Identifying and / or treating cancer

Abstract

The present invention relates generally to the identification and / or treatment of cancer, particularly cancers in which the gastrin-releasing peptide receptor (GRPR) is expressed. In particular embodiments, the present invention relates to the identification and / or treatment of prostate cancer, particularly GRPR-expressing metastatic castration-resistant prostate cancer.

Description

[Technical Field]

[0001] The present invention relates generally to the identification and / or treatment of cancer, particularly cancers in which the gastrin-releasing peptide receptor (GRPR) is expressed. In particular embodiments, the present invention relates to the identification and / or treatment of prostate cancer, particularly GRPR-expressing metastatic castration-resistant prostate cancer. [Background technology]

[0002] Prostate cancer (PCa) is the second most common malignancy in men worldwide. The American Cancer Society estimates that 268,490 new cases of PCa will be diagnosed in the United States (US) in 2022, accounting for approximately 27% of all new estimated cancer cases in men and 14% of all new estimated cancer cases. The incidence of PCa correlates with age, ranging from 30% in patients aged 40–50 years to 50–80% in patients aged 80 years or older. The median age of patients diagnosed with PCa is 67 years, and the median age of death is 81 years. The etiology of the disease is unknown, but major risk factors include older age, ethnicity, and a positive family history. Many patients with PCa have indolent disease, and their serum prostate-specific antigen (PSA) levels are tracked without further treatment. At initial presentation, 74% of patients have localized disease, 13% have regional disease, 7% have metastatic disease, and the remaining 6% are classified as unknown. Since 2000, the 5-year relative survival rate for localized or regional PCa has exceeded 97%. However, for metastatic (distant) PCa, the 5-year survival rate drops dramatically to 30%. 20-40% of patients experience rising PSA levels (biochemical recurrence or failure) within 10 years of primary PCa treatment. Approximately 25-35% of patients with recurrent disease have locally recurrent disease, 20-25% have metastatic disease, and 45-55% have both.

[0003] The gastrin-releasing peptide receptor (GRPR) is a transmembrane G protein-coupled receptor with various physiological functions in the gastrointestinal tract and nervous system. Its pharmacological activities, through binding of its ligand, gastrin-releasing peptide (GRP), include stimulating the release of hormones such as gastrin and somatostatin, as well as gastric and intestinal smooth muscle contraction. Gastrin-releasing peptide receptor expression is upregulated in many human cancers, including PCa, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumor (GIST), and its normal biodistribution is primarily concentrated in the pancreas and gastrointestinal tract. The correlation between GRPR expression and clinical features in PCa, such as Gleason score, disease stage, and PSA level, has been evaluated, but results remain inconclusive. Indeed, recent studies have demonstrated the efficacy of gallium-68-labeled GRPR-targeting agents across all PSA levels in biochemically recurrent PCa. 68 The uptake of Ga-RM2) was shown.

[0004] Although several GRPR-targeted imaging and theranostic agents are in clinical trials, none are currently widely available or approved by regulatory agencies. GRPR expression has been reported in PCa, with expression seen in 75–100% of analyzed samples. Furthermore, 68 Ga-RM2, 68 Ga-NeoB, or 68 Clinical trials using GRPR-targeted imaging agents, such as Ga-SB3, have reported high uptake in primary PCa lesions and metastases, with positive / detection rates ranging from 31% to 100% in some studies. However, no clinical therapeutic studies targeting GRPR have been reported to date. 177 In patients with metastatic castration-resistant prostate cancer (mCRPC) who are ineligible for Lu-PSMA-617 therapy 177 For the first time, a human dosimetry study of Lu-RM2 revealed 4.5 GBq 177Lu-RM2 was shown to be well tolerated by all four patients, with no observed side effects. Rapid clearance from normal organs was observed, while therapeutically relevant absorbed doses to the tumor were recorded. Summary of the Invention [Problem to be solved by the invention]

[0005] Prostate cancer patients, especially based on prostate-specific membrane antigen (PSMA) expression 177 There is a need to improve outcomes for patients with gastrin-releasing peptide receptor (GRPR)-expressing cancers, including patients diagnosed with mCRPC, who are ineligible for Lu-PSMA-617 therapy. [Means for solving the problem]

[0006] The present inventors have developed a radiolabeled antagonist of GRPR for diagnosing and treating prostate cancer. One such product is copper-complexed MeCOSar-PEG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH (Cu-SAR-BBN). Cu-SAR-BBN is a radioactive form of copper (radionuclide), copper-64 ( 64 Cu) and then copper-67 ( 67 This "theranostic" approach is well established in neuroendocrine tumors with the use of approved products: NETSPOT® or Detectnet™ for imaging and LUTATHERA® for treatment. These products consist of DOTA-octreotate, which targets somatostatin receptor-positive lesions, but uses a different radionuclide (gallium-68 for imaging [ 68 Ga] or 64 Cu and Lutetium-177 for Treatment[ 177 Similarly, the prostate-specific membrane antigen (PSMA) targeting agent Locametz® ( 68Ga-PSMA-11) and Pluvicto™ ( 177 Lu-PSMA-617) were recently approved by the US FDA as an imaging agent for patient selection and a therapeutic agent for metastatic castration-resistant prostate cancer (mCRPC), respectively. Targeted radionuclide therapy achieves antitumor effects by administering higher doses of radiation than for diagnostic purposes, with the radionuclides used in treatment imparting much greater energy to cellular structures such as deoxyribonucleic acid (DNA), resulting in cytotoxicity of targeted cells. The effectiveness of this treatment depends on delivering the highest possible radiation dose to the tumor while avoiding damage to normal organs and tissues. This is achieved through highly specific, high-affinity binding to receptors overexpressed on tumors. Several GRPR-targeted radiopharmaceuticals for therapy are disclosed herein. To date, 67 No clinical trials using Cu-labeled products have been reported. 67 Cu 177 It was determined to have similar properties to Lu. Both have similar maximum energies (577 keV, respectively). 30 and 498 keV 31 ) and therefore have a similar potential range in tissue. Furthermore, preclinical efficacy studies in tumor-bearing mice have shown 67 Cu-tracer 177 It was shown to be as effective as the Lu-tracer.

[0007] Accordingly, a first aspect of the present invention provides a method of treating a patient diagnosed with a GRPR-expressing cancer, comprising administering to a patient an effective amount of: 67 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0008] [ka]

[0009] (wherein R is CH3C(O)-); ( 67 Cu-SAR-BBN) administering wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0010] In certain embodiments, the GRPR-expressing cancer is selected from prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumor (GIST).

[0011] In a second aspect, the present invention provides a method of treating a patient diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer, comprising administering to a patient an effective amount of: 67 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0012] [ka]

[0013] (wherein R is CH3C(O)-); ( 67 Cu-SAR-BBN) administering wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0014] In a third aspect, the present invention also provides a method for producing a medicament for the treatment of rhesus macular degeneration comprising: 177 1. A method of treating a patient diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer who is ineligible for treatment with Lu-PSMA-617, comprising administering to said patient an effective amount of: 67 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0015] [ka]

[0016] (wherein R is CH3C(O)-); ( 67 Cu-SAR-BBN) administering wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

[0017] In a fourth aspect, the present invention provides a method for identifying and treating a patient diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer, comprising: (i) an effective amount of 64 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0018] [ka]

[0019] (wherein R is CH3C(O)-); ( 64 Cu-SAR-BBN) administering The aforementioned 64 the dose of radiation delivered by the Cu radioisotope is sufficient to identify one or more lesions associated with said cancer; (ii) an effective amount of 67 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0020] [ka]

[0021] (wherein R is CH3C(O)-); ( 67 Cu-SAR-BBN) administering The aforementioned 67the dose of radiation delivered by the Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer; The present invention provides a method comprising:

[0022] In a fifth aspect, the present invention provides a method for producing a pharmaceutical composition comprising: 177 1. A method for identifying and treating patients diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer who are ineligible for treatment with Lu-PSMA-617, comprising: (i) an effective amount of 64 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0023] [ka]

[0024] (wherein R is CH3C(O)-); ( 64 Cu-SAR-BBN) administering The aforementioned 64 the dose of radiation delivered by the Cu radioisotope is sufficient to identify one or more lesions associated with said cancer; (ii) an effective amount of 67 A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope:

[0025] [ka]

[0026] (wherein R is CH3C(O)-); ( 67 Cu-SAR-BBN) administering The aforementioned 67 the dose of radiation delivered by the Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer; The present invention provides a method comprising:

[0027] In one particular embodiment, in relation to all aspects, the stereochemistry of the peptide portion of the compound of formula (I) is shown as follows:

[0028] [ka]

[0029] In some embodiments of the present invention, to identify one or more lesions, 64 The dose of radiation delivered by the Cu radioisotope is about 100 MBq to about 300 MBq. 64 The dose of radiation delivered by the Cu radioisotope is about 100 MBq, about 120 MBq, about 140 MBq, about 160 MBq, about 180 MBq, about 200 MBq, about 220 MBq, about 240 MBq, about 260 MBq, about 280 MBq, or about 300 MBq.

[0030] In certain embodiments of the present invention, to reduce the size of one or more lesions associated with cancer 67 The dose of radiation provided by the Cu radioisotope is about 4 GBq, about 6 GBq, about 8 GBq, about 10 GBq, about 12 GBq, about 14 GBq, about 16 GBq, about 18 GBq, about 20 GBq, about 22 GBq or about 24 GBq.

[0031] In certain embodiments of the methods of treating cancer disclosed herein, 67 A compound of Formula (I) complexed with a Cu radioisotope is administered once. 67 In another embodiment, the compound of formula (I) complexed with a Cu radioisotope is administered more than once to the same subject. 67 A compound of formula (I) complexed with a Cu radioisotope is administered two, three, four or five times to the same subject.

[0032] As mentioned above, the compound of formula (I) targets gastrin-releasing peptide receptor (GRPR) associated with various cancer types.In certain embodiments, the cancer is breast cancer.In other embodiments, the cancer is a specific subset or type of breast cancer.In some embodiments, the breast cancer is associated with the expression of one or more of estrogen, progesterone or HER2 receptors.

[0033] Different subtypes of breast cancer are classified according to the conventional 18 They exhibit varying levels of sensitivity to FDG-PET imaging, which 18 This means that the use of FDG-PET imaging cannot necessarily identify all breast cancer lesions. For example, 18 FDG has a lower sensitivity for ER+ / PR+ breast cancer when compared to triple-negative (i.e., ER / PR / HER2-negative) subtypes. As seen in Figures 1-6, subjects with clinical progression of metastatic ER+ / PR+ / HER2- were 18 FDG-PET and 64 Imaging was performed using Cu-Sar-BBN. Compared with conventional imaging using FDG, 64 Combined patient analysis of images taken after Cu-Sar-BBN administration showed higher mean total tumor volume, SUV max and the total number of lesions. 64 These results suggest that the use of Cu-Sar-BBN may provide a more comprehensive assessment of the lesions of interest. For example, Figure 2 shows 18 Figure 4 shows a subject with classical lobular breast cancer with widespread metastases throughout, with a calculated mean total tumor volume four times larger than the tumor volume calculated by imaging with FDG. Conventional imaging with FDG identified fewer than three lesions, but 64 Imaging of the same subjects after administration of Cu-Sar-BBN identified at least 19 lesions. In a further aspect, the present invention provides a method for producing a pharmaceutical composition comprising: 67Provided is a method for predicting a patient's response to treatment of cancer with a compound of formula (I) complexed with Cu, comprising detecting and enumerating circulating tumor DNA (ctDNA) associated with one or more genes in the patient, and correlating the amount of ctDNA detected with the patient's response to said treatment, wherein the cancer is a GRPR-expressing cancer and the one or more genes are selected from the group consisting of BRCA1, BRCA2, RB, and p53. 67 The method for predicting a patient's response to treatment with Cu includes, in particular, determining whether the patient is receiving a compound of formula (I) when ctDNA detected in the patient indicates that the induced response does not result in a decrease in the size of one or more lesions of the cancer associated with the group. 67 This means that Cu may not be administered. [Brief explanation of the drawings]

[0034] [Figure 1] A patient with clinical progression of metastatic ER+ / PR+ / HER2- invasive ductal carcinoma requiring restaging was imaged with 18FDG-PET (A). The same patient received 200 MBq of 64Cu-Sar-BBN and was imaged by PET (B). [Figure 2] A patient with clinical progression of metastatic ER+ / PR+ / HER2- classical lobular breast cancer requiring restaging was imaged with 18FDG-PET (A). The same patient received 200 MBq of 64Cu-Sar-BBN and was imaged with PET (B). The patient's biopsy showed metastases in the liver. PET imaging after 64Cu-Sar-BBN administration demonstrated a higher SUVmax than imaging with conventional FDG techniques. The total tumor volume detected by 64Cu-Sar-BBN was approximately four times larger than that detected by FDG imaging, strongly suggesting that identification of cancerous lesions can be achieved with 64Cu-Sar-BBN. This figure also shows that 64Cu-Sar-BBN was able to localize lesions that were not detected by conventional FDG imaging. [Figure 3]A patient with clinical progression of metastatic ER+ / PR+ / HER2- invasive ductal carcinoma requiring restaging was imaged with 18FDG-PET (A). The same patient received 200 MBq of 64Cu-Sar-BBN and was imaged by PET (B). The patient's biopsy showed metastases in the liver. Imaging with 64Cu-Sar-BBN revealed lesions not detected by conventional FDG imaging. [Figure 4] A patient with clinical progression of metastatic ER+ / PR+ / HER2- invasive ductal carcinoma requiring restaging was imaged with 18FDG-PET (A). The same patient received 200 MBq of 64Cu-Sar-BBN and was imaged with PET (B). The patient's biopsy showed metastases in the chest wall. The total tumor volume detected by 64Cu-Sar-BBN was larger than that detected by FDG imaging, strongly suggesting that identification of cancerous lesions can be achieved by 64Cu-Sar-BBN. [Figure 5] A patient with clinical progression of metastatic ER+ / PR+ / HER2- classical lobular breast cancer requiring restaging was imaged with 18FDG-PET (A). The same patient received 200 MBq of 64Cu-Sar-BBN and was imaged by PET (B). Maximum intensity projection and axial slices of the patient after imaging with 18FDG-PET (C) and 64Cu-Sar-BBN PET (D) are also provided. The patient's biopsy showed metastases in the skin. 64Cu-Sar-BBN imaging identified various tumors throughout the patient, whereas conventional imaging with FDG did not reveal any tumors. This again strongly suggests that 64Cu-Sar-BBN can achieve identification of cancerous lesions. [Figure 6] A patient with clinical progression of metastatic ER+ / PR+ / HER2- invasive ductal carcinoma requiring restaging was imaged with 18FDG-PET (A). The same patient received 200 MBq of 64Cu-Sar-BBN and was imaged by PET (B). The patient's biopsy showed metastases in the pleura. Imaging with 64Cu-Sar-BBN revealed lesions not detected by conventional FDG imaging. [Figure 7] A patient with prostate cancer after radical prostatectomy showed consecutive negative PSMA-PET scans as determined by 68Ga-PSMA-11 imaging (A). Other imaging modalities, such as bone scan (B) and 18FDG-PET (C), also failed to identify recurrent lesions. The patient was administered 200 MBq of 64Cu-Sar-BBN, and the resulting PET images (D and E) revealed the presence of additional lesions. Imaging with 64Cu-Sar-BBN revealed lesions not detected by conventional imaging modalities. [Figure 8] A patient with prostate cancer after radical prostatectomy showed consecutive negative PSMA-PET scans as determined by 68Ga-PSMA-11 imaging (A). Other imaging modalities, such as bone scan (B), also failed to identify recurrent disease. The patient was administered 200 MBq of 64Cu-Sar-BBN, and the resulting PET images (C and D) revealed the presence of additional lesions in the prostate. [Figure 9] A patient with prostate cancer after radical prostatectomy showed consecutive negative PSMA-PET scans as determined by 68Ga-PSMA-11 imaging (A). The patient was administered 200 MBq of 64Cu-Sar-BBN, and the resulting PET images (B and C) revealed the presence of additional lesions in the prostate that were not detected by conventional imaging modalities. [Figure 10] A patient with prostate cancer after radical prostatectomy showed consecutive negative PSMA-PET scans as determined by 68Ga-PSMA-11 imaging (A and B). The patient was administered 200 MBq of 64Cu-Sar-BBN, and the resulting PET image (C) revealed the presence of additional lesions not detected by conventional imaging modalities. DETAILED DESCRIPTION OF THE INVENTION

[0035] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to mean the inclusion of the specified integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0036] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For purposes of the present invention, the following terms are defined below.

[0038] As used herein, 177 Reference to Lu-PSMA-617 refers to the following compound:

[0039] [ka]

[0040] As used herein, in certain embodiments, a patient 177 As used herein, one skilled in the art can determine such patient groups based on the following criteria: 68 Ga-PSMA-11 or 18 F-DCFPyL uptake is negative (less than or equal to liver parenchymal uptake) or any one lesion larger than the size criteria is negative [size criteria: organ ≥ 1 cm, lymph node ≥ 2.5 cm, bone (soft tissue component) ≥ 1 cm]. 68Ga-PSMA-11 is:

[0041] [ka]

[0042] 18 F-DCFPyL is:

[0043] [ka]

[0044] In some embodiments, 67 The dose of radiation delivered by the Cu radioisotope is from about 6 GBq to about 56 GBq. 67 The dose of radiation delivered by the Cu radioisotope is about 6 GBq, about 10 GBq, or about 14 GBq. 67 The dose of radiation delivered by the Cu radioisotope is greater than about 14 GBq. 67 The dose of radiation delivered by the Cu radioisotope is about 20 GBq, about 25 GBq, about 30 GBq, about 35 GBq, about 40 GBq, about 45 GBq, about 50 GBq, or about 55 GBq. 67 The dose of radiation delivered by the Cu radioisotope is the maximum dose tolerated by the subject.

[0045] In some embodiments, the prostate cancer is GRPR-expressing metastatic castration-resistant prostate cancer (GRPRmCRPC), and in certain embodiments, is progressive GRPRmCRPC despite prior androgen deprivation therapy and at least one of enzalutamide and / or abiraterone (or other such androgen receptor pathway inhibitors).

[0046] In a further embodiment, the patient is a male subject with castrate levels of serum / plasma testosterone of less than about 50 ng / dL or less than about 1.7 nmol / L.

[0047] In a further embodiment, the patient is 67 Male subjects who have a prostate-specific antigen (PSA) value of 50 or greater for more than three weeks prior to administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope.

[0048] In a further embodiment, the patient has: 67 After one, two, three or four therapeutic administration cycles of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope, the patient experiences a percentage decrease in PSA and / or alkaline phosphatase (ALP) and / or lactate dehydrogenase (LDA) biomarkers.

[0049] In a further embodiment, the method comprises administering an effective amount of: 67 The method includes administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope.

[0050] In a further embodiment, the method comprises: 67 The method comprises administering to a subject at least two doses, spaced about 6-14 weeks apart, by IV slow infusion over about 30 minutes to about 60 minutes, of an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope, at a dose that provides a 6-14 GBq level. In other embodiments, the method comprises administering to a subject at least three doses. In other embodiments, the method comprises administering to a subject at least four doses.

[0051] In an embodiment, the method comprises the steps of: (a) detecting the presence of HIV by PET, SPECT and / or CT, preferably by PET, preferably after each treatment cycle; 64 The method further includes radioimaging the subject with Cu-SAR-BBN.

[0052] In one embodiment, a positive PET and / or CT scan is 64Based on visualization of Cu-SAR-BBN (Formula (I)) PET / CT scan, 1-hour positron emission tomography (PET) / computed tomography (CT) scans showed at least one known lesion. 64 Cu-SAR-BBN uptake (standardized uptake value [SUV] max) is higher than that in the gastrointestinal tract.

[0053] The present inventors have found that the compound of formula (I) according to the above embodiment 64 Images of the subject obtained by PET and / or CT after administration of the Cu-complexed compound are used to treat GRPR-expressing metastatic castration-resistant prostate cancer. 67 It is believed that the corresponding dose of Cu complexing compounds can be directed or at least aided. Thus, one advantage of the present invention is that Cu radioisotopes can be 64 From Cu 67 By substituting Cu, the same BBN binding compound can be used in a complete diagnostic (specific) treatment regimen.

[0054] Therefore, the present inventors also believe that the administration of more than one dose (i.e., multiple treatment cycles) of the compounds and preparations described herein for treating GRPR-expressing metastatic castration-resistant prostate cancer will result in greater accumulation of radioisotopes in target sites.Without wishing to be bound by theory, the present inventors believe that the use of the radiolabeled compounds described herein makes it possible to deliver higher doses of radiation without increasing expected adverse effects.Therefore, this will result in greater efficacy in treatment.To evaluate the effectiveness of treatment, the diagnostic (identification) method disclosed herein above can be used before or during treatment cycles.

[0055] Without wishing to be bound by theory, the inventors believe that administering more than one dose of the formulations described herein to treat GRPR-expressing metastatic castration-resistant prostate cancer results in a higher absorbed dose at the cancer site, which in turn results in greater efficacy of the treatment. This means that repeated administration of a formulation containing a compound of Formula (I) complexed with a radioisotope may result in greater subject survival compared to a single administration of a formulation disclosed herein. In certain embodiments, the method comprises sequential administration of more than one dose of the compound described in the first and second aspects. In some embodiments, the sequential administrations are administered about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks apart (e.g., about 4-14 weeks apart). In certain embodiments, the sequential administrations are administered about 6 weeks apart. In certain embodiments, the total dose of radiation delivered to the subject's bone marrow is less than about 2 Gy. In another embodiment, the total dose of radiation delivered to the subject's kidney is less than about 23 Gy.

[0056] The treatment methods of embodiments 1 and 2 include multiple doses of a compound of formula (I) and a radioisotope. 67 The administration of Cu complexes may include administration of the same or different doses. In some embodiments, when multiple doses are administered, the second and any subsequent doses may be higher than the original dose. In some embodiments, multiple doses are administered, and the doses are the same. In other embodiments, multiple doses are administered, and the doses are different. Those skilled in the art will understand that because the methods discussed herein incorporate the use of radioisotopes, there is a maximum total dose of radiation that can be administered to a subject. In some embodiments, multiple doses are administered until the cumulative dose of radiation delivered to the subject's kidney reaches about 23 Gy. In some embodiments, multiple doses are administered until the cumulative dose of radiation delivered to the subject's bone marrow reaches about 2 Gy.

[0057] In certain embodiments, the compound of formula (I) 64 / 67The Cu-complexed compound is administered as an aqueous formulation intended for intravenous (IV) administration. In another embodiment, the aqueous formulation is administered by slow infusion. In a preferred embodiment, the aqueous formulation is administered intravenously by slow infusion, for example, over about 30 to 60 minutes.

[0058] In certain embodiments, the compound of formula (I) 64 The Cu-complexed compound is administered as an aqueous formulation intended to be administered intravenously (IV) by slow bolus infusion.

[0059] In certain embodiments, the compound of formula (I) 67 The Cu-complexed compound is administered as an aqueous formulation intended to be administered intravenously (IV) by slow infusion over a period of about 30 minutes to about 60 minutes, preferably 30 minutes.

[0060] 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 a 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-administering a cationic amino acid that competitively inhibits the reabsorption of the compound of Formula (I) and, therefore, the radioisotope. In some embodiments, the method of the second aspect further includes the administration of a formulation containing one or more amino acids, or a salt thereof. In some embodiments, the one or more amino acids are in cationic form. In some embodiments, the formulation containing one or more amino acids includes lysine or a salt thereof. In other embodiments, the formulation containing one or more amino acids includes arginine or a salt thereof. In a preferred embodiment, the method includes the administration of a formulation containing lysine and arginine, or a salt thereof.

[0061] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compounds, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic acid classes of organic acids, 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 also include those in which the main compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts.Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid through any of several known methods.Alternatively, alkali metal salts and alkaline earth metal salts can be prepared by reacting a compound with a suitable base through various known methods. The following are further examples of acid salts which can be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.Further information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. For drugs that are solid, it will be understood by those skilled in the art that the compounds, drugs and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and the specified formula.

[0062] Injectable formulations of the compounds of the present invention include pharmaceutically acceptable sterile aqueous solutions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. The formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media immediately before use. Pharmaceutical formulations may further comprise a pH control agent. Examples of suitable pH control agents include hydrochloric acid, sodium hydroxide, etc. Identifying preferred pH ranges (if appropriate) and suitable excipients is routine in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press).

[0063] The preparation of the present invention disclosed herein can be provided in pharmaceutically acceptable carrier or diluent.As those skilled in the art will understand, the selection of pharmaceutically acceptable carrier or diluent depends on the route of administration and the nature of the condition and subject being treated.Specific carrier or diluent and administration route can be easily determined by those skilled in the art.Carrier or diluent and administration route should be carefully selected to ensure the activity of the compound of formula (I) when it reaches the site of action.

[0064] The pharmaceutical forms suitable for injection include sterile injection solution or dispersion and sterile powder for preparing sterile injection solution.Such forms should be stable under the conditions of manufacture and storage, and can be protected from reduction, oxidation and microbial contamination.For injection, the composition of the present invention can be formulated in aqueous solution, suitable physiologically compatible buffer solution, such as Hanks' solution, Ringer's solution or physiological saline buffer solution.

[0065] For treating GRPR-expressing metastatic castration-resistant prostate cancer, the compound of formula (I) 67 The inventors have found that the sarcofazine fragment of formula (I) has a strong affinity for copper isotopes and is able to complex and retain the radioisotope for a time sufficient for therapeutic purposes, even after administration to a subject. 67 The Cu radioisotope has a half-life of approximately 60 hours and undergoes beta decay, making the isotope suitable for local radiotherapy. 67 The decay of the Cu radioisotope involves gamma rays, 67 Treatment of a subject administered a compound of Formula (I) complexed with Cu can be monitored and imaged by single photon emission computed tomography (SPECT). 67 The method of treating a subject in need thereof by administering a compound of formula (I) complexed with Cu includes monitoring and / or imaging by SPECT.Other imaging techniques during treatment, such as MRI and CT, can also be used.In a preferred embodiment, the treatment method includes imaging by SPECT and / or CT.

[0066] For radiographic imaging purposes, the dose of radiation delivered must be sufficient to provide an image of sufficient quality without overdosing the patient. 64 The amount of the radiolabeled compound of formula (I) complexed with a Cu radioisotope can be determined based on the subject's body weight. 67 The dose of radiation administered and delivered to a subject by a Cu radioisotope depends on the subject's body weight and 64 The quality of the image obtained by radioimaging after administration of a compound of Formula (I) complexed with a Cu radioisotope can be determined based on both the quality of the image obtained by radioimaging after administration of a compound of Formula (I) complexed with a Cu radioisotope. 64 Using a radiolabeled compound of formula (I) complexed with a Cu radioisotope, 67 The distribution of the corresponding compound of formula (I) complexed with a Cu radioisotope is modeled.

[0067] The units of radioactivity listed herein are given in grays (Gy) or becquerels (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 explicitly listed herein can also be used.

[0068] As used herein, the term "treating" or "treatment" and grammatical equivalents refer to any and all uses of curing the specified cancer, preventing, inhibiting, or delaying the establishment of the disease, or preventing, hindering, inhibiting, or reversing the progression of the disease. Therefore, terms such as "treating" should be considered in their broadest context. For example, treatment does not necessarily mean that a patient is treated until complete recovery. When a disease exhibits or is characterized by multiple symptoms, treatment or prevention does not necessarily cure, prevent, hinder, inhibit, or reverse all of the symptoms, but may prevent, hinder, inhibit, or reverse one or more of the symptoms.

[0069] As used herein, the term "cancer" broadly encompasses neoplastic diseases characterized by abnormal cell growth that has the potential to invade or spread to other parts of the body. Cancer may be benign, meaning that it does not spread to other parts of the body. Cancer may be malignant, meaning that cancer cells can spread through the circulatory or lymphatic system. The term as used herein includes all malignant, i.e., cancerous, disease states. Cancer may exist as a tumor.

[0070] As used herein, the term "tumor" refers to any malignant cancerous or precancerous cell growth. This term particularly relates to solid tumors or carcinomas. When cancer is present in the prostate, it is called "prostate cancer," which is typically characterized by increased and / or elevated serum prostate-specific antigen (PSA) levels and overexpression of PSMA membrane protein. A subject has prostate cancer, which may be primary and localized to the prostate. Prostate cancer may metastasize and spread to other parts of the subject. A subject may also have recurrent prostate cancer, which is characterized by an increase in PSA within 10 years of treatment for primary prostate cancer.

[0071] 64 Cu / 67Other types of GRPR-expressing cancers that can be treated or imaged by administration of Cu-Sar-BBN include prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, as well as gastrinoma and gastrointestinal stromal tumors (GISTs).

[0072] There are various forms of prostate cancer, each characterized by the location of cancer, the cell type involved in cancer (i.e., histology) and the level of patient's prostate-specific antigen (PSA).Prostate cancer can also be described by the stage and / or grade of cancer, for example, according to Gleason score, tumor size and / or location, the presence of one or more tumors in lymph nodes and the degree of metastasis.One form of prostate cancer includes metastatic castration-resistant prostate cancer (mCRPC).Proven progressive mCRPC is based on at least one or more of the following criteria: Serum / plasma prostate-specific antigen (PSA) progression, defined as two consecutive increases in PSA above the previous baseline value measured at least 1 week earlier, with a minimum of 2.0 ng / mL; b. Soft tissue progression, defined as a 20% or greater increase in the sum of diameters (SOD) of all target lesions (short axis for nodal lesions and long axis for non-nodal lesions) based on the smallest target lesion since the start of the last metastatic cancer-directed treatment (excluding hormonal therapy) or the appearance of one or more new lesions; and c. Progression of bone disease: disease measurable by bone scan or new bone lesions; d.GRPR(positive 64 Cu-SAR-BBN scan) and express one of the above criteria to define it as GRPR-positive mCRPC.

[0073] There are also various forms of breast cancer, characterized by whether the cancer is invasive or non-invasive, its location, and the presence / sensitivity of certain receptors on the cancer cells. For example, non-invasive breast cancer has abnormal cells that are contained within the ducts (milk ducts) or lobules (lobules) of the breast and have not spread to surrounding tissue, while invasive forms of the same cancer have spread to surrounding tissue. Breast cancer types can be classified according to the receptors present on the cancer cells. For example, hormone receptor-positive breast cancer exhibits sensitivity to estrogen and / or progesterone, while HER2-positive breast cancer exhibits increased human epidermal growth factor receptor 2 (HER2) on the cell surface. Breast cancer can also be classified according to whether the cancer is localized or has spread to lymph nodes or more distant parts of the body.

[0074] The methods disclosed herein for treating cancer include the treatment of GRPR-expressing breast cancer, which can be further characterized according to the subtypes described above.

[0075] The term "patient" as used herein refers to a mammal, including humans, primates, livestock animals (e.g., sheep, pigs, cows, horses, donkeys), laboratory animals (e.g., mice, rabbits, rats, guinea pigs), performance and show animals (e.g., horses, livestock, dogs, cats), companion animals (e.g., dogs, cats), and captive wild animals. Preferably, the mammal is a human or laboratory animal. Even more preferably, the mammal is a human male.

[0076] The term "therapeutically effective amount" or "effective amount" refers to an amount sufficient to produce a beneficial or desired clinical result. An effective amount can be administered in one or more doses. For radioimaging purposes, an effective amount is sufficient to image the localization of a compound of Formula (I) administered to a subject for detection of decay products from a radioisotope complexed with the compound. For therapeutic purposes, an effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow, and / or delay the progression of cancer.

[0077] Radiographic progression-free survival (rPFS) was 67 rPFS is defined as the time from the date of Cu-SAR-BBN treatment to radiographic progression on bone scan, radiographic soft tissue progression, or death from any cause, whichever occurs first. rPFS can be displayed as Kaplan-Meier curves and summary statistics (median and rPFS at 6, 9, and 12 months). In certain embodiments, the method provides rPFS of greater than 6 months to greater than 5 years.

[0078] In some embodiments, the effective amount is an amount effective to induce one of the following: Complete Response (CR): Disappearance of all target lesions. All pathological lymph nodes must be reduced to less than 10 mm in their short axis. Disappearance of all target lesions. All pathological lymph nodes (target or non-target) must be reduced to less than 10 mm in their short axis: Partial response (PR): At least a 30% reduction in the sum of the diameters of target lesions compared to baseline sum of the diameters.

[0079] A treatment plan typically involves several cycles (e.g., 1, 2, 3, 4, 5, or 6) of treatment, with the cycles continuing until the condition is improved. Again, the optimal number of cycles and the interval between each treatment cycle will depend on several factors, such as the subject's height and weight, the severity of the condition being treated, the health (or lack thereof) of the subject being treated, and previous response to radiation therapy and / or the extent of the condition as determined by radioimaging.

[0080] The formulations defined herein for the treatment methods can be administered parenterally, with intravenous administration being preferred. In some embodiments, an aqueous formulation containing a radiolabeled compound of Formula (I) is administered intravenously, either by bolus injection or infusion.

[0081] It will be understood that the specific dose of the radiolabeled compound of Formula (I) for any particular subject will depend on various factors, including, for example, the age, weight, and indication of the individual being treated, the time of administration, the excretion rate, and any combination with other treatments or therapies. Single or multiple administrations can be performed at dose levels and patterns selected by the treating physician. The administration regimen can be adjusted to provide an optimal therapeutic response. For example, a given dose delivering a certain amount of radiation can be calculated as a fraction of the total radiation delivered to the subject. The administration regimen can include the administration of multiple doses of the radiolabeled compound of Formula (I), the doses being the same or different. In some embodiments, the method of treating prostate cancer described herein can include the administration of multiple doses of the compound of Formula (I) complexed with a copper-67 radioisotope, the doses being the same. In other embodiments, the method includes the administration of multiple doses, the second and subsequent doses being higher than the first dose administered to the subject. For example, a first dose may deliver a first dose level of about 6 GBq, and a second, subsequent dose may deliver a dose of about 10 GBq. In some embodiments, the doses administered for therapeutic or therapeutic purposes are used to localize cancer sites, estimate the amount of compound retained by the subject (and subsequently the amount of radioactivity delivered), and assess the nature of the cancer site. 64 This is determined by prior radioimaging of the subject by administering a compound of formula (I) complexed with a Cu radioisotope. The inventors believe that the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for both radioimaging and radiotherapy represents a theranostic approach to GRPR-expressing metastatic castration-resistant prostate cancer.

[0082] That is, the method disclosed herein, which is the present method for radioimaging and treatment of GRPR-expressing metastatic castration-resistant prostate cancer, in which a compound of formula (I) is administered with a different isotope, represents a theranostic approach to the treatment of such cancer, i.e., a therapeutic and diagnostic (specific) approach, in which the administration of a compound of formula (I) may also be complexed with a radioisotope that allows for radioimaging of the subject. 67This is because administering a compound of formula (I) complexed with Cu enables treatment of the subject. Radioimaging allows visualization (identification) of where the compound of formula (I) accumulates, which corresponds to the treatment site. Without wishing to be bound by theory, the inventors believe that the methods and uses disclosed herein enable more effective treatment of GRPR-expressing metastatic castration-resistant prostate cancer. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a copper radioisotope allows for the delivery of higher doses of radioactivity in a single administration. Because the compound of formula (I) is specific to the GRPR membrane protein and retains the copper radioisotope for a longer period of time (compared to other metal chelators), radioactivity is delivered to the cancer site and localized more efficiently. The compound of formula (I) also exhibits better clearance from vital organs. This, in turn, reduces off-target effects of the radioisotope and limits undesired damage to healthy tissues due to the dissociation of the radioisotope and subsequent circulation. The better clearance and retention of the radiolabeled compound of formula (I) at the target cancer site leads to higher contrast images and subsequent more reliable diagnostic images.The ability to deliver a more sustained radiation dose by administering the compound of formula (I) complexed with copper radioisotope also leads to an overall more efficient treatment, since less compound of formula (I) and radioisotope are required.If the required radiation is delivered in a smaller dose, this leads to better tolerance of the treatment by the subject.

[0083] The present invention also contemplates combination therapy in which the radiolabeled compound of formula (I) described herein is co-administered with other suitable agents that can promote the desired therapeutic outcome. The term "co-administered" refers to simultaneous administration in the same formulation or two different formulations via the same or different routes, or sequential administration via the same or different routes. The term "concurrently" refers to the administration of more than one formulation administered to a subject at the same time. The term "concurrently" means that the active agents are administered at substantially the same time. The term "sequential" administration refers to a time difference of seconds, minutes, hours, or days between the administration of the agents. Administration can be in any order.

[0084] Because the methods disclosed herein involve the administration of a radioisotope that emits ionizing radiation, co-administration of one or more amino acids with an aqueous formulation containing a radiolabeled compound of Formula (I) disclosed herein can prevent or limit nephrotoxicity due to radiopharmaceutical retention. The one or more amino acids co-administered to a subject undergoing treatment for cancer associated with overexpression of the GRPR membrane protein competitively inhibit the reabsorption of the radiolabeled compound of Formula (I) by the proximal tubules of the kidney. The inventors believe that limiting the reuptake of the radiolabeled compound of Formula (I), and thus reducing nephrotoxicity in the subject, allows for the administration of higher doses of the compound, thereby increasing the efficacy of treatment. The methods disclosed herein for treating cancer further include administering one or more amino acids, or salts thereof, to a subject. In one embodiment, the formulation containing one or more amino acids or salts thereof is: 67 The compound of formula (I) is co-administered with an aqueous formulation comprising a compound of formula (I) complexed with a Cu radioisotope. In one embodiment, the one or more amino acids comprise lysine or a salt thereof. In another embodiment, the one or more amino acids comprise arginine or a salt thereof. In a preferred embodiment, the method for treating cancer further comprises administering lysine and / or arginine, or a salt thereof. In a preferred embodiment, the method for treating cancer further comprises administering lysine and arginine, or a salt thereof. In a preferred embodiment, the method for treating cancer disclosed herein comprises administering lysine and arginine, or a salt thereof, and 67 The present invention further includes co-administration of a compound of Formula (I) complexed with a Cu radioisotope. In some embodiments, one or more amino acids, or salts thereof, are administered as an intravenous infusion. In some embodiments, the formulation comprising one or more amino acids comprises L-lysine or a salt thereof. In other embodiments, the formulation comprising one or more amino acids comprises L-arginine or a salt thereof. In some embodiments, the one or more amino acids are present as hydrochloride salts. In some embodiments, the one or more amino acids are each present at a concentration of about 2.5% w / v.

[0085] The methods of the present invention may further comprise administering an antiemetic. In one embodiment, the methods of the present invention further comprise administering an antiemetic to the subject. In some embodiments, the antiemetic is 67 It is administered simultaneously with or prior to the administration of a compound of formula (I) complexed with Cu.

[0086] The methods of treatment disclosed herein include: 67 The method of treatment disclosed herein involves administering a formulation comprising a compound of formula (I) complexed with Cu. The formulation can be administered intravenously, for example, by slow intravenous infusion. 67 The method may include a single administration of a formulation comprising a compound of Formula (I) complexed with Cu, or more than one administration of the same or different formulations. In certain embodiments, the method of treating cancer includes: 67 In another embodiment, the method comprises administering one dose of an aqueous formulation comprising a compound of Formula (I) complexed with Cu. 67 In another embodiment, the method comprises administering two doses of an aqueous formulation comprising a compound of Formula (I) complexed with Cu. 67 In another embodiment, the method comprises administering three doses of an aqueous formulation comprising a compound of Formula (I) complexed with Cu. 67 The method comprises administering four doses of an aqueous formulation comprising a compound of formula (I) complexed with Cu. When four doses are administered: 67 The maximum planned cumulative administered activity of Cu-SAR-BBN will not exceed critical organ dose limits (23 Gy to kidney and 2 Gy to bone marrow) over four doses.

[0087] If more than one administration is required, the interval between administrations of the formulation may be from about 6 weeks to about 14 weeks. 67The method comprises administering more than one dose of an aqueous formulation comprising a compound of Formula (I) complexed with Cu, wherein the doses are administered about 6 weeks apart. In another embodiment, the method comprises administering more than one dose, wherein the doses are administered about 8 weeks apart. In another embodiment, the method comprises administering more than one dose, wherein the doses are administered about 10 weeks apart. In another embodiment, the method comprises administering more than one dose, wherein the doses are administered about 12 weeks apart. In another embodiment, the method comprises administering more than one dose, wherein the doses are administered about 14 weeks apart. In some embodiments, the treatment methods discussed herein comprise: 67 The method includes administering two or more doses of a formulation comprising a compound of Formula (I) complexed with Cu, and the time between doses can be the same. In some embodiments, the method includes administering two or more doses of the formulation, and the time between doses is approximately the same, for example, about 6 weeks between each dose, about 8 weeks between each dose, about 10 weeks between each dose, about 12 weeks between each dose, or about 14 weeks between each dose. In other embodiments, the time between doses can be different, for example, about 6 weeks between the first and second doses, and about 8 weeks between the second and third doses. In other embodiments, different time between doses are also contemplated, and the time between two consecutive doses can be about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks.

[0088] In one embodiment, the method of treating GRPR-expressing metastatic castration-resistant prostate cancer comprises: 67 It involves administering one dose of a formulation comprising a compound of formula (I) complexed with Cu. 67 In some embodiments where a formulation comprising a compound of Formula (I) complexed with Cu is administered more than once, the formulations administered each time may be the same or different. If the formulations are different, the 67 Compounds of formula (I) complexed with Cu can deliver different doses of radioactivity, for example, about 6 GBq, about 10 GBq, about 14 GBq, about 18 GBq, about 22 GBq, or about 24 GBq. In one embodiment, compounds of formula (I) are administered for methods of treating cancer associated with overexpression of the GRPR membrane antigen. 67An aqueous formulation of a compound of Formula (I) complexed with Cu delivers a dose of radiation of about 6 GBq to about 24 GBq to a subject. In one embodiment, the compound is administered for a method of treating cancer associated with overexpression of the GRPR membrane antigen. 67 An aqueous formulation of a compound of Formula (I) complexed with Cu delivers a dose of radiation of about 6 GBq to about 14 GBq to a subject. In one embodiment, the aqueous formulation delivers a dose of about 4 GBq. In another embodiment, the aqueous formulation delivers a dose of about 6 GBq. In another embodiment, the aqueous formulation delivers a dose of about 8 GBq. In another embodiment, the aqueous formulation delivers a dose of about 9 GBq. In another embodiment, the aqueous formulation delivers a dose of about 10 GBq. In another embodiment, the aqueous formulation delivers a dose of about 12 GBq. In yet another embodiment, the aqueous formulation delivers a dose of about 14 GBq. In another embodiment, the aqueous formulation delivers a dose of about 16 GBq. In another embodiment, the aqueous formulation delivers a dose of about 18 GBq. In another embodiment, the aqueous formulation delivers a dose of about 20 GBq. In another embodiment, the aqueous formulation delivers a dose of about 22 GBq. In another embodiment, the aqueous formulation delivers a dose of about 24 GBq.

[0089] or, 67 The dose of radioactivity delivered by the compound of formula (I) complexed with Cu is the maximum dose tolerated by each individual subject. Those skilled in the art will understand that the maximum tolerated dose varies between subjects. The inventors have found that administering a compound of formula (I) containing a radioisotope suitable for imaging can visualize not only the distribution and uptake of the radiolabeled compound, but also the tolerance that the subject has to a given dose. If the subject appears to be able to tolerate the dose well and other physiological measures (e.g., liver and kidney function) are satisfactory, this information can be used to determine a higher dose of radiation specific to the subject. In one embodiment, the method disclosed herein: 67 The method includes assessing the subject's tolerance to a dose of a compound of Formula (I) complexed with Cu and modifying the dose of radioactivity delivered to the subject in subsequent administrations. Those skilled in the art will appreciate that nuclear medicine imaging, the ability to determine baseline levels of radiation and 67It will be appreciated that a variety of techniques may be used, including comparing post-administration levels of Cu complexed with a compound of formula (I), comparing the size and number of lesions before and after administration, and monitoring biochemical markers by one or more diagnostic assays of the tissue.

[0090] Accordingly, the present invention also provides a method of treating GRPR-expressing metastatic castration-resistant prostate cancer, comprising administering to a subject 67 The present invention provides a method in which the dose of a compound of formula (I) complexed with Cu is subject-specific and determined by a combination of imaging and physiological assay techniques. In some embodiments, the dose is determined by administering a compound of formula (I) complexed with an appropriate radioisotope to a subject, followed by imaging the subject over a period of time to obtain one or more images that can be used to determine the suitability of the administered dose for the subject. In some embodiments, the imaging can be performed by one or more techniques, such as PET, SPECT, CT, and MRI. Without wishing to be bound by theory, the inventors believe that the methods disclosed herein are effective in treating patients with GRPR-expressing metastatic castration-resistant prostate cancer, and 177 We believe this will enable more refined and personalized plans to treat cancer in patients diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer who are ineligible for treatment with Lu-PSMA-617. In a further aspect, the present invention provides a method for producing a pharmaceutical composition comprising: 67 Provided is a method for predicting a patient's response to treatment of cancer with a compound of formula (I) complexed with Cu, comprising detecting and enumerating circulating tumor DNA (ctDNA) associated with one or more genes in the patient, and correlating the amount of ctDNA detected with the patient's response to said treatment, wherein the cancer is a GRPR-expressing cancer and the one or more genes are selected from the group consisting of BRCA1, BRCA2, RB, and p53. In certain embodiments, the GRPR-expressing cancer is selected from prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumor (GIST). As used herein, the term "circulating tumor DNA" (ctDNA) refers to fragments of DNA in the blood of a cancer patient that are released from the cancer patient's cancerous cells (e.g., tumor cells) via apoptosis, necrosis, or active release. 67 According to the method for predicting a patient's response to cancer treatment using a compound of formula (I) complexed with Cu, as disclosed herein, the patient's ctDNA is obtained and quantified by suitable means. The nature and amount of ctDNA analyzed depends on the nature of the patient and the cancer. Once determined, the nature and amount of ctDNA can be compared with benchmark values ​​to determine whether the patient is responding. 67 It can be predicted whether a patient will respond (or not) to treatment with a compound of formula (I) complexed with Cu. In certain embodiments, the ctDNA analyzed is associated with BRCA1. In other embodiments, the ctDNA analyzed is associated with BRCA2. In other embodiments, the ctDNA analyzed is associated with RB. In other embodiments, the ctDNA analyzed is associated with p53.

[0091] Reference herein to any prior publication (or information derived therefrom) or any known matter is not, and should not be construed as, an acknowledgement or admission or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification pertains.

[0092] Those skilled in the art will understand that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications within its spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated herein, individually or collectively, and any and all combinations of more than any one of said steps or features.

[0093] Example The following examples are illustrative of the present disclosure and should not be construed as limiting in any way the general nature of the illustrative disclosure throughout this specification.

[0094] Example 1 64 Cu-SAR-BBN and 67 Preparation of Cu-SAR-BBN The synthesis of SAR-BBN begins with the solid-phase synthesis of a linear 9-amino acid chain (peptide), which is then supplemented with a PEG spacer and (Boc) 4~5 This is followed by on-resin coupling of the MeCOSar solution-phase chelator. A final capping step with ZL-Ala-OH (Boc) 4~5 Any peptide chain not coupled with MeCOSar is terminated. The completed peptide is cleaved from the resin, globally deprotected, purified by reverse-phase high-performance liquid chromatography (RP-HPLC), and salt exchanged to acetate.

[0095] Solid Phase Peptide Synthesis Amino acids are added sequentially via a proven chemical sequence that involves deprotecting the terminal amino group, activating the carboxyl group of the next amino acid, and then washing the resulting peptide before starting the next step. 4~5 MeCOSar-(PEG)4-D-Phe-Gln(Trt)-Trp(Boc)-Ala-Val-Gly-His(Trt)-Sta-Leu-Rink resin is prepared using an 11-cycle process.

[0096] Resin cleavage and global deprotection The resin-bound, fully protected SAR-BBN peptide is treated with trifluoroacetic acid in the presence of a cation scavenger to cleave the peptide from the resin and remove all acid-labile protecting groups, i.e., the Boc group on MeCOSar and the orthogonal protecting groups on the peptide. The crude product solution is then lyophilized using the following sequence: the product solution is pre-frozen (-60 °C) as a shell on the inner surface of a round-bottom flask and placed on a vacuum manifold at ambient temperature. The maximum achievable vacuum (0.1-0.4 mBar) is applied to the lyophilizer until the product is confirmed dry by manual checking for solid ice, typically after 30-48 h. The crude product, MeCOSar-(PEG)4-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, is then analyzed by RP-HPLC to confirm the quality of the material and by mass spectrometry to confirm that the product is fully deprotected (removal of all Boc groups).

[0097] purification The crude SAR-BBN is then subjected to preliminary RP-HPLC purification as the trifluoroacetate salt. Fractions from each purification run are collected in tubes and analyzed by analytical HPLC; fractions of acceptable purity are combined and lyophilized under the same conditions.

[0098] Acetate exchange The trifluoroacetate salt form is exchanged into the acetate salt form by preparative RP-HPLC using an eluent system of ammonium acetate and acetic acid (AcOH) in water / acetonitrile.

[0099] Freeze drying of bulk materials Bulk SAR-BBN acetate is lyophilized under the conditions described above for crude SAR-BBN. The product is weighed into screw-cap storage bottles, vacuum-sealed, and refrigerated before aliquoting into vials in the desired amounts for radiolabeling.

[0100] In a 5 mL solution of sodium phosphate buffer (0.1 M, pH 6.5–7.0) containing sodium gentisate (5.7 mg), 64Cu]CuCl2 (1000–2000 MBq, 100–500 μL, 0.05 M HCl) was added to SAR-BBN (60 μg). 64 Cu-SAR-BBN was prepared. The reaction mixture was incubated at room temperature for 25 minutes, after which the reaction mixture was filtered through a 0.22 μm filter into a sterile product vial. The reaction was quenched by adding 10 mL of 7.5% aqueous ethanol containing sodium ascorbate (1.17 g) through a 0.22 μm filter to the sterile product vial. 64 Cu-SAR-BBN was produced in an average radiochemical yield of 84% with radiochemical purity of over 95%.

[0101] In a 14 mL solution of sodium phosphate buffer (0.1 M, pH 6.5–7.0) containing sodium gentisate (11.4 mg), 64 Cu]CuCl2 (6000–12000 MBq, 100–500 μL, 0.05 M HCl) was added to SAR-BBN (120 μg). 67 Cu-SAR-BBN was prepared. The reaction mixture was incubated at room temperature for 25 minutes, after which the reaction mixture was filtered through a 0.22 μm filter into a sterile product vial. The reaction was quenched by adding 13 mL of 8% aqueous ethanol containing sodium ascorbate (2.27 g) through a 0.22 μm filter to the sterile product vial. 64 Cu-SAR-BBN was produced in an average radiochemical yield of 86% with radiochemical purity of over 95%.

[0102] Example 2 - Non-clinical studies Several non-clinical studies were carried out to confirm the natural stable Cu( nat Cu), 64 Cu or 67 The biodistribution, in vivo safety and tolerability, as well as tumor imaging and efficacy of SAR-BBN labeled with either Cu were determined.

[0103] PCa xenograft mouse model 64Injection of Cu-Sar-BBN demonstrated high uptake and retention of the radiolabeled compound over 24 hours (19.6% injected activity (IA) / g at 1 hour and 7.9% IA / g at 24 hours after injection). These results compare favorably with other GRPR-targeting ligands in similar preclinical models.

[0104] In mice 67 Preclinical efficacy data for Cu-SAR-BBN demonstrated statistically significant tumor growth inhibition and increased survival compared to the control group in a PCa xenograft study.

[0105] A repeat dose toxicity study of the compound of formula (I) was conducted in male and female mice, administered weekly by IV injection for four weeks. nat Abnormal clinical signs in mice treated with Cu-Sar-BBN were observed only on the day of injection. nat Although fully reversible microscopic findings were observed in male mice treated with Cu-Sar-BBN, these findings were not considered adverse, and no other clinical abnormalities, significant changes in body weight or food intake, or effects on hematology, blood biochemistry, or urinalysis were observed. This confirms the efficacy of Cu-Sar-BBN in both male and female mice. nat It is demonstrated that no adverse event levels are observed at 2 mg / kg for Cu-Sar-BBN.

[0106] Example 3 67 Biodistribution of Cu-Sar-BBN In healthy male and female mice, 67 The biodistribution of Cu-SAR-BBN was investigated. 67 Effective blood clearance of Cu-SAR-BBN was demonstrated in male (0.79±0.22% IA / g) and female (1.06±0.18% IA / g) mice at 1 h, which further decreased over time. Expression of GRPR in the pancreas resulted in high initial pancreatic uptake, with the highest accumulated activity at 1 h in both male and female mice (19.43±9.98% IA / g and 22.32±10.54% IA / g, respectively). 67Over 75% and 97% of Cu-SAR-BBN activity was cleared at 4 and 24 hours, respectively. Similar rapid clearance profiles were seen in other GRPR-expressing organs, specifically the adrenal gland and stomach. 67 Cu-SAR-BBN showed low kidney uptake in both male and female mice (3.79±0.542% IA / g and 6.15±0.73% IA / g, respectively) even at 1 h, which further decreased with time, suggesting fast renal clearance. Liver and intestinal uptake 67 This suggests that hepatobiliary clearance of Cu-SAR-BBN also exists, which consistently decreased over 24 to 216 hours. Blood data demonstrated rapid clearance of blood pool activity as well as relatively rapid clearance of renal and hepatic activity.

[0107] Total dose calculations from mouse biodistribution studies revealed that therapeutic 67 Cu-SAR-BBN and diagnostic 64 It is now possible to calculate organ radiation dose extrapolations for adult males for both Cu, SAR, and BBN. 67 For Cu-SAR-BBN, the highest absorbed dose is estimated to be the liver at 0.109 mGy / MBq, followed by the bladder wall at 0.641 mGy / MBq. 64 For Cu-SAR-BBN, the maximum absorbed doses were estimated to be in the bladder wall and liver, with values ​​of 0.070 mGy / MBq and 0.040 mGy / MBq, respectively. 64 The effective whole-body dose of Cu-SAR-BBN was estimated to be 0.018 mSv / MBq for an adult male.

[0108] These results suggest that 64 Cu-SAR-BBN and 67 Demonstrates targeted delivery of Cu-SAR-BBN and demonstrates therapeutic efficacy of the radiolabeled compound in human GRPR-expressing cancers.

[0109] The blood data showed rapid clearance of blood pool activity and relatively rapid clearance of kidney and liver activity. These dosimetric results indicated that red bone marrow 67 The pancreas is likely to be the dose-limiting organ for Cu-SAR-BBN, with an estimated absorbed dose of 0.023 mGy / MBq. The pancreas is estimated to be the organ with the highest absorbed dose (0.303 mGy / MBq), with the kidneys estimated to have an absorbed dose of 0.070 mGy / MBq. No clear dose limit for radiation therapy for the pancreas has been identified in the literature, and the pancreas is not yet considered an organ at risk in radiation therapy planning.

[0110] In the exam 67 The absorbed dose from the planned administered activity of Cu-SAR-BBN was evaluated against the bone marrow absorbed dose limit of 2 Gy (shown in Table 1). To reach the kidney threshold of 2 Gy, an adult male would need approximately 87 GBq of radiation. 67 It has been estimated that the administered activity of Cu-SAR-BBN would be required to provide the desired dose. The proposed dose levels have a total administered activity range of 6-56 GBq, which would result in a total absorbed dose to bone marrow of 0.138-1.288 Gy, which is well below the established limits for all proposed doses.

[0111] Example 4 - Formulation of Sar-BBN 64 Cu-Sar-BBN and 67 Both Cu-Sar-BBN are formulated as sterile solutions for IV injection suitable for human use.

[0112] 64 Cu-SAR-BBN and 67 Cu-SAR-BBN is stored at room temperature in sealed, sterile, pyrogen-free glass vials with an expiration date on the label. 64 Cu-SAR-BBN and 67 The shelf life of Cu-SAR-BBN is indicated on the product label.

[0113] Example 5 - For radiographic imaging 64 Administration of Cu-Sar-BBN 200MBq dose 64 Cu-Sar-BBN was administered to subjects by slow intravenous bolus injection. Subjects were imaged by PET / CT, and the images were analyzed to detect 64 The location, size and volume of any cancerous lesions present, as indicated by the decay products of the Cu radioisotope, were determined.

[0114] Using the image of the target generated above, 67 Suitability for treatment of cancer (if present) with Cu-Sar-BBN was determined.

[0115] Example 6 - Conventional treatment in breast cancer patients 18 FDG PET or 64 Imaging diagnosis using Cu-Sar-BBN PET For women with clinical progression of metastatic ER+ / PR+ / HER2- breast cancer requiring restaging 18 FDG was administered and images of each patient were acquired by PET. 64 Cu-Sar-BBN PET (200MBq 64 Cu-Sar-BBN was administered by IV injection) 18 PET imaging was performed within 2 weeks of FDG imaging. Qualitative interpretation of PET studies was performed by a board-certified nuclear medicine physician. Quantitative analysis was performed using MIM Software, Cleveland. 18 FDG and 64 Comparisons of images obtained from each subject after both Cu-Sar-BBN administrations can be seen in Figures 1-6 (see Table 1). 64 1 shows that Cu-Sar-BBN-targeted GRPR receptors localized lesions in subjects that were not identified during imaging with other modalities. [Table 1]

[0116] Example 7 - Conventional treatment in prostate cancer patients 18 FDG PET or64 Imaging diagnosis using Cu-Sar-BBN PET Four post-radical prostatectomy men had consecutive negative PSMA-PET scans ( 68 The patients showed biochemical recurrence with 1000 ng / mL of PD-L1 receptor agonist (PSMA-11). Conventional imaging modalities, including bone scan, CT, and occasionally whole-body MRI, were unable to identify the site of recurrence. All patients had a mean of 200 MBq of PD-L1 receptor agonist (PSMA-11). 64 Cu[Cu]Cu-SAR-BBN was administered intravenously for 60 minutes for uptake. Between 60 and 180 minutes after injection, patients were scanned with their arms elevated, from the crown to the mid-thigh, for 2 minutes in each bed position. Low-dose CT scans were performed for attenuation correction and anatomical localization. 18 FDG and 64 A comparison of the images obtained from each subject after both administrations of Cu-Sar-BBN can be seen in Figures 7-10. 64 1 shows that Cu-Sar-BBN-targeted GRPR receptors localized lesions in subjects that were not identified during imaging with other modalities.

[0117] Example 8 67 Subject eligibility for treatment with Cu-Sar-BBN Obtained by PET / CT 64 Images of subjects receiving Cu-Sar-BBN 64 When showing the Cu-Sar-BBN bond, 64 Cu and 67 Cu is a theranostic pair, so the target 67 This suggests that this is suitable for treatment with Cu-Sar-BBN.

[0118] Example 9 - For treatment 67 Administration of Sar-BBN of 6 GBq dose, 67 A compound of formula (I) complexed with a Cu radioisotope (i.e. 67 Cu-SarBBN) 64Cu-Sar-BBN was administered to subjects determined to have GRPR-associated cancerous lesions identified by post-administration radiographic imaging.

[0119] A further dose of 6 GBq was administered to the same patient 6 weeks after the first dose.

[0120] After a period of at least 2 days (i.e., to allow for clearance of the 67Cu-Sar-BBN), the subject was administered an additional dose of 200 MBq of 64Cu-Sar-BBN and the subject was imaged by PET / CT. 64 After administration of Cu-Sar-BBN ( 67 Images taken (both before and after administration of Cu-Sar-BBN) were used to determine the progression of any lesions present in the subjects.

[0121] Example 10 - Determination of Efficacy of Sar-BBN Efficacy Assessment Tumor response assessment Tumor measurements for disease assessment were performed using bone scans and CT / MRI, and response was assessed according to PCWG3 (Prostate Cancer Working Group 3) guidelines. If patients showed evidence of progression by bone scan alone, a confirmatory scan (i.e., 64 administration of Cu-Sar-BBN and subsequent imaging) was performed, and the images were further evaluated.

[0122] Example 11 - Qualitative Analysis of Scans 64 Cu-SAR-BBN PET / CT and baseline standard of care images will be evaluated to identify the number of lesions detected. Lesion-level analysis will be performed. 64 The number of GRPR-expressing lesions seen on Cu-SAR-BBN PET / CT screening scans will be compared with the number of lesions seen on baseline standard of care imaging.

[0123] Baseline standard of care images used for comparison: · CT or MRI scan for soft tissue disease. · Bone scan for bone lesions.

[0124] Example 12 - Detection and quantification of ctDNA Blood was collected from the patient and analyzed using the CELLSEARCH® Circulating Tumor Cell Kit (Janssen Diagnostics, Raritan, NJ). The determined volume / quantity of circulating tumor cells (CTCs) or ctDNA is then compared to, for example, expected values ​​for healthy patients or values ​​previously determined for the patient. CTC counts are reported as follows: · Preferably no more than 4 cells per 7.5 mL of blood. More than 5 cells per 7.5 mL of blood is undesirable.

[0125] Therefore, the CTC or ctDNA levels correlate with prognosis and response to treatment.

Claims

1. 1. A method of treating a patient diagnosed with a GRPR-expressing cancer comprising administering to a patient an effective amount of: ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Chemistry 1】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) administering wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

2. 2. The method of claim 1, wherein the GRPR-expressing cancer is selected from prostate cancer, breast cancer, glioma, ovarian cancer, lung cancer, and gastrinoma and gastrointestinal stromal tumor [GIST].

3. 1. A method of treating a patient diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer, comprising administering to a patient an effective amount of: ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Chemistry 2】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) administering wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

4. １７７ 1. A method of treating a patient diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer who is ineligible for treatment with Lu-PSMA-617, comprising administering to said patient an effective amount of: ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Transformation 3】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) administering wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.

5. 1. A method for identifying and treating a patient diagnosed with GRPR cancer, comprising: (i) an effective amount of ６４ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Chemistry 4】 (Wherein R is CH ３ C(O)—; ( ６４ (Cu-S--BBN) administering The aforementioned ６４ the dose of radiation delivered by the Cu radioisotope is sufficient to identify one or more lesions associated with said cancer; (ii) an effective amount of ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Transformation 5】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) administering The aforementioned ６７ the dose of radiation delivered by the Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer; A method comprising:

6. 1. A method for identifying and treating a patient diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer, comprising: (iii) an effective amount of: ６４ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Transformation 6】 (Wherein R is CH ３ C(O)—; ( ６４ (Cu-S--BBN) administering The aforementioned ６４ the dose of radiation delivered by the Cu radioisotope is sufficient to identify one or more lesions associated with said cancer; (iv) an effective amount of ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Transformation 7】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) administering The aforementioned ６７ the dose of radiation delivered by the Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer; A method comprising:

7. １７７ 1. A method for identifying and treating patients diagnosed with GRPR-expressing metastatic castration-resistant prostate cancer who are ineligible for treatment with Lu-PSMA-617, comprising: (iii) an effective amount of: ６４ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Transformation 8】 (Wherein R is CH ３ C(O)—; ( ６４ (Cu-S--BBN) administering The aforementioned ６４ the dose of radiation delivered by the Cu radioisotope is sufficient to identify one or more lesions associated with said cancer; (iv) an effective amount of ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Chemistry 9】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) administering The aforementioned ６７ the dose of radiation delivered by the Cu radioisotope is sufficient to reduce the size of the one or more lesions associated with the cancer; A method comprising:

8. The stereochemistry of the peptide portion of the compound of formula (I) is shown below: 【Chemistry 10】 8. The method according to any one of claims 1 to 7.

9. The aforementioned ６４ 8. The method of claim 5, 6 or 7, wherein the dose of radiation delivered by the Cu radioisotope is about 200 MBq.

10. The patient ６７ 10. The method of any one of claims 1 to 9, wherein 1, 2, 3 or 4 doses of Cu-SAR-BBN are administered.

11. ６７ 11. The method of claim 10, wherein the maximum planned cumulative administered activity of Cu-SAR-BBN does not exceed the critical organ dose limits (23 Gy to kidney and 2 Gy to bone marrow) over four administrations.

12. 12. The method of any one of claims 1 to 11, wherein the patient is a male subject with a castrate level of serum / plasma testosterone of less than about 50 ng / dL or less than about 1.7 nmol / L.

13. 5. The method of claim 3 or 4, wherein the GRPR-expressing metastatic castration-resistant prostate cancer (GRPRmCRPC) is progressive GRPRmCRPC despite prior androgen deprivation therapy and at least one of enzalutamide and / or abiraterone (or other such androgen receptor pathway inhibitors).

14. the patient has: ６７ 14. The method of any one of claims 1 to 13, wherein the patient experiences a percentage decrease in PSA and / or alkaline phosphatase (ALP) and / or lactate dehydrogenase (LDA) biomarkers after 1, 2, 3 or 4 therapeutic administration cycles of the compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope.

15. An effective amount of ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Chemistry 11】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) The use of The use wherein the dose of radiation delivered by said radioisotope is sufficient to reduce the size of one or more lesions associated with said cancer.

16. In the manufacture of a medicament for treating a patient diagnosed with a GRPR-expressing cancer, an effective amount of ６７ A compound of formula (I) or a pharmaceutically acceptable salt thereof complexed to a Cu radioisotope: 【Chemistry 12】 (Wherein R is CH ３ C(O)—; ( ６７ (Cu-S--BBN) The use of The use wherein the dose of radiation delivered by said radioisotope is sufficient to reduce the size of one or more lesions associated with said cancer.

17. ６７ 1. A method for predicting a patient's response to treatment of cancer with a compound of formula (I) complexed with Cu, comprising the steps of detecting and enumerating circulating tumor DNA (ctDNA) associated with one or more genes in the patient, and correlating the amount of detected ctDNA with the patient's response to the treatment, wherein the cancer is a GRPR-expressing cancer and the one or more genes are selected from the group consisting of BRCA1, BRCA2, RB, and p53.

18. ６７ 1. A method for predicting a patient's response to treatment of cancer with a compound of formula (I) complexed with Cu, comprising the steps of detecting and enumerating circulating tumor DNA (ctDNA) associated with one or more genes in the patient, and correlating the amount of detected ctDNA with the patient's response to the treatment, wherein the cancer is a GRPR-expressing cancer and the one or more genes are selected from the group consisting of BRCA1, BRCA2, RB, and p53.

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