Labeled inhibitors of prostate specific membrane antigen (PSMA), and their use as imaging agents and pharmaceutical agents for 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 relates generally to the field of radiopharmaceuticals and to methods for treating various stages of prostate cancer. and its use in nuclear medicine as a tracer and imaging agent. [Background technology]

[0002] 2. Background of the Invention Prostate cancer (PCa) is the leading cancer in the population of the United States and European countries. At least 1 to 2 million men suffer from prostate cancer, and the disease affects one in six men between the ages of 55 and 85. It is estimated that more than 300,000 new cases of prostate cancer are diagnosed each year in the United States. The mortality rate of this disease is second only to lung cancer. Current anatomical methods, such as magnetic resonance (MR) imaging and ultrasound, are not yet available for clinical imaging of prostate cancer. It is currently used worldwide for surgery, radiation therapy, chemotherapy and minimally invasive treatments. Currently, however, only 100% of patients with recurrent, metastatic, and androgen-dependent There is no effective treatment for upright prostate cancer.

[0003] Radiolabeled choline analogues [ 18 F] Fluorodihydrotestosterone ([ 18 F]FDHT), anti-1-a Mino-3-[ 18 F]fluorocyclobutyl-1-carboxylate (anti[18F]F-FACBC, [ 11 C] Acetate and 1-(2-deoxy-2-[ 18 F]fluoro-L-arabinofuranosyl)-5-methyluracil (-[ 18 F]F A variety of experimental low molecular weight PCa imaging agents, such as MAU, are currently being pursued clinically ( 1; Non-patent literature 2; Non-patent literature 3; Non-patent literature 4; Non-patent literature 5; Non-patent literature 6; Non-patent literature 7; 8). Each operates by a different mechanism and offers specific advantages, e.g. 11 C] Ko Disadvantages of phosphorus include low urinary excretion and the short physical half-life of positron-emitting radionuclides. has.

[0004] Tumors may express unique proteins associated with their malignant phenotype or may express proteins that are distinct from normal It is well known that tumor cells can overexpress many normal constitutive proteins in vivo. The expression of different proteins on the surface of the cytoplasm is important in determining the phenotypic identity and biochemical composition of the tumor. Probing the activity of certain tumors provides an opportunity to diagnose and characterize disease. Radioactive molecules that selectively bind to tumor cell surface proteins can be used to non-invasively image tumors This provides an attractive route for imaging and therapy. These drugs target the prostate-specific membrane antigen (PSMA) (Non-Patent Document 9; Non-Patent Document 10; Non-Patent Document 11). Document 11; Non-patent document 12; Patent document 1).

[0005] PSMA is abundant and restricted on the surface of PCa, particularly in androgen-independent advanced and metastatic disease It is a transmembrane 750 amino acid type II glycoprotein with high expression (Non-Patent Document 13). The latter is important because all PCa becomes androgen independent over time. PSM A is abundant in all stages of the disease (prostate (2) have limited expression, are not shed into the circulation, and are presented on the cell surface and act as an enzyme or signaling The PSMA gene is located on the short arm of chromosome 11. and functions as both a folate hydrolase and a neuropeptidase. It has neuropeptidase function equivalent to glutamate carboxypeptidase II (GCPII). It is called "brain PSMA" and converts N-acetylaspartylglutamate (NAAG) into N-acetylglutamate. Glutamate (glutamatergic) conversion is accelerated by breaking down into spartate (NAA) and glutamate. It can regulate the migration of 10 6 Up to 10 PSMA molecules are present, and radioactive It has further been suggested as an ideal target for imaging and therapy using nuclide-based techniques. (Non-Patent Document 15).

[0006] A radioimmunoconjugate of the anti-PSMA monoclonal antibody (mAb) 7E11 (PROSTASCINT®) Known as a cytometric scan, this is currently used to diagnose prostate cancer metastasis and recurrence. However, this agent tends to produce images that are difficult to interpret (16; Non-Patent Document 17; Non-Patent Document 18). More recently, a molecule that binds to the extracellular domain of PMSA has been reported. A monoclonal antibody has been developed, which is radiolabeled and used to detect PMSA-positive pre-existing cells in animals. It has been shown to accumulate in prostate tumor models. Diagnosis and tumor detection using monoclonal antibodies is hampered by the poor penetration of monoclonal antibodies into solid tumors. It is restricted.

[0007] Selective targeting of cancer cells with radiopharmaceuticals for either imaging or therapeutic purposes is difficult. 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 123 I and131 Various radionuclides such as I Species are known to be useful for radioimaging or cancer radiotherapy. Glutamate-urea-glutamate (GUG) or glutamate bound to a nuclide-ligand conjugate Several compounds containing glutamic acid-urea-lysine (GUL) recognition factors have high affinity for PSMA. It has been shown to exhibit compatibility. [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 novel method to rapidly visualize and specifically target prostate cancer for delivery of radiation therapy New drugs are needed.

[0011] Thus, the subject of the present invention is to provide a method for the detection, treatment and management of prostate cancer by using a method that interacts with PSMA. Develop ligands bearing suitable radionuclides that offer promising novel targeting options for To do so. [Means for solving the problem]

[0012] Summary of the Invention The solution of the above problem is achieved by providing the embodiments characterized in the claims. is achieved.

[0013] The inventors have identified novel compounds that are useful radiopharmaceuticals and methods for treating various stages of prostate cancer. They have found use as tracers, imaging agents in nuclear medicine for treatment.

[0014] Novel imaging agents with structural modifications in the linker region have demonstrated improved tumor targeting properties and pharmacokinetics The pharmacophore interacts with each side chain of PSMA. Three available carboxyl groups and one as part of the zinc complex in the active center. In addition to these obligatory interactions, the inventors have also The lipophilic interactions in the Car region could be optimized.

[0015] That is, the gist of the present invention is [1] Formula (Ia) or (Ib): [ka] , during the ceremony [Table A-1] Compounds of [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] The compound according to [1], [3] The following: [ka] [ka] [ka] [ka] [ka] The compound according to [1] or [2], [4] Use of a compound according to any one of [1] to [3] for the preparation of a radiolabeled compound. [5] A metal complex comprising a radionuclide and a compound according to any one of [1] to [3]. [6] The radionuclide is: 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 64 Cu, 153 Gd, 155 Gd, 157 Gd, 2 13 Bi, 225 The metal complex according to [5], wherein Ac is Ac or Fe. [7] A compound according to any one of [1] to [3], or a metal complex according to [5] or [6]. or a pharma- ceutically acceptable salt or ester thereof, and a pharmaceutical composition comprising a carrier; [8] A compound according to any one of [1] to [3] for use in an imaging method in a patient. or the metal complex according to [5] or [6], [9] A method for diagnosing prostate cancer and / or its metastasis, comprising the steps of: or the metal complex according to [5] or [6].

[10] A compound according to [1] to [ 3) A compound according to any one of the above or a metal complex according to the above [5] or [6]. Regarding. Effect of the Invention

[0016] In accordance with the present invention, a labeled inhibitor of prostate specific membrane antigen (PSMA) is provided for the treatment of prostate cancer. and their use as pharmaceutical agents. [Brief description of the drawings]

[0017] [Figure 1] Figure 1: PET imaging of MB17. Whole-body coronal microPET images of athymic male nude mice bearing LNCaP tumor xenografts. Tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB17 were assessed by dynamic microPET scans. Approximately 15MBq was injected per mouse. Graph A shows the time-activity curves for kidney and bladder, respectively, and graph B shows the time-activity curves for heart, muscle and tumor, respectively. Values ​​are expressed as mean SUV (standardized uptake value). [Diagram 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 shows PMSA-specific uptake in tumor and kidney. Data are presented as mean % ID / g tissue ± SD (n=3). [Diagram 3] Figure 3: PET imaging of MB4. Whole-body coronal microPET images of athymic male nude mice bearing LNCaP tumor xenografts. [68Ga]MB4 tumor targeting efficiency and pharmacokinetic properties were assessed with dynamic microPET scans. Approximately 15 MBq was injected per mouse. Graph A shows the time-activity curves for kidney and bladder, respectively, and graph B shows the time-activity curves for heart, muscle and tumor, respectively. Values ​​are expressed as mean SUV (standardized uptake value). [Figure 4]Figure 4: Organ distribution expressed as % ID / g tissue ± SD (n=5) 24 h after injection of 0.06 nmol 177Lu-labeled MB17. Organ distribution with 177Lu shows that the high initial kidney uptake almost completely disappeared after 24 h (2.13 ± 1.36% ID / g), while the tumor uptake remained high and even increased (10.58 ± 4.50% ID / g). Other organs such as liver (0.08 ± 0.03% ID / g), lung (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 after 24 h (tumor / blood: 1058; tumor / muscle; 529). [Diagram 5] Figure 5: PET imaging of MB2. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB2 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 6] Figure 6: PET imaging of MB3. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB3 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 7] Figure 7: PET imaging of MB10. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB10 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 8] Figure 8: PET imaging of MB17.D. Whole-body coronal microPET images of athymic male nude mice bearing LNCaP tumor xenografts. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB17.D were assessed by dynamic microPET scans. 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-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB22 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 10] Figure 10: PET imaging of MB24. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB24 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 11] Figure 11: PET imaging of MB25. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB25 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 12] Figure 12: PET imaging of MB31. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB31 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 13] Figure 13: PET imaging of MB33. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB33 were assessed by dynamic microPET scans. Approximately 15 MBq was injected per mouse. [Figure 14] Figure 14: PET imaging of MB35. Whole-body coronal microPET images of an athymic male nude mouse bearing a LNCaP tumor xenograft. The tumor targeting efficiency and pharmacokinetic properties of [68Ga]MB35 were assessed by dynamic microPET scans. 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. Photographs cover a time course of 20-40 min (top row), 40-60 min (middle row) and 120-140 min (bottom row). [Figure 16] Figure 16: MB-17 vs. MB-17.D. Whole-body coronal microPET images of athymic male nude mice bearing LNCaP tumor xenografts. The tumor targeting efficiency and pharmacokinetic properties of stereoisomers MB-17 and MB-17D were directly compared 2 hours after injection. [Figure 17a] Figure 17: Human PET / CT imaging 68Ga-labeled MB17. (a) First clinical experiment with 68Ga-labeled MB17 PET / CT shows detection of small lymph node metastases 1 hour after injection, primarily due to high radiotracer uptake. Red arrows indicate a representative lesion with an SUVmax of 36.5 1 hour after injection and a tumor-to-background ratio of 52.1. MIP = maximum intensity emission of PET 1 hour after injection. [Figure 17b] (b) A significant advantage of 68Ga-labeled MB17 PET / CT is its highly sensitive detection of 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 value of 14. Two months later, 3.3 GBq of 177Lu-labeled MB17 was applied. At this point, the amount of PSA in the blood reached a value of 38. After the first cycle, the PSA level dropped 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. The treatment showed a significant effect on the tumor lesions and PSA value, resulting in a decrease in bone pain. (b) The graph shows the significant effect on the decreased PSA value after the first application of a therapeutic dose of 177Lu-labeled MB17. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description of the Invention The present invention provides radiopharmaceuticals, tracers, imaging agents and the like for the treatment of various stages of prostate cancer. Its use in nuclear medicine as an imaging agent.

[0019] Thus, the present invention relates to compounds of general formula (Ia) or (Ib): [ka] In the formula [Table 1] The present invention relates to a compound wherein

[0020] Unless otherwise stated, in the present invention, an "alkyl" group (preferably, C ~C 10 ) can be linear or branched, unsubstituted or substituted. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentanyl, n-hexane xanyl. The corresponding cycloalkyl compounds preferably have 3 to 10 carbon atoms. The same applies to

[0021] "Aryl" refers to an aromatic monocyclic group having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group may suitably be one or more alkyl groups, such as an alkyl group. Preferred aryl groups are phenyl, benzyl or naphthyl. It is.

[0022] The Z group is preferably -CO2H, but may also be -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, -PO4H2, etc. It can be easily substituted with any biosteric substituent, e.g., in "The Practice of Medicinal Plants." See "Inal Chemistry" (Academic Press New York, 1996), p. 203.

[0023] Within the meaning of the invention, all radicals are, unless otherwise stated in the radical definition, All possible subgroups thereof are considered to be disclosed. .

[0024] In a preferred embodiment, the motif that specifically binds to the cell membrane of a neoplastic cell is a motif that specifically binds to the cell membrane of a prostate cancer cell, and in particular, the PSMA according to the following formula in Scheme 1: Contains a glutamic acid-urea-lysine motif.

[0025] Thus, the preferred molecule of the present invention comprises three main components (Scheme 1): hydrophilic PSMA A binding motif (Glu-urea-Lys; = Glu-NH-CO-NH-Lys), a flexible linker and preferably DOTA The chelating agent is

[0026] Scheme 1: Structures of preferred compounds of the invention [ka]

[0027] Different preferred linkers are shown below, as described above, where R= - Glu-urea-Lys , R'= - DOTA (as a preferred example for the chelating agent). [ka] [ka] [ka] [ka]

[0028] Preferred compounds of the invention are, for example: [ka] [ka] [ka] [ka] [ka] It is.

[0029] The invention also relates to pharma- ceutically acceptable salts of the compounds of general formula (Ia) and / or (Ib). The invention also relates to solvates of the compounds, including salts and active metabolites of the compounds. and, where appropriate, tautomers of the compounds of general formula (Ia) and / or (Ib), including prodrug formulations. Concerning isomers.

[0030] "Pharmaceutically acceptable salt" refers to a pharma- ceutically acceptable organic or inorganic salt of a compound of the invention. Representative pharma- ceutically acceptable salts include, for example, salts of alkali metal ions. salts of alkali metals, alkaline earth salts, ammonium salts, water-soluble and water-insoluble salts, e.g. acetates, Carbonate, chloride, gluconate, glutamate, lactate, laurate, malate or or tartrates.

[0031] The term "prodrug" refers to a drug that undergoes a chemical transformation by metabolic processes upon administration to a patient, and The term "precursor of a drug" refers to a compound that will become an active pharmaceutical agent after the formation of the compound represented by formula (Ia) and / or (Ib). Exemplary prodrugs of the compounds of formula (I) are esters and amides, preferably fatty acid esters. wherein the prodrug formulation is an alkyl ester of the aryl group, by simple transformations including hydrolysis, oxidation or reduction in any of the other modes of Suitable prodrugs include, for example, enzyme-degradable linkers (e.g., carbamazepines, bamate, phosphate, N-glycoside or disulfide groups) to enhance solubility (e.g. For example, tetraethylene glycol, polysaccharides, formic acid or glucuronic acid, etc. Such prodrugs of the compounds of the invention include those of formula (Ia) and / or (Ib). and the prodrug is a compound of the general formula (Ia) such that the desired pharmaceutical effect is obtained. and / or can be converted into a substance of formula (Ib).

[0032] Some compounds of formula (Ia) and / or (Ib) may be present as racemates, their enantiomers, and optionally their diastereomeric forms, as well as all possible mixtures thereof. It is contained in the form of a thing.

[0033] According to the invention, all chiral C atoms have D- and / or L-configuration and are Combinations within the compound are also possible, i.e. some of the chiral C atoms may be in the D configuration. the others may be in the L configuration.

[0034] The compounds obtained may be of any of their enantiomers and / or diastereomers. , can be separated by any known method (see, for example, Allinger, NL and Elliel EL in " Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971). Enantiomer separation One possible method of isolation is the use of chromatography.

[0035] The invention also relates to a compound of formula (Ia) or (Ib) of the invention, together with a therapeutically effective amount of an active ingredient, An organic or synthetic compound that is suitable for the intended administration and that interacts with the active ingredient without causing any interference. The present invention relates to pharmaceutical preparations comprising an inorganic, solid or liquid pharma- ceutically acceptable carrier.

[0036] The phrase "pharmaceutically acceptable" is used herein to mean any compound that is within the scope of sound medical judgment. , with reasonable benefit without undue toxicity, irritation, allergic response, or other problems or complications. Compounds, substances and compositions suitable for use in contact with patient tissues, commensurate with the benefit / risk ratio and / or used to refer to dosage form.

[0037] A "patient" includes animals such as humans, monkeys, cows, horses, cats or dogs. The animal can be a mammal, such as a non-primate or a primate (eg, monkeys and humans). In one embodiment, the patient is a human.

[0038] Generally, the compounds of formula (Ia) or (Ib) or pharmaceutical compositions thereof are administered orally or parenterally. It may be administered by any route, usually by injection or infusion.

[0039] "Parenteral route of administration" means a form of administration other than enteral and topical administration, usually by injection. , without being limited thereto, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal Intratracheal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injections and and injection.

[0040] The dosage of the compounds according to the invention is determined based on patient-specific parameters such as age, weight, sex, and severity of the disease. The dosage is determined by a physician based on the dosage. The dosage is preferably 0.00001 mg / kg to 10 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 medicines are prepared, for example, according to common galenic methods. solutions or suspensions, plain tablets or dragees, hard or soft gelatin capsules, They are suitably formulated in the form of suppositories, ovules, and injection preparations.

[0042] The compounds of the invention may, if appropriate, be administered in the presence of further active substances as well as excipients common to pharmaceutical compositions. The agent may be formulated with a carrier, for example, talc, arabic, or other suitable carriers, depending on the formulation to be produced. Gum, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous Aqueous carriers, fatty bodies of animal or vegetable origin, paraffin derivatives, glycols (especially poly ethylene glycol), various plasticizers, dispersing or emulsifying agents, pharma- ceutically compatible gases (e.g. For example, air, oxygen, carbon dioxide, etc., may be formulated with a preservative.

[0043] To produce a liquid formulation, sodium chloride solution, ethanol, sorbitol, glycerol, Phosphorus, olive oil, peanut oil, propylene glycol or ethylene glycol, etc. The following additives may be used:

[0044] When a solution for infusion or injection is used, the solution is preferably an aqueous solution or suspension. For example, the active ingredient itself or mannitol, lactose, glucose, albumin, It is possible to prepare the drug immediately before use from a lyophilized formulation containing a carrier such as ethanol. The liquids are sterilized and, where appropriate, contain excipients, such as preservatives, stabilizers, emulsifiers, solubilizers, buffers, etc. Sterilization may be performed, if appropriate, on the composition. The sterile solution may be obtained by filtration using a small-pore filter through which the solution may be lyophilized. Small amounts of antibiotics may also be added to ensure maintenance.

[0045] The phrases "effective amount" or "therapeutically effective amount" as used herein refer to any medical treatment. Some effect in at least a subpopulation of cells in an animal with a reasonable benefit / risk ratio that is applicable A compound comprising the compound of the invention or other active ingredient effective to produce the desired therapeutic effect of A therapeutically effective amount for a compound of the invention means an amount of an agent, substance or composition that is effective to prevent or control a disease. The term "therapeutic agent" refers to an amount of therapeutic agent, alone or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of a disease. When used in reference to the compounds of the invention, the term refers to a compound that enhances or improves the overall treatment. Reduce or avoid the symptoms or causes of a disease, or reduce the therapeutic effectiveness or or a synergistically enhancing amount.

[0046] As used herein, the term "treat" or "treatment" refers to any treatment including diagnosis, prophylaxis, The term "treatment" is also intended to include prevention, therapy and cure.

[0047] The terms "prevent," "preventing," and "prevention" ) refers to the prevention or treatment of disease onset, recurrence or progression in a patient resulting from administration of a prophylactic or therapeutic agent. refers to prevention of spread.

[0048] The compounds of formula (Ia) and / or (Ib) of the invention are used as radioimaging agents or Different radionuclides are complexed with chelating agents depending on their use as radiopharmaceuticals. Exemplary radionuclides 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 of the oxidizing agent include Er and Fe. Then, the radionuclide 111 In, 90 Y, 68 Ga, 64 Cu, 153 Gd, 155 Gd, 213 Bi, 225Ac, Fe or 17 7 This is Lu.

[0049] As mentioned above, the conjugates of the compounds of formula (Ia) or (Ib) are effective in inhibiting the proliferation of rapidly proliferating cells, such as PS Suitable for use as radioimaging or therapeutic agents for the treatment of MA-expressing prostate cancer cells. According to the present invention, the complex may comprise one or more radionuclides. are called "radiopharmaceuticals."

[0050] The preferred imaging method is positron emission tomography (PET) or single photon emission computed tomography. This is a spectroscopic computed tomography (SPECT).

[0051] Thus, in one embodiment, a radionuclide and a compound of formula (Ia) or formula (Ib), or a salt thereof , solvates, stereoisomers or tautomers, as well as complexes including pharma- ceutically acceptable carriers. A pharmaceutical composition comprising the conjugate is provided.

[0052] According to another aspect, pharmaceutical compositions suitable for in vivo imaging and radiotherapy are provided. Suitable pharmaceutical compositions may be prepared as elemental, i.e. radioactive iodine or as a compound of formula (Ia) and / or or a radioactive metal chelate complex of the compound of formula (Ib), A radioactive imaging agent or radioisotope having a radionuclide in a quantity sufficient for imaging together with a radioactive vehicle. Radiotherapy agents may be included. Human serum albumin; aqueous buffer solutions, such as Tris(hydrometh)amine; (ethyl)aminomethane (and its salts), phosphates, citrates, bicarbonates, etc.; sterile physiological Salt solutions; and chloride salts and / or bicarbonate salts or salts of calcium, potassium, sodium A regulated ion solution containing the normal plasma cations, such as sodium and magnesium. The radioactive vehicle, such as a liquid, should be suitable for injection or inhalation.

[0053] The concentration of imaging or therapeutic agent in the radioactive vehicle is selected to provide satisfactory imaging. For example, when using an aqueous solution, the dosage should be about 1.0 to 100 milliliters. However, the dose actually administered to patients for imaging or therapeutic purposes is The duration of the imaging or therapeutic agent is determined by the treating physician. The imaging or therapeutic agent is administered within the patient for approximately 1 hour to 10 days. should be administered to maintain a constant 10-fold increase in blood pressure, but longer or shorter doses are acceptable. Therefore, convenient ampoules containing 1-10 mL of the aqueous solution may be prepared.

[0054] Imaging may be performed, for example, by injecting an imaging composition in an amount sufficient to provide adequate imaging. Scan with a suitable imaging or scanning machine, such as a laminograph or gamma camera. In certain embodiments, imaging of an area of ​​a patient can be performed in a conventional manner. The method includes the steps of: (i) administering to a patient a diagnostically effective amount of a compound complexed to a radionuclide; (ii) exposing an area of ​​the patient to a scanning device; and (ii) obtaining an image of the area of ​​the patient. In certain embodiments, the imaged region is the head or thorax. The compounds and conjugates of formula (Ia) and / or (Ib) target the PSMA protein.

[0055] Thus, in some embodiments, spleen tissue, kidney tissue, or PSMA-expressing tumor tissue. A method of imaging tissue such as a medicament for imaging comprising administering to said tissue a radionuclide and a compound of formula (Ia) and / or a compound of formula (Ib) is provided.

[0056] The amount of a compound of the invention, or a metal and a compound of formula (Ia) and / or (Ib) administered to a patient or a salt, solvate, stereoisomer or tautomer complex thereof. The amount will depend on the imaging being performed, the nature of the tissue being targeted for imaging or treatment, and The physician determines the weight and medical history of the patient who will be imaged or treated with the radiopharmaceutical. The usual use depends on several physiological factors.

[0057] Thus, in another aspect, the invention provides a method for administering to a patient a therapeutically effective amount of a radionuclide and a complex. The compounds of formula (Ia) and / or (Ib) or pharma- ceutically acceptable salts of said complexes are also or a solvate thereof to treat a patient suffering from a cell proliferative disease or disorder. Specifically, the present invention provides a method for treating a patient using a compound, pharmaceutical composition or Cellular proliferative diseases or disorders that may be treated or imaged using radiopharmaceuticals include, e.g. cancers in the lungs, liver, kidneys, bones, brain, spinal cord, bladder, etc., such as prostate cancer and / or It is metastasis of prostatic cancer.

[0058] The synthesis of the compounds of the present invention is described in detail in the Examples section. An example is shown in Scheme 2 for a conjugated PSMA inhibitor. However, those skilled in the art may , for example, the reaction can be modified using a different chelating agent. Thus, this scheme The compounds of the present invention should not be construed as limiting only to DOTA chelators.

[0059] Scheme 2 [ka]

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

[0061] Novel chelator conjugates with structural modifications in the linker region The imaging agents have improved tumor targeting properties and pharmacokinetics. The antibody has three carboxyl groups that can interact with the side chains of PSMA, as well as a ligand in the active center. In addition to these obligatory interactions, In addition, the inventors were able to optimize the lipophilic interactions in the linker region.

[0062] Preclinical evaluation includes in vitro assays (affinity, internalization) and in vivo This includes microPET screening and organ distribution.

[0063] The compounds of the present invention have been shown to be more potent than known reference compounds in terms of renal clearance and tumor enrichment. The binding affinity of the PSMA inhibitors of the present invention can be influenced by linker modifications. The substance has two cyclic motives and at least one aromatic moiety in the linker region. This appears to result in the preferred and high affinity compounds MB4 and MB17. In this regard, a very promising compound is MB17.

[0064] Thus, the compounds of the present invention are also confirmed by organ distribution and small animal PET imaging. The present invention provides a novel PSMA targeting probe with optimal characteristics. They also show differential tumor uptake with early enrichment in the bladder and also in the kidney. In terms of therapeutic use, this is comparable to other PSMA inhibitors. This provides a clear clinical advantage for the compounds of the present invention compared to the In this study, the compounds of the present invention, particularly MB17, showed rapid background clearance and The compound shows a substantial reduction in enrichment in the thyroid and kidney, but the compound accumulates further in PSMA-expressing tumors. Also, the first in vivo treatment with MB17 showed promising data (Figures 17 and 18). reference).

[0065] The following examples explain the invention in more detail but are not intended to illustrate the invention in any way. It is not intended to be limited to only the illustrated embodiments. EXAMPLES

[0066] Working Example Example 1: Synthesis of DOTA-conjugated inhibitors DOTA-conjugated PSMA inhibitors are synthesized via solid-phase peptide synthesis (Skip et al. In the first step, 3 mmol of bis(tert-butyl)-L-glutamic acid hydrochloride and A mixture of 3 mL of N-ethyldiisopropylamine (DIPEA) in 200 mL of dry CH2Cl2 was dissolved in 1 mmol of Add 10 mL of riphosgene to a solution of dry CH2Cl2 at 5 °C for 3 h to obtain the cation of the glutamyl moiety. The isocyanate was generated in situ. After the reaction, 0.5 mmol of resin-fixed (2-chloro-trimethylsilyl) Add ε-allyloxycarbonyl-protected lysine and stir gently for 4 hours. The resin was removed by filtration, and 50 mg of tetrakis-(triphenyl)para in 4 mL of CH2Cl2 was added. The allyloxy protecting group was removed using 400 μL morpholine and 400 μL diethyl ether for 2 h.

[0067] Subsequent synthesis of the peptidomimetic PSMA binding motif was performed following standard Fmoc protocols. The coupling of the following linker moieties was carried out using 2 mmol of the corresponding Fmoc-protected acid, 3. Performed using 96 mmol of HBTU and 2 mmol of N-ethyl-diisopropylamine. 3.95 equiv. After activation with 1000 mg of HBTU and DIPEA for 2 h, 4 equiv. of tris(t-bu)-DO relative to resin loading was added. TA (Chematech) was reacted with a final volume of 3 mL DMF. The product was cleaved from the resin in a 2 mL mixture of silane and water (95:2.5:2.5).

[0068] Chelation using HBTU-activated DOTA-NHS ester (CheMatech) or DOTA-TFP ester The drug 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] The analysis of the synthesized molecules was performed using a linear AB gradient (0% B to 100% B, 6 min) at a flow rate of 4 mL / min (analysis) or 6 min. Purification was performed using reversed-phase high-performance liquid chromatography (RP-HPLC; ChromolithRP-18e, 100 × 4.6 mm; 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, Germany) The rmany was equipped with a UV and gamma detector (Bioscan; Washington, USA). UV absorbance was measured at 214 nm The measurements were performed using a MALDI-MS Daltonics Microflex system (Bruker Daltonics, Bremen, Germany). Mass spectrometry was performed using

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

[0071] Radiolabeling of compounds gave radiochemical yields of >97% after 15 min at 95 °C and was analyzed by RP-HPLC and and 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 hydrochloride and 1.5 mL of N- A mixture of ethyldiisopropylamine (DIPEA) and 1 mmol triphosgene in 10 mL of dry CH2Cl2 was The solution was added at 0°C for 4 hours to generate isocyanates of the glutamyl moieties in situ. The reaction mixture was stirred at 25 °C for 1 h, after which 0.5 mmol of resin-bound (2-chloro-trimethylsilyl) in 4 mL DCM was added. Add ε-allyloxycarbonyl-protected lysine and stir gently for 16 minutes. The resin was removed by filtration, and 30 mg of tetrakis(triphenyl)para in 4 mL of CH2Cl2 was added. The allyloxy protecting group was removed using 400 μL morpholine and 400 μL sodium chloride for 3 h. In the following, 4-(Fmoc-aminomethyl)benzoic acid (MB4) or Fmoc-3-(2-naphthyl)-L-arabinanyl and trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (MB17) Each of the three couplings was carried out in a final volume of 4 mL DMF using 2 mmol of Fmoc-protected acid, 1.96 mmol of HBTU and and 2 mmol of N-ethyldiisopropylamine. After activation with DIPEA for 2 h, 4 equivalents of tris(t-bu)-DOTA (Chemate ch) was reacted for 3 hours in a final volume of 3 mL DMF. The product was cleaved from the resin in a 2 mL mixture of ran and water (95:2.5:2.5). and the purified product was analyzed using analytical RP-HPLC and MALDI-MS. .

[0073] To prepare the stereoisomer of MB17(L), MB-17D, the synthesis was carried out using Fmoc-3(2-naphthyl)-D-aryl. Unless otherwise stated, MB17 is the L-stereoisomer in this description. It means sexual body.

[0074] Example 4: Coupling to various chelating agents [ka] Chelating agents (DOTA, NOTA, NODAGA, DTPA, CHX-DTPA, PCTA, Do3A) were synthesized by solid phase synthesis on MB17. Typically, 13 μmol of the antibody 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 with 20% piperidine in DMF for 5 min twice. Five washes were continued.

[0075] 1.5 to 4 equivalents of chelating agent (depending on the chelating agent), 0.98 x n キレート剤 HATU (if necessary) ) and 10 equivalents of DIPEA were dissolved in 500 μl of DMF and the solution was pumped into the syringe containing the resin. The resin was then washed with DMF, methanol, DCM and dichloromethane and incubated overnight. It was washed five times with ethyl ether and dried in vacuum.

[0076] To investigate the state of the reaction, a test separation was used, which consisted of filtering a small amount of resin with DCM. Add 100 μl of separation solution containing 95% TFA, 2.5% water, and 2.5% TIPS to the tip of the filter. After 30 min of incubation, the solution was pipetted into ice-cold diethyl ether. The diethyl ether was discarded and the remaining pellet was diluted with 35 μl of ACN:H2O (1:1 ) and analyzed by HPLC (0–100% ACN in water within 5 min) and LC / MS.

[0077] If the desired product was obtained, the complete peptide was cleaved from the resin. The dry resin was aliquoted in 500 μl of cleavage solution. The solution was incubated for 2 hours in 95% TFA, 2.5% H2O, and 2.5% TIPS. The resulting solution was cooled on ice. Mix with diethyl ether and centrifugal separation (4000 min -1 Discard the supernatant and add a new flask. Diethyl ether was added and the container was shaken vigorously to resuspend the pellet. The solution was centrifuged again. Distance (4000min -1 The pellet was then dried in vacuum and finally The cells were then resuspended in 1 ml of ACN:H2O (1:1).

[0078] Purification was achieved by preparative HPLC and the peak was purified by analytical HPLC (0-100% ACN in water within 5 min) and The extracts were analyzed by HPLC and LC / MS, and those containing the product were pooled and lyophilized.

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

[0080] 68 Ga labeling For PET scans, CHX-DTPA 68 Labeled with Ga. 1 ml 68 Ga, using 0.6M HCl 68 Ge / 68 The Ga-derived material was eluted with 298 μl NaOAc buffer and 1 μl of 10 mM CHX-D in DMSO. The TPA solution was added and incubated for 5 minutes. Then, the product was purified using the SOLA cartridge. The product was purified. It was washed with 0.9% NaCl solution and eluted with ethanol. The ethanol was evaporated at 4°C, and the remaining product was diluted with 100 μl of 0.9% NaCl solution and 10 μl of phosphoric acid. Dissolved in buffer.

[0081] Example 6: IC 50 Measurement of values MultiScreen Filter Plate HTS -DV was plated in 100 μl PBS supplemented with 1% BSA per well. The cells were incubated with 100 mM NaCl in 50 μl Opti-MEM for 30 min at room temperature. After removing the PBS / BSA solution, the cells were 5 LNC aP cells were applied to each well. Different concentrations of compounds (in each well) were added in 300 μl Opti-MEM. (resulting in concentrations of 0, 0.5, 1, 2.5, 5, 10, 25, 50, 100, 500, 1000 and 5000 nM) were -3μl 150nM in MEM 125 The resulting solution was mixed with a solution of I-labeled MIP-1466. 50 μl of the resulting solution was added to each well. and each concentration was diluted in quadruples by pipetting. Radioactively labeled ligand at a concentration of 0.75 nM and unlabeled ligand at the concentrations mentioned above. The plates were then incubated for 45 minutes at room temperature on a shaker.

[0082] After incubation, cells were washed 2× with 100 μl ice-cold PBS and 1× with 200 μl ice-cold PBS. Finally, the filters were collected and the remaining radioactivity was measured using a gamma counter. The curve was measured for 5 minutes.

[0083] The data from the gamma counter were evaluated using Graphpad Prism to determine the radiolabeled MIP-1095. Inhibitory concentration 50 (IC 50 ) was achieved. [Table 2]

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

[0085] Example 8: Measurement of competitive binding affinity To compare a series of novel compounds, competitive binding affinity assays were performed using the PSMA-expressing cell line LNCaP. To measure specific cellular uptake, cells were incubated with 2-(HO) The enzyme-based NAALADase assay was performed using 100% NAALADase. The inhibitory ability was also examined.

[0086] cell culture For binding studies and in vivo experiments, LNCaP cells (metastatic lesions of human prostate cancer, ATCC 62161) were used. RL-1740) 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 and 5% CO2. Trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA; 0.25% trypsin, 0.0 The cells were harvested using 2% EDTA (all PAA, Austria) and washed with PBS.

[0087] Cell binding and internalization Competitive cell binding assays and internalization experiments were performed as previously described (Eder et al. 2012). Separately, add the respective cells (10 per well) 5 ) was used as a radioactive ligand (68Ga-labeled [Glu-urea-Lys(Ahx )]2-HBED-CC (Schafer et al., 2012) and 12 different concentrations of analytes (0–5000 nM, 100 μL / well). After incubation, the cells were incubated in the presence of 100 μl ... Washing was performed using a γ-ray counter (Packard Cobb, Billerica, MA). The cell-bound radioactivity was measured using a 50% inhibitory concentration (IC50) of 100 mM NaCl. , was calculated by fitting the data using a nonlinear regression algorithm (GraphPad Software). The experiment was performed three times.

[0088] 24 hours prior to incubation to measure specific cellular uptake and internalization. 10 5 The cells were seeded onto poly-L-lysine-coated 24-well cell culture plates. After washing, the cells were incubated with 25 nM of radiolabeled compound for 45 min at 37°C and 4°C, respectively. -(phosphonomethyl)pentanedioic acid (500 μM final concentration, PMPA, Axxora, Loerrach, Germany) Specific cellular uptake was measured by competitive blocking. Cells were washed four times with 1 mL of ice-cold PBS. To terminate vesicle uptake, the cells were then soaked in 0.5 mL glycine HCl in PBS (50 mM, pH = 2.8) for 5 min. The surface-bound fraction was removed by incubating the cells twice with 0.5 mL of ice-cold PBS. The cells were washed with 1 mL of ice-cold PBS and incubated for 2 h at 37 °C. The surface-bound and internalized fractions were measured using a gamma counter. 0 6 Cellular uptake was calculated as the percentage of the initially added radioactivity bound to cells [%ID / 10 6 cell].

[0089] Naaladase assay Recombinant human PSMA (rhPSMA, R&D systems, Wiesbaden, Germany) was diluted in assay buffer (50 The substrate Ac-Asp-Glu (Sigma, Taufk) was diluted to 0.4 μg / mL in 0.5 mM HEPES, 0.1 M NaCl, pH 7.5. 40 μM final concentration) was added to the natGa-labeled specimen and to the assay buffer in a final volume of 125 μL. The mixture was mixed at concentrations ranging from 0.05 nM to 1000 nM in PBS. The mixture was added to 125 μL of rhPSMA solution (0.4 μg / mL). The mixture was combined with 100 ml of 10 ... 0 μL of 15 mM ortho-phthaldialdehyde (Sigma, Taufkirchen, Germany) solution was added to all The reaction mixture was then added to the vial and incubated at ambient temperature for 10 minutes. The data were loaded onto F16 Black Maxisorp plates (Nunc, Langenselbold, Germany) and analyzed at 330 nm and The plate was read using a microplate reader (DTX-880, Beckman, MA) at excitation and emission wavelengths of 450 nm and 450 nm, respectively. Reads were generated using GraphPad (GraphPad Software, Inc., Krefeld, Germany). Data were analyzed using a one site-total binding regression algorithm (California, USA). was analyzed.

[0090] Biodistribution 5 × 10 in the right trunk of 7- to 8-week-old male BALB / c nu / nu mice (Charles River Laboratories) 6 LNCaP cells (in 50% Matrigel; Becton Dickinson, Heidelberg, Germany) were inoculated subcutaneously. Tumors were allowed to grow to a size of approximately 1 cm3. Radiolabeled compounds were injected into the tail vein (1 μg / kg). The animals were sacrificed 1 hour after injection. The organs of interest were excised and The radioactivity was measured using a gamma counter and the % Calculated as ID / g.

[0091] MicroPET For microPET studies, 10–25 MBq of radiolabeled compound (approximately 0.5 nmol) in a volume of 0.15 ml was Mice bearing LNCaP tumor xenografts were injected via the lateral tail vein. Anesthetized animals (2% sevoflurane) were Flurane, Abbott, Wiesbaden, Germany) was used with an Inveon small animal PET scanner (Siemens, Knoxville, VA, USA). The subjects were placed in a prone position in a 20-minute PET scan and a 20-minute static scan. A scan was performed; see Figures 1, 3, and 5-14. [Table 3] [Table 4]

[0092] This example demonstrates that the binding affinity of PSMA inhibitors can be affected by linker modifications. The two cyclic motives and at least one Aromatic moieties appear to be preferred and occur in the high affinity compounds MB4 and MB17. The novel variant by our group showed low nanomolar affinity for the LNCap cell line, with 48% affinity at 37°C. ID / 10 6 The former study revealed that the PSMA targeting activity was specifically internalized into the cells in addition to the binding affinity. The internalization properties of targeted probes are crucial for high in vivo tumor uptake and retention. Therefore, MB17 is essential for organ distribution and aortic motility. This represents a novel PSMA-targeting probe with optimal characteristics that were also confirmed by subject PET imaging. MB17 shows high PSMA-specific tumor uptake (Figure 2). Dynamic PET imaging of MB17 ( Figure 2) shows early enrichment in the bladder and also maximal renal uptake (the highest point on the time-activity curve). was observed as early as 15 min after injection of the radioactive tracer and was already substantially reduced after 20 min. In terms of therapeutic use, this is a clear advantage of MB17 compared to other PSMA inhibitors. In the PET schematic (Figure 1), MB17 shows rapid background clearing. The results show a substantial decrease in enrichment in the kidney at 1 h and 2 h after injection, but not in PSMA-expressing tumors. The more the concentration of the metal, the more it accumulates and is maintained.

[0093] Also, 177 The organ distribution of Lu (Figure 4) showed high initial renal uptake, which was almost completely eliminated after 24 hours. (2.13±1.36% ID / g), whereas tumor uptake remains high and even increases (10.58± The liver (0.08±0.03% ID / g), lung (0.11±0.13% ID / g) and spleen ( Other organs showed very low uptake, including the 0.13±0.05%ID / g organ. resulted in extremely high tumor-to-background ratios after 24 h (tumor / blood: 1058; Tumor / muscle:529).

[0094] Table A indicates that chemical modifications in the linker region of the molecule may improve biological properties, e.g. affinity. It is clearly confirmed that MB17 and MB4 affect the internalization efficiency of the cells. and show the most promising binding properties.

[0095] Example 9: Clinical Data on MB17 PET / CT imaging was performed using the Ga-68 labeled radiotracer MB17 (see FIG. 17).

[0096] Used in radiopharmaceutical products 68 Ge / 68 The Ga-producing material was provided by IDB-Holland BV (Baarle-Nassau, Th The disposable cassette kit and GMP- Chemicals containing compliant grade precursors are available from ABX advanced biochemical compounds (Radeberg, Germany). Chromolith Performance RP-18e column (100x4.6 mm The Ultimate 3000 HPLC system (Dionex) (Acetate, Merck) and a NaI radiation detector (Raytest) were used. The mixture was diluted with 100% TFA (A, water + 0.1% TFA (B); gradient: 0.5 min 95% B, 10.0 min 80% A, flow rate: 2 mL / min). The remaining solvent was analyzed for radiochemical purity using a 6850 Series gas chromatograph (Ag Endotoxin testing was performed using Endosafe®- This was performed using a PTS device (Charles River).

[0097] Dissolve 2 µg of MB17 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 The Ga generating material was diluted with 10 mL of 0.6 M HCl and 9 mL of ultrapure water. The mixture was then eluted with eluent. The precipitate was transferred to a 50 mL flask (Size M) and eluted into a preheated reaction vessel (100°C) using 5M 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 preconditioned. The solution was transferred to a C18 cartridge (Waters Sep-Pak light) containing 9 mL of ultrapure water (10 mL EtOH / 10 mL ultrapure water). The reaction vessel was rinsed with pure water and passed through the C18 cartridge. The final product was washed with 2 mL of EtOH / HO (v:v 1:1) from the C18 cartridge. The solution was eluted, filter sterilized (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 Ga-MB17 complex solution was administered intravenously A bolus was administered to the patient.

[0098] Example 10: 177 Human therapy using Lu-labeled MB17 For therapeutic purposes, the PSMA ligand MB17 was radiolabeled with Lu-177. 177 LuCl3 is Perkin Elmer (4 GBq, NEZ307D, 0.04 M HCl) was obtained from Imagine Pharmaceuticals, Inc. 80 nmoles of MB17 was dissolved in 5 μL of 20% ascorbic acid The solution was dissolved in 400 μL of sodium acetate buffer (0.4 M, pH 5) supplemented with 177 LuCl3 The plates were transferred to a 50-well plate and incubated at 95°C for 10 minutes. Finally, 2 mL of 0.9% NaCl was added. ITLC and radio-HPLC were performed to determine the identity of the chromatographically isolated ...

[0099] 177 Lu-labeled MB17 was administered to patients as an intravenous bolus (5 mL, slowly within 30 seconds). Intravenous administration was achieved by infusion of 0.9% NaCl for 4.5 hours, starting 0.5 hours prior to administration. reference.

Claims

1. A compound selected from the following formula X: 【Chemistry 1】 (wherein R′ is a chelating agent). A pharma- ceutically acceptable salt, solvate, solvate of said salt, or tautomer thereof.

2. The 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)pentanedioic acid (NODAGA); (d) 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-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-hydroxysuccinamide (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), or (o) The compound according to claim 1, which is 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

3. A metal complex comprising the compound of claim 1 or 2, in which a radioactive nuclide is complexed to the chelating agent.

4. The metal complex of claim 3, wherein the radioactive nuclide is selected from the group consisting of 89Zr, 44Sc, 111In, 90Y, 66Ga, 67Ga, 68Ga, 177Lu, 99mTc, 64Cu, 67Cu, 149Tb, 152Tb, 155Tb, 161Tb, 153Gd, 155Gd, 157Gd, 213Bi, 225Ac, 230U, 223Ra, 165Er, 123I, 131I, and Fe.

5. The metal complex of claim 4, wherein said radioactive nuclide is selected from the group consisting of 177 Lu, 161 Tb, and 225 Ac.

6. A stereoisomer of the compound of claim 1 or 2.

7. (1) a compound according to claim 1 or 2, and (2) Pharmaceutically acceptable carrier A composition comprising:

8. The composition of claim 7, further comprising a pharma- ceutically acceptable excipient different from the pharma- ceutically acceptable carrier.

9. (1) The metal composite of claim 3, and (2) Pharmaceutically acceptable carrier A composition comprising:

10. The composition of claim 9, wherein the radionuclide is selected from the group consisting of 89Zr, 44Sc, 111In, 90Y, 66Ga, 67Ga, 68Ga, 177Lu, 99mTc, 64Cu, 67Cu, 149Tb, 152Tb, 155Tb, 161Tb, 153Gd, 155Gd, 157Gd, 213Bi, 225Ac, 230U, 223Ra, 165Er, 123I, 131I, and Fe.

11. The composition of claim 10, wherein the radionuclide is selected from the group consisting of 177 Lu, 161 Tb, and 225 Ac.

12. The composition of claim 9, further comprising a pharma- ceutically acceptable excipient different from the pharma- ceutically acceptable carrier.

13. The composition of claim 9, which is a buffered solution.

14. (1) A stereoisomer of claim 6, and (2) Pharmaceutically acceptable carrier A composition comprising:

15. The composition of claim 14, further comprising a pharma- ceutically acceptable excipient different from the pharma- ceutically acceptable carrier.

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