Figure 18. reference.

Claims

1. Compounds selected from the following formula X: 【Chemistry 1】 (In the formula, R' is as follows: (a) N,N''-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid (HBED-CC), (b) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA), (c) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanioic acid (NODAGA), (d) 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), (e) 1,4,7-Triazacyclononane phosphinic acid (TRAP), (f) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid](NOPO), (g) 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), (h) N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinate (DFO), (i) Diethylenetriaminepentaacetic acid (DTPA), (j) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), (k) 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), (l) p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), (m) 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), (n) 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and, (o) Selected from 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA) A pharmaceutically acceptable salt, solvate, solvate of the salt, or tautomer thereof.

2. A metal composite comprising the compound of claim 1, wherein a radionuclide is complexed with the chelating agent.

3. Said radionuclide is ８９ Zr, ４４ Sc, １１１ In, ９０ Y, ６６ Ga, ６７ Ga, ６８ Ga, １７７ Lu, ９９ｍ Tc, ６４ Cu, ６７ Cu, １４９ Tb, １５２ Tb, １５５ Tb, １６１ Tb, １５３ Gd, １５５ Gd, １５７ Gd, ２１３ Bi, ２２５ Ac, ２３０ U, ２２３ Ra, １６５ The metal complex according to claim 2, which is selected from the group consisting of Er and Fe.

4. The aforementioned radioactive nuclide is １７７ Lu, １６１ Tb, and ２２５ A metal composite according to claim 3, selected from the group consisting of Ac.

5. Stereoisomers of the compound according to claim 1.

6. (1) The compound of claim 1, and (2) Pharmaceutically acceptable carriers A composition containing the following:

7. The composition according to claim 6, further comprising a pharmaceutically acceptable excipient different from the pharmaceutically acceptable carrier.

8. (1) The metal composite according to claim 2, and (2) Pharmaceutically acceptable carriers A composition containing the following:

9. The aforementioned radioactive nuclide is ８９ Zr, ４４ Sc, １１１ In, ９０ Y, ６６ Ga, ６７ Ga, ６８ Ga, １７７ Lu, ９９ｍ Tc, ６４ Cu, ６７ Cu, １４９ Tb, １５２ Tb, １５５ Tb, １６１ Tb, １５３ Gd, １５５ Gd, １５７ Gd, ２１３ Bi, ２２５ Ac, ２３０ U, ２２３ Ra, １６５ The composition according to claim 8, selected from the group consisting of Er and Fe.

10. The aforementioned radioactive nuclide is １７７ Lu, １６１ Tb, and ２２５ The composition according to claim 9, selected from the group consisting of Ac.

11. The composition according to claim 8, further comprising a pharmaceutically acceptable excipient different from the pharmaceutically acceptable carrier.

12. The composition according to claim 8, which is a buffered solution.

13. (1) Stereoisomers of claim 5, and (2) Pharmaceutically acceptable carriers A composition containing the following:

14. The composition according to claim 13, further comprising a pharmaceutically acceptable excipient different from the pharmaceutically acceptable carrier.

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