Complex comprising PSMA-targeting compound linked to lead or thorium radionuclide

Abstract

To provide compounds for addressing challenges, such as relatively low radiobiological effectiveness (RBE) and suboptimal biodistribution.SOLUTION: The present invention relates to complexes comprising a prostate-specific membrane antigen (PSMA) targeting compound linked to a radionuclide, such as 212 Pb or 227Th, through a TCMC or DOTA chelating moiety. These compounds and pharmaceutical compositions comprising them can be used for medical applications. These applications include the treatment of prostate cancer, and the complexes allow dual targeting of cancers.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to 212 a complex comprising a PSMA-targeting compound linked to a radionuclide such as Pb or 227 Th. These compounds, and pharmaceutical compositions containing them, can be used for medical applications. These applications include the treatment of prostate cancer, and the complex enables dual targeting of cancer. Peptide and peptidomimetic PSMA-targeting urea derivatives are 212 linked to a chelator for complexing 227 Pb and

Background Art

[0002] Prostate cancer is one of the most common causes of cancer-related death in men. In particular, there is a great need for new and effective treatments in hormone-refractory advanced diseases. Skeletal metastasis is a frequent problem in advanced diseases, and therefore, the α-particle emitter 223 Ra (Xofigo) has been introduced as a bone-specific therapy for patients with advanced prostate cancer suffering from skeletal metastasis.

[0003] As a bone-accumulating 223 Ra shows significant clinical benefits to patients, but its action is limited to bone metastasis and does not target soft tissue metastasis.

[0004] There are several carrier molecules for radioligand targeting of prostate-specific membrane antigen (PSMA). Lutetium-177-labeled PSMA-617 ( 177 Lu-PSMA-617) is the most advanced compound in clinical development for use in radionuclide therapy.

[0005] The molecule operates in a suitable manner, 177 Lu and 225It provides a tumor-to-normal tissue ratio relevant to longer-lived (i.e., several-day half-life) radionuclides including Ac, but shows high uptake in the kidneys in the early stage (typically several hours after injection). 212 For shorter-lived radionuclides such as Pb (half-life of 10.6 hours), the initial kidney uptake means potential toxicity problems.

[0006] Therefore, it is advantageous to use PSMA ligands with less kidney uptake, which does not reduce tumor uptake. The PSMA ligand molecule is composed of (1) a PSMA binding region, (2) a linker region, and (3) a chelator, and accordingly, the linker region connects (1) and (3). The linker region is also used to adjust molecular size, polarity, etc. to affect in vivo distribution characteristics. The PSMA binding regions (motifs) used in PSMA-11 and PSMA I&T, as well as 131 I and 211 the PSMA-617 such as the At-labeled PSMA-binding ligand are structures found in some molecules of this class developed by several different inventors and researchers.

[0007] Since all current ligands in the tests have issues such as relatively low radiobiological effectiveness (RBE) and sub-optimal biodistribution, new compounds containing the PSMA region are approved. There is also a need for improved α-emitters that can target both bone metastases and soft tissue metastases.

[0008] The present invention relates to compounds that address these issues.

Summary of the Invention

[0009] An aspect of the present invention relates to the complex of the present invention, where compound X is linked to a radionuclide such as 212 Pb or 227 Th by a chelate moiety Z.

[0010] In one embodiment of the present invention, the radionuclide is212 It is Pb.

[0011] In another embodiment of the present invention, the radionuclide is 227 Th.

[0012] The chelating moiety Z can be selected from the group consisting of acyclic chelators, cyclic chelators, cryptands, crown ethers, porphyrins, or cyclic or acyclic polyphosphonates, DOTMP, EDTMP, bisphosphonates, DOTA, DOTA derivatives, pamidronate conjugated to DOTA, TCMC, TCMC derivatives, pamidronate conjugated to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A.

[0013] In one embodiment of the present invention, the linker is DOTA or a DOTA derivative.

[0014] In another embodiment of the present invention, the linker is TCMC or a TCMC derivative.

[0015] 227Th Regarding this, octadentate hydroxypyridinone-containing ligands such as 3,2-HOPO are particularly suitable.

[0016] Aspects of the present invention relate to a radiopharmaceutical composition according to the present invention for use as a medicament.

[0017] Aspects of the present invention relate to a radiopharmaceutical composition according to the present invention for use in the treatment of soft tissue or bone diseases.

[0018] In one embodiment of the present invention, the bone disease is selected from the group consisting of cancer with skeletal metastases to the breast, prostate, kidney, lung, bone, or multiple myeloma, or non-cancerous diseases causing undesirable calcification including ankylosing spondylitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0020] Detailed Description of the Invention Several abbreviations are used. A peptide mimetic (also called peptidomimetic) is a small protein-like chain designed to mimic a peptide. These generally arise from the modification of existing peptides or by following a similar system that mimics peptides such as peptoids or β-peptides. Regardless of the approach, the modified chemical structure is designed to favorably modulate molecular properties such as stability or biological activity. This plays a role in the development of drug-like compounds from existing peptides. These modifications involve changes to the peptide that do not occur naturally (such as a modified backbone or incorporation of non-natural amino acids). Based on similarity to the precursor peptide, peptide mimetics can be classified into four classes (A - D), where A is characterized by the greatest similarity and D by the least similarity. Classes A and B contain peptide-like scaffolds, whereas classes C and D contain small molecules.

[0021] PSMA: Prostate-specific membrane antigen. Synonyms: PSMA, prostate-specific cancer antigen, PSM, FGCP, FOLH, GCP2, mGCP, GCPII, NAALAD1, NAALA-dase, FOLH1, glutamate carboxypeptidase 2, glutamate carboxypeptidase II, membrane glutamate carboxypeptidase, N-acetylated-α-linked acidic dipeptidase I, pteroylpoly-γ-glutamate carboxypeptidase, holylpoly-γ-glutamate carboxypeptidase, folate hydrolase 1, prostate-specific membrane antigen, cell growth inhibitory protein-27 DOTMP: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid) EDTMP: Ethylenediaminetetra(methylenephosphonic acid) EDTA: Ethylenediaminetetraacetic acid p-SCN-Bn-DOTA: 2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid DOTA: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid, and also used for benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (e.g., those conjugated to monoclonal antibodies) p-SCN-Bn-TCMC: 2-(4-Isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoyl methyl)-cyclododecane TCMC: 1,4,7,10-Tetraaza-1,4,7,10-tetra-(2-carbamoyl methyl)-cyclododecane, and also used for benzyl-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoyl methyl) cyclododecane (e.g., those conjugated to monoclonal antibodies) mAb: Monoclonal antibody HOPO: Me-3,2-HOPO 227Octadentate hydroxypyridinone for Th complexation, 4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid and derivatives Ligand 1: p-SCN-Bn-TCMC-PSMA Ligand 1, p-SCN-Bn-TCMC-PSMA, etc. Ligand 2: p-SCN-Bn-DOTA-PSMA Ligand 2, p-SCN-Bn-DOTA-PSMA, etc.

[0022] In the following, the same abbreviations are used for versions in which some or all of the acid, salt or chelator are separated.

[0023] The present invention 212 relates to a small molecule urea derivative-based single- and dual-targeting property solution as a prostate cancer cell targeting agent for carrying Pb. This is for purification 212 may be used with Pb, or, accordingly, for PSMA antigen-expressing cells mainly associated with the progression of metastatic prostate cancer and to some extent also with other types of cancer 224 where Ra functions as a skeletal therapy and 212 the Pb urea derivative may be used in the state of a dual-targeting solution that functions as a systemic therapy.

[0024] It is known in the art that urea-based compounds linked to chelator groups facilitate the targeting of radionuclides to PSMA-expressing cells. Radionuclides evaluated for radiotherapy using PSMA targeting include 177 Lu, 211 At, 213 Bi, and 225 Ac.

[0025] The present invention is in the field of radiolabeled therapeutic agents. According to the present invention, radiolabeled derivatives of urea-based prostate-specific membrane antigen (PSMA) inhibitors are disclosed.

[0026] Accordingly, the present invention relates to 212 a complex comprising a compound X linked to a radionuclide such as 227 Pb or

[0027] a linker wherein the compound X is a peptide or peptidomimetic urea derivative suitable for targeting PSMA-expressing cells and tissues. 177 Lu, 213 Bi, 225 Ac, 212 Pb or 227 Th, and the like, and the compound X is linked to a radionuclide by a chelating molecule Z.

[0028] In one embodiment of the present invention, the radionuclide is 212 Pb.

[0029] In another embodiment of the present invention, the radionuclide is 227 Th.

[0030] In another embodiment of the present invention, the radionuclide is 177 Lu.

[0031] In a further embodiment of the present invention, the radionuclide is 213 Bi or 212 Bi.

[0032] In yet another embodiment of the present invention, the radionuclide is 225 Ac.

[0033] The complexing agent, linker, or chelating molecule Z in the present invention is understood to encompass derivatives of the above compounds (for example, derivatives of EDTMP, DOTA such as p-SCN-Bn-DOTA, and TCMC such as p-SCN-Bn-TCMC, etc.). Such derivatives will, of course, 224 have a higher stability constant compared to that for Ra 212 and it is understood that they must maintain the ability to complex Pb.

[0034] The chelating moiety Z can be selected from the group consisting of acyclic chelators, cyclic chelators, cryptands, crown ethers, porphyrins, or cyclic or acyclic polyphosphonates, DOTMP, EDTMP and bisphosphonate derivatives, DOTA, DOTA derivatives such as p-SCN-Bn-DOTA, pamidronate bound to DOTA, TCMC, TCMC derivatives such as p-SCN-Bz-TCMC, pamidronate bound to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, oxo-Do3A.

[0035] In one embodiment of the present invention, the linker is DOTA or a DOTA derivative such as p-SCN-Bn-DOTA.

[0036] In another embodiment of the present invention, the linker is TCMC or a TCMC derivative such as p-SCN-Bn-TCMC.

[0037] The complexing agent can be linked via a carbon skeleton that enables all the "binding arms" of the chelating molecule to interact with the metal. Alternatively, one of its arms can be used as the linker.

[0038] Suitable chelators include, for example, DOTA derivatives such as p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bz-DOTA) and DOTA-NHS-ester.

[0039] Thus, for p-SCN-Bn-DOTA or p-SCN-Bn-TCMC, the complexing agent can be linked to other parts of the compound via a carbon skeleton (C-skeleton).

[0040] In one embodiment, the linker is an octadentate hydroxypyridinone-containing ligand such as 3,2-HOPO. Such ligands typically contain at least one chelating group of the following substituted pyridine structure (I): -17-R,I {wherein R is an optional N-substituent and thus may be absent or may be a hydrocarbon, OH, O-hydrocarbon, SH and S-hydrocarbon group, where any or each hydrocarbon moiety is independently selected from short hydrocarbyl groups such as C1-C8 hydrocarbons including C1-C8 alkyl, alkenyl or alkynyl groups, or may be selected from OH or O-hydrocarbon}, and R may also contain a linker moiety and / or a coupling moiety as shown below. In formula I, the groups R2-R6 may each independently be selected from H, OH, =O, short hydrocarbons (described herein), linker moieties (described herein) and / or coupling moieties (described herein). Usually, at least one of the groups R-R6 will be OH. Usually, at least one of the groups R2-R6 will be =O.

[0041] Typically, at least one of the groups R~R6 will be a linker moiety. Preferably, exactly one of the groups R2~R6 will be =0. Preferably, exactly one of the groups R~R6 will be OH. Preferably, exactly one of the groups R~R6 will be a linker moiety (as described herein). The remaining groups R~R6 may be any of the moieties shown herein, but are preferably H. If the linker moiety or any additional linker, the template or chelating group attached to the linker moiety does not contain a coupling moiety, then one of the groups R~R6 is preferably a coupling moiety (as described herein).

[0042] In a preferred embodiment, one of the groups R~R6 is OH, and one of R2~ is =0, and the OH and =0 groups will be present on adjacent atoms of the ring. Thus, in a preferred embodiment, OH and =0 can be present on atoms 1,2; 2,3; 3,2; 3,4; or 4,3 (numbering from the assumed nitrogen).

[0043] An octadentate ligand having at least one chelating moiety {where the OH and =0 groups are present at the 3 and 2 positions respectively} is highly preferred. The octadentate ligand may have 2, 3 or 4 such chelating groups, where 2 or 4 such groups are particularly preferred.

[0044] In a particular embodiment, the urea-based PSMA targeting complex is bone-accumulating for dual targeting by (1) PSMA cell targeting and (2) targeting of bone metastases associated with bone synthesis by radium cations 224 Ra or 223 in a Ra mixture 212 Pb or 227 labeled with Th.

[0045] Including those described in WO2011098611, US20170319721, Ramdahl et al. (Bioorganic & Medicinal Chemistry Letters Volume 26, Issue 17, 1 September 2016, Pages 4318 - 4321), and Hagemann et al. (Mol Cancer Ther. 2016 Oct;15(10):2422 - 2431. Epub 2016 Aug 17) 227 A complexing agent for Th was conjugated to a urea derivative for PSMA targeting. The complexing agents referred to herein are incorporated herein by reference.

[0046] Accordingly, one embodiment of the present invention is 212 Regarding a PSMA - targeting urea derivative containing a TCMC group such as p - SCN - Bn - TCMC for chelating Pb.

[0047] Another embodiment of the present invention is 227 Regarding a PSMA - targeting urea derivative containing HOPO for chelating Th.

[0048] A further embodiment of the present invention is 212 Pb or 227 Regarding a PSMA - targeting urea derivative containing DOTA such as p - SCN - Bn - TCMC labeled with either Th.

[0049] In a further embodiment, the complexing agent does not complex or substantially 224 does not complex Ra in the drug solution. 224 does not complex Ra.

[0050] In an even further embodiment, the complexing agent complexes with a higher stability constant for Pb than for 224 Ra. 212 complexes with a higher stability constant for Pb than for Ra.

[0051] In one embodiment,[[]] 212 the stability constant of Pb is 224At least 2 times, such as at least 4 times, at least 8 times, or at least 10 times higher affinity for Ra.

[0052] In certain embodiments, the complexing agent is selected from the group consisting of ligand - bound DOTAs such as ligand - bound p - SCN - Bn - DOTA, or ligand - bound TCMCs such as ligand - bound p - SCN - Bn - TCMC.

[0053] The ligand may be an antibody or a polypeptide.

[0054] In a further embodiment, 224 Ra and 212 The amount of Pb is in radioactive equilibrium.

[0055] In an even further embodiment, 212 Pb to 224 The radioactivity ratio (in MBq units) of Pb to Ra is, for example, 0.5 - 2, such as 0.8 - 1.5, such as 0.8 - 1.3, or preferably such as 0.9 - 1.15.

[0056] In the context of this specification, the term "radioactive equilibrium" relates to the ratio in MBq units between two radionuclides that become the same or substantially the same over a long period of time. For example 212 Pb and 224 The term "radioactivity ratio" between Ra and 212 Pb to 224 Ra relates to the ratio in MBq units. Figure 5 shows a table (Table 2) of the change in this radioactivity ratio over time. After 2 days, 212 Pb to 224 It was found that a radioactive equilibrium of 1.1 was established for the radioactivity ratio (7.3 divided by 6.8) between Ra. Therefore, in Figure 5, 212 Pb and 224 It was also found that the radioactive equilibrium between Ra was reached approximately 2 days later.

[0057] In the context of this specification, the terms "complexing agent", "scavenger", "linker", "chelating molecule Z", and "chelator" are used interchangeably. These terms preferably form complexes with Pb in accordance with chelation and with significant strength when measured in a test system, while having no significant effect on radium due to the presence of the complex when measured in that test system. 212 with respect to agents that can form complexes with Pb and, when measured in that test system, do not significantly affect radium due to the presence of the complex.

[0058] Examples of test systems include in vitro biodistribution and cation exchangers or size retention or centrifugal concentration cartridges for chelate-antibody binding of radionuclides in vitro. Alternatively, thin layer chromatography may be used as a test system.

[0059] In the context of this specification, "capture" (or complexation) is defined as at least 50% binding by thin layer chromatography (TLC), centrifugal concentration separation, or biodistribution profile. This means, for example, that for small molecule chelators, 212 less than at least 50% of the blood uptake of Pb. If blood uptake is not a reliable indicator, for antibody-conjugated chelators, it is at least 50% binding by TLC analysis.

[0060] In one embodiment of the present invention, it is at least 60% binding.

[0061] In another embodiment of the present invention, it is at least 70% binding.

[0062] In another embodiment of the present invention, it is at least 80% binding.

[0063] In another embodiment of the present invention, it is at least 85% binding.

[0064] In another embodiment of the present invention, it is at least 90% binding.

[0065] (A single or multiple) compounds may also 212 be able to complex more radionuclides than Pb.

[0066] In one embodiment of the present invention, the compound and / or complex has a concentration of 1 ng / mL to 1 g / mL.

[0067] In another embodiment of the present invention, the compound and / or complex has a concentration of 100 ng to 10 mg / mL.

[0068] The complex can contain 1, 2, 3, 4, 5 or more compounds.

[0069] In one embodiment, the solution has a volume such as 100 μL to 1000 mL, 500 μL to 100 mL, such as 1 mL to 10 mL.

[0070] In one embodiment of the present invention, it is the radioactivity of the solution such as 1 kBq to 1 GBq, 10 kBq to 100 MBq, such as 100 kBq to 10 MBq.

[0071] In another embodiment of the present invention, it is the radioactivity of the solution of 100 kBq to 100 MBq.

[0072] In another embodiment of the present invention, the complexing agent is bound to a compound selected from the group consisting of (a single or multiple) peptide-like urea derivatives having an affinity for PSMA.

[0073] In another embodiment of the present invention, the complexing agent is a chelator TCMC such as p-SCN-Bn-TCMC or DOTA such as p-SCN-Bn-DOTA bound to a compound selected from the group consisting of monoclonal antibodies, polyclonal antibodies, antibody fragments, synthetic proteins, peptides, hormones, hormone derivatives, vitamins or vitamin derivatives.

[0074] For dosing purposes, pure 212 Pb solution may be used. Alternatively, 212In a mixture with Pb 224 For the purpose of dual targeting, the latter may be used, i.e., according to the urea derivative carrier, 224 Ra targets bone metastases, and 212 Pb targets systemic cancer.

[0075] 224 When a solution containing Ra is administered, these are 224 Ra and 212 Pb / 212 Bi until an equilibrium state is reached between them, and can be stored for some time, for example, for more than 1 day, preferably at least 2 days, between 1 - 2 days or 1 - 3 days, etc. This ensures a radioactivity ratio of 0.83 - 1.14 212 From Pb 224 To Ra. This can be achieved by the manufacturer, for example, by simply holding the product for about 1 day or so before shipment.

[0076] Alternatively, 212 Pb may be added to the 224 Ra solution to obtain a specific radionuclide ratio. For example, when the soft tissue whole - body tumor tissue volume is much larger than the skeletal whole - body tumor tissue volume, a pure 212 Pb preparation or a solution with a high 212 Pb to 224 Ra ratio may be used.

[0077] The non - overlapping side - effect characteristics of the cationic radium and α - emitter bound to the PSMA - binding urea derivative make the mixture of 224 Ra cations and 212 Pb - PSMA targeting agents particularly attractive. Because, at least with respect to the skeletal component, two different compounds target lesions independently, so that each compound can be used at a lower dosage to produce anti - tumor activity.

[0078] Maintaining radium as mainly uncomplexed or slightly complexed cations is important as it ensures maximum uptake in bone and bone metastases and also ensures convenient excretion of the products excreted mainly through the intestine.

[0079] As the complexing agent is added to the radium solution, the radioactive daughter nuclide can be made bone- or tumor-accumulating, enhancing the therapeutic effectiveness of the radium solution instead of causing health hazards. However, it must be a complexing agent that does not negatively affect the bone-accumulating property of radium. For example, the TCMC-labeled urea derivative can excrete 212 Pb during the transportation and storage between the manufacturing site and the hospital where the product is administered.

[0080] It is possible to reduce the sensitivity by adding a radiolysis inhibitor, but tumor-targeting peptides and peptide analogs are often more sensitive to radiolysis, so probably they must be supplied in kit form where they are added several hours to a few minutes before the administration of the 224 Ra solution.

[0081] It is known in the art that calixarenes and EDTA can complex radium to some extent and can also complex lead and bismuth. However, in recent studies, we have found a chelator that, when measured by biodistribution measurements in vivo, will complex the longest-lived daughter nuclide 212 Pb quickly and with appropriate stability while leaving radium mainly uncomplexed or only slightly complexed. Selective complexation can be used to give at least lead bone- or tumor-accumulating properties while maintaining the advantageous properties of radium for treating bone diseases such as bone metastases. The 212 Pb complex targeting bone or tumor cells 212 results in the α emitter 212 Bi from the decay of 212Pb is used as an indirect α - ray source for irradiating target cells or tissues. Besides TCMC and DOTA 224 Other potential chelates that may be suitable for Ra daughter nuclide capture include, but are not limited to, phorphyrins, DTPA, and DTPA derivatives, and also carboxyls linked to DOTA.

[0082] Lead - 212 224 is the longest - lived among the progeny from Ra and stands out, and it is a short - lived α - emitter 212 and is a in - vivo generator of Bi, so it is the most important for the complex. 212 When the Pb - chelate is incorporated into bone or tumor cells, 212 Bi may also be retained in the target. In a Ra solution in equilibrium with its progeny, 224 there is 212 more than 10 - fold Pb relative to Bi atoms. Thus, in these solutions 212 the radiation dose produced from Bi atoms is not much, 212 so it is probably not an amount that is toxicologically important compared to the Ra and 224 Bi decay series. 212 The amount of Bi is comparable to the amount of Pb that indirectly produces α - particles in the Ra series, and this has not been a major problem regarding the registration and clinical use of Ra in equilibrium with its progeny. 212 However, if high - level chelation is also required for Bi in the injection solution, since bismuth in aqueous solution tends to be in a state not suitable for chelation, it may be necessary to add a stabilizer such as NaI or HI at least in some cases. 223 for the treatment of bone metastases, the currently approved α - pharmaceuticals, namely, 211 are in equilibrium with their progeny 223 and this has not been a major problem regarding the registration and clinical use of Ra.

[0083] However, for 212 Bi in the injection solution, if high - level chelation is also required, since bismuth in aqueous solution tends to be in a state not suitable for chelation, it may be necessary to add a stabilizer such as NaI or HI at least in some cases.

[0084] For the treatment of bone metastases, the currently approved α - pharmaceuticals, that is, 223When compared to Ra, the novel solutions described herein should provide a product with improved properties for the treatment of skeletal metastases, as in one embodiment they can enable the targeting of daughter radionuclides to circulating cancer cells and, to some extent, also to soft tissue metastases. This should prevent recurrence from the metastatic regrowth of bone cancer originating from CTCs.

[0085] Another aspect is that 223 with respect to Ra 224 the shorter half-life of Ra can actually result in some benefit when the radium is embedded in the bone matrix. Due to the high density of bone salts, the range of alpha particles is strongly reduced in bone compared to soft tissue. Particularly in rapidly mineralizing regions such as osteosarcoma metastases, the embedding process can be significant when using volume-seeking alpha pharmaceuticals.

[0086] Therefore, 224 Ra should improve the tumor dose as it is not, on average, embedded as much at the time of decay.

[0087] 224 Novel 212 diseases for which Pb solutions with and without Ra can be used include, but are not limited to, primary and metastatic cancers, autoimmune diseases, and atherosclerosis. The product can be administered intravenously or locally including intraperitoneally, or in a limb perfusion setting.

[0088] The chelators used in the novel solutions may be acyclic as well as cyclic chelators, cryptands, crown ethers, porphyrins, and cyclic or acyclic polyphosphonates including DOTMP and EDTMP. Also, bisphosphonates (e.g., pamidronate) conjugated to DOTA, TCMC, or analogs may 224 be used as scavengers in Ra solutions.

[0089] Therapeutic 224 in Ra solutions 212The amount of Pb may be moderately to not overly high (i.e., at equilibrium, 224 1.1 times that of Ra), which a person skilled in the art may claim. Correcting for the difference in half-lives, 223 when a person skilled in the art assumes a Ra dosage similar to that used with 224 Ra, the dosage will be approximately 150 kBq per kg of body weight.

[0090] At equilibrium, this corresponds to ( 212 when Pb is chelated quantitatively) a dosage of 11.5 MBq of 212 Pb-antibody conjugate in the 5 liters of blood of a 70 kg patient. The number of circulating tumor cells per ml is generally less than 10 cells, so 212 therefore, there are less than 50,000 tumor cells in total in 5 l of blood. If only one out of 100,000 injected 212 Pb-antibody binding molecules binds to a tumor cell, this corresponds to approximately 127 212 Pb atoms per cell, meaning at least 0.0023 Bq, and it is Pb atoms per cell, meaning at least 0.0023 Bq, and it is 212 reported that an average of 25 cell-bound 212 Pb can kill 90% of a cell population, so it is very destructive.

[0091] Compound Aspects of the present invention relate to a compound X linked to a chelating molecule Z, having the following formula (I):

[0092]

Chemical formula

[0093] {In the formula, W is a PSMA-targeting ligand; A 4 is a divalent linking moiety, ring, or combination thereof containing 1 to 10 carbon atoms in the bond or chain, where at least one carbon atom is optionally substituted with O, -NR 3 -, or -C(O)-; G is C=O, C=S, C-NH2, or C-NR3 and; R 1 is a hydrogen or a carboxylic acid protecting group; R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl; R 11 R 12 R 13 R 14 R 15 and 16 R 17 and 18 R R 19 is selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; m is an integer from 1 to 6; and o is an integer from 0 to 4, where when o is greater than 1, each R 19 is the same or different} or a pharmaceutically acceptable salt thereof.

[0094] Aspects of the invention relate to a complex according to the invention, or a pharmaceutically acceptable salt thereof, wherein A 4 is a bond, (CH2) n -HC(O)-, -(OCH2CH2) n -, -(HCH2CH2) n -, -H(CO)CH2-, -HC(0)CH2(OCH2CH2) n -, or -HC(0)CH2(HCH2CH2) n -; and L is a bond, (CH2) n -(OCH2CH2) n -, (HCH2CH2) n -, or -C(0)(CH2) n -{wherein n is independently 1, 2, or 3}. Aspects of the present invention relate to a complex according to the present invention, or a pharmaceutically acceptable salt thereof, wherein A 4 is a bond, -(OCH2CH2) n -, or -HC(0)CH2(OCH2CH2) n -; and L is a bond, or -(OCH2CH2) n -{wherein n is independently 1 or 2}.

[0095] Aspects of the present invention relate to a complex according to the present invention, or a pharmaceutically acceptable salt thereof, wherein W has the following structure:

[0096]

Chemical formula

[0097] {wherein R 20 and R 21 are each independently an amino acid residue linked via its amino group to an adjacent -C(O)- group}.

[0098] Aspects of the present invention relate to a complex according to the present invention, or a pharmaceutically acceptable salt thereof, wherein W has the following structure:

[0099]

Chemical formula

[0100] {wherein R is hydrogen or a carboxylic acid protecting group}.

[0101] Aspects of the present invention relate to a complex according to the present invention, or a pharmaceutically acceptable salt thereof, and to the following structure:

[0102]

Chemical formula

[0103] {wherein R 17having an aryl or a pharmaceutically acceptable salt thereof.

[0104] Aspects of the invention relate to a complex according to the invention, or a pharmaceutically acceptable salt thereof, wherein the complex is linked / chelated to four Ns, 212 and has a radionuclide such as Pb, of the following PSMA-617:

[0105]

Chemical formula

[0106] as follows.

[0107] Aspects of the invention relate to a complex according to the invention, wherein DOTA units, p-SCN-Bz-DOTA, etc. are replaced by TCMC units such as p-SCN-Bz-TCMC.

[0108] The linker of PSMA-617 may also be covalently linked to a C atom of the backbone instead of the linkage to N as seen in the above figure.

[0109] Thus, the urea derivative may have a backbone C-linkage or N-linkage DOTA or TCMC bond.

[0110] Regarding the backbone-C-linked p-SCN-Bn-DOTA or p-SCN-Bn-TCMC bond, the compound is as follows:

[0111]

Chemical formula

[0112] {wherein Z is as follows:

[0113]

Chemical formula

[0114] (wherein X is -OH or NH2)} is. For p-SCN-Bn-DOTA, X is -OH, and for p-SCN-Bn-TCMC, X is NH2.

[0115] This means that the backbone-C linked p-SCN-Bn-DOTA or p-SCN-Bn-TCMC is as follows:

[0116]

Chemical formula

[0117] {wherein X is -OH or NH2}.

[0118] The backbone-C linked p-SCN-Bn-DOTA is as follows:

[0119]

Chemical formula

[0120] is.

[0121] Therefore, an aspect of the present invention relates to a compound that is p-SCN-Bn-DOTA-PSMA ligand 2.

[0122] The backbone-C linked p-SCN-Bn-TCMC is as follows:

[0123]

Chemical formula

[0124] is.

[0125] Therefore, an aspect of the present invention relates to a compound that is the p-SCN-Bn-TCMA-PSMA ligand 1 or p-SCN-Bn-DOTA-PSMA ligand 2 disclosed above and in the examples.

[0126] (as shown in the examples) The p-SCN-Bn-TCMC-PSMA ligand (ligand 1) and the p-SCN-Bn-DOTA-PSMA ligand (ligand 2) are linked to the rest of the compound via a carbon skeleton (C skeleton), and have an extended linker region containing an isothiocyanatobenzyl linker, and also, in contrast to PSMA-617 which has a shorter linker region, a carbon-substituted chelator that does not contain all four chelator arms is also used, and one of the chelator arms is used as the linker attachment site. These differences cause significantly different biodistributions of the radiolabeled products, and since it reduces kidney exposure compared to PSMA-617, the subsequent examples in this specification show that it is more suitable for targeting 212 Pb to PSMA-expressing tumors.

[0127] In one embodiment of the present invention, the compounds of the present invention such as the p-SCN-Bn-TCMC-PSMA ligand 1 and the p-SCN-Bn-DOTA-PSMA ligand 2 may exist in the form of trifluoroacetate salts.

[0128] CTT1401 and CTT1403 with TCMC or DOTA variants, and derivatives (Choy et al, 2017) can also be used 212 with Pb in the complexes of the present invention.

[0129] In accordance with preparing the PSMA-binding urea derivatives according to the present invention using readily available amino groups or another group suitable for the bond, p-SCN-Bn-TCMC may be bound to the PSMA-binding compound. Subsequent purification may be required before radiolabeling with 224 Ra-containing and Ra-free 212 Pb.

[0130] Accordingly, in one embodiment of the present invention, the linker is p-SCN-Bn-TCMC. One embodiment of the present invention relates to a complex according to the present invention, wherein the linker-chelator is p-SCN-Bn-TCMC. One embodiment of the present invention relates to a complex according to the present invention, wherein the linker is p-SCN-Bn-DOTA. In other words, -p-SCN-Bn is the end portion of the linker region attached to the TCMC or DOTA chelator group via a carbon skeleton.

[0131] Human serum albumin can be used to extend the half-life of drugs. Accordingly, in certain embodiments, according to the present invention 212 The Pb-labeled PSMA-binding urea derivative further comprises a group capable of binding to albumin to extend the circulation half-life of the radiolabeled product.

[0132] A further embodiment of the present invention relates to a complex according to the present invention, wherein according to the present invention 212 The Pb-labeled PSMA-binding urea derivative further comprises human serum albumin that is directly bound to the complex or bound to the complex, for example, through liposomes.

[0133] Pharmaceutical composition Typically, an important element of a pharmaceutical composition is a buffer solution that maintains the chemical integrity of the radioimmunoconjugate to a substantial degree and is physiologically acceptable for injection into a patient.

[0134] In one aspect of the present invention, the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers and / or adjuvants.

[0135] Acceptable pharmaceutical carriers include, but are not limited to, non-toxic buffers, fillers, isotonic solutions, etc. More specifically, the pharmaceutical carrier can be, but is not limited to, standard physiological saline (0.9%), half-strength physiological saline, lactated Ringer's solution, 5% dextrose, 3.3% dextrose / 0.3% physiological saline. The physiologically acceptable carrier can contain a radiolytic stabilizer, such as ascorbic acid, to protect the integrity of the radiopharmaceutical during storage and transportation.

[0136] Aspects of the present invention relate to pharmaceutical compositions comprising a complex, diluent, carrier, surfactant, and / or excipient according to the present invention.

[0137] Aspects of the present invention are single-agent 212 relating to a Pb-labeled ligand. This would be a compound of the present invention complexed using Pb and without using any additional radionuclides such as 212 Ra. 224

[0138] Aspects of the present invention 212 relate to a double-targeting solution containing a Pb-labeled ligand and a cation or weak complexing 224 containing Ra. This would be a compound of the present invention complexed using Pb together with 224 Ra present as 224 Ra. 212

[0139] Aspects of the present invention relate to pharmaceutical compositions comprising a compound and / or complex according to the present invention, further 224 comprising Ra. 224 Ra can be a cation. 224 The addition of Ra, for example, 212 enables double-targeting when present together with Pb.

[0140] Aspects of the present invention relate to pharmaceutical compositions comprising a complex according to the present invention, where the radioactivity is from 100 kBq to 100 MBq per dose.

[0141] Aspects of the invention relate to pharmaceutical compositions comprising a complex according to the invention, where 224 Ra and 212 the amounts of Pb are in a state of radioactive equilibrium.

[0142] Aspects of the invention relate to pharmaceutical compositions comprising a complex according to the invention, where 212 the radioactivity ratio (MBq) between Pb and 224 Ra is 0.5 - 2, such as 0.8 - 1.5, or such as 0.8 - 1.3, or preferably such as 0.9 - 1.15.

[0143] Kit The solution must be prepared physiologically suitable for injection, either at an intensive manufacturing site or, generally, by a kit system consisting of 2 - 4 vials, becoming physiologically suitable for injection upon combination of the kit vials. Aspects of the invention relate to a kit comprising a first vial containing a radioactive pharmaceutical composition according to the invention and a second vial containing a neutralizing solution for adjusting the pH and / or isotonicity of the radioactive pharmaceutical composition prior to administration to a patient.

[0144] For example, with respect to monoclonal antibodies, it is usually desirable to maintain the self - dose of alpha particles that results in a radioactive pharmaceutical solution of less than 0.5 kGy in order to avoid reduced binding properties due to radiolysis. Thus, several hours to 10 minutes before injection, a kit system in which a ligand bound to a chelator is 224 added to a solution of Ra (including daughter nuclides) is recommended for concentrated solutions intended for remote shipment and depends on the radiolysis resistance of the radioactive ligand produced.

[0145] Aspects of the invention are: 224A first vial containing a Ra solution; a second vial containing a complexing agent selected from the group consisting of p-SCN-Bn-DOTA-PSMA ligand, p-SCN-Bn-TCMC-PSMA ligand, acyclic chelator, cyclic chelator, cryptand, crown ether, porphyrin or cyclic or acyclic polyphosphonate, DOTMP, EDTMP, bisphosphonate derivative, DOTA, DOTA derivative, pamidronate bound to DOTA, TCMC, TCMC derivative, pamidronate bound to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, wherein the complexing agent can complex the daughter nuclide of 212 Pb or the like 224 Ra and wherein the complexing agent does not complex Ra in the drug solution; and optionally, instructions for mixing the first vial and the second vial to thereby form a pharmaceutical composition that can be administered immediately to a patient 1 minute to 12 hours after mixing. 224 A kit comprising.

[0146] In one embodiment of the present invention, the kit is for use as a medicament. In a specific embodiment, the term " 224 Ra solution" should be understood to mean that 224 Ra is advantageous in solution and is not linked to a surface such as, for example, a resin. In certain embodiments, the kit includes a third vial containing a neutralizing solution for adjusting the pH and / or isotonicity of the radiopharmaceutical solution prior to administration to a patient.

[0147] In a further preferred embodiment, 224 the amount of Ra and 212 Pb in the first vial is in a state of radioactive equilibrium.

[0148] In yet another preferred embodiment, the 212 Pb to 224The radioactivity ratio (MBq) between Ra is 0.5 to 2, such as 0.8 to 1.5, such as 0.8 to 1.3, or 0.9 to 1.15.

[0149] In yet another embodiment, the first vial has a radioactivity within the range of 100 kBq to 100 MBq.

[0150] In one embodiment of the present invention, the chelator-binding ligand is added to the Ra (including daughter nuclides) solution 30 minutes to 5 hours before injection, such as 1 to 3 hours before injection. 224 Ra (including daughter nuclides) solution.

[0151] In one embodiment of the present invention, the chelator-binding ligand is added to the Ra (including daughter nuclides) solution 1 minute to 20 minutes before injection. 224 Ra (including daughter nuclides) solution.

[0152] In one embodiment of the present invention, the chelator-binding ligand is added to the Ra (including daughter nuclides) solution 1 minute to 10 minutes before injection. 224 Ra (including daughter nuclides) solution.

[0153] A kit with a chelate-labeled protein or peptide in one vial and an Ra solution in another vial, such that the two contents are mixed 1 minute to 12 hours before administration, also forms part of the present invention. In certain embodiments, the mixing is carried out several hours (such as 5 hours) to 30 minutes before administration to the patient so that Pb and / or 224 Bi binds to the chelate. 212 Pb and / or 212 Bi binds.

[0154] In one embodiment of the present invention, the two contents are mixed 30 minutes to 1 hour before injection.

[0155] In one embodiment of the present invention, the two contents are mixed 1 minute to 20 minutes before injection.

[0156] In an embodiment of the present invention, the two contents are mixed 1 minute to 10 minutes before injection.

[0157] Optionally, a third vial containing a liquid used for dilution and isotonicity adjustment before administration of the radiopharmaceutical solution may be used. If necessary, this third vial 212 may contain EDTMP and be capable of chelating Bi.

[0158] Medical applications Aspects of the invention relate to a radiopharmaceutical composition according to the invention for use as a medicament.

[0159] In one embodiment of the invention, the disease is cancer.

[0160] Aspects of the invention relate to a radiopharmaceutical composition according to the invention for use in the treatment of soft tissue diseases and / or bone diseases. The treatment is specific for PSMA-expressing diseases including soft tissue and bone diseases.

[0161] In one embodiment of the invention, the bone disease is selected from the group consisting of cancer with soft tissue metastasis and / or skeletal metastasis to the breast, prostate, kidney, lung, bone, or multiple myeloma.

[0162] In one embodiment of the invention, the cancer is prostate cancer. The cancer may also be breast cancer. The cancer may also be kidney cancer. The cancer may also be lung cancer. The cancer may also be bone cancer. The cancer may also be multiple myeloma. The cancer may be a metastasis from these types of cancer.

[0163] In one embodiment of the invention, the solution is administered at a dose in the range of 50 - 150 kBq per kg of body weight, for example, 50 - 100 kBq per kg of body weight.

[0164] Aspects of the invention relate to a method for treating a malignant or non-malignant disease by administering a radiopharmaceutical composition according to the invention to an individual in need thereof.

[0165] This is purified 212It may be used together with a Pb-labeled ligand, or, correspondingly, for cells expressing the PSMA antigen related to the progression of metastatic prostate cancer, 224 Ra functions as a skeletal therapy, and 212 It may be used in the state of a dual-targeting solution in which a Pb urea derivative functions as a systemic therapy.

[0166] Therefore, the complexes and solutions of the present invention can be used for the treatment of metastatic prostate cancer.

[0167] Another embodiment related to the present invention is, correspondingly, 212 Pb is complexed by the urea-based PSMA targeting agent disclosed herein, and the cation 224 Ra relates to a pharmaceutical solution having dual-targeting properties that targets bone metastases by calcium-like bone uptake.

[0168] Method for preparation Aspects of the present invention relate to a method for providing a radiopharmaceutical composition according to the present invention, the method being: a first solution, wherein 224 Ra and 212 Prepare a first solution in which the amounts of Pb are in a state of radioactive equilibrium; a second solution containing a complexing agent selected from the group consisting of p-SCN-Bn-DOTA-PSMA ligand, p-SCN-Bn-TCMC-PSMA ligand, acyclic chelator, cyclic chelator, cryptand, crown ether, porphyrin or cyclic or acyclic polyphosphonate, DOTMP, EDTMP, bisphosphonate, DOTA, DOTA derivative, pamidronate bound to DOTA, TCMC, TCMC derivative, pamidronate bound to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, wherein the complexing agent is 212 Capable of complexing daughter nuclides of 224 Ra such as Pb, and wherein the complexing agent is 224Prepare a second solution that does not complex Ra; and mix the first composition and the second composition, thereby providing a pharmaceutical composition according to the present invention, and provide a method comprising this.

[0169] PSMA derivative PSMA (prostate-specific cancer antigen, PSM, FGCP, FOLH, GCP2, mGCP, GCPII, NAALAD1, NAALA peptidase, FOLH1, glutamate carboxypeptidase 2, glutamate carboxypeptidase II, membrane glutamate carboxypeptidase, N-acetylated-α-linked acidic dipeptidase I, pteroylpoly-γ-glutamate carboxypeptidase, holylpoly-γ-glutamate carboxypeptidase, folate hydrolase 1, prostate-specific membrane antigen, also called cell growth inhibitory protein 27) is a prostate epithelial cell membrane antigen of type II transmembrane protein, and consists of a short NH2-terminal cytoplasmic domain, a hydrophobic transmembrane region, and a large extracellular domain. PSMA is an enzyme encoded by the FOLH1 (folate hydrolase 1) gene in humans. Human GCPII contains 750 amino acids and has a weight of about 84 kDa.

[0170] The expression of PSMA is limited to some healthy tissues such as lacrimal and salivary glands, proximal renal tubules, epididymis, ovaries, the luminal side of the ileum, and astrocytes in the central nervous system (CNS); healthy prostate expresses relatively little PSMA, and it is confined within the apical epithelium of the secretory ducts. In these non-malignant tissues, the uptake of PSMA-targeted probes can be limited by the intact blood-brain barrier, the healthy proximal luminal small intestine, and the incomplete cytoplasmic expression of PSMA in the normal prostate. PSMA is most associated with the fact that it is expressed in most primary prostate tumors, regardless of high androgen independence, metastatic disease, or androgen status.

[0171] Small molecule PSMA inhibitors are zinc-binding compounds and can be classified into three types: 1) phosphonate compounds, phosphate compounds, and phosphoramidate compounds; 2) thiols; and 3) ureas. Urea derivatives seem to have particularly interesting properties as carriers for radionuclides for diagnosis and treatment.

[0172] The latest invention relates to 212 the use of Pb-urea derivatives. It may be combined with androgen deprivation therapy to enhance PSMA expression for better uptake of radioligands (Bakht et al., 2017).

[0173] Radioactivity level 212 When a Pb-labeled urea derivative is used alone, the radioactivity level will typically be from 1 MBq to 500 MBq per patient, more typically from 10 to 100 MBq per patient.

[0174] 212 In equilibrium with Pb 224 When Ra is complexed with a PSMA-binding urea derivative, the dosage will typically be from 0.1 MBq to 100 MBq per patient, more typically from 1 to 20 MBq per patient. In a particular embodiment, 227 the PSMA-targeted complex-based urea derivative according to the invention labeled with Th is osteotropic for dual targeting 223 yielding Ra.

[0175] 227 Th may be pure or in various amounts of 223 Ra, for example, 227 10%, 50%, 100%, or 250% of Ra compared to Th 223 and may contain Ra.

[0176] General rule It should be understood that any and all features and / or aspects previously discussed in connection with the compounds according to the invention are applicable by analogy to the methods described herein.

[0177] The following drawings and examples are provided below to illustrate the present invention. Since they are intended to be useful for explanation, they should not be construed as limitations in any form.

Example

[0178] In the following examples, the xenograft model used was typically a tumor model having an intermediate level of PSMA-ligand uptake of 10 - 15% of the dose injected per gram (%ID / g) in mouse xenografts with Lu-PSMA-617, in contrast to the PC3 PIP model used by other researchers which generally shows 30 - 40% ID / g uptake of mouse xenografts. 177 It is a tumor model with an intermediate level of PSMA-ligand uptake of 10 - 15% of the dose injected per gram (%ID / g) in mouse xenografts with Lu-PSMA-617.

[0179] Example 1. Novel PSMA-binding chelator ligand compared with PSMA-617 Background: There are several carrier molecules for the radioligand targeting of prostate-specific membrane antigen (PSMA). Lutetium-177-labeled PSMA-617 ( 177 Lu-PSMA-617) is a compound in the most advanced clinical development stage for use in radionuclide therapy. This molecule operates in a suitable manner and 177 Lu and 225 results in a relevant tumor-to-normal tissue ratio for longer-lived (i.e., half-lives of several days) radionuclides including Ac, but shows high uptake in the kidneys at early time points (typically a few hours after injection). 212For shorter-lived radionuclides such as Pb (half-life of 10.6 hours), initial kidney uptake means potential toxicity issues. Therefore, it is advantageous to use PSMA ligands with less kidney uptake, which does not reduce tumor uptake. The PSMA ligand molecule is composed of (1) a PSMA binding region, (2) a linker region, and (3) a chelator, and accordingly, the linker region connects (1) and (3). The linker region is also used to adjust properties such as molecular size and polarity to affect in vivo distribution characteristics. The PSMA binding regions (motifs) used in PSMA-11 and PSMA I&T, as well as 131 I and 211 including the At-labeled PSMA-binding ligand, the PSMA binding regions (motifs) used in PSMA-617 are structures seen in several molecules of this class developed by several different inventors and researchers.

[0180] As described above, the p-SCN-Bn-TCMC-PSMA ligand has an extended linker region containing an isothiocyanatobenzyl linker and also uses a carbon-substituted chelator that does not include all four chelator arms, in contrast to PSMA-617 which has a shorter linker region, and uses one of the chelator arms as a linker attachment. These differences cause significantly different biodistributions of the radiolabeled products, and since it reduces kidney exposure compared to PSMA-617, 212 Regarding the targeting of Pb, the following examples in this specification show that p-SCN-Bn-TCMC-PSMA ligand 1 is more suitable.

[0181] Materials and Methods: PSMA ligand precursors for radiolabeling were synthesized by a commercial synthetic manufacturing facility that is a subcontractor.

[0182] PSMA-617 was synthesized according to the procedures described in the literature. The p-SCN-Bn-TCMC precursor was synthesized according to the procedures described in the literature. In the final synthesis step, the TCMC-PSMA ligand was synthesized by conjugating p-SCN-Bn-TCMC to the amino group of the PSMA-binding ligand intermediate. Both PSMA-617 and the TCMC-Bn-PSMA ligand 1 were purified by HPLC to >98% purity, dried, and stored as trifluoroacetate salts. The structure and molecular weight were determined by 1 1H-NMR and MS analysis.

[0183] The trifluoroacetate salt of the p-SCN-Bn-TCMC-PSMA ligand 1 has the chemical formula C 65 H 86 F 12 N 14 O 21 S and has a molecular weight of 1659.52 g / mol.

[0184] Chemical name (IUPAC): (((1S)-1-carboxy-5-((2S)-3-(naphthalen-2-yl)-2-((1r,4S)-4-((3-(4-((1,4,7,10-tetrakis(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)methyl)cyclohexane-1-carboxamide)propanamide)pentyl)carbamoyl)-L-glutamic acid; trifluoroacetic acid (1:4)

[0185] The trifluoroacetate salt of PSMA-617 has the chemical formula C 57 H 75 F 12 N9O 24 and has a molecular weight of 1498.25 g / mol.

[0186]

Chemical Structure

[0187] The trifluoroacetate salt of the p-SCN-Bn-TCMC-PSMA ligand 1

[0188]

Chem.

[0189] Trifluoroacetate salt of PSMA-617

[0190] As described above, the p-SCN-Bn-TCMC-PSMA ligand has an extended linker region containing a benzyl linker and also uses a carbon-substituted chelator that does not contain all four chelator arms, in contrast to PSMA-617 which has a shorter linker region, and uses one of the chelator arms as the linker attachment site. These chemical differences cause significantly different biodistributions of the radiolabeled products and, since it reduces kidney exposure compared to PSMA-617, it is more suitable for targeting 212 Pb, as shown in the following examples, makes it more suitable for targeting.

[0191] In conclusion, novel molecules are described that have the same PSMA binding region as PSMA-617 but different linker regions and different chelation properties.

[0192] Example 2. 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, 177 Carbon-substituted pSCN-Bn-DOTA-PSMA ligand 2 for radiolabeling methods using Lu, etc. Compared to PSMA-617, the ligand has a larger size and has both a p-SCN-Bn-DOTA group, i.e., a different linker region and a different DOTA-chelator version that does not contain all four chelator arms for chelating radionuclides compared to PSMA-617.

[0193] p-SCN-Bn-DOTA-PSMA ligand 2 is a DOTA analogue of the p-SCN-Bn-TCMC-PSMA ligand 1 described in Example 1 and has a carbon linker to a chelator backbone that does not contain the remaining chelator groups for interacting with the radiolabel, and thus is expected to improve the stability of the chelate after radiolabeling compared to the radionuclide-labeled PSMA-617.

[0194] Due to the addition of the lipophilic benzyl unit within the linker region and the large size of the molecule, lower renal uptake is expected compared to PSMA-617. This molecule can be synthesized in the same manner as the p-SCN-Bn-TCMC-PSMA ligand 1, following the use of a DOTA-based precursor instead of a TCMC-based precursor in the final step of the synthesis.

[0195]

Chemical formula

[0196] Trifluoroacetate salt of p-SCN-Bn-DOTA-PSMA ligand 2

[0197] The trifluoroacetate salt of p-SCN-Bn-DOTA-PSMA ligand 2 has the chemical formula C 65 H 82 F 12 N 10 O 25 S and has a molecular weight of 1663.46 g / mol.

[0198] Due to the carbon that replaces the attachment part to DOTA, this molecule has very favorable properties for radiolabeling with radionuclides suitable for positron emission tomography (PET) such as 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, and moreover, 68 Ga.

[0199] Accordingly, a novel PSMA-binding molecule, p-SCN-Bn-DOTA-PSMA ligand 2, suitable for use in radioactive ligand imaging and therapy is described.

[0200] In conclusion, a carbon-substituted pSCN-Bn-DOTA-PSMA ligand 2 is described that has different properties with respect to size and chelation characteristics compared to PSMA-617.

[0201] Example 3. Radionuclides Tested Lutetium-177 was purchased as LuCl3, dissolved in dilute HCl, and ready to use. 177 Lead-212 was obtained from a Ra-based solution. 224 Radon-224 was prepared from Th bound to an actinide resin (Eichrom Technologies, LLC) by eluting a column containing the actinide resin with 1 M HCl. The eluate was purified by a second Ac-resin column and the eluate was evaporated to dryness using a gentle stream of nitrogen gas with a gas inlet and outlet cap placed on a heating block at about 110 °C in a distillation vial. When the solvent was gone from the distillation vial, usually 200 - 400 μl of 0.1 M HCl was added to dissolve the residue. 228 228 228 228

[0202] Example 4. Radioactive Labeling of PSMA-Binding Ligands Typically, 177 Lu and 224 Ra / 212The Pb solution was adjusted to the desired volume and pH 5 - 6 with HCl accompanied by 10% 5M ammonium acetate. The PSMA-binding ligand was dissolved in 0.1M HCl accompanied by 0.5M ammonium acetate up to a concentration of 1 mg / ml. Usually, a concentration of 20 micrograms per 1 ml of the radioactive solution was used. The reaction mixture was incubated on a shaker for 15 - 30 minutes and usually, the labeling was evaluated by thin layer chromatography. The lead-212 labeling was carried out at room temperature or 37 °C using p-SCN-Bn-TCMC-PSMA ligand 1, while the 177 Lu-labeling and 212 Pb-labeling of PSMA-617 was carried out at 90 °C. Typical radiochemical labeling yields were in the range of 90 - 100% for the compounds and radionuclides tested and those providing a concentration of more than 1 μg per 20 μl were used. In conclusion, the radiolabeling of both ligands was successful. The novel p-SCN-Bn-TCMC-PSMA ligand 1 had to be labeled at high temperature 177 in contrast to 212 Lu-PSMA-617 and could be radiolabeled at room temperature using

[0203] Example 5: Thin layer chromatography analysis Thin layer chromatography (TLC) was performed using chromatography strips (Model #150-772, Biodex Medical Systems Inc, Shirley, NY, USA). A formulation buffer (FB) consisting of 7.5% human serum albumin and 5 mM EDTA in DPBS, adjusted to approximately pH 7 with NaOH, was mixed with the antibody conjugate in a 2:1 ratio at least 5 minutes prior to application to the strip for measuring free radionuclides. A small beaker containing approximately 0.5 ml of 0.9% NaCl was used to place the sample spotted strips. Generally, 1 - 4 μl of the sample was added to the strip at approximately 10% above the bottom of the strip. After the solvent front had migrated approximately 20% from the top of the strip, the strip was cut in half and each half was placed into a 5 ml test tube for counting. In this system, the radiolabeled ligand remains in the bottom half while the radionuclide complexed with EDTA migrates to the top. 212 Both cations of 177 Pb and

[0204]

[0205] As a conclusion, a TLC system is used that enables rapid measurement of radiolabel yields to effectively distinguish between radioligands and free radionuclides. Example 6. 224 Separation of 212 Pb from The radiolabeled ligand can accordingly be 224 used as a component of a 224 Ra dual - targeted solution where 224 Ra targets bone diseases and the ligand targets systemic metastatic diseases. Alternatively, 212 a 212 Ra - generating solution can be used to produce a 224 Pb - labeled ligand by in situ labeling, i.e., 212To the Pb solution, 2 μl (1 μg / μl) of p-SCN-Bn-TCMC-PSMA ligand 1 or PSMA-617 was added and reacted as described to 212 create a Pb-labeled ligand. 212 To purify the Pb-PSMA ligand, the product was added to approximately 10 μl of formulation buffer consisting of 7% bovine serum albumin, 10 mM EDTA, and 10 mg / ml ascorbic acid. The reaction mixture was then added to a Sephadex G-10 column PD MiniTrap G-10 (GE Healthcare Life Sciences) and eluted with 0.9% NaCl. 212 The eluate containing Pb, typically the fractions eluted after application of 0.7 - 1.5 ml, was collected, analyzed by gamma counter and TLC, and a radioligand binding assay was performed. The product purification procedure had a high radiochemical yield (usually >80%) and typically 212 reached less than 0.4% compared to the Pb-labeled ligand 224 and had a high radiochemical purity of Ra.

[0206] In conclusion, p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 224 in the presence of Ra 212 can be radiolabeled with Pb and an integrated 224 dual-targeting solution for targeting bone metastases with Ra and 212 targeting systemic tumor cells with the Pb-labeled PSMA ligand was produced.

[0207] Using a Sephadex G-10 gel filtration column, both 212 Pb-labeled PSMA ligands tested had a recovery of over 80% and less than 0.4% 224 leakage of Ra in solution 224 and were separated from Ra to produce highly purified 212 Pb-labeled PSMA radioligands for independent PSMA targeting.

[0208] Example 7.212 In vitro Stability Test of Pb-Labeled Ligand 224 Ra / 212 The radiolabeled ligand in the Ra / Pb solution was mixed 1:1 with PBS or bovine serum albumin and incubated at 37 °C for up to 48 hours. TLC analysis was performed at 1 hour, 4 hours, 24 hours, and 48 hours of incubation.

[0209] The data are shown in Table 1, and 212 Pb 224 after it is produced from Ra, continuously reacts with the ligand and shows that even after 48 hours, a high percentage of radiochemical purity is maintained. Therefore, the PSMA ligand is suitable for in situ production of radioligands for intensive production and shipment to end-users 224 corresponding to the use of Ra solution.

[0210] Table 1. 212 Radiochemical Purity of Pb-TCMC-PSMA Ligand 1 and 212 Pb-PSMA-617 in PBS and FBS

[0211]

Table 1

[0212] Conclusion: The data 212 show that p-SCN-Bn-TCMC-PSMA Ligand 1 and PSMA-617 labeled with Pb are stable in Ra solution over a long period of time and show that they are suitable for intensive production of immediately available products and shipment to end-users. Such solutions may be used for the treatment of cancer. 224

[0213] Example 8. 212 Prostate Cancer Cell Binding of p-SCN-Bn-TCMC-PSMA Ligand 1 and PSMA-617 Labeled with Pb ​The cell binding rate was measured by adding approximately 1 ng of a radioactive ligand to 0.2 ml of C4-2 cells (5×10 7 cells per ml) in a 5-ml test tube, incubating for 1 hour before measuring the applied radioactivity, washing the cells three times with 0.5 ml of 0.5% bovine serum albumin in DPBS, and then recounting the washed cell pellet. From multiple experiments, it was found that the % binding was in the range of 40 - 53% after subtracting non-specific binding. Non-specific binding was measured by blocking the cells with an excess of 10 μg / ml of unlabeled ligand before adding the radioactive ligand. No significant difference in cell binding was seen between the radioactive labeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617. As a conclusion, the radioactive ligands of radioactive labeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 have similar cell binding characteristics in vitro, and it was shown that p-SCN-Bn-TCMC-PSMA ligand 1 has the ability to bind to the relevant antigen.

[0214] Example 9. Radiolytic stability of p-SCN-Bn-TCMC-PSMA ligand 1 evaluated by radioactive ligand binding ability and TLC analysis using prostate cancer cells Table 2 shows the cell binding rate measured by adding approximately 1 ng of a radioactive ligand to 0.2 ml of C4-2 cells (5×10 7 cells per ml) in a 5-ml test tube, incubating for 1 hour before measuring the applied radioactivity, washing the cells three times with 0.5 ml of 0.5% bovine serum albumin in DPBS, and then recounting the washed cell pellet. The initial radioactivity of the solution was approximately 5 MBq / ml, and it resulted in absorbed radiation doses of approximately 1.8 Gy after 24 hours and 3.3 Gy after 48 hours to the solution. The data (Table 2) show a slight decrease at the longest exposure time, but generally, relatively strong radiolytic resistance of the ligand was observed, and it 224 is applicable regardless of the presence or absence of 224 Ra removal for the production of the Ra-based generator solution in a concentrated form and shipment to the end user.

[0215] Table 2 224 When retained in Ra solution 212 Binding ability of Pb-p-SCN-Bn-TCMC-PSMA ligand 1

[0216]

Table 2

[0217] Conclusion: The data show that 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 is stable in Ra solution over a long period of time and that since it is produced from Ra 224 the PSMA ligand can complex Pb, such that such a solution may be used for the treatment of cancer, provided that the absorbed radiation dose is maintained below about 2 kGy 224 and is produced from Ra 212 and the PSMA ligand can complex Pb, such that such a solution may be used for the treatment of cancer, provided that the absorbed radiation dose is maintained below about 2 kGy

[0218] Example 10. Biodistribution of radiolabeled ligands in nude mice bearing C4-2 PSMA-positive xenografts 212 Pb and 177 p-SCN-Bn-TCMC-PSMA ligand 1 labeled with Lu and PSMA-617 224 Ra / 212 The biodistribution of the Pb solution was compared by intravenous injection at various time points after injection in nude mice bearing C4-2 xenografts. Each group usually consisted of three mice 212 Pb labeling exceeded 92% for the product

[0219] 177 Lu vs 212 Since very high levels of radionuclide were used with respect to Pb compared to Lu 177 the molar concentration of the ligand was significantly lower for Lu-PSMA-617. About 16 kBq of 224 Ra / 212Pb, i.e., approximately 0.2 nmol of ligand per mouse, was injected into each animal. The animals were paralyzed by cervical dislocation and then sacrificed, after which they were dissected and tissue samples, blood samples, and urine samples were collected. The weight of the samples was measured and counted using a gamma counter.

[0220] Example 11. In mice, 212 Comparison of tumor binding and kidney uptake of p-SCN-Bn-TCMC-PSMA ligand 1 labeled with Pb and PSMA-617 212 p-SCN-Bn-TCMC-PSMA ligand 1 labeled with Pb and accompanied by PSMA-617 224 Ra / 212 The biodistribution of the Pb solution was compared after intravenous injection in nude mice bearing C4-2 xenografts after injection. Three mice per group. 212 Pb labeling exceeded 92% for both products. The molar concentration of the ligand was the same for both products, i.e., 12.5 nmol per 1 MBq. Approximately 16 kBq of 224 Ra / 212 Pb, i.e., approximately 0.2 nmol of ligand per mouse, was injected into each animal. The animals were paralyzed by cervical dislocation and then sacrificed, after which they were dissected and tissue samples, blood samples, and urine samples were collected. The weight of the samples was measured and counted using a gamma counter. Results: 4 hours after injection, 212 The ratio of Pb-p-SCN-Bn-TCMC-PSMA ligand 1 to PSMA-617 was as follows: tumor 1.35; kidney 0.20; blood 1.21; liver 2.67; spleen 0.71. It was confirmed by counting samples after 3 days of storage that the 224 Ra biodistribution was not significantly altered by any of the PSMA-directed ligands. Discussion: 212 The Pb p-SCN-Bn-TCMC-PSMA ligand 1 212Compared with Pb-PSMA-617, it shows a significantly different biodistribution, and moreover, what is particularly noteworthy is that it is very low, and the preferred ratio of uptake in the kidneys as kidneys is expected to be the main dose-limiting factor for normal tissues related to PSMA radioligand therapy using relatively short-lived α emitters (Figure 1). In conclusion, 212 The Pb-p-SCN-Bn-TCMC-PSMA ligand 1, compared with PSMA-617, 212 shows a very promising biodistribution at the early time points, which is important when using shorter-lived radionuclides such as Pb.

[0221] Example 12. In mice, 212 the tumor binding and kidney uptake of Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and 177 Lu-labeled PSMA-617 were compared. Methods: 212 The tumor and kidney uptake of Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and 177 Lu-labeled PSMA-617 were compared at 1 hour and 4 hours after administration of the product by intravenous injection into nude mice bearing C4-2 xenografts as described in Example 9. Results: The tumors and kidneys were the tissues that took up the most radioactivity. As an example, 212 the tumor and kidney uptake of Pb-p-SCN-Bn-TCMC-PSMA were 13.9 and 8.1 percent injected dose per gram (%ID / g) of the injected dose, respectively, at 4 hours after injection. 177 The tumor and kidney uptake of Lu-PSMA-617 were 13.6 and 17.4%ID / g, respectively, 4 hours after injection. It is worth noting that the molar amount of the injected ligand was very small in PSMA-617, and it is known to reduce kidney uptake, but still, the new 212 Pb-labeled compound showed less kidney uptake. The tumor-to-kidney ratio at the 4-hour time point was as follows: 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1, 1.7;177 Lu-PSMA-617, 0.8.

[0222] The average tumor-to-kidney ratio determined at 1 hour after administration was 212 0.40 for Pb-p-SCN-Bn-TCMC-PSMA ligand 1, and 177 0.17 for Lu-PSMA-617. As a conclusion, 212 Despite the high molar ligand concentration regarding Pb-p-SCN-Bn-TCMC-PSMA ligand 1, it 177 showed a better tumor-to-kidney ratio compared to Lu-PSMA-617, and it 212 indicated that it is very suitable for Pb-based α-emitting radioligand therapy.

[0223] Example 13. Biodistribution of a 212 single-targeted solution containing Pb-p-SCN-Bn-TCMC-PSMA ligand 1 in mice bearing PSMA-positive xenografts For the reaction with p-SCN-Bn-TCMC-PSMA ligand 1 as described 212 Pb / 224 Ra solution was used to purify 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 using a Sephadex G-10 gel filtration column, and approximately 30 kBq and 300 ng of the purified radioligand product were injected per animal unit. The data are shown in Table 3. As described above, renal radioactivity is reduced relatively rapidly, while tumor uptake shows good retention. The tumor-to-tissue ratio (Table 4) 212 indicates the suitability for radioligands targeted with Pb.

[0224] As a conclusion, 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 shows relevant targeting properties for use in radioligand therapy for PSMA-expressing prostate cancer.

[0225] Table 3. At various time points after injection 212Biodistribution of Pb-p-SCN-Bn-TCMC-PSMA Ligand 1

[0226] [Table 3]

[0227] Table 4. Tumor-to-tissue ratios of 212 Pb-p-SCN-Bn-TCMC-PSMA Ligand 1 at various time points

[0228] [Table 4]

[0229] Example 14. Dosage Since the radiation energy produced for the two radionuclides consists mainly of α particles, only α particles were considered in the following estimates.

[0230] 212 Pb and its short-lived daughters 212 produce an average of 7.8 MeV of α-ray emission per atom of Pb. 212 The half-life of Pb is 10.6 hours. 213 Bi and its short-lived daughters 213 produce an average of 8.4 MeV of α energy per atom of Bi. 213 The half-life of Bi is 46 minutes. It was considered to be an equivalent dose to 5 Sv / Gy of α particles. Therefore, 1 Bq of 212 Pb produces an equivalent α-ray dose of 1×(10.6×60 / 46)×7.8 / 8.4 = 12.6 Bq of 213 Bi when it completely decays.

[0231] The salivary gland, kidney, and red bone marrow were reported to be the dose-limiting tissues for 213 Bi and 225 Ac complexed to PSMA-617 (Kratochwil, et al, 2018). Based on the imaging of PSMA-617 labeled with a radionuclide suitable for positron emission tomography detection, in tumors, 90% of 212 reaches 70% of the 213 Bi atoms with respect to

[0232] 213 It is considered to be 70% of all tissues with Bi-PSMA-617. 212 Regarding Pb-PSMA-617 uptake, it is considered that 50% decays in the salivary glands, 30% in the kidneys, and 20% in the bone marrow.

[0233] The energy per 1 Bq and 212 Pb- and 213 According to the correction of the relative decay rate of Bi-labeled PSMA-617, 212 the dose assessment of Pb-PSMA-617 is 213 presented in Table 5 together with the previously published data for Bi- and 225 Ac-labeled PSMA-617. Similarly, 212 using the mouse data comparison of Pb-p-SCN-Bn-TCMC-PSMA ligand 1 and 212 Pb-PSMA-617 and assuming a similar tissue uptake rate in humans, 212 the dose estimate of Pb-p-SCN-Bn-TCMC-PSMA ligand 1 is presented in Table 5.

[0234] Table 5. Dose assessment assuming similar stability and affinity of similar products regardless of radionuclide

[0235]

Table 5

[0236] 225 Ac- and 213Both Bi-labeled PSMA-617 have been reported to be clinically used and shown potent antitumor radioactivity. Based on the estimates of this example, 212 The Pb-labeled urea-based PSMA inhibitor is shown to be a very promising therapeutic tool for PSMA-expressing cancers.

[0237] Example 15. Dual targeting 224 The Ra cation and 212 Dose estimate of the Pb-labeled PSMA-targeted urea derivative 212 In equilibrium with the Pb-labeled PSMA-binding urea derivative 224 Use Ra. For a dose of 150 kBq of 224 Ra, the total radioactivity administered is 10.5 MBq in a 70 kg human. Using the published dosimetry for the Ra cation in prostate cancer patients and 223 correcting for the half-life difference between 224 Ra and 223 Ra, assuming the same biodistribution, and considering the different residence times in various tissues, 224 it was found that Ra would result in 0.006 Gy to the kidneys, 0.029 Gy to the salivary glands, and 0.26 Gy to the red bone marrow per 1 MBq administered, and for the tumor, 5 times the red bone marrow uptake, i.e., 1.3 Gy.

[0238] Since an equivalent dose of 5 Sv / Gy is assumed for the α-particle dose, in Table 6, the data are replaced with Sv per injected dose (10.5 MBq / patient).

[0239] Table 6. 224 The Ra cation + 212 Pb-labeled PSMA-binding urea derivative * Dose evaluation

[0240]

Table 6

[0241] Example 15. 227Dose Estimation of Th-Labeled PSMA Binding Urea Derivatives In this example, 177 Lu is considered to be labeled with the p-SCN-Bn-DOTA-PSMA ligand 2 or the HOPO-derived version of this molecule. In this estimate, in patients 223 the test of Ra and in patients suffering from prostate cancer 225 is based on the adaptation of data from the test of Ac-PSMA-617 (Chittenden et al., 2015, Kratochwil et al, 2017, 2018).

[0242] It is considered that the equivalent dose is 5 Sv per 1 Gy for alpha particle radiation.

[0243] produced in tissue 223 Ra is considered to decay locally. 227 produced from the systemic circulation of Th 223 40% of the Ra produced is considered to be retained within the skeleton. Only the alpha particle dose accounts for more than 95% of the total radiation energy produced by this component.

[0244] In tissues (salivary gland, kidney and tumor) with a longer residence time for the radiolabeled PSMA urea derivative, 227 the cumulative radioactivity of Ra generated from Th 223 is considered to be 20% of Th and 5% in the red bone marrow. In various tissues 227 the 20% and 5% of radium generated from Th are assumed to be in equilibrium with the alpha radioactive progeny radionuclides, and thus each radium decay produces substantially 26.4 MeV of alpha ray emission, whereas 227 Th produces the same 5.9 MeV alpha. 227 225

[0245] 225 Ac and 227 since the residence time is short compared to the half-lives of Th 227 the cumulative radioactivity of Th is 225 Ac( 225It is considered to be 10% higher compared to (not considering the Ac descendants). The total α dose per Ac atom is considered to be 27.7 MeV from the decay of the parent nuclide and the α radioactive descendants. 225 It is considered to be the total α dose of 27.7 MeV per Ac atom.

[0246] Also, the red bone marrow dose and the skeletal tumor dose are 227 created during the systemic circulation of the Th-product, etc. 223 It is considered to be enhanced by a factor of 2 with respect to the red bone marrow dose due to the skeletal uptake of Ra.

[0247] The data is presented in Table 7. The data shows the favorable tumor-to-tissue ratios for the Th-labeled PSMA-binding urea derivative. 227 It shows the favorable tumor-to-tissue ratios for the Th-labeled PSMA-binding urea derivative.

[0248] Table 7. 227 Dose estimates of equivalent doses for organs and tumors to be noted for the Th-labeled PSMA-binding urea derivative (MBq / patient)

[0249]

Table 7

[0250] The products described in this specification are considered to be usable in single-treatment or repeated-treatment modalities.

[0251] As a conclusion, 212 Pb or 227 The dose estimates for the PSMA-targeted urea derivatives labeled with Th show promising tumor-to-tissue ratios indicating that clinical benefits from use may be expected.

[0252] Example 16. Comparative treatment experiment using Lu-PSMA-617 and 177 Lu-PSMA-617 and 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 in nude mice bearing C4-2 xenografts For male nude mice, C4-2-PSMA-positive human prostate cells were inoculated into the flanks, and after 2 weeks, the tumors had reached a diameter of 5-7 mm. Groups of 8 animals each were given physiological saline, 52 MBq of 177 Lu-PSMA-617 or 320 kBq of 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1. When the tumor size reached 20 mm, the animals were sacrificed due to animal welfare requirements. Tumor doses were calculated based on the following assumptions: For the 177 effective half-life of Lu-PSMA-617 in the tumor over 3 days, 10% of the injected dose per gram of decay in the tumor, and 80% of the radiation from the decay in the tumor was absorbed in the tumor, and the radiation energy was 0.15 MeV per decay. 212 For Pb, since the effective half-life was considered to be 10.6 hours, 10% of the injected dose per gram of decay in the tumor, and 100% of the radiation in the tumor was absorbed in the tumor, with 212 100% retention of Pb and its daughters and a radiation energy of 8 MeV per decay. Tumor dose measurements for the injected radioactivity were, respectively, 177 on average 35.9 Gy to the tumor with Lu-PSMA-617 and 212 2.06 Gy to the tumor in the Pb-p-SCN-Bn-TCMC-PSMA ligand 1 group.

[0253] Results: On day 30 after treatment, the data showed survival rates of 0%, 12.5%, and 75% in the physiological saline group, 177 Lu-PSMA-617 group, and 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 group, respectively (Figure 2). The median survival times were 15 days, 20 days, and >30 days (not reached) in the physiological saline group, 177 Lu-PSMA-617 group, and 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 group, respectively.

[0254] In conclusion, the data indicate that the radiation dose evaluation177 Delivered with Lu-PSMA-617, despite showing a radiation dose 17 times higher in Gy units, 212 1 pair of Pb-p-SCN-Bn-TCMC-PSMA ligand 177 shows a strong tumor growth delay with Lu-PSMA-617. Therefore, 212 1 pair of Pb-p-SCN-Bn-TCMC-PSMA ligand 177 the relative biological effectiveness (RBE) of Lu-PSMA-617 was at least 17. Usually, an RBE of 2 - 5 is expected for α-emitters versus β-emitters, so this high relative biological effectiveness for the therapeutic level of α-emitters was hardly predicted. and

[0255] References A chelator effective for the complexation of thorium-227.

[0256]

Chemical formula

[0257] Matters 1. Compound X, which is a urea derivative suitable for targeting PSMA-expressing cells and tissues.

[0258] 2. 212 Pb, 177 Lu, 213 Bi, 225 Ac or 227 a complex containing compound X linked to Th, wherein the compound X is a urea derivative suitable for targeting PSMA-expressing cells and tissues.

[0259] 3. The compound X is linked to 212 Pb or 227 Th by a chelating molecule Z, the compound according to item 1 or the complex according to item 2.

[0260] 4. The chelating moiety Z is selected from the group consisting of acyclic chelators, cyclic chelators, cryptands, crown ethers, porphyrins, or cyclic or acyclic polyphosphonates, DOTMP, EDTMP, bisphosphonates, DOTA, DOTA derivatives such as p-SCN-Bn-DOTA, pamidronate bound to DOTA, TCMC, TCMC derivatives such as p-SCN-Bn-TCMC, pamidronate bound to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, and is a compound or complex according to any one of items 1 to 3.

[0261] 4. The linker is DOTA or a DOTA derivative, and is a compound or complex according to any one of items 1 to 4.

[0262] 5. The linker is a DOTA derivative such as p-SCN-Bn-DOTA, and is a compound or complex according to any one of items 1 to 4.

[0263] 6. The linker is TCMC or a TCMC derivative, and is a compound or complex according to any one of items 1 to 4.

[0264] 7. The linker is a TCMC derivative such as p-SCN-Bn-TCMC, and is a compound or complex according to any one of items 1 to 4 or 6.

[0265] 8. The linker is an octadentate hydroxypyridinone-containing ligand such as 3,2-HOPO, and is a compound or complex according to any one of items 1 to 7.

[0266] 9. The compound X linked to the chelating molecule Z is the following formula (I):

[0267]

Chem.

[0268] {wherein, W is a PSMA targeting ligand; A 4 is a divalent linking moiety, ring, or combination thereof containing 1 to 10 carbon atoms in the linkage or chain, wherein at least one carbon atom is optionally substituted with O, -NR 3 -, or -C(O)-; G is C=O, C=S, C-NH2, or C-NR 3 ; R 1 is hydrogen or a carboxylic acid protecting group; R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl; R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently hydrogen, alkyl, alkoxyl, or R 17 and R 18 are each independently hydrogen, alkyl, aryl, or alkylaryl; R 19 is selected from the group consisting of alkyl, alkoxyl, halide, haloalkyl, and CN; m is an integer from 1 to 6; and o is an integer from 0 to 4, where when o is greater than 1, each R 19 is the same or different}, a compound or complex according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof.

[0269] 10. wherein said A 4 is a bond, (CH2) n, -HC(O)-, -(OCH2CH2) n , -(HCH2CH2) n , -H(CO)CH2-, -HC(0)CH2(OCH2CH2) n , or -HC(0)CH2(HCH2CH2) n -; and L is a bond, (CH2) n , -(OCH2CH2) n , (HCH2CH2) n , or -C(0)(CH2) n -{wherein n is independently 1, 2, or 3}, the compound or complex according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof.

[0270] 11. Said A 4 is a bond, -(OCH2CH2) n , or -HC(0)CH2(OCH2CH2) n -; and L is a bond or -(OCH2CH2) n -{wherein n is independently 1 or 2}, the compound or complex according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof.

[0271] 12. Said W has the following structure:

[0272]

Chemical formula

[0273] {wherein R 20 and R 21 are each independently an amino acid residue linked to an adjacent -C(O)- group via its amino group}, the compound according to any one of items 1 to 11 or

[0274] 13. Said W has the following structure:

[0275] [Chemistry]

[0276] The compound or complex according to any one of items 1 to 12 having {wherein R is hydrogen or a carboxylic acid protecting group}, or a salt thereof acceptable as a medicine.

[0277] 14. The following structure:

[0278] [Chemistry]

[0279] {wherein R 17 is aryl} or a salt thereof acceptable as a medicine, the compound or complex according to any one of items 1 to 13, or a salt thereof acceptable as a medicine.

[0280] 15. The complex is 212 PSMA-617 as follows, in which radionuclides such as Pb can be linked / chelated to 4 Ns:

[0281] [Chemistry]

[0282] The compound or complex according to any one of items 1 to 14, or a salt thereof acceptable as a medicine.

[0283] 16. The compound or complex according to item 15, wherein the DOTA unit is replaced by a TCMC unit.

[0284] 17. The compound or complex according to any one of items 15 to 16, wherein the DOTA is p-SCN-Bn-DOTA and the TCMC is p-SCN-Bn-TCMC.

[0285] 18. The compound or complex according to any one of items 15 to 17, wherein the p-SCN-Bn-DOTA or p-SCN-Bn-TCMC is a skeleton C-linked to a urea derivative (PSMA).

[0286] 19. The compound is the following skeleton-C-linked p-SCN-Bn-DOTA or p-SCN-Bn-TCMC:

[0287]

Chemical formula

[0288] {In the formula, Z is the following:

[0289]

Chemical formula

[0290] (wherein X is -OH or NH2)}; the compound or complex according to any one of items 15 to 18.

[0291] 20. The compound is the following skeleton-C-linked p-SCN-Bn-DOTA or p-SCN-Bn-TCMC:

[0292]

Chemical formula

[0293] {wherein X is -OH or NH2}; the compound or complex according to any one of items 15 to 19.

[0294] 21. The compound is the following skeleton-C-linked p-SCN-Bn-DOTA, namely, p-SCN-Bn-DOTA-PSMA-ligand 2:

[0295]

Chemical formula

[0296] The compound or complex according to any one of items 15 to 20, which is as described.

[0297] 22. The compound according to any one of items 15 to 20, which is the following skeleton-C-linked p-SCN-Bn-TCMC, that is, p-SCN-Bn-TCMC-PSMA ligand 1:

[0298]

Chemical formula

[0299] The compound or complex according to any one of items 15 to 20, which is as described.

[0300] 23. 212 A PSMA-targeted urea derivative containing a TCMC group for chelating Pb.

[0301] 24. 227 A PSMA-targeted urea derivative containing HOPO for chelating Th.

[0302] 25. 212 Pb or 227 A PSMA-targeted urea derivative containing DOTA labeled with either Th.

[0303] 26. A pharmaceutical composition comprising the compound or complex according to any one of items 1 to 21 and / or the PSMA-targeted urea derivative according to any one of items (claims) 15 to 17, and a diluent, a carrier, a surfactant, and / or an excipient.

[0304] 27. 224 The radioactive pharmaceutical composition according to item 26, further comprising Ra.

[0305] 28. The radioactive pharmaceutical composition according to any one of items 26 to 27, wherein the radioactivity is 100 kBq to 100 MBq per dose.

[0306] 29. The 224 Ra and 212 The radioactive pharmaceutical composition according to any one of items 26 to 28, wherein the amounts of Ra and Pb are in a radioactive equilibrium state.

[0307] 30. The 212 Radioactivity ratio (MBq) between Pb and 224 Ra is 0.5 to 2, such as 0.8 to 1.5, or 0.8 to 1.3, or preferably 0.9 to 1.15, etc., and the radioactive pharmaceutical composition according to any one of items 26 to 29.

[0308] 31. The following: - A first vial containing the radioactive pharmaceutical composition according to any one of items 26 to 30, and - A second vial containing a neutralizing solution for adjusting the pH and / or isotonicity of the radioactive pharmaceutical composition before administration to a patient, A kit containing the above.

[0309] 32. The following: - 224 Ra, 212 Pb, and / or 227 A first vial containing Th; - A second vial containing a complexing agent selected from the group consisting of acyclic chelators, cyclic chelators, cryptands, crown ethers, porphyrins, or cyclic or acyclic polyphosphonates, DOTMP, EDTMP, bisphosphonate derivatives, DOTA, DOTA derivatives, pamidronate conjugated to DOTA, TCMC, TCMC derivatives, pamidronate conjugated to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, or a compound according to any one of items 1 to 21, wherein the complexing agent 212 such as Pb 224 is capable of complexing the daughter nuclides of Ra, and wherein the complexing agent 224 does not complex Ra in the pharmaceutical solution; and - Optionally, instructions for mixing the first vial and the second vial to form a pharmaceutical composition that can be immediately administered to a patient 1 minute to 12 hours after mixing. A kit comprising

[0310] 33. The kit according to any one of claims 31 to 32, wherein the kit is for use as a medicament.

[0311] 34. A radiopharmaceutical composition according to any one of items 18 to 22 for use as a medicament.

[0312] 35. A radiopharmaceutical composition according to any one of items 18 to 22 for use in the treatment of bone diseases.

[0313] 36. The radiopharmaceutical composition for use according to item 35, wherein the bone disease is selected from the group consisting of cancer with skeletal metastases to the breast, prostate, kidney, lung, bone, or multiple myeloma, or non-cancerous diseases causing unwanted calcification including ankylosing spondylitis.

[0314] 37. The radioactive pharmaceutical composition for use according to any one of items 34 to 36, wherein the solution is administered at a dose within the range of 50 to 150 kBq per 1 kg of body weight, for example, 50 to 100 kBq per 1 kg of body weight.

[0315] 38. A method for treating a malignant or non-malignant disease by administering the radioactive pharmaceutical composition according to any one of items 26 to 30 to an individual in need thereof.

[0316] 39. A method for providing a radioactive pharmaceutical composition according to any one of items 26 to 30, the method comprising the following: a) A first solution, wherein 224 a first solution in which the amounts of Ra and 212 Pb are in a state of radioactive equilibrium is prepared; b) A second solution containing a complexing agent selected from the group consisting of acyclic chelators, cyclic chelators, cryptands, crown ethers, porphyrins or cyclic or acyclic polyphosphonates, DOTMP, EDTMP, bisphosphonates, DOTA, DOTA derivatives, pamidronate bound to DOTA, TCMC, TCMC derivatives, pamidronate bound to TCMC, antibody-conjugated DOTA, antibody-conjugated TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, wherein the complexing agent 212 such as Pb 224 can complex daughter nuclides of Ra, and wherein the complexing agent 224 does not complex Ra is prepared; and c) Mixing the first composition and the second composition, thereby providing a pharmaceutical composition according to any one of items 26 to 30, A method comprising.

Claims

1. A compound comprising a PSMA unit and a chelate unit, wherein the PSMA unit is a carbon skeleton linked to the chelate unit, and the compound has the following formula: 【Chemical 1】 {In the formula, X is -NH ２ or -OH}, and the compound is as described.

2. The compound has the following formula: [Chemical Formula 2] The compound according to claim 1, which is the p-SCN-Bn-TCMC-PSMA ligand 1 of.

3. The compound has the following formula: [Chemical Formula 3] The compound according to claim 1, which is the p-SCN-Bn-DOTA-PSMA ligand 2 of.

4. ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac or ２２７ A complex comprising the compound according to any one of claims 1 to 3, complexed with a radionuclide selected from the group consisting of Th.

5. The compound according to claim 2 (p-SCN-Bn-TCMC-PSMA ligand 1), ２１２ The complex according to claim 2, which is complexed with Pb.

6. The compound according to claim 2 (p-SCN-Bn-DOTA-PSMA ligand 2) is ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac or ２２７ The complex according to claim 3, which is complexed with Th.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, or the complex according to any one of claims 4 to 6, and a diluent, a carrier, a surfactant and / or an excipient.

8. ２２４ The radiopharmaceutical composition according to claim 7, further comprising Ra.

9. ２２４ The amount of Ra and ２１２ Pb is in a state of radioactive equilibrium, the radioactive pharmaceutical composition according to claim 8.

10. The above-mentioned ２１２ Pb pair ２２４ The radioactivity ratio (MBq) of Ra is 0.5 to 2, for example, 0.8 to 1.5, or 0.8 to 1.3, or preferably 0.9 to 1.

15. The radiopharmaceutical composition according to any one of claims 9 to 10.

11. The radioactive pharmaceutical composition according to any one of claims 7 to 10, wherein the composition is administered at an activity of 100 kBq to 100 MBq per dose.

12. The radioactive pharmaceutical composition according to any one of claims 7 to 11 for use as a medicament.

13. The radioactive pharmaceutical composition according to any one of claims 7 to 11 for use in the treatment of PSMA-expressing diseases including soft tissue diseases and bone diseases.

14. The radioactive pharmaceutical composition for use according to claim 13, wherein the bone disease is selected from the group consisting of skeletal metastases from cancer to the breast, prostate, kidney, lung, bone, or multiple myeloma.

15. The radioactive pharmaceutical composition for use according to any one of claims 12 to 14, wherein the solution is administered at a dose in the range of 50 to 150 kBq per kg of body weight.

16. A method for treating a malignant or non-malignant disease by administration to an individual in need thereof of the radioactive pharmaceutical composition according to any one of claims 7 to 11.

17. A first vial containing the radioactive pharmaceutical composition according to any one of claims 7 to 11, and A second vial containing a neutralizing solution for adjusting the pH and / or isotonicity of the radioactive pharmaceutical composition before administration to a patient, A kit comprising.

18. ２２４ Ra, ２１２ Pb and / or ２２７ a first vial containing a solution containing Th, and A second vial containing the compound according to any one of claims 1 to 3, A kit comprising.

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