Diagnostic and / or treatment methods for neuroendocrine carcinoma

Abstract

The present invention provides for delivering targeted radiation doses for the diagnosis and treatment of neuroendocrine cancers, particularly neuroblastoma in children. 64 Cu / 67 The present invention relates to a diagnostic method and / or radiotherapy comprising administering a compound of formula (I) that has formed a complex with a Cu radioisotope.

Description

[Technical Field]

[0001] The present invention is for delivering a targeted dose of radiation for imaging and / or treatment of neuroendocrine cancers, particularly neuroblastoma in children. 64 Cu / 67 The present invention relates to a radioimaging method and / or radiotherapy, comprising administering a specific compound that has formed a complex with a Cu radioisotope. [Background technology]

[0002] The neuroendocrine system is responsible for the production, storage, and secretion of peptides and hormones. Neuroendocrine cancers often manifest as tumors, typically occurring in the gastrointestinal tract and respiratory system, but can also occur in other parts of the body, such as the adrenal glands, nervous system, and skin. Common sites for neuroendocrine tumors include the large intestine, appendix, small intestine, pancreas, stomach, and lungs.

[0003] Neuroblastoma is a neuroendocrine cancer that develops in the early nerve tissue (neuroblasts) of the sympathetic nervous system and can occur 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 mortality. Given the complexity and diversity of neuroblastoma, many factors influence the outcome. For example, whether the cancer regresses spontaneously 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.

[0004] The diagnosis of neuroendocrine cancer is usually made using a combination of tests, including biopsy, blood tests, endoscopy, ultrasound, X-ray, CT scans, MRI scans, and nuclear medicine imaging such as PET scans. Tests such as biopsy enable a definitive diagnosis, but this first requires identifying the location of the cancer. Other tests, such as PET scans, allow for a simultaneous evaluation of the entire subject to determine the presence of cancer. Nuclear medicine imaging requires the administration of an appropriate radiotracer that binds to the cancer site. For successful imaging, the administered drug must selectively bind to the cancer site, retain and deliver the radioisotope to the cancer site, persist for a sufficient duration to obtain a high-quality image, and cause little to no side effects to the subject. Cancer treatment is typically associated with various side effects and adverse events related to the treatment method. These adverse events may be severe enough to limit or prematurely discontinue the prescribed course of treatment, or they may have detrimental effects on the patient.

[0005] Patients are classified into three categories: low-risk, intermediate-risk, and high-risk. Generally, low-risk patients show excellent event-free survival and overall survival (OS) with observation alone or minimal therapeutic intervention. Outcomes for intermediate-risk patients, who are mainly treated with surgery and chemotherapy, have improved, and many research groups are focusing on using biological markers to further reduce the treatment burden on this group of children.

[0006] Patients with high-risk neuroblastoma account for approximately half of all new cases each year. This group requires multidisciplinary treatment to improve survival rates, including induction chemotherapy, surgery, radiotherapy, high-dose chemotherapy with autologous stem cell transplantation, and maintenance therapy with biological agents and immunotherapy. However, even with such aggressive treatment strategies, a significant number of patients experience relapses and ultimately die from the disease.

[0007] Although the pathological understanding of neuroblastoma has advanced in recent years, there is no established radical treatment for high-risk refractory or recurrent neuroblastoma patients. Recurrent neuroblastoma patients often develop metastatic tumors resistant to standard treatments, and the treatment goal is often not cure but rather extension of survival and control of symptoms. The 1-year and 4-year overall survival rates remain only 57% and 20% respectively. To improve the outcomes of these patients, new treatment strategies are needed. By replacing 131 I in 123 I with 131 I, radiopharmaceuticals suitable for the treatment of neuroblastoma and other neuroendocrine tumors become possible. However, the use of 131 I-MIBG for neuroblastoma is still at the experimental stage and is currently only used in clinical trials. Furthermore, 131 I-MIBG therapy is a very complex and logistically difficult process due to the long half-life of 131 I (8 days).

Summary of the Invention

Problems to be Solved by the Invention

[0010] The diagnostic methods for neuroendocrine carcinoma or neuroblastoma disclosed herein are based on the current standard of care model, i.e. 123 It is more effective compared to I-MIBG administration followed by imaging studies. In the current standard model, 123 Imaging after I-MIBG administration is performed by SPECT, but the resulting images are typically of low resolution, which can limit the physician's ability to make a clinical diagnosis and determine the patient's treatment plan. According to the method disclosed herein, the inventors, 64 We believe that administering Cu-Sartate followed by PET imaging will allow for more efficient and accurate patient evaluation, thus enabling the diagnosis of neuroendocrine carcinoma and neuroblastoma. 64 Images obtained by PET after Cu-Sartate administration have high resolution (see Figure 1) and high specificity, making it easier to identify the nature and location of the target tumor and providing a clearer diagnosis for the subject.

[0011] The inventors have also discovered that by administering a compound of formula (I) that has formed a complex with a copper radionuclide, high doses of radiation can be delivered to the target site while simultaneously suppressing off-target effects of the radiation. Thus, undesirable damage to healthy tissue and associated side effects are minimized. While not wishing to be bound by theory, the inventors have found that the radiolabeled complex of the compound of formula (I) exhibits higher specificity for the somatostatin receptor and better retains the radioisotope. 67 We believe that forming complexes with Cu will improve the treatment of neuroendocrine cancers. This will facilitate targeting to the cancer site and reduce leakage and loss of radioisotopes. Because the radioactivity is localized to the cancer site, adverse events such as off-target radiation effects and damage to healthy tissue are reduced. In addition to reducing radiation-related adverse events, we believe that the method disclosed herein also reduces adverse events that are generally classified according to known and accepted criteria in the art for adverse event reporting. By reducing off-target radiation damage and minimizing adverse events, the quality of treatment for patients will improve, patient comfort and compliance will increase, and as a result, treatment outcomes will improve.

[0012] The inventors also said, 67 It was also discovered that the compound of formula (I) that forms a complex with Cu has improved retention of radioisotopes, allowing for irradiation of the target with higher doses of radiation. According to the method disclosed herein, higher doses of radiation can be administered (and tolerated), 67 The treatment of neuroendocrine cancer with the compound of formula (I) that forms a complex with Cu is improved, resulting in increased survival rates for the patients.

[0013] The inventors also believe that the radiolabeled compound of formula (I) provides a diagnostic method for neuroendocrine cancer that can be used in combination with the therapies discussed herein. That is, one of the main advantages of the present invention is that the compound of formula (I) can be used for both the diagnosis and treatment of cancer simply by switching the Cu radioisotope species. When the compound of formula (I) is coordinated with 64Cu copper, this complex can be used in combination with PET and / or CT imaging to visualize the in vivo distribution and localization of the radiolabeled compound, thereby revealing the expression sites on the membrane and potentially cancerous sites. 64 Based on the information provided by imaging the localization of the Cu-labeled compound, an appropriate copper radioisotope, for example, 67 The compound of formula (I) coordinated with Cu can be used for therapeutic purposes because it binds to and localizes to the same site determined by imaging of the target. After administering the radiolabeled compound of formula (I) for therapeutic purposes, imaging of the target using SPECT, PET, and / or CT can be performed to confirm the localization of the radiolabeled compound and targeted therapy.

[0014] In one embodiment, the present invention provides a method for treating neuroendocrine cancer, the method comprising a therapeutically effective dose, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the radiation dose delivered by the radioactive isotope is sufficient to reduce the size of one or more cancer-related lesions.

[0015] In one embodiment, the present invention provides a method for treating neuroendocrine cancer, the method comprising a therapeutically effective dose, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the aqueous preparation is administered in the same amount or less of the compound of formula (I) one, two, or three more times as desired. Here, it is delivered to the target bone marrow. 67 The total dose of Cu radiation is less than approximately 2 Gy, and the total dose of radiation delivered to the target kidney is less than approximately 30 Gy.

[0016] In another embodiment, the present invention provides a method for treating neuroblastoma, the method comprising a therapeutically effective dose, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the dose of radiation delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with neuroblastoma.

[0017] In another embodiment, the present invention provides a method for treating neuroendocrine cancer, the method comprising a therapeutically effective dose, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. In this case, the subjects do not experience any adverse events classified as Grade 3 or higher.

[0018] In other embodiments, subjects do not experience any adverse events classified as Grade 2 or higher.

[0019] In other embodiments, subjects do not experience any adverse events classified as Grade 1 or higher.

[0020] In another embodiment, the present invention also provides a method for treating neuroblastoma, the method comprising a therapeutically effective dose, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. In this case, the subjects do not experience any adverse events classified as Grade 3 or higher.

[0021] In other embodiments, subjects do not experience any adverse events classified as Grade 2 or higher.

[0022] In other embodiments, subjects do not experience any adverse events classified as Grade 1 or higher.

[0023] In a further embodiment, the present invention provides a method for treating neuroendocrine tumors, the method comprising a therapeutically effective dose, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the radiation dose does not impose any dose-limiting toxicity on the subject.

[0024] In another embodiment, the present invention provides a method for treating neuroendocrine cancer in patients requiring treatment, the method comprising: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The compound or a pharmaceutically acceptable salt thereof is administered intravenously at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg.

[0025] In yet another embodiment, the present invention provides a method for treating neuroblastoma, wherein the method uses a therapeutically effective amount. 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the aqueous formulation is administered one, two, or three more times in the same or lower amount of the compound of formula (I). Here, it is delivered to the target bone marrow. 67 The total dose of Cu radiation is less than approximately 2 Gy, and the total dose of radiation delivered to the target kidney is less than approximately 30 Gy.

[0026] In another embodiment, the present invention provides a method for treating neuroblastoma in patients requiring treatment, the method comprising: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The compound or a pharmaceutically acceptable salt thereof is administered intravenously at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg.

[0027] In one embodiment, with respect to a second or third aspect, the method may further include the following steps: 2) Repeat treatment cycle 1) one, two, or three more times with the same or a lower amount of the compound of formula (I), such that the total amount of radiation delivered to the patient's kidneys does not exceed 30 Gy.

[0028] In a further embodiment, the present invention provides a method for treating neuroendocrine cancer in patients requiring treatment, the method comprising: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The compound or a pharmaceutically acceptable salt thereof is administered intravenously at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg, and 2) Repeat treatment cycle 1) one, two, or three more times with the same or a lower amount of the compound of formula (I), such that the total amount of radiation delivered to the patient's kidneys does not exceed 30 Gy.

[0029] In a further embodiment, the present invention provides a method for treating neuroblastoma in patients requiring treatment, the method comprising: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The compound or a pharmaceutically acceptable salt thereof is administered intravenously at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg, and 2) Repeat treatment cycle 1) one, two, or three more times with the same or a lower amount of the compound of formula (I), such that the total amount of radiation delivered to the patient's kidneys does not exceed 30 Gy.

[0030] In certain embodiments, the total amount of radiation delivered as a result of administration of the compound of formula (I) will not be such that, based on the patient's body weight, the amount of radiation delivered to the kidney exceeds approximately 30 Gy, approximately 29 Gy, approximately 28 Gy, approximately 27 Gy, approximately 26 Gy, approximately 25 Gy, approximately 24 Gy, or approximately 23 Gy.

[0031] In certain embodiments, the effectiveness of the treatment method can be evaluated by a diagnostic method disclosed herein, which is 64 This can be performed during a treatment cycle using a Cu radioisotope. Therefore, one of the advantages of the present invention is that 64 Cu radioactive isotopes 67 Simply switching to a Cu radioisotope allows the same compound of formula (I) to be used for both the diagnosis and treatment of tumors, and also enables tracking of the progression of the treatment regime.

[0032] In one embodiment, with respect to the above aspect, the neuroendocrine carcinoma is neuroblastoma. In one embodiment, with respect to the above aspect, the neuroendocrine carcinoma is high-risk neuroblastoma. In one embodiment, with respect to the above aspect, the neuroendocrine carcinoma is high-risk neuroblastoma in children. In one embodiment, with respect to the above aspect, the patient is a child, adolescent, or adult.

[0033] In some embodiments, 67 The radiation dose delivered by the Cu radioactive isotope 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, 67 The radiation dose delivered to a target by a Cu radioisotope is individually adjusted to suit the target. In certain embodiments, the radiation dose administered to the target is determined by pre-radiation imaging, which involves administering a compound of formula (I) that has formed a complex with an appropriate radioisotope to the target.

[0034] In one embodiment, the treatment method further includes monitoring of the subject by radiographic imaging using PET, SPECT, and / or CT. In some embodiments, the monitoring of the subject by radiographic imaging may be performed between treatment cycles.

[0035] In certain embodiments, the methods disclosed herein do not cause any adverse events classified as Grade 3 or higher according to CTCAE v5.0.

[0036] In other embodiments, the methods disclosed herein do not cause any adverse events classified as Grade 2 or higher according to CTCAE v5.0.

[0037] In other embodiments, the methods disclosed herein do not cause any adverse events classified as Grade 2 or higher according to CTCAE v5.0.

[0038] In a further embodiment, the present invention provides a method for radiographic imaging of neuroendocrine cancer, the method being 64 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the amount of radiation delivered by the radioactive isotope is approximately 2 MBq / kg.

[0039] In a further embodiment, the present invention provides a method for radiographic imaging of neuroblastoma, the method being 64 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the amount of radiation delivered by the radioactive isotope is approximately 2 MBq / kg.

[0040] Therefore, the present invention also relates to radiographic imaging of neuroendocrine cancers. 64 The present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof that forms a complex with a Cu radioisotope, preferably the total amount of radiation delivered to an adult patient by the radioisotope from one or more doses of the aqueous formulation being about 150 to about 250 MBq, or about 200 MBq.

[0041] While we do not wish to be bound by theory, the inventors believe that administering the formulations described herein multiple times for the treatment of neuroendocrine cancer increases the absorbed radiation dose at the cancer site and improves the therapeutic effect. This means that repeated administration of formulations containing the compound of formula (I) in complex with a radioisotope may improve the survival rate of the subject compared to a single administration of the formulations disclosed herein. A method of the first embodiment may include administering multiple aqueous formulations of a complex containing the compound of formula (I) and a radioisotope.

[0042] In one embodiment, the method includes administering two or more doses of the aqueous formulation described in the first embodiment in succession. In some embodiments, two doses of the aqueous formulation described in the first embodiment are administered. In other embodiments, three doses of the aqueous formulation described in the first embodiment are administered. In further embodiments, four doses of the aqueous formulation described in the first embodiment are administered. In other embodiments, more than four doses of the aqueous formulation described in the first embodiment are administered.

[0043] In some embodiments, the aqueous formulation is administered at intervals of approximately 1 to 16 weeks. In one embodiment, the aqueous formulation is administered at intervals of approximately 1 week. In some embodiments, the aqueous formulation is administered at intervals of approximately 1 to 12 weeks. In further embodiments, the aqueous formulation is administered at intervals of approximately 1 to 10 weeks. In some embodiments, the aqueous formulation is administered at intervals of approximately 1 to 8 weeks. In some embodiments, the aqueous formulation is administered at intervals of approximately 1 to 6 weeks. In some embodiments, the aqueous formulation is administered at intervals of approximately 1 to 4 weeks. In some embodiments, the aqueous formulation is administered at intervals of approximately 1 to 2 weeks. In some embodiments, the aqueous formulation is administered in succession at intervals of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or approximately 16 weeks. In one embodiment, the total dose of radiation delivered to the target bone marrow is less than approximately 2 Gy. In another embodiment, the total dose of radiation delivered to the target kidney is less than approximately 23-28 Gy. In yet another embodiment, the total dose of radiation delivered to the target submandibular gland is less than approximately 24 Gy.

[0044] The methods of the above embodiments may include multiple administrations of a complex containing the compound of formula (I) and a radioisotope, where the administered doses may be the same or different. In some embodiments, when multiple doses are administered, the doses from the second dose onward are higher than the initial dose. In some embodiments, multiple doses are administered until the cumulative dose of radiation delivered to the target kidney reaches approximately 23 Gy. In some embodiments, multiple doses are administered until the cumulative dose of radiation delivered to the target submandibular gland reaches approximately 24 Gy, but does not exceed 28 Gy.

[0045] 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.

[0046] The methods disclosed herein involve the administration of a radioisotope that emits ionizing radiation. Because the kidneys are responsible for blood filtration, the kidneys of a subject administered a formulation containing the compound of formula (I) and a radioisotope are at risk of absorbing unwanted radiation as a result of active reabsorption and retention of the radiolabeled compound of formula (I). Prevention of nephrotoxicity can be achieved by co-administration of a cationic amino acid that competitively inhibits the reabsorption of the compound of formula (I) and thus the radioisotope. In some embodiments, the method of the first embodiment further includes the administration of a formulation containing one or more amino acids, or salts thereof. In some embodiments, the one or more amino acids are cationic. In some embodiments, the formulation containing one or more amino acids contains lysine, or a salt thereof. In other embodiments, the formulation containing one or more amino acids contains arginine, or a salt thereof. In preferred embodiments, the method includes administering a formulation containing lysine and arginine, or salts thereof.

[0047] In a further embodiment, the present invention relates to the manufacture of an aqueous formulation for the treatment of neuroendocrine cancer, 67 Compound of formula (I) that forms a complex with a Cu radioisotope: [ka] Equation (I) or provide the use of a pharmaceutically acceptable salt thereof, Here, the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0048] In yet another aspect, the present invention relates to the manufacture of an aqueous formulation for the treatment of neuroblastoma, 67 Compound of formula (I) that forms a complex with a Cu radioisotope: [ka] Equation (I) or provide the use of a pharmaceutically acceptable salt thereof, Here, the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with neuroblastoma.

[0049] In another aspect, the present invention relates to the manufacture of a therapeutically effective amount of a drug for the treatment of neuroendocrine cancer. 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The use of the compound or a pharmaceutically acceptable salt thereof is provided. In this case, the administration of the drug was not accompanied by any adverse events classified as Grade 3 or higher.

[0050] In other embodiments, drug administration is not associated with any adverse events classified as Grade 2 or higher.

[0051] In other embodiments, drug administration is not associated with any adverse events classified as Grade 1 or higher.

[0052] In another aspect, the present invention relates to the manufacture of a therapeutic agent for neuroblastoma, which is therapeutically effective. 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The use of the compound or a pharmaceutically acceptable salt thereof is provided. In this case, the administration of the drug was not accompanied by any adverse events classified as Grade 3 or higher.

[0053] In other embodiments, drug administration is not associated with any adverse events classified as Grade 2 or higher.

[0054] In other embodiments, drug administration is not associated with any adverse events classified as Grade 1 or higher.

[0055] In a further embodiment, the present invention relates to the manufacture of a therapeutically effective amount of a drug for the treatment of neuroendocrine tumors, 67 Formula (I) shows the formation of a complex with a Cu radioisotope: [ka] Equation (I) The use of the compound or a pharmaceutically acceptable salt thereof is provided. Here, the radiation dose does not impose any dose-limiting toxicity on the subject.

[0056] In other embodiments, drug administration is not associated with any adverse events classified as Grade 3 or higher.

[0057] In other embodiments, drug administration is not associated with any adverse events classified as Grade 2 or higher.

[0058] In other embodiments, drug administration is not associated with any adverse events classified as Grade 1 or higher.

[0059] In some embodiments, 67 The radiation dose delivered by the Cu radioactive isotope is approximately 75 MBq / kg, 175 MBq / kg, 275 MBq / kg, 375 MBq / kg, or 475 MBq / kg.

[0060] In another embodiment, the present invention is for the treatment of neuroendocrine cancer, 67 This invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof that has formed a complex with a Cu radioisotope.

[0061] In another aspect, neuroendocrine carcinoma is a neuroendocrine tumor. In certain embodiments, the neuroendocrine tumor is a pediatric neuroendocrine tumor.

[0062] In preferred embodiments, the neuroendocrine tumor is neuroblastoma. In some embodiments, the subjects are under 10 years of age, under 5 years of age, or under 1 year of age. In some embodiments, the neuroblastoma is high-risk neuroblastoma. In some embodiments, the neuroblastoma is high-risk neuroblastoma that has not responded to prior chemotherapy, radiotherapy, and / or surgery. In other embodiments, the subjects are about under 30 years of age, about under 25 years of age, about under 20 years of age, or about under 15 years of age.

[0063] 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 explanation of the drawing]

[0064] [Figure 1] Images of a patient who underwent SPECT after administration of 123I-MIBG (A) and a patient who underwent PET after administration of 64Cu-Sartate (B). The PET images after 64Cu-Sartate administration show higher resolution compared to the SPECT images after 123I-MIBG administration. Furthermore, PET / 64Cu-Sartate images can identify lesions that were not observed with SPECT / 123I-MIBG imaging. [Modes for carrying out the invention]

[0065] Detailed description Throughout this specification and the subsequent claims, unless otherwise specified in the context, the word “comprise,” and variations such as “comprises” and “comprising,” shall be understood to mean including, but not excluding, any other integers or steps or groups of integers or steps.

[0066] As used herein, the terms “about” or “approximately” mean within a range of tolerance for a particular value as determined by those skilled in the art, which depends in part on the method by which the value is measured or determined, i.e., the limits of the measuring system.

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains. For the purposes of the present invention, the following terms are defined as follows:

[0068] The compound of formula (I) contains an octreotate ligand and a sarcophagin and can target somatostatin receptors, particularly type 2 (SSTR2) receptors. This compound is also called "MeCOSar" or "SARTATE" and contains a macrocyclic sarcophagin fragment (i.e., 5-[[8-amino-3,6,10,13,16,19-hexazabicyclo-[6.6.6]eico-1-yl)amino]-5-oxopentanyl) 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: [ka] Equation (I)

[0069] The compound of formula (I) contains multiple stereocenters. The present invention also encompasses all stereoisomers of this compound and its salts, such as enantiomers and diastereomers.

[0070] The term "pharmaceutically acceptable salt" refers to a salt of the above compound that retains the desired biological activity, and includes pharmaceutically acceptable acid addition salts and base addition salts. A suitable pharmaceutically acceptable acid addition salt of the compound of formula (I) can be prepared from an inorganic or organic acid. Examples of such inorganic acids include 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 the classes of aliphatic, alicyclic, aromatic, heterocyclic, carboxylic acid, and sulfonic acid, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Pharmaceutically acceptable salts include those in which the main compound functions as an acid and reacts with a suitable base to form, for example, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and choline salts. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid using any known method. Alternatively, alkali metal salts and alkaline earth metal salts can be prepared by reacting a compound with a suitable base using a variety of known methods. The following are further examples of salts obtained by reaction with inorganic or organic acids: acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivaphosphate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.Additional information regarding pharmaceutically acceptable salts is provided in Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA 1995. For solid pharmaceuticals, it will be understood by those skilled in the art that the compounds, pharmaceuticals, 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 specific formulas.

[0071] The injectable formulation contains a pharmaceutically acceptable sterile aqueous solution. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. The formulation may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by incorporating various antimicrobial and antifungal agents such as parabens, chlorobutanol, and phenolsorbic acid. The addition of isotonic agents such as sugars and sodium chloride may also be desirable. The absorption of the injectable formulation can be slowed by adding agents that delay absorption, such as aluminum monostearate or gelatin. The injectable formulation can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection medium immediately before use. The pharmaceutical formulation may further contain pH adjusters. Examples of suitable pH adjusters include hydrochloric acid and sodium hydroxide. Identifying preferred pH ranges (where appropriate) and suitable excipients is a routine practice in the art and is described, for example, in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press).

[0072] The formulations disclosed herein may be provided in pharmaceutically acceptable carriers or diluents. As will be understood by those skilled in the art, the choice of a pharmaceutically acceptable carrier or diluent depends on the route of administration, as well as the condition and nature of the target being treated. Specific carriers or diluents and routes of administration can be readily determined by those skilled in the art. The carrier or diluent and route of administration are used for the compound of formula (I) both before and after administration. 67 The choice should be made carefully to ensure that complexes with Cu radioisotopes are not damaged.

[0073] Suitable pharmaceutical forms for injection include sterile injection solutions or dispersions, as well as sterile powders for the preparation of sterile injection solutions. These forms should be stable under manufacturing and storage conditions and can be preserved against reduction, oxidation, and microbial contamination. For injection, the compositions of the present invention can be formulated in aqueous solutions, preferably physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.

[0074] For imaging or treatment of neuroendocrine carcinoma, the compound of formula (I) is used. 64 Cu or 67 It forms complexes with copper radioisotopes. The inventors have discovered that the sarcophagin fragment of formula (I) has a strong affinity for copper isotopes and can form and retain complexes with radioisotopes for a sufficient period of time for imaging and therapeutic purposes, even after administration to a subject. 67 The half-life of the Cu radioisotope is approximately 60 hours, and it undergoes beta decay, making it suitable for localized radiotherapy. 67 The decay of the radioactive isotope Cu is accompanied by gamma rays, 67 The treatment of subjects administered with the compound of formula (I) that forms a complex with Cu can be monitored and imaged by single-photon emission computed tomography (SPECT). In one embodiment, 67A method for treating a target requiring treatment by administering a compound of formula (I) that forms a complex with Cu includes monitoring and / or imaging by single-photon emission computed tomography. Other imaging techniques such as MRI and CT may also be used during treatment. In a preferred embodiment, the treatment method is 64 This includes imaging by SPECT and / or CT using Cu radioisotopes. 64 The radioactive isotope of Cu has a half-life of approximately 12 hours and undergoes beta decay accompanied by positron emission. 64 The compound of formula (I) that forms a complex with Cu is suitable for use as a radioimaging agent. The inventors of the present invention, 64 By combining the half-life of Cu with the binding affinity of the octreotate fragment to SSTR2, we found that the administration of a radiolabeled compound can be used for radiographic imaging. 64 Since Cu decays by positron emission, the location of the radiolabeled compound of formula (I) in the imaged area can be identified by radiographic imaging using positron emission tomography (PET), thereby identifying the site of neuroendocrine tumors.

[0075] For the purpose of treatment, 67 The amount of radiation administered and delivered to a subject by a Cu radioisotope is determined by the subject's body weight, 64 This can be determined based on both the quality of the image obtained by radiographic imaging after administration of the compound of formula (I) that has formed a complex with a Cu radioisotope. In some embodiments, 64 A radiolabeled compound of formula (I) that forms a complex with a Cu radioisotope is, 67 This is used to model the distribution of the corresponding compound of formula (I) that forms a complex with a Cu radioisotope.

[0076] The units of radioactivity used herein are expressed in gray (Gy) or becquerel (Bq). It will be understood that radiation doses can be converted from one unit to another using known conversion factors, and that other units of radioactivity not expressly stated herein may also be used.

[0077] In some embodiments, the radiation dose 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 certain embodiments, the radiation dose 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 certain embodiments, the radiation dose is 64 It is delivered by a Cu radioactive isotope. In other embodiments, the radiation dose is 67 It is delivered by a cu radioactive isotope.

[0078] As used herein, “treat,” “prevent,” “prevent,” and grammatically synonymous terms refer to any use of the terms “treat,” “cure,” “prevent,” and grammatically synonymous terms relating to treating the neuroendocrine tumors described herein, preventing, delaying, or slowing the onset of the disease, or preventing, inhibiting, delaying, or reversing the progression of the disease. Therefore, terms such as “treat” and “prevent” should be interpreted in the broadest context. For example, “treat” does not necessarily mean that the patient is treated until they are completely recovered. If a disease presents with or is characterized by multiple symptoms, treatment or prevention does not necessarily have to treat, prevent, inhibit, delay, or reverse all of these symptoms, but may prevent, inhibit, delay, or reverse one or more of them.

[0079] As used herein, the term “subject” refers to mammals and includes humans, primates, domesticated animals (e.g., sheep, pigs, cattle, horses, donkeys), laboratory animals (e.g., mice, rabbits, rats, guinea pigs), performance and show animals (e.g., horses, domesticated animals, dogs, cats), companion animals (e.g., dogs, cats), and wild animals in captivity. Preferably, the mammal is a human or a laboratory animal. More preferably, the mammal is a human.

[0080] In this specification, the term “cancer” broadly encompasses neoplastic diseases characterized by abnormal cell proliferation and the potential for invasion or metastasis to other parts of the body. Cancer may be benign, in which case it does not metastasize to other parts of the body. Cancer may be malignant, in which case cancer cells may metastasize via the circulatory or lymphatic system. The term used herein includes all malignant, i.e., cancerous disease conditions. Cancer may exist as a tumor.

[0081] In this specification, the term “neuroendocrine carcinoma” refers to cancer in which the neuroendocrine system is responsible for the production, storage, and secretion of peptides and hormones. Neuroendocrine carcinomas often present as tumors, typically occurring in the gastrointestinal or respiratory tract, but can also occur in other sites such as the adrenal glands, nervous system, and skin. Common sites of neuroendocrine tumors include the colon and appendix, small intestine, pancreas, stomach, and lungs. In certain embodiments, neuroendocrine carcinoma exists as a tumor. In certain embodiments, neuroendocrine carcinoma is a tumor in the patient’s colon. In other embodiments, neuroendocrine carcinoma is a tumor in the patient’s appendix. In other embodiments, neuroendocrine carcinoma is a tumor in the patient’s small intestine. In other embodiments, neuroendocrine carcinoma is a tumor in the patient’s pancreas. In other embodiments, neuroendocrine carcinoma is a tumor in the patient’s stomach. In other embodiments, neuroendocrine carcinoma is a tumor in the patient’s lungs.

[0082] In this specification, the term “neuroblastoma” refers to a neuroendocrine cancer that develops in the early nerve tissue (i.e., neuroblasts) of the sympathetic nervous system. Neuroblastomas can develop anywhere in the sympathetic nervous system, including the adrenal glands, neck, chest, and spinal cord. In certain embodiments, the neuroblastoma originates from the patient’s adrenal glands. In other embodiments, the neuroblastoma originates from the tissue of the neck. In other embodiments, the neuroblastoma originates from the tissue of the chest. In other embodiments, the neuroblastoma originates from the tissue of the spinal cord.

[0083] As used herein, the term “child(s)” refers to subjects under the age of 18. In one embodiment, a child is an adolescent, for example, between about 13 and about 18 years of age. In another embodiment, a child is a toddler, for example, between about 1 and about 3 years of age. In yet another embodiment, a child is an infant, for example, under 1 year of age. In a particular embodiment, the subject is a child, aged 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or under 1 year of age.

[0084] The term "therapeutic effective dose" or "effective dose" refers to a quantity sufficient to produce a beneficial or desirable clinical outcome. An effective dose may be administered in one or more doses. For radioimaging purposes, an effective dose is sufficient to obtain an image showing the localization of the compound of formula (I) administered to a subject by detecting decay products from radioisotopes complexed with the compound. For therapeutic purposes, an effective dose is usually sufficient to alleviate, improve, stabilize, recover, delay, and / or slow the progression of neuroendocrine carcinoma.

[0085] Furthermore, the treatment plan typically involves multiple cycles of radiation therapy, which are continued until symptoms improve. Again, the optimal number of cycles and the intervals between each treatment cycle depend on several factors, including the patient's height and weight, the severity of the symptoms being treated, the patient's health status (or lack thereof), and their past response to radiation therapy and / or radioimation.

[0086] Formulations for methods of treating neuroendocrine tumors as defined herein can be administered parenterally, and intravenous administration is preferred. In one embodiment, an aqueous formulation comprising the radiolabeled compound of formula (I) is administered intravenously by either a bolus or slow infusion. In one embodiment, 67 The compound of formula (I), radiolabeled with a Cu radioisotope, is administered intravenously by slow infusion.

[0087] The aqueous formulation containing the compound of formula (I) may also contain sodium chloride. In some embodiments, the formulation contains physiological saline. In certain embodiments, the physiological saline contains about 0.9% sodium chloride. In some embodiments, the aqueous formulation contains a buffer. In some embodiments, the buffer contains phosphate ions. In some embodiments, the buffer contains sodium phosphate. In some embodiments, the buffer is a sodium phosphate buffer at a concentration of about 0.1 M.

[0088] Aqueous formulations containing the compound of formula (I) may contain other excipients. In certain embodiments, the formulation contains an antioxidant. In other embodiments, the formulation contains one or more antioxidants. In some embodiments, the formulation contains gentisic acid or a salt thereof. In some embodiments, the formulation contains a sodium salt of gentisic acid or sodium gentisate. In certain embodiments, the formulation contains gentisic acid at a concentration of about 0.056% w / v. In other embodiments, the formulation contains gentisic acid at a concentration of about 0.72 mg / ml or less. In other embodiments, the formulation contains ascorbic acid or a salt thereof. In some embodiments, the formulation contains a sodium salt of ascorbic acid or sodium ascorbate. In some embodiments, the formulation contains ascorbic acid at a concentration of about 50 mg / ml or less. In some embodiments, the formulation contains ethanol. In some embodiments, the formulation contains ethanol at a concentration of about 10% v / v.

[0089] In certain embodiments, an aqueous formulation administered as part of a treatment method for neuroendocrine carcinoma or neuroblastoma is67 The formulation comprises a compound of formula (I) that forms a complex with a Cu radioisotope or a pharmaceutically acceptable salt thereof, sodium phosphate buffer, gentisic acid or a salt thereof, and ascorbic acid or a salt thereof. In certain embodiments, the aqueous formulation further comprises physiological saline.

[0090] In certain embodiments, an aqueous formulation administered as part of a treatment method for neuroendocrine carcinoma or neuroblastoma is 67 The solution comprises a compound of formula (I) that forms a complex with a Cu radioisotope, or a pharmaceutically acceptable salt thereof, sodium phosphate buffer, gentisic acid or a salt thereof, ascorbic acid or a salt thereof, and physiological saline.

[0091] In certain embodiments, an aqueous formulation administered as part of a treatment method for neuroendocrine carcinoma or neuroblastoma is 67 The solution contains a compound of formula (I) that forms a complex with a Cu radioisotope, or a pharmaceutically acceptable salt thereof, a sodium phosphate buffer solution of about 0.1 M, gentisic acid or a salt thereof in an amount of about 0.72 mg / ml or less, ascorbic acid or a salt thereof in an amount of about 50 mg / ml or less, and physiological saline.

[0092] In certain embodiments, an aqueous formulation administered as part of a radiographic imaging method for neuroendocrine carcinoma or neuroblastoma is 67 The formulation comprises a compound of formula (I) that forms a complex with a Cu radioisotope or a pharmaceutically acceptable salt thereof, ethanol, and gentisic acid or a salt thereof. In certain embodiments, the aqueous formulation further comprises physiological saline.

[0093] In certain embodiments, an aqueous formulation administered as part of a radiographic imaging method for neuroendocrine carcinoma or neuroblastoma is 67 This includes compounds of formula (I) that form complexes with Cu radioisotopes, or pharmaceutically acceptable salts thereof, ethanol, gentisic acid or salts thereof, and physiological saline.

[0094] In certain embodiments, an aqueous formulation administered as part of a radiographic imaging method for neuroendocrine carcinoma or neuroblastoma is67 The solution contains a compound of formula (I) that forms a complex with a Cu radioisotope, or a pharmaceutically acceptable salt thereof, about 10% v / v of ethanol, about 0.056% w / v or less of gentisic acid or a salt thereof, and physiological saline.

[0095] It will be understood that the specific dose of the radiolabeled compound of formula (I) for a particular target depends on various factors, such as the age, weight and indication of the individual being treated, the timing of administration, the rate of excretion, and concomitant use of other therapies. Single or multiple doses are possible, and the dose level and administration pattern are selected by the physician. A wide range of doses may be applicable. The administration regimen can be adjusted to obtain the optimal therapeutic response. For example, a predetermined dose that delivers a certain amount of radiation can be calculated as a percentage of the total radiation dose delivered to the target. The administration regimen may include multiple doses of the radiolabeled compound of formula (I), in which case the doses may be the same or different. In some embodiments, the treatment method for neuroendocrine carcinoma is 67 The method includes multiple administrations of the compound of formula (I) that forms a complex with Cu, in which case the dose of radiation administered is the same. In other embodiments, the method includes multiple administrations, in which case the dose of radiation from the second dose onward is higher than the dose of radiation administered to the subject.

[0096] In some embodiments, the method includes the administration of two doses of the aqueous formulation described herein. In some embodiments, the method includes the administration of three doses of the aqueous formulation described herein. In some embodiments, the method includes the administration of four doses of the aqueous formulation described herein. In some embodiments, the method includes the administration of five doses of the aqueous formulation described herein. In some embodiments, the method includes the administration of six doses of the aqueous formulation described herein. In some embodiments, the method includes the administration of seven or more doses of the aqueous formulation described herein.

[0097] The radioimaging method using radiolabeled complexes of the compound of formula (I) disclosed herein enables the diagnosis of neuroendocrine cancer in subjects. When combined with therapeutic methods involving the administration of compounds of formula (I) with different isotopes, the methods disclosed herein constitute a theranostic approach to the treatment of neuroendocrine cancer, i.e., a therapeutic and diagnostic approach. This allows for the treatment of subjects by administering compounds of formula (I) that have been complexed with appropriate radioisotopes for the purpose of radioimaging the subject, whereas instead 67 This is because the target can be treated by administering the same compound of formula (I) that forms a complex with Cu. Radiographic imaging allows visualization of the location where the compound of formula (I) accumulates, corresponding to the treatment site. While we do not wish to be constrained by theory, the inventors believe that the methods and uses disclosed herein will enable more effective treatment of neuroendocrine carcinomas. The compound of formula (I) or a pharmaceutically acceptable salt thereof 67 When used in combination with a copper radioisotope, a higher radioactivity dose can be delivered in a single dose. The compound of formula (I) is specific to SSTR2 and retains the copper radioisotope for a longer period (compared to other metal chelators), so the radioactivity is delivered to the cancer site and localized more efficiently. The compound of formula (I) also has good clearance from major organs. This reduces off-target effects of the radioisotope and suppresses unwanted damage to healthy tissue caused by the dissociation and subsequent circulation of the radioisotope. The improved clearance of the radiolabeled compound of formula (I) and its retention at the target cancer site results in high-contrast images, and consequently, improved reliability of diagnostic images. Administering the compound of formula (I) complexed with a copper radioisotope allows for the delivery of a more sustained radiation dose, reducing the amount of compound of formula (I) and radioisotope required, and improving overall therapeutic efficiency. Because the required radiation dose is delivered at a lower dose, tolerability is improved and adherence to the treatment plan is also improved.

[0098] The present invention relates to a method for the treatment of neuroendocrine carcinoma in subjects requiring treatment. In one embodiment, the neuroendocrine carcinoma is neuroblastoma. In one embodiment, the neuroblastoma is pediatric neuroblastoma. In some embodiments, the subjects are treated with surgery and / or chemotherapy. In some embodiments, the subjects require additional treatment, such as induction chemotherapy, surgery, radiotherapy (different from the method disclosed herein), high-dose chemotherapy with autologous stem cell salvage, and / or maintenance therapy with biological agents and immunotherapy.

[0099] The therapeutic methods disclosed herein are for the treatment of neuroendocrine carcinoma in a subject. In some embodiments, neuroendocrine carcinoma is a tumor. In some embodiments, neuroendocrine carcinoma is found in the digestive system, respiratory system, nervous system, or skin. In preferred embodiments, neuroendocrine carcinoma is found in the nervous system. In other embodiments, neuroendocrine tumor is a meningioma. In another embodiment, neuroendocrine tumor is a gastrointestinal tumor. In another embodiment, neuroendocrine tumor is a pancreatic tumor. In another embodiment, neuroendocrine tumor is a lung tumor. In another embodiment, neuroendocrine tumor is a gastric tumor. In another embodiment, neuroendocrine tumor is Merkel cell carcinoma. In another embodiment, neuroendocrine tumor is neurofibromatosis.

[0100] In one embodiment, neuroendocrine carcinoma is neuroblastoma. In another embodiment, neuroblastoma is pediatric neuroblastoma. In certain embodiments, neuroblastoma is found in the early nerve tissue of the sympathetic nervous system. In some embodiments, neuroblastoma is found in the adrenal glands, neck, chest, and spinal cord.

[0101] In preferred embodiments, the neuroendocrine tumor is neuroblastoma. In some embodiments, the subjects are under 10 years of age, under 5 years of age, or under 1 year of age. In some embodiments, the neuroblastoma is high-risk neuroblastoma. In some embodiments, the neuroblastoma is high-risk neuroblastoma that has not responded to prior chemotherapy, radiotherapy, and / or surgery.

[0102] It will be understood that the specific dose of the radiolabeled compound of formula (I) for a particular target depends on various factors, including, for example, the age, weight and indication of the individual being treated, the timing of administration, the rate of excretion, and concomitant use with other treatments or therapies. In a preferred embodiment, the target is a human.

[0103] In some embodiments, the subjects are infants. In this specification, the term “infant” refers to subjects aged approximately 1 to 12 months. In some embodiments, the subjects are infants aged approximately 12 months, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, or 3 months.

[0104] In other embodiments, the subjects are children. In this specification, the term “child” refers to subjects aged approximately 1 to approximately 10 years. In some embodiments, the subjects are children at least 1 year old. In some embodiments, the subjects are children aged 1 to approximately 10 years. In other embodiments, the subjects are approximately 10 years, approximately 9 years, approximately 8 years, approximately 7 years, approximately 6 years, approximately 5 years, approximately 4 years, approximately 3 years, approximately 2 years, approximately 1 year, or less than 1 year old.

[0105] In other embodiments, the subjects are young people. In this specification, the term “young people” refers to subjects who are about 10 to about 19 years of age. In other embodiments, the subjects are young people who are about 10 to about 19 years of age. In other embodiments, the subjects are about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, or about 19 years of age.

[0106] In some embodiments, the subjects are adults. In this specification, the term “adult” refers to subjects who are approximately 19 years of age or older. In certain embodiments, the subjects are adults with neuroblastoma who have been previously diagnosed with neuroblastoma.

[0107] In some embodiments, the subject's weight is approximately 5 kg, 6 kg, 7 kg, 8 kg, 9 kg, 10 kg, 11 kg, 12 kg, 13 kg, 14 kg, 15 kg, 16 kg, 18 kg, 20 kg, 22 kg, 24 kg, 26 kg, 28 kg, 30 kg, 35 kg, 40 kg, 45 kg, 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 105 kg, 110 kg, 115 kg, or 120 kg.

[0108] Single or multiple doses are possible at the dosage level and administration pattern selected by the attending physician. A wide range of dosages can be applied. The administration regimen can be adjusted to achieve the optimal therapeutic effect. For example, a predetermined dose that delivers a certain amount of radiation can be calculated as a percentage of the total radiation dose delivered to the subject. The administration regimen consists of multiple administrations of the radiolabeled compound of formula (I), with the doses being the same or different. In some embodiments, the treatment method for neuroendocrine carcinoma involves multiple administrations of the compound of formula (I) that has formed a complex with a copper radioisotope, with each dose being the same. In other embodiments, the method involves multiple administrations, where the second and subsequent doses are higher than the first dose administered to the subject. In some embodiments, the dose administered for therapeutic or therapeutic purposes is used to locate the cancer site, estimate the amount of compound retained in the subject (and subsequently the amount of radioactivity delivered), and assess the nature of the cancer site. 64 The outcome is determined by prior radioimaging of the subject by administering the compound of formula (I) in which a complex has been formed with a Cu radioisotope. The inventors believe that using the compound of formula (I) or a pharmaceutically acceptable salt thereof for both radioimaging and radiotherapy constitutes a theranostic approach to neuroendocrine carcinoma. While not wishing to be bound by theory, the inventors believe that the use of compounds that can be used in a theranostic manner provides a more customized approach to cancer treatment.

[0109] By combining the administration of compounds of formula (I) having different isotopes with a method for radioimaging neuroendocrine cancer, the method disclosed herein constitutes a theranostic approach, i.e., a therapeutic and diagnostic approach, to the treatment of such cancers. This is because the administration of compounds of formula (I), when combined with a radioimaging method of the target, can also form complexes with radioisotopes that enable such cancers, 67 This is because the target can be treated by administering the compound of formula (I) that forms a complex with Cu. Radiographic imaging allows visualization of the location where the compound of formula (I) accumulates, corresponding to the treatment site. While we do not wish to be constrained by theory, the inventors believe that the methods and uses disclosed herein will enable more effective treatment of neuroendocrine cancers. By using the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a copper radioisotope, it is possible to deliver a higher radioactivity dose in a single dose. The compound of formula (I) is specific to neuroendocrine cancers and retains the copper radioisotope for a longer period (compared to other metal chelating agents), so that the radioactivity is delivered to the cancer site and localized more efficiently. The compound of formula (I) also has good clearance from major organs. This reduces off-target effects of the radioisotope and suppresses undesirable damage to healthy tissue caused by the dissociation and subsequent circulation of the radioisotope. Improved clearance and retention of the radiolabeled compound of formula (I) in the target cancer site result in higher-contrast images, thus improving the reliability of diagnostic images. Combined administration of the compound of formula (I) with a copper radioisotope allows for the delivery of a more sustained radiation dose, reducing the amount of the compound of formula (I) and radioisotope required, and improving overall treatment efficiency. Because the required radiation dose is delivered with a lower dosage, the patient's tolerance to treatment is improved.

[0110] The methods of the present invention also envision combination therapies in which the radiolabeled compound of formula (I) described herein is used in combination with other suitable agents that can enhance the desired therapeutic or prophylactic outcome. The term “combination” means simultaneous administration of the same formulation or two different formulations via the same or different routes, or sequential administration via the same or different routes. The term “combination” means administration of multiple formulations, which are administered to the subject simultaneously. “Simultaneous” means that the active agents are administered substantially simultaneously. “Continuous” administration means that there is a time difference of several seconds, several minutes, several hours, or several days between the administrations of the agents. Administration can be carried out in any order.

[0111] Since the methods disclosed herein relate to the administration of radioisotopes that emit ionizing radiation, co-administration of an aqueous formulation containing the radiolabeled compound of formula (I) disclosed herein with one or more amino acids can prevent or suppress nephrotoxicity caused by the retention of the radiopharmaceutical. One or more amino acids co-administered to subjects receiving treatment for neuroendocrine cancer competitively inhibit the reabsorption of the radiolabeled compound of formula (I) by the proximal tubules of the kidney. The inventors believe that by limiting the reuptake of the radiolabeled compound of formula (I) and thereby reducing nephrotoxicity in the subject, it becomes possible to administer higher doses of the compound, resulting in improved therapeutic efficiency. The methods for treating neuroendocrine cancer disclosed herein further include administering one or more amino acids or salts thereof to the subject. In one embodiment, the formulation containing one or more amino acids or salts thereof is 67It is administered in combination with an aqueous formulation containing a compound of formula (I) that has formed a complex with a Cu radioisotope. In one embodiment, one or more amino acids include lysine or a salt thereof. In another embodiment, one or more amino acids include arginine or a salt thereof. In a preferred embodiment, the method for treating neuroendocrine carcinoma further comprises the administration of lysine and / or arginine, or salts thereof. In a preferred embodiment, the method for treating neuroendocrine carcinoma further comprises the administration of lysine and arginine, or salts thereof. In a preferred embodiment, the method for treating neuroendocrine carcinoma includes lysine and arginine, or salts thereof, 67 The present invention further includes co-administration with a compound of formula (I) that has formed a complex with a Cu radioisotope. In some embodiments, 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, one or more amino acids are present as hydrochloride salts. In some embodiments, one or more amino acids are present at a concentration of about 2.5% w / v each.

[0112] In one embodiment, the treatment method for neuroendocrine cancer is a therapeutically effective amount 67 The method involves administering an aqueous formulation containing a compound of formula (I) that forms a complex with Cu or a pharmaceutically acceptable salt thereof, and an aqueous formulation of one or more amino acids, to a subject requiring it. In a preferred embodiment, 67 A formulation containing a radiolabeled compound of formula (I) that forms a complex with Cu and a formulation containing one or more amino acids are administered simultaneously. In another preferred embodiment, the formulation containing one or more amino acids is 67 The compound of formula (I) that forms a complex with Cu is administered to the subject before administration.

[0113] In this specification, the term “amino acid” refers to a molecule containing both an amino functional group and a carboxyl functional group. Amino acids are natural or unnatural amino groups and may exist in equilibrium with the amphoteric form. Amino acids may contain modifications at either the amino terminus and / or the carboxyl terminus, or they may contain a free amino group or a free carboxyl group. Further modifications of the amino acid side chain or additional substitutions in other parts of the amino acid are also considered.

[0114] These amino acids are widely found in nature. They 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).

[0115] The method of the present invention may further include the administration of an antiemetic. In one embodiment, the method of the present invention further includes the administration of an antiemetic to a subject. In some embodiments, the antiemetic is 67 It is administered simultaneously with, or prior to, the compound of formula (I) that forms a complex with Cu.

[0116] In this specification, the classification of adverse events related to the methods disclosed herein conforms to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 issued by the National Cancer Institute (NCI). CTCAE is a descriptive term used in the art for reporting adverse events (AEs). A grade (or severity) scale is used to classify each AE term. According to the CTCAE definition, "An adverse event (AE) is an undesirable, unexpected sign, symptom (including abnormal clinical laboratory values), or illness that occurs temporarily in connection with the use of a medical procedure or treatment, whether or not it is related to the medical procedure or treatment." Previous versions of the CTCAE may also be used, but a more comprehensive explanation of the grading in the latest version (v5.0) is provided below: [Table 1] Activities of daily living (ADL) *Instrumental activities of daily living (ADL) refer to activities such as preparing meals, shopping for groceries and clothes, using the telephone, and managing money. **Self-care ADL refers to activities such as bathing, dressing, eating, using the toilet, taking medication, and not being bedridden.**

[0117] In this specification, for example, a Grade 2 AE refers to an event having the severity described in the table above. Those skilled in the art will understand that an AE is first identified according to the organ-specific major classification (SOC) described in CTCAE v5.0, and then graded according to the table above.

[0118] In certain embodiments of the methods disclosed herein, the subjects do not experience any adverse events classified as Grade 3 or higher, according to the definitions provided for in the CTCAE.

[0119] In certain embodiments of the methods disclosed herein, subjects do not experience any adverse events classified as Grade 2 or higher according to the definitions provided for in the CTCAE.

[0120] In other embodiments, the subjects do not experience any adverse events classified as Grade 1 or higher according to the definitions provided for in the CTCAE.

[0121] In other embodiments, the subject does not experience any adverse events classified as Grade 1 or Grade 2 according to the definitions provided in CTCAE.

[0122] In other embodiments, the subject does not experience any adverse events classified as Grade 1, Grade 2, or Grade 3 according to the definitions provided in CTCAE.

[0123] References to prior art (or information derived therefrom) or known matters in this specification do not constitute, and should not be construed as, an endorsement, acceptance, or suggestion that such prior art (or information derived therefrom) or known matters constitute part of the common general knowledge in the field of study to which this specification pertains.

[0124] Those skilled in the art will understand that the inventions described herein are subject to modifications and alterations other than those specifically described. It should be understood that the present invention encompasses all such modifications and alterations that fall within the true spirit and scope of the invention. The present invention also includes all steps, features, compositions and compounds mentioned or indicated individually or collectively herein, as well as any combination of any two or more of the aforementioned steps or features.

[0125] Examples The following examples are illustrative of this disclosure and should not be construed as limiting in any way the general nature of the explanatory disclosures throughout this specification. [Examples]

[0126] 67 Dosage selection for cu-SARTATE (Formula I) During the dose escalation phase of this study, patients 67Cu-SARTATE was administered as a single dose. The dose levels used during the escalation phase were 75 MBq / kg, 175 MBq / kg, 275 MBq / kg, and 375 MBq / kg.

[0127] Preliminary data from the group of patients administered 75 MBq / kg and the group of patients administered 175 MBq / kg (all of whom had 67 completed a single treatment cycle of Cu-SARTATE) showed that no dose-limiting toxicity (DLT) has been reported to date. This result 67 indicates that the administration of Cu-SARTATE is highly tolerable and suggests the possibility of using high doses of at least 275 MBq / kg.

[0128] Table 1 shows the estimated mean radiation doses of 64 Cu]Cu-SARTATE from three subjects in the PET and SPECT imaging diagnosis of a study targeting meningioma patients (see Bailey et al., J. Nucl. Med. (2022)). The organ dose per MBq was highest in the spleen, followed by the kidneys, liver, adrenal glands, and small intestine. This 64 was consistent for both 67 Cu]Cu-SARTATE and 64 Cu]Cu-SARTATE. This data can be extrapolated to the dose estimates of 67 Cu]Cu-SARTATE and

[0129] Table 1: In meningioma patients [ 64 Cu]Cu-SARTATE and [ 67 Estimated average radiation dose of Cu]Cu-SARTATE

Table 2

[0130] Once the dose escalation phase is completed and an acceptable safety and tolerance profile is established, in the cohort expansion phase, patients will 67Cu-SARTATE can be administered for two treatment cycles. In peptide receptor radionuclide therapy (PRRT), it has been shown that the higher the cumulative radiation dose administered, the higher the absorbed dose to the tumor, which correlates with efficacy. This has 67 been observed in preclinical trials of Cu-SARTATE, and repeated administration has led to improved survival compared to single administration.

[0131] The dose-limiting organs in PRRT are usually the kidneys and bone marrow. The kidneys are at risk due to active reabsorption and retention of radiopharmaceuticals. To reduce nephrotoxicity, concomitant administration of positively charged amino acids that competitively inhibit the reabsorption of radioactive peptides by the proximal renal tubules is often carried out. Simultaneous infusion of a cocktail of basic amino acids such as lysine and arginine has been shown to reduce the uptake of radiopharmaceuticals into the kidneys by about 33%, allowing for higher therapeutic doses to be administered. The total radiation dose limiting to the kidneys by external beam radiotherapy (EBRT) is estimated to be 23 Gy, and more conservatively, 18 Gy in some cases.

[0132] To avoid nephrotoxicity, 67 the modeled cumulative administered radioactivity of Cu-SARTATE does not exceed 23 Gy to the kidneys. If the planned cumulative administered radioactivity over the entire treatment cycle exceeds this modeled limit, the administered radioactivity of Cu-SARTATE after the second and subsequent administrations can be adjusted so that the modeled kidney radiation dose does not exceed a total of 23 Gy. The maximum allowable cumulative administered radioactivity based on body weight is calculated for each participant, and examples of doses are shown in Table 2. 67

[0133] The proposed kidney radiation dose limit of 23 Gy does not take into account the radiation exposure to the kidneys from past treatments with radiopharmaceuticals. Based on the protocol requirements, participants who have received PRRT treatment are excluded, so past radiotherapy is 131 likely to be only I-MIBG therapy and / or EBRT. 131 ​The dose levels administered during I-MIBG therapy vary depending on the institution's protocol and range from 37 to 666 MBq / kg. This is particularly relevant in high-risk refractory or recurrent neuroblastoma patients. 131 The reported renal absorbed dose after I-MIBG therapy was 0.164 mGy / MBq, which is considered relatively low compared to radiopharmaceuticals targeting SSTRs. 131 The main target organs receiving the highest radiation dose during I-MIBG therapy are the liver, lungs, and bone marrow, and the main side effects are primarily hematological.

[0134] Similarly, other previous studies have not considered previous radiation therapy that may have affected renal function, except that they confirmed that all patients had adequate renal function before participating in the trial.

[0135] However, to mitigate the risk of potential cumulative nephrotoxicity, within the past 12 months 131 Participants who have received I-MIBG therapy or EBRT to the kidney are required to have a higher estimated glomerular filtration rate (eGFR) compared to participants who have not received such therapy. Furthermore, participants who have received EBRT to both kidneys or one functioning kidney within the past 12 months will be excluded. Therefore, it is important to ensure that only participants with good renal reserve after previous radiotherapy are included. [Examples]

[0136] 64 Dose measurement of cu-SARTATE 64 The radiation dose of Cu-Sartate was determined using a method for establishing radiation doses. i) 64 Acquired 1, 4, 12, 24 and / or 48 hours after Cu-SARTATE injection. 64 The following was determined using a Cu-SARTATE PET / CT scan: a. 64 Organ absorbed dose (mGy / MBq) and effective dose (mSv / MBq) from Cu-SARTATE b.67 Modeled organ absorbed dose (mGy / MBq) from Cu-SARTATE c. Do not exceed the tolerable limits of specific organs (23 Gy to the kidneys, 2 Gy to the bone marrow). 64 Modeled and estimated total cumulative administered radioactivity (GBq) of Cu-SARTATE ii) If the target has an appropriate level of residual radioactivity, additional scans can be performed later. [Examples]

[0137] 67 Dose measurement of cu-SARTATE 67 The radiation dose of Cu-Sartate could be determined using a method for establishing radiation dose. i) 67 Acquired 1, 4, 12, 24 and / or 48 hours after Cu-SARTATE injection. 67 Using Cu-SARTATE SPECT / CT scans (with additional scans performed later if appropriate residual radiation levels remained in the participant), the following was determined: a. 67 Organ absorbed dose (mGy / MBq) and effective dose (mSv / MBq) from Cu-SARTATE b. 67 Modeled organ absorbed dose (mGy / MBq) from Cu-SARTATE c. Do not exceed the tolerable limits of specific organs (23 Gy to the kidneys, 2 Gy to the bone marrow). 67 Modeled and estimated total cumulative administered radioactivity (GBq) of Cu-SARTATE ii) If the target has an appropriate level of residual radioactivity, additional scans can be performed later. [Examples]

[0138] 67 Calculation of the maximum dose of cu-SARTATE It can be administered without exceeding the renal limit of 23 Gy. 67 The maximum dose of Cu-SARTATE is based on the patient's weight. Based on the maximum dose to the kidney,67 The maximum cumulative dose of Cu-SARTATE can be calculated (see Table 2). Based on the patient's weight, if the renal upper limit is 30 Gy, 67 The maximum cumulative dose of Cu-SARTATE can also be calculated. A similar cumulative dose can also be calculated based on the upper limit of the kidney function.

[0139] Table 2: Based on body weight 67 Maximum cumulative dose of cu-SARTATE [Table 3]

Claims

1. A treatment method for neuroendocrine cancer, At a therapeutically effective dose, 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 1】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the aqueous preparation is administered in the same amount or less of the compound of formula (I) one, two, or three more times as desired. Here, it is delivered to the target bone marrow. 67 The total dose of Cu radiation is less than approximately 2 Gy, and the total dose of radiation delivered to the target kidney is less than approximately 30 Gy, according to the method.

2. A treatment method for neuroendocrine cancer, At a therapeutically effective dose, 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 2】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Herein, the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with cancer, in a method.

3. A method for treating neuroendocrine cancer in patients requiring treatment, below: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) formed a complex with a Cu radioisotope: 【Transformation 3】 Equation (I) The compound or a pharmaceutically acceptable salt thereof is intravenously infused at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg. A method that includes doing so.

4. A treatment method for neuroblastoma, At a therapeutically effective dose, 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 4】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the aqueous formulation is administered one, two, or three more times in the same or lower amount of the compound of formula (I). Here, it is delivered to the target bone marrow. 67 The total dose of Cu radiation is less than approximately 2 Gy, and the total dose of radiation delivered to the target kidney is less than approximately 30 Gy, according to the method.

5. A treatment method for neuroblastoma, At a therapeutically effective dose, 67 Formula (I) formed a complex with a Cu radioisotope: 【Transformation 5】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Herein, the dose of radiation delivered by the radioactive isotope is sufficient to reduce the size of one or more lesions associated with neuroblastoma, in a method.

6. A treatment method for neuroendocrine cancer, At a therapeutically effective dose, 67 Formula (I) formed a complex with a Cu radioisotope: 【Transformation 6】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the subject is a method that does not experience any adverse events classified as Grade 3 or higher.

7. A treatment method for neuroblastoma, at a therapeutically effective amount, 67 forming a complex with a Cu radioisotope of formula (I): 【Transformation 7】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the subject is a method that does not experience any adverse events classified as Grade 3 or higher.

8. The method according to claim 6 or 7, wherein the subjects do not experience any adverse events classified as Grade 2 or higher.

9. The method according to claim 6 or 7, wherein the subjects do not experience any adverse events classified as Grade 1 or higher.

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

11. A treatment method for neuroendocrine tumors, At a therapeutically effective dose, 67 Formula (I) formed a complex with a Cu radioisotope: 【Transformation 8】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the radiation dose is determined by a method that does not impose any dose-limiting toxicity on the subject.

12. The method according to claim 11, wherein the subjects do not experience any adverse events classified as Grade 3 or higher.

13. The method according to claim 11, wherein the subjects do not experience any adverse events classified as Grade 2 or higher.

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

15. A treatment method for neuroblastoma in patients who require treatment, below: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 9】 Equation (I) The compound or a pharmaceutically acceptable salt thereof is intravenously infused at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg. A method that includes doing so.

16. A method for treating neuroendocrine cancer in patients requiring treatment, below: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 10】 Equation (I) The compound or a pharmaceutically acceptable salt thereof is administered intravenously at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg, and 2) Repeat treatment cycle 1) one, two, or three more times with the same or a lower amount of the compound of formula (I), such that the total amount of radiation delivered to the patient's kidneys does not exceed 30 Gy. A method that includes doing so.

17. A method for treating neuroblastoma in patients requiring treatment, below: 1) Optionally, administer an amino acid solution to the patient, followed by, 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 11】 Equation (I) The compound or a pharmaceutically acceptable salt thereof is administered intravenously at a therapeutically effective dose of approximately 75 MBq / kg to approximately 475 MBq / kg, and 2) Repeat treatment cycle 1) one, two, or three more times with the same or a lower amount of the compound of formula (I), such that the total amount of radiation delivered to the patient's kidneys does not exceed 30 Gy. A method that includes doing so.

18. 67 The method according to any one of claims 1 to 17, wherein the radiation dose delivered by the Cu radioactive isotope is about 75 MBq / kg, about 175 MBq / kg, about 275 MBq / kg, about 375 MBq / kg, or about 475 MBq / kg.

19. The method according to any one of claims 1 to 18, wherein multiple doses of a formulation defined in any one of claims 1 to 15 are administered, and the doses are the same or different.

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

21. The method according to 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 effectiveness of the treatment method 64 The compound of formula (I) that forms a complex with a Cu radioisotope, or a pharmaceutically acceptable salt thereof, can be evaluated by PET or SPECT during a treatment cycle, where, 64 The method according to any one of claims 1 to 23, wherein the radiation dose delivered by Cu is approximately 2 MBq / kg.

25. The method preferably involves a diagnostically effective amount. 64 The method according to any one of claims 1 to 23, further comprising radioimaging of a target by PET and / or CT using a compound of formula (I) or a pharmaceutically acceptable salt thereof that has formed a complex with a Cu radioisotope.

26. A method for radiographic imaging of neuroendocrine carcinoma, 64 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 12】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the radiation dose delivered by the radioactive isotope is approximately 2 MBq / kg, according to the method.

27. A method for radiographic imaging of neuroblastoma, 64 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 13】 Equation (I) This involves administering an aqueous formulation of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. Here, the radiation dose delivered by the radioactive isotope is approximately 2 MBq / kg, according to the method.

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

29. The method according to claim 28, wherein the infant is approximately 13 months to approximately 12 months old.

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

31. The method according to claim 30, wherein the target is a child aged approximately 1 to 10 years.

32. The method according to any one of claims 1 to 27, wherein the subject is a young person.

33. The method according to claim 32, wherein the target is a young person aged approximately 10 to 19 years old.

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 an aqueous formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises gentisic acid or a salt thereof.

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

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

40. In the manufacture of aqueous formulations for the treatment of neuroendocrine cancer, 67 Compound of formula (I) that forms a complex with a Cu radioisotope: 【Chemistry 14】 Equation (I) or the use of a pharmaceutically acceptable salt thereof, Here, the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

41. In the manufacture of aqueous formulations for the treatment of neuroblastoma, 67 Compound of formula (I) that forms a complex with a Cu radioisotope: 【Chemistry 15】 Equation (I) or the use of a pharmaceutically acceptable salt thereof, Here, the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

42. In the manufacture of drugs for the treatment of neuroendocrine cancer, the therapeutically effective amount 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 16】 Equation (I) The use of the compound or a pharmaceutically acceptable salt thereof, Here, drug administration is considered to be without any adverse events classified as Grade 3 or higher.

43. In the manufacture of drugs for the treatment of neuroblastoma, the therapeutically effective amount 67 Formula (I) formed a complex with a Cu radioisotope: 【Chemistry 17】 Equation (I) The use of the compound or a pharmaceutically acceptable salt thereof, Here, drug administration is considered to be without any adverse events classified as Grade 3 or higher.

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

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

46. In the manufacture of drugs for the treatment of neuroendocrine tumors, the therapeutically effective amount 67 Formula (I) formed a complex with a Cu radioisotope: [Chemistry 18] Equation (I) The use of the compound or a pharmaceutically acceptable salt thereof, Here, the radiation dose is used in a way that does not impose any dose-limiting toxicity on the subject.

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

48. The use of the drug according to claim 46, wherein the administration of the drug is not accompanied by any adverse event classified as Grade 2 or higher.

49. The use of the drug according to claim 46, wherein the administration of the drug is not accompanied by any adverse event classified as Grade 1 or higher.

50. The use according to claim 46, wherein the administration of the drug is not accompanied by 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 gentisic 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 gentisic acid or a salt thereof and ascorbic acid or a salt thereof.

54. For the treatment of neuroendocrine cancer, 67 Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof that has formed a complex with a Cu radioisotope.

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

56. For the treatment of neuroblastoma, 67 Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof that has formed a complex with a Cu radioisotope.

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