Methods for diagnosing and / or treating neuroendocrine cancer

Abstract

The present invention relates to a method of diagnosis and / or radiotherapy comprising administering a compound of formula (I) and a 64Cu / 67Cu radioisotope to deliver targeted radiation doses for the diagnosis and treatment of neuroendocrine cancer, in particular neuroblastoma in children. Formula (I)

Description

[0001] field

[0002] This invention relates to methods of radiographic imaging and / or radiotherapy, the methods comprising administering and 64 Cu / 67 Specific compounds complexed with the radioisotope Cu are used to deliver targeted doses of radiation for imaging and / or treatment of neuroendocrine carcinomas, particularly neuroblastomas in children.

[0003] background

[0004] The body's neuroendocrine system is responsible for producing, storing, and secreting peptides and hormones. Neuroendocrine carcinomas typically present as tumors and are usually found in the gastrointestinal or respiratory system, but they can also occur in other locations, such as the adrenal glands, nervous system, and skin. Specific locations of neuroendocrine tumors include the large intestine and appendix, small intestine, pancreas, stomach, and lungs.

[0005] Neuroblastoma is a neuroendocrine carcinoma that forms in the early neural tissue (neuroblasts) of the sympathetic nervous system and can exist anywhere in the system, including the adrenal glands, neck, chest, and spinal cord. Neuroblastoma most commonly occurs in infants and young children under the age of five and accounts for approximately 13% of childhood cancer deaths. Given the complexity and heterogeneity of neuroblastoma, many factors determine the outcome. For example, whether the cancer spontaneously regresses or metastasizes and becomes resistant to treatment may be related to the age at diagnosis, the stage of the disease, and the molecular, cellular, and genetic characteristics of the disease.

[0006] Diagnosis of neuroendocrine carcinomas is typically achieved through a combination of techniques, including biopsy, blood tests, endoscopy, ultrasound, X-ray, CT scans, MRI scans, and nuclear medicine imaging (such as PET scans). While techniques such as biopsy can allow for a definitive diagnosis, this requires first locating the cancer. Other techniques, such as PET scans, allow for a single evaluation of the entire subject to determine the presence of cancer. The use of nuclear medicine imaging requires the administration of a suitable radioactive tracer that binds to the cancer site. For imaging to be successful, the administered agent must selectively bind to the cancer site, retain and deliver the radioactive isotope to the cancer site for a sufficient duration to allow for images of adequate quality, and also induce little or no side effects on the subject. Cancer treatment is often accompanied by a variety of side effects and adverse events, which are related to the form of treatment. Often, adverse events experienced by patients may be severe enough to limit or prematurely terminate the prescribed treatment course, or otherwise have a detrimental effect on the patient.

[0007] Patients are categorized into low-risk, intermediate-risk, and high-risk groups. Generally, patients with low-risk disease have excellent event-free survival and overall survival (OS) with only observation or minimal treatment intervention. Outcomes for patients with intermediate-risk disease, primarily treated with surgery and chemotherapy, have improved to such a point that many teams are focusing on using biomarkers to help further reduce treatment in this group of children.

[0008] Patients with high-risk disease account for approximately half of all new neuroblastoma cases each year. To improve their survival chances, this class requires multimodal treatment, including induction chemotherapy, surgery, radiation therapy, high-dose chemotherapy with autologous stem cell salvage, and maintenance therapy with biological and immunotherapies. However, even with this aggressive treatment strategy, a significant number of patients still relapse and ultimately die from the disease.

[0009] Despite advances in understanding the pathogenesis of neuroblastoma in recent years, no established curative treatment options exist for patients with high-risk refractory or recurrent disease. Patients with recurrent disease often develop metastatic tumors resistant to standard therapies, and the treatment goal is frequently not cure, but rather prolonging survival and controlling symptoms. The 1-year and 4-year overall survival (OS) rates remain at only 57% and 20%, respectively. New treatment strategies are needed to improve outcomes in these patients. The use of meso-iodobenzylguanidine (MIBG) in... 123 I displacement 131 I made it possible to obtain therapeutic radiopharmaceuticals suitable for treating neuroblastoma and other neuroendocrine tumors. However, 131 The use of I-MIBG for neuroblastoma remains experimental, and it is currently only used in clinical trials. Furthermore, due to... 131 I has a long half-life (8 days). 131 I-MIBG treatment is an extremely complex and difficult-to-schedule procedure. Despite using 131 I-MIBG single-agent molecular radiotherapy has shown some efficacy in relapsed or refractory populations, but the overall response rate (ORR) is only 36%, the median time to progression is approximately 5 months, and significant toxicities have been observed in most patients. Furthermore, approximately 10% of patients have MIBG-incompatible diseases and are not suitable for treatment.

[0010] There is still a need to develop targeted diagnostics and / or therapies for neuroendocrine carcinomas that deliver the highest tolerable dose of radioactivity while minimizing unwanted off-target effects and protecting patients from adverse treatment-related effects, and, in terms of diagnosis, provide images of sufficient quality to better diagnose the cancer. Invention Overview

[0012] This invention provides a method for diagnosing and / or treating neuroendocrine carcinomas, particularly neuroblastomas, said method by administering... 64 Cu / 67 The compound of formula (I) is a somatostatin analog containing octreotate and sarcophagine fragments, which can be radiolabeled with a copper radioisotope. The compound of formula (I) coordinates with and retains the copper radioisotope and also exhibits high affinity binding to the somatostatin receptor, allowing for targeted radiation delivery to tumor sites expressing this receptor. Since neuroblastoma has been shown to express somatostatin receptor 2 (SSTR2), the compound of formula (I) is suitable for specifically targeting neuroblastoma sites and other neuroendocrine carcinomas expressing the same receptor.

[0013] The methods disclosed in this article for diagnosing neuroendocrine carcinoma or neuroblastoma are similar to the current standard of care model (i.e., application of...). 123 Compared to I-MIBG followed by imaging, it is more effective. According to the current standard model, applying 123 Imaging after I-MIBG is performed via SPECT, but the resulting images are typically low-resolution and may limit physicians' ability to make clinical diagnostic and treatment decisions for patients. Based on the method disclosed herein, the inventors of this invention believe that applying… 64 Cu-Sartate, followed by PET imaging, provides a more effective and accurate evaluation of the patient and thus the diagnosis of neuroendocrine carcinoma and neuroblastoma in such patients. Due to the administration of... 64 Images obtained via PET after Cu-Sartate have higher resolution (see...). Figure 1 Its high specificity makes it easier to determine the nature and location of any tumors in the subject and can provide the subject with a more definitive diagnosis.

[0014] The inventors of this invention have also discovered that administering a compound of formula (I) complexed with a copper radionuclide allows for the delivery of high doses of radiation to the desired site while limiting off-target effects. Therefore, this minimizes undesirable damage to healthy tissues and related side effects. Not wishing to be bound by theory, the inventors of this invention believe that, with 67The Cu-complexed compounds of formula (I) allow for improved treatment of neuroendocrine carcinomas because the radiolabeled complexes exhibit higher specificity for somatostatin receptors and better retention of the radioisotope. This then allows for better targeting of the cancer site and reduced leakage or loss of the radioisotope. Since the radioactivity is localized at the cancer site, this reduces adverse events such as off-target radiation effects and damage to healthy tissues. In addition to reducing adverse radiation-related effects, the inventors of this invention believe that the methods disclosed herein also generally reduce adverse effects classified according to adverse event reporting criteria known and accepted in the art. The reduction in off-target radiation damage and the minimization of adverse events allow for better patient treatment, improved patient comfort and compliance, and subsequently, improved treatment outcomes.

[0015] The inventors of this invention have also discovered that, due to the improved preservation of radioactive isotopes, and 67 Compounds of formula (I) with Cu complexes allow for the administration of larger doses of radiation to subjects. Because larger doses of radiation can be administered (and tolerated) according to the methods disclosed herein, they can be used in conjunction with… 67 Treatment of neuroendocrine carcinomas with Cu-complexed compounds of formula (I) was improved, leading to longer survival in subjects.

[0016] The inventors of this invention also believe that the radiolabeled compound of formula (I) provides a method for diagnosing neuroendocrine carcinomas, which can be used in combination with treatment methods as discussed herein. That is, one of the main advantages of this invention is that the compound of formula (I) can be used for both diagnosing and treating cancer by simply switching between Cu radioactive isotope species. When the compound of formula (I) is combined with… 64 When coordinated with Cu, the complex can be used in combination with PET and / or CT imaging to visualize the biodistribution and localization of the radiolabeled compound, which in turn indicates the site of membrane expression and potential carcinogenesis. Based on the... 64 Imaging the location of Cu-labeled compounds provides information, along with suitable copper radioisotopes (e.g., 67 Compounds of formula (I) that coordinate with Cu can be used for therapeutic purposes because the compound will bind to and locate at the same site as identified by imaging the subject. For therapeutic purposes, the subject can be imaged by SPECT, PET, and / or CT after administration of the radiolabeled compound of formula (I) to confirm the localization and targeted therapy of the radiolabeled compound.

[0017] In one aspect, the present invention provides a method for treating neuroendocrine carcinoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0018]

[0019] Formula (I)

[0020] The radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0021] In one aspect, the present invention provides a method for treating neuroendocrine carcinoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0022]

[0023] Formula (I)

[0024] Optionally, the aqueous formulation is applied once, twice, or three times in the same or lower amount of the compound of formula (I);

[0025] The bone marrow of the subject was delivered thereto. 67 The total dose of Cu radiation was less than about 2 Gy, and the total dose of radiation delivered to the kidneys of the subject was less than about 30 Gy.

[0026] In another aspect, the present invention provides a method for treating neuroblastoma, the method comprising administering a therapeutically effective dose of [a specific drug / treatment] to a subject in need. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0027]

[0028] Formula (I)

[0029] The radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the neuroblastoma.

[0030] In another aspect, the present invention provides a method for treating neuroendocrine carcinoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0031]

[0032] Formula (I)

[0033] The subjects in question did not experience any adverse events classified as Grade 3 or higher.

[0034] In other implementations, the subject does not experience any adverse events classified as Grade 2 or higher.

[0035] In other implementations, the subject does not experience any adverse events classified as Grade 1 or higher.

[0036] On the other hand, the present invention also provides a method for treating neuroblastoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0037]

[0038] Formula (I)

[0039] The subjects in question did not experience any adverse events classified as Grade 3 or higher.

[0040] In other implementations, the subject does not experience any adverse events classified as Grade 2 or higher.

[0041] In other implementations, the subject does not experience any adverse events classified as Grade 1 or higher.

[0042] In another aspect, the present invention provides a method for treating neuroendocrine tumors, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0043]

[0044] Formula (I)

[0045] The radiation dose mentioned therein is not related to any dose-limiting toxicity in the subjects.

[0046] In another aspect, the present invention provides a method for treating neuroendocrine carcinoma in patients requiring such treatment, the method comprising:

[0047] 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof:

[0048]

[0049] Formula (I).

[0050] In another aspect, the present invention provides a method for treating neuroblastoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0051]

[0052] Formula (I)

[0053] Optionally, the aqueous formulation is applied once, twice, or three times in the same or lower amount of the compound of formula (I);

[0054] The bone marrow of the subject was delivered thereto. 67 The total dose of Cu radiation was less than about 2 Gy, and the total dose of radiation delivered to the kidneys of the subject was less than about 30 Gy.

[0055] In another aspect, the present invention provides a method for treating neuroblastoma in patients requiring such treatment, the method comprising:

[0056] 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof:

[0057]

[0058] Formula (I).

[0059] In one implementation scheme and with reference to the second or third aspect, the method may also further include the following steps:

[0060] 2) Repeat treatment cycle 1) once, twice, or three times at the same or lower dose of formula (I) so that the total radiation dose delivered to the patient’s kidneys does not exceed 30 Gy.

[0061] In another aspect, the present invention provides a method for treating neuroendocrine carcinoma in patients requiring such treatment, the method comprising:

[0062] 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof:

[0063]

[0064] Formula (I),

[0065] and

[0066] 2) Repeat treatment cycles 1) once, twice, or three times at the same or lower dose as in formula (I) such that the total dose delivered to the patient based on the patient’s weight does not exceed 30 Gy for renal limitation.

[0067] In another aspect, the present invention provides a method for treating neuroblastoma in patients requiring such treatment, the method comprising:

[0068] 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof:

[0069]

[0070] Formula (I),

[0071] and

[0072] 2) Repeat treatment cycles 1) once, twice, or three times at the same or lower dose as in formula (I) such that the total dose delivered to the patient based on the patient’s weight does not exceed 30 Gy for renal limitation.

[0073] In some embodiments, the total radiation dose delivered due to the administration of the compound of formula (I) will not result in a radiation dose delivered to the kidneys exceeding about 30 Gy, about 29 Gy, about 28 Gy, about 27 Gy, about 26 Gy, about 25 Gy, about 24 Gy, or about 23 Gy (based on the patient’s weight).

[0074] In a specific implementation plan, the effectiveness of the treatment method can be assessed using the diagnostic methods disclosed herein, which can be used between treatment cycles. 64 The Cu radioactive isotope is used. Therefore, one advantage of this invention is that it allows for the simple use of... 64 Cu radioisotope switching to 67 Cu radioisotopes can be used with compounds of the same formula (I) for both diagnosis and treatment of tumors, as well as advancements in treatment regimens.

[0075] In one embodiment and with reference to the above aspects, the neuroendocrine carcinoma is neuroblastoma. In one embodiment and with reference to the above aspects, the neuroendocrine carcinoma is high-risk neuroblastoma. In one embodiment and with reference to the above aspects, the neuroendocrine carcinoma is high-risk neuroblastoma in children. In one embodiment and with reference to the above aspects, the patient is a child, adolescent, or adult.

[0076] In some implementation schemes, by 67 The radiation dose delivered by the Cu radioisotope is approximately 75 MBq / kg, approximately 175 MBq / kg, approximately 275 MBq / kg, approximately 375 MBq / kg, or approximately 475 MBq / kg. In some embodiments, by 67 The radiation dose delivered to the subject by the Cu radioisotope is specifically tailored to the subject. In some embodiments, the radiation dose delivered to the subject is determined by prior radiographic imaging of the subject using a compound of formula (I) complexed with a suitable radioisotope.

[0077] In one embodiment, the treatment method further includes monitoring the subject via radiographic imaging through PET, SPECT, and / or CT. In some embodiments, the monitoring of the subject via radiographic imaging can be performed between treatment cycles.

[0078] In some implementations, the methods disclosed herein do not result in any adverse events classified as Grade 3 or higher according to CTCAE v5.0.

[0079] In other implementations, the methods disclosed herein do not result in any adverse events classified as Grade 2 or higher according to CTCAE v5.0.

[0080] In other implementations, the methods disclosed herein do not result in any adverse events classified as Grade 2 or higher according to CTCAE v5.0.

[0081] In another aspect, the present invention provides a method for radiographic imaging of neuroendocrine carcinoma, the method comprising administering to a subject with... 64 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0082]

[0083] Formula (I)

[0084] The radiation dose delivered by the radioactive isotope is approximately 2 MBq / kg.

[0085] On the other hand, the present invention provides a method for radiographic imaging of neuroblastoma, the method comprising administering to a subject in need of such imaging a radiographic device... 64 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0086]

[0087] Formula (I)

[0088] The radiation dose delivered by the radioactive isotope is approximately 2 MBq / kg.

[0089] Therefore, the present invention also provides a similar 64 The use of a Cu radioisotope complex of a compound of formula (I) or a pharmaceutically acceptable salt thereof for radioimaging of neuroendocrine carcinomas, preferably, by administering more than one dose of an aqueous formulation, wherein the total radiation dose delivered to an adult patient by the radioisotope is about 150 to about 250 MBq, or about 200 MBq.

[0090] Not wishing to be bound by theory, the inventors of this invention believe that administering more than one dose of the formulation described herein for the treatment of neuroendocrine carcinoma results in a higher dose of radiation absorbed at the cancer site, leading to greater therapeutic efficacy. This means that repeated administration of a formulation containing a compound of formula (I) complexed with a radioisotope can result in longer survival of the subject compared to a single administration of the formulation disclosed herein. The method of the first aspect may include administering multiple doses of an aqueous formulation containing a complex of a compound of formula (I) and a radioisotope.

[0091] In one embodiment, the method includes sequentially applying more than one dose of the aqueous formulation described in the first aspect. In some embodiments, two doses of the aqueous formulation described in the first aspect are applied. In other embodiments, three doses of the aqueous formulation described in the first aspect are applied. In still other embodiments, four doses of the aqueous formulation described in the first aspect are applied. In yet another embodiment, more than four doses of the aqueous formulation described in the first aspect are applied.

[0092] In some embodiments, the aqueous formulation is administered at sequential dose intervals of about 1 week to about 16 weeks. In one embodiment, the aqueous formulation is administered at sequential dose intervals of about 1 week. In some embodiments, the aqueous formulation is administered at sequential dose intervals of about 1 to about 12 weeks. In another embodiment, the aqueous formulation is administered at sequential dose intervals of about 1 to about 10 weeks. In some embodiments, the aqueous formulation is administered at sequential dose intervals of about 1 to about 8 weeks. In some embodiments, the aqueous formulation is administered at sequential dose intervals of about 1 to about 6 weeks. In some embodiments, the aqueous formulation is administered at sequential dose intervals of about 1 to about 4 weeks. In some embodiments, the aqueous formulation is administered at sequential dose intervals of about 1 to about 2 weeks. In one embodiment, the aqueous formulation is administered at sequential dose intervals of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or about 16 weeks. In one embodiment, the total radiation dose delivered to the bone marrow of the subject is less than about 2 Gy. In another embodiment, the total radiation dose delivered to the subject's kidney is less than about 23-28 Gy. In another embodiment, the total radiation dose delivered to the subject's submandibular gland is less than about 24 Gy.

[0093] The methods described above may include administering multiple doses of a complex containing a compound of formula (I) and a radioactive isotope, wherein the administered doses may be the same or different. In some embodiments, in the case of administering multiple doses, a second and any subsequent dose is higher than the original dose. In some embodiments, multiple doses are administered until the cumulative radiation dose delivered to the kidneys of the subject reaches about 23 Gy. In some embodiments, multiple doses are administered until the cumulative radiation dose delivered to the submandibular gland of the subject reaches about 24 Gy and does not exceed 28 Gy.

[0094] 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.

[0095] The method disclosed herein involves administering a radioactive isotope that emits ionizing radiation. Since the kidneys are responsible for blood filtration, the kidneys of subjects who have been administered a preparation containing a compound of formula (I) and a radioactive isotope are at risk of absorbing unwanted radiation due to the active reabsorption and retention of the radiolabeled compound of formula (I). Nephrotoxicity can be prevented by co-administering a cationic amino acid that competitively inhibits the reabsorption of the compound of formula (I), and thus inhibits the reabsorption of the radioactive isotope. In some embodiments, the method of the first aspect further includes administering a preparation containing one or more amino acids or salts thereof. In some embodiments, the one or more amino acids are in cationic form. In some embodiments, the preparation containing one or more amino acids contains lysine or a salt thereof. In other embodiments, the preparation containing one or more amino acids contains arginine or a salt thereof. In a preferred embodiment, the method includes administering a preparation containing lysine and arginine or a salt thereof.

[0096] In another aspect, the present invention provides a method similar to... 67 Use of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of aqueous formulations for the treatment of neuroendocrine carcinomas:

[0097]

[0098] Formula (I),

[0099] The radiation dose delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0100] On another front, the present invention provides a... 67 Use of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of aqueous formulations for the treatment of neuroblastoma:

[0101]

[0102] Formula (I),

[0103] The radiation dose delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with the neuroblastoma.

[0104] On the other hand, the present invention provides a therapeutically effective amount of... 67 Use in the preparation of a medicament for the treatment of neuroendocrine carcinoma by a Cu radioisotope complex of formula (I) or a pharmaceutically acceptable salt thereof:

[0105]

[0106] Formula (I)

[0107] The administration of the drug is not associated with any adverse event classified as Grade 3 or higher.

[0108] In other embodiments, the administration of the drug is not associated with any adverse event classified as Grade 2 or higher.

[0109] In other embodiments, the administration of the drug is not related to any adverse event classified as Grade 1 or higher.

[0110] On the other hand, the present invention also provides a therapeutically effective amount of... 67 Use in the preparation of a Cu radioisotope-encapsulated compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of neuroblastoma:

[0111]

[0112] Formula (I)

[0113] The administration of the drug is not associated with any adverse event classified as Grade 3 or higher.

[0114] In other embodiments, the administration of the drug is not associated with any adverse event classified as Grade 2 or higher.

[0115] In other embodiments, the administration of the drug is not related to any adverse event classified as Grade 1 or higher.

[0116] In another aspect, the present invention provides a therapeutically effective amount of... 67 Use in the preparation of a medicament for the treatment of neuroendocrine tumors by a Cu radioisotope complex of formula (I) or a pharmaceutically acceptable salt thereof:

[0117]

[0118] Formula (I)

[0119] The radiation dose mentioned therein is not related to any dose-limiting toxicity in the subjects.

[0120] In other embodiments, the administration of the drug is not associated with any adverse event classified as Grade 3 or higher.

[0121] In other embodiments, the administration of the drug is not associated with any adverse event classified as Grade 2 or higher.

[0122] In other embodiments, the administration of the drug is not related to any adverse event classified as Grade 1 or higher.

[0123] In some implementation schemes, by 67 The radiation dose delivered by the Cu radioisotope is approximately 75 MBq / kg, approximately 175 MBq / kg, approximately 275 MBq / kg, approximately 375 MBq / kg, or approximately 475 MBq / kg.

[0124] On the other hand, the present invention provides a similar 67 Use of Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof for the treatment of neuroendocrine carcinomas.

[0125] On the other hand, the neuroendocrine carcinoma is a neuroendocrine tumor. In some embodiments, the neuroendocrine tumor is a pediatric neuroendocrine tumor.

[0126] In a preferred embodiment, the neuroendocrine tumor is a neuroblastoma. In some embodiments, the subject is less than 10 years old, less than 5 years old, or less than 1 year old. In some embodiments, the neuroblastoma is a high-risk neuroblastoma. In some embodiments, the neuroblastoma is a high-risk neuroblastoma that does not respond to prior chemotherapy, radiation therapy, and / or surgery. In other embodiments, the subject is less than about 30 years old, less than about 25 years old, less than about 20 years old, or less than about 15 years old.

[0127] In another embodiment, the neuroendocrine tumor is a meningioma. In another embodiment, the neuroendocrine tumor is a gastrointestinal tumor. In another embodiment, the neuroendocrine tumor is a pancreatic tumor. In another embodiment, the neuroendocrine tumor is a lung tumor. In another embodiment, the neuroendocrine tumor is a gastric tumor. In another embodiment, the neuroendocrine tumor is Merkel cell carcinoma. In another embodiment, the neuroendocrine tumor is neurofibromatosis. Brief description of the attached diagram

[0129] Figure 1 The patient was given (A) 123 I-MIBG and imaging via SPECT followed by treatment in (B) of the same patient. 64 The image after Cu-Sartate was applied and then imaged via PET. 64 Images obtained via PET imaging after Cu-Sartate administration are compared to those obtained after application. 123 Images obtained via SPECT after I-MIBG showed better resolution. Furthermore, images obtained via PET / 64 The images obtained using Cu-Sartate can determine the location via SPECT / 123No other lesions were observed during I-MIBG imaging.

[0130] Detailed Explanation

[0131] Throughout this specification and the following claims, unless the context otherwise requires, the words “comprise” and variations thereof (such as “comprises” and “comprising”) shall be understood to mean including the said integer or step or group of integers or steps, but not excluding any other integer or step or group of integers or steps.

[0132] As used herein, the terms “about” or “approximately” mean within an acceptable margin of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0133] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. For the purposes of this invention, the following terms are defined below.

[0134] The compound of formula (I) contains an octreotate ligand and sarcophagine and is capable of targeting the somatostatin receptor, specifically the type 2 (SSTR2) receptor. This compound may be referred to as "MeCOSar" or "SARTATE" and contains a macrocyclic sarcophagine fragment (i.e., 5-[[8-amino-3,6,10,13,16,19-hexaazabicyclo-[6.6.6]eicosano-1-yl)amino]-5-oxo-pentyl) and an octreotate fragment (i.e., D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH). The compound of formula (I) has the following structure:

[0135]

[0136] Formula (I).

[0137] The compound of formula (I) contains multiple stereocenters. The invention also considers all stereoisomers of the compound and its salts, such as enantiomers and diastereomers.

[0138] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound identified above, and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of formula (I) can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic 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 can be selected from aliphatic, cyclic aliphatic, 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, alkyl sulfonic acids, and aryl sulfonic acids. Pharmaceutically acceptable salts also include those in which the main compound acts 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 also understand that acid addition salts can be prepared by reacting the compound with a suitable inorganic or organic acid using any of a variety of known methods. Alternatively, alkali metal and alkaline earth metal salts can be prepared by reacting the compound with a suitable base using a variety of known methods. The following are additional examples of acid salts that can be obtained by reacting with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, digluconate, cyclopentanepropionate, dodecyl sulfates, ethanesulfonates, glucono-heptate, glycerophosphates, hemisulfates, heptahydrates, fumarates, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrates, neopentanoate, propionate, succinates, tartrates, thiocyanates, toluenesulfonate, mesylate, and undecanoate. Further information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA 1995. When the pharmaceutical preparation is in the form of a solid, those skilled in the art will understand that the compounds, pharmaceutical preparations, and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified chemical formulas.

[0139] Injectable formulations comprise pharmaceutically acceptable sterile aqueous solutions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media 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. Formulations may also contain excipients such as preservatives, wetting agents, emulsifiers, and dispersants. By including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolic sorbic acid, etc., protection against microbial action can be ensured. It is also desirable to include isotonic agents such as sugars, sodium chloride, etc. Extended absorption of the injectable drug form can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable formulations can be sterilized, for example by filtration through a bacterial trap or by incorporation into a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media just before use. Pharmaceutical formulations may also contain pH control agents. Examples of suitable pH control agents include hydrochloric acid, sodium hydroxide, etc. The determination of preferred pH ranges (where appropriate) and suitable excipients is routine practice in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRCPress).

[0140] The formulations disclosed herein may be provided in pharmaceutically acceptable carriers or diluents. As those skilled in the art will understand, the choice of a pharmaceutically acceptable carrier or diluent will depend on the route of administration, the nature of the condition to be treated, and the subject. Those skilled in the art can readily determine the specific carrier or diluent and the route of administration. Careful selection of the carrier or diluent and the route of administration is necessary to ensure the efficacy of the compound of formula (I) and... 67 The complex of the Cu radioisotope remains intact both before and after application.

[0141] Suitable pharmaceutical forms for injectable applications include sterile injectable solutions or dispersions, as well as sterile powders for preparing sterile injectable solutions. Such forms should be stable under preparation and storage conditions and can be preserved free from reduction, oxidation, and microbial contamination. For injection, the compositions of the present invention can be formulated in an aqueous solution, appropriately in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0142] For the purpose of imaging or treating neuroendocrine carcinoma, the compound of formula (I) is combined with... 64 Cu or 67Cu radioisotope complexation. The inventors of this invention have discovered that the sarcophagine fragment of formula (I) has a strong affinity for copper isotopes and can complex with radioisotopes and remain for a sufficient period of time for imaging and therapeutic purposes, even after administration to the subject. 67 The half-life of the radioactive isotope Cu is approximately 60 hours and undergoes beta decay, making it suitable for local radiotherapy. Because... 67 The decay of radioactive Cu isotopes is accompanied by gamma radiation, which can therefore be monitored and imaged using single-photon emission computed tomography (SPECT). 67 Treatment of the subject with a Cu-complexed compound of formula (I). In one embodiment, by administration of a compound of formula (I) with Cu. 67 Methods of treating subjects with Cu-complexed compounds of formula (I) include monitoring and / or imaging single-photon emission computed tomography (SPECT). Other imaging techniques, such as MRI and CT, may also be used during treatment. In a preferred embodiment, the method of treatment includes using... 64 Radioactive Cu isotopes are imaged using SPECT and / or CT. Because 64 Radioactive isotopes of Cu have a half-life of approximately 12 hours and undergo β decay with positron emission, therefore they are similar to... 64 Compounds of formula (I) complexed with Cu are suitable for use as radiographic imaging agents. The inventors of this invention have discovered that... 64 The half-life of Cu, along with the binding affinity of the octreotate fragment to SSTR2, means that the application of radiolabeled compounds can be used for radiographic imaging. Because... 64 Cu decays through positron emission, thus radiographic imaging via positron emission tomography (PET) allows for the localization of radiolabeled compounds of formula (I) in the subject to be imaged, and subsequently the identification of neuroendocrine tumor sites.

[0143] For therapeutic purposes, based on the subject's weight and by administration with... 64 The quality of the image obtained by radiographic imaging after complexing a Cu radioisotope with a compound of formula (I) can be determined by the amount of Cu radioisotope involved. 67 The radiation dose administered and delivered to the subject using a Cu radioisotope. In some implementations, a similar radiation dose is used... 64 To simulate the corresponding Cu radioisotope complex with radiolabeled compounds of formula (I). 67 Distribution of Cu radioisotope complexes of compounds of formula (I).

[0144] The units of radioactivity listed herein are given in gray (Gy) or becquerel (Bq). It should be understood that radiation dose can be converted from one unit to another using known conversion factors, and can also be expressed in other units of radioactivity not explicitly listed herein.

[0145] In some embodiments, the radiation dose to be administered to the subject is approximately 75 MBq / kg, approximately 100 MBq / kg, approximately 125 MBq / kg, approximately 150 MBq / kg, approximately 175 MBq / kg, approximately 200 MBq / kg, approximately 225 MBq / kg, approximately 250 MBq / kg, approximately 275 MBq / kg, approximately 300 MBq / kg, approximately 325 MBq / kg, approximately 350 MBq / kg, approximately 375 MBq / kg, approximately 400 MBq / kg, approximately 425 MBq / kg, approximately 450 MBq / kg, or approximately 475 MBq / kg. In some embodiments, the radiation dose to be administered to the subject is approximately 75 MBq / kg, approximately 175 MBq / kg, approximately 275 MBq / kg, approximately 375 MBq / kg, or approximately 475 MBq / kg. In some embodiments, the radiation dose is determined by... 64 Cu radioisotope delivery. In other embodiments, the radiation dose is delivered by... 67 Cu radioisotope delivery.

[0146] As used herein, the terms “treating,” “treatment,” “preventing,” “prevention,” and their grammatical equivalents refer to any and all uses of correcting the aforementioned neuroendocrine tumors, preventing, delaying, or postponing the onset of the disease, or otherwise preventing, hindering, delaying, or reversing the progression of the disease. Therefore, the terms “treating” and “preventing,” etc., should be considered in their broadest context. For example, treatment does not necessarily mean treating the patient until complete recovery. In cases where the disease presents with multiple symptoms or is characterized by multiple symptoms, treatment or prevention does not necessarily require correcting, preventing, hindering, delaying, or reversing all of the stated symptoms, but may prevent, hinder, delay, or reverse one or more of the stated symptoms.

[0147] As used herein, the term "subject" refers to a mammal and includes humans, primates, livestock (e.g., sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), performance and exhibition animals (e.g., horses, livestock, dogs, cats), companion animals (e.g., dogs, cats), and captive wild animals. Preferably, the mammal is a human or a laboratory test animal. Even more preferably, the mammal is a human.

[0148] As used herein, the term "cancer" broadly encompasses a neoplastic disease characterized by abnormal cell growth that has the potential to invade or spread to other parts of the body. Cancer can be benign, meaning it does not spread to other parts of the body. Cancer can be malignant, meaning that cancer cells can spread through the circulatory or lymphatic system. As used herein, the term includes all malignant (i.e., cancerous) disease states. Cancer can manifest as a tumor.

[0149] As used herein, the term "neuroendocrine carcinoma" refers to cancer of the body's neuroendocrine system, which is responsible for producing, storing, and secreting peptides and hormones. Neuroendocrine carcinomas typically present as tumors and are usually located in the gastrointestinal or respiratory system, but they can also be found in other sites, such as the adrenal glands, nervous system, and skin. Specific sites of neuroendocrine tumors include the large intestine and appendix, small intestine, pancreas, stomach, and lungs. In some embodiments, the neuroendocrine carcinoma presents as a tumor. In some embodiments, the neuroendocrine carcinoma is a tumor in the patient's large intestine. In other embodiments, the neuroendocrine carcinoma is a tumor in the patient's appendix. In other embodiments, the neuroendocrine carcinoma is a tumor in the patient's small intestine. In other embodiments, the neuroendocrine carcinoma is a tumor in the patient's pancreas. In other embodiments, the neuroendocrine carcinoma is a tumor in the patient's stomach. In other embodiments, the neuroendocrine carcinoma is a tumor in the patient's lungs.

[0150] As used herein, the term neuroblastoma refers to a neuroendocrine carcinoma in which cancer forms in the early neural tissue (i.e., neuroblasts) of the sympathetic nervous system. Neuroblastomas can be present in any location within the sympathetic nervous system, including the adrenal glands, neck, chest, and spinal cord. In some embodiments, the neuroblastoma originates in the patient's adrenal glands. In other embodiments, the neuroblastoma originates in neck tissue. In other embodiments, the neuroblastoma originates in chest tissue. In other embodiments, the neuroblastoma originates in spinal cord tissue.

[0151] As used herein, the term "child" or "children" refers to a subject under the age of 18. In one embodiment, the child may be an adolescent, for example, aged from about 13 to about 18 years. In another embodiment, the child may be a toddler, for example, aged from about 1 to about 3 years. In yet another embodiment, the child may be an infant, for example, aged less than 1 year. In some embodiments, the subject is a child and is 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less than 1 year old.

[0152] The term "therapeutic effective dose" or "effective dose" is a dose sufficient to produce a beneficial or desired clinical outcome. An effective dose may be administered once or multiple times. For radiographic imaging purposes, an effective dose is sufficient to enable images to show the location of the compound of formula (I) administered to the subject, due to the detection of decay products from a radioactive isotope complexed with said compound. For therapeutic purposes, an effective dose is generally sufficient to alleviate, improve, stabilize, reverse, slow, and / or delay the progression of neuroendocrine carcinoma.

[0153] Furthermore, treatment regimens will typically include multiple radiation therapy cycles, which will continue until such a time has passed, for example, when the condition has improved. Again, the optimal number of cycles and the interval between each treatment cycle will depend on many factors, such as the subject's height and weight, the severity of the condition being treated, the subject's health condition (or lack thereof), and their previous response to radiation therapy and / or radioimaging.

[0154] The formulations for the treatment of neuroendocrine tumors as defined in this specification can be administered parenterally, with intravenous administration being preferred. In one embodiment, an aqueous formulation comprising a radiolabeled compound of formula (I) is administered intravenously by rapid bolus or slow infusion. In one embodiment, the formulation is used... 67 The Cu radioisotope-labeled compound of formula (I) is administered intravenously via slow infusion.

[0155] Aqueous formulations containing the compound of formula (I) may be formulations containing sodium chloride. In some embodiments, the formulation comprises an aqueous saline solution. In some embodiments, the aqueous saline solution contains about 0.9% sodium chloride. In some embodiments, the aqueous formulation comprises a buffer solution. In some embodiments, the buffer solution contains phosphate ions. In some embodiments, the buffer solution comprises sodium phosphate. In some embodiments, the buffer solution is a sodium phosphate buffer solution with a concentration of about 0.1 M.

[0156] Aqueous formulations containing compounds of formula (I) may contain other excipients. In some embodiments, the formulation contains an antioxidant. In other embodiments, the formulation contains one or more antioxidants. In some embodiments, the formulation contains gentianic acid or a salt thereof. In some embodiments, the formulation contains gentianic acid or sodium gentioate as a sodium salt. In some embodiments, the formulation contains gentianic acid at a concentration of about 0.056% w / v. In other embodiments, the formulation contains gentianic acid at a concentration not exceeding about 0.72 mg / ml. In other embodiments, the formulation contains ascorbic acid or a salt thereof. In some embodiments, the formulation contains ascorbic acid or sodium ascorbate as a sodium salt. In some embodiments, the formulation contains ascorbic acid at a concentration not exceeding about 50 mg / ml. In some embodiments, the formulation contains ethanol. In some embodiments, the formulation contains ethanol at a concentration of about 10% v / v.

[0157] In some embodiments, the aqueous formulation administered as part of a method for treating neuroendocrine carcinoma or neuroblastoma comprises a compound of formula (I) complexed with the radioisotope 67Cu or a pharmaceutically acceptable salt thereof, a sodium phosphate buffer solution, gentianic acid or a salt thereof, and ascorbic acid or a salt thereof. In some embodiments, the aqueous formulation further comprises a saline solution.

[0158] In some embodiments, the aqueous formulation administered as part of a method for treating neuroendocrine carcinoma or neuroblastoma comprises a compound of formula (I) complexed with a 67Cu radioisotope or a pharmaceutically acceptable salt thereof, a sodium phosphate buffer solution, gentianic acid or a salt thereof, ascorbic acid or a salt thereof, and a saline solution.

[0159] In some embodiments, the aqueous formulation administered as part of a method for treating neuroendocrine carcinoma or neuroblastoma comprises a compound of formula (I) complexed with a 67Cu radioisotope or a pharmaceutically acceptable salt thereof, a sodium phosphate buffer solution of about 0.1 M concentration, gentian acid or a salt thereof in an amount not exceeding about 0.72 mg / ml, ascorbic acid or a salt thereof in an amount not exceeding about 50 mg / ml, and saline solution.

[0160] In some embodiments, the aqueous formulation applied as part of a method for radiographic imaging of neuroendocrine carcinoma or neuroblastoma comprises a compound of formula (I) complexed with the radioisotope 67Cu or a pharmaceutically acceptable salt thereof, ethanol, and gentianic acid or a salt thereof. In some embodiments, the aqueous formulation further comprises a saline solution.

[0161] In some embodiments, the aqueous formulation applied as part of a method for radioimaging neuroendocrine carcinoma or neuroblastoma comprises a compound of formula (I) complexed with a 67Cu radioisotope or a pharmaceutically acceptable salt thereof, ethanol, gentianic acid or a salt thereof, and a saline solution thereof.

[0162] In some embodiments, the aqueous formulation applied as part of a method for radioimaging neuroendocrine carcinoma or neuroblastoma comprises a compound of formula (I) complexed with a 67Cu radioisotope or a pharmaceutically acceptable salt thereof, an amount of ethanol of about 10% v / v, an amount of gentian acid or a salt thereof of no more than about 0.056% w / v, and saline solution.

[0163] It should be understood that the specific dose of the radiolabeled compound of formula (I) for any particular subject will depend on a variety of factors, including, for example, the age, weight, and indication of the individual to be treated, the timing of administration, the excretion rate, and the combination with any other treatments or therapies. Single or multiple administrations may be performed, with the dose level and mode chosen by the treating physician. A wide dose range can be applied. Dosing regimens can be adjusted to provide the optimal therapeutic response. For example, a given dose delivering a certain amount of radiation can be calculated as a portion of the total radiation to be delivered to the subject. Dosing regimens may include administering multiple doses of the radiolabeled compound of formula (I), wherein the doses may be the same or different. In some embodiments, the method of treating neuroendocrine carcinoma includes administering with… 67 Multiple doses of a Cu-complexed compound of formula (I) are administered, wherein the applied radiation doses are identical. In other embodiments, the method includes administering multiple doses, wherein a second and subsequent radiation dose is higher than the first dose administered to the subject.

[0164] In some embodiments, the method includes administering two doses of the aqueous formulation described herein. In some embodiments, the method includes administering three doses of the aqueous formulation described herein. In some embodiments, the method includes administering four doses of the aqueous formulation described herein. In some embodiments, the method includes administering five doses of the aqueous formulation described herein. In some embodiments, the method includes administering six doses of the aqueous formulation described herein. In some embodiments, the method includes administering seven or more doses of the aqueous formulation described herein.

[0165] The method disclosed herein, involving the application of a radiolabeled complex of a compound of formula (I) for radioimaging, allows for the diagnosis of neuroendocrine carcinoma in a subject. Combined with a treatment method involving the application of a compound of formula (I) with a different isotope, the method disclosed herein represents a theranostic approach to the treatment of neuroendocrine carcinoma, i.e., a treatment and diagnostic approach. This is because the application of a compound of formula (I) complexed with a suitable radioisotope is used for the purpose of radioimaging the subject, while the application of a compound of formula (I) complexed with a suitable radioisotope is used for radioimaging the subject, while the application of a compound of formula (I) complexed with a different radioisotope is used for radioimaging the subject. 67 Compounds of the same formula (I) complexed with Cu allow for the treatment of subjects. Radiographic imaging allows visualization of the accumulation sites of compounds of formula (I), which then correspond to treatment sites. Not wishing to be bound by theory, the inventors of this invention believe that the methods and uses disclosed herein allow for more effective treatment of neuroendocrine carcinomas. The use of compounds of formula (I) or pharmaceutically acceptable salts thereof with… 67 The combination of Cu radioisotopes allows for the delivery of higher doses of radioactivity in a single dose. Because compounds of formula (I) are specific to SSTR2 and retain the copper radioisotope for a longer period (compared to other metal chelators), the radioactivity is delivered and localized more efficiently to the cancer site. Compounds of formula (I) also exhibit better clearance from critical organs. This, in turn, reduces any off-target effects of the radioisotope and limits unwanted damage to healthy tissue due to dissociation and subsequent circulation of the radioisotope. The better clearance and retention of the radiolabeled compounds of formula (I) at the targeted cancer site results in higher-contrast imaging, and subsequently, more reliable diagnostic images. The ability to deliver a more sustained dose of radiation by administering compounds of formula (I) complexed with a copper radioisotope also leads to more efficient treatment overall, as smaller amounts of both the compound of formula (I) and the radioisotope are required. This results in better tolerability and adherence to treatment protocols when the necessary radiation is delivered in smaller doses.

[0166] The method of the present invention relates to treating neuroendocrine carcinoma in a subject with this need. In one embodiment, the neuroendocrine carcinoma is neuroblastoma. In one embodiment, the neuroblastoma is pediatric neuroblastoma. In some embodiments, the subject has received prior treatment with surgery and / or chemotherapy. In some embodiments, the subject requires additional therapy, such as induction chemotherapy, surgery, radiation therapy (different from the methods disclosed herein), high-dose chemotherapy with autologous stem cell salvage and / or biological and immunotherapies for maintenance therapy.

[0167] The treatment methods disclosed herein are for treating neuroendocrine carcinoma in a subject. In some embodiments, the neuroendocrine carcinoma is a tumor. In some embodiments, the neuroendocrine carcinoma is located in the gastrointestinal system, respiratory system, nervous system, or skin. In a preferred embodiment, the neuroendocrine carcinoma is located in the nervous system. In other embodiments, the neuroendocrine tumor is a meningioma. In another embodiment, the neuroendocrine tumor is a gastrointestinal tumor. In another embodiment, the neuroendocrine tumor is a pancreatic tumor. In another embodiment, the neuroendocrine tumor is a lung tumor. In another embodiment, the neuroendocrine tumor is a gastric tumor. In another embodiment, the neuroendocrine tumor is Merkel cell carcinoma. In another embodiment, the neuroendocrine tumor is neurofibromatosis.

[0168] In one embodiment, the neuroendocrine carcinoma is a neuroblastoma. In another embodiment, the neuroblastoma is a pediatric neuroblastoma. In some embodiments, the neuroblastoma is located in the early neural tissue of the sympathetic nervous system. In some embodiments, the neuroblastoma is located in the adrenal glands, neck, chest, and spinal cord.

[0169] In a preferred embodiment, the neuroendocrine tumor is a neuroblastoma. In some embodiments, the subject is less than 10 years old, less than 5 years old, or less than 1 year old. In some embodiments, the neuroblastoma is a high-risk neuroblastoma. In some embodiments, the neuroblastoma is a high-risk neuroblastoma that does not respond to prior chemotherapy, radiation therapy, and / or surgery.

[0170] It should be understood that the specific dose of the radiolabeled compound of formula (I) for any particular subject will depend on a variety of factors, including, for example, the age, weight, and indication of the individual to be treated, the time of administration, the excretion rate, and the combination with any other treatments or therapies. In a preferred embodiment, the subject is a human.

[0171] In some embodiments, the subject is an infant. As used herein, the term "infant" refers to a subject aged from about 1 day to about 12 months. In some embodiments, the subject is an infant aged about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, or about 3 months.

[0172] In other embodiments, the subject is a child. As used herein, the term "child" means a subject aged from about 1 year to about 10 years. In some embodiments, the subject is a child at least 1 year old. In some embodiments, the subject is a child aged from 1 year to about 10 years. In other embodiments, the subject is about 10 years old, about 9 years old, about 8 years old, about 7 years old, about 6 years old, about 5 years old, about 4 years old, about 3 years old, about 2 years old, about 1 year old, or less than 1 year old.

[0173] In other embodiments, the subject is an adolescent. As used herein, the term "adolescent" means a subject aged approximately 10 to approximately 19 years. In other embodiments, the subject is an adolescent aged approximately 10 to approximately 19 years. In other embodiments, the subject is approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, or approximately 19 years old.

[0174] In some embodiments, the subject is an adult. As used herein, the term "adult" means a subject who is over approximately 19 years of age. In some embodiments, the subject is an adult with neuroblastoma, wherein the adult has an early diagnosis of neuroblastoma.

[0175] In some embodiments, the subject has a weight of about 5 kg, about 6 kg, about 7 kg, about 8 kg, about 9 kg, about 10 kg, about 11 kg, about 12 kg, about 13 kg, about 14 kg, about 15 kg, about 16 kg, about 18 kg, about 20 kg, about 22 kg, about 24 kg, about 26 kg, about 28 kg, about 30 kg, about 35 kg, about 40 kg, about 45 kg, about 50 kg, about 55 kg, about 60 kg, about 65 kg, about 70 kg, about 75 kg, about 80 kg, about 85 kg, about 90 kg, about 95 kg, about 100 kg, about 105 kg, about 110 kg, about 115 kg, or about 120 kg.

[0176] It can be administered in a single or multiple doses, with the dose level and mode selected by the treating physician. A wide dose range is applicable. The dosing regimen can be adjusted to provide an optimal therapeutic response. For example, a given dose delivering a certain amount of radiation can be calculated as a portion of the total radiation to be delivered to the subject. The dosing regimen may include administering multiple doses of a radiolabeled compound of formula (I), wherein the doses are the same or different. In some embodiments, a method for treating neuroendocrine carcinoma includes administering multiple doses of a compound of formula (I) complexed with a copper radioisotope, wherein the doses are the same. In other embodiments, the method includes administering multiple doses, wherein a second and subsequent dose is higher than the first dose administered to the subject. In some embodiments, by administering with... 64 Compounds of formula (I) complexed with the Cu radioisotope are used to determine the dosage to be administered for therapeutic or therapeutic purposes by pre-treatment radioimaging of the subject, in order to locate the cancer site, estimate the amount of compound retained by the subject (and the amount of radioactivity subsequently delivered), and assess the nature of the cancer site. The inventors of this invention believe that the use of compounds of formula (I) or pharmaceutically acceptable salts thereof for both radioimaging and radiotherapy represents a therapeutic approach to neuroendocrine carcinoma. Not wishing to be bound by theory, the inventors of this invention believe that the use of compounds that can be used in a therapeutic manner provides a more targeted approach to cancer treatment.

[0177] The method disclosed herein, combined with a method for radioimaging neuroendocrine carcinomas in which a compound of formula (I) with different isotopes is administered, represents a therapeutic approach to treating such cancers, namely a treatment and diagnostic approach. This is because the administration of the compound of formula (I) can also complex with a radioactive isotope that allows for radioimaging of the subject, while the administration of the compound with… 67The Cu-chelated compound of formula (I) allows for the treatment of subjects. Radiographic imaging allows visualization of the accumulation site of the compound of formula (I), which then corresponds to the treatment site. Not wishing to be bound by theory, the inventors of this invention believe that the methods and uses disclosed herein allow for more effective treatment of neuroendocrine carcinomas. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a copper radioisotope allows for the delivery of higher doses of radioactivity in a single dose. Because the compound of formula (I) is specific to neuroendocrine carcinomas and retains the copper radioisotope for a longer period (compared to other metal chelators), the radioactivity is delivered and localized more effectively to the cancer site. The compound of formula (I) also exhibits better clearance from critical organs. This, in turn, reduces any off-target effects of the radioisotope and limits undesirable damage to healthy tissue due to the dissociation and subsequent circulation of the radioisotope. The better clearance and retention of the radiolabeled compound of formula (I) at the targeted cancer site results in higher contrast images and subsequently more reliable diagnostic images. The ability to deliver a more sustained dose of radiation by applying a compound of formula (I) complexed with a copper radioisotope also results in more efficient treatment overall, as smaller amounts of the compound of formula (I) and the radioisotope are required. This leads to better treatment tolerance in subjects when the necessary radiation is delivered in smaller doses.

[0178] The methods of the present invention also contemplate combination therapy, wherein a radiolabeled compound of formula (I) as described herein is co-administered with other suitable agents that may promote the desired therapeutic or preventative outcome. The term "co-administered" 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 "concurrent" means administration of more than one formulation, wherein the formulations are administered simultaneously to the subject. The term "simultaneously" means that the active agents are administered substantially simultaneously. The term "sequential" administration refers to a time difference of seconds, minutes, hours, or days between the administration of the agents. Administration can be in any order.

[0179] Because the methods disclosed herein involve the administration of a radioactive isotope emitting ionizing radiation, co-administration of one or more amino acids with an aqueous formulation containing a radiolabeled compound of formula (I) as disclosed herein can prevent or limit nephrotoxicity caused by radiopharmaceutical retention. Co-administration of one or more amino acids to a subject undergoing treatment for neuroendocrine carcinoma competitively inhibits the reabsorption of the radiolabeled compound of formula (I) by the proximal tubules of the kidney. The inventors of the present invention believe that limiting the reabsorption of the radiolabeled compound of formula (I) and thus reducing nephrotoxicity in the subject allows for the administration of higher doses of the compound and thus improves treatment efficacy. The methods for treating neuroendocrine carcinoma disclosed herein also include administering one or more amino acids or salts thereof to a subject. In one embodiment, a formulation containing one or more amino acids or salts thereof is co-administered with an aqueous formulation containing a radiolabeled compound of formula (I) as disclosed herein. 67 An aqueous formulation of a compound of formula (I) complexed with a Cu radioisotope is administered co-administered. In one embodiment, the one or more amino acids comprise lysine or a salt thereof. In another embodiment, the one or more amino acids comprise arginine or a salt thereof. In a preferred embodiment, the method for treating neuroendocrine carcinoma further comprises administering lysine and / or arginine or a salt thereof. In a preferred embodiment, the method for treating neuroendocrine carcinoma further comprises administering lysine and arginine or a salt thereof. In a preferred embodiment, the method for treating neuroendocrine carcinoma further comprises co-administering lysine and arginine or a salt thereof and with... 67 A compound of formula (I) complexed with a Cu radioisotope. In some embodiments, the one or more amino acids or salts thereof are administered by intravenous infusion. In some embodiments, the formulation containing one or more amino acids comprises L-lysine or a salt thereof. In other embodiments, the formulation containing one or more amino acids comprises L-arginine or a salt thereof. In some embodiments, the one or more amino acids are present as hydrochloride salts. In some embodiments, each of the one or more amino acids is present at a concentration of about 2.5% w / v.

[0180] In one embodiment, the method for treating neuroendocrine carcinoma includes administering a therapeutically effective dose of [a specific drug / method] to a subject in need. 67 An aqueous formulation of a Cu-complexed compound of formula (I) or a pharmaceutically acceptable salt thereof, and an aqueous formulation of one or more amino acids. In a preferred embodiment, concurrent administration of a compound comprising... 67 A Cu-complexed radiolabeled compound of formula (I) and one or more amino acids. In another preferred embodiment, it is administered with... 67 Before administering a Cu-complexed compound of formula (I), the subject is given a formulation containing one or more amino acids.

[0181] As used herein, the term "amino acid" refers to a molecule containing both amino and carboxyl functional groups. The amino acid may be natural or non-natural and may be in equilibrium with its zwitterionic form. The amino acid may have modifications at its amino and / or carboxyl terminus, or may contain free amino or carboxyl groups. Further modifications to the side chains of the amino acid or additional substitutions at other parts of the amino acid are also considered.

[0182] In some embodiments, the amino acids 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), tryptophan (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).

[0183] 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 and... 67 Compounds of formula (I) that are Cu-complexed are administered in parallel or before them.

[0184] As used herein, the classification of adverse events related to the methods disclosed herein is based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 published by the National Cancer Institute (NCI). CTCAE is the descriptive terminology used in the field for reporting adverse events (AEs). Each AE term is classified using a grading (or severity) scale. According to the definition provided in CTCAE, “An adverse event (AE) is any unfavorable and unexpected sign (including abnormal laboratory findings), symptom, or illness that is temporally located in relation to the use of a medical treatment or procedure and may be considered related to or none "Closed". Previous CTCAE versions can also be used, but the following reproduces the broader description of the level from the latest version (v5.0):

[0185]

[0186] Activities of Daily Living (ADL) Instrumental ADLs include preparing meals, buying groceries or clothes, using the telephone, and managing money. Self-care ADLs refer to bathing, dressing and undressing, eating by oneself, using the toilet, taking medication, and not being bedridden.

[0187] As used herein, for example, a Grade 2 AE is referred to as an event having the severity described in the table above. Those skilled in the art will understand that an AE is initially determined according to the Systemic Organ Classification (SOC) as described in CTCAE v5.0, and then subsequently graded according to the table above.

[0188] In some embodiments of the methods disclosed herein, the subject does not experience any adverse events classified as Grade 3 or higher, as defined in CTCAE.

[0189] In some embodiments of the methods disclosed herein, the subject does not experience any adverse events classified as Grade 2 or higher, as defined in CTCAE.

[0190] In other implementations, the subject does not experience any adverse events classified as Grade 1 or higher, as defined in CTCAE.

[0191] In other implementations, the subject does not experience any adverse events classified as Grade 1 or 2, as defined in CTCAE.

[0192] In other implementations, the subject does not experience any adverse events classified as Grade 1, 2, or 3, as defined in CTCAE.

[0193] References to any prior publications (or information obtained from them) or any known matters in this specification are not and should not be construed as an acknowledgment or endorsement or any implication that such prior publications (or information obtained from them) or known matters constitute part of the general knowledge of the technical field to which this specification pertains.

[0194] Those skilled in the art will understand that the invention described herein can be varied and modified in addition to those specifically described. It should be understood that the invention includes all such variations and modifications falling within its spirit and scope. The invention also includes all steps, features, compositions, and compounds individually or collectively mentioned or indicated in this specification, as well as any combination and all combinations of any two or more of said steps or features.

[0195] Example

[0196] The following examples illustrate the present disclosure and should not be construed as limiting the general nature of the disclosure described throughout this specification in any way.

[0197] Example 1 - 67 Dosage selection of Cu-SARTATE (Formula I)

[0198] During the dose escalation phase of the study, patients received 67 Cu-SARTATE is administered as a single dose. The dosage levels used in the escalation phases are 75 MBq / kg, 175 MBq / kg, 275 MBq / kg, and 375 MBq / kg.

[0199] From the patient cohort receiving 75 MBq / kg and the patient cohort receiving 175 MBq / kg (all patients have received...) 67 Preliminary data from a single treatment cycle of Cu-SARTATE show that no dose-limiting toxicities (DLTs) have been reported to date. These results indicate that... 67 CU-SARTATE administration was well tolerated, suggesting that higher doses of at least 275 MBq / kg may be used.

[0200] The PET and SPECT imaging components of the trial in three subjects with meningiomas [ 64 The mean radiation dosimetric estimate of Cu-SARTATE (see Cu-SARTATE) J . Nucl . Med (2022) Bailey et al.) show this in Table 1. The highest organ dose per MBq was in the spleen, followed by the kidneys, liver, adrenal glands, and small intestine. This is for [ 64 Cu]Cu-SARTATE and [ 67 The Cu-SARTATE values ​​are consistent. This data can then be extrapolated to estimate the percentage of children with […]. 64 Cu]Cu-SARTATE and [ 67 Dosimetry of Cu]Cu-SARTATE.

[0201] Table 1. In patients with meningioma [ 64 Cu]Cu-SARTATE and [ 67 Average radiation dosimetric estimate of Cu]Cu-SARTATE

[0202]

[0203] Once the dose escalation phase is complete and acceptable safety and tolerability characteristics have been established, two doses can be administered to patients in the cohort expansion phase. 67Cu-SARTATE treatment cycles. In peptide receptor radionuclide therapy (PRRT), greater cumulative administered activity leads to a higher absorbed radiation dose to the tumor, and this has been shown to be correlated with efficacy. This has been demonstrated in... 67 In preclinical studies of Cu-SARTATE, repeated administration was observed to result in longer survival than a single administration.

[0204] The dose-limiting organs in PRRT are typically the kidneys and bone marrow. The kidneys are at risk due to the active reabsorption and retention of the radiopharmaceutical. To reduce nephrotoxicity, co-administration of positively charged amino acids is often performed, which competitively inhibit the reabsorption of radiopharmaceuticals by the proximal tubules. Co-injection of a mixture of basic amino acids such as lysine and arginine has been shown to reduce renal uptake of the radiopharmaceutical by approximately 33%, allowing for the administration of higher therapeutic doses. The dose-limiting total radiation to the kidneys (derived from external beam radiotherapy (EBRT)) can be exemplified as 23 Gy, or more conservatively as 18 Gy.

[0205] To avoid nephrotoxicity, 67 The modeled cumulative administered activity of Cu-SARTATE will not exceed 23 Gy for the kidneys. If the planned cumulative administered activity over the entire treatment cycle exceeds this modeling limit, adjustments can be made to reduce it. 67 The activity of the second and subsequent administrations of Cu-SARTATE was determined to ensure that the modeling renal radiation dose would not exceed a total of 23 Gy. The maximum permissible cumulative administered activity based on body weight was calculated for each participant, with example doses depicted in Table 2.

[0206] The proposed 23 Gy renal radiation dose limit will not take into account radiation exposure to the kidneys from previous radiopharmaceutical treatments. Based on the requirements of this protocol, previous radiation therapy may only involve… 131 I-MIBG treatment and / or EBRT were excluded because participants treated with PRRT were excluded. 131 The dosage level administered during I-MIBG treatment can vary depending on the institution's protocol, ranging from 37 to 666 MBq / kg. It has been reported that in high-risk refractory or recurrent neuroblastoma patients, [the following is a separate, unrelated sentence:] [The ... 131 The renal uptake dose after I-MIBG treatment was 0.164 mGy / MBq, which is considered relatively low compared to SSTR-targeted radiopharmaceuticals. 131 During I-MIBG treatment, the primary target organs with the highest radiation dose are the liver, lungs, and bone marrow, and most of the major adverse effects are hematologic.

[0207] Similarly, other previous studies did not consider any prior radiation therapy that might affect kidney function, but simply ensured that all patients had adequate kidney function before entering the trial.

[0208] However, in order to mitigate the potential risk of cumulative nephrotoxicity, previous [measures were taken]. 131 Participants who have received I-MIBG treatment (within 12 months of treatment) or EBRT on the kidneys (at any time) will need to have a higher estimated glomerular filtration rate (eGFR) than participants who have not received these treatments. Furthermore, participants who have undergone EBRT affecting both kidneys or a single functional kidney within the past 12 months will be excluded. Therefore, it is important to ensure that only participants with good renal functional reserve following prior radiation therapy are excluded.

[0209] Example 2 - 64 Dosimetry of Cu-SARTATE

[0210] Determined using methods used to establish radiation dose 64 Radiation dosimetry of Cu-Sartate.

[0211] i) During injection 64 Acquired at 1, 4, 12, 24 and / or 48 hours after Cu-SARTATE 64 Cu-SARTATE PET / CT scans were used to determine:

[0212] a. Absorbed dose (mGy / MBq) and effective dose (mSv / MBq) from organs derived from 64Cu-SARTATE

[0213] b. From 67 Modeled absorbed dose of Cu-SARTATE in organs (mGy / MBq)

[0214] c. Not exceeding the tolerance limits of specific organs (23 Gy for kidneys, 2 Gy for bone marrow). 67 Modeling of Cu-SARTATE to estimate total cumulative applied activity (GBq)

[0215] ii) If there is still a sufficient residual activity level in the subject, additional follow-up scans can be performed.

[0216] Example 3 - 67 Dosimetry of Cu-SARTATE

[0217] The method used to establish radiation dose can be used to determine 67 Radiation dosimetry of Cu-Sartate.

[0218] i) During injection67 Acquired 1, 4, 12, 24 and / or 48 hours after Cu-SARTATE 67 Cu-SARTATE SPECT / CT scan (further follow-up scans if sufficient residual activity levels remain in the participant) to determine:

[0219] a. from 67 Organ-absorbed dose (mGy / MBq) and effective dose (mSv / MBq) of Cu-SARTATE

[0220] b. From 67 Modeled absorbed dose of Cu-SARTATE in organs (mGy / MBq)

[0221] c. Not exceeding the tolerance limits of specific organs (23 Gy for kidneys, 2 Gy for bone marrow). 67 Modeling of Cu-SARTATE to estimate total cumulative applied activity (GBq)

[0222] ii) If there is still a sufficient residual activity level in the subject, further follow-up scans may be performed.

[0223] Example 4 - Calculation 67 Maximum dose of Cu-SARTATE

[0224] It can be administered within the renal limit of no more than 23 Gy. 67 The maximum dose of Cu-SARTATE is based on the patient's weight. Based on the maximum dose to the kidneys, it can then be calculated. 67 The maximum cumulative dose of Cu-SARTATE is shown in Table 2. It can also be calculated based on a renal upper limit of 30 Gy according to the patient's weight. 67 The maximum cumulative dose of Cu-SARTATE can also be calculated based on the upper limit of the kidney.

[0225] Table 2. 67 Cu-SARTATE maximum cumulative dose based on body weight

[0226]

Claims

1. A method for treating neuroendocrine carcinoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof. Formula (I) Optionally, the aqueous formulation is applied once, twice, or three times in the same or lower amount of the compound of formula (I); The bone marrow of the subject was delivered thereto. 67 The total dose of Cu radiation was less than about 2 Gy, and the total dose of radiation delivered to the kidneys of the subject was less than about 30 Gy.

2. A method for treating neuroendocrine carcinoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof. Formula (I) The radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

3. A method for treating neuroendocrine carcinoma in a patient requiring such treatment, the method comprising: 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof: Formula (I).

4. A method for treating neuroblastoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof. Formula (I) Optionally, the aqueous formulation is applied once, twice, or three times in the same or lower amount of the compound of formula (I); The bone marrow of the subject was delivered thereto. 67 The total dose of Cu radiation was less than about 2 Gy, and the total dose of radiation delivered to the kidneys of the subject was less than about 30 Gy.

5. A method for treating neuroblastoma, the method comprising administering to a subject in need a therapeutically effective dose of [the drug / method / etc.] 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof. Formula (I) The radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the neuroblastoma.

6. A method for treating neuroendocrine carcinoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof: Formula (I) The subjects in question did not experience any adverse events classified as Grade 3 or higher.

7. A method for treating neuroblastoma, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / treatment]. 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof: Formula (I) The subjects in question did not experience any adverse events classified as Grade 3 or higher.

8. The method of claim 6 or 7, wherein the subject does not experience any adverse events classified as grade 2 or higher.

9. The method of claim 6 or 7, wherein the subject does not experience any adverse events classified as Grade 1 or higher.

10. The method of claim 6 or 7, wherein the subject does not experience any adverse events classified as Grade 1, Grade 2 or Grade 3.

11. A method for treating neuroendocrine tumors, the method comprising administering to a subject in need a therapeutically effective dose of [a specific drug / method / etc.] 67 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof: Formula (I) The radiation dose was not related to any dose-limiting toxicity in the subjects.

12. The method of claim 11, wherein the subject does not experience any adverse events classified as grade 3 or higher.

13. The method of claim 11, wherein the subject does not experience any adverse events classified as grade 2 or higher.

14. The method of claim 11, wherein the subject does not experience any adverse events classified as Grade 1 or higher.

15. A method for treating neuroblastoma in a patient requiring such treatment, the method comprising: 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof: Formula (I).

16. A method for treating neuroendocrine carcinoma in a patient requiring such treatment, the method comprising: 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof: Formula (I), and 2) Repeat treatment cycles 1) once, twice, or three times at the same or lower dose as in formula (I) such that the total dose delivered to the patient based on the patient’s weight does not exceed 30 Gy for renal limitation.

17. A method for treating neuroblastoma in a patient requiring such treatment, the method comprising: 1) Optionally administer an amino acid infusion to the patient, followed by an IV infusion of approximately 75 MBq / kg to approximately 475 MBq / kg of a therapeutically effective dose. 67 Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof: Formula (I), and 2) Repeat treatment cycles 1) once, twice, or three times at the same or lower dose as in formula (I) such that the total dose delivered to the patient based on the patient’s weight does not exceed 30 Gy for renal limitation.

18. The method according to any one of claims 1 to 17, wherein the method is derived by the... 67 The radiation dose delivered to the subjects by the Cu radioisotope was approximately 75 MBq / kg, approximately 175 MBq / kg, approximately 275 MBq / kg, approximately 375 MBq / kg, or approximately 475 MBq / kg.

19. The method according to any one of claims 1 to 18, wherein multiple doses of the formulation as defined in any one of claims 1 to 5 are administered, wherein the doses are the same or different.

20. The method according to any one of claims 1 to 11, wherein the method further comprises applying an aqueous formulation containing one or more amino acids or their salts.

21. The method of claim 20, wherein the amino acid comprises lysine and / or arginine or a salt thereof.

22. The method according to any one of claims 1 to 3, wherein the neuroendocrine carcinoma is a neuroendocrine tumor.

23. The method according to any one of claims 4 to 6, wherein the neuroblastoma is a pediatric neuroblastoma.

24. The method according to any one of claims 1 to 23, wherein it can be achieved by using with between treatment cycles. 64 The effectiveness of the treatment method is evaluated by PET or SPECT using a Cu radioisotope complex of formula (I) or a pharmaceutically acceptable salt thereof. 64 The radiation dose delivered by Cu is approximately 2 MBq / kg.

25. The method according to any one of claims 1 to 23, wherein the method further comprises radiographic imaging of the subject by PET and / or CT, preferably using a diagnostically effective dose of... 64 A Cu radioisotope complex of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

26. A method for radiographic imaging of neuroendocrine carcinoma, the method comprising administering to a subject in need of such imaging a radiographic image of a neuroendocrine carcinoma. 64 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof: Formula (I) The radiation dose delivered by the radioactive isotope is approximately 2 MBq / kg.

27. A method for radiographic imaging of neuroblastoma, the method comprising administering to a subject in need of such imaging and... 64 Aqueous preparations of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof: Formula (I) The radiation dose delivered by the radioactive isotope is approximately 2 MBq / kg.

28. The method according to any one of claims 1 to 27, wherein the subject is an infant.

29. The method of claim 28, wherein the subject is an infant aged about 3 months to about 12 months.

30. The method according to any one of claims 1 to 27, wherein the subject is a child.

31. The method of claim 30, wherein the subject is a child aged from about 1 year to about 10 years.

32. The method according to any one of claims 1 to 27, wherein the subject is an adolescent.

33. The method of claim 32, wherein the subject is an adolescent aged about 10 to about 19 years.

34. The method according to any one of claims 1 to 27, wherein the subject is an adult.

35. The method according to any one of claims 1 to 34, wherein the aqueous formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises gentianic acid or a salt thereof.

36. The method according to any one of claims 1 to 34, wherein the aqueous formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises ascorbic acid or a salt thereof.

37. The method according to any one of claims 1 to 34, wherein the aqueous formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises gentianic acid or a salt thereof and ascorbic acid or a salt thereof.

38. The method according to any one of claims 1 to 37, wherein the aqueous formulation of the compound comprising formula (I) or a pharmaceutically acceptable salt thereof further comprises ethanol.

39. The method according to any one of claims 1 to 38, wherein the aqueous formulation of the compound comprising formula (I) or a pharmaceutically acceptable salt thereof further comprises a saline solution.

40. with 67 Use of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of aqueous formulations for the treatment of neuroendocrine carcinomas: Formula (I), The radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

41. with 67 Use of Cu radioisotope-encapsulated compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of aqueous formulations for the treatment of neuroblastoma: Formula (I), The radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the neuroblastoma.

42. The effective therapeutic dose and 67 Use in the preparation of a medicament for the treatment of neuroendocrine carcinoma by a Cu radioisotope complex of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) The administration of the drug is not associated with any adverse event classified as Grade 3 or higher.

43. The effective therapeutic dose and 67 Use in the preparation of a Cu radioisotope-encapsulated compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of neuroblastoma: Formula (I) The administration of the drug is not associated with any adverse event classified as Grade 3 or higher.

44. The use according to claim 42 or 43, wherein the administration of said drug is not related to any adverse event classified as Grade 2 or above.

45. The use according to claim 42 or 43, wherein the administration of said drug is not related to any adverse event classified as Grade 1 or above.

46. ​​The effective therapeutic dose and 67 Use in the preparation of a medicament for the treatment of neuroendocrine tumors by a Cu radioisotope complex of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) The radiation dose was not related to any dose-limiting toxicity in the subjects.

47. The use according to claim 46, wherein the administration of said drug is not related to any adverse event classified as Grade 3 or above.

48. The use according to claim 46, wherein the administration of the drug is unrelated to any adverse event classified as Grade 2 or higher.

49. The use according to claim 46, wherein the administration of the drug is unrelated to any adverse event classified as Grade 1 or higher.

50. The use according to claim 46, wherein the administration of the drug is unrelated to any adverse event classified as Grade 1, Grade 2 or Grade 3.

51. The use according to any one of claims 40 to 50, wherein the drug further comprises gentianic acid or a salt thereof.

52. The use according to any one of claims 40 to 50, wherein the drug further comprises ascorbic acid or a salt thereof.

53. The use according to any one of claims 40 to 50, wherein the drug further comprises gentianic acid or a salt thereof and ascorbic acid or a salt thereof.

54. with 67 Use of Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof for the treatment of neuroendocrine carcinomas.

55. The use according to claim 54, wherein the neuroendocrine carcinoma is a neuroendocrine tumor.

56. with 67 Use of Cu radioisotope complexes of formula (I) or pharmaceutically acceptable salts thereof for the treatment of neuroblastoma.

Images