Shielding agents and their use

Abstract

To provide compositions for treating PSMA expressing cancers by combining one or more radiotherapeutics agents with one or more shielding agents.SOLUTION: The present invention provides a composition for treating cancer, wherein the composition comprises a therapeutically effective amount of a radiolabeled therapeutic, and wherein the composition is administered in combination with an effective amount of a shielding agent. Preferably, the radiolabeled therapeutic is the compound Ia-Lu or Ia-Ac.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority under Title 35, U.S.C., Section 119(e) to U.S. Provisional Application No. 62 / 734,690, filed September 21, 2018, the entire disclosure of which is incorporated herein by reference.

[0002] Technical Field The present invention relates to compounds useful as shielding agents for PSMA therapy. The present invention relates to methods for treating PSMA-expressing cancer using a combination of one or more radiotherapeutic agents and one or more shielding agents. The present invention relates to imaging methods using a combination of one or more imaging agents containing radionuclides and one or more shielding agents. The present invention also relates to methods for producing the shielding agents. [Background technology]

[0003] Prostate-specific membrane antigen (PSMA) is a type II cell-surface membrane-bound glycoprotein with a molecular weight of approximately 110 kD. It contains an intracellular segment (amino acids 1–18), a transmembrane domain (amino acids 19–43), and an extensive extracellular domain (amino acids 44–750). The functions of the intracellular segment and transmembrane domain are currently thought to be unimportant, while the extracellular domain is involved in several distinct activities. PSMA plays a role in the central nervous system, where it metabolizes N-acetyl-aspartylglutamate (NAAG) to glutamine and N-acetylaspartate. Therefore, it is sometimes referred to as N-acetyl-alpha-linked acidic dipeptidase (NAALADase). PSMA is also sometimes referred to as folate hydrolase I (FOLH I) or glutamate carboxypeptidase II (GCP II) because of its role in the proximal small intestine in removing gamma-linked glutamate from poly-gamma-glutamate folates and alpha-linked glutamate from peptides and small molecules.

[0004] PSMA is named primarily for its high expression level in prostate cancer cells; however, its specific function in prostate cancer cells remains unclear. PSMA expression is highly restricted in humans, present only in a small number of cells in salivary gland tissue, kidney tissue, small intestine, and large intestine. PSMA is overexpressed in malignant prostate tissue compared to other organs in the human body, such as the kidney, proximal small intestine, and salivary glands. Higher PSMA expression is associated with aggressive, metastatic, and castration-resistant disease. Tumor expression in prostate cancer is typically 100-1,000-fold higher. Unlike many other membrane-bound proteins, PSMA undergoes rapid internalization into cells in a manner similar to cell surface-bound receptors such as vitamin receptors. PSMA is internalized through clathrin-coated pits and can then be recycled to the cell surface or trafficked to lysosomes. It has been suggested that dimeric and monomeric forms of PSMA are interconvertible, but direct evidence of this interconversion is controversial. Even so, only the dimer of PSMA has enzymatic activity, not the monomer.

[0005] PSMA is also expressed in the angiogenesis of other tumors, such as thyroid cancer, renal clear cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, and soft tissue sarcoma, as well as breast cancer. These cancers represent a wide range of tumors with a wide variety of histological subtypes, growth rates, and cell cycle times. In some cases, cancers are embedded within normal tissues with diverse radiation resistance. Furthermore, hypoxic regions of large deposits can also result in radiation resistance. These and other factors are known to result in different intrinsic responses to conventional external beam radiation therapy.

[0006] Although PSMA activity on the cell surface of prostate cells is currently under investigation, the present inventors have recognized that PSMA represents a viable target for the selective and / or specific delivery of biologically active agents, including drug compounds, or combinations of biologically active agents, to such prostate cells. One such drug compound is represented by Formula I [ka] where: 177 Lu forms a complex with this compound to form I-Lu, 225 Ac complexes with compound I to form I-Ac, which is useful for the treatment of cancer as described in WO 2015 / 055318. Compounds I-Lu and I-Ac can be prepared according to the methods described in WO 2015 / 055318, which are incorporated by reference for the preparation of compounds I-Lu and I-Ac as described in Examples 3 and 5.

[0007] Another such drug compound is Compound Ia (also referred to as (3S,10S,14S)-3-[(naphthalen-2-yl)methyl]-1,4,12-trioxo-1-[(1R,4S)-4-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetamido]methyl]cyclohexyl]-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid). [ka] where: 177 Lu forms a complex with the compound Ia to form I-Lu, 225 Ac is complexed with compound Ia-Ac, which is useful for the treatment of cancer as described in WO 2015 / 055318. Compounds Ia-Lu and Ia-Ac can be prepared according to the methods described in WO 2015 / 055318, which are incorporated by reference for the preparation of compounds Ia-Lu and Ia-Ac as described in Examples 3 and 5.

[0008] Compound I or Ia can be described as a small molecule that specifically binds to PSMA (prostate-specific membrane antigen) expressed on the surface of prostate cancer cells. Compound I or Ia is ... 177 Lu and 225The urea-based pharmacophore ligand may be characterized as consisting of a urea-based pharmacophore ligand capable of complexing with PSMA (I-Lu, I-Ac, Ia-Lu, or Ia-Ac); and a linker attached to a ligand and a chelator. Without being bound by theory, it is believed that the urea-based pharmacophore ligand allows the drug to bind to and be internalized by PSMA at disease sites. Furthermore, it is believed that binding of I-Lu, I-Ac, Ia-Lu, or Ia-Ac can result in internalization via endocytosis, which can provide sustained retention of the ligand and its bound radioactive cargo within cancer cells.

[0009] Previous clinically used radioligand therapy (RLT) has been shown to be effective in treating thyroid cancer. 131 for the treatment of I and bone metastases 223 Radium or 89 Contains elements that emit alpha radiation, such as strontium.

[0010] 177 Lu has a half-life of 6.7 days. It travels randomly through approximately 20-80 cells or 0.5-2 mm of tissue, emitting a 0.5 MeV energy combinatorial wave consisting of negatively charged beta particles (electrons) that cause primarily base damage and single-strand breaks. At high doses, these lesions can interact and convert sublethal damage (SLD) or potentially lethal damage (PLD) into irreparable lethal damage. 177 Lu also emits 113 Kv and 208 kV radiation that can be used for imaging.

[0011] 225 Ac, in contrast, has a half-life of 9.9 days and emits alpha particles with an energy of 8.38 MV. Only 0.5% of the energy is released as 142 kV proton radiation. Thus, the majority of the emitted particles are positively charged and are approximately 8,000 times larger than beta particles. Furthermore, the energy from these particles is deposited over relatively short distances (two to three cells). The result is dense and severe tissue damage in the form of double-strand breaks with multiple damage sites, indicating irreparable, lethal damage. This is referred to as high linear energy transfer (LET) or high-density ionization, and results in an absorbed dose three to seven times greater than that of beta particles.

[0012] Any isotope ( 177 Lu or 225 The type of cell damage inflicted by Ac) is expected to differ due to differences in the characteristics of each warhead. 177 Lu provides a longer path length for radiation and may therefore be more effective in delivering radiation to neighboring cells. The majority of single-strand breaks offer the opportunity to repair sublethal damage (SLD) and / or potentially lethal damage (PLD), which, especially in the presence of oxygen, provides optimal conditions for normal tissue repair. In contrast, 225 Ac delivers extremely intense, high-LET radiation, with much more limited potential for normal tissue repair. The radiobiological effectiveness of alpha radiation is at least five times that of beta radiation, and dosage must take into account radiobiological effectiveness (RBE). 225 Ac therapy is also more effective in hypoxic tumor regions because the type of DNA damage delivered does not require the presence of oxygen. 225 A possible disadvantage of Ac therapy is that the short path length can result in a large amount of damaging radiation accumulated only within a short distance of 2-4 cells.

[0013] Another such compound is PSMA-imaging agent conjugate 2a (also referred to as (2R,5S,8S,12S,15S,29S,33S)-8-amino-12,15-dibenzyl-5-(carboxymethyl)-1-mercapto-4,7,11,14,17,26,31-heptaoxo-3,6,10,13,16,25,30,32-octaazapentatriacontane-2,29,33,35-tetracarboxylic acid). [ka] is. 99mTc (or a similar radioactive metal isotope) can be complexed with conjugate 2a as described in WO 2009 / 026177 and is useful for imaging patients as described in WO 2009 / 026177. PSMA imaging agent conjugate 2a can be prepared according to the methods described in WO 2009 / 026177, which are incorporated by reference for the preparation of PSMA imaging agent conjugate 2a, as described in the Examples.

[0014] Another such compound is PSMA-imaging agent conjugate 4 (4,6,12,19-tetraazadocosane-1,3,7-tricarboxylic acid, also referred to as 22-[3-[[[2-[[[5-(2-carboxyethyl)-2-hydroxyphenyl]methyl](carboxymethyl)amino]ethyl](carboxymethyl)amino]methyl]-4-hydroxy-phenyl]-5,13,20-trioxo-,(3S,7S)). [ka] where 67 Ga or 68 Ga (or similar radioactive metal isotopes) is Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler C, Mier W, et al, 68 Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012; 23: 688-97, which forms a complex with this conjugate and is useful for cancer imaging. PSMA imaging agent conjugate 4 can be prepared according to the method described in (Eder, 2012), which is incorporated by reference for the preparation of PSMA imaging agent conjugate 4 as described in the Examples.

[0015] For the treatment of diseases 177 Lu and 225 Ac or 99mTc and 67 Ga or 68 The use of PSMA conjugates containing radionuclides such as Ga leads to off-target delivery of radionuclides.Without being bound by theory, it is believed that this off-target delivery occurs in the tissues containing PSMA-expressing cancer cells where PSMA is expressed.For example, the biodistribution experiments using radiolabeled PSMA compounds and contrast agent conjugates as described herein show the accumulation of radionuclides in tissues such as kidney.It would be advantageous to develop a compound that is useful as a shielding agent administered in the method of treating or imaging patients using radiolabeled PSMA compounds and contrast agent conjugates. Summary of the Invention

[0016] In some embodiments, the present invention provides compounds useful as shielding agents for PSMA. 177 Lu or 225 In some embodiments, the present invention provides a method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound (radiolabeled therapeutic agent) comprising a radionuclide such as Ac in combination with one or more shielding agents of the present invention. 99m Tc, 67 Ga or 68 A method of imaging in a patient is provided which comprises administering an effective amount of a conjugate (imaging agent conjugate) containing a radionuclide such as Ga in combination with one or more shielding agents of the present invention.

[0017] In some embodiments, the present invention provides a method for treating cancer in a patient, comprising administering a therapeutically effective amount of compound Ia-Lu or Ia-Ac in combination with an effective amount of a shielding agent, such as a shielding agent described herein. In some embodiments, the method comprises administering a combination of Ia-Lu and Ia-Ac.

[0018] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a therapeutically effective amount of an imaging agent conjugate, e.g.,67 Ga, 68 Ga or 99m A method of imaging a patient is provided, comprising administering an imaging agent conjugate 3 or 4 labeled with a radionuclide, such as Tc, in combination with an effective amount of a shielding agent, e.g., a shielding agent described herein.

[0019] In some embodiments, the present invention provides the use of compound Ia-Lu or Ia-Ac for treating cancer in a patient in combination with an effective amount of a shielding agent, such as a shielding agent described herein.In some embodiments, the use comprises administering to a patient a combination of a therapeutically effective amount of compound Ia-Lu and a therapeutically effective amount of compound Ia-Ac.

[0020] In some embodiments, the present invention provides a method for imaging a patient, comprising administering to the patient a therapeutically effective amount of a shielding agent as described herein in combination with the agent. 67 Ga, 68 Ga or 99m The present invention provides the use of an imaging agent conjugate such as imaging agent conjugate 3 or 4 labeled with a radionuclide such as Tc.

[0021] In some embodiments, the present invention provides the use of compound Ia-Lu or Ia-Ac in combination with an effective amount of a shielding agent described herein in the manufacture of a medicament useful for treating cancer in a patient. In some embodiments, the medicament comprises a therapeutically effective combination of compounds Ia-Lu and Ia-Ac.

[0022] In some embodiments, the present invention provides a method for the preparation of a medicament for use in combination with an effective amount of a shielding agent described herein in imaging a patient, comprising: 67 Ga, 68 Ga or 99m The present invention provides the use of an imaging agent conjugate such as imaging agent conjugate 3 or 4 labeled with a radionuclide such as Tc.

[0023] In some aspects of these embodiments, the cancer is a PSMA-expressing cancer. In some aspects of these embodiments, the compound or imaging agent conjugate is at least about 98 percent pure. In some embodiments, the cancer is selected from the group consisting of glioma, carcinoma, sarcoma, lymphoma, melanoma, mesothelioma, nasopharyngeal carcinoma, leukemia, adenocarcinoma, and myeloma.

[0024] In some aspects of these embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, metastatic breast cancer, fallopian tube cancer, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, metastasis The cancer is selected from the group consisting of mCRPC, thyroid cancer, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumor, glioma, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma. In some aspects of these embodiments, the cancer is prostate cancer. In some aspects of these embodiments, the cancer is metastatic prostate cancer.

[0025] In some aspects of these embodiments, the combination of compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac is administered in a parenteral dosage form, hi some aspects of these embodiments, the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.

[0026] In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 2 GBq to about 13 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 4 GBq to about 11 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 5 GBq to about 10 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 9 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6.5 GBq to about 8.5 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7 GBq to about 8 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 15 GBq to about 200 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 25 GBq to about 185 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 35 GBq to about 150 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 40 GBq to about 100 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu is about 44 GBq. In some aspects of these embodiments, the maximum length of treatment for a subject is about 19 to 23 months.

[0027] In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 20 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 4 MBq to about 14 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq to about 10 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 6 MBq to about 8 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 4 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2 MBq to about 3 MBq. In some aspects of these embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2.5 MBq.

[0028] In other embodiments, the methods and uses described herein further comprise imaging of PSMA expression by the cancer. In some of these embodiments, the imaging process is performed before the administering process. In some of these embodiments, the imaging process is performed after the administering process. In some of these embodiments, the imaging is performed by imaging selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH.

[0029] In some aspects of these embodiments, the imaging described herein is a compound represented by Formula 2 [ka] [During the ceremony, R' is hydrogen or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted. or a pharmaceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate.

[0030] In some aspects of these embodiments, the imaging described herein is a compound of Formula 3 [ka] [During the ceremony, R' is hydrogen or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide. or a pharmaceutically acceptable salt thereof. In some aspects of these embodiments, M in the conjugate or pharmaceutically acceptable salt thereof is selected from the group consisting of a gallium isotope, an indium isotope, a copper isotope, a technetium isotope, and a rhenium isotope. In some aspects of these embodiments, M in the conjugate or pharmaceutically acceptable salt thereof is a technetium isotope.

[0031] In some aspects of these embodiments, the PSMA ligand-imaging agent conjugate has the formula 2a [ka] or a pharmaceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate.

[0032] In some aspects of these embodiments, the PSMA ligand-imaging agent conjugate has the formula 3a [ka] or a pharmaceutically acceptable salt thereof.

[0033] In some aspects of these embodiments, the imaging described herein is a compound of Formula 4 [ka] or a pharmaceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate. 67 Ga or 68 It's Ga.

[0034] In some aspects of these embodiments, the imaging described herein comprises detecting a compound of formula I-Lu or Ia-Lu administered for therapeutic purposes.

[0035] In other aspects, the methods and uses described herein further comprise determining the patient's PSMA status by imaging. In some aspects of these embodiments, the determining step occurs before the administering step. In some aspects of these embodiments, the determining step occurs after the administering step. In some aspects of these embodiments, the imaging is SPECT imaging. In some aspects of these embodiments, the patient's PSMA status correlates with the patient's clinical benefit. In some aspects of these embodiments, the clinical benefit is selected from the group consisting of tumor growth inhibition, stable disease, partial response, and complete response. In some aspects of these embodiments, the clinical benefit is stable disease. In some aspects of these embodiments, the PSMA-positive lesions exhibit functionally active PSMA.

[0036] In some aspects of these embodiments, the determinations described herein are carried out according to Formula 2 [ka] [During the ceremony, R' is hydrogen or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted. or a pharmaceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate.

[0037] In some aspects of these embodiments, the determinations described herein are carried out according to Formula 3 [ka] [During the ceremony, R' is hydrogen or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted. or a pharmaceutically acceptable salt thereof, wherein M is a cation of the radionuclide.

[0038] In some aspects of these embodiments, M in the conjugate or pharmaceutically acceptable salt thereof is selected from the group consisting of a gallium isotope, an indium isotope, a copper isotope, a technetium isotope, and a rhenium isotope. In some aspects of these embodiments, M in the imaging agent conjugate or pharmaceutically acceptable salt thereof is a technetium isotope. In some aspects of these embodiments, the PSMA ligand-imaging agent conjugate is represented by Formula 2a [ka] or a pharmaceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate.

[0039] In some aspects of these embodiments, the PSMA ligand-imaging agent conjugate has the formula 3a [ka] or a pharmaceutically acceptable salt thereof.

[0040] In some aspects of these embodiments, the determinations described herein are carried out according to Formula 4 [ka] or a pharmaceutically acceptable salt thereof, wherein a radionuclide is attached to the conjugate. 67 Ga or 68 It's Ga.

[0041] In some aspects of these embodiments, the determining described herein comprises detecting a compound of formula I-Lu or Ia-Lu administered for therapeutic purposes.

[0042] In some embodiments, a shielding agent useful in connection with the present invention and various methods described herein is [ka] [ka] [ka] [ka] The compound may be a compound selected from the group consisting of:

[0043] In some embodiments, the present invention provides [ka] [ka] The present invention provides a compound selected from the group consisting of:

[0044] Particular embodiments are described by the following enumerated clauses: 1. A compound selected from the group consisting of: [ka] [ka]

[0045] 2. A method of treating cancer in a patient comprising administering a therapeutically effective amount of a radiolabeled therapeutic agent in combination with an effective amount of a shielding agent. 3. The method according to paragraph 2, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. 4. The method according to item 2 or 3, wherein the cancer is prostate cancer. 5. The method according to any one of items 2 to 4, wherein the cancer is metastatic prostate cancer. 6. The method according to any one of Items 2 to 4, wherein the cancer is metastatic castration-resistant prostate cancer.

[0046] 7. Shielding agent, [ka] [ka] [ka] Item 7. The method according to any one of Items 2 to 6, wherein the compound is selected from the group consisting of:

[0047] 8. Shielding agent [ka] [ka] Item 7. The method according to any one of Items 2 to 6, wherein the compound is selected from the group consisting of:

[0048] 9. A compound for treating cancer in a patient in need of treatment in combination with a therapeutically effective amount of a radiolabeled therapeutic agent selected from the group consisting of: [ka] [ka] [ka]

[0049] 10. The compound according to paragraph 9, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. 11. The compound according to item 9 or 10, wherein the cancer is prostate cancer. 12. The compound according to any one of items 9 to 11, wherein the cancer is metastatic prostate cancer. 13. The compound according to any one of items 9 to 11, wherein the cancer is metastatic castration-resistant prostate cancer.

[0050] 14. Use of a compound selected from the group consisting of: in the manufacture of a medicament for treating cancer in a patient in combination with a therapeutically effective amount of a radiolabeled therapeutic agent: [ka] [ka] [ka]

[0051] 15. The use according to item 14, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. 16. The use according to item 14 or 15, wherein the cancer is prostate cancer. 17. The use according to any one of items 14 to 16, wherein the cancer is metastatic prostate cancer. 18. The use according to any one of items 14 to 16, wherein the cancer is metastatic castration-resistant prostate cancer. 19. A method of imaging cancer in a patient comprising administering an effective amount of a shielding agent in combination with an effective amount of a contrast agent conjugate. 20. Contrast agent 99mTc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 20. The method according to Item 19, wherein the imaging agent conjugate 4 is Ga-labeled. 21. The method of item 19 or 20, wherein the cancer is prostate cancer. 22. The method according to any one of items 19 to 21, wherein the cancer is metastatic prostate cancer. 23. The method according to any one of items 19 to 22, wherein the cancer is metastatic castration-resistant prostate cancer.

[0052] 24. Shielding agent, [ka] [ka] [ka] 24. The method according to any one of items 19 to 23, wherein the compound is selected from the group consisting of:

[0053] 25. Shielding agent, [ka] [ka] 24. The method according to any one of items 19 to 23, wherein the compound is selected from the group consisting of:

[0054] 26. A compound selected from the group consisting of: [ka] [ka] [ka]

[0055] 27. 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 27. The compound according to item 26, which is Ga-labeled imaging agent conjugate 4. 28. The compound according to item 26 or 27, wherein the cancer is prostate cancer. 29. The compound according to any one of items 26 to 28, wherein the cancer is metastatic prostate cancer. 30. The compound according to any one of items 26 to 28, wherein the cancer is metastatic castration-resistant prostate cancer.

[0056] 31. Use of a compound selected from the group consisting of: in the manufacture of a medicament for imaging cancer in a patient in combination with an effective amount of an imaging agent conjugate: [ka] [ka] [ka]

[0057] 32. 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 32. The use according to Item 31, wherein the imaging agent conjugate 4 is Ga-labeled. 33. The use according to item 31 or 32, wherein the cancer is prostate cancer. 34. The use according to any one of items 31 to 33, wherein the cancer is metastatic prostate cancer. 35. The use according to any one of items 31 to 34, wherein the cancer is metastatic castration-resistant prostate cancer. [Brief explanation of the drawings]

[0058] [Figure 1]10 is a graph showing the biodistribution of 30 nmol / kg of 99mTC contrast agent conjugate 3a in nude mice with or without co-administration of 0.5 μmol / kg of a shielding agent. For each tissue, the graph shows 99mTC contrast agent conjugate 3a (leftmost bar), 99mTC contrast agent conjugate 3a + Compound 1a (second bar from the left), 99mTC contrast agent conjugate 3a + Compound 1b (third bar from the left), 99mTC contrast agent conjugate 3a + Compound 1d (third bar from the right), 99mTC contrast agent conjugate 3a + Compound 1c (second bar from the right), and 99mTC contrast agent conjugate 3a + Compound 1e (rightmost bar). [Figure 2] 1 shows graphs depicting the biodistribution of 30 nmol / kg of 99mTC contrast agent conjugate 3a in nude mice with or without co-administration of 10 μmol / kg of a shielding agent. For each tissue, the graph shows: 99mTC contrast agent conjugate 3a (leftmost bar), 99mTC contrast agent conjugate 3a + Compound 1j (second bar from the left), 99mTC contrast agent conjugate 3a + Compound 1k (middle bar), 99mTC contrast agent conjugate 3a + Compound 1f (second bar from the right), and 99mTC contrast agent conjugate 3a + competitor PMPA (rightmost bar). [Figure 3] 10 is a graph showing the biodistribution of 30 nmol / kg of 99mTC contrast agent conjugate 3a in nude mice with or without co-administration of 0.5 μmol / kg of a shielding agent. For each tissue, the graph shows: 99mTC contrast agent conjugate 3a (leftmost bar), 99mTC contrast agent conjugate 3a + Compound JHU-2545 (E1) (second bar from the left), 99mTC contrast agent conjugate 3a + Compound JHU-2545 (E2) (third bar from the left), 99mTC contrast agent conjugate 3a + Compound 1l (E1) (third bar from the right), 99mTC contrast agent conjugate 3a + Compound 1l (E2) (second bar from the right), and 99mTC contrast agent conjugate 3a + 1 μmol / kg of Compound 1f (rightmost bar). [Figure 4]1 shows graphs showing the biodistribution of 30 nmol / kg of 99mTC contrast agent conjugate 3a in nude mice with or without co-administration of 1 μmol / kg of a shielding agent. For each tissue, graph shows 99mTC contrast agent conjugate 3a (left bar), 99mTC contrast agent conjugate 3a + Compound 1a (right bar). [Figure 5] 1 shows graphs showing the biodistribution of 30 nmol / kg of 99mTC contrast agent conjugate 3a in nude mice with or without co-administration of 1 μmol / kg of a shielding agent. For each tissue, graph shows 99mTC contrast agent conjugate 3a (left bar), 99mTC contrast agent conjugate 3a + Compound 1d (right bar). [Figure 6] Figure 1 shows the biodistribution of 30 nmol / kg 67Ga-Ia in nude mice with or without co-administration of 10 μmol / kg shielding agent. For each tissue, the graph shows 67Ga-Ia (leftmost bar), 67Ga-Ia + Compound 1i (second bar from the left), 67Ga-Ia + Compound 1g (middle bar), 67Ga-Ia + Compound 1h (second bar from the right), and 67Ga-Ia + competitor PMPA (rightmost bar). [Figure 7] 1 is a graph showing tumor and kidney biodistribution (tumor / kidney or T / K ratio) of 99mTC contrast agent conjugate 3a in nude mice at various pre-treatment doses (μmol / kg) of the shielding agent of the present invention: (▲) 99mTC contrast agent conjugate 3a + Compound 1a; (▪) 99mTC contrast agent conjugate 3a + Compound 1d; (▼) 99mTC contrast agent conjugate 3a + Compound 1n. [Figure 8]

[0023] Figure 1 shows the biodistribution of 30 nmol / kg of 99mTC contrast agent conjugate 3a in nude mice bearing 22RV1 tumors co-administered with 1 μmol / kg of shielding agent over 4 hours. The graph shows that the S-enantiomer of shielding agent 1d was more active than the R-enantiomer, providing an improved tumor / kidney ratio for 99mTC contrast agent conjugate 3a. For each tissue, the graph shows 99mTC contrast agent conjugate 3a + Compound 1d (S-enantiomer) (left bar), and 99mTC contrast agent conjugate 3a + Compound 1d (R-enantiomer) (right bar). [Figure 9]

[0023] Figure 1 shows the biodistribution of 30 nmol / kg Ia-Lu in nude mice bearing LNCaP tumors with or without co-administration of 1 μmol / kg of a shielding agent over 4 hours. The graph shows that both shielding agent 1d (S-enantiomer) and shielding agent 1m provided improved Ia-Lu tumor / kidney ratios. For each tissue, the graph shows Ia-Lu alone (left bar), Ia-Lu + Compound 1m (middle bar), and Ia-Lu + Compound 1d (S-enantiomer) (right bar). DETAILED DESCRIPTION OF THE INVENTION

[0059] definition As used herein, "functionally active PSMA" refers to a cell membrane-associated glycoprotein that binds to a PSMA ligand. It is understood that PSMA ligands, such as those described in U.S. Patent Publication No. US2010 / 0324008A1, which is incorporated herein by reference, are known to those skilled in the art.

[0060] As used herein, "clinical benefit" means a patient's response to treatment with the combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac, where response includes overall patient survival, the ability to undergo four or more treatment cycles (e.g., four weeks of treatment) of the combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac, inhibition of tumor growth, stable disease, partial response, and / or complete response, among other clinical benefits as defined by the U.S. Food and Drug Administration.

[0061] As used herein, "inhibition of tumor growth" means a reduction in tumor size, complete disappearance of the tumor, or growth of the tumor by less than 30% in a patient during the course of therapy with a combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac.

[0062] As used herein, "stable disease" means that there is no substantial progression of disease in a patient during the course of therapy with a combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac.

[0063] As used herein, "partial response" means a 30% or greater reduction in tumor size in a patient treated with a combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac.

[0064] As used herein, "complete response" means the disappearance of detectable disease in a patient treated with the combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac.

[0065] As used herein, "prior treatment" means that the patient has been treated with at least one prior therapy known in the art. It is understood that the prior treatment can be any treatment known to those skilled in the art, including, but not limited to, chemotherapy, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, hyperthermia, etc. Prior treatment can include systemic therapy, including, but not limited to, treatment with abiraterone, orteronel, galeterone, ceviteronel, apalutamide, enzalutamide, palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafenib, and combinations thereof.

[0066] As used herein, the term "alkyl" includes a chain of carbon atoms that may be optionally branched. In some embodiments, alkyl is advantageously limited in length, ranging from C1 to C 24 , C1~C 12, C1-C8, C1-C6, and C1-C4. Specifically, alkyl groups of such particularly limited lengths, including C1-C8, C1-C6, and C1-C4, may be referred to as lower alkyl. It is understood herein that shorter alkyl, alkenyl, and / or alkynyl groups can impart less lipophilicity to a compound and, as a result, have different pharmacokinetic behavior. In some embodiments, references to alkyl in each instance are understood to refer to alkyl, and optionally lower alkyl, as defined herein. Specific alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. As used herein, a "carboxyalkyl" group includes a combination of an "alkyl" group and a "carboxy" group as described herein. As used herein, a "hydroxyalkyl" group includes a combination of an "alkyl" group and a "hydroxy" group as described herein. As used herein, an "aminoalkyl" group includes a combination of an "alkyl" group and an "amino" group as described herein.

[0067] As used herein, the term "heteroalkyl" includes a chain of atoms that contains both carbon and at least one heteroatom, and may be optionally branched. Particular heteroatoms include nitrogen, oxygen, and sulfur. In some variations, particular heteroatoms also include phosphorus and selenium.

[0068] As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups having 6 to 14 ring carbon atoms, each of which may be optionally substituted. Specific aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups having 5 to 10 ring atoms, each of which may be optionally substituted. Specific aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like. According to the present invention, the term "heteroarylalkyl" includes a combination of an "alkyl" group as described herein with a "heteroaryl" group as described herein. The term "arylalkyl" as used herein includes a combination of an "alkyl" group as described herein with an "aryl" group as described herein, for example, a benzyl group.

[0069] As used herein, the term "optionally substituted" includes the replacement of hydrogen atoms on an optionally substituted group with other functional groups. Such other functional groups specifically include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. Specifically, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid is optionally substituted.

[0070] As used herein, the term "administration" includes all means of introducing compounds I-Lu, Ia-Lu, I-Ac or Ia-Ac and / or PSMA ligand-imaging agent conjugates described herein into a patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, etc. Combinations of compounds I-Lu or Ia-Lu and compounds I-Ac or Ia-Ac and / or PSMA ligand-imaging agent conjugates described herein can be administered in unit dosage forms and / or formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and solvents.

[0071] As used herein, "becquerel" refers to the SI-derived unit of radioactivity as commonly understood by those skilled in the art. One becquerel is defined as the amount of radioactive material that decays into one nucleus per second. Thus, a becquerel is a unit of radioactivity per second, s -1 The becquerel is known to those skilled in the art as a successor to the former curie (Ci), a non-SI radioactivity unit based on the activity of one gram of radium-226. A curie is 3.7 10¹⁰s -1 or 37 GBq.

[0072] As used herein, "curie" or "Ci," as commonly known by those skilled in the art, refers to a unit of radioactivity named after the French physicist and chemist Marie Curie. The prefixes milli and micro come from the metric system and represent .001 and .000001, respectively. Thus, a millicurie (mCi) is .001 curie. A microcurie (μCi) is .000001 curie.

[0073] Detailed Description Any embodiment of the numbered paragraphs provided in the Summary above, or any combination thereof, is contemplated in combination with any embodiment described in the Detailed Description section of this patent application.

[0074] In some embodiments, the methods described herein can be used for both human clinical medicine and veterinary applications.Therefore, "patient" can be administered the compound I-Lu, Ia-Lu, I-Ac or Ia-Ac and / or PSMA ligand-imaging agent conjugate described herein in combination with the shielding agent described herein, and the patient can be human, or in the case of veterinary applications, can be experimental animals, agricultural animals, domestic animals or wild animals.In some embodiments, the patient can be human, experimental animals such as rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, domestic animals such as dogs, cats and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and captive wild animals such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins and whales.

[0075] In various embodiments, the cancers described herein can be tumorigenic cancer cell populations, including benign and malignant tumors, or the cancers can be non-tumorigenic. Cancers can arise naturally or through processes such as mutations present in a patient's germline or somatic mutations, or cancers can be chemically, virally, or radiation-induced. Cancers applicable to the inventions described herein include, but are not limited to, glioma, carcinoma, sarcoma, lymphoma, melanoma, mesothelioma, nasopharyngeal carcinoma, leukemia, adenocarcinoma, and myeloma.

[0076] In some embodiments, the cancer can be lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, metastatic breast cancer, fallopian tube cancer, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureter cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumors, glioma, brain stem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0077] Compound Ia has the formula [ka] where 177 Lu forms a complex with this compound in Ia-Lu, 225 Ac forms a complex with the compound in Ia-Ac.

[0078] In other embodiments, any of a variety of PSMA ligand-imaging agent conjugates detectable by PET imaging, SPECT imaging, etc. may be used. The exact method of imaging is not limited to the imaging agents described herein. Collectively, the PSMA ligand-imaging agent conjugates described herein useful for imaging, including those described by the formula and agents useful for PET imaging, SPECT imaging, etc., are referred to as "PSMA ligand-imaging agent conjugates."

[0079] The shielding agent useful in the present invention can be any shielding agent capable of blocking off-target binding of the radiolabeled compounds described herein to PSMA. Suitable shielding agents include, but are not limited to, those described in U.S. Patent Publication US2017 / 0226141, Majer, P. et al., "Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedoic Acid (2-PMPA)" J. Med. Chem., 59, 2810-2819 (2016), and Nedelcovych M. et al., "Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester" Mol. Pharmaceutics, 14, 3248-3257 (2017), the disclosures of which are incorporated by reference. Suitable examples of shielding agents include, but are not limited to, those shown in Table 1. [Table 1-1] [Table 1-2]

[0080] In some embodiments, the compound I-Lu, Ia-Lu, I-Ac or Ia-Ac and / or PSMA ligand-imaging agent conjugate described herein binds to PSMA expressed on cancer cells. In some embodiments, the shielding agent described herein binds to PSMA. In a specific embodiment, the compound I-Lu, Ia-Lu, I-Ac or Ia-Ac and / or PSMA ligand-imaging agent conjugate can differentially bind to PSMA on cancer cells compared to normal cells due to the preferential expression (or overexpression) of PSMA on cancer cells. In some embodiments, the shielding agent described herein can inhibit the off-target binding of the compound I-Lu, Ia-Lu, I-Ac or Ia-Ac and / or PSMA ligand-imaging agent conjugate to, for example, PSMA expressed on hepatocytes.

[0081] In some embodiments, the compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugates described herein can be administered in a formulation combined with one or more pharmaceutically acceptable carriers. The choice of carrier is highly dependent on factors such as the particular method of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for delivering the compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugates described herein and methods for their preparation are readily apparent to those skilled in the art. Furthermore, the shielding agents described herein can be formulated in a formulation combined with one or more pharmaceutically acceptable carriers. The choice of carrier is highly dependent on factors such as the particular method of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. Such compositions and methods for their preparation can be found, for example, in Remington: The Science & Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005), which is incorporated herein by reference.

[0082] In some specific embodiments, pharmaceutically acceptable carriers include any and all physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., and combinations thereof. In some embodiments, the carrier is suitable for parenteral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Additional active compounds can also be included in the compositions of the present invention.

[0083] In various embodiments, liquid formulations may include suspensions and solutions.Such formulations include carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be produced by reconstituting solids.

[0084] In some embodiments, aqueous suspensions may contain the active substance in admixture with suitable excipients. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides, such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate; or one or more colorants.

[0085] In certain embodiments, dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Additional excipients, for example, coloring agents, may also be present.

[0086] Suitable emulsifiers may be naturally occurring gums, such as gum acacia or tragacanth; naturally occurring phosphatides, such as soybean lecithin; and partial esters derived from fatty acids and hexitols, including, for example, sorbitan monooleate, and the condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0087] In other embodiments, isotonic substances, such as sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride, may be included in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition a substance that delays absorption, for example, monostearate salts and gelatin.

[0088] Specific forms for oral administration include tablets, capsules, elixirs, syrups, and the like.

[0089] A wide range of acceptable doses is contemplated herein, including doses ranging from about 1 MBq to about 4 MBq of I-Ac or Ia-Ac, depending on the type of cancer, route of administration, and / or whether the compounds I-Lu or I-Lu, I-Ac or Ia-Ac, and / or PSMA ligand-imaging agent conjugates described herein are administered locally or systemically. In some embodiments, acceptable dosages of I-Lu or Ia-Lu are contemplated herein in GBq units, including doses ranging from about 2 GBq to about 13 GBq. Doses may be single or divided and may be administered according to a wide range of protocols, including qd, bid, tid, or every other day, every other week (biw), weekly, monthly, quarterly, etc. In each of these cases, the therapeutically effective amounts described herein are understood to correspond to the dosage examples or, alternatively, to the total daily, weekly, monthly, or quarterly dose, as determined by the administration protocol. In some embodiments, the combination of Formula I-Lu or Ia-Lu and I-Ac or Ia-Ac can be administered on independent schedules, such as once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

[0090] In some embodiments, the compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugate described herein may be administered directly into the bloodstream, muscle, or internal organs.Such suitable parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intraventricular, intraurethral, ​​intrasternal, intracranial, intratumoral, intramuscular, and subcutaneous delivery.Suitable means for parenteral administration include needle-type (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0091] In certain specific embodiments, parenteral formulations are typically aqueous solutions that may contain carriers or excipients such as salts, carbohydrates, and buffers (preferably pH 3-9); however, for some applications, they may be more suitably formulated as sterile, non-aqueous solutions used for conjugation with a suitable solvent, such as sterile water or pyrogen-free water, or as a dry form. In other embodiments, any of the liquid formulations described herein is applicable for parenteral administration of Compound 1 or a PSMA ligand-imaging agent conjugate described herein. Preparation of parenteral formulations under sterile conditions, e.g., by lyophilization under sterile conditions, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. In certain embodiments, the solubility of Compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or a PSMA ligand-imaging agent conjugate used in the preparation of a parenteral formulation may be increased by appropriate formulation techniques, such as the incorporation of a solubility-enhancing agent.

[0092] In various embodiments, formulations for parenteral administration can be formulated for immediate and / or modified release. In certain specific embodiments, the active substances of the present invention (i.e., compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugate) can be administered in sustained-release formulations, such as compositions containing sustained-release polymers. The active compounds I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugates can be prepared using carriers that protect the compounds I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugates against rapid release, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactose copolymers, polyglycol copolymers (PGLA), can be used. Methods for preparing such formulations are generally known to those skilled in the art. In another embodiment, compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or a PSMA ligand-imaging agent conjugate described herein or a composition comprising compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or a PSMA ligand-imaging agent conjugate may be administered sequentially, where appropriate.

[0093] In some embodiments, a kit is provided. If compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or a PSMA ligand-imaging agent conjugate is administered in combination with a shielding agent described herein, two or more pharmaceutical compositions can be formulated in the form of a kit suitable for sequential or co-administration of the compositions. Such a kit comprises two or more separate pharmaceutical compositions, at least one of which comprises compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or a PSMA ligand-imaging agent conjugate described herein, and the other of which comprises at least one shielding agent described herein, and a means for separately maintaining the compositions, such as a divided container or divided foil packet. In another embodiment, a composition comprising one or more of compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or a PSMA ligand-imaging agent conjugate described herein and at least one shielding agent described herein is provided in a container with a label providing instructions for use in patient selection and / or patient treatment.

[0094] In some embodiments, sterile injectable solution can be prepared by incorporating the required amount of active substance into a suitable solvent using one or a combination of the above-mentioned components as needed, followed by filtration sterilization.Generally, dispersion is prepared by incorporating compound I-Lu, or I-Lu, I-Ac, or Ia-Ac and / or PSMA ligand-imaging agent conjugate into a sterile solvent containing a dispersion medium and any additional components described above.For sterile powder preparation of sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying, which obtains a powder of the active ingredient plus any additional desired component from the solution previously sterile-filtered, or these components can be sterile-filtered together.

[0095] The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentration. The carrier can be, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof. In some embodiments, proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0096] Dose levels for compounds I-Lu or Ia-Lu and I-Ac or Ia-Ac can be measured in GBq and MBq, respectively. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 2 GBq to about 20 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 2 GBq to about 13 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 4 GBq to about 11 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 5 GBq to about 10 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 9 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6 GBq to about 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 6.5 GBq to about 8.5 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7 GBq to about 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 15 GBq to about 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 25 GBq to about 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 35 GBq to about 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is in the range of about 40 GBq to about 100 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is about 44 GBq. In some embodiments, the maximum length of treatment for a subject is about 19 to 23 months.

[0097] In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 2 GBq to 20 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 2 GBq to 13 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 4 GBq to 11 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 5 GBq to 10 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 6 GBq to 9 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 6 GBq to 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 6.5 GBq to 8.5 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 7 GBq to 8 GBq. In some embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 15 GBq to 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 25 GBq to 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 35 GBq to 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 40 GBq to 100 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu is 44 GBq. In some embodiments, the maximum length of treatment for a subject is about 19 to 23 months.

[0098] In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 20 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 4 MBq to about 14 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq to about 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 6 MBq to about 8 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq to about 7 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 1 MBq to about 4 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2 MBq to about 3 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is about 2.5 MBq.

[0099] In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 1 MBq to 20 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 1 MBq to 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 4 MBq to 14 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq to 10 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 6 MBq to 8 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq to 7 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 1 MBq to 4 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 2 MBq to 3 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq. In some embodiments, the therapeutically effective amount of I-Ac or Ia-Ac is 2.5 MBq.

[0100] The PSMA ligand-imaging agent conjugates, compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac, and shielding agents described herein may contain one or more asymmetric centers, or alternatively may be capable of existing as multiple stereoisomers. Accordingly, the present invention should be understood to include pure stereoisomers as well as mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. The PSMA ligand-imaging agent conjugates, compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac, and shielding agents described herein may exist as geometric isomers. Accordingly, the present invention should be understood to include pure geometric isomers or mixtures of geometric isomers. For example, shielding agent 1c has the formula [ka] It is of the type.

[0101] Those skilled in the art will recognize that shielding agent 1c has a chiral center and therefore can exist in two enantiomeric forms. [ka] Recognize that this is the case.

[0102] It is understood that the disclosure of shielding agent 1c set forth above also includes disclosure of the R-enantiomer and S-enantiomer of shielding agent 1c. Similarly, disclosure of other shielding agents, PSMA ligand-imaging agents, and compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac also includes disclosure of their respective enantiomers, diastereomers, etc.

[0103] It is understood that the PSMA ligand-imaging agent conjugates and compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac and shielding agents described herein can exist in unsolvated and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. The PSMA ligand-imaging agent conjugates and compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac and shielding agents described herein can exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0104] In another embodiment, compositions and / or dosage forms for administration of compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac are made from compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5% purity. In another embodiment, compositions and / or dosage forms for administration of compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac are made from compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5% purity.

[0105] In another embodiment, compositions and / or dosage forms for administration of a PSMA ligand-imaging agent conjugate are made from a PSMA ligand-imaging agent conjugate that is at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5% pure. In another embodiment, compositions and / or dosage forms for administration of a PSMA ligand-imaging agent conjugate are made from a PSMA ligand-imaging agent conjugate that is at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5% pure.

[0106] In another embodiment, compositions and / or dosage forms for administration of a radiolabeled PSMA ligand-imaging agent conjugate are made from a PSMA ligand-imaging agent conjugate of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5% radiochemical purity. In another embodiment, compositions and / or dosage forms for administration of a PSMA ligand-imaging agent conjugate are made from a PSMA ligand-imaging agent conjugate of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5% radiochemical purity.

[0107] The purity of compounds I-Lu, I-Ac, Ia-Lu and Ia-Ac or PSMA ligand-imaging agent conjugates described herein can be measured using any conventional technique, including various chromatographic or spectroscopic techniques such as high pressure or high performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy, TLC, UV absorbance spectroscopy, fluorescence spectroscopy, and the like.

[0108] In another embodiment, the compounds I-Lu, I-Ac, Ia-Lu and Ia-Ac or PSMA ligand-imaging agent conjugates described herein are provided in a sterile container or package.

[0109] In some embodiments, the clinical benefit of patients treated with the combination of compound I-Lu or Ia-Lu and compound I-Ac or Ia-Ac is characterized as overall survival (OS).As used herein, the term "overall survival (OS)" refers to the time from the date of randomization to the date of death from any cause.

[0110] In some embodiments, the clinical benefit of patients treated with compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac can be characterized using the Response Evaluation in Solid Tumors (RECIST) criteria. Specifically, the criteria were adapted from the original WHO handbook (3), taking into account the measurement of the longest diameter of all target lesions; complete response (CR) - the disappearance of all target lesions; partial response (PR) - a reduction of at least 30% in the sum of the longest diameters of target lesions, based on the baseline sum of the longest diameters; stable disease (SD) - neither a sufficient reduction to qualify as a partial response nor a sufficient increase to qualify as disease progression, based on the smallest sum of the longest diameters since the start of treatment; progressive disease (PD) - an increase of at least 20% in the sum of the longest diameters of lesions, based on the smallest sum of the longest diameters recorded since the start of treatment, or the appearance of one or more new lesions. In another aspect, the overall disease response rate (ORR) can be a clinical benefit, calculated as the percentage of patients who achieve the best CR or PR response. Overall disease control rate (DCR) can be another clinical benefit and is calculated as the proportion of patients who achieve a best CR, PR, or SD response. In some embodiments, response can be disease control rate (DCR) measured by RECIST v1.1 criteria.

[0111] In another embodiment, the clinical benefit of a patient treated with compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac can be characterized as radiological progression-free survival (rPFS). As used herein, "progression-free survival (rPFS)" refers to the time from randomization to the date of radiological disease progression or death from any cause as specified in the Prostate Cancer Working Group 3 (PCWG3) Guidelines. See, for example, Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations from the Prostate Cancer Clinical Trials Work Group 3. J Clin Oncol 2016;34(12):1402-18. In another embodiment, the clinical benefit of a patient treated with compound 1 refers to the time to the first symptomatic skeletal event (SSE). This is understood to mean a clinically significant pathological fracture, surgery or radiation to bone, or spinal cord compression. As used herein, "time to first symptomatic skeletal event" means the time from the date of randomization to the date of first new symptomatic pathologic fracture, spinal cord compression, tumor-related orthopedic intervention, or need for radiation therapy to relieve bone pain, whichever occurs first.

[0112] In a specific example, overall survival is the time to death for a patient, defined as the number of days from the first day the patient received protocol treatment (C1D1) to the date of the patient's death. All death events can be included, regardless of whether the event occurred while the patient was taking the study drug or after discontinuing the study drug. If the patient does not die, then the data can be censored at the last study visit, or the date of last contact, or the last day the patient was known to be alive, whichever is later.

[0113] Alternatively, the clinical benefit of patients as a result of treatment with compound I-Lu, Ia-Lu, I-Ac or Ia-Ac can be characterized as tumor growth inhibition, which can be identified in patients, for example, through follow-up imaging of patients after treatment with the compound.For example, tumor growth inhibition can be characterized by measuring tumor size in patients after administration of compound I-Lu, Ia-Lu, I-Ac or Ia-Ac by any imaging technique described herein, and tumor growth inhibition is indicated by stable tumor size or a decrease in tumor size.It is understood that identifying tumor growth inhibition can be achieved using various techniques and is not limited to the imaging methods described herein (e.g., CT, MRI, PET imaging, SPECT imaging or chest X-ray).

[0114] The embodiments described in the Detailed Description and Summary of the Invention may be combined with each of the following numbered paragraphs to the extent that such embodiments are not mutually exclusive. 1. A compound selected from the group consisting of: [ka] [ka]

[0115] 2. A method of treating cancer in a patient comprising administering a therapeutically effective amount of a radiolabeled therapeutic agent in combination with an effective amount of a shielding agent. 3. The method according to paragraph 2, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. 4. The method according to item 2 or 3, wherein the cancer is prostate cancer. 5. The method according to any one of items 2 to 4, wherein the cancer is metastatic prostate cancer. 6. The method according to any one of Items 2 to 4, wherein the cancer is metastatic castration-resistant prostate cancer.

[0116] 7. Shielding agent, [ka] [ka] [ka] Item 7. The method according to any one of Items 2 to 6, wherein the compound is selected from the group consisting of:

[0117] 8. Shielding agent [ka] [ka] [ka] Item 7. The method according to any one of Items 2 to 6, wherein the compound is selected from the group consisting of:

[0118] 9. A compound selected from the group consisting of: [ka] [ka] [ka]

[0119] 10. The compound according to paragraph 9, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. 11. The compound according to item 9 or 10, wherein the cancer is prostate cancer. 12. The compound according to any one of items 9 to 11, wherein the cancer is metastatic prostate cancer. 13. The compound according to any one of items 9 to 11, wherein the cancer is metastatic castration-resistant prostate cancer.

[0120] 14. Use of a compound selected from the group consisting of: in the manufacture of a medicament for treating cancer in a patient in combination with a therapeutically effective amount of a radiolabeled therapeutic agent: [ka] [ka] [ka]

[0121] 15. The use according to item 14, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. 16. The use according to item 14 or 15, wherein the cancer is prostate cancer. 17. The use according to any one of items 14 to 16, wherein the cancer is metastatic prostate cancer. 18. The use according to any one of items 14 to 16, wherein the cancer is metastatic castration-resistant prostate cancer. 19. A method of imaging cancer in a patient comprising administering an effective amount of a contrast agent conjugate in combination with an effective amount of a shielding agent. 20. Contrast agent 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 20. The method according to Item 19, wherein the imaging agent conjugate 4 is Ga-labeled. 21. The method of item 19 or 20, wherein the cancer is prostate cancer. 22. The method according to any one of items 19 to 21, wherein the cancer is metastatic prostate cancer. 23. The method according to any one of items 19 to 22, wherein the cancer is metastatic castration-resistant prostate cancer.

[0122] 24. Shielding agent, [ka] [ka] [ka] 24. The method according to any one of items 19 to 23, selected from the group consisting of:

[0123] 25. Shielding agent, [ka] [ka] 24. The method according to any one of items 19 to 23, selected from the group consisting of:

[0124] 26. A compound selected from the group consisting of: [ka] [ka] [ka]

[0125] 27. Contrast agent conjugates 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 27. The compound according to item 26, which is Ga-labeled imaging agent conjugate 4. 28. The compound according to item 26 or 27, wherein the cancer is prostate cancer. 29. The compound according to any one of items 26 to 28, wherein the cancer is metastatic prostate cancer. 30. The compound according to any one of items 26 to 28, wherein the cancer is metastatic castration-resistant prostate cancer.

[0126] 31. A compound selected from the group consisting of: in the manufacture of a medicament for treating cancer in a patient in combination with an effective amount of an imaging agent conjugate: [ka] [ka] [ka]

[0127] 32. Contrast agent conjugates 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 32. The use according to Item 31, wherein the imaging agent conjugate 4 is Ga-labeled. 33. The use according to item 31 or 32, wherein the cancer is prostate cancer. 34. The use according to any one of items 31 to 33, wherein the cancer is metastatic prostate cancer. 35. The use of any one of items 31 to 34, wherein the cancer is metastatic castration-resistant prostate cancer.

[0128] In another embodiment, the methods described herein include the following examples. The examples further illustrate additional features of various embodiments of the present invention. However, it should be understood that the examples are illustrative and should not be construed as limiting other embodiments of the present invention. Furthermore, it is recognized that other types of examples are included in the various embodiments of the present invention. Furthermore, it is understood that all ranges described herein, e.g., ranges relating to the various examples, are exemplary and not intended to be limiting. One of ordinary skill in the art will understand that lower and upper limits, e.g., about 1 to about 20, include all possible values ​​included within the lower and upper limits, and include all possible ranges of values ​​available through a set of possible values ​​included within the lower and upper limits. [Example]

[0129] Example 1: Preparation of Compound 1a [ka] Step 1: Preparation of (S)-1-benzyl 5-octyl 2-((tert-butoxycarbonyl)amino)pentanedioate: To a stirred solution of Boc-Glu-OBn (1.00 g, 2.96 mmol, 1.00 equiv.), n-octanyl alcohol (699 μL, 4.44 mmol, 1.50 equiv.), DIPEA (1.54 mL, 8.88 mmol, 3.00 equiv.), and DMAP (36.2 mg, 0.296 mmol, 10 mol%) in 29.6 mL of DCM was added HATU (1.35 g, 3.55 mmol, 1.20 equiv.). The reaction was maintained at room temperature for 5 h, then diluted with 100 mL of DCM and washed with 30 mL of 2 M HCl (aqueous), 30 mL of water, 30 mL of brine, dried over NaSO, and filtered. The solution was concentrated under reduced pressure. The desired product was further purified by silica chromatography (5–85% EtOAc in petroleum ether) to give a white solid (1.04 g, 81.1%).

[0130] Shielding agents 1m and 1n were prepared according to the same method using 1-butanol and 1-dodecanol instead of 1-octanol, respectively.

[0131] Step 2: Preparation of (S)-dibenzyl 2-((phenoxycarbonyl)amino)pentanedioate: In a 100 mL round-bottom flask at 0 °C, L-glutamic acid dibenzyl para-toluenesulfonate (5.00 g, 10.0 mmol, 1.00 equiv.) and 4-nitrophenyl chloroformate (1.64 g, 10.5 mmol, 1.05 equiv.) were dissolved in 30.3 mL of dichloromethane and stirred under argon for 30 min. Diisopropylethylamine (3.80 mL, 22.0 mmol, 2.20 equiv.) was added dropwise at 0 °C, and the reaction mixture was stirred for 5 min, warmed to room temperature, and stirred for an additional 30 min. The reaction mixture was then concentrated to a light yellow oil. The product was further purified by silica chromatography (0-55% ethyl acetate in petroleum ether) to afford the desired product as a white solid (3.54 g, 78.1%).

[0132] Step 3: Preparation of (S)-dibenzyl 2-(3-((S)-1-(benzyloxy)-5-(octyloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate: (S)-1-Benzyl 5-octyl 2-((tert-butoxycarbonyl)amino)pentanedioate (500 mg, 1.11 mmol, 1.00 equiv) was dissolved in dry DCM (5.00 mL). The solution was cooled to 0 °C, TFA (5.00 mL) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 30 min. DCM and TFA were concentrated under reduced pressure, and the residue was dissolved in toluene (2 mL × 3) to azeotrope off traces of TFA. The crude product was dissolved in 2.22 mL of DCM and slowly added at 0 °C to a stirred solution of EC3517 (496 mg, 1.11 mmol, 1.00 equiv) in 2.22 mL of DCM. Diisopropylethylamine (424 μL, 2.44 mmol, 2.20 equiv) was added dropwise at 0 °C, and the reaction mixture was stirred for 30 min before warming to room temperature. After stirring the reaction mixture at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The product was extracted with DMC (25 mL × 3) from 50 mL of water. The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and concentrated. The product was further purified by silica gel chromatography (10-100% EtOAc in petroleum ether) to give the desired product as a dark oil (678 mg, 87.0%).

[0133] Step 4: Preparation of (S)-2-(3-((S)-1-carboxy-4-(octyloxy)-4-oxobutyl)ureido)pentanedioic acid (1a): The purified (S)-dibenzyl 2-(3-((S)-1-(benzyloxy)-5-(octyloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (441 mg, 0.628 mmol, 1.00 equiv.) was dissolved in 6.28 mL of THF / methanol (3:2). Under a strong argon stream, 10% Pd / C (66.6 mg, 0.0628 mmol, 10 mol%) was added. The headspace was evacuated and refilled with argon and hydrogen (×2). The reaction mixture was then stirred at room temperature for 6 h. The crude product was filtered through a 45 μm nylon / fiberglass membrane and concentrated. The product was further purified by reverse-phase chromatography (0.1% TFA in aqueous buffer, 0–30% ACN). After lyophilization for 2 days, the desired product was obtained as a white solid (210 mg, 77.3%).

[0134] Example 2: Preparation of Compound 1c [ka] Step 1: Preparation of 5-(3-(benzyloxy)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione: Dicyclohexylcarbodiimide (DCC) (2.66 g, 12.9 mmol, 1.25 equiv.) was added portionwise over 1 h to a solution of 3-hydroxybenzylpropionic acid (2.00 g, 10.3 mmol, 1.00 equiv.), Meldrum's acid (2.08 g, 14.4 mmol, 1.40 equiv.), diisopropylethylamine (DIPEA) (5.01 mL, 28.8 mmol, 2.8 equiv.), and 4-(dimethylamino)pyridine (DMAP) (159 mg, 1.30 mmol, 10 mol%) in 103 mL of DCM at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight (16 h). The white precipitate was filtered, and the filtrate was washed three times with 10% KHSO (aq.), washed with brine, dried over NaSO, and filtered. The solution was acidified with acetic acid (7.08 mL, 124 mmol, 12 equiv) at -10 °C, and sodium borohydride (NaBH4) (584 mg, 15.45 mmol, 1.5 equiv) was added in portions over 1 h. The reaction mixture was stirred overnight (16 h) at -10 °C, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The desired product was further purified by silica chromatography (5-50% EtOAc in petroleum ether) to give a white solid (2.47 g, 82%). LC / MS and 1 1 H NMR spectral analysis was consistent with the assigned structure of the desired product.

[0135] Step 2: Preparation of tert-butyl 5-(benzyloxy)-2-methylenepentanoate: 5-(3-(benzyloxy)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.25 g, 4.28 mmol, 1.00 equiv.) and Eschenmoser's salt (N,N-dimethylmethyleneiminium iodide) (1.97 g, 10.7 17.2 mmol, 2.50 equiv.) were added to a dry round-bottom flask. The top was evacuated and backfilled with argon. 42.8 mL of anhydrous tert-butyl alcohol (tBuOH) was added to the solid. The reaction mixture was heated to 65 °C and stirred for 30 min. The reaction was concentrated under high vacuum, and the residue was loaded onto a silica column and purified by chromatography (0-80% EtOAc in petroleum ether) to give the desired product as a clear oil (856 mg, 72.5%). LC / MS and 1 1 H NMR spectral analysis was consistent with the assigned structure of the desired product.

[0136] Step 3: Preparation of tert-butyl 5-(benzyloxy)-2-((diethoxyphosphoryl)methyl)pentanoate: At 0 °C, a 2 M solution of trimethylaluminum in hexane (5.80 mL, 2.90 mmol, 1.00 equiv) was added to a stirred solution of diethyl phosphite (373 μL, 2.90 mmol, 1.00 equiv) in 41.4 mL of dichloromethane (DCM). The reaction mixture was stirred at 0 °C for 30 min. A solution of tert-butyl 5-(benzyloxy)-2-methylenepentanoate (800 mg, 2.90 mmol, 1.00 equiv) in 7.25 mL of dichloromethane was slowly added, and the reaction mixture was then allowed to warm to room temperature. The reaction mixture was stirred at room temperature overnight (17 h). The reaction was quenched with 10 mL of 2 M HCl (aqueous) and extracted with diethyl ether (10 mL × 3). The organic layers were combined, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The product was further purified by silica chromatography (10-85% EtOAc in petroleum ether) to give the desired product as a clear oil (906 mg, 79.7%). 1 1 H NMR spectral analysis was consistent with the assigned structure of the desired product.

[0137] Step 4: Preparation of tert-butyl 2-((diethoxyphosphoryl)methyl)-5-hydroxypentanoate: tert-Butyl 5-(benzyloxy)-2-((diethoxyphosphoryl)methyl)pentanoate (450 mg, 1.09 mmol, 1.00 equiv) was dissolved in 10.9 mL of tetrahydrofuran (THF), and argon was bubbled through the solution for 15 minutes. Under a strong argon stream, 10% Pd / C (57.7 mg, 0.055 mmol, 5 mol%) was added. The headspace was evacuated and refilled with argon and hydrogen (×2). The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was filtered through a pad of Celite and washed with 10 mL of dichloromethane. The solution was then concentrated, and the residue was placed under high vacuum for 1 hour to give the desired product as a colorless oil. The crude product was used without further purification.

[0138] Step 4: Preparation of 5-(tert-butoxy)-4-((diethoxyphosphoryl)methyl)-5-oxopentyl nonanoate: To a stirred solution of nonanoic acid (130 μL, 0.743 mmol, 1.20 equiv.), tert-butyl 2-((diethoxyphosphoryl)methyl)-5-hydroxypentanoate (200 mg, 0.619 mmol, 1.00 equiv.), DIPEA (301 μL, 1.73 mmol, 2.8 equiv.), and DMAP (8.0 mg, 0.0619 mmol, 10 mol%) in 7.43 mL of DCM was added HATU (306 mg, 0.805 mmol, 1.30 equiv.). The reaction was stirred at room temperature for 5 h, then diluted with 20 mL of DCM and washed with 10 mL of 2 M HCl (aq.), 10 mL of water, 10 mL of brine, dried over NaSO, and filtered. The solution was concentrated under reduced pressure. The desired product was further purified by silica chromatography (5-75% EtOAc in petroleum ether) to give a white solid (255 mg, 58.5%). 1 1 H NMR spectral analysis was consistent with the assigned structure of the desired product.

[0139] Step 6: Preparation of 5-(nonanoyloxy)-2-(phosphonomethyl)pentanoic acid (1c): To a stirred solution of 5-(tert-butoxy)-4-((diethoxyphosphoryl)methyl)-5-oxopentyl nonanoate (200 mg, 0.432 mmol, 1.00 equiv) in 2.2 mL of DCM at 0 °C was slowly added 2.2 mL of trifluoroacetic acid (TFA). The reaction was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated under reduced pressure, and the residue was taken up in toluene and concentrated under high vacuum (×3). The crude product was dissolved in 4.32 mL of anhydrous DCM, and bromotrimethylsilane (342 μL, 2.59 mmol, 6.00 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then allowed to warm slowly to room temperature. It was then stirred overnight (12 h), concentrated under reduced pressure, and the residue was taken up in toluene and concentrated under high vacuum (×3). The resulting residue was dissolved in ACN / HO (4:1, 5 mL) and stirred for 30 minutes. The reaction mixture was concentrated, loaded onto a C18 column, and analyzed by reverse phase chromatography (0-35% ACN in 0.1% TFA aqueous buffer). After 2 days of lyophilization, the desired product was obtained as a colorless oil (94 mg, 62.0%). LC / MS and 1 1 H NMR spectral analysis was consistent with the assigned structure of the desired product.

[0140] Example 3: Preparation of Compound 1d [ka] Step 1: 1-(tert-butyl)-5-dodecyl-2-((diethoxyphosphoryl)methyl)pentanedioate (1-3): To a solution of compound 1 (0.092 g, 0.27 mM), prepared according to the method described in Nedelcovych (2017), in dry DCM (3 mL) was added 1-dodecanol (0.101 g, 0.54 mM) and DIPEA (0.142 mL, 0.82 mM), respectively. HATU (0.124 g, 0.33 mM) and DMAP (3.32 mg, 0.03 mM) were added. The reaction was stirred at RT for 1 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The reaction mixture was concentrated and dried. The residue was purified using a Combiflash (SiO2) column eluting with 0–100% ethyl acetate in petroleum ether to give pure 1-3 (0.107 g, 78%).

[0141] Step 2: 5-Dodecoxy-2-(tert-butoxycarbonyl)-5-oxopentylphosphonic acid (1-4): To a solution of 1-3 (0.096 g, 0.19 mM) in dry DCM (3 mL) at 0 °C under an argon atmosphere, TMSBr (0.116 g, 0.76 mM) was added very slowly over 5 min. The reaction was allowed to warm to RT over 2 h and stirred for 18 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The DCM was removed, and the TMSBr was azeotroped with toluene (3 × 3 mL) and dried. The residue was dissolved in acetonitrile / water (5:1; 6 mL) and stirred at RT for 30 min. The mixture was concentrated under reduced pressure and azeotroped with toluene (3 × 3 mL) and dried. The crude des-ethyl 1-4 (0.086 g, quantitative) was used directly in the next reaction.

[0142] Step 3: Synthesis of 5-dodecoxy-5-oxo-2-(phosphonomethyl)pentanoic acid (1d): To a solution of des-ethyl 1-4 (0.086 g, 0.19 mM) in dry DCM (2 mL) at 0 °C, trifluoroacetic acid (2 mL) was added very slowly over 5 min. The reaction was allowed to warm to RT and stirred for 2 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The TFA / DCM was removed and dried. The residue was dissolved in DMSO and purified by Biotage column (C18 The pure fractions were combined, the acetonitrile was removed, and the residue was lyophilized to give 1d (0.062 g, 83%).

[0143] Compound 1b was prepared according to the same method as compound 1d, except that 1-octanol was used instead of 1-dodecanol.

[0144] Example 4: Preparation of Compound 1e [ka] Step 1: Preparation of 1-(tert-butyl)-2-((diethoxyphosphoryl)methyl)-5-(octylamino)-5-oxopentanoate (1-1): To a solution of compound 1 (0.100 g, 0.30 mM), prepared according to the method described in Nedelcovych (2017) cited above, in dry DCM (3 mL) was added 1-octylamine (0.077 g, 0.59 mM) and DIPEA (0.155 mL, 0.892 mM), respectively. HATU (0.135 g, 0.36 mM) was added. The reaction was warmed and stirred at RT for 1 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The reaction mixture was concentrated to dryness. The residue was purified using a Combiflash (SiO2) column, eluting with 0–100% ethyl acetate in petroleum ether to give pure 1-1 (0.088 g, 66%).

[0145] Step 2: Preparation of 5-(octylamino)-2-(tert-butoxycarbonyl)-5-oxopentylphosphonic acid (1-2): To a solution of compound 1-1 (0.088 g, 0.20 mM) in dry DCM (3 mL) at 0 °C under an argon atmosphere, TMSBr (0.119 g, 0.78 mM) was added very slowly over 5 min. The reaction was allowed to warm to RT over 2 h and stirred for 24 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The DCM was removed, and the TMSBr was azeotroped with toluene (3 × 5 mL) and dried. The residue was dissolved in acetonitrile / water (5:1; 6 mL) and stirred at RT for 30 min. The crude product, compound 1-2 (0.077 g, quantitative), was concentrated under reduced pressure, azeotroped with toluene (3 × 5 mL), and dried. It was used directly in the next reaction.

[0146] Step 3: Preparation of 5-(octylamino)-5-oxo-2-(phosphonomethyl)pentanoic acid (1e): To a solution of des-ethyl 1-2 (0.077 g, 0.20 mM) in dry DCM (2.5 mL) was added trifluoroacetic acid (2.5 mL) very slowly over 5 min at 0 °C. The reaction was allowed to warm to RT and stirred for 20 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The TFA / DCM was removed and dried. The residue was dissolved in DMSO and purified by Biotage column (C 18 The pure fractions were combined, the acetonitrile was removed, and the residue was lyophilized to give compound 1e (0.040 g, 60%).

[0147] Biological Examples: Example 5: Biodistribution of the shielding agent of the present invention The shielding agent of the present invention was administered in combination with the contrast agent of the present invention, and the biodistribution was analyzed. The results are shown in Figures 1 to 9. The present invention includes the following aspects. [Item 1] A compound selected from the group consisting of: [C1] JPEG0007748438000079.jpg214159 [Case 2] JPEG0007748438000080.jpg99159 [Item 2] A method for treating cancer in a patient, comprising administering a therapeutically effective amount of a radiolabeled therapeutic agent in combination with an effective amount of a shielding agent. [Item 3] The method according to Item 2, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. [Item 4] The method according to Item 2 or 3, wherein the cancer is prostate cancer. [Item 5] The method according to any one of Items 2 to 4, wherein the cancer is metastatic prostate cancer. [Item 6] The method according to any one of Items 2 to 4, wherein the cancer is metastatic castration-resistant prostate cancer. [Item 7] The shielding agent is [C3] JPEG0007748438000081.jpg214159 [C4] JPEG0007748438000082.jpg235159 [5] JPEG0007748438000083.jpg70159 Item 7. The method according to any one of items 2 to 6, wherein the compound is selected from the group consisting of: [Item 8] Shielding agent [6] JPEG0007748438000084.jpg148161 [7] JPEG0007748438000085.jpg166162 Item 7. The method according to any one of items 2 to 6, wherein the compound is selected from the group consisting of: [Item 9] A compound selected from the group consisting of: [8] JPEG0007748438000086.jpg213159 [9] JPEG0007748438000087.jpg235159 [C10] JPEG0007748438000088.jpg69113 [Item 10] The compound according to Item 9, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. [Item 11] The compound according to Item 9 or 10, wherein the cancer is prostate cancer. [Item 12] The compound according to any one of Items 9 to 11, wherein the cancer is metastatic prostate cancer. [Item 13] The compound according to any one of Items 9 to 11, wherein the cancer is metastatic castration-resistant prostate cancer. [Item 14] Use of a compound selected from the group consisting of: in the manufacture of a medicament for treating cancer in a patient in combination with a therapeutically effective amount of a radiolabeled therapeutic agent: [C11] JPEG0007748438000089.jpg85154 [C12] JPEG0007748438000090.jpg194161 [C13] JPEG0007748438000091.jpg240161 [Item 15] The use according to Item 14, wherein the radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac. [Item 16] The use according to Item 14 or 15, wherein the cancer is prostate cancer. [Item 17] The use according to any one of Items 14 to 16, wherein the cancer is metastatic prostate cancer. [Item 18] The use according to any one of Items 14 to 16, wherein the cancer is metastatic castration-resistant prostate cancer. [Item 19] A method for imaging cancer in a patient, comprising administering an effective amount of an imaging agent conjugate in combination with an effective amount of a shielding agent. [Item 20] Contrast agent 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 20. The method according to Item 19, wherein the imaging agent conjugate 4 is Ga-labeled. [Item 21] The method according to Item 19 or 20, wherein the cancer is prostate cancer. [Item 22] The method according to any one of Items 19 to 21, wherein the cancer is metastatic prostate cancer. [Item 23] The method according to any one of Items 19 to 22, wherein the cancer is metastatic castration-resistant prostate cancer. [Item 24] The shielding agent is [C14] JPEG0007748438000092.jpg89159 [C15] JPEG0007748438000093.jpg193159 [C16] JPEG0007748438000094.jpg237159 24. The method according to any one of items 19 to 23, wherein the compound is selected from the group consisting of: [Item 25] The shielding agent is [C17] JPEG0007748438000095.jpg213159 [C18] JPEG0007748438000096.jpg95158 24. The method according to any one of items 19 to 23, wherein the compound is selected from the group consisting of: [Item 26] A compound selected from the group consisting of: [C19] JPEG0007748438000097.jpg87156

[20] JPEG0007748438000098.jpg192159

[21] JPEG0007748438000099.jpg245162 [Item 27] ​​Contrast agent conjugate 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 27. The compound according to item 26, which is Ga-labeled imaging agent conjugate 4. [Item 28] The compound according to item 26 or 27, wherein the cancer is prostate cancer, or the compound according to any one of items 26 to 28. [Item 29] The compound according to any one of Items 26 to 28, wherein the cancer is metastatic prostate cancer. [Item 30] The compound according to any one of Items 26 to 28, wherein the cancer is metastatic castration-resistant prostate cancer. [Item 31] Use of a compound selected from the group consisting of the following in the manufacture of a medicament for imaging cancer in a patient in combination with an effective amount of an imaging agent conjugate: [C22] JPEG0007748438000100.jpg149159

[23] JPEG0007748438000101.jpg235159

[24] JPEG0007748438000102.jpg138158 [Item 32] Contrast agent conjugate 99m Tc-labeled contrast agent conjugate 3a or 67 Ga or 68 Item 32. The use according to Item 31, wherein the imaging agent conjugate 4 is Ga-labeled. [Item 33] The use according to Item 31 or 32, wherein the cancer is prostate cancer. [Item 34] The use according to any one of Items 31 to 33, wherein the cancer is metastatic prostate cancer. [Item 35] The use according to any one of Items 31 to 34, wherein the cancer is metastatic castration-resistant prostate cancer.

Claims

1. 1. A composition for treating cancer, comprising a therapeutically effective amount of a radiolabeled therapeutic agent, and the composition is administered in combination with an effective amount of a shielding agent, the shielding agent comprising: 【Chemical 1】 A composition selected from the group consisting of:

2. The radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac, wherein compound Ia has the following structure: 【Chemistry 2】 10. The composition of claim 1, wherein

3. The composition of claim 1 or 2, wherein the cancer is prostate cancer.

4. The composition according to any one of claims 1 to 3, wherein the cancer is metastatic prostate cancer.

5. The composition according to any one of claims 1 to 3, wherein the cancer is metastatic castration-resistant prostate cancer.

6. A composition for treating cancer, the composition comprising: 【Chemistry 3】 and the composition is administered in combination with a therapeutically effective amount of a radiolabeled therapeutic agent; The radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac, and compound Ia has the following structure: 【Chemistry 4】 The composition of claim 1,

7. The composition of claim 6 , wherein the cancer is prostate cancer.

8. The composition of claim 6 or 7, wherein the cancer is metastatic prostate cancer.

9. The composition of claim 6 or 7, wherein the cancer is metastatic castration-resistant prostate cancer.

10. 1. A medicament for treating cancer in a patient in combination with a therapeutically effective amount of a radiolabeled therapeutic agent, comprising: 【Chemistry 5】 A pharmaceutical comprising a compound selected from the group consisting of:

11. The radiolabeled therapeutic agent is compound Ia-Lu or Ia-Ac, wherein compound Ia has the following structure: 【Chemistry 6】 The pharmaceutical composition according to claim 10, which has the formula:

12. The pharmaceutical composition according to claim 10 or 11, wherein the cancer is prostate cancer.

13. The pharmaceutical composition according to any one of claims 10 to 12, wherein the cancer is metastatic prostate cancer.

14. The pharmaceutical composition according to any one of claims 10 to 12, wherein the cancer is metastatic castration-resistant prostate cancer.

15. 1. A composition for imaging cancer, the composition comprising an effective amount of an imaging agent conjugate, the composition being administered in combination with an effective amount of a shielding agent, the shielding agent comprising: 【Chemistry 7】 A composition selected from the group consisting of:

16. Contrast agent ９９ｍ Tc-labeled imaging agent conjugate 3a or ６７ Ga or ６８ Ga-labeled imaging agent conjugate 4, The conjugate 3a has the following structure: 【Chemistry 8】 and The conjugate 4 has the following structure: 【Chemistry 9】 16. The composition of claim 15, wherein

17. The composition of claim 15 or 16, wherein the cancer is prostate cancer.

18. The composition according to any one of claims 15 to 17, wherein the cancer is metastatic prostate cancer.

19. The composition according to any one of claims 15 to 17, wherein the cancer is metastatic castration-resistant prostate cancer.

20. A composition for imaging cancer, the composition comprising: 【Chemistry 10】 and the composition is administered in combination with a therapeutically effective amount of an imaging agent conjugate; the imaging agent is a 99m Tc-labeled imaging agent conjugate 3a or a 67 Ga- or 68 Ga-labeled imaging agent conjugate 4; The conjugate 3a has the following structure: 【Chemistry 11】 and The conjugate 4 has the following structure: 【Chemistry 12】 The composition of claim 1,

21. 21. The composition of claim 20, wherein the cancer is prostate cancer.

22. 22. The composition of claim 20 or 21, wherein the cancer is metastatic prostate cancer.

23. 22. The composition of claim 20 or 21, wherein the cancer is metastatic castration-resistant prostate cancer.

24. 1. A medicament for imaging cancer in a patient in combination with a therapeutically effective amount of an imaging agent conjugate, comprising: 【Chemistry 13】 A pharmaceutical comprising a compound selected from the group consisting of:

25. Contrast agent ９９ｍ Tc-labeled imaging agent conjugate 3a or ６７ Ga or ６８ Ga-labeled imaging agent conjugate 4, The conjugate 3a has the following structure: 【Chemistry 14】 and The conjugate 4 has the following structure: 【Chemistry 15】 The pharmaceutical composition of claim 24, which has the formula:

26. The pharmaceutical composition of claim 24 or 25, wherein the cancer is prostate cancer.

27. The pharmaceutical composition according to any one of claims 24 to 26, wherein the cancer is metastatic prostate cancer.

28. The pharmaceutical composition according to any one of claims 24 to 26, wherein the cancer is metastatic castration-resistant prostate cancer.

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