How to diagnose and / or treat prostate cancer

Abstract

The present invention generally relates to a method for diagnosing and / or treating cancer associated with overexpression of PSMA membrane proteins, or a method for reducing PSA levels in a subject. The present invention also relates to a method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a radioisotope to a subject in need, and delivering a dose of radiation to a specific site for treating cancer.

Description

[Technical Field]

[0001] The present invention relates to a diagnostic method and radiotherapy using radiographic imaging, which generally involves administering a specific compound complexed with a radioisotope to deliver a single dose of radiation to a specific site for imaging or treating prostate cancer. [Background technology]

[0002] Prostate cancer is the second most common cancer and the second most prevalent cancer in men worldwide, accounting for 9.5% of all new cancers in 2018. The incidence of prostate cancer is variable and correlates with age, with a prevalence of 30% in men aged 40-50 and between 50% and 80% in men over 80. At initial diagnosis, 80% of patients have localized prostate cancer, 12% have regional cancer, and 4% have metastatic cancer. The five-year survival rate is 99% for patients with localized or regional prostate cancer, but drops to approximately 30% for patients with metastatic cancer.

[0003] Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein expressed in normal, benign, and malignant prostate tissue. PSMA expression increases with the aggressiveness of prostate tumors, the presence of metastatic disease, and cancer recurrence. For example, PSMA expression is 100 to 1000 times higher in prostate adenocarcinoma than in benign prostate tissue, increases with androgen loss, and peaks in high-grade, castration-resistant prostate cancer. While PSMA expression levels correlate with disease progression, some cases of prostate cancer do not show increased PSMA expression on biopsy.

[0004] The PSMA membrane protein is expressed in normal prostate tissue and its expression increases in cancerous tissue, but it is also expressed in other healthy tissues, such as salivary glands, duodenal mucosa, proximal tubular cells, and some neuroendocrine cells in the colonic crypts. Even if a therapy that specifically targets the PSMA membrane protein is developed, the presence of the protein in healthy tissue often means that undesirable extra-site damage can occur.

[0005] Current treatment methods for prostate cancer are: 99m This includes using radioactive isotopes of Tc in combination with MRI and CT imaging, but this method has limitations in terms of sensitivity and specificity for prostate cancer. 18 While the use of F-FDG offers some improvement, the low sensitivity of this technique limits its use in the diagnosis of prostate cancer.

[0006] To use radioisotopes to diagnose and treat prostate cancer, it is necessary to use ligands that can coordinate with the desired radioisotope and target a selected site. While urea-based ligands are known to target PSMA membrane proteins, such ligands have not been approved for use by the FDA. 177 Lu-PSMA shows some promise, but toxicity to patients and undesirable radiation damage to healthy tissues have also been observed.

[0007] There is still a need for patient-tolerant regimens with limited off-target effects to diagnose and / or treat cancers associated with PSMA membrane protein expression, particularly prostate cancer. [Overview of the project]

[0008] The present invention provides a method for radioimaging and / or treating cancer associated with overexpression of PSMA membrane antigen, comprising administering a compound of formula (I) or a salt thereof, complexed with a suitable radioisotope, to a subject requiring such treatment. The compound of formula (I) comprises a symmetrical sarcofazine fragment having the ability to complex with copper (Cu) ions, and two urea fragments known to bind to the type II transmembrane glycoprotein of prostate-specific membrane antigen (PSMA). Each urea fragment is bound to sarcofazine by the same linker, resulting in a molecule of the target structure. The urea fragments contain lysine and glutamic acid residues, where the lysine fragment of each urea is bound to the linker. 64 When a complex is formed with a Cu radioisotope and administered to a target, positron emission tomography (PET) imaging reveals the location where the radiolabeled complex is localized. And the compound of formula (I) 67 When complexed with a Cu radioisotope and administered to a target, a therapeutic effect may be recognized in the treatment of cancer associated with the expression of PSMA membrane protein. Since the urea fragment of formula (I) binds to PSMA, the localization of the compound is likely to signal regions where PSMA membrane protein is overexpressed, indicating the presence of cancer. Without being constrained by theory, the inventors believe that the presence of two groups in the compound of formula (I) that have the ability to bind to PSMA membrane protein results in greater affinity to the membrane protein and thus improves binding. This has advantages in both imaging cancer and treating said cancer.

[0009] PSMA is expressed in normal, benign, and malignant prostate tissue, and the expression of this membrane protein increases with tumor aggressiveness, metastatic disease, and recurrence. For example, PSMA levels are 100 to 1000 times higher in prostate adenocarcinoma than in benign prostate tissue.

[0010] Because PSMA is also expressed in healthy tissues (e.g., salivary glands, duodenal mucosa, proximal tubular cells, and subsets of neuroendocrine cells in the colonic crypts), administering radiolabeled compounds that attempt to target PSMA often results in undesirable extrasite effects and damage to healthy tissue.

[0011] The inventors have developed a complex with a copper radioactive isotope, formula (I): [ka] We found that administration of the compound shown or a pharmaceutically acceptable salt thereof can deliver high doses of radiation to cancer sites overexpressing PSMA membrane proteins.

[0012] Because the compound of formula (I) exhibits specificity for PSMA membrane proteins, it reduces the binding of other compounds containing copper radioisotopes. This sequentially reduces the severity and incidence of adverse events in patients, meaning that the treatment is more tolerable. Furthermore, the inventors have found that because the compound of formula (I) exhibits greater retention of copper radioisotopes and greater binding at the target site, the amount of radiolabeled compound administered can be reduced. The inventors believe that the radiolabeled compound of formula (I) could be used in radioimaging and radiotherapy of cancers that overexpress PSMA membrane proteins, because the compound of formula (I) binds to and localizes at the site where the protein is expressed. 67 After administering a Cu-labeled compound of formula (I), imaging of the target using PET, SPECT, and / or CT may be performed to confirm the localization of the radiolabeled compound and the targeted therapy. This is because the same dimer compound... 64It can be achieved by radiolabeling with Cu. When a compound of formula (I) labeled with a copper radioisotope is administered and then imaged, this makes it possible to determine the location of the radiolabeled compound and thus the location of the cancer associated with the expression of the PSMA membrane protein. The PSMA membrane protein is expressed in normal tissues as well, while in cancerous tissues, it expresses a relatively high level of the PSMA membrane protein. As a result, PSMA is "overexpressed", i.e., expressed at a higher concentration than in normal tissues.

[0013] In one aspect, the present invention is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of 67 a compound of formula (I) complexed with a Cu radioisotope:

Chemical formula

[0014] In another aspect, the present invention is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of 67 a compound of formula (I) complexed with a Cu radioisotope:

Chemical formula

[0015] In some embodiments, 67The dose of radiation delivered by the Cu radioactive isotope is approximately 4 GBq, approximately 8 GBq, approximately 12 GBq, approximately 16 GBq, approximately 20 GBq, or approximately 24 GBq. In some embodiments, 67 The dose of radiation delivered by the Cu radioactive isotope is greater than approximately 12 GBq. In other embodiments, 67 The dose of radiation delivered by the Cu radioisotope is greater than approximately 16 GBq. In other embodiments, 67 The dose of radiation delivered by the Cu radioactive isotope is greater than approximately 20 GBq. In other embodiments, 67 The dose of radiation delivered by the Cu radioactive isotope is the maximum dose that the subject can tolerate.

[0016] In a particular embodiment, the present invention relates to a method for treating cancer, wherein a therapeutically effective amount is administered to the target subject as needed. 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The treatment involves administering an aqueous formulation of the compound shown or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with the expression or overexpression of PSMA membrane proteins. 67 This invention provides a method in which the dose of radiation delivered by a Cu radioactive isotope is approximately 4 GBq.

[0017] In some embodiments, the present invention is a method for treating cancer, wherein a therapeutically effective amount is delivered to the target that requires it. 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The treatment involves administering an aqueous formulation of the compound shown or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with the expression or overexpression of PSMA membrane proteins. 67 This invention provides a method in which the dose of radiation delivered by a Cu radioactive isotope is approximately 8 GBq.

[0018] In some embodiments, the present invention is a method for treating cancer, wherein a therapeutically effective amount is delivered to the target that requires it. 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The treatment involves administering an aqueous formulation of the compound shown or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with the expression or overexpression of PSMA membrane proteins. 67 This invention provides a method in which the dose of radiation delivered by a Cu radioactive isotope is approximately 12 GBq.

[0019] In one embodiment, the cancer is prostate cancer. In another embodiment, the cancer is metastatic prostate cancer. In yet another embodiment, the prostate cancer is PSMA-expressing metastatic castration-resistant prostate cancer (mCRPC).

[0020] In a further embodiment, the prostate cancer is PSMA-expressing metastatic castration-resistant prostate cancer (mCRPC) and is progressive despite previously administered androgen deprivation therapy, at least enzalutamide and / or abiraterone (or other such androgen receptor pathway inhibitors).

[0021] In further embodiments, the subjects are male subjects with castration levels of less than approximately 50 ng / dL or less than approximately 1.7 nanomoles / L of serum / plasma testosterone.

[0022] The inventors have found that administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need may result in a decrease in prostate-specific antigen (PSA) levels when the compound of formula (I) is complexed with a Cu radioisotope. While not intended to be theoretically constrained, the inventors believe that administration of the compound of formula (I) complexed with a Cu radioisotope resulted in a reduction in the size of lesions associated with prostate cancer present in the subjects. Exposure of lesions to radioactive decay products associated with the Cu radioisotope leads to a reduction in the size and / or volume of lesions in the subjects. This may be shown in Figures 5, 6, 7, or 8, where 67 The size of the lesions was reduced after administration of the compound of formula (I) complexed with a Cu radioisotope. Furthermore, as shown in Figures 5, 6, 7, or 8, in certain embodiments, two doses 67 After administering the compound of formula (I) complexed with a Cu radioisotope, i.e., after two cycles of treatment, the lesion cannot be detected by PET imaging. Therefore, in certain embodiments, the present invention relates to a method for treating cancer, comprising one or more doses 67 The present invention provides a method in which no cancer-associated lesions are detected after administering a compound of formula (I) that has formed a complex with a Cu radioisotope. In a particular embodiment, the present invention provides a method for treating cancer, comprising two doses 67 The present invention provides a method in which no cancer-associated lesions are detected after administering a compound of formula (I) that has formed a complex with a Cu radioisotope. In another embodiment, the present invention provides a method for treating cancer, comprising three doses 67 The present invention provides a method in which cancer-associated lesions are not detected after administration of a compound of formula (I) complexed with a Cu radioisotope. Given the characteristics of the lesions (i.e., associated with prostate cancer), the inventors believe that the reduction in lesion size resulting from the compound of formula (I) leads to a decrease in PSA levels in the subjects.

[0023] Therefore, according to a further embodiment, the present invention is a method for reducing prostate-specific antigen (PSA) levels in a subject, and applies to the subject requiring the reduction.67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a method comprising administering an effective amount of the compound shown, or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0.1 ng / ml, and in this case, the subject has a prostate gland.

[0024] In certain embodiments, the subject's PSA level before administration is above approximately 0.1 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 1 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 10 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 100 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 500 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 1000 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 1500 ng / ml. In other embodiments, the subject's PSA level before administration is above approximately 2000 ng / ml.

[0025] In yet another embodiment, the present invention relates to a method for reducing prostate-specific antigen (PSA) levels in a subject, wherein the subject requires... 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a method comprising administering an effective amount of the compound shown, or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0 ng / ml, and in this case, the subject does not have a prostate gland.

[0026] In some embodiments, approximately four weeks after administration of the compound of formula (I), the reduction in the subject's PSA level is between approximately 20% and approximately 80% compared to the subject's PSA level before administration of the compound of formula (I). In some embodiments, approximately four weeks after administration of the compound of formula (I), the subject's PSA level decreases by approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, or approximately 80% compared to the subject's PSA level before administration of the compound of formula (I). In other embodiments, approximately four weeks after administration of the compound of formula (I), the subject's PSA level decreases by more than 80% compared to the subject's PSA level before administration of the compound of formula (I). In other embodiments, approximately four weeks after administration of the compound of formula (I), the subject's PSA level decreases by more than 90% compared to the subject's PSA level before administration of the compound of formula (I). In other embodiments, approximately four weeks after administration of the compound of formula (I), the subject's PSA level decreases by more than 95% compared to the subject's PSA level before administration of the compound of formula (I). In other embodiments, approximately four weeks after administration of the compound of formula (I), the subject's PSA level decreases by more than 99% compared to the subject's PSA level before administration of the compound of formula (I).

[0027] In some embodiments, the method involves a second dose 67 The method further comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof that has formed a complex with a Cu radioisotope, wherein the dose of radiation delivered by the second administration of the compound of formula (I) is the same as or different from the dose of radiation delivered by the first administration of the compound of formula (I). In some embodiments, the dose of radiation delivered by the second administration of the compound of formula (I) is the same as the dose of radiation delivered by the first administration of the compound of formula (I).

[0028] Second dose 67If the patient is to be administered a compound of formula (I) in complex with a Cu radioisotope or a pharmaceutically acceptable salt thereof, the second dose is administered about four weeks after the first dose. In certain embodiments, the second dose is administered at least four weeks after the first dose. In certain embodiments, the second dose is administered at least six weeks after the first dose. In other embodiments, the second dose is administered about eight weeks after the first dose. In other embodiments, the second dose is administered about twelve weeks after the first dose. In some embodiments, the second dose is administered about six months, twelve months, eighteen months, twenty-four months, thirty months, or thirty-six months after the first dose.

[0029] The inventors have found that the PSA level of a subject decreases after administration of a compound of formula (I) complexed with a Cu radioisotope or a pharmaceutically acceptable salt thereof. In some embodiments, the PSA level of the subject decreases after first administration of a compound of formula (I) complexed with a Cu radioisotope or a pharmaceutically acceptable salt thereof. In other embodiments, the PSA level of the subject decreases after second administration of a compound of formula (I) complexed with a Cu radioisotope or a pharmaceutically acceptable salt thereof. This may be shown in Figure 4, where 67 While a single dose of the compound (I) complexed with a Cu radioisotope resulted in a decrease in the target PSA level, further administration of the compound brought the PSA level to an undetectable level.

[0030] In certain embodiments, approximately two weeks after administration of the compound of formula (I) in complex with a Cu radioisotope or a pharmaceutically acceptable salt thereof, the reduction in the subject's PSA level is approximately 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the subject's PSA level before administration of the compound.

[0031] In certain embodiments, approximately two weeks after a second dose of the compound of formula (I) in complex with a radioisotope or a pharmaceutically acceptable salt thereof, the reduction in the subject's PSA level is approximately 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the subject's PSA level before administration of the compound.

[0032] The inventors have found that administration of at least one dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is complexed with a Cu radioisotope, results in a decrease in PSA levels in the subjects. Furthermore, the inventors have found that after a certain period of time, PSA is undetectable in the subjects after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, with a detection limit of approximately 0.01 ng / ml.

[0033] In certain embodiments, PSA is not detected in the subjects after administration of the compound of formula (I) complexed with a Cu radioisotope or a pharmaceutically acceptable salt thereof. In other embodiments, PSA is not detected in the subjects approximately four weeks after administration of the compound of formula (I) complexed with a Cu radioisotope or a pharmaceutically acceptable salt thereof.

[0034] In further embodiments, the subject is 67 This study is for men whose prostate-specific antigen (PSA) levels are higher than 2 ng / ml or higher for at least three weeks prior to administration of an aqueous formulation of the compound of formula (I) in complex with a Cu radioisotope or a pharmaceutically acceptable salt thereof. However, some individuals with PSA levels below 2.0 ng / ml may also have prostate cancer. 67 An aqueous preparation of the compound of formula (I) in complex with a Cu radioisotope or a pharmaceutically acceptable salt thereof may be administered.

[0035] In further embodiments, the subject is 67After administering a compound of formula (I) complexed with a Cu radioisotope, or a pharmaceutically acceptable salt thereof, in a single treatment cycle, a decrease in the percentages of PSA, alkaline phosphatase (ALP), and lactate dehydrogenase (LDA) biomarkers is experienced compared to a baseline established before treatment.

[0036] In a further embodiment, the method is 67 The method involves administering an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is complexed with a Cu radioisotope, to a subject in one, two, three, or four treatment cycles.

[0037] In a further embodiment, the method is 67 The treatment involves administering an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in complex with a Cu radioisotope, to a subject by slow IV infusion over approximately 30 to 60 minutes, in at least two doses, spaced approximately 6 to 14 weeks apart, at a dose providing 4 to 24 GBq.

[0038] In one embodiment, the method further preferably includes radiographic imaging of the subject by PET, SPECT, and / or CT after each processing cycle.

[0039] In one embodiment, positive PET, SPECT, and / or CT scans are performed. 64 This is based on visualizing PET / SPECT / CT scans of Cu-SAR-bisPSMA (Formula (I)), and here we have at least one known lesion. 64 Cu-SAR-bisPSMA uptake (standard uptake [SUN]max) is higher than liver uptake during a 1-hour PET / CT / SPECT scan.

[0040] In addition, the present invention provides a method for subjecting cancer to radiographic imaging, wherein the target subject is as required. 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a method comprising administering an aqueous formulation of the compound shown or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with the expression or overexpression of a PSMA membrane protein, and the dose of radiation delivered by the radioisotope is approximately 200 MBq / kg.

[0041] In a specific embodiment of the above-described model, the compound of formula (I) is formula (Ia): [ka] It has the structure shown in [image / diagram].

[0042] In a particular embodiment of the above-described aspect, the method further includes the step of acquiring an image of the subject using PET / SPECT and / or CT.

[0043] The present inventors, in accordance with the above-described embodiments, 64 Images of a target obtained by PET / SPECT and / or CT after administration of a Cu-labeled compound of formula (I) are used to treat cancer associated with the expression or overexpression of PSMA membrane proteins. 67 It is thought that the corresponding dose of the Cu-labeled compound of formula (I) can be determined. Therefore, one of the advantages of the present invention is that the Cu radioactive isotope 64 From Cu 67 By substituting with Cu, the same dimeric compound can be used in a complete diagnostic-therapeutic regimen.

[0044] Thus, the inventors also believe that administering the aqueous formulation described herein for treating cancer associated with overexpression of PSMA membrane antigen in multiple doses (i.e., multiple treatment cycles) results in a greater accumulation of radioisotopes at the target site. While not intended to be theoretically constrained, the inventors believe that the use of the radiolabeled compounds described herein allows for the delivery of greater doses of radiation without increasing anticipated side effects. This, therefore, results in greater efficacy in treatment. The diagnostic methods described herein may be used before or during treatment cycles to evaluate the effectiveness of treatment.

[0045] While not intended to be theoretically binding, the inventors believe that administration of one or more doses of the formulations described herein for treating cancer associated with overexpression of PSMA membrane proteins will enhance the absorption of radiation dose at the cancer site, thereby increasing the efficacy of the treatment. This means that repeated administration of formulations containing the compound of formula (I) in complex with a radioisotope may result in an increased survival rate of the subject compared to a single dose of the formulations disclosed herein. A method of a second embodiment comprises administering an aqueous formulation of a complex containing the compound of formula (I) and a radioisotope in multiple doses. In one embodiment, the method comprises administering one or more doses of the aqueous formulation described in the second embodiment in succession. In some embodiments, the successive doses of the aqueous formulation are administered at intervals of about 6 weeks to about 16 weeks. In one embodiment, the successive doses of the aqueous formulation are administered at intervals of about 6 weeks. In one embodiment, the total dose of radiation delivered to the bone marrow of the subject is less than about 2 Gy. In yet another embodiment, the total dose of radiation delivered to the target kidney is less than approximately 23 Gy. In yet another embodiment, the total dose of radiation delivered to the target submandibular gland is less than approximately 24 Gy.

[0046] The methods disclosed herein involve administering a complex containing the compound of formula (I) and a radioisotope in multiple doses (the doses administered may be the same or different). In some embodiments, when multiple doses are administered, the second and subsequent doses may be higher than the first dose. In some embodiments, multiple doses (the doses are the same) are administered. In yet another embodiment, multiple doses (the doses are different) are administered. Those skilled in the art will understand that because the methods disclosed herein incorporate the use of radioisotopes, there is an upper limit to the total dose of radiation that a subject can tolerate. In some embodiments, multiple doses are administered until the accumulated dose of radiation delivered to the subject's kidney reaches about 23 Gy. In some embodiments, multiple doses are administered until the accumulated dose of radiation delivered to the subject's submandibular gland reaches about 24 Gy.

[0047] In one embodiment, the aqueous formulation is administered intravenously. In another embodiment, the aqueous formulation is administered by slow infusion. In a preferred embodiment, the aqueous formulation is administered intravenously by slow infusion, for example, over a period of about 30 to 60 minutes.

[0048] Methods disclosed herein involve administering a radioisotope that emits ionizing radiation. Because the kidneys are involved in filtering blood, when a formulation containing the compound of formula (I) and the radioisotope is administered, the kidneys of the target are at risk of actively reabsorbing the radiolabeled compound of formula (I) and, as a result of its retention, absorbing unwanted radiation. Prevention of nephrotoxicity can be achieved by co-administration of the compound of formula (I) and a cationic amino acid that competitively inhibits the reabsorption of the radioisotope. In some embodiments, the method of the second embodiment further includes administering a formulation containing one or more amino acids or salts thereof. In some embodiments, one or more amino acids are in a cationic form. In some embodiments, the formulation containing one or more amino acids contains lysine or a salt thereof. In other embodiments, the formulation containing one or more amino acids contains arginine or a salt thereof. In preferred embodiments, the method includes administering a formulation containing lysine and arginine, or salts thereof.

[0049] In a further embodiment, the present invention relates to the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, in the required area. 67 A method for measuring the dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof that has formed a complex with a Cu radioisotope, wherein the subject is: 64 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a method comprising administering an aqueous formulation of a compound represented by or a pharmaceutically acceptable salt thereof.

[0050] While not intended to be theoretically restrictive, the inventors believe that the solution defined in the second aspect provides a more targeted method for treating cancer associated with the expression or overexpression of PSMA membrane proteins in a subject. As used herein, references to PSMA membrane protein expression also refer to overexpression of the same protein.

[0051] In another embodiment, the present invention is: 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof in the manufacture of an aqueous formulation for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 The present invention provides a use in which the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer and / or mediate a decrease in prostate-specific antigen (PSA) levels.

[0052] In another embodiment, the present invention is: 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof in the manufacture of an aqueous formulation for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 The present invention provides a use in which the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0053] In yet another embodiment, the present invention also, 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides the use of a compound represented by or a pharmaceutically acceptable salt thereof in the preparation of an aqueous formulation for lowering PSA levels in a subject, wherein the subject's PSA level prior to administration of the aqueous formulation is above approximately 0.1 ng / ml, and in this case, the subject has a prostate gland.

[0054] In another embodiment, the present invention is: 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides the use of a compound represented by or a pharmaceutically acceptable salt thereof in the preparation of an aqueous formulation for lowering PSA levels in a subject, wherein the subject's PSA level prior to administration of the aqueous formulation is above approximately 0 ng / ml, and in this case, the subject does not have a prostate.

[0055] In further embodiments, the present invention is 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof in the manufacture of an aqueous formulation for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 This provides a use case where the dose of radiation delivered by the Cu radioactive isotope is approximately 4 GBq.

[0056] In further embodiments, the present invention is 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof in the manufacture of an aqueous formulation for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 This provides a use case where the dose of radiation delivered by the Cu radioactive isotope is approximately 8 GBq.

[0057] In further embodiments, the present invention is 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof in the manufacture of an aqueous formulation for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 This provides a use case where the dose of radiation delivered by the Cu radioactive isotope is approximately 12 GBq.

[0058] In some embodiments, in the formulation 67 The dose of radiation delivered by the Cu radioisotope is approximately 4 GBq, approximately 8 GBq, approximately 12 GBq, approximately 16 GBq, approximately 20 GBq, or approximately 24 GBq. In some embodiments, the formulation is 67 The dose of radiation delivered by the Cu radioactive isotope is greater than approximately 12 GBq. In other embodiments, 67 The dose of radiation delivered by the Cu radioisotope is greater than approximately 16 GBq. In other embodiments, 67 The dose of radiation delivered by the Cu radioactive isotope is greater than approximately 20 GBq. In other embodiments, 67 The dose of radiation delivered by the Cu radioisotope is greater than approximately 24 GBq. In other embodiments, the formulation contains 67 The dose of radiation delivered by a Cu radioactive isotope is the maximum dose that can be tolerated by the subject.

[0059] In a further embodiment, the present invention is 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] This invention provides the use of the compound shown or a pharmaceutically acceptable salt thereof for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins.

[0060] In another embodiment, the present invention is: 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 The present invention provides a use in which the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0061] In a further embodiment, the present invention also, 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The use of the compound shown or a pharmaceutically acceptable salt thereof for the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, wherein 67 The present invention provides a use in which the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer and / or mediate a decrease in prostate-specific antigen (PSA) levels.

[0062] In a specific embodiment of the above-described model, the compound of formula (I) is formula (Ia): [ka] It has the structure shown in [image / diagram].

[0063] In one embodiment of the above-described model, the cancer associated with the expression or overexpression of the PSMA membrane protein is prostate cancer. In another embodiment, the cancer is metastatic prostate cancer. In yet another embodiment, the prostate cancer is metastatic castration-resistant prostate cancer with PSMA expression. In other embodiments, the prostate cancer is resistant to conventional androgen deprivation therapy and / or treatment with androgen receptor pathway inhibitors. In some embodiments, the androgen receptor pathway inhibitor is enzalutamide or abiraterone.

[0064] In another aspect, the present invention is 67Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a use of the compound shown or a pharmaceutically acceptable salt thereof to lower the prostate-specific antigen (PSA) level in a subject requiring such use, wherein the subject's PSA level prior to administration is above approximately 0.1 ng / ml, and in this case, the subject has a prostate.

[0065] In another embodiment, the present invention is: 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a use of the compound shown or a pharmaceutically acceptable salt thereof to lower the prostate-specific antigen (PSA) level in a subject requiring such use, wherein the subject's PSA level prior to administration is above approximately 0 ng / ml, and in this case, the subject does not have a prostate. [Brief explanation of the drawing]

[0066] [Figure 1] (A) Shows PET-CT images of subjects with T4 spinal lesions after administration of 64Cu-SAR-bisPSMA. (B) Shows SPECT-CT images of the same subjects with T4 spinal lesions 48 hours after administration of the first cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq. (C) Shows SPECT-CT images of the same subjects with T4 spinal lesions 48 hours after administration of the third cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq. (D) Shows SPECT-CT images of the same subjects with T4 spinal lesions 48 hours after administration of the fourth cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq.

[0067] [Figure 2](A) Shows PET-CT images of subjects with C1 spinal lesions after administration of 64Cu-SAR-bisPSMA. (B) Shows SPECT-CT images of the same subjects with C1 spinal lesions 48 hours after administration of the first cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq. (C) Shows SPECT-CT images of the same subjects with C1 spinal lesions 48 hours after administration of the third cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq. (D) Shows SPECT-CT images of the same subjects with C1 spinal lesions 48 hours after administration of the fourth cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq.

[0068] [Figure 3] (A) Shows a PET-CT image of a subject with a lesion in the right scapula after administration of 64Cu-SAR-bisPSMA. (B) Shows a SPECT-CT image of the same subject with a lesion in the right scapula 48 hours after administration of the first cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq. (C) Shows a SPECT-CT image of the same subject with a lesion in the right scapula 48 hours after administration of the third cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq. (D) Shows a SPECT-CT image of the same subject with a lesion in the right scapula 48 hours after administration of the fourth cycle of treatment using 67CuSAR-bisPSMA at a dose of 4 GBq.

[0069] [Figure 4] This graph shows the PSA levels (ng / ml) of subjects at various time points before treatment with 67Cu-SAR-bisPSMA (dashed line) and after the first and second doses of 67Cu-SAR-bisPSMA. Administration of 67Cu-SAR-bisPSMA resulted in a decrease in PSA levels from 47.2 ng / ml (baseline before administration) to 0.3 ng / ml. After administration of the second dose of 67Cu-SAR-bisPSMA, the PSA level in the subjects fell below the detection limit, with the lower limit of the detection limit being 0.05 ng / ml.

[0070] [Figure 5] The images show PET scans of prostate cancer before treatment with 67Cu-SAR-bisPSMA, showing the presence of lesions before treatment with 67Cu-SAR-bisPSMA (left image, [SUVmax] 140.1), and after two administrations of 67Cu-SAR-bisPSMA (right image). The pre-treatment image clearly shows the presence of lesions in the subjects, but the comparative image taken after two cycles of 67Cu-SAR-bisPSMA treatment does not visualize any lesions (i.e., there is no uptake of 64Cu-SAR-bisPSMA). This indicates that a complete response (i.e., no detectable cancer after treatment) is observed after administration of 67Cu-SAR-bisPSMA.

[0071] [Figure 6] These are PET images of a patient with metastatic castration-resistant prostate cancer, showing the uptake of 64Cu-SAR-bisPSMA before treatment (A) and after treatment with 67Cu-SAR-bisPSMA for two cycles at a dose of 8 GBq per ion (B). The image taken before treatment shows the presence of a lesion (see arrow), while the image taken after treatment shows a reduction in the size of the same lesion.

[0072] [Figure 7] These are CT images of a patient with metastatic castration-resistant prostate cancer, showing the uptake of 64Cu-SAR-bisPSMA before treatment (A) and after treatment with 67Cu-SAR-bisPSMA for two cycles at a dose of 8 GBq per minute (B). The image taken before treatment clearly shows the presence of lesions (see arrows), but after treatment with 67Cu-SAR-bisPSMA, the same lesions are not visible under the same conditions.

[0073] [Figure 8]These are PET / CT images of a patient with metastatic castration-resistant prostate cancer, showing the uptake of 64Cu-SAR-bisPSMA before treatment (A) and after treatment with 67Cu-SAR-bisPSMA for two cycles at a dose of 8 GBq per minute (B). The image taken before treatment clearly shows the presence of lesions (see arrows), but after treatment with 67Cu-SAR-bisPSMA, the same lesions are not visible under the same conditions. [Modes for carrying out the invention]

[0074] Throughout this specification and the attached claims, unless otherwise specified in the context, the word “includes” and variations such as “contains” will also be understood to imply that they include a specified integer or process, or a group of integers or processes, but do not exclude any other integer or process, or a group of integers or processes.

[0075] As used herein, the terms “about” or “approximately” mean a range of acceptable error for a particular value as measured by those skilled in the art, which will depend to some extent on how that value is measured or determined, i.e., on the limits of the measuring system.

[0076] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. For the purposes of the present invention, the following terms are defined below:

[0077] The compound of formula (I) contains two ligands supporting a urea functional group and sarcofazine, the two ligands binding to sarcofazine via linker groups to provide a symmetrical molecule. The compound of formula (I) has the ability to bind to the PSMA membrane antigen, which is often overexpressed in cancer tissue, particularly prostate tissue. The compound may also be called "Sar-bisPSMA" and contains a macrocyclic sarcofazine fragment (i.e., 5-[[8-amino-3,6,10,13,16,19-hexazabicyclo-[6.6.6]eico-1-yl)amino]-5-oxo-pentanyl) and two urea fragments (i.e., lysine-urea-serine). The compound of formula (I) has the following structural formula: [ka] This is shown.

[0078] Compounds of formula (I) contain multiple stereocenters. All stereoisomers of the compound and its salts, such as enantiomers and diastereomers, are also included in the present invention. In certain embodiments, a compound of formula (I) is defined as formula (Ia): [ka] It has the structure shown in [image / diagram].

[0079] The term "pharmaceutically acceptable salt" refers to a salt of the above-mentioned compound that retains the desired biological activity, and includes pharmaceutically acceptable acid addition salts and base addition salts. A suitable pharmaceutically acceptable acid addition salt of the compound of formula (I) can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic acids and sulfonic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Medicinally acceptable salts also include those in which the principal compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further understand that acid addition salts can be produced by any of many known methods through the reaction of a compound with a suitable inorganic or organic acid. Alternatively, alkali and alkaline earth metal salts can also be produced by various known methods through the reaction of a compound with a suitable base. Further examples of acid salts that can be obtained by reaction with inorganic or organic acids include: acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.Further information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of solid pharmaceuticals, those skilled in the art will understand that the compounds, pharmaceuticals, and salts of the present invention may exist in different crystalline or polymorphic forms, all of which fall within the scope of the present invention and specific formulations.

[0080] The injectable formulation of the present invention contains a pharmaceutically acceptable sterile aqueous solution. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. The formulation may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Microbial action can be reliably prevented by incorporating various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to incorporate isotonic agents such as sugars and sodium chloride. To extend the absorption of the injectable pharmaceutical form, absorption-delaying agents such as aluminum monostearate and gelatin may be incorporated. The injectable formulation can be sterilized, for example, by filtration through a bacterial-retaining filter, or by being formulated in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. Pharmaceutical formulations may further contain pH adjusters. Examples of suitable pH adjusters include hydrochloric acid and sodium hydroxide. Identifying preferred pH ranges (where appropriate) and suitable excipients is customary in the art, as described, for example, in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press).

[0081] Formulations of the present invention, as disclosed herein, may be provided in a pharmaceutically acceptable carrier or diluent. As those skilled in the art will recognize, the choice of a pharmaceutically acceptable carrier or diluent will depend on the route of administration and the nature of the symptoms and target to be treated. Individual carriers or diluents and routes of administration can be readily determined by those skilled in the art. The carriers or diluents and routes of administration must be carefully selected to ensure that the compound of formula (I) becomes active when it reaches the site of action.

[0082] Pharmaceutical forms suitable for injection include sterile injectable solutions or dispersions, and sterile powders for the manufacture of sterile injectable solutions. Such forms should be stable under manufacturing and storage conditions and can be stored antagonistically against reduction, oxidation, and microbial contamination. When injected, the compositions of the present invention may be formulated in aqueous solution, preferably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer.

[0083] For the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins, the compound of formula (I) is complexed with a radioisotope. The inventors have found that the sarcofazine fragment of formula (I) has a strong affinity for copper isotopes and has the ability to form and retain complexes with radioisotopes for a sufficient time for therapeutic purposes, even after administration to the subject. The compound of formula (I) can form complexes with copper isotopes. In one embodiment, the compound of formula (I) 67 This may provide a complex that can be used in the treatment of cancer associated with the expression or overexpression of PSMA membrane proteins by forming a complex with a Cu radioisotope. 67 The half-life of the Cu radioactive isotope is approximately 60 hours, and it undergoes beta decay, thus becoming suitable for localized radiotherapy. 67 The decay of the radioactive isotope Cu is accompanied by gamma radiation, therefore the target 67Treatment with a compound of formula (I) complexed with Cu can be monitored and imaged using single-photon emission computed tomography (SPECT). In one embodiment, 67 The treatment method for a target requiring treatment involves administering a compound of formula (I) in complex with Cu, and includes monitoring and / or imaging by SPECT. Other imaging techniques, such as MRI and CT, may be used during treatment. In preferred embodiments, the treatment method includes imaging by SPECT and / or CT. Any reference to PSMA membrane protein expression used herein also refers to the overexpression of the same protein.

[0084] To achieve the objective of radiographic imaging, the dose of radiation delivered should be sufficient to provide images of adequate quality without administering an overdose to the patient. The dose of radiation administered for the purpose of radiographic imaging (followed by, 64 The amount of the radiolabeled compound of formula (I) complexed with the Cu radioisotope can be determined based on the subject's body weight. 67 The dose of radiation administered and delivered to a subject by a Cu radioactive isotope is determined by the subject's body weight. 64 This can be determined based on both the quality of the image obtained via radioimaging after administration of the compound of formula (I) complexed with a Cu radioisotope. In some embodiments, 64 Using a radiolabeled compound of formula (I) that has formed a complex with a Cu radioisotope 67 The distribution of the corresponding compound of formula (I) that forms a complex with a Cu radioisotope is modeled. In some embodiments, the radiation imaging of the target is 64 This is performed after administering a compound of formula (I) that has formed a complex with a Cu radioisotope. In other embodiments, radiation imaging of the target is performed. 67 This is performed after administering a compound of formula (I) that has formed a complex with a Cu radioisotope. In some embodiments, imaging of the target is performed. 67 The procedure is performed after administering the compound of formula (I) that has formed a complex with a Cu radioactive isotope, in which case... 67A compound of formula (I) labeled with Cu is administered for therapeutic purposes.

[0085] As shown in Figures 1 to 3, the inventors of the present invention have found that 67 We have found that by administering a compound of formula (I) radiolabeled with a Cu radioisotope, it is possible to perform radioimaging for up to 96 hours after administration of the compound. Although we do not intend to be constrained by theory, we believe that the compound of formula (I) described herein exhibits a long retention period in the target, enabling radioimaging of the target for a certain period even after administration of the radiolabeled compound. In certain embodiments, radioimaging of the target is performed as follows: 67 This is performed after administering a compound of formula (I) radiolabeled with a Cu radioisotope. In some embodiments, the radioimation of the target is performed. 67 The procedure is performed approximately 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, or 96 hours after administration of the compound of formula (I) radiolabeled with a Cu radioisotope.

[0086] The units of radioactivity used herein are expressed in gray (Gy) or becquerel (Bq). It should be understood that radiation doses can be converted from one unit to another using known conversion factors, and that other units of radioactivity not explicitly stated herein may also be used.

[0087] The terms “treat,” “prevent,” and “prevent,” as used herein, and their grammatical synonyms, mean any use relating to treating a cancer described herein, preventing, delaying, or slowing the establishment of the disease, or preventing, inhibiting, delaying, or reversing the progression of the disease. Thus, terms such as “treat,” “prevent,” etc., should be considered in their broadest context. For example, treatment does not necessarily mean treating a patient until they are completely recovered. Where a disease presents with or is characterized by multiple signs, treatment or prevention does not necessarily have to treat, prevent, inhibit, delay, or reverse all of the signs, but may prevent, inhibit, delay, or reverse one or more of them.

[0088] As used herein, the term “cancer” broadly encompasses neoplastic diseases characterized by abnormal cell proliferation that may invade or spread to other parts of the body. Cancer may be benign, meaning it does not spread to other parts of the body. Cancer may be malignant, meaning its cancer cells may spread through the circulatory or lymphatic system. As used herein, the term encompasses all malignant, i.e., cancerous conditions. Cancer may exist as a tumor.

[0089] As used herein, the term “tumor” means any malignant cancerous or precancerous cell proliferation. The term may include leukemia, but is particularly directed towards solid tumors or carcinomas. When cancer is located in the prostate, it is referred to as “prostate cancer.” It is typically characterized by elevated and / or high levels of serum prostate-specific antigen (PSA), as well as expression or overexpression of PSMA membrane protein. A subject may have prostate cancer, where the cancer is primary and localized in the prostate. The prostate cancer may have metastasized and spread to other parts of the subject. A subject may also have recurrent prostate cancer, characterized by increased PSA within 10 years of treatment for primary prostate cancer.

[0090] In certain embodiments, the method is effective in treating prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC) expressing PSMA. In certain embodiments, the mCRPC is progressive despite prior androgen deprivation therapy, at least one of enzalutamide and / or abiraterone (or other such androgen receptor pathway inhibitors).

[0091] A documented progressive mCRPC is based on at least one of the following criteria: i) Progression of serum / plasma prostate-specific antigen (PSA): Defined as two consecutive increases in PSA compared to the previous normal value measured at least one week prior (minimum value is 0.1 ng / ml); ii) Progression of soft tissue: defined as a 20% or greater increase in the sum of the diameter (SOD) of all targeted lesions based on the sum of the smallest diameters (short axis for lymph node lesions, long axis for non-lymph node lesions) since the initiation of the last treatment directed at metastatic cancer (excluding hormone therapy), or the appearance of one or more new lesions; and iii) Progression of bone disease: Disease or new bone lesions that can be evaluated by bone scans.

[0092] As used herein, the term “subject” means mammal, and includes humans, primates, domestic animals (e.g., sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), performance and show animals (e.g., horses, domestic animals, dogs, cats), companion animals (e.g., dogs, cats), and wild animals in captivity. Preferably, the mammal is a human or a laboratory test animal. More preferably, the mammal is a male human.

[0093] The terms "therapeutably effective dose" or "effective dose" refer to a quantity sufficient to produce a beneficial or desirable clinical outcome. An effective dose may be administered in one or more doses. For radioimaging purposes, an effective dose is sufficient to indicate the localization of the administered compound to the target by detecting decay products derived from a radioisotope that form a complex with the compound of formula (I). For therapeutic purposes, an effective dose is typically sufficient to alleviate, improve, stabilize, reverse, delay, and / or slow cancer progression.

[0094] Radiological progression-free survival (rPFS) is, 67 rPFS is defined as the earlier of the following periods: from the date of initial treatment with CuSAR-bisPSMA to radiation-induced worsening of bone scans, radiation-induced soft tissue worsening, or death from any cause. rPFS will be presented in Kaplan-Meyer curves and summarized statistics (median and rPFS at 6, 9, and 12 months). In certain embodiments, the method provides rPFS from more than 6 months to more than 5 years.

[0095] In some embodiments, the effective amount is as follows: Complete response (CR): Disappearance of all targeted lesions. All pathological lymph nodes must have shrunk to less than 10 mm in the short axis. Disappearance of all targeted lesions. Any pathological lymph node (either targeted or non-target) must have shrunk to less than 10 mm in the short axis; Partial response (PR): The sum of the diameters of target lesions is reduced by at least 30% relative to the sum of straight needle diameters at baseline. This is an effective amount to induce one of them.

[0096] The treatment regimen typically consists of multiple treatment cycles (e.g., 1, 2, 3, 4, 5 or 6 cycles), and the cycles will be repeated until the symptoms have improved a certain number of times. Once again, the optimal number of cycles and the intervals between each treatment cycle will depend on a number of factors such as the height and weight of the subject, the severity of the symptoms to be treated, the health status (or lack thereof) of the subject being treated, and the subject's previous response to radiotherapy, and / or the degree of the symptoms measured through radiographic imaging.

[0097] The inventors have found that a treatment regimen with one or more treatment cycles using a radioactively labeled compound of formula (I) results in the treatment of the subject as shown by a decrease in the uptake of the compound, as illustrated in FIGS. 1 to 3. Since the decrease in the uptake of the compound indicates a low concentration or expression of the PSMA receptor, the inventors believe that the administration of a radioactively labeled compound of formula (I) according to one or more of the methods disclosed herein results in the treatment of prostate cancer in a subject in need thereof.

[0098] The formulation defined in the treatment method herein may be administered parenterally, with intravenous administration being preferred. In one embodiment, an aqueous formulation containing a radioactively labeled compound of formula (I) is administered intravenously either by bolus injection or by slow infusion. In another separate embodiment, 67 A compound of formula (I) radioactively labeled with a Cu radioisotope is administered intravenously by slow infusion.

[0099] It will be understood that the specific dose of the radiolabeled compound of formula (I) for any individual subject will depend on various factors, including, for example, the age, weight and indication of the individual being treated, the timing of administration, the rate of excretion, and any combination with other treatments or therapies. Single or multiple doses may be administered, and the physician may select the dose levels and patterns. A wide range of doses may be applicable. The administration regimen may be adjusted to obtain the optimal therapeutic response. For example, a predetermined dose that delivers a specific amount of radiation may be calculated as a percentage of the total radiation delivered to the subject. The administration regimen may include the administration of multiple doses of the radiolabeled compound of formula (I), which may be the same or different doses. In some embodiments, a method for treating cancer associated with overexpression of PSMA membrane protein includes administering multiple doses of the compound of formula (I) complexed with a copper radioisotope, which may be the same dose. In other embodiments, the method includes administering multiple doses, where the second and subsequent doses are higher than the first dose administered to the subject. In some embodiments, the dose administered for therapeutic or therapeutic purposes is used to identify the cancer site, estimate the amount of compound retained by the target (and the amount of radioactivity subsequently delivered), and assess the nature of the cancer site. 64 The determination is made by administering the compound of formula (I), which is complexed with a Cu radioisotope, and pre-imaging the subject with radiography. The inventors believe that the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in both radioimaging and radiotherapy represents a theranostic solution to cancer associated with overexpression of PSMA membrane proteins. While not intended to be theoretically constrained, the inventors believe that the use of such theranostic compounds provides a more individualized solution for cancer therapy.

[0100] A method of administering a compound of formula (I) having different isotopes, combined with a method of radioimaging cancer associated with overexpression of PSMA membrane proteins, provides a theranostic solution, i.e., a therapeutic and diagnostic solution for the treatment of such cancer. This is because the administration of the compound of formula (I) can also complex with radioisotopes that enable radioimaging of the target, while 67 Administration of the compound of formula (I) in complex with Cu enables treatment of the target. Radioimaging allows visualization of the location where the compound of formula (I) accumulates and corresponds to the treatment site. While not intended to be theoretically constrained, the inventors believe that the methods and uses disclosed herein will enable more effective treatment of cancer associated with overexpression of PSMA membrane proteins. By using the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a copper radioisotope, a higher dose of radioactivity can be delivered in a single dose. Because the compound of formula (I) is specific to PSMA membrane proteins and retains the copper radioisotope for a longer period (compared to other metal chelating agents), its radioactivity is more effectively delivered and localized to the cancer site. The compound of formula (I) also exhibits good clearance from major organs. This subsequently reduces the off-target effects of the radioisotope and limits undesirable damage to healthy tissue caused by the dissociation and subsequent circulation of the radioisotope. Improved clearance of the radiolabeled compound of formula (I) and longer retention at the targeted cancer site result in higher-contrast images and subsequent more reliable diagnostic images. The delivery of more sustained radiation doses by administering the compound of formula (I) complexed with a copper radioisotope also leads to more efficient overall treatment, as smaller amounts of the compound and radioisotope of formula (I) are required. When the required radiation is delivered at a lower dose, this results in greater tolerance for treatment by the patient.

[0101] The methods of the present invention relate to the treatment of cancer associated with overexpression of the PSMA membrane protein in subjects requiring treatment. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is non-metastatic prostate cancer. In one embodiment, the cancer is metastatic prostate cancer. In yet another embodiment, the prostate cancer is castration-resistant prostate cancer with PSMA expression. In some subjects, the prostate cancer is resistant to previous treatments using prior androgen deprivation therapy and / or androgen receptor pathway inhibitors. Examples of such inhibitors include abiraterone, enzalutamide, apalutamide, and darolutamide. In some embodiments, the subject may display PSA progression, i.e., an increase in serum PSA levels. In some embodiments, the subject may display soft tissue progression, which may manifest as an increase in the number of lesions detected and visualized by radiographic imaging by the methods defined herein. In some embodiments, the subject may display cancer progression, which may manifest as bone disease, e.g., progression of one or more bone lesions detected by bone scans. In some embodiments, the subject has received chemotherapy prior to treatment according to one or more embodiments of the present invention. In other embodiments, the subject has received one or more lines of treatment (i.e., other treatment options) prior to treatment according to one or more embodiments of the present invention. In some embodiments, the subject has received two, three, four, or five lines of treatment prior to treatment according to one or more embodiments of the present invention.

[0102] In some subjects, prostate cancer exists as metastatic castration-resistant prostate cancer (mCPC), defined as prostate cancer that has spread or metastasized to other locations in the subject. A decrease in PSA levels is initially observed after the subject's prostatectomy (i.e., removal of the prostate), followed by chemotherapy and / or radiotherapy, although in some subjects, an increase in PSA levels is observed as a result of one or more metastases. We have found that treating subjects with mCPC characterized by elevated PSA levels with a radiolabeled compound of formula (I) results in a decrease in the subjects' PSA levels. Now, in conjunction with the results shown in Figures 1 to 3, in which the reduced uptake of the radiolabeled compound of formula (I) indicates a decrease in the expression of PSMA related to the cancer or tumor site, we believe that administration of the radiolabeled compound of formula (I) results in a treatment of prostate cancer in the subjects.

[0103] Therefore, the present invention relates to a method for reducing prostate-specific antigen (PSA) levels in a subject, and applies to the subject requiring the method. 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a method comprising administering an effective amount of the compound shown or a pharmaceutically acceptable salt thereof to the subject prior to administration, wherein the subject has a PSA level greater than approximately 0.1 ng / ml, and in this case, the subject has a prostate gland.

[0104] The present invention also provides a method for reducing prostate-specific antigen (PSA) levels in a subject, wherein the subject requires... 67 Complex formation with a radioactive isotope of Cu, formula (I): [ka] The present invention provides a method comprising administering an effective amount of the compound shown or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0.05 ng / ml, and in this case, the subject does not have a prostate gland.

[0105] Although we do not intend to restrict this with theory, the inventors of this invention, 67 We believe that the PSA level of a subject prior to administration of the compound of formula (I) complexed with a Cu radioisotope will depend on whether or not the subject has a prostate. For example, if a patient has previously had their prostate removed, detecting PSA in that patient's blood may indicate the presence of prostate cancer (or prostate-related cancer). In other patients with an intact (i.e., present) prostate, the amount of PSA detected is related to the presence or absence of prostate cancer (or prostate-related cancer).

[0106] The target PSA level is measured by one or more known analytical methods, such as blood collection and subsequent analysis. The increase or decrease in the target PSA level is determined in relation to an initial level measured before treatment with the radiolabeled compound of formula (I). In some embodiments, the target PSA level decreases after treatment with one or more doses of the radiolabeled compound of formula (I) compared to the target PSA level before treatment. In certain embodiments, the target PSA level decreases after treatment with one cycle of the radiolabeled compound of formula (I). In certain embodiments, the target PSA level decreases after treatment with two cycles of the radiolabeled compound of formula (I). In certain embodiments, the target PSA level decreases after treatment with three cycles of the radiolabeled compound of formula (I). In certain embodiments, the target PSA level decreases after treatment with four or more cycles of the radiolabeled compound of formula (I).

[0107] In certain embodiments, the PSA level of a subject decreases after administration of the radiolabeled compound of formula (I) one or more times. In certain embodiments, the PSA level of the subject decreases by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or about 99% compared to the PSA level of the same subject before treatment with the radiolabeled compound of formula (I). In certain embodiments, the decrease in the PSA level of the subject is associated with a decrease in the uptake of the radiolabeled compound of formula (I) as measured by imaging with SPECT-CT or PET-CT.

[0108] In certain embodiments, the PSA level of the subject before administration is above about 0.1 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 1 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 10 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 100 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 500 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 1000 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 1500 ng / ml. In other embodiments, the PSA level of the subject before administration is above about 2000 ng / ml.

[0109] In some embodiments, more than one dose of 67 a compound of formula (I) complexed with a Cu radioisotope is administered to the subject. In certain embodiments, two doses of 67 a compound of formula (I) complexed with a Cu radioisotope are administered to the subject. In other embodiments, three doses of 67 a compound of formula (I) complexed with a Cu radioisotope are administered to the subject.

[0110] 67In the administration of a two-dose compound of formula (I) complexed with a Cu radioisotope, the second dose is administered at least four weeks after the first dose. In other embodiments, the second dose is administered at least six weeks after the first dose. In other embodiments, the second dose is administered at least eight weeks after the first dose. In other embodiments, the second dose is administered at least twelve weeks after the first dose. In other embodiments, the second dose is administered at least six months after the first dose. In other embodiments, the second dose is administered at least twelve months after the first dose. In other embodiments, the second dose is administered at least eighteen months after the first dose. In other embodiments, the second dose is administered at least twenty-four months after the first dose. In other embodiments, the second dose is administered at least thirty months after the first dose. In other embodiments, the second dose is administered at least thirty-six months after the first dose. In other embodiments, the second dose is administered at least four years after the first dose. In other embodiments, the second dose is administered at least five years after the first dose.

[0111] In some embodiments, the target PSA level decreases after two administrations of the radiolabeled compound of formula (I) at a dose of 4 GBq each. In some embodiments, the target PSA level decreases after three administrations of the radiolabeled compound of formula (I) at a dose of 4 GBq each. In some embodiments, the target PSA level decreases after four administrations of the radiolabeled compound of formula (I) at a dose of 4 GBq each. In some embodiments, the target PSA level decreases after two administrations of the radiolabeled compound of formula (I) at a dose of 8 GBq each. In some embodiments, the target PSA level decreases after three administrations of the radiolabeled compound of formula (I) at a dose of 8 GBq each. In some embodiments, the target PSA level decreases after four administrations of the radiolabeled compound of formula (I) at a dose of 8 GBq each. In some embodiments, the target PSA level decreases after two administrations of the radiolabeled compound of formula (I) at a dose of 12 GBq each. In some embodiments, the target PSA level decreases after three administrations of the radiolabeled compound of formula (I) at a dose of 12 GBq each. In some embodiments, the target PSA level decreases after four administrations of the radiolabeled compound of formula (I) at a dose of 12 GBq each.

[0112] The present invention also envisions combination therapies in which the radiolabeled compound of formula (I) described herein may be co-administered with other suitable agents that can promote the desired therapeutic effect. The term "co-administration" means simultaneous administration of the same formulation or two different formulations via the same or different routes, or sequential administration via the same or different routes. The term "combination" means administration of multiple formulations, in which case the formulations are administered to the subject simultaneously. The term "simultaneously" means that the activators are administered substantially simultaneously. The term "sequentially" means that there is a time difference of several seconds, several minutes, several hours, or several days between the administration of the drugs. The administration may be in any order.

[0113] Because the methods disclosed herein relate to the administration of radioisotopes that emit ionizing radiation, co-administration of one or more amino acids with an aqueous formulation containing the radiolabeled compound of formula (I) disclosed herein may prevent or limit nephrotoxicity caused by the retention of the radiopharmaceutical. One or more amino acids co-administered to subjects being treated for cancer associated with overexpression of PSMA membrane protein competitively inhibit the reabsorption of the radiolabeled compound of formula (I) by the proximal tubules of the kidney. The inventors believe that limiting the reuptake of the radiolabeled compound of formula (I), and thus reducing nephrotoxicity in the subject, can increase the dose of the administered compound and thus improve the efficiency of the treatment. The cancer treatment methods disclosed herein further include administering one or more amino acids, or salts thereof, to a subject. In one embodiment, the formulation containing one or more amino acids, or salts thereof, 67 It is co-administered with an aqueous formulation containing a compound of formula (I) complexed with a Cu radioisotope. In one embodiment, one or more amino acids comprise lysine or a salt thereof. In another embodiment, one or more amino acids comprise arginine or a salt thereof. In a preferred embodiment, the method for treating cancer further comprises administering lysine and / or arginine, or salts thereof. In a preferred embodiment, the method for treating cancer further comprises administering lysine and arginine, or salts thereof. In a preferred embodiment, the method for treating cancer disclosed herein comprises lysine and arginine, or salts thereof, 67 The present invention further includes co-administration with a compound of formula (I) complexed with a Cu radioisotope. In some embodiments, one or more amino acids or salts thereof are administered by intravenous injection. In some embodiments, the formulation containing one or more amino acids contains L-lysine or a salt thereof. In other embodiments, the formulation containing one or more amino acids contains L-arginine or a salt thereof. In some embodiments, one or more amino acids are present as hydrochloride salts. In some embodiments, one or more amino acids are present at a concentration of about 2.5% w / v each.

[0114] In one embodiment, a method for treating cancer associated with overexpression of PSMA membrane protein involves delivering a therapeutically effective amount to the target that requires it. 67 The procedure involves administering an aqueous formulation of a compound of formula (I) complexed with Cu or a pharmaceutically acceptable salt, and an aqueous formulation of one or more amino acids. In a preferred embodiment, 67 A formulation comprising a radiolabeled compound of formula (I) complexed with Cu and one or more amino acids is administered simultaneously. In another preferred embodiment, a formulation comprising one or more amino acids is: 67 The compound of formula (I), which forms a complex with Cu, is administered to the subject before administration.

[0115] As used herein, the term "amino acid" refers to a molecule containing both an amino functional group and a carbonyl functional group. Amino acids may be natural or unnatural, and may be in their zwitterionic form or in equilibrium. Amino acids may contain modifications at either the amino and / or carboxyl terminus, or may contain a free amino group or a carboxyl group. Further modifications of the amino acid side chain, or additional substitutions of other parts of the amino acid, are also conceivable.

[0116] As used herein, natural amino acids refer to the L or D forms of 20 amino acids that are commonly found in nature. These are glycine (Gly, G), alanine (Ala, A), valine (Val, V), leucine (Leu, L), isoleucine (Ile, I), methionine (Met, M), proline (Pro, P), phenylalanine (Phe, F), tryprophan (Trp, W), serine (Ser, S), threonine (Thr, T), asparagine (Asn, N), glutamine (Gln, Q), tyrosine (Tyr, Y), cysteine ​​(Cys, C), lysine (Lys, K), arginine (Arg, R), histidine (His, H), aspartic acid (Asp, D), and glutamic acid (Glu, E).

[0117] The method of the present invention may further include administering an antiemetic. In one embodiment, the method of the present invention further includes administering an antiemetic to a subject. In some embodiments, the antiemetic is 67 It is administered simultaneously with or prior to the compound of formula (I) that forms a complex with Cu.

[0118] The treatment methods disclosed herein are 67 The treatment method disclosed herein includes administering a formulation containing a compound of formula (I) in complex with Cu. The formulation may be administered intravenously, for example, by slow intravenous injection. 67 The method may include administering a single dose of a formulation containing a compound of formula (I) in complex with Cu, or administering the same or different formulations multiple times. In one embodiment, the method for treating cancer is: 67 The method comprises administering a single dose of an aqueous formulation containing a compound of formula (I) in complex with Cu. In another embodiment, the method is 67 The method comprises administering two doses of an aqueous formulation containing a compound of formula (I) in complex with Cu. In another embodiment, the method is 67 The procedure involves administering three doses of an aqueous formulation containing a compound of formula (I) that forms a complex with Cu. In yet another embodiment, the method is 67 The procedure involves administering four doses of an aqueous formulation containing a compound of formula (I) that forms a complex with Cu.

[0119] If multiple doses are required, the interval between administrations of the formulation may be approximately 1 week to approximately 14 weeks or longer. In one embodiment, the method 67The method comprises administering an aqueous formulation containing a compound of formula (I) in complex with Cu in multiple doses, with the doses administered at intervals of approximately one week. In another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately two weeks. In yet another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately four weeks. In yet another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately six weeks. In yet another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately eight weeks. In yet another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately ten weeks. In yet another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately twelve weeks. In yet another embodiment, the method comprises administering multiple doses, with the doses administered at intervals of approximately fourteen weeks. In some embodiments, the therapeutic methods described herein are: 67 The method includes administering a formulation containing a compound of formula (I) in complex with Cu in two or more doses, where the time between doses may be the same. In some embodiments, the method includes administering two or more doses of the formulation, where the time between doses is approximately the same, for example, about one week between doses, about two weeks between doses, about four weeks between doses, about six weeks between doses, about eight weeks between doses, about ten weeks between doses, about twelve weeks between doses, and about fourteen weeks between doses. In other embodiments, the time between doses may be different, for example, about six weeks between the first and second doses, and about eight weeks between the second and third doses. Other embodiments with different time between doses are also conceivable, where the time between two consecutive doses may be about one week, two weeks, four weeks, about six weeks, about eight weeks, about ten weeks, about twelve weeks, about fourteen weeks, or about sixteen weeks.

[0120] In other embodiments, the second dose is administered at least four weeks after the first dose. In certain embodiments, the second dose is administered about six weeks after the first dose. In other embodiments, the second dose is administered about eight weeks after the first dose. In other embodiments, the second dose is administered about twelve weeks after the first dose. In some embodiments, the second dose is administered about six months, twelve months, eighteen months, twenty-four months, thirty months, or thirty-six months after the first dose. In other embodiments, the second dose is administered about four years after the first dose. In other embodiments, the second dose is administered about five years after the first dose.

[0121] In one embodiment, a method for treating cancer associated with the overexpression of PSMA membrane proteins is: 67 The method includes administering a single dose of a formulation containing the compound of formula (I) in complex with Cu. 67 In some embodiments in which a formulation containing the compound of formula (I) in complex with Cu is administered multiple times, the formulation administered each time may be the same or different. If the formulations are different, each formulation contains 67 Compounds of formula (I) complexed with Cu can deliver different doses of radioactivity, for example, about 4 GBq, about 8 GBq, about 12 GBq, about 16 GBq, about 20 GBq, or about 24 GBq. In one embodiment, they are administered in a method for treating cancer associated with overexpression of PSMA membrane antigen. 67 An aqueous formulation of the compound of formula (I) in complex with Cu delivers a dose of radiation of approximately 4 GBq to approximately 24 GBq to a target. In one embodiment, the aqueous formulation delivers a dose of approximately 4 GBq. In another embodiment, the aqueous formulation delivers a dose of approximately 6 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 8 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 10 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 12 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 16 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 20 GBq. In yet another embodiment, the aqueous formulation delivers a dose of approximately 24 GBq.

[0122] In a particular embodiment, a method for treating cancer associated with the overexpression of PSMA membrane proteins involves multiple doses. 67 The procedure involves administering a compound of formula (I) in which a Cu radioisotope has formed a complex with the compound, with each dose being approximately 4 GBq. In other embodiments, each dose is approximately 8 GBq. In other embodiments, each dose is approximately 12 GBq.

[0123] Or, 67 The dose of radioactivity delivered by the compound of formula (I) in complex with Cu is the maximum dose tolerated by each individual subject. Those skilled in the art will recognize that the maximum tolerated dose varies among subjects. The inventors have found that administration of the compound of formula (I) with an imaging-suitable radioisotope not only visualizes the distribution and uptake of the radiolabeled compound, but also visualizes the subject's tolerance to a given dose. If the subject appears to tolerate the dose well and other physiological measurements (e.g., liver and kidney function) are satisfactory, this information can be used to determine a higher dose of radiation that is specific to the subject. In one embodiment, the method disclosed herein is: 67 The process includes evaluating the tolerance of a target to a dose of a compound of formula (I) complexed with Cu, and modifying the dose of radioactivity delivered to the target at subsequent doses. Those skilled in the art will know how to image the nucleus, determine the baseline level of radiation, and 67 It will be recognized that various techniques may be used, including determining uptake by comparing levels after administration of the compound of formula (I) complexed with Cu, comparing the size and number of lesions before and after administration, and monitoring biochemical markers via one or more diagnostic assays.

[0124] Accordingly, the present invention is a method for treating cancer associated with overexpression of PSMA membrane protein, wherein the subject is administered 67The present invention provides a method for determining the dose of a compound of formula (I) complexed with Cu, which is specific to the subject and determined by a combination of imaging and physiological assay techniques. In one embodiment, the dose is determined by administering a compound of formula (I) complexed with a suitable radioisotope to a subject, followed by imaging the subject over time to obtain one or more images that can be used to measure the suitability of the dose administered to the subject. In some embodiments, imaging can be performed by one or more techniques such as PET, SPECT, and CT. While not intended to be theoretically restrictive, the inventors believe that the method disclosed herein will enable more advanced and individualized regimens for treating cancer in subjects associated with overexpression of PSMA membrane proteins.

[0125] No reference in this specification to prior art (or information derived therefrom) or to any known matter constitutes, and should not be treated as such, an endorsement, acceptance, or suggestion that such prior art (or information derived therefrom) or known matter constitutes part of the common general knowledge in the field of research to which this specification relates.

[0126] Those skilled in the art will understand that the inventions described herein are susceptible to modifications and alterations beyond those specifically described. It should be understood that the invention encompasses all such modifications and alterations within its spirit and scope. The invention also encompasses all processes, features, compositions, and compounds mentioned or indicated herein, individually or comprehensively, and any combination of two or more such processes or features.

[0127] Examples The following embodiments are illustrative of the disclosure and should not be construed as limiting the general characteristics of the disclosure described herein.

[0128] Example 1- 64Cu-SAR bisPSMA PET / CT scan 64 After administering Cu-SAR bisPSMA at the specified time, quantitative PET / CT imaging was performed. 67 Confirm eligibility for treatment with CuSAR-bisPSMA; 64 Evaluate the in vivo distribution of Cu-SAR bisPSMA; or calculate dose measurements. 64 Using Cu-SAR bis PSMA PET / CT scans, 64 Cu-SARbisPSMA 67 This study investigates the dosimetry, biodistribution, and potential therapeutic effects of CuSAR-bisPSMA.

[0129] Example 2 - 67 CuSAR-bisPSMA SPECT / CT scan 67 Using quantitative SPECT / CT imaging of CuSAR-bisPSMA, 67 Evaluate the in vivo distribution of CuSAR-bisPSMA or calculate the dose. Quantitative analysis will be performed using standard methods.

[0130] Example 3- 64 Cu-SAR bisPSMA and 67 Dose measurement of Cu-SAR-bisPSMA Radiation dose measurements may be taken using methods for measuring radiation dose (if necessary).

[0131] Dose measurement analysis is, 64 Data obtained 1, 4, 12, 24, and 48 hours after injection of Cu-SAR bisPSMA. 64 Using Cu-SAR bisPSMA PET / CT scans (additional scans may be performed afterward if sufficient activity levels remain in the subjects), the following: i) 64 Absorbed dose (mGy / MBq) and effective dose (mSv / MBq) in organs derived from Cu-SAR bisPSMA; ii) 67Modeled absorbed dose (mGy / MBq) in organs derived from Cu-SAR-bisPSMA; iii) Not exceeding the specific organ tolerance limit (23 Gy in the kidney, 2 Gy in the bone marrow, and 24 Gy in the submandibular gland), 67 Modeled estimated total cumulative dose radioactivity (GBq) of Cu-SAR-bisPSMA To decide.

[0132] 67 Data were obtained at 1, 4, 12, 24, and 48 hours, respectively, after administration of Cu-SAR-bisPSMA. 67 Dose measurement analysis is performed from Cu-SAR-bisPSMA SPECT / CT scans (Note: If sufficient activity levels remain in the individuals involved, additional scans may be performed afterward). 67 The absorbed dose (MGy / MBq) in organs using Cu-SAR-bisPSMA was determined.

[0133] Using a copper-specific method 64 Cu-SAR bisPSMA and 67 Dose measurements were calculated using both Cu-SAR and bisPSMA. 64 Using Cu-SAR bis PSMA PET / CT data 67 We modeled Cu-SAR-bisPSMA dose measurement.

[0134] Example 4 - Measurement of PSA Levels To measure PSA levels in the blood, up to 15 mL of blood is obtained from the patient for analysis according to an established protocol, and the patient's PSA level is measured using a blood test.

[0135] The target PSA level will be monitored at a later date, for example, every two weeks, four weeks, or six weeks, using the same process. Additional blood samples will be collected and analyzed using the same method. This also allows for a comparison of the target PSA level over time.

[0136] Example 5- 67 Processing with Cu-SAR-bisPSMA - Single-line volume Generally, patients 67 Cu-SAR-bisPSMA is administered by intravenous infusion over approximately 30 minutes, and the amount (i.e., volume) of the infusion is determined by the dose that would have been administered to the patient.

[0137] Six patients received a single dose of 4 GBq 67 No patients reported dose-limiting toxicity (DLT) after receiving Cu-SAR-bisPSMA. Three patients reported a single dose of 8 GBq. 67 No patients reported DLT after receiving Cu-SAR-bisPSMA. Six patients received a single 12 GBq dose. 67 None of the patients who received Cu-SAR-bisPSMA reported DLT.

[0138] Example 6- 67 Cu-SAR-bisPSMA processing - Multiple line volume Generally, patients 67 Cu-SAR-bisPSMA was administered by intravenous infusion over approximately 30 minutes, with the amount (i.e., volume) of the infusion determined by the dose that would have been administered to the patient. A second dose of the same dose was provided to the same patient at least 4 weeks later.

Claims

1. A method of treating cancer, and for those who need it, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 1】 The treatment involves administering an aqueous formulation of the compound shown or a pharmaceutically acceptable salt thereof in a therapeutically effective amount, wherein the cancer is associated with the expression or overexpression of PSMA membrane proteins. ６７ A method wherein the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

2. A method of treating cancer, and for those who need it, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 2】 The treatment involves administering an aqueous formulation of the compound shown or a pharmaceutically acceptable salt thereof in a therapeutically effective amount, wherein the cancer is associated with the expression or overexpression of PSMA membrane proteins. ６７ A method wherein the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer and / or mediate a decrease in the target PSA level.

3. The method according to claim 1 or 2, wherein the cancer is prostate cancer.

4. The method according to claim 3, wherein the cancer is metastatic prostate cancer.

5. The method according to claim 3 or 4, wherein the prostate cancer is PSMA-expressing metastatic castration-resistant prostate cancer (mCRPC).

6. A method for lowering prostate-specific antigen (PSA) levels in a subject, wherein the subject requires the method to be used. ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Transformation 3】 A method comprising administering an effective amount of the compound shown, or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0.1 ng / ml, and in this case, the subject has a prostate gland.

7. A method for lowering prostate-specific antigen (PSA) levels in a subject, wherein the subject requires the method to be used. ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 4】 A method comprising administering an effective amount of the compound shown, or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0 ng / ml, and in this case, the subject does not have a prostate gland.

8. ６７ The method according to any one of claims 1 to 7, wherein the dose of radiation delivered by the Cu radioactive isotope is approximately 50 MBq / kg to approximately 400 MBq / kg.

9. The method according to any one of claims 1 to 8, further comprising radiographic imaging of the object by PET and / or CT.

10. ６７ The method according to any one of claims 1 to 9, wherein the dose of radiation delivered by the Cu radioisotope is about 4 GBq, about 8 GBq, about 12 GBq, about 16 GBq, about 20 GBq, or about 24 GBq.

11. The method according to any one of claims 1 to 10, wherein the dose is delivered multiple times, and the doses may be the same or different.

12. The method according to claim 11, wherein multiple doses are administered at intervals of 6 to 16 weeks.

13. The method according to any one of claims 1 to 12, wherein the total dose of radiation delivered to the target bone marrow is less than approximately 2 Gy, the total dose of radiation delivered to the target kidney is less than approximately 23 Gy, and / or the total dose of radiation delivered to the target submandibular gland is less than approximately 24 Gy.

14. For use in the treatment of cancer associated with the expression or overexpression of the PSMA membrane protein in a subject needing such treatment, ６７ Complexed with a Cu radioisotope, of formula (I): 【Transformation 5】 A method for determining the dose of a compound represented by, or a pharmaceutically acceptable salt thereof, ６４ A method comprising administering to a subject an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is complexed with a Cu radioisotope.

15. The subject is subjected to radiographic imaging, ６４ The method according to claim 14, further comprising the step of measuring the incorporation of a compound of formula (I) that has formed a complex with a Cu radioisotope.

16. The method according to claim 14 or 15, further comprising the step of performing one or more physiological assays on a target.

17. The compound of formula (I) is given by formula (Ia): 【Transformation 6】 The method according to any one of claims 1 to 16, having the structure shown in [the provided text].

18. In the manufacture of aqueous formulations for treating cancer associated with the expression or overexpression of PSMA membrane antigen, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Transformation 7】 The use of the compound shown, or a pharmaceutically acceptable salt thereof, wherein ６７ Use of a Cu radioisotope where the dose of radiation delivered is sufficient to reduce the size of one or more lesions associated with the cancer.

19. In the manufacture of aqueous formulations for treating cancer associated with the expression or overexpression of PSMA membrane antigen, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Transformation 8】 The use of the compound shown, or a pharmaceutically acceptable salt thereof, wherein ６７ Use of a Cu radioisotope where the dose of radiation delivered is sufficient to reduce the size of one or more lesions associated with the cancer and / or lower the prostate-specific antigen (PSA) level of the target.

20. The use according to claim 18 or 19, wherein the cancer is prostate cancer.

21. The use according to claim 20, wherein the cancer is metastatic prostate cancer.

22. The use according to claim 20 or 21, wherein the prostate cancer is PSMA-expressing metastatic castration-resistant prostate cancer.

23. In the manufacture of aqueous formulations for reducing prostate-specific antigen (PSA) levels in subjects requiring a reduction in PSA levels, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 9】 Use of the compound indicated by or an effective amount of a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0.1 ng / ml, and in this case, the subject has a prostate gland.

24. In the manufacture of aqueous formulations for reducing prostate-specific antigen (PSA) levels in subjects requiring a reduction in PSA levels, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 10】 Use of the compound indicated by or an effective amount of a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0 ng / ml, and in this case, the subject does not have a prostate gland.

25. The use according to any one of claims 17 to 19, wherein the dose of radiation delivered by the radioisotope is about 4 GBq, about 8 GBq, about 12 GBq, about 16 GBq, about 20 GBq, or about 24 GBq.

26. For the treatment of cancer associated with the expression or overexpression of PSMA membrane protein, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 11】 The use of the compound shown or a pharmaceutically acceptable salt thereof, wherein ６７ The dose of radiation delivered by the Cu radioisotope is sufficient to reduce the size of one or more lesions associated with cancer.

27. For the treatment of cancer associated with the expression or overexpression of PSMA membrane protein, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 12】 The use of the compound shown, or a pharmaceutically acceptable salt thereof, wherein ６７ A method in which the dose of radiation delivered by a Cu radioisotope is sufficient to reduce the size of one or more lesions associated with cancer and / or mediate a decrease in prostate-specific antigen (PSA) levels.

28. The use according to claim 26 or 27, wherein the cancer is prostate cancer.

29. The use according to claim 28, wherein the cancer is metastatic prostate cancer.

30. The use according to claim 28 or 29, wherein the prostate cancer is a metastatic castration-resistant prostate cancer expressing PSMA.

31. For the reduction of prostate-specific antigen (PSA) levels in subjects requiring a reduction in PSA levels, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 13】 The use of the compound indicated, or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0.1 ng / ml, and in this case, the subject has a prostate gland.

32. For the reduction of prostate-specific antigen (PSA) levels in subjects requiring a reduction in PSA levels, ６７ Formula (I): Complex formation with Cu radioactive isotopes: 【Chemistry 14】 The use of the compound indicated, or a pharmaceutically acceptable salt thereof, wherein the subject's PSA level prior to administration is above approximately 0 ng / ml, and in this case, the subject does not have a prostate gland.

33. The use according to any one of claims 26 to 32, wherein the dose of radiation delivered by the radioisotope is about 4 GBq, about 8 GBq, about 12 GBq, about 16 GBq, about 20 GBq, or about 24 GBq.

34. The compound of formula (I) is given by formula (Ia): 【Chemistry 15】 The use according to any one of claims 26 to 33, having the structure shown in [the provided text].

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