PSMA-targeted radioligand therapy regimen

Abstract

This specification describes radiopharmaceuticals for the treatment of PSMA-expressing cancers, as well as methods and / or uses of such compounds for the treatment of PSMA-expressing cancers, such as metastatic castration-resistant prostate cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application relates to U.S. Provisional Application No. 63 / 514,849, filed on 21 July 2023. The entire contents of said application are incorporated herein by reference.

[0002] This disclosure relates to radiopharmaceuticals targeting prostate-specific membrane antigens (PSMAs) and their use in the treatment of PSMA-expressing cancers, such as metastatic castration-resistant prostate cancer (mCRPC). [Background technology]

[0003] Prostate cancer (PC) is the leading cause of cancer-related deaths in men worldwide, with an estimated 1.4 million new cases and 375,000 deaths reported in 2020 (Wang et al. 2022, Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019. Frontiers in Public Health). 10–20% of prostate cancer tumors become resistant to androgen deprivation therapy, such as drug therapy or surgical castration, progressing to metastatic castration-resistant prostate cancer (mCRPC) (Juzeniene et al. 2021, Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer. Cancers).

[0004] Over the past decade, new treatment options for mCRPC patients have been approved, including novel anti-hormone therapies, PARP inhibitors, radiopharmaceuticals, immunotherapy, and chemotherapy. Despite these advances, mCRPC remains incurable, partly due to the heterogeneity among and within patients with the disease. Therefore, there is an urgent need for personalized, highly effective targeted therapies for mCRPC patients.

[0005] Targeted radioligand therapy (RLT) offers the potential for specific and tumor-selective treatment of cancerous lesions by utilizing cell surface receptors primarily expressed on malignant cells, such as prostate-specific membrane antigen (PSMA). PSMA is an attractive target for prostate cancer treatment because it is highly expressed on cancer cells, including mCRPC cells, while its expression is much lower in normal tissues. Therefore, PSMA may be a viable target for RLT with minimal radioactivity-related side effects. Specifically, RLT utilizing radiolabeled small molecule inhibitors of PSMA that bind to PSMA with high affinity and are internalized and retained within targeted PSMA-expressing cells (i.e., malignant cells) may be used to identify and treat PSMA-positive mCRPC lesions. [Overview of the project]

[0006] In one embodiment, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 6 MBq to 8 MBq. The subjects have previously received chemotherapy.

[0007] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 6 MBq to 8 MBq. The subjects are those who have not previously received chemotherapy.

[0008] In another aspect, the Disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I) or (II) to the subject, [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (I) or (II) is radiolabeled with an alpha-emitting radionuclide, The radiolabeled compound of formula (I) or (II) is administered in doses of approximately 6 MBq to approximately 8 MBq. The subjects have previously received chemotherapy.

[0009] In another aspect, the Disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I) or (II) to the subject, [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (I) or (II) is radiolabeled with an alpha-emitting radionuclide, The radiolabeled compound of formula (I) or (II) is administered in doses of approximately 6 MBq to approximately 8 MBq. The subjects are those who have not previously received chemotherapy.

[0010] In another embodiment, the present disclosure provides a method for treating prostate cancer in a subject requiring treatment, comprising administering a radiopharmaceutical to the subject in a dose of about 6 MBq to about 8 MBq, wherein the radiopharmaceutical is a compound of formula (I). [ka] The compound of formula (I) is 225 The cells are radiolabeled with Ac, and the subjects have previously received chemotherapy.

[0011] In yet another aspect, the disclosure provides a method for treating prostate cancer in a subject requiring treatment, the method comprising administering a radiopharmaceutical to the subject in a dose of about 6 MBq to about 8 MBq, the radiopharmaceutical being a compound of formula (I), [ka] The compound of formula (I) is 225 The cells were radiolabeled with Ac, and the subjects had not previously received chemotherapy.

[0012] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 6 MBq to 14 MBq. The subjects have previously received chemotherapy.

[0013] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 6 MBq to 14 MBq. The subjects are those who have not previously received chemotherapy.

[0014] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 8 MBq to 10 MBq. The subjects have previously received chemotherapy.

[0015] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 8 MBq to 10 MBq. The subjects are those who have not previously received chemotherapy.

[0016] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), or (IV) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration, or [ka] The compounds of formula (I), (II), or (IV) are radiolabeled with alpha-emitting radionuclides. The radiolabeled compounds of formula (I), (II), or (IV) are administered in doses of approximately 6 MBq to approximately 14 MBq. The subjects have previously received chemotherapy.

[0017] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), or (IV) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration, or [ka] The compounds of formula (I), (II), or (IV) are radiolabeled with alpha-emitting radionuclides. The radiolabeled compounds of formula (I), (II), or (IV) are administered in doses of approximately 6 MBq to approximately 14 MBq. The subjects are those who have not previously received chemotherapy.

[0018] In another embodiment, the present disclosure provides a method for treating prostate cancer in a subject requiring treatment, comprising administering a radiopharmaceutical to the subject in a dose of about 8 MBq to about 10 MBq, wherein the radiopharmaceutical is a compound of formula (I). [ka] The compound of formula (I) is 225 The cells are radiolabeled with Ac, and the subjects have previously received chemotherapy.

[0019] In yet another aspect, the Disclosure provides a method for treating a subject in need of treatment for prostate cancer, the method comprising administering a radiopharmaceutical to the subject in a dose of about 8 MBq to about 10 MBq, the radiopharmaceutical being a compound of formula (I), [ka] The compound of formula (I) is 225 The cells were radiolabeled with Ac, and the subjects had not previously received chemotherapy.

[0020] In another embodiment, the present disclosure provides a method for treating prostate cancer in a subject requiring treatment, comprising administering a radiopharmaceutical to the subject in a dose of about 6 MBq to about 14 MBq, wherein the radiopharmaceutical is a compound of formula (II). [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (II) is 225 The cells are radiolabeled with Ac, and the subjects have previously received chemotherapy.

[0021] In yet another aspect, the present disclosure provides a method of treating a subject having a need for treatment of prostate cancer, the method comprising administering to the subject a radiopharmaceutical at a dose of from about 6 MBq to about 14 MBq, the radiopharmaceutical being a compound of formula (II),

Chemical formula

Mode for Carrying Out the Invention

[0022] PSMA is a transmembrane glycoprotein of about 100 kDa with folate hydrolase, carboxypeptidase, and internalization activity, and shows low expression in normal prostate tissue, kidney, duodenum, salivary gland, lacrimal gland, brain, and intestine. The increase in PSMA expression is significantly related to the degree of differentiation and progression of mCRPC. Therefore, PSMA-targeted ligands may selectively accumulate in malignant cells, providing opportunities for the development of imaging and treatment of mCRPC. By systemic administration of RLT targeting PSMA, widespread bone metastases and extraosseous metastases can be treated simultaneously, and radiotoxicity to healthy tissues can be suppressed.

[0023] Currently, β - emitting radionuclides 177 Lu is the most clinically used radionuclide in RLT for the treatment of PSMA-expressing cancers such as prostate cancer. However, alpha particles have significantly higher energy and shorter path lengths (<0.1 mm) than beta - particles, so when interacting with cell nuclei, double-strand DNA breaks are more likely to occur (i.e., higher cytotoxicity). Therefore, there is great interest in the use of alpha particles in PSMA-targeted RLT in the treatment of prostate cancer including mCRPC.

[0024] Accordingly, this specification describes compounds radiolabeled with alpha-emitting radionuclides targeting PSMA, corresponding pharmaceutical compositions, and their use in subjects requiring treatment of PSMA-expressing cancers.

[0025] In one embodiment, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 6 MBq to 14 MBq, for example, approximately 6 MBq to 8 MBq, or approximately 8 MBq to 10 MBq. The subjects have previously received chemotherapy.

[0026] In another aspect, the present disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a PSMA-binding ligand to the subject, the PSMA-binding ligand being radiolabeled with an alpha-emitting radionuclide. Radiolabeled PSMA-binding ligands are administered in doses of approximately 6 MBq to 14 MBq, for example, approximately 6 MBq to 8 MBq, or approximately 8 MBq to 10 MBq. The subjects are those who have not previously received chemotherapy.

[0027] Specifically, this disclosure provides a method for treating PSMA-expressing cancer in subjects requiring treatment, the method comprising administering a compound of formula (I), (II), or (IV) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration, or [ka] The compounds of formula (I), (II), or (IV) are radiolabeled with alpha-emitting radionuclides.

[0028] This specification also provides a method for treating prostate cancer in subjects requiring treatment, the method comprising administering a radiopharmaceutical to the subject in doses of about 6 MBq to about 10 MBq, for example, about 6 MBq to about 8 MBq, or about 8 MBq to about 10 MBq, the radiopharmaceutical being a compound of formula (I), [ka] The compound of formula (I) is 225 It is radiolabeled with Ac.

[0029] This specification also provides a method for treating prostate cancer in subjects requiring treatment, the method comprising administering a radiopharmaceutical to the subject in a dose of approximately 6 MBq to approximately 14 MBq, wherein the radiopharmaceutical is a compound of formula (II). [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (II) is 225 It is radiolabeled with Ac.

[0030] Details of the disclosure are described in the attached description below. Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but this specification describes exemplary methods and materials. Other features, purposes, and advantages of this disclosure will become apparent from the description and claims. In this specification and claims, singular nouns are also plural nouns unless the context explicitly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0031] definition Unless otherwise specified, the terms, procedures, and techniques used herein in relation to analytical chemistry, organic synthesis, and pharmaceutical chemistry are well-known and commonly used in the art. Standard techniques can be used for chemical synthesis and chemical analysis. Such techniques and procedures are, for example, published in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is incorporated herein by reference for all purposes. Where permitted, all patents, applications, published applications and other publications, and other data referenced throughout the disclosure are incorporated herein by reference in their entirety.

[0032] As used herein, the terms "alpha-emitting radionuclides" and "alpha-emitting bodies" primarily refer to radionuclides that decay by alpha decay (e.g., 225 Ac) and radioactive nuclides that decay by branching decay (e.g., β) - It decays through decay and alpha decay. 213 Includes Bi)

[0033] In this specification, the term “radiopharmaceutical” is used to refer to pharmaceutical compounds such as peptides, oligonucleotides, small molecules, and antibodies that are radiolabeled with a radionuclide. A radiopharmaceutical may be a radioligand. In some embodiments, a radiopharmaceutical refers to a radiolabeled compound of this disclosure (i.e., a compound of formula (I), (II), or (IV) (above), or a compound of formula (III) or (V) (below)). In other embodiments, a radiopharmaceutical refers to a radiolabeled compound known in the art.

[0034] As used herein, the term "beta-minus emitting radiopharmaceutical" refers to β - This refers to radiopharmaceuticals that are radiolabeled with radioactively emitting radionuclides. - Electrolytic radionuclides undergo beta decay during the process of natural decay. -It is a radionuclide that emits particles. An example of beta-minus emitting radiopharmaceuticals that can be included in beta-minus emitting radiopharmaceuticals. - Radial-emitting radionuclides are, 177 Lu, 161 Tb, 131 I, 90 Y, 67 Cu, and 47 This includes, but is not limited to, Sc.

[0035] As used herein, the term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues in a reasonable benefit-to-risk ratio without causing excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0036] As used herein, the terms “to treat,” “to treat,” or “to treat” mean to reduce, suppress, weaken, reduce, halt, or stabilize the onset or progression of a disorder or disease.

[0037] As used herein, the terms “prevention” or “prevention” mean, if the disability or disease has not occurred, that there will be no onset of the disability or disease, and if the disability or disease has already occurred, that there will be no further onset of the disability or disease. The ability to prevent some or all of the symptoms associated with the disability or disease will also be considered.

[0038] The terms “administer,” “to administer,” and “administer” refer to administering the compounds disclosed herein, or other indicated compounds, to a patient via any appropriate route. Specifically, the compounds disclosed herein may be administered orally or parenterally, preferably by parenterally such as injection or infusion, which may be performed intravenously, intramuscularly, intra-arterially, subcutaneously, intradermally, intraperitoneally, etc. Depending on the route of administration, the compounds disclosed herein may be administered as a pharmaceutical composition further comprising appropriate components such as carriers, solvents, and excipients commonly known in the art. Herein, the term “pharmaceutical composition” is defined as a mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent, administered to a subject, for example, a human, for the purpose of preventing or treating a particular disease or condition affecting a human.

[0039] As used herein, the terms “radiolabeling” (or “chelation” or “complexing”) mean that a non-radioactive compound is labeled with a radioactive isotope. Radiolabeling can be achieved, for example, by chelation or complex formation with a suitable radionuclide and a chelating agent. 18 As in the case of F, it can also refer to the chemical substitution of one group on a compound with a radioactive nuclide.

[0040] Furthermore, within the scope of the present invention, and particularly in relation to the compounds of this disclosure, any element shall include all isotopes and isotopic mixtures of the element, whether naturally occurring or synthesized, in natural abundance or in isotopically enriched forms. For example, the expression hydrogen is, 1 H, 2 H (i.e., deuterium or D), and 3 It contains H (i.e., tritium or T). In some embodiments, the compounds described herein are 2 It contains the H (i.e., deuterium) isotope. For example, -C (1~6) The groups represented by alkyl include not only -CH3 but also CD3, and not only CH2CH3 but also CD2CD3, etc. Similarly, references to carbon and oxygen are, respectively,12 C, 13 C and 14 C, and 15 O, 16 O, 17 O, and 18 Contains O. The isotopes may be radioactive or non-radioactive isotopes. The radiolabeled compounds of this disclosure are 3 H, 11 C, 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 It may include radioactive isotopes selected from the group including Br. In some embodiments, the radioactive isotopes are 3 H, 11 C, and 18 It is selected from group F.

[0041] As used herein, the terms “carrier” or “pharmaceutically acceptable carrier” include any and all solvents, dispersions, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption retarders, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, fragrances, dyes, etc., and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289–1329). Their use in therapeutic or pharmaceutical compositions is considered unless conventional carriers are incompatible with the active ingredient.

[0042] Unless otherwise specified, the conventional definitions of terms apply to all formulas and groups, and conventional stable valencies are assumed and achieved.

[0043] Where used herein, the term “about” is to be understood by those skilled in the art and varies to some extent depending on the context in which it is used. Where used herein, when referring to measurable values ​​such as quantity or duration, the term “about” means to include a variation of ±10% from the specified value (including ±5%, ±1%, and ±0.1%), provided that such variation is appropriate for performing the disclosed method.

[0044] In this disclosure, the articles "a" and "an" are used to refer to one or more (e.g., at least one) grammatical objects of the article. For example, "element" means one or more elements.

[0045] compound This disclosure provides a radiopharmaceutical for the treatment or prevention of PSMA-expressing cancer, comprising a PSMA-binding ligand radiolabeled with an alpha-emitting radionuclide.

[0046] In some embodiments of this disclosure, the PSMA-binding ligands are PSMA-617, PSMA I&T (PSMA I&T (zadabotide glaxetan) means the "cold" ligand (a ligand that does not contain radionuclides) of [177Lu]Lu-PSMA I&T (INN: lutetium (177Lu) zadabotide glaxetan), which is commercially available from ABX (Radeberg, Germany)), PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, BAY-2315487, TLX591, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPS The drug is selected from the group consisting of MA-10.1, LudotadiPep, PNT2001, PNT2002, PSMA-7, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, PSMA-62, PSMA-1, PSMA-1-DOTA, SAR-bis-PSMA, ITM-22, ITM-24D, PMI-21, DOTA-h11B6, FPI-1434, Pergifatamab, NG001, ADVC001, RPS-072, and RPS-074.

[0047] In some embodiments, the PSMA-binding ligand is selected from the group consisting of PSMA-617, PSMA I&T, PSMA-62, PSMA-1-DOTA, and PSMA-R2. In a particular embodiment, the PSMA-binding ligand is selected from the group consisting of PSMA-617, PSMA I&T, and PSMA-R2.

[0048] As those skilled in the art will understand, the PSMA-binding ligands described above can be radiolabeled with beta-minus, positron- or alpha-emitting radionuclides, such as the following radiopharmaceutical compounds: 64Cu / 225Ac-DOTA-TLX592 (Telix), 67Cu-SAR-bisPSMA (Clarity), 212Pb-NG001 (ART BIO), 212Pb-ADVC001 (AdvanCell), 225Ac-RPA-074, 225Ac-pergifatamab, and 227Th-Carboxy-HOPO-PSMA (Bayer), 225Ac-ITM-22 (Ac-PSMA-TTM*), ITM, and 225Ac-PSMA-R2 (Novartis).

[0049] In various embodiments of this disclosure, radiopharmaceuticals comprising PSMA-binding ligands radiolabeled with alpha-emitting radionuclides include [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan), [177Lu]Lu-EB-PSMA-617 (Evans blue modified [177Lu]Lu-PSMA-617), and [177Lu]Lu-PSMA I&T (lutetium (177Lu) zadavotide glaxetan), [161Tb]Tb-PSMA-617 (terbium (161Tb) bipivotide tetraxetan), [161Tb]Tb-EB-PSMA-617 (Evans blue modified [161Tb]Tb-PSMA-617), and [161Tb]Tb-PSMA I&T (terbium (161Tb) zadabotide galaxetane), preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan) or [161Tb]Tb-PSMA-617 (terbium (161Tb) bipivotide tetraxetan), more preferably [177Lu]Lu-PSMA-617 (lutetium (177Lu) bipivotide tetraxetan), is selected from the group consisting of I&T (terbium (161Tb) zadabotide galaxetane), where 177Lu and 161Tb are replaced with 225Ac.

[0050] This disclosure also provides radiopharmaceuticals for the treatment of PSMA-expressing cancers, the radiopharmaceuticals being compounds of formulas (I), (II), (III), (IV), and (V). [ka] Glutamate and lysine adjacent to urea are in an L-configuration. [ka] The compounds of formulas (I), (II), (III), (IV), and (V) are radiolabeled with alpha-emitting radionuclides.

[0051] In some embodiments, the radiopharmaceutical is a compound of formula (I), (II), and (IV), [ka] Glutamate and lysine adjacent to urea are in an L-configuration, and [ka] The compounds of formulas (I), (II), and (IV) are radiolabeled with alpha-emitting radionuclides.

[0052] In some embodiments, the radiopharmaceutical is a compound of formulas (I) and (II), [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compounds of formulas (I) and (II) are radiolabeled with alpha-emitting radionuclides.

[0053] In some embodiments, the alpha-emitting radionuclide is 225 Ac, 211 At, 213 Bi, 212 Bi, 212 Pb, 223 Ra, 224 Ra, 149 Tb, and 227 Selected from the group consisting of Th. In a further embodiment, the alpha-emitting radionuclide is 225 Ac,212 Pb, and 227 Selected from the group consisting of Th. In further embodiments, the alpha-emitting radionuclide is 225 It is Ac.

[0054] In a particular embodiment, the radiopharmaceutical is a compound of formula (I), [ka] The compound of formula (I) is 225 It is radiolabeled with Ac.

[0055] Methods for preparing and using the compound of formula (I) are described, for example, in U.S. Patent No. 10,398,791, which is incorporated herein by reference in its entirety.

[0056] In a particular embodiment, the radiopharmaceutical is a compound of formula (II), [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (II) is 225 It is radiolabeled with Ac.

[0057] Methods for preparing and using the compound of formula (II) are described, for example, in the examples of this application, see, for example, Examples 1 and 3.

[0058] In a particular embodiment, the radiopharmaceutical is a compound of formula (III), [ka] The compound of formula (III) is 225 It is radiolabeled with Ac.

[0059] Methods for preparing and using the compound of formula (III) are, for example, described in WO2019 / 115547 (the compound of formula (III) is, among them, PSMA-62 and DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 It is described in [-EuE]-TMA) and the whole is incorporated herein by reference.

[0060] In a particular embodiment, the radiopharmaceutical is a compound of formula (IV), [ka] The compound of formula (IV) is 225 It is radiolabeled with Ac.

[0061] Methods for preparing and using the compound of formula (IV) are described, for example, in Weineisen et al. J Nucl Med 2015;56:1169-1176; and in Chatalic, Theranostics, 6(6),849-861(2016), US11,129,912, and US11,491,246, which are incorporated herein by reference in their entirety.

[0062] In a particular embodiment, the radiopharmaceutical is a compound of formula (V), [ka] The compound of formula (V) is 225 It is radiolabeled with Ac.

[0063] Methods for preparing and using the compound of formula (V) are described, for example, in Wang et al. Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers (Basel). 2021 13(3):417, and WO2023 / 086833, paragraph

[0132] , which are incorporated herein by reference in their entirety.

[0064] Treatment method This disclosure provides a method for treating or prophylacticizing PSMA-expressing cancer in subjects requiring such treatment, the method comprising administering a radiopharmaceutical comprising a PSMA-binding ligand radiolabeled with an alpha-emitting radionuclide to the subject, the radiopharmaceutical being administered in doses of about 6 MBq to about 14 MBq, for example, about 6 MBq to about 8 MBq, or about 8 MBq to about 10 MBq. The PSMA-binding ligand is as described above.

[0065] In some embodiments, the present disclosure provides a method for treating a subject requiring treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), (III), (IV), or (V) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration. [ka] Compounds of formula (I), (II), (III), (IV), or (V) are radiolabeled with alpha-emitting radionuclides, and The radiolabeled compounds of formulas (I), (II), (III), (IV), or (V) are administered in doses of approximately 6 MBq to approximately 10 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq.

[0066] In particular, this disclosure provides a method for treating PSMA-expressing cancer in subjects requiring treatment, the method comprising administering a compound of formula (I) or (II) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration. Compounds of formula (I), (II), (III), (IV), or (V) are radiolabeled with alpha-emitting radionuclides, and The radiolabeled compounds of formulas (I), (II), (III), (IV), or (V) are administered in doses of approximately 6 MBq to approximately 10 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq.

[0067] In some embodiments, the subjects have previously received chemotherapy. Alternatively, in some embodiments, the subjects have not previously received chemotherapy.

[0068] Accordingly, in one embodiment, the present disclosure provides a method for treating a subject requiring treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), (III), (IV), or (V) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration. [ka] Compounds of formula (I), (II), (III), (IV), or (V) are radiolabeled with alpha-emitting radionuclides. The radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 6 MBq to approximately 10 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq, and The subjects have previously received chemotherapy.

[0069] In certain embodiments, this method involves administering a compound of formula (I) or (II) to a target, [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (I) or (II) is radiolabeled with an alpha-emitting radionuclide, The radiolabeled compound of formula (I) or (II) is administered in doses of approximately 6 MBq to approximately 10 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq, and The subjects have previously received chemotherapy.

[0070] In one or more embodiments, the prior chemotherapy includes the administration of a taxane.

[0071] In another aspect, the Disclosure provides a method for treating a subject in need of treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), (III), (IV), or (V) to the subject. [ka] Glutamate and lysine adjacent to urea are in an L-configuration. [ka] Compounds of formula (I), (II), (III), (IV), or (V) are radiolabeled with alpha-emitting radionuclides. The radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 6 MBq to approximately 14 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq, or 6 MBq, or 7 MBq, or 8 MBq, or 9 MBq, or 10 MBq, or 11 MBq, or 12 MBq, or 13 MBq, or 14 MBq, and The subjects are those who have not previously received chemotherapy.

[0072] In certain embodiments, this method involves administering a compound of formula (I) or (II) to a target, [ka] Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (I) or (II) is radiolabeled with an alpha-emitting radionuclide, The radiolabeled compound of formula (I) or (II) is administered in doses of approximately 6 MBq to approximately 14 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq, or 6 MBq, or 7 MBq, or 8 MBq, or 9 MBq, or 10 MBq, or 11 MBq, or 12 MBq, or 13 MBq, or 14 MBq, and The subjects are those who have not previously received chemotherapy.

[0073] In some embodiments, the method includes administering a compound of formula (I) to a target. In other embodiments, the method includes administering a compound of formula (II) to a target. In yet another embodiment, the method includes administering a compound of formula (III) to a target. In yet another embodiment, the method includes administering a compound of formula (IV) to a target. In yet another embodiment, the method includes administering a compound of formula (V) to a target.

[0074] In some embodiments, the method comprises administering a compound of formula (I), (II), (III), (IV), or (V), wherein the compound is 225 Ac, 211 At, 213 Bi, 212 Bi, 212 Pb, 223 Ra, 224 Ra, 149 Tb, and 227 The radioactively labeled radionuclides are selected from the group consisting of Th. In further embodiments, the method comprises administering a compound of formula (I), (II), (III), (IV), or (V), wherein the compound is 225 Ac, 212 Pb, and227 The radioactively labeled radionuclides are selected from the group consisting of Th. In further embodiments, the method comprises administering a compound of formula (I), (II), (III), (IV), or (V), the compound being radioactively labeled with an alpha-emitting radionuclide, the alpha-emitting radionuclide being 225 It is Ac.

[0075] Typically, the amount of radiopharmaceuticals, such as radiolabeled compounds of formulas (I), (II), (III), (IV), or (V), administered to a subject requiring them is determined based on the amount of radiation administered to the subject. The amount of radiation is expressed as a unit dose (MBq) or radiation dose per kg of body weight (kBq / kg). In this method, the radiolabeled compounds are administered in unit doses of approximately 6 MBq to approximately 14 MBq, for example, approximately 6 MBq to approximately 8 MBq, or approximately 8 MBq to approximately 10 MBq, or 6 MBq, or 7 MBq, or 8 MBq, or 9 MBq, or 10 MBq, or 11 MBq, or 12 MBq, or 13 MBq, or 14 MBq.

[0076] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 6.5 MBq to 14 MBq, for example, about 6.5 MBq to 10 MBq or 6.5 MBq to 8 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 7 MBq to 8 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 7.5 MBq to 8 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 6 MBq to 7.5 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of approximately 6 MBq to 7 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of approximately 6 MBq to 6.5 MBq.

[0077] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 6.5 MBq to 7.5 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 7 MBq to 7.5 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 6 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 7 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 8 MBq.

[0078] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 7.5 MBq to 10 MBq, for example, about 8 MBq to 10 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 8.5 MBq to 10 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 9 MBq to 10 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 9.5 MBq to 10 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 7 MBq to 8 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 8 MBq to 9.5 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 9 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 10 MBq.

[0079] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 9.5 MBq to 14 MBq, for example, about 10 MBq to 14 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 10.5 MBq to 14 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 11 MBq to 14 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 11.5 MBq to 14 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 10 MBq to 11 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 10 MBq to 11.5 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 10 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 11 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of about 12 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 13 MBq. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in a dose of about 14 MBq.

[0080] Alternatively, in the methods disclosed herein, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) can be administered as a radiation dose per kg of body weight. In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of about 80 kBq / kg body weight to about 200 kBq / kg body weight, for example, about 80 kBq / kg body weight to about 120 kBq / kg body weight. In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of about 80 kBq / kg body weight to about 180 kBq / kg body weight. In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of about 80 kBq / kg body weight to about 150 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 80 kBq / kg body weight to approximately 120 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 80 kBq / kg body weight to approximately 110 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 80 kBq / kg body weight to approximately 100 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 80 kBq / kg body weight to approximately 90 kBq / kg body weight.

[0081] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 90 kBq / kg body weight to approximately 120 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 100 kBq / kg body weight to approximately 120 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 110 kBq / kg body weight to approximately 120 kBq / kg body weight.

[0082] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 90 kBq / kg body weight to approximately 180 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 100 kBq / kg body weight to approximately 180 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 110 kBq / kg body weight to approximately 180 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 120 kBq / kg body weight to approximately 180 kBq / kg body weight. In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 130 kBq / kg body weight to approximately 180 kBq / kg body weight. In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 140 kBq / kg body weight to approximately 180 kBq / kg body weight.

[0083] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 85 kBq / kg body weight to approximately 165 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 85 kBq / kg body weight to approximately 145 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 85 kBq / kg body weight to approximately 125 kBq / kg body weight.

[0084] In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 85 kBq / kg body weight to approximately 115 kBq / kg body weight.

[0085] In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 85 kBq / kg body weight to approximately 105 kBq / kg body weight. In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered in doses of approximately 85 kBq / kg body weight to approximately 100 kBq / kg body weight.

[0086] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 90 kBq / kg body weight to approximately 115 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 100 kBq / kg body weight to approximately 110 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 100 kBq / kg body weight to approximately 115 kBq / kg body weight.

[0087] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 80 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 90 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 100 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 110 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 120 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 130 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 140 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 150 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 160 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 170 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 180 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 190 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 200 kBq / kg body weight.

[0088] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 85 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 95 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 105 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 115 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 125 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 135 kBq / kg body weight. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 145 kBq / kg body weight.

[0089] The radiolabeled compound of formula (I), (II), (III), (IV), or (V) can be administered to a subject approximately every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 5 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 7 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5-6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5-7 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6-7 weeks.

[0090] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every four weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every five weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every six weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every seven weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every eight weeks.

[0091] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or 8 to 10 MBq, every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6.5 MBq to 8 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7 MBq to 8 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7.5 MBq to 8 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 14 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 4 to 8 weeks.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 13.5 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 13.5 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 13 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 13.5 MBq every 4 to 8 weeks.

[0092] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 9.5 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every approximately 4 to 8 weeks.

[0093] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 8 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 8 MBq every approximately 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 14 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every 4 to 8 weeks.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 4 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 4 to 8 weeks.

[0094] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or approximately 8 to 10 MBq, every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6.5 MBq to 8 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7 MBq to 8 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7.5 MBq to 8 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every approximately 6 to 8 weeks.

[0095] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 9 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 9 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 8.5 MBq every approximately 6 to 8 weeks.

[0096] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 14 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 14 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 14 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 14 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 14 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 12.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 10.5 MBq every approximately 6 to 8 weeks.

[0097] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 11.5 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every approximately 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 6 to 8 weeks.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 6 to 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6 to 8 weeks.

[0098] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 to 8 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 to 8 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 to 8 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 to 8 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 to 7.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every approximately 6 weeks.

[0099] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 to 10 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 to 10 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 to 10 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 to 10 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 8.5 MBq every approximately 6 weeks.

[0100] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10–14 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5–14 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11–14 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5–14 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 10.5 MBq every approximately 6 weeks.

[0101] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 8.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 11.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 12.5 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every approximately 6 weeks.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 6 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every approximately 6 weeks.

[0102] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or approximately 8 to 10 MBq, every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 8 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 8 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every approximately 8 weeks.In some embodiments, the radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered at doses of approximately 8 MBq to 8.5 MBq every approximately 8 weeks. In certain embodiments, the compound of formula (I) is used. 225 Ac radiolabeled compounds are administered at doses of approximately 8 MBq to 10 MBq every 8 weeks.

[0103] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 11.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 12.5 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every approximately 8 weeks.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 8 weeks. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every approximately 8 weeks.

[0104] As is common in radiotherapy, in order to deliver the total dose of radiation necessary to eradicate PSMA-expressing cancer, this method may involve administering a radiolabeled compound of formula (I), (II), (III), (IV), or (V) approximately every 4 to 8 weeks over several cycles. For example, the dose of the radiolabeled compound of this disclosure may be administered approximately every 4 to 8 weeks over 4 to 6 cycles.

[0105] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 8 weeks over 5 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 to 6 weeks over 4 to 6 cycles.

[0106] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 to 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 to 8 weeks over 5 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 to 8 weeks over 6 cycles.

[0107] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4-5 weeks over 4-6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4-7 weeks over 4-6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5-8 weeks over 4-6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5-6 weeks over 4-6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5-7 weeks over 4-6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6-7 weeks over 4-6 cycles.

[0108] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 7 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 8 weeks over 4 to 6 cycles. In certain embodiments, the radiolabeled compound of formula (I) 225 Ac radiolabeled compounds are administered at doses of approximately 8 MBq to 10 MBq every 8 weeks over 4 to 6 cycles.

[0109] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every four weeks over four cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every four weeks over six cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every six weeks over four cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every six weeks over six cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every eight weeks over four cycles. In certain embodiments, the radiolabeled compound of formula (I) 225Ac radiolabeled compounds are administered at doses of approximately 8 MBq to 10 MBq every approximately 8 weeks over 4 cycles. In some embodiments, radiolabeled compounds of formula (I), (II), (III), (IV), or (V) are administered every approximately 8 weeks over 6 cycles. In certain embodiments, the compound of formula (I) 225 Ac radiolabeled compounds are administered in doses of approximately 8 MBq to 10 MBq every 8 weeks over 6 cycles.

[0110] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 7 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 7 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 4 weeks over 5 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 6 weeks over 5 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 8 weeks over 5 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 5 weeks over 5 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered approximately every 7 weeks over 5 cycles.

[0111] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or approximately 8 to 10 MBq, every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6.5 MBq to 8 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7 MBq to 8 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7.5 MBq to 8 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every 4 to 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 12 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 12 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5 MBq to 12 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12.5 MBq to 13.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq to 13 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq to 13.5 MBq every 4 to 8 weeks over 4 to 6 cycles.

[0112] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5 MBq to 12.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq to 12.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12.5 MBq to 13.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq to 13.5 MBq every 4 to 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 4 to 8 weeks over 4 to 6 cycles.

[0113] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or approximately 8 to 10 MBq, every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 6.5 MBq to 8 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7 MBq to 8 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at doses of approximately 7.5 MBq to 8 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every 6 to 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 8.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 14 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 14 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5 MBq to 14 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 10.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq to 13.5 MBq every 6 to 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq to 12.5 MBq every 6 to 8 weeks over 4 to 6 cycles.

[0114] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5 MBq to 12.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 11.5 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12.5 MBq to 13.5 MBq every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq to 13.5 MBq every 6 to 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6 to 8 weeks over 4 to 6 cycles.

[0115] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or approximately 8 to 10 MBq, approximately every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 8 MBq, approximately every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 8 MBq, approximately every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8 MBq, approximately every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every 6 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 8.5 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5 MBq to 12 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 12.5 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12.5 MBq to 13.5 MBq every six weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq to 13 MBq every 6 weeks over 4 to 6 cycles.

[0116] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 11.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 12.5 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every 6 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 6 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6 weeks over 4 to 6 cycles.

[0117] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or approximately 8 to 10 MBq, approximately every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 8 MBq, approximately every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 8 MBq, approximately every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8 MBq, approximately every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 7 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq to 6.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 10 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 10 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9.5 MBq to 10 MBq every 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 9 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq to 8.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 14 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 14 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11.5 MBq to 14 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 12.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 12 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq to 11.5 MBq every 8 weeks over 4 to 6 cycles.

[0118] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6.5 MBq to 7.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq to 7.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7.5 MBq to 8.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8.5 MBq to 9.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq to 9.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10.5 MBq to 11.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 11.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq to 12.5 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every approximately 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every approximately 8 weeks over 4 to 6 cycles.In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 8 weeks over 4 to 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every approximately 8 weeks over 4 to 6 cycles.

[0119] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 6 to 14 MBq, for example, approximately 6 to 8 MBq or 8 to 10 MBq, every 6 to 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 6 MBq every 6 to 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 7 MBq every 6 to 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 8 MBq every 6 to 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 6-8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 6-8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 6-8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 6-8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 6-8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6-8 weeks over 4 cycles.

[0120] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6–14 MBq, for example, approximately 6–8 MBq or approximately 8–10 MBq, approximately every 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq, approximately every 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq, approximately every 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq, approximately every 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every approximately 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every approximately 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every approximately 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 6 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6 weeks over 4 cycles.

[0121] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6–14 MBq, for example, approximately 6–8 MBq or approximately 8–10 MBq, approximately every 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq, approximately every 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq, approximately every 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq, approximately every 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every approximately 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every approximately 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every approximately 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 8 weeks over 4 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 8 weeks over 4 cycles.

[0122] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6–14 MBq, for example, approximately 6–8 MBq or approximately 8–10 MBq, every 6–8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq every 6–8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq every 6–8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq every 6–8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every 6-8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every 6-8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every 6-8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every 6-8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every 6-8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6-8 weeks over 6 cycles.

[0123] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6–14 MBq, for example, approximately 6–8 MBq or approximately 8–10 MBq, approximately every 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 6 MBq, approximately every 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 7 MBq, approximately every 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 8 MBq, approximately every 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every approximately 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every approximately 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every approximately 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 6 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every 6 weeks over 6 cycles.

[0124] In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 6–14 MBq, for example, approximately 6–8 MBq or approximately 8–10 MBq, approximately every 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 6 MBq, approximately every 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 7 MBq, approximately every 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered in doses of approximately 8 MBq, approximately every 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 9 MBq every approximately 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 10 MBq every approximately 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 11 MBq every approximately 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 12 MBq every approximately 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 13 MBq every approximately 8 weeks over 6 cycles. In some embodiments, the radiolabeled compound of formula (I), (II), (III), (IV), or (V) is administered at a dose of approximately 14 MBq every approximately 8 weeks over 6 cycles.

[0125] In certain embodiments, the radiolabeled compound of formula (I) is administered in doses of 6–14 MBq, for example, 6–8 MBq or 8–10 MBq, approximately every 8 weeks over 4 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered in doses of 6–8 MBq, approximately every 6 weeks over 4 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered in doses of 6–8 MBq, approximately every 6 weeks over 6 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered in doses of 7–12 MBq, approximately every 6 weeks over 4 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered in doses of 7–12 MBq, approximately every 6 weeks over 6 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered in doses of 10–14 MBq, approximately every 6 weeks over 4 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered in doses of 10–14 MBq, approximately every 6 weeks over 6 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered at a dose of 8–10 MBq approximately every 6 weeks over 4 cycles. In certain embodiments, the radiolabeled compound of formula (II) is administered at a dose of 8–10 MBq approximately every 6 weeks over 6 cycles.

[0126] In the methods described herein, PSMA-expressing cancer can be any cancer that exhibits high PSMA expression compared to the corresponding healthy cells or tissues. For example, in various prostate and salivary gland cancers, the PSMA expression level of malignant cells is significantly increased compared to healthy cells. In one or more embodiments of the methods described herein, PSMA-expressing cancer is prostate cancer. In some embodiments, if PSMA-expressing cancer is prostate cancer, then that prostate cancer is metastatic prostate cancer. In certain embodiments, metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0127] In various embodiments of the method of this disclosure, the subject has received prior treatment with at least one of the beta-minus-emitting radiopharmaceuticals and androgen receptor pathway inhibitors (ARPIs).

[0128] In some embodiments, the subject has received pre-treatment with a beta-minus emitting radiopharmaceutical. In some embodiments, the beta-minus emitting radiopharmaceutical 177 comprises Lu. In some embodiments, the beta-minus emitting radiopharmaceutical 177 is a Lu-PSMA targeting agent. In further embodiments, the beta-minus emitting radiopharmaceutical is a Lu-PSMA targeting agent selected from 177Lu-PSMA-617 or 177Lu-PSMA I&T 177 In certain embodiments, when the beta-minus emitting radiopharmaceutical is 177 a Lu-PSMA targeting agent, 177 the Lu-PSMA targeting agent is 177Lu-PSMA-617. In some embodiments, the subject has received pre-treatment with one or more beta-minus emitting radiopharmaceuticals. In some embodiments, the subject has received pre-treatment with one beta-minus emitting radiopharmaceutical. In some embodiments, the subject has received pre-treatment with two or more beta-minus emitting radiopharmaceuticals.

[0129] In some embodiments, the subject has received pre-treatment with an ARPI. Suitable ARPIs that may have been previously administered to the subject include, but are not limited to, ketoconazole, abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, and nilutamide. In some embodiments, the subject has received pre-treatment with one or more, or two or more, ARPIs. In some embodiments, the subject has received pre-treatment with one ARPI. In some embodiments, the subject has received pre-treatment with two different ARPIs. In some embodiments, the subject has received pre-treatment with three or more different ARPIs.

[0130] In some embodiments, the subjects are treatment-naive. In some embodiments, the subjects are inexperienced with beta-negative releasing drugs and ARPIs. In some embodiments, the subjects have received prior treatment with beta-negative releasing drugs and ARPIs. In some embodiments, the subjects have received prior treatment with beta-negative releasing drugs but not with ARPIs. In some embodiments, the subjects have not received prior treatment with beta-negative releasing drugs but have received prior treatment with ARPIs.

[0131] In some embodiments of the methods disclosed herein, subjects either did not respond to prior treatment with beta-negative emitting radiopharmaceuticals and / or ARPIs, or their PSMA-expressing cancer progressed after administration of prior treatment.

[0132] In various embodiments of the methods of this disclosure, PSMA-expressing cancers are determined to be resistant to one or more of the following: chemotherapy, beta-negative emitting radiopharmaceuticals, and ARPIs. In some embodiments, PSMA-expressing cancers are determined to be resistant to chemotherapy. In some embodiments, PSMA-expressing cancers are determined to be resistant to beta-negative emitting radiopharmaceuticals. In some embodiments, PSMA-expressing cancers are determined to be resistant to ARPIs. In some embodiments, PSMA-expressing cancers are determined to be resistant to chemotherapy and beta-negative emitting radiopharmaceuticals. In some embodiments, PSMA-expressing cancers are determined to be resistant to chemotherapy and ARPIs. In some embodiments, PSMA-expressing cancers are determined to be resistant to beta-negative emitting radiopharmaceuticals and ARPIs. In some embodiments, PSMA-expressing cancers are determined to be resistant to all of the following: chemotherapy, beta-negative emitting radiopharmaceuticals, and ARPIs.

[0133] Accordingly, in some embodiments, the methods disclosed herein are used as first-line, second-line, third-line, or fourth-line treatments for PSMA-expressing cancers. In some embodiments, the methods disclosed herein are used as first-line treatments. In other embodiments, the methods disclosed herein are used as second-line, third-line, or fourth-line treatments. In some embodiments, the methods disclosed herein are used as second-line treatments. In some embodiments, the methods disclosed herein are used as third-line treatments. In some embodiments, the methods disclosed herein are used as fourth-line treatments.

[0134] Specific embodiments of treatment methods Specifically, this specification provides a method for treating prostate cancer in subjects requiring treatment, the method comprising administering a radiopharmaceutical to the subject in doses of about 6 MBq to about 14 MBq, for example, about 6 MBq to about 8 MBq, or about 8 MBq to about 10 MBq, the radiopharmaceutical being a compound of formula (I), [ka] The compound of formula (I) is 225 It is radiolabeled with Ac.

[0135] In some embodiments of the disclosed method, the subject has previously received chemotherapy. Alternatively, in some embodiments, the subject has not previously received chemotherapy.

[0136] Accordingly, in some embodiments, this specification provides a method for treating a subject in need of treatment for prostate cancer, the method comprising administering a radiopharmaceutical to the subject in a dose of about 6 MBq to about 8 MBq, the radiopharmaceutical being a compound of formula (I), [ka] The compound of formula (I) is 225 The cells are radiolabeled with Ac, and the subjects have previously received chemotherapy.

[0137] In some embodiments, provided herein is a method of treating a subject having a need for treating prostate cancer, the method comprising administering to the subject a radiopharmaceutical at a dose of from about 8 MBq to about 10 MBq, wherein the radiopharmaceutical is a compound of formula (I),

Chem.

[0138] In some embodiments, the previous chemotherapy comprises administration of a taxane.

[0139] In other embodiments, provided herein is a method of treating a subject having a need for treating prostate cancer, the method comprising administering to the subject a radiopharmaceutical at a dose of from about 6 MBq to about 8 MBq, wherein the radiopharmaceutical is a compound of formula (I),

Chem.

[0140] In other embodiments, provided herein is a method of treating a subject having a need for treating prostate cancer, the method comprising administering to the subject a radiopharmaceutical at a dose of from about 8 MBq to about 10 MBq, wherein the radiopharmaceutical is a compound of formula (I),

Chem.

[0141] In some embodiments of the method of treating a patient requiring treatment for prostate cancer, the prostate cancer is metastatic prostate cancer. In further embodiments, the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0142] In some embodiments of the method described herein, the radiopharmaceutical is administered in a dose of 6 MBq. In some embodiments, the radiopharmaceutical is administered in a dose of 7 MBq. In some embodiments, the radiopharmaceutical is administered in a dose of 8 MBq. In some embodiments, the radiopharmaceutical is administered in a dose of 9 MBq. In some embodiments, the radiopharmaceutical is administered in a dose of 10 MBq.

[0143] In some embodiments of the methods described herein, the radiopharmaceutical is administered to the subject approximately every 4 to 8 weeks. In further embodiments, the radiopharmaceutical is administered approximately every 6 to 8 weeks. In even further embodiments, the radiopharmaceutical is administered every 6 weeks. In even further embodiments, the radiopharmaceutical is administered every 8 weeks.

[0144] In some embodiments of the method described herein, the radiopharmaceutical is administered in doses of 6 to 8 MBq or 8 to 10 MBq approximately every 4 to 8 weeks. In some embodiments of the method described herein, the radiopharmaceutical is administered in doses of 6 MBq approximately every 6 to 8 weeks. In some embodiments, the radiopharmaceutical is administered in doses of 7 MBq approximately every 6 to 8 weeks. In some embodiments, the radiopharmaceutical is administered in doses of 8 MBq approximately every 6 to 8 weeks. In some embodiments, the radiopharmaceutical is administered in doses of 9 MBq approximately every 6 to 8 weeks. In some embodiments, the radiopharmaceutical is administered in doses of 10 MBq approximately every 6 to 8 weeks.

[0145] In some embodiments of the method described herein, the radiopharmaceutical is administered at a dose of 6 MBq approximately every 6 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 7 MBq approximately every 6 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 8 MBq approximately every 6 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 9 MBq approximately every 6 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 10 MBq approximately every 6 weeks.

[0146] In some embodiments of the method described herein, the radiopharmaceutical is administered at a dose of 6 MBq approximately every 8 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 7 MBq approximately every 8 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 8 MBq approximately every 8 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 9 MBq approximately every 8 weeks. In some embodiments, the radiopharmaceutical is administered at a dose of 10 MBq approximately every 8 weeks.

[0147] Radiopharmaceuticals may be administered to subjects requiring them every 4 to 8 weeks over several cycles. For example, in the method for treating prostate cancer described herein, the radiopharmaceutical may be administered every 4 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiopharmaceutical is administered every 6 to 8 weeks over 4 to 6 cycles. In some embodiments, the radiopharmaceutical is administered every 4 to 8 weeks over 4 cycles. In a particular embodiment, the radiopharmaceutical is administered every 6 to 8 weeks over 4 cycles. In a further embodiment, the radiopharmaceutical is administered every 8 weeks over 4 cycles. In yet another embodiment, the radiopharmaceutical is administered every 6 weeks over 4 cycles.

[0148] In some embodiments, the radiopharmaceutical is administered approximately every 4–8 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered approximately every 6–8 weeks over 6 cycles. In a particular embodiment, the radiopharmaceutical is administered approximately every 6 weeks over 6 cycles. In further embodiments, the radiopharmaceutical is administered approximately every 8 weeks over 6 cycles.

[0149] In some embodiments of the method described herein, the radiopharmaceutical is administered in doses of 6–8 MBq or 8–10 MBq approximately every 4–8 weeks over 4–6 cycles. In some embodiments of the method described herein, the radiopharmaceutical is administered in doses of 6–8 MBq or 8–10 MBq approximately every 6–8 weeks over 4–6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 6 MBq approximately every 6–8 weeks over 4–6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 7 MBq approximately every 6–8 weeks over 4–6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 8 MBq approximately every 6–8 weeks over 4–6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 9 MBq approximately every 6–8 weeks over 4–6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 10 MBq approximately every 6–8 weeks over 4–6 cycles.

[0150] In some embodiments of the method described herein, the radiopharmaceutical is administered in doses of 6 to 8 MBq or 8 to 10 MBq at intervals of approximately 6 to 8 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 6 MBq at intervals of approximately 6 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 6 MBq at intervals of approximately 8 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 7 MBq at intervals of approximately 6 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 7 MBq at intervals of approximately 8 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 8 MBq at intervals of approximately 6 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 8 MBq at intervals of approximately 8 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 9 MBq at intervals of approximately 6 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 9 MBq at intervals of approximately 8 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered at a dose of 10 MBq approximately every 6 weeks over 4 cycles. In some embodiments, the radiopharmaceutical is administered at a dose of 10 MBq approximately every 8 weeks over 4 cycles.

[0151] In some embodiments of the method described herein, the radiopharmaceutical is administered in doses of 6–8 MBq or 8–10 MBq approximately every 6–8 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 6 MBq approximately every 6 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 6 MBq approximately every 8 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 7 MBq approximately every 6 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 7 MBq approximately every 8 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 8 MBq approximately every 6 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 8 MBq approximately every 8 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 9 MBq approximately every 6 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered in doses of 9 MBq approximately every 8 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered at a dose of 10 MBq approximately every 6 weeks over 6 cycles. In some embodiments, the radiopharmaceutical is administered at a dose of 10 MBq approximately every 8 weeks over 6 cycles.

[0152] In certain embodiments, the radiopharmaceutical is administered in doses of 6–8 MBq, 7–9 MBq, or 8–10 MBq approximately every 8 weeks over 4 cycles. In certain embodiments, the radiopharmaceutical is administered in doses of 6–8 MBq approximately every 8 weeks over 4 cycles. In certain embodiments, the radiopharmaceutical is administered in doses of 8–10 MBq approximately every 8 weeks over 4 cycles.

[0153] In various embodiments of the methods for treating PSMA-expressing cancer in subjects requiring treatment, as described herein, the subjects have received prior treatment with at least one beta-minus-emitting radiopharmaceutical and an androgen receptor pathway inhibitor (ARPI). In various embodiments, the beta-minus-emitting radiopharmaceutical is [ 177It is a Lu]Lu-PSMA targeted radiopharmaceutical.

[0154] In some embodiments, the subjects are inexperienced with beta-negative releasing drugs and ARPIs. In some embodiments, the subjects have received prior treatment with beta-negative releasing drugs and ARPIs. In some embodiments, the subjects have received prior treatment with beta-negative releasing drugs but not with ARPIs. In some embodiments, the subjects have not received prior treatment with beta-negative releasing drugs but have received prior treatment with ARPIs.

[0155] In some embodiments, subjects have received prior treatment with taxane-based chemotherapy, beta-minus-emitting radiopharmaceuticals, and ARPI.

[0156] In some embodiments, the subjects were those who did not respond to prior treatment, i.e., beta-minus emitting radiopharmaceuticals and / or ARPI, or whose PSMA-expressing cancer progressed after administration of prior treatment. In some embodiments, the subjects were those who received taxane-based chemotherapy, ARPI, 177 The subject has received prior treatment with Lu]Lu-PSMA targeted radiopharmaceutical, and the subject is [ 177 Has the PSMA-expressing cancer progressed while being treated with Lu]Lu-PSMA-targeted radiopharmaceutical, or is the subject [ 177 The patient relapsed after treatment with Lu]Lu-PSMA targeted radiopharmaceutical.

[0157] In various embodiments, PSMA-expressing cancers have been determined to be resistant to one or more of the following: chemotherapy, beta-minus-emitting radiopharmaceuticals, and ARPIs.

[0158] In the methods herein for treating PSMA-expressing cancer in subjects, subjects may experience undesirable side effects, such as xerostomia (dry mouth). In some embodiments, subjects have either previously experienced or are suffering from xerostomia up to grade 1. In some embodiments of this method, subjects have either not previously experienced or are suffering from xerostomia up to grade 2.

[0159] The methods described herein may involve administering xerostomia relief agents to subjects for the control, prevention, or treatment of xerostomia. Various types of xerostomia relief agents may be used, for example, those described in Alessandro Villa et al., Diagnosis and management of xerostomia and hyposalivation, Therapeutics and Clinical Risk Management 2015:11 45-51 and Yanli Li et al., Diagnosis, Prevention, and Treatment of Radiotherapy-Induced Xerostomia: A Review, Hindawi Journal of Oncology Volume 2022, Article ID 7802334, 15 pages, which are incorporated herein by reference.

[0160] In some embodiments, the subject receives palliative therapy for xerostomia simultaneously with the radiopharmaceutical described herein. In some embodiments, the subject receives palliative therapy for xerostomia after being administered the radiopharmaceutical described herein. In some embodiments, the subject receives palliative therapy for xerostomia before being administered the radiopharmaceutical described herein.

[0161] In some embodiments, PSMA-expressing cancer is PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

[0162] In some embodiments, subjects have been reported to have received advanced prior treatment for metastatic castration-resistant prostate cancer (mCRPC). For example, subjects with advanced prior treatment may be reported to have received at least two prior treatments. In various embodiments, subjects have been reported to have a high systemic tumor volume. Systemic tumor volume can be assessed using the diagnostic methods described in the examples (e.g., PET / CT). Patients with a high systemic tumor volume may be reported to have bone metastases and / or visceral metastases.

[0163] Pharmaceutical composition Furthermore, this specification also provides pharmaceutical compositions comprising a radiolabeled compound of formula (I), (II), (III), (IV), or (V) and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutically acceptable carrier, diluent, or excipient may be any type of solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid.

[0164] Pharmaceutical compositions may be administered parenterally. As used herein, the term “parenteral” refers to methods of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intra-articular injections and infusions. Therefore, in certain embodiments, the composition is formulated to be delivered by any of these routes of administration. Pharmaceutical compositions may be formulated for parenteral administration and administered by parenteral administration. Specifically, the pharmaceutical compositions of this disclosure may be formulated for intravenous administration and administered by intravenous administration.

[0165] In certain embodiments, a parenteral injectable pharmaceutical composition comprises a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, or sterile powder for reconstitution into a sterile injectable solution or dispersion immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintenance of the required particle size in the case of dispersions, and the use of surfactants. These compositions may also contain additives such as preservatives, wetting agents, emulsifying agents, chelating agents, buffering agents, and dispersing agents.

[0166] In some embodiments, the pharmaceutical composition comprises a chelating agent for sequestering radionuclides deposited therein. Any chelating agent known in the art that forms a complex with an alpha-emitting radionuclide may be included in the pharmaceutical compositions described herein. In various embodiments, the pharmaceutical composition comprises DTPA. Additional exemplary chelating agents that may be included in the pharmaceutical compositions of the present disclosure are described in Holik, et al. “The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide, Bifunctional Chelator, and Pharmacokinetics Modifying Linker.” Molecules 27.10 (2022): 3062 and Kostelnik, Thomas I., and Chris Orvig. “Radioactive main group and rare earth metals for imaging and therapy.” Chemical reviews 119.2 (2018): 902-956, both of which are incorporated herein by reference in their entirety.

[0167] The pharmaceutical composition of the present disclosure may further comprise a stabilizer, such as a free radical scavenger, etc., to prevent the self-radiolysis of the radioligand of the present invention. Suitable stabilizers for inclusion in the disclosed pharmaceutical compositions include, but are not limited to, 2,5-dihydroxybenzoic acid or its salts, ascorbic acid or its salts, gentisic acid or its salts, methionine, histidine, melatonin, N-acetylmethionine, ethanol, amino acid infusion, or any combination thereof. In some embodiments, the pharmaceutical composition comprises a gentisic acid stabilizer. In some embodiments, the pharmaceutical composition comprises an ascorbic acid stabilizer. In some embodiments, the pharmaceutical composition comprises a stabilizer comprising gentisic acid and ascorbic acid.

[0168] In some embodiments, the pharmaceutical composition comprises one or more buffers for maintaining the pH at about 3-5. Suitable buffers include, but are not limited to, acetates, citrates, tris, lactates, tartrates, and their acidic forms. <00009​​​​​​​​​​​​​​​​​​ Formulations containing [225Ac]Ac-PSMA-R2 and DTPA were prepared as ready-to-use 1 MBq / ml solutions for injection / infusion according to Table 1. [Table 1]

[0173] Example 2: [ 225 Formulations using Ac]Ac-PSMA-R2 and DMSA Radiation labeling scheme: [ka]

[0174] PSMA-R2 reconfiguration A vial containing 1 mg of PSMA-R2 was mixed with 1 mL of water to obtain a 1000 ppm solution.

[0175] Preparation of pharmaceutical raw materials (DS) Labeling: 10 mL glass vial 225 120 μL of AcCl30.1 N HCl (calibration: Day 1, 08:00, 91.49 MBq, 1186 μL) was added. The glass vial was sealed and the dose was measured using a dose analyzer (5.925 MBq, Day 7, 14:48). PSMA-R2 solution (47 μL) was added, followed by Tris buffer 0.25 M pH 8 (318 μL). The pH of the resulting reaction mixture (total volume 485 μL) was measured using a pH strip (Macherey-Nagel pH-Fix 7.5-9.5) and was found to be pH 7.9. The reaction mixture was heated at 95°C for 20 minutes using a heating block (Labnet, AccuBlock Digital Dry Bath). The solution was allowed to cool to room temperature over 10 minutes. Radiolabeling was performed with a peptide mass (micrograms) to activity (MBq) ratio of 8. The peptide mass was 47.4 micrograms, the MBq / microgram peptide ratio at use was 0.125, and the MBq / microgram peptide ratio (ART) was 1.270.

[0176] Preparation of DMSA solution 1.79 mg of DMSA (meso-2,3-dimercaptosuccinic acid) (Sigma Aldrich) was taken in a 1.5 mL centrifuge tube and 0.895 mL of water was added. The suspension was stirred with a vortex mixer until completely dissolved to obtain a uniform solution of 2 mg / mL DMSA.

[0177] Preparation of sodium ascorbate solution L-Ascorbic acid (302.34 mg, 1.7 mmol) and sodium hydroxide (69.85 mg, 1.7 mmol) were taken on a pre-tared balance and then transferred to a 50 mL Falcon vial. Water (11.72 mL) was added to obtain a 26.83 mg / mL sodium ascorbate solution.

[0178] Pharmaceutical (DP) preparations Solutions of sodium ascorbate (596 μL) and DMSA (148 μL) were pipetted and transferred to a 1.5 mL centrifuge tube. The resulting solution was transferred with a 1 mL syringe to a 10 mL reaction vial ( 225 containing [Ac]Ac-PSMAR2 DS solution). The syringe was used to transfer 3 x 1 mL of normal saline (0.9% sodium chloride) to the reaction vial. Finally, 1.695 mL of normal saline was added to obtain a 1 MBq / mL solution. The final volume of the formulation was 5.925 mL. The final pH of the formulation was 7.5.

[0179] A small amount (about 100 μL) was taken for iTLC analysis (RP-18 F254S, 5M Aq NH4OAc / H2O / MeOH 3:2:7.5, details described later). Acquisition of the TLC plate by an alpha scanner was performed more than 18 hours after development. This time is the period until 225Ac reaches secular equilibrium and the migrated daughter nuclides decay. In radio-iTLC analysis, a radiochemical purity (RCP) of 99% or more was shown.

[0180] Example 3: 225 Compound (II) of formula radiolabeled with Ac ( 225 Dose escalation study (Ac-PSMA-R2) Summary: Previously, 177Lu-labeled PSMA-targeted radioligand therapy (e.g., lutetium) 177 Lu) Pivotide tetraxetan or lutetium 177 In men with highly prior treatment PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who are receiving or not receiving zadavotidoglaxetan (Lu) 225 A study to determine the safe and effective dose of Ac-PSMA-R2.

[0181] Primary outcome criteria: Dosage increase 1 : Incidence and severity of dose-limiting toxicity (DLT) during the first cycle of treatment (time frame: up to 6 weeks after the first 225Ac-PSMA-R2 administration). Determine the recommended expanded dose (RDE) and corresponding regimen for 225Ac-PSMA-R2 monotherapy in PSMA-positive mCRPC in the following groups: Group 1: Participants who received prior treatment with 177Lu-labeled PSMA-targeted RLT (post-177Lu). Group 2: Participants who had not received prior treatment with 177Lu-labeled PSMA-targeted RLT (177Lu pre-treatment). Dosage increase 2 : Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during the first treatment cycle (time frame: up to 6 weeks after the first 225Ac-PSMA-R2 administration). The distribution of adverse events is determined by analyzing the frequency of treatment-related adverse events (TEAEs), serious adverse events (TESAEs), and deaths due to AEs through monitoring of relevant clinical and laboratory safety parameters. Dosage expansion 1 Overall response rate (ORR) (Time frame: evaluated up to approximately 15 months from the date of the first administration of 225Ac-PSMA-R2 to the earlier of the date of radiological progression or death from any cause). The overall response rate (ORR) is defined according to the Blinded Independent Review Committee (BICR) and the modified RECIST v1.1 (RECIST: Criteria for Evaluating Response Rates in Solid Tumors) of the Prostate Cancer Working Group 3 (PCWG3), as the percentage of participants who showed the best overall response (BOR) among complete response (CR) or partial response (PR) in soft tissue, provided there is no bone progression according to PCWG3. CR and PR must be re-evaluated and confirmed at least four weeks after the response criteria were first met. Dosage expansion 2 : Percentage of participants who achieved a prostate-specific antigen (PSA) response of 50 (PSA50) (Time frame: From the first dose of 225Ac-PSMA-R2 to the 30-day safety follow-up, evaluated for up to approximately 15 months). The PSA50 response rate is defined as the percentage of participants who achieved a reduction of 50% or more in PSA from baseline, as confirmed by a second PSA measurement taken at least four weeks later.

[0182] Secondary outcome criteria: Dosage increase 3 : Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) (time frame: up to 6 months after the last 225Ac-PSMA-R2 administration). The distribution of adverse events is determined by analyzing the frequency of treatment-related adverse events (TEAEs), serious adverse events (TESAEs), and deaths due to AEs through monitoring of relevant clinical and laboratory safety parameters. Dosage expansion 3 : Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) (Time frame: From the first administration of 225Ac-PSMA-R2 to 30 days of safety follow-up, evaluated for up to approximately 15 months). The distribution of adverse events is determined by analyzing the frequency of treatment-related adverse events (TEAEs), serious adverse events (TESAEs), and deaths due to AEs through monitoring of relevant clinical and laboratory safety parameters. Dosage gradual increase and dose expansion 1Frequency of interruption, dose reduction, discontinuation, and dose intensity for each treatment (time frame: cycles 1-6 (1 cycle = 6 weeks)). The tolerability of the investigational drug is evaluated by summarizing the number and reasons for dose deferral and dose reduction. Dose intensity is also summarized in a table by treatment group. Dosage increase 4 Overall response rate (ORR) (Time frame: evaluated up to approximately 15 months from the date of the first administration of 225Ac-PSMA-R2 to the earlier of the date of radiological progression or death from any cause). The overall response rate (ORR) is defined according to the BICR and the modified RECIST v1.1 of the Prostate Cancer Working Group 3 (PCWG3), as the percentage of participants who showed the best overall response (BOR) among complete responses (CR) or partial responses (PR) in soft tissue, provided there is no bone progression according to PCWG3. CR and PR must be re-evaluated and confirmed at least four weeks after the response criteria are first met. Dosage gradual increase and dose expansion 2 Disease control rate (DCR) (Time frame: Evaluated up to approximately 15 months from the date of first administration of 225Ac-PSMA-R2 to the earlier of the date of radiological progression or death from any cause). Disease control rate (DCR) is defined as the proportion of participants who achieved the best overall response (BOR) among complete response (CR), partial response (PR), or stable disease (SD), in accordance with central and local reviews and the PCWG3's revised RECIST v1.1. Dosage gradual increase and dose expansion 3 Best Overall Response (BOR) (Time frame: evaluated up to approximately 15 months from the date of the first administration of 225Ac-PSMA-R2 to the earlier of the date of radiological progression or death from any cause). • Best Overall Response (BOR) is defined to derive the Overall Response Rate (ORR), which includes either a complete response rate (CR) or a partial response rate (PR). The BOR is determined from the sequence of overall responses. Dosage gradual increase and dose expansion 4: Radiographic progression-free survival (rPFS) (Time frame: From the date of first administration of 225Ac-PSMA-R2 to the earlier of the date of radiographic progression or death from any cause, up to approximately 15 months). • Radiographic progression-free survival (rPFS) is defined as the period (in months) from the date of the first administration of 225Ac-PSMA-R2 to the date of radiographic progression as described in the PCWG3 guidelines, or to death from any cause. Dosage gradual increase and dose expansion 5 Overall survival (OS) (Time frame: From the first dose of 225Ac-PSMA-R2 to death from any cause, evaluated up to approximately 15 months). Overall survival (OS) is defined as the period (in months) from the date of first administration of 225Ac-PSMA-R2 to the date of death from any cause. If it is not known that a participant has died, OS is terminated at the last known date (before the closing date) that the participant was alive. Dosage gradual increase and dose expansion 6 Duration of Response (DoR) (Time frame: Evaluated up to approximately 15 months from the date of the first reported response (CR or PR) to the date of the first reported progression or death from any cause). The duration of response (DOR) is defined as the period (in months) from the date of the first reported response (CR or PR) in a participant who has shown a response, to the date of the first reported progression according to PCWG3 modified RECIST v1.1, or to death from any cause. Dosage gradual increase and dose expansion 7 : Time to the first symptomatic bone event (SSE) (Time frame: From the date of first administration of 225Ac-PSMA-R2 to the earlier of the date of SSE or the date of death from any cause, up to approximately 15 months). The time to the first symptomatic bone event (SSE) is defined as the period (in months) from the first dose of 225Ac-PSMA-R2 to the date of the SSE or death from any cause. The date of the SSE is the earlier of the following dates: pathological fracture, spinal cord compression, tumor-related orthopedic intervention, need for radiation therapy to alleviate bone pain, or death from any cause. Dosage gradual increase and dose expansion 8: Percentage of participants showing a biochemical reaction. Timeframe: Up to approximately 15 months, from the first dose of 225Ac-PSMA-R2 to 30 days of safety follow-up. • A biochemical reaction measured by prostate-specific antigen (PSA), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH).

[0183] During the first cycle of treatment (timeframes: Day 1 of Cycle 1 (before administration (before infusion begins), during infusion, immediately before or at the end of infusion, after administration (5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours)), Day 2 of Cycle 1 (24 hours), Day 3 of Cycle 1 (48 hours), Day 4 of Cycle 1 (72 hours)), venous whole blood samples will be collected for the following activity-based pharmacokinetic characterization. · Dosage increase 4 Area under the serum concentration-time curve (AUClast) of 225Ac-PSMA-R2 from zero time to the time of the last quantifiable concentration. AUClasts are listed and summarized using descriptive statistics. · Dosage increase 5 Area under the plasma concentration-time curve (AUCinf) for 225Ac-PSMA-R2 from zero time to infinity. AUCinf is listed and summarized using descriptive statistics. · Dosage increase 6 :225Ac-PSMA-R2 maximum plasma concentration (Cmax). Cmax is listed and summarized using descriptive statistics. · Dosage increase 7 :Total systemic clearance (CL) after intravenous administration of 225Ac-PSMA-R2. CL is listed and summarized using descriptive statistics. · Dosage increase 8 Observed drug concentration rise time (Tmax) for 225Ac-PSMA-R2. Tmax is listed and summarized using descriptive statistics. · Dosage increase 9 Volume of distribution (Vz) of 225Ac-PSMA-R2 in the end-phase after intravenous drainage. Vz is listed and summarized using descriptive statistics. · Dosage gradually increased to 10The final removal half-life (T1 / 2) of 225Ac-PSMA-R2. T1 / 2 is listed and summarized using descriptive statistics. · Dosage expansion 4 Area under the serum concentration-time curve (AUClast) of 225Ac-PSMA-R2 from zero time to the time of the last quantifiable concentration. AUClasts are listed and summarized using descriptive statistics. · Dosage increase 5 Area under the plasma concentration-time curve (AUCinf) for 225Ac-PSMA-R2 from zero time to infinity. AUCinf is listed and summarized using descriptive statistics. · Dosage expansion 6 : Maximum plasma concentration (Cmax) of 225Ac-PSMA-R2. Cmax is listed and summarized using descriptive statistics. · Dosage expansion 7 :Total systemic clearance (CL) after intravenous administration of 225Ac-PSMA-R2. CL is listed and summarized using descriptive statistics. · Dosage expansion 8 Observed drug concentration rise time (Tmax) for 225Ac-PSMA-R2. Tmax is listed and summarized using descriptive statistics. · Dosage increase 9 Volume of distribution (Vz) of 225Ac-PSMA-R2 in the end-phase after intravenous drainage. Vz is listed and summarized using descriptive statistics. · Dosage increase 10 The final removal half-life (T1 / 2) of 225Ac-PSMA-R2. T1 / 2 is listed and summarized using descriptive statistics.

[0184] Estimated number of participants: 100 Research group: Group 1-177Lu after treatment 1) Dose escalation: All eligible participants in mCRPC who have received extensive prior treatment and are unresponsive to 177Lu-labeled PSMA-targeted RLTs will be administered a starting dose of 7 megabecquerels (MBq) of 225Ac-PSMA-R2 to determine the maximum tolerated dose / expanded recommended dose (MTD / RDE) for group 1.

[0185] 2) Dose expansion: Once the RDE for Group 1 is determined, participants who are unresponsive / partially responsive to 177Lu-labeled PSMA-targeted RLT, or who require retreatment / re-challenge after 177Lu-labeled PSMA-targeted RLT treatment, will be enrolled in the group 1 dose expansion.

[0186] Group 2-177Lu before treatment 1) Dose escalation: All eligible participants in mCRPC who have received prior treatment with androgen receptor pathway inhibitors (ARPIs) or computed tomography (CT) but have not received treatment with 177Lu-labeled PSMA-targeted RLTs (177Lu-labeled PSMA-targeted RLT treatment naiveté) will be administered a dose of 225Ac-PSMA-R2 one level higher than the RDE of Group 1 as the starting dose to determine the MTD / RDE of Group 2.

[0187] 2) Dose expansion: Once the RDE for group 2 is determined, participants who have not received 177Lu-labeled PSMA-targeted RLT with high doses of soft tissue and visceral lesions, and participants with diffuse bone metastases, will be enrolled in the dose expansion for group 2.

[0188] Alternatively, if RDE1 cannot be determined, group 2 will begin dose escalation evaluation with a dose of 7 MBq of 225Ac-PSMA-R2 based on Novartis's decision. Early initiation of group 2 is supported by new safety and preliminary efficacy data obtained from dose escalation in group 1.

[0189] Assigned intervention: • Drug: 225Ac-PSMA-R2 (compound of formula (II)) ·Radiation:68Ga-PSMA-R2 • Radiopharmaceutical preparation kit

[0190] Detailed explanation This is an open-label, Phase I / II, multicenter study involving two treatment groups (Group 1 and Group 2). Each group has a dose-escalation phase, and once the maximum tolerated dose / recommended escalation dose (MTD / RDE) is determined in each phase, the study continues to the expansion phase in each group.

[0191] In the dose escalation phase, the MTD / RDE of 225Ac-PSMA-R2 will be established based on an established Bayesian logistic regression model (BLRM). Adaptive BLRM will be implemented according to the principle of dose escalation with overdose control (EWOC) to control the risk of DLT in future study participants. The decision to escalate the dose will be made by the principal investigator and Novartis during the dose escalation meeting (DEM) based on safety and tolerability information (BLRM summary of DLT risk) and PK and preliminary efficacy information.

[0192] In the dose expansion phase, we will evaluate the antitumor activity (overall response rate (ORR) and prostate-specific antigen 50 (PSA50) response rate according to the modified RECIST 1.1 of the Prostate Cancer Working Group 3 (PCWG3)), as well as further evaluate the safety, tolerability, and pharmacokinetics of 225Ac-PSMA-R2.

[0193] Eligibility: Study target age: 18 years and older Gender of research subjects: Male Accepting healthy volunteers: No

[0194] Main selection criteria: -68Ga-PSMA-R2: Evidence of PSMA-positive disease by PET / CT, determined to be eligible by central interpretation. - Reports of progressive mCRPC - Appropriate organ function (bone marrow reserve, liver, kidneys) - The patient has previously undergone orchiectomy and / or is currently receiving ARPI and taxane-based chemotherapy, and has previously received 177Lu-PSMA-RLT (dose escalation and expansion in Group 1) or has not received 177Lu-PSMA-RLT (dose escalation and expansion in Group 2).

[0195] Main exclusion criteria: -225Ac-PSMA-R2 therapy within 28 days of scheduled C1D1, any other investigational drug -225Ac-PSMA-R2 therapy with any systemic anticancer therapy within 28 days of scheduled C1D1 - Uncontrollable pain or incompatibility that may cause participants to lose the ability to follow imaging procedures. - History of CNS metastasis and symptomatic spinal cord compression, or clinical or radiological findings indicating imminent spinal cord compression. - History of uncontrolled cardiovascular disease - Diagnosis of other malignancies that are expected to alter life expectancy or that may interfere with disease assessment. - Other selection / exclusion criteria defined in the protocol may apply.

[0196] Based on the results of the above dose escalation study, the R2PD for administering the compound of formula (II) at doses of 4 MBq, 5 MBq, 6 MBq, 7 MBq, 8 MBq, 9, 10 MBq, 11 MBq, 12 MBq, 13 MBq, or 14 MBq, preferably 4, 7, 10, 12, or 14 MBq, more preferably 7 or 10 MBq, and even more preferably 7 MBq, is determined.

[0197] Example 4: 225 Dose escalation study of a compound of formula (I) radiolabeled with Ac Summary: Previously, 177Lu-labeled PSMA-targeted radioligand therapy (e.g., lutetium) 177 ) Pivotide tetraxetan or lutetium ( 177 In men with highly prior treatment PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who are receiving or not receiving zadavotidoglaxetan (Lu) 225 A study to determine the safe and effective dose of Ac-PSMA-617.

[0198] Detailed explanation PSMA-positive disease ( 68 Approximately 60 patients (determined by Ga-PSMA-11 PET / CT) will be assigned to one of three groups (20 patients per group). Group A: Patients who have previously received chemotherapy and androgen receptor pathway inhibitors (ARPIs) 177Not receiving Lu-PSMA targeted agents (especially 177Lu-PSMA-617 or 177Lu-PSMA I&T), ·Group B- 177 No prior experience with Lu-PSMA targeted therapy. • Group C- and earlier ARPI and 177 Lu-PSMA targeting agents (especially 177Lu-PSMA-617 or 177Lu-PSMA I&T).

[0199] Registered patients will receive intravenous treatment once every 8 weeks (±1 week) for a maximum of 6 cycles. 225 Ac-PSMA-617 will be administered. Dose escalation will be carried out using a Bayesian logistic regression model (Table 2). In each group, at least 3 patients will be treated at each dose and evaluated for at least 6 weeks before considering patient enrollment to the next dose. The maximum tolerated dose will be the dose at which the posterior probability of target toxicity exceeds 50% (at least 6 patients will be treated at this dose and observed for 6 weeks). Patients may receive supportive care but not combination therapy with anticancer drugs. Secondary endpoints include overall safety and tolerability, response according to RECIST v1.1 (overall response rate, duration of response, disease control rate), progression-free survival (radiological disease progression, clinical progression, and PSA progression), biochemical response, and health-related quality of life (HRQoL). Safety follow-up will be conducted. 225 The follow-up is conducted for approximately 60 days after the last dose of Ac-PSMA-617, or until subsequent anti-cancer treatment. Long-term follow-up includes HRQoL, survival rate, and treatment updates every 3 months (±1 month) for 12 months. [Table 2]

[0200] Primary outcome criteria: 1. Recommended Phase 2 dose (RP2D) (Time frame: From 6 weeks after C1D1 in each administration cohort until enrollment is complete, with an average of 1.5 years to determine the RP2D). • The RP2D for each group (groups A, B, and C) is defined as the dose level that is well-tolerated (i.e., below the MTD) and where additional findings (e.g., long-term tolerability) may influence the determination of the RP2D. If the MTD is not identified even at the highest dose level tested, the RP2D can be determined based on data demonstrating sufficient tolerability and therapeutic efficacy.

[0201] Secondary outcome criteria: Percentage of participants experiencing treatment-related adverse events - Timeframe: Day 1 / infusion day to 60 days post-infusion. Safety is measured by the percentage of participants who experience treatment-related adverse events (events that began after the first dose of the study drug, or events that existed before the start of treatment but increased in severity based on recommended terminology).

[0202] Overall Performance Rate (ORR) -Timeframe: For the first 24 weeks, 225Ac-PSMA-617 was administered every 8 weeks after the initial dose, and thereafter every 12 weeks until the final consultation, for an average of 2.5 years. Overall response rate (ORR) is defined as the proportion of participants who showed the best overall response, either complete response (CR) or partial response (PR), as measured by RECIST v1.1.

[0203] Duration of response (DOR) -Time frame: Every 8 weeks after the first dose of 225Ac-PSMA-617 for the first 24 weeks, then every 12 weeks until the end of treatment, for an average of 2.5 years. The duration of response (DOR) is defined, according to RECIST v1.1, as the period from the date of the first reported response (CR or PR) to the date of the first radiologically reported disease progression or death due to the disease.

[0204] Disease control rate (DCR) -Time frame: For the first 24 weeks, 225Ac-PSMA-617 was administered every 8 weeks after the initial dose, and thereafter every 12 weeks until the end-of-treatment consultation, for an average of 2.5 years. Disease control rate (DCR) is the proportion of participants who achieved the best overall response, either complete response (CR), partial response (Pr), or stable disease (SD), according to RECIST v1.1.

[0205] Progression-free survival (PFS)-Timeframe: For the first 24 weeks, every 8 weeks after the initial dose of 225Ac-PSMA-617, and thereafter every 12 weeks until the end-of-treatment consultation, with an average duration of 2.5 years. Progression-free survival (PFS) is defined as the period from day 1 of cycle 1 (C1 D1) to radiological, clinical, or prostate-specific antigen [PSA]-based progression-free survival, or detection by an event defined as follows: As outlined in Prostate Cancer Working Group 3 (PCWG3) and RECIST 1.1, radiological disease progression is determined from bone scans and contrast-enhanced CT / MRI. • Clear clinical progress PSA progression is defined as the day when PSA increases by 25% or more from its lowest value, with an absolute increase of 2 ng / mL or more, and is confirmed by a second consecutive value obtained at least three weeks later. PSA increases within the first 12 weeks are ignored. If no decrease from baseline is reported, the baseline PSA is considered the lowest value. The progression date is the date of the first occurrence, not the date of confirmation (PCWG3 guidance).

[0206] Percentage of participants who showed a biochemical reaction -Measured using prostate-specific antigen (PSA), timeframes: baseline, days 1, 15, 29, and 43 of each cycle (1 cycle = 8 weeks ± 1 week), end of treatment, and every 3 months during the 12-month follow-up period. Prostate-specific antigen is a glycoprotein considered a biomarker of treatment response in men with prostate cancer. A 50 percent (%) decrease in PSA from baseline to the end of the study was considered a PSA response.

[0207] Significant changes in alkaline phosphatase (ALP) levels - Time frame: Baseline, Cycle 1 and Cycle 2 (weekly), Cycle 3 to Cycle 6 (bi-weekly) (1 cycle = 8 weeks + / - 1 week). Safety is measured by a significant change in alkaline phosphatase (ALP) levels after baseline compared to baseline.

[0208] Significant changes in lactate dehydrogenase (LDH) levels- Time frame: Baseline, Cycle 1 and Cycle 2 (weekly), Cycle 3 to Cycle 6 (bi-weekly) (1 cycle = 8 weeks + / - 1 week). Safety is measured by a significant change in lactate dehydrogenase (LDH) levels after baseline compared to baseline.

[0209] Changes from the baseline of the European Quality of Life (EuroQol) - 5-Domain 5-Level Scale (EQ-5D-5L). Timeframe: Baseline, Day 1 of each cycle (1 cycle = 8 weeks + / - weeks), End of treatment, mean 2.5 years. EQ-5D-5L is a standardized participant-completed questionnaire that measures health-related quality of life and converts its score into an index value or utility score. EQ-5D-5L consists of two components: a health status profile and an optional visual analog scale (VAS). The EQ-5D health status profile consists of five aspects: mobility, self-care, daily living activities, pain / discomfort, and anxiety / depression. Each aspect has five levels: 1 = no problem, 2 = minor problem, 3 = moderate problem, 4 = serious problem, 5 = very serious problem. A higher score indicates a higher level of problem in each of the five aspects.

[0210] Changes from baseline in the functional assessment of cancer treatment- Prostate (FACT-P) Questionnaire; Timeframe: Baseline, Day 1 of each cycle (1 cycle = 8 weeks + / - weeks), End of treatment, mean 2.5 years. FACT-P assesses symptoms / problems associated with prostate cancer and its treatment. It is a combination of FACT-General and the Prostate Cancer Subscale (PCS). FACT-General (FACT-G) is a 27-item quality of life (QoL) measure that provides a total score and subscale scores for physical (0-28), functional (0-28), social (0-28), and emotional well-being (0-24). The total score ranges from 1 to 108, with higher scores indicating better performance for both the total score and subscale scores. The PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (range 0-48, higher scores indicating better performance). The FACT-P total score is the sum of the five subscale scores of the FACT-P questionnaire, with a range of 0 to 156. A higher score indicates a higher level of functioning and a better quality of life.

[0211] Change from baseline in the simplified pain assessment form. - Shortened Version (BPI-SF) Questionnaire: Pain Severity Score; Timeframe: Baseline, Day 1 of each cycle (1 cycle = 8 weeks + / - weeks), End of treatment, mean 2.5 years. The BPI-SF is a public tool for assessing pain, including severity and interference scores. The BPI-SF is an 11-item self-report questionnaire designed to assess participants' pain severity and its impact on daily life. The pain severity score is the mean of questions 3, 4, 5, and 6 of the BPI-SF (questions asking about the degree of pain, ranked from 0 [no pain] to 10 [the worst pain imaginable]). Progression of pain severity is defined as a score increase of 30% or more from baseline without a reduction in analgesic use.

[0212] Change from baseline in the simplified pain assessment form.- Shortened BPI-SF Questionnaire: Pain Interference Score; Timeframe: Baseline, Day 1 of each cycle (1 cycle = 8 weeks + / - weeks), End of treatment, mean 2.5 years. The BPI-SF is a publicly available tool for assessing pain, including severity and interference scores. The BPI-SF is an 11-item self-report questionnaire designed to assess the severity of pain and its impact on daily life for participants. The Pain Interference Score is the mean of seven BPI-SF questions (questions asking about the degree of interference of activity due to pain), ranked from 0 (no interference) to 10 (complete interference). Progression of pain interference is defined as a score increase of 50% or more from baseline without a reduction in analgesic use.

[0213] Change from baseline on the Xerostomia-Related Quality of Life Scale (XeQOLS) - Duration: Baseline, day 1 of each cycle (1 cycle = 8 weeks + / - 1 week), end of treatment, and every 3 months during the 12-month follow-up period. XeQOLS is a validated patient-reported 15-item assessment scale with four domains: physical functioning, pain / discomfort, personal / psychological functioning, and social functioning. The score is the average of all responses across all domains, ranging from 0 to 4, with higher scores indicating a greater burden of xerostomia. A negative change from baseline indicates an improvement in the burden of xerostomia.

[0214] Eligibility: Study target age: 18 years and older Gender of research subjects: Male Accepting healthy volunteers: No

[0215] Main selection criteria: - Patients need to be able to understand and sign the approved ICF. - The patient must be able to understand and comply with all protocol requirements. - Patients must be 18 years of age or older. - The patient's ECOG performance status must be between 0 and 2. - The patient must be confirmed to have prostate cancer histologically, pathologically, and / or cytologically. - Patients must undergo a 68Ga-PSMA-11 PET / CT scan within 28 days of joining the study, as described in the imaging manual, and obtain a positive result. - The patient must be recovered from or stable at baseline with any clinically significant toxicity associated with previous prostate cancer treatment, or at grade 2 or less. - Determine the progression of the disease being treated before enrollment. Progressive disease for study participation is defined as one or more of the following: 1. PSA progression: PSA levels have risen two or more times with an interval of more than one week from the baseline measurement. If the rise in PSA is merely a sign of progression, the minimum starting value is 2.0 ng / mL. 2. Progression of soft tissue or visceral disease according to RECIST 1.1 criteria: The sum of the diameters of all target lesions (SOD) (short axis for lymph node lesions, long axis for non-lymph node lesions) increases by 20% or more based on the minimum SOD since the start of treatment, or the appearance of one or more new lesions. 3. Bone progression: Two or more new lesions on bone scan. - The patient must have sufficient organ function (bone marrow reserve, liver function, kidney function). - Healthy, known HIV-positive patients with a low risk of AIDS-related outcomes are eligible. HIV testing is required. - Patients with a partner who may become pregnant must use an appropriate barrier-protective method of contraception, as deemed acceptable by the principal investigator, throughout the study period and for six months after the last dose of the study drug. - Targets of Group A The patient must have previously undergone orchiectomy and / or be undergoing ongoing androgen deprivation therapy, have serum testosterone levels at castration levels (<50 ng / dL or <1.7 nmol / L), and have previously received cytotoxic chemotherapy and novel androgen axis agents (e.g., abiraterone or enzalutamide). The patient must also not have previously received 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T). - Targets of Group B(South Africa only): Patients must be undergoing ongoing androgen deprivation therapy (ADT) and have previously undergone orchiectomy or been medically castrated using an LHRH agonist / antagonist to adequately suppress serum testosterone (<50 ng / dL), but must not have previously received cytotoxic chemotherapy or novel androgen axis agents (e.g., abiraterone or enzalutamide). These patients must not have received 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T). - Targets of group C To adequately suppress serum testosterone (<50 ng / dL), patients must be undergoing ongoing androgen deprivation therapy (ADT) and have previously undergone orchiectomy or been medically castrated using an LHRH agonist / antagonist. Patients must have received at least one cycle of 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T) at least six weeks after study enrollment, and their biochemical and radiological response to treatment must have been evaluated. Prior exposure with ARPI and / or chemotherapy is not required.

[0216] Main exclusion criteria: - Pretreatment with strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, or hemispheric irradiation. - Any investigational drug within 28 days of study registration. - Known hypersensitivity to the components or analogues of the test treatment. - Other concurrent cytotoxic chemotherapy, targeted therapy, biological agents, immunotherapy, radioligand therapy, or investigational drug therapy. - Blood transfusions solely for the purpose of qualifying for participation in research. Patients with a history of CNS metastasis must have received treatment (surgery, radiotherapy, gamma knife), be neurologically stable, asymptomatic, and not be receiving corticosteroids to maintain neurological integrity. Patients with epidural disease, tubal disease, and a history of spinal cord injury are eligible if those areas have been treated, are stable, and are neurologically unimpaired. - Clinical or radiological findings indicating symptomatic spinal cord compression or imminent spinal cord compression. - Serious comorbidities (as determined by the principal investigator) including, but not limited to, uncontrolled infections, active hepatitis B or C, or other serious comorbidities that, in the opinion of the principal investigator, would impede participation in or cooperation with the study. - Diagnosed with other malignancies that may alter life expectancy or interfere with disease assessment. Patients with a history of malignancy who have remained disease-free for more than three years are eligible.

[0217] Based on the results of the above dose escalation studies, the recommended Phase 2 dose (RP2D) of the 225Ac-labeled compound of formula (I) is 6 MBq or 8 MBq.

[0218] Example 5: 225 Phase 2 test design of compound (I) radiolabeled with Ac Summary: This study targeted men with mCRPC after chemotherapy (e.g., taxanes). 225 Ac-PSMA-617( 225 A randomized study comparing formula (I)) radiolabeled with Ac versus standard treatment (BSoC).

[0219] Number of participants: 141

[0220] Selection criteria: - Patients with progressive PSMA PET+mCRPC - Patients who have previously received ARPI, taxane, or Lu-PSMA RLT.

[0221] Exclusion criteria: - Patients with xerostomia grade 2 or higher

[0222] Stratification factors: - Time to radiological / biochemical progression in the previous Lu case (less than 6 months vs. more than 6 months) - Previous Lu cycle count (4 or less vs. greater than 4)

[0223] Research details: This is a randomized trial. The ratio of patients receiving 225Ac-PSMA-617 (treatment) to patients receiving BSoC (control) is 2:1. Patients in the treatment group receive 225Ac-PSMA-617 intravenously at the RP2D dose (determined in Example 4) for 4 cycles every 8 weeks. • All patients will undergo PSMA PET imaging after Cycle 2. • All patients will receive relief for dry mouth according to the protocol.

[0224] Primary evaluation criteria: Radiographic progression-free survival (rPFS) as assessed by blinded independent central review (BICR) using PCWG3.

[0225] Secondary evaluation criteria: ·Overall survival (OS) • Overall response rate (ORR), disease control rate (DCR), and duration of response (DOR) using the revised RECIST 1.1 from PCWG3. • Time to the onset of the first symptomatic bone disease (TTSSE) • Biochemical reactions ·Safety • Health-related quality of life (HRQoL) Characterization of PK by blood radioactivity during Cycle 1

[0226] Exploration goal: • Evaluate molecular biomarkers related to treatment response, resistance, and / or safety. • We will investigate the relationship between imaging diagnosis using PSMA SPECT and the effectiveness of treatment with 225Ac-PSMA-617.

[0227] Example 6: 225 Phase 3 test design of the compound of formula (I) radiolabeled with Ac Summary: This study targeted men with mCRPC who had received prior chemotherapy and were diagnosed with 225Ac-PSMA-617. 225 A randomized study comparing formula (I)) radiolabeled with Ac versus standard treatment (BSoC).

[0228] Number of participants: 684

[0229] Selection criteria: - Patients with progressive PSMA PET+mCRPC - Patients who have previously received ARPI and Lu-PSMA RLT

[0230] Exclusion criteria: - Patients with xerostomia grade 2 or higher - Patients who have previously received taxanes

[0231] Stratification factors: - Time to radiological / biochemical progression in the previous Lu case (less than 6 months vs. more than 6 months) - Previous Lu cycle count (4 or less vs. greater than 4) - ECOG performance status (0-1 vs 2)

[0232] Research details: This is a randomized trial. The ratio of patients receiving 225Ac-PSMA-617 (treatment) to patients receiving BSoC (control) is 2:1. Patients in the treatment group receive 225Ac-PSMA-617 intravenously at the RP2D dose (determined in Example 4) for 4 cycles every 8 weeks. • All patients will undergo PSMA PET imaging after Cycle 2. • All patients will receive relief for dry mouth according to the protocol.

[0233] Primary evaluation criteria: overall survival

[0234] Secondary evaluation criteria: • rPFS using PCWG3 standards • ORR, DCR, DOR using the modified PCWG3 version RECIST 1.1 • Time to the onset of the first symptomatic bone disease (TTSSE) • Biochemical reactions ·Safety HRQoL Characterization of PK by blood radioactivity during Cycle 1

[0235] Exploration goal: • Evaluate molecular biomarkers related to treatment response, resistance, and / or safety. • We will investigate the relationship between imaging diagnosis using PSMA SPECT and the effectiveness of treatment with 225Ac-PSMA-617.

[0236] Example 7: 225 Phase 2 test design supporting a Phase 3 dose of 10 MBq of the compound of formula (I) (225Ac-PSMA-617) radiolabeled with Ac. Summary: Patients with PSMA-positive mCRPC cancer who have been treated with androgen receptor pathway inhibitors (ARPIs) and chemotherapy (e.g., taxanes), and who have been treated with [177Lu]Lu-PSMA targeted therapy (e.g., lutetium). 177 Lu) Pivotide tetraxetan or lutetium 177 In men whose disease progressed during or after administration of Lu) zadavotidoglaxetan, 225Ac-PSMA-617 ( 225 A study to gather additional information to support a Phase 3 dose of 10 MBq of formula (I)) radiolabeled with Ac (see Example 8 for Phase 3 study design).

[0237] Primary outcome criteria: Data collection: Additional data on 225Ac-PSMA-617 at doses of 8 MBq and 10 MBq to support a phase 3 dose of 10 MBq for 225Ac-PSMA-617 in PSMA-positive mCRPC patients who have progressed during or after ARPI and taxane-based chemotherapy. · Prostate-specific antigen response (PSA50): The percentage of participants who showed a decrease of 50% or more from baseline in their second PSA measurement, which was performed more than 4 weeks later. · safety : Types, incidence, and severity of adverse events (AEs) and serious adverse events (SAEs), as well as mortality. · Tolerance : Interruption, dose reduction, discontinuation, dose intensity, and duration of exposure.

[0238] Secondary outcome criteria: Activity evaluation: Antitumor activity of 225Ac-PSMA-617 (8 MBq and 10 MBq). · Radiographic progression-free survival (rPFS) : From the date of randomization to the date on which the first radiographic disease progression, as assessed by the principal investigator and according to the modified RECIST v1.1 criteria of the Prostate Cancer Working Group 3 (PCWG3) (RECIST: response criteria for solid tumors), is reported, or to the date of death from any cause, whichever comes first. · Progression-free survival (PFS) : From the date of randomization to the earlier of the date of the first reported progression (radiological progression according to the modified RECIST v1.1 criteria of PCWG3, clinical progression, or PSA progression according to PCWG3) or death from any cause, as assessed by the principal investigator. · Overall response rate (ORR) : In the absence of bone progression according to PCWG3, the percentage of participants who demonstrated the best overall response (BOR) among confirmed complete response (CR) or partial response (PR) in soft tissue, based on tumor response data assessed by the principal investigator and the modified PCWG3 version, RECIST v1.1. · Disease control rate (DCR) : In the absence of bone progression according to PCWG3, the percentage of participants with BOR (Body Orientation Reduction) confirmed in soft tissue as CR, PR, SD (Stable Disease), or non-CR / non-progressive disease (PD), based on tumor response data assessed by the principal investigator and the modified PCWG3 version, RECIST v1.1. · Overall survival (OS) : The period from the date of randomization to the date of death from any cause.

[0239] Safety of 225Ac-PSMA-617: Characterizing the safety profile of 225Ac-PSMA-617 at 8 MBq and 10 MBq. · Other safety evaluation items Changes in clinical laboratory values, vital signs, and ECG. ·

[0240] Exploration goal: Characterize salivary gland function under the influence of 1.225Ac-PSMA-617 (8 MBq and 10 MBq). 2.225Ac-PSMA-617 (8 MBq and 10 MBq) is used to assess patient-reported disease-related symptoms and health-related quality of life (HRQoL). 3. Use 225Ac-PSMA-617 (8 MBq and 10 MBq) to assess changes in patient-reported pain severity. Characterize the molecular biomarker 4.225Ac-PSMA-617 (8 MBq and 10 MBq). 5. Evaluate the effect of 225Ac-PSMA-617 (8 MBq and 10 MBq) on the QTc interval, including concentration / QT assessment. 6. Evaluate dose measurements of 6.225Ac-PSMA-617 (8 MBq and 10 MBq) and further evaluate doses to vital organs (e.g., kidneys, bone marrow, and salivary glands) and tumors. Characterizing the pharmacokinetic profiles of 7.225Ac-PSMA-617 (8 MBq and 10 MBq). This study characterizes the in vivo distribution of 8.225Ac-PSMA-617 (8 MBq and 10 MBq).

[0241] Detailed explanation In this embodiment, the patient was treated with ARPI and taxane-based chemotherapy, 177 This document describes the Phase 2 portion of a two-arm, randomized, open-label, international, multicenter Phase 2 / 3 trial evaluating the efficacy and safety of 225Ac-PSMA-617 compared to best standard of care (BSoC) at the discretion of the principal investigator in adult participants with PSMA-positive mCRPC whose disease has progressed during or after Lu]Lu-PSMA targeted therapy.

[0242] At least 12 eligible participants will be randomly selected in a 1:1 ratio and administered 225Ac-PSMA-617 at either 8 MBq (arm 1) or 10 MBq (arm 2). Randomization will not be stratified. Participants will receive intravenous administration of 225Ac-PSMA-617 (1 MBq / mL dose intensity) once every 8 weeks for 4 cycles (1 cycle = 8 weeks), according to their assigned treatment group, and may be permitted to receive up to 6 cycles in total, including 2 additional cycles (referred to as 4(+2) cycles). The primary analysis will be conducted after at least 12 participants have received at least one dose, been followed for 12 weeks, and undergone a single time-point imaging. The purpose of this primary analysis is to collect additional information supporting 10 MBq as the phase 3 dose of 225Ac-PSMA-617. The Phase 3 dose will be evaluated based on all available efficacy, safety, and tolerability data, including data from Example 4 (Phase 1 trial (published as clinical trial ID NCT04597411 “AcTION” trial)) and Example 5 (Phase 2 trial). Safety follow-up will be conducted approximately 56 days after the last dose of 225Ac-PSMA-617, or before any subsequent anti-cancer treatment. Participants receiving the study treatment 225Ac-PSMA-617 will continue safety follow-up every 12 weeks, 24 weeks, and 48 weeks at years 1-2, 3, and 4-5 of the long-term follow-up period (LTFU). During this long-term follow-up, adverse events (AEs) such as xerostomia, xerophthalmos, and myelosuppression associated with the study treatment, nephrotoxicity and secondary malignancies (regardless of causal relationship), and serious adverse events (SAEs) causally related to the study treatment will be reported. Survival rates, treatment updates, hematological, chemical, PSA and other biomarkers, estimated glomerular filtration rate based on body weight, creatinine and cystatin C, and patient-reported outcome (PRO) information will be collected on a voluntary basis.

[0243] Eligibility: This study will enroll adult male participants (18 years of age or older) with PSMA-positive mCRPC cancer that has progressed during or after treatment with ARPI and taxane-based chemotherapy.

[0244] Main selection criteria: Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. • Histopathological and / or cytological confirmation of prostate adenocarcinoma. • Reporting of progressive mCRPC Participants must have a PSMA-positive disease as assessed by a PSMA PET / CT scan using an approved PSMA contrast agent, in accordance with the protocol instructions, and eligibility will be determined by the sponsor's central image interpretation rules. • Castration levels of serum / plasma testosterone (less than 50 ng / dL or less than 1.7 nmol / L). • The patient had previously received ARPI and taxane-based chemotherapy, and the disease progressed during or after [177Lu]Lu-PSMA targeted therapy. In the setting of metastatic hormone-sensitive prostate cancer (mHSPC), prior treatment exposure to ARPI and taxane-based chemotherapy is acceptable. Participants must have at least one metastatic lesion present on screening / baseline CT, MRI, or bone scan images obtained 28 days prior to randomization. Except for alopecia, all clinically significant toxicity associated with previous treatments (i.e., previous chemotherapy, radiotherapy) must be reduced to Grade 2 or lower. • Appropriate organ function (bone marrow reserve, liver, kidneys)

[0245] Main exclusion criteria • Within 6 weeks of randomization, the patient has received one of the following prior treatments: strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, hemispheric irradiation. 177 Lu-PSMA and 177 Lu-DOTA targeted therapy. • Investigational drug administered within 28 days prior to the randomization date. • Any use made before the day of randomization 225 Ac-based investigational compound. • Known hypersensitivity to any of the treatments or similar classes of drugs being studied. • The patient has a history of CNS metastasis, is neurologically unstable or symptomatic, is receiving corticosteroids to maintain neurological integrity and symptomatic spinal cord compression, or has clinical or radiological findings indicating imminent spinal cord compression. • A history or current diagnosis of ECG abnormalities that pose a significant risk to safety. • Concurrent severe acute or chronic nephropathy (based on Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2024) KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int;105(4S):S117-S314 (KDIGO 2024 guideline)). • A serious, uncontrolled co-infection that the principal investigator determines would interfere with participation in or cooperation with the study. • Diagnosis of other active malignancies in the past three years that may alter life expectancy or interfere with disease assessment. • Baseline xerostomia is grade 2 or higher according to the Common Terminology Criteria for Adverse Events v.5 (CTCAE v.5).

[0246] Other selection / exclusion criteria defined in the protocol may apply.

[0247] Based on the results of the above study, the dose of formula (I) radiolabeled with 225Ac will be 8 MBq or 10 MBq in the Phase 3 portion of the study. For example, if the data obtained suggests that the benefit / risk profile of 10 MBq of 225Ac-PSMA-617 is acceptable, the 10 MBq dose will be considered in Phase 3. If the data obtained suggests that the benefit / risk profile of 8 MBq of 225Ac-PSMA-617 is more acceptable, the 8 MBq dose will be considered in Phase 3.

[0248] Example 8: Phase 3 trial comparing the 225Ac-labeled compound of formula (I) (225Ac-PSMA-617) with best standard treatment. overview: [ 177 A phase 3, open-label, international, multicenter, randomized study comparing 225Ac-PSMA-617 with best-in-class standard of care (BSoC) in adult participants with PSMA-positive metastatic castration-resistant prostate cancer that has progressed during or after Lu]Lu-PSMA targeted therapy.

[0249] Primary outcome criteria: 1. After receiving treatment with ARPI and taxane-based chemotherapy, 177 This study will determine whether treatment with 225Ac-PSMA-617 extends radiological progression-free survival (rPFS), as assessed by the modified RECIST v1.1 of PCWG3, compared to participants with PSMA-positive mCRPC who experienced disease progression during or after Lu]Lu-PSMA targeted therapy. · rPFS : The period from the date of randomization to the date of the first reported radiographic disease progression as assessed by Blinded Independent Central Review (BICR) and the modified RECIST v1.1 criteria of the Prostate Cancer Working Group 3 (PCWG3), or death from any cause, whichever comes first.

[0250] 2. After receiving treatment with ARPI and taxane-based chemotherapy, 177 This study will determine whether treatment with 225Ac-PSMA-617 extends overall survival (OS) in PSMA-positive mCRPC patients who experience disease progression during or after Lu]Lu-PSMA targeted therapy, compared to patients treated with BSoC of the investigator's choice. · OS : The period from the date of randomization to the date of death from any cause.

[0251] Secondary outcome criteria: This study evaluates radiographic progression-free survival (rPFS-PET) using PSMA PET imaging in participants treated with 1.225Ac-PSMA-617 and BSoC as selected by the principal investigator. · rPFS-PET : The period from the date of randomization to the date of the first radiographic disease progression reported by PSMA PET imaging, or the earlier of the date of death from any cause.

[0252] 2.225 We evaluate progression-free survival (PFS) in participants treated with Ac-PSMA-617 and BSoC at the discretion of the principal investigator. · PFS : From the date of randomization to the earlier of the date of the first reported progression (radiological progression according to the modified RECIST v1.1 criteria of PCWG3, clinical progression, or PSA progression according to PCWG3) or death from any cause, as assessed by the principal investigator.

[0253] 3. Evaluate the overall response rate (ORR) of participants treated with 3.225Ac-PSMA-617 and BSoC as selected by the principal investigator. · ORR : In the absence of bone progression according to PCWG3, the percentage of participants who showed the best overall response (BOR) among confirmed complete response (CR) or partial response (PR) in soft tissue, based on tumor response data by BICR assessment and the modified PCWG3 version of RECIST v1.1. In addition, ORR of soft tissue only according to the modified PCWG3 version of RECIST v1.1 is analyzed.

[0254] 4.225 We will compare and evaluate disease control rates (DCR) in participants treated with Ac-PSMA-617 and BSoC as selected by the principal investigator. · DCR :Percentage of participants with BOR (Body Orthopedic Ratio) confirmed in soft tissue, CR, PR, SD (Stable Disease), or non-CR / non-progressive disease (PD), based on tumor response data from BICR assessment and the modified PCWG3 version of RECIST v1.1, in the absence of bone progression according to PCWG3.

[0255] 5.225 The duration of response (DoR) will be evaluated in participants treated with Ac-PSMA-617 and BSoC as selected by the principal investigator. · DoR Based on tumor response data from BICR, in the absence of bone progression according to PCWG3, the period from the date of the first reported response (CR or PR) according to the modified PCWG3 version of RECIST v1.1, to the date on which radiographic progression of soft tissue was first recorded, or the earlier of the date of death from any cause.

[0256] 6. Evaluate the time to first radiological soft tissue progression (TTSTP) in participants treated with Ac-PSMA-617 and BSoC at the discretion of the principal investigator. · TTSTP : The period from the randomization date to the date of soft tissue progression on radiographic imaging, as assessed by BICR, according to the modified RECIST v1.1 soft tissue rules of PCWG3.

[0257] 7. We evaluate the time to the first symptomatic skeletal event (TTSSE) in participants treated with Ac-PSMA-617 and BSoC at the discretion of the principal investigator. · TTSSE : From the date of randomization to the date on which the need for pathological fracture, spinal cord compression, tumor-related orthopedic intervention, or radiation therapy to alleviate bone pain first arose, or death from any cause, whichever comes first.

[0258] We will evaluate the biochemical response detected by prostate-specific antigen (PSA) half-retention (PSA50) in participants treated with 8.225Ac-PSMA-617 and BSoC at the discretion of the principal investigator. · PSA50 : The percentage of participants who showed a decrease of 50% or more from baseline in their second PSA measurement, which was performed more than 4 weeks later.

[0259] 9. In both treatment arms, assess patient-reported disease-related symptoms and health-related quality of life (HRQoL). • Change from baseline in the FACT-P prostate cancer subscale (PCS). The time to deterioration of the FACT-P total score is defined as the time from randomization to the first occurrence of deterioration with a score decrease of at least 10 points from baseline, or death from any cause, whichever comes first.

[0260] 10. Evaluate changes in patient-reported pain severity in both treatment arms. · The period during which the pain is at its worst. : Time from randomization until the occurrence of the greatest pain exacerbation item (BPI-SF) increasing by at least 30% from baseline, or increasing by at least 2 points from baseline, or death from any cause, whichever comes first.

[0261] Evaluate the safety and tolerability of formula (I) radiolabeled with 11.225Ac. Safety evaluation items: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), clinical laboratory values, vital signs, and changes in ECG. • Tolerability assessment items: Interruption of administration, dose reduction, discontinuation of administration, administration intensity, and duration of exposure.

[0262] Exploration goal: Characterizing the pharmacokinetic profile of 1.225Ac-PSMA-617. 2.225 Evaluate the dosimetry of Ac-PSMA-617 and further evaluate the dose to vital organs (e.g., kidneys, bone marrow, and salivary glands) and tumors. 3. Evaluate molecular and imaging biomarkers related to treatment response or resistance. 4.225Ac-PSMA-617 and BSoC will be evaluated to assess the effects of PSMA expression in salivary glands (SG) and kidneys (KD). 5. Investigate health-related quality of life and other patient-reported outcomes (PROs) in both treatment arms. We will investigate the renal safety biomarker and early detection of renal dysfunction using 6.225Ac-PSMA-617 versus BsoC. 7. Considering known ADRs for xerostomia, we characterize salivary gland function based on the effects of 225Ac-PSMA-617 versus BSoC. 8. Evaluate the relationship between exposure / dose measurements and related clinical efficacy and / or safety endpoints.

[0263] Detailed explanation In this embodiment, the patient was treated with ARPI and taxane-based chemotherapy, 177 This report describes the Phase 3 portion of a two-arm, randomized, open-label, international, multicenter Phase 2 / 3 trial evaluating the efficacy and safety of 225Ac-PSMA-617 compared to best standard of care (BSoC) at the investigator's discretion in adult participants with PSMA-positive mCRPC who have experienced disease progression during or after Lu]Lu-PSMA targeted therapy. A total of 420 eligible participants were randomly assigned in a 2:1 ratio to receive either 225Ac-PSMA-617 (investigation arm) or BSoC at the investigator's discretion (control arm). Randomization was previously [ 177 Patients are stratified by time to progression in Lu]Lu-PSMA targeted therapy (≤6 months vs. >6 months), prior cabazitaxel treatment (with vs. without), and presence of liver metastases (with vs. without). These stratification factors are selected based on their association with OS and PFS and are relevant prognostic factors in mCRPC.

[0264] Clinical Arm: Participants randomly assigned to receive 225Ac-PSMA-617 will receive 10 MBq of 225Ac-PSMA-617 once every 8 weeks for 4 cycles (1 cycle = 8 weeks), and may receive an additional 2 cycles at the discretion of the principal investigator, up to a total of 6 cycles (referred to as 4(+2) cycles). If incoming data suggest that the benefit / risk profile of 8 MBq of 225Ac-PSMA-617 is more acceptable, the 8 MBq dose will be considered in Phase 3.

[0265] Control Arm: Participants randomly assigned to a BSoC (control arm) selected by the principal investigator will be treated with the BSoC of the principal investigator's choice (ARPI, taxane, carboplatin, radium-223 dichloride, and cyplucel-T, as detailed in Table 3), with the total treatment duration varying depending on the selected regimen and the principal investigator's considerations. Since the BSoC treatment regimen may differ from 225Ac-PSMA-617, the PSMA PET / CT scan schedule will be determined on a weekly basis to match the investigational arm, meaning that PSMA PET / CT scans will be performed up to three times every 16 weeks depending on the completion of treatment. Conventional imaging evaluations for the BSoC arm will be performed every 8 weeks from baseline, regardless of the regimen selected by the principal investigator. [Table 3-1] [Table 3-2]

[0266] Following completion of treatment with 225Ac-PSMA-617 or selected BSoC, after radiological progression is observed according to the BICR, or after discontinuation of the study treatment for any reason, participants will make an End of Treatment (EoT) visit and enter post-treatment follow-up (including a 56-day safety follow-up period and a long-term follow-up (LTFU) period of up to 5 years after EoT). The efficacy assessment of the primary endpoint, rPFS, will be performed every 8 weeks (±7 days) after the first dose of the study treatment for the first 24 weeks, and thereafter every 12 weeks according to the BICR until radiological progression is confirmed, in order to control for bias that may arise from errors in progression assessment (Dodd et al 2008). Participants randomized to the control arm are not permitted to cross over to the 225Ac-PSMA-617 arm.

[0267] Eligibility: This study will enroll adult male participants (18 years or older) with PSMA-positive mCRPC cancer who have progressed during or after treatment with ARPI and taxane-based chemotherapy.

[0268] Main selection criteria: • The ECOG performance status is between 0 and 2. • Histopathological and / or cytological confirmation of prostate adenocarcinoma. • Report of progressive mCRPC. • Participants will undergo PSMA using an approved PSMA contrast agent, following the instructions of the protocol. Participants must have a PSMA-positive disease as assessed by PET / CT scan, and eligibility will be determined by the sponsor's central image interpretation rules. • Castration levels of serum / plasma testosterone (less than 50 ng / dL or less than 1.7 nmol / L). • The patient had previously received ARPI and taxane-based chemotherapy, and the disease progressed during or after [177Lu]Lu-PSMA targeted therapy. In the setting of metastatic hormone-sensitive prostate cancer (mHSPC), prior treatment exposure to ARPI and taxane-based chemotherapy is acceptable. Participants must have at least one metastatic lesion present on screening / baseline CT, MRI, or bone scan images obtained 28 days prior to randomization. Except for alopecia, all clinically significant toxicity associated with previous treatments (i.e., previous chemotherapy, radiotherapy) must be reduced to Grade 2 or lower. • Appropriate organ function (bone marrow reserve, liver, kidneys)

[0269] Main exclusion criteria • Within 6 weeks of randomization, the patient has received one of the following prior treatments: strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, hemispheric irradiation, 177Lu-PSMA, or 177Lu-DOTA targeted therapy. • Any investigational drug administered within 28 days prior to the randomization date. • Any use made before the day of randomization 225 Ac-based investigational compound. • Known hypersensitivity to any of the treatments or similar classes of drugs being studied. • History of CNS metastasis and symptomatic spinal cord compression, or clinical or radiological findings indicating imminent spinal cord compression. • A history or current diagnosis of ECG abnormalities that pose a significant risk to safety. • Concurrent occurrence of severe acute or chronic nephropathy (based on the KDIGO 2024 guidelines). • A serious, uncontrolled co-infection that the principal investigator determines would interfere with participation in or cooperation with the study. • In the past three years, you have been diagnosed with other active malignancies that may alter your life expectancy or interfere with disease assessment. • Baseline xerostomia is grade 2 or higher according to CTCAE v.5. • History of uncontrolled cardiovascular disease

[0270] Other selection / exclusion criteria defined in the protocol may apply.

Claims

1. A method for treating a subject with PSMA-expressing cancer, the method comprising administering a compound of formula (I) or (II) to the subject. 【Chemistry 1】 Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (I) or (II) is radiolabeled with an alpha-emitting radionuclide, The radiolabeled compound of formula (I) or (II) is administered in a dose of approximately 6 MBq to approximately 8 MBq. The subject is the method described above, which has previously received chemotherapy.

2. A method for treating a subject with PSMA-expressing cancer, the method comprising administering a compound of formula (I) or (II) to the subject. 【Chemistry 2】 Glutamate and lysine adjacent to urea are in an L-configuration. The compound of formula (I) or (II) is radiolabeled with an alpha-emitting radionuclide, The radiolabeled compound of formula (I) or (II) is administered in a dose of approximately 6 MBq to approximately 8 MBq. The subject is the method described above, and the subject has not previously received chemotherapy.

3. The alpha-emitting radionuclide is ２２５ Ac, ２１１ At, ２１３ Bi, ２１２ Bi, ２１２ Pb, ２２３ Ra, ２２４ Ra, １４９ Tb, and ２２７ The method according to claim 1 or 2, selected from the group consisting of Th.

4. The alpha-emitting radionuclide is, ２２５ The method according to claim 3, wherein it is Ac.

5. The method according to any one of claims 1 to 4, wherein the dose is approximately 6 MBq.

6. The method according to any one of claims 1 to 4, wherein the dose is approximately 8 MBq.

7. The method according to any one of claims 1 to 6, wherein the dose of the compound of formula (I) or (II), (III), (IV), or (V) is administered to the subject approximately every 4 to 8 weeks.

8. The method according to any one of claims 1 to 7, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 6 to 8 weeks.

9. The method according to claim 8, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every six weeks.

10. The method according to claim 8, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every eight weeks.

11. The method according to any one of claims 1 to 9, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 4 to 8 weeks over 4 to 6 cycles.

12. The method according to claim 11, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 6 to 8 weeks over 4 to 6 cycles.

13. The method according to claim 11, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 4 to 8 weeks over 4 cycles.

14. The method according to claim 13, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 6 to 8 weeks over 4 cycles.

15. The method according to claim 14, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every six weeks over four cycles.

16. The method according to claim 14, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every eight weeks over four cycles.

17. The method according to any one of claims 1 to 9, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 4 to 8 weeks over 6 cycles.

18. The method according to claim 17, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every 6 to 8 weeks over 6 cycles.

19. The method according to claim 18, wherein the dose of the compound of formula (I), (II), (III), (IV), or (V) is administered to the subject approximately every six weeks over six cycles.

20. The method according to any one of claims 1-19, wherein the PSMA-expressing cancer is prostate cancer.

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

22. The method according to claim 21, wherein the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

23. The method according to any one of claims 1 to 22, wherein the aforementioned prior chemotherapy includes the administration of a taxane.

24. The method according to any one of claims 1 to 23, wherein the subject has received prior treatment with a beta-negative emitting radiopharmaceutical.

25. The method according to claim 24, wherein the beta-negative emitting radiopharmaceutical is a 177Lu-PSMA targeting agent.

26. The method according to claim 25, wherein the 177Lu-PSMA targeting agent is 177Lu-PSMA-617 or 177Lu-PSMA I&T.

27. The method according to claim 26, wherein the 177Lu-PSMA targeting agent is 177Lu-PSMA-617.

28. The method according to any one of claims 1 to 27, wherein the subject has received prior treatment with an androgen receptor pathway inhibitor (ARPI).

29. The method according to any one of claims 1 to 28, wherein the PSMA-expressing cancer has been determined to be resistant to one or more of the following: chemotherapy, beta-minus-emitting radiopharmaceuticals, and ARPIs.

30. The method according to any one of claims 1 and 3-28, wherein the subject has not responded to the prior chemotherapy, or the PSMA-expressing cancer has progressed after administration of the prior chemotherapy.

31. A method for treating prostate cancer in a subject requiring treatment, the method comprising administering a radiopharmaceutical to the subject in a dose of approximately 6 MBq to approximately 8 MBq, wherein the radiopharmaceutical is a compound of formula (I). 【Transformation 3】 The compound of formula (I) is ２２５ The method wherein the subject is radiolabeled with Ac and has previously undergone chemotherapy.

32. A method for treating prostate cancer in a subject requiring treatment, the method comprising administering a radiopharmaceutical to the subject in a dose of approximately 6 MBq to approximately 8 MBq, wherein the radiopharmaceutical is a compound of formula (I). 【Chemistry 4】 The compound of formula (I) is ２２５ The method wherein the subject is radiolabeled with Ac and has not previously received chemotherapy.

33. The method according to claim 31 or 32, wherein the prostate cancer is metastatic prostate cancer.

34. The method according to claim 33, wherein the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

35. The aforementioned prior chemotherapy is the method according to any one of claims 31-34, comprising the administration of a taxane.

36. The method according to any one of claims 31-35, wherein the radiopharmaceutical is administered in a dose of about 6 MBq.

37. The method according to any one of claims 31-35, wherein the radiopharmaceutical is administered in a dose of about 8 MBq.

38. The method according to any one of claims 31 to 37, wherein the radiopharmaceutical is administered approximately every 4 to 8 weeks.

39. The method according to claim 38, wherein the radiopharmaceutical is administered approximately every 6 to 8 weeks.

40. The method according to claim 39, wherein the radiopharmaceutical is administered approximately every six weeks.

41. The method according to claim 39, wherein the radiopharmaceutical is administered approximately every eight weeks.

42. The method according to any one of claims 31-38, wherein the dose of the radiopharmaceutical is administered to the subject approximately every 4-8 weeks over 4-6 cycles.

43. The method according to claim 42, wherein the dose of the compound of formula (I) is administered to the subject every 6 to 8 weeks over 4 to 6 cycles.

44. The method according to claim 42, wherein the dose of the radiopharmaceutical is administered to the subject approximately every 4 to 8 weeks over 4 cycles.

45. The method according to claim 44, wherein the dose of the compound of formula (I) is administered to the subject approximately every 6 to 8 weeks over 4 cycles.

46. The method according to claim 45, wherein the dose of the compound of formula (I) is administered to the subject approximately every six weeks over four cycles.

47. The method according to claim 45, wherein the dose of the compound of formula (I) is administered to the subject approximately every eight weeks over four cycles.

48. The method according to any one of claims 31-38, wherein the dose of the radiopharmaceutical is administered to the subject approximately every 4 to 8 weeks over 6 cycles.

49. The method according to claim 48, wherein the dose of the compound of formula (I) is administered to the subject approximately every 6 to 8 weeks over 6 cycles.

50. The method according to claim 49, wherein the dose of the compound of formula (I) is administered to the subject approximately every six weeks over six cycles.

51. The method according to any one of claims 31-50, wherein the subject has received prior treatment with at least one of the radiopharmaceuticals or androgen receptor pathway inhibitors (ARPIs).

52. The method according to any one of claims 31 to 51, wherein the PSMA-expressing cancer has been determined to be resistant to one or more of the following: chemotherapy, radiopharmaceuticals, and ARPIs.

53. The method according to claim 51, wherein the subject did not respond to the prior treatment, or the PSMA-expressing cancer progressed after the administration of the prior treatment.

54. The method according to any one of claims 1 to 53, wherein the subject has not previously experienced an adverse event of grade 2 or higher xerostomia, or the subject does not suffer from grade 2 or higher xerostomia.

55. The method according to any one of claims 1 to 54, wherein the subject simultaneously receives palliative treatment for xerostomia.

56. A method for treating a subject requiring treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), or (IV) to the subject, 【Transformation 5】 Glutamic acid and lysine adjacent to urea are in an L-configuration, or 【Transformation 6】 The compounds of formula (I), (II), or (IV) are radiolabeled with alpha-emitting radionuclides. The radiolabeled compound of formula (I), (II), or (IV) is administered in doses of approximately 6 MBq to approximately 14 MBq. The subject is the method described above, which has previously received chemotherapy.

57. A method for treating a subject requiring treatment for PSMA-expressing cancer, the method comprising administering a compound of formula (I), (II), or (IV) to the subject, 【Transformation 7】 Glutamic acid and lysine adjacent to urea are in an L-configuration, or 【Transformation 8】 The compounds of formula (I), (II), or (IV) are radiolabeled with alpha-emitting radionuclides. The radiolabeled compound of formula (I), (II), or (IV) is administered in doses of approximately 6 MBq to approximately 14 MBq. The subject is the method described above, and the subject has not previously received chemotherapy.

58. The alpha-emitting radionuclide is, ２２５ Ac, ２１１ At, ２１３ Bi, ２１２ Bi, ２１２ Pb, ２２３ Ra, ２２４ Ra, １４９ Tb, and ２２７ The method according to claim 56 or 57, selected from the group consisting of Th.

59. The method according to any one of claims 56-58, wherein the dose of formula (I), (II), or (IV) is about 6 MBq, about 8 MBq, about 9 MBq, about 10 MBq, about 11 MBq, about 12 MBq, about 13 MBq, or about 14 MBq.

60. The alpha-emitting radionuclide is, ２２５ The method according to claim 58, wherein the result is Ac.

61. The method according to claim 60, wherein the radiolabeled compound of formula (I) is administered in a dose of about 8 MBq to about 10 MBq.

62. The method according to claim 60, wherein the radiolabeled compound of formula (II) is administered in a dose of about 6 MBq to about 14 MBq.

63. The method according to claim 60, wherein the radiolabeled compound of formula (IV) is administered in a dose of about 6 MBq to about 14 MBq.

64. The method according to any one of claims 56-63, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 4 to 8 weeks.

65. The method according to any one of claims 56-64, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 6 to 8 weeks.

66. The method according to claim 65, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every six weeks.

67. The method according to claim 65, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every eight weeks.

68. The method according to any one of claims 56-63, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 4 to 8 weeks over 4 to 6 cycles.

69. The method according to claim 68, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 6 to 8 weeks over 4 to 6 cycles.

70. The method according to claim 68, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 4 to 8 weeks over 4 cycles.

71. The method according to claim 69, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 6 to 8 weeks over 4 cycles.

72. The method according to claim 71, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every six weeks over four cycles.

73. The method according to claim 71, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every eight weeks over four cycles.

74. The method according to any one of claims 56-63, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 4 to 8 weeks over 6 cycles.

75. The method according to claim 74, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every 6 to 8 weeks over 6 cycles.

76. The method according to claim 75, wherein the dose of the compound of formula (I), (II), or (IV) is administered to the subject approximately every six weeks over six cycles.

77. The method according to any one of claims 56-76, wherein the PSMA-expressing cancer is prostate cancer.

78. The method according to claim 77, wherein the prostate cancer is metastatic prostate cancer.

79. The method according to claim 78, wherein the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

80. The method according to claim 79, wherein the subject is reported to have a high amount of systemic tumor tissue.

81. The aforementioned prior chemotherapy is the method according to any one of claims 56-80, comprising the administration of a taxane.

82. The method according to any one of claims 56-81, wherein the subject has received prior treatment with a beta-negative emitting radiopharmaceutical.

83. The method according to claim 82, wherein the beta-negative emitting radiopharmaceutical is a 177Lu-PSMA targeting agent.

84. The method according to claim 83, wherein the 177Lu-PSMA targeting agent is 177Lu-PSMA-617 or 177Lu-PSMA I&T.

85. The method according to any one of claims 56-84, wherein the subject has received prior treatment with an androgen receptor pathway inhibitor (ARPI).

86. The method according to any one of claims 56-85, wherein the PSMA-expressing cancer has been determined to be resistant to one or more of the following: chemotherapy, beta-minus-emitting radiopharmaceuticals, and ARPIs.

87. The method according to any one of claims 56 and 58-86, wherein the subject has received prior treatment with taxane-based chemotherapy, beta-minus-emitting radiopharmaceuticals, and ARPIs.

88. The aforementioned beta-minus emitting radiopharmaceutical is, １７７ The method according to claim 87, wherein the Lu]Lu-PSMA targeted radiopharmaceutical.

89. The aforementioned target is the [ １７７ The PSMA-expressing cancer progressed while the subject was being treated with the Lu]Lu-PSMA-targeted radiopharmaceutical, or the subject was the [ １７７ The method according to claim 88, wherein the PSMA-expressing cancer recurs after treatment with a Lu]Lu-PSMA-targeted radiopharmaceutical.

90. The method according to any one of claims 56 and 57-89, wherein the subject has not responded to the prior chemotherapy, or the PSMA-expressing cancer has progressed after administration of the prior chemotherapy.

91. A method for treating prostate cancer in a subject requiring treatment, the method comprising administering a radiopharmaceutical to the subject in a dose of about 8 MBq to about 10 MBq, wherein the radiopharmaceutical is a compound of formula (I). 【Chemistry 9】 The compound of formula (I) is ２２５ The method wherein the subject is radiolabeled with Ac and has previously undergone chemotherapy.

92. A method for treating prostate cancer in a subject requiring treatment, the method comprising administering a radiopharmaceutical to the subject in a dose of 8 MBq to about 10 MBq, wherein the radiopharmaceutical is a compound of formula (I). 【Chemistry 10】 The compound of formula (I) is ２２５ The method wherein the subject is radiolabeled with Ac and has not previously received chemotherapy.

93. The method according to claim 91 or 92, wherein the prostate cancer is metastatic prostate cancer.

94. The method according to claim 93, wherein the metastatic prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

95. The method according to claim 94, wherein the subject is reported to have severe pre-treatment mCRPC.

96. The method according to claim 94 or 95, wherein the subject is reported to have a high amount of systemic tumor tissue.

97. The aforementioned prior chemotherapy is the method according to any one of claims 91-96, comprising the administration of a taxane.

98. The method according to any one of claims 91 to 97, wherein the radiopharmaceutical is administered approximately every 4 to 8 weeks.

99. The method according to claim 98, wherein the radiopharmaceutical is administered approximately every 6 to 8 weeks.

100. The method according to claim 99, wherein the radiopharmaceutical is administered approximately every six weeks.

101. The method according to claim 99, wherein the radiopharmaceutical is administered approximately every eight weeks.

102. The method according to any one of claims 91-97, wherein the dose of the radiopharmaceutical is administered to the subject approximately every 4-8 weeks over 4-6 cycles.

103. The method according to claim 102, wherein the dose of the compound of formula (I) is administered to the subject approximately every 6 to 8 weeks over 4 to 6 cycles.

104. The method according to claim 102, wherein the dose of the radiopharmaceutical is administered to the subject approximately every 4 to 8 weeks over 4 cycles.

105. The method according to claim 102, wherein the dose of the compound of formula (I) is administered to the subject approximately every 6 to 8 weeks over 4 cycles.

106. The method according to claim 105, wherein the dose of the compound of formula (I) is administered to the subject approximately every six weeks over four cycles.

107. The method according to claim 105, wherein the dose of the compound of formula (I) is administered to the subject approximately every eight weeks over four cycles.

108. The method according to any one of claims 91-97, wherein the dose of the radiopharmaceutical is administered to the subject approximately every 4 to 8 weeks over 6 cycles.

109. The method according to claim 108, wherein the dose of the compound of formula (I) is administered to the subject approximately every 6 to 8 weeks over 6 cycles.

110. The method according to claim 109, wherein the dose of the compound of formula (I) is administered to the subject approximately every six weeks over six cycles.

111. The method according to claim 103, wherein the dose of the compound of formula (I) is administered to the subject approximately every eight weeks over four to six cycles.

112. The method according to any one of claims 91 to 111, wherein the subject has received prior treatment with at least one of a radiopharmaceutical and an androgen receptor pathway inhibitor (ARPI).

113. The method according to any one of claims 91 to 112, wherein the prostate cancer has been determined to be resistant to one or more of the following: chemotherapy, radiopharmaceuticals, and ARPIs.

114. The method according to claim 112, wherein the subject has not responded to the prior treatment, or the prostate cancer has progressed after the administration of the prior treatment.

115. The method according to any one of claims 91-114, wherein the subject has not previously experienced an adverse event of grade 2 or higher xerostomia, or the subject does not suffer from grade 2 or higher xerostomia.

116. The method according to any one of claims 91-114, wherein the subject simultaneously receives palliative treatment for xerostomia.

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