Complexes containing PSMA-targeting compounds linked to lead or thorium radionuclides

Abstract

To provide compounds that addresses challenges such as a 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 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 Pb or 227 The present invention relates to complexes comprising PSMA-targeting compounds linked to radionuclides such as Th. 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 for dual targeting of cancer. Peptide and peptidomimetic PSMA-targeting urea derivatives can be used for radiotherapy applications. 212 Pb and 227 They are linked to chelators to complex Th. They can be used for single and dual targeting. [Background technology]

[0002] Prostate cancer is one of the most common causes of cancer-related deaths in men. There is a great need for new and effective treatments, especially in hormone-refractory late-stage disease. Skeletal metastases are a frequent problem in late-stage disease, and therefore alpha particle emitters are a promising treatment option. 223 Ra (Xofigo) has been introduced as a bone-specific therapy for late-stage prostate cancer patients with skeletal metastases.

[0003] As for bone accumulation, 223 Although Ra shows significant clinical benefit to patients, its effect is restricted to bone metastases and does not target soft tissue metastases.

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

[0005] The molecule operates in a suitable manner, 177 Lu and 225It produces tumor-to-normal tissue ratios that are relevant for longer-lived (i.e., half-lives of several days) radionuclides, including Ac, but exhibits high kidney uptake early on (typically several hours after injection). 212 For shorter-lived radionuclides such as Pb (half-life of 10.6 h), early renal uptake represents a potential toxicity problem.

[0006] Therefore, it would be advantageous to use a PSMA ligand that has less renal uptake, but 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, whereby the linker region connects (1) and (3). The linker region is also used to adjust the molecular size, polarity, etc. to affect the in vivo distribution characteristics. PSMA-11 and PSMA I&T, and 131 I and 211 The PSMA-binding region (motif) used in PSMA-617, such as the At-labeled PSMA-binding ligand, is a structure found in several molecules of this class developed by several different inventors and researchers.

[0007] Novel compounds containing the PSMA domain will be approved because all current ligands in trials have challenges, including relatively poor radiation biological effectiveness (RBE) and suboptimal biodistribution. There is also a need for improved alpha emitters that can target both bone and soft tissue metastases.

[0008] The present invention relates to compounds that address these issues. Summary of the Invention

[0009] An embodiment of the present invention relates to a complex of the present invention, wherein compound X is bound by a chelating moiety Z. 212 Pb or 227 It is linked to a radionuclide such as Th.

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

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

[0012] The chelating moiety Z may 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 bound to DOTA, TCMC, TCMC derivatives, pamidronate bound to TCMC, antibody-bound DOTA, antibody-bound TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A.

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

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

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

[0016] An aspect of the present invention relates to a radiopharmaceutical composition according to the present invention for use as a medicament.

[0017] An aspect of the present invention relates to a radiopharmaceutical composition according to the present invention for use in the treatment of a soft tissue or bone disorder.

[0018] In one embodiment of the invention, the bone disease is selected from the group consisting of skeletal metastases from cancer to the breast, prostate, kidney, lung, bone, or multiple myeloma, or non-cancerous diseases that cause unwanted calcification, including ankylosing spondylitis. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows the biodistribution of 212Pb 2 hours after injection of 212Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617, respectively, in the presence of 224Ra. [Diagram 2] FIG. 2 shows the survival rate of mice receiving C4-2 PSMA-positive xenografts following treatment with saline, 52 MBq of 177Lu-OSMA-617, and 0.32 MBq of 212Pb-p-SCN-Bn-TCMC-PSMA Ligand 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description of the Invention Several abbreviations are used. Peptide mimetics (also called peptidomimetics) are small protein-like chains designed to mimic peptides. They commonly arise from the modification of existing peptides or by designing analogous systems that mimic peptides, such as peptoids or β-peptides. Regardless of the approach, altered chemical structures are designed to favorably tune 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 peptides that do not occur in nature (such as altered backbones or the incorporation of non-natural amino acids). Based on their similarity to precursor peptides, peptidomimetics can be divided into four classes (A-D), with A being characterized by the greatest similarity and D being characterized 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 acid dipeptidase I, pteroyl poly-γ-glutamate carboxypeptidase, folyl poly-γ-glutamate carboxypeptidase, folate hydrolase 1, prostate-specific membrane antigen, cell proliferation 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, also used for benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (e.g., conjugated to a monoclonal antibody) p-SCN-Bn-TCMC: 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane TCMC: 1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane, also used for benzyl-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)cyclododecane (e.g., conjugated to a monoclonal antibody) mAb: Monoclonal antibody HOPO: Me-3,2-HOPO, 227Octadentate hydroxypyridinone, 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 for complexation of Th 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 partial or complete isolated versions of the acid, salt or chelator.

[0023] The present invention relates to 212 This paper presents a small molecule urea derivative-based single- and dual-targeting solution as a prostate cancer cell targeting agent for carrying Pb. 212 Pb or accordingly against PSMA antigen expressing cells, which are primarily associated with the progression of metastatic prostate cancer, and to some extent other types of cancer as well. 224 Ra functions as a skeletal treatment and 212 The Pb urea derivative may be used in a dual-targeting solution, acting as a systemic therapy.

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

[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] Thus, the present invention provides 212 Pb or 227 The present invention relates to a complex comprising a compound X linked to a radionuclide such as Th, said compound X being a peptide or peptidomimetic urea derivative suitable for targeting PSMA-expressing cells and tissues.

[0027] Linker An embodiment of the present invention relates to a complex of the present invention, wherein the compound X is bound to a chelating molecule Z. 177 Lu, 213 Bi, 225 Ac, 212 Pb or 227 It is linked to a radionuclide such as Th.

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

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

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

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

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

[0033] The complexing agent, linker or chelating molecule Z in the present invention is understood to encompass derivatives of the above compounds, such as derivatives of EDTMP, DOTA, e.g., p-SCN-Bn-DOTA, and TCMC, e.g., p-SCN-Bn-TCMC. Such derivatives are, of course, 224 With a higher stability constant compared to Ra 212 It is understood that the ability to complex Pb must be maintained.

[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-bound DOTA, antibody-bound TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, oxo-Do3A.

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

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

[0037] The complexing agent may be linked via a carbon backbone that allows all the "binding arms" of the chelator molecule to interact with the metal, or alternatively, one of the arms may be used as a 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-esters.

[0039] Thus, for p-SCN-Bn-DOTA or p-SCN-Bn-TCMC, the complexing agent may be linked to the rest of the compound via the carbon backbone (C backbone).

[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, 0-hydrocarbon, SH and S-hydrocarbon group, characterized in that either 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 0-hydrocarbon. R may also include a linker moiety, as shown below, and / or a coupling moiety, as also shown below. In formula I, the groups R2-R6 may each independently be selected from H, OH, =0, short hydrocarbons (as described herein), linker moieties (as described herein) and / or coupling moieties (as described herein). Typically, at least one of the groups R-R6 will be OH. Typically, at least one of the groups R2-R6 will be =0.

[0041] Typically, at least one of the groups R to R6 will be a linker moiety. Preferably, exactly one of the groups R2 to R6 will be =0. Preferably, exactly one of the groups R to R6 will be OH. Preferably, exactly one of the groups R to R6 will be a linker moiety (as described herein). The remaining groups R to R6 may be any of the moieties set forth herein, but are preferably H. If the linker moiety or any additional linker, template or chelating group attached to the linker moiety does not comprise a coupling moiety, then one of the groups R to 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 on adjacent atoms of the ring. Thus, in a preferred embodiment, the OH and =0 can be on atoms 1,2; 2,3; 3,2; 3,4; or 4,3 (numbering from the assumed nitrogen), respectively.

[0043] Highly preferred are octadentate ligands having at least one chelating moiety, where the OH and =0 groups are in positions 3 and 2, respectively. The octadentate ligand may have 2, 3 or 4 such chelating groups, where 2 or 4 such groups are especially preferred.

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

[0045] 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 Complexing agents for Th were conjugated to urea derivatives for PSMA targeting. The complexing agents mentioned herein are incorporated by reference.

[0046] Thus, one embodiment of the present invention comprises: 212 Concerning PSMA-targeted urea derivatives containing TCMC groups, such as p-SCN-Bn-TCMC, for chelating Pb.

[0047] Another embodiment of the present invention comprises: 227 This study relates to PSMA-targeted urea derivatives containing HOPO for chelating Th.

[0048] A further embodiment of the present invention comprises 212 Pb or 227 The present invention relates to PSMA-targeted urea derivatives, including DOTA, such as p-SCN-Bn-TCMC, labeled with either Th or β-

[0049] In a further embodiment, the complexing agent is 224 Does not complex Ra or does not substantially complex Ra 224 Does not complex Ra.

[0050] In still yet further embodiments, the complexing agent is 224 than against Ra 212 It complexes with Pb with a high stability constant.

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

[0052] In certain embodiments, the complexing agent is selected from the group consisting of ligand-bound DOTA, such as ligand-bound p-SCN-Bn-DOTA, or ligand-bound TCMC, 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 yet a further embodiment, 212 Pb vs. 224 The radioactivity ratio of Ra (in MBq units) is 0.5 to 2, such as 0.8 to 1.5, such as 0.8 to 1.3, or preferably 0.9 to 1.15.

[0056] In the context of this specification, the term "radiostatic equilibrium" refers to a ratio in MBq between two radionuclides that becomes equal or substantially equal over time. For example, 212 Pb and 224 The term "radioactivity ratio" between Ra and 212 Pb vs. 224 In Figure 5 there is a table (Table 2) showing the evolution of this radioactivity ratio over time. After 2 days, 212 Pb vs. 224 It was found that a radioactive equilibrium of 1.1 was established with respect to the radioactivity ratio between Ra (7.3 divided by 6.8). Thus, in Figure 5, 212 Pb and 224 It was also found that radiation equilibrium with Ra was reached after about two days.

[0057] In the context of this specification, the terms "complexing agent", "scavenger", "linker", "chelating molecule Z" and "chelator" are used interchangeably. These terms refer to a compound that, preferably following chelation and with significant strength when measured in a test system, 212 The present invention relates to an agent capable of forming a complex with Pb, while radium is not significantly affected by the presence of the complex as measured in the test system.

[0058] Test systems include cation exchange or size retention or centrifugal concentration cartridges for in vitro biodistribution and 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 enrichment separation or biodistribution profile. This is, for example, the case of small molecule chelators. 212 This means at least 50% of the Pb is uptaken into the blood. Where blood uptake is not a reliable indicator, for antibody-linked chelators, this means at least 50% binding by TLC analysis.

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

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

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

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

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

[0065] The compound(s) may also be 212 It can complex more radionuclides than Pb.

[0066] In one embodiment of the invention, the compounds and / or complexes are at a concentration of 1 ng / mL to 1 g / mL.

[0067] In another embodiment of the invention, the compounds and / or complexes are at a concentration of 100 ng to 10 mg / mL.

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

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

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

[0071] In another embodiment of the invention, the radioactivity of the solution is between 100 kBq and 100 MBq.

[0072] In another embodiment of the invention, the complexing agent is conjugated to a compound selected from the group consisting of peptidomimetic urea derivative(s) having affinity for PSMA.

[0073] In another embodiment of the invention, the complexing agent is the 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 a monoclonal antibody, a polyclonal antibody, an antibody fragment, a synthetic protein, a peptide, a hormone, a hormone derivative, a vitamin, or a vitamin derivative.

[0074] For medicinal purposes, pure 212 A Pb solution may be used. Alternatively, 212In mixtures with Pb 224 The latter may be used for dual targeting purposes, 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 It may be stored for a period of time, for example, one day or more, preferably at least two days, one to two days, or one to three days, until an equilibrium state between Bi and Zn is reached. This is a 0.83 to 1.14 212 From Pb 224 Ensure the radioactivity ratio to Ra. This can be accomplished by the manufacturer, for example, by simply holding the product for a day or so prior to shipping.

[0076] or, 212 Pb to obtain specific radionuclide ratios 224 For example, if the soft tissue tumor burden is much greater than the skeletal tumor burden, pure 212 Pb preparation or high 212 Pb vs. 224 A solution having a Ra ratio may be used.

[0077] The non-overlapping side effect profiles of cationic radium and α-emitters coupled to PSMA-binding urea derivatives provide a novel therapeutic approach for dual targeting. 224 Ra cations and 212 This makes a mixture of Pb-PSMA targeting agents particularly attractive because, at least in terms of the backbone components, two distinct compounds would target the lesion independently, allowing lower doses of each compound to be used to produce antitumor activity.

[0078] Maintaining radium primarily as an uncomplexed or slightly complexed cation is important because this ensures maximal uptake in bone and skeletal metastases and also favorable excretion of the product, which is primarily excreted through the intestine.

[0079] By adding a complexing agent to the radium solution, the radioactive daughter nuclide can be made to accumulate in bone or tumors, enhancing the therapeutic effectiveness of the radium solution at the expense of becoming a health hazard. However, the complexing agent must not negatively affect the bone accumulation of radium. For example, TCMC-labeled urea derivatives can be used to reduce the amount of TCMC that occurs in the radium solution during transport and storage between the manufacturing site and the hospital where the product is administered. 212 Pb can be discharged.

[0080] Although it is possible to reduce sensitivity by adding radiolysis inhibitors, tumor-targeting peptides and peptidomimetics are often more sensitive to radiolysis and therefore likely have a longer shelf life. 224 These must be supplied in kit form to be added several hours to minutes before administration of the Ra solution.

[0081] It is known in the art that calixarenes and EDTA can complex radium to some extent, and also lead and bismuth. However, in recent studies, we have shown that calixarenes complex the longest-lived daughter nuclide while leaving radium largely uncomplexed or only slightly complexed, as measured by in vivo biodistribution measurements. 212 We have found a chelator that will complex Pb quickly and with suitable stability. Selective complexation can be used to at least allow lead to accumulate in bone or tumors while preserving the beneficial properties of radium for treating bone diseases such as skeletal metastases. Targeting to bone or tumor cells 212 The Pb complex is 212 Alpha emitters from the decay of Pb 212 Bi is produced. Therefore, β emitters 212Pb is used as an indirect alpha source to irradiate target cells or tissues. Besides TCMC and DOTA, 224 Other potential chelators that may be suitable for trapping Ra daughter nuclides include, but are not limited to, phorphyrins, DTPA, and DTPA derivatives, as well as carboxyls linked to DOTA.

[0082] Lead-212 is 224 By far the longest-lived of the descendants of Ra, and it is the short-lived alpha emitter 212 This is of utmost importance for the complex, since it is the biogenerator of Bi. 212 When Pb-chelates are taken up into bone or tumor cells, 212 Bi may also be retained in the target. 224 In Ra solution, 212 For Bi atoms 212 Pb is present 10 times more than in these solutions. 212 The amount of radiation produced by Bi atoms is not very large, 224 Ra and 212 Compared to the Bi decay series, this is probably not a toxicologically significant amount. 212 The amount of Bi is 223 Indirectly produces alpha particles in the Ra series 211 Pb, which is in equilibrium with the progeny. 223 This did not pose any significant problems for the registration and clinical use of Ra.

[0083] However, in the infusion 212 If a high degree of chelation were to be required for Bi as well, it may be necessary, at least in some cases, to add a stabilizer such as NaI or HI, since bismuth in aqueous solution tends to exist in a state that is not favorable for chelation.

[0084] The current approved alpha medicines for the treatment of skeletal metastases, namely: 223Compared with Ra, the novel solution described herein, in one embodiment, can target daughter nuclides to circulating cancer cells and, to some extent, to soft tissue metastases, so it should provide a product with improved properties for the treatment of skeletal metastases. This can prevent recurrence from metastatic regrowth of bone cancer caused by CTCs.

[0085] Another aspect is 223 Against Ra 224 The shorter half-life of Ra may actually be of some benefit when radium is embedded in bone matrix. Due to the high density of bone minerals, the range of alpha particles is strongly reduced in bone versus soft tissue. Especially in rapidly mineralizing areas such as bone cancer metastases, the embedding process may be significant when using volume-seeking alpha medicines.

[0086] Therefore, 224 Ra should improve the tumor dose since it is on average less embedded at the time of decay.

[0087] 224 New products with and without Ra 212 Diseases for which the Pb solution may be used include, but are not limited to, primary and metastatic cancers, autoimmune diseases, and arteriosclerosis. The product may 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, cyclic or acyclic polyphosphonates, including DOTMP and EDTMP. Also, bisphosphonates (e.g., pamidronate) conjugated to DOTA, TCMC, or the like may be used. 224 It may be used as a scavenger in Ra solutions.

[0089] Therapeutic 224 In Ra solution 212The amount of Pb should be moderate to moderate (i.e., at equilibrium, 224 One skilled in the art could argue that the difference in half-life is corrected for, but 223 Similar to what is done with Ra 224 Assuming Ra dosages are those of skill in the art, the administered dosage would be approximately 150 kBq per kg of body weight.

[0090] At equilibrium, this means that ( 212 When Pb is quantitatively chelated, 11.5 MBq in 5 liters of blood from a 70 kg patient 212 This translates into a dosage of Pb-antibody conjugate. The number of circulating tumor cells per ml is typically less than 10 cells, so there are less than 50,000 tumor cells in total in 5 liters of blood. 212 If only one of the Pb-antibody binding molecules binds to a tumor cell, this represents approximately 127 Pb-antibody binding molecules per cell. 212 equivalent to at least 0.0023 Bq of Pb atoms, which means an average of 25 cell-bound 212 Pb is reported to kill 90% of the cell population and is therefore highly destructive.

[0091] compound An embodiment of the present invention relates to a compound X linked to a chelating molecule Z, having the following formula (I): [ka]

[0092] {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 a bond or chain, where at least one carbon atom is optionally O, -NR 3 - or substituted with -C(O)-; G is C=O, C=S, C-NH2, or C-NR 3 and; R1 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 are the same or different}, or a pharma- ceutically acceptable salt thereof.

[0093] An aspect of the present invention relates to a complex according to the present invention, or a pharma- ceutically 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}. An aspect of the present invention relates to a complex according to the present invention, or a pharma- ceutically acceptable salt thereof, wherein A 4is 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}.

[0094] An embodiment of the present invention relates to a complex according to the present invention, or a pharma- ceutically acceptable salt thereof, wherein W has the following structure: [ka] {In the formula, R 20 and R 21 are each independently an amino acid residue linked through its amino group to the adjacent -C(O)- group.

[0095] An embodiment of the present invention relates to a complex according to the present invention, or a pharma- ceutically acceptable salt thereof, wherein W has the following structure: [ka] where R is hydrogen or a carboxylic acid protecting group.

[0096] An aspect of the present invention relates to a complex according to the present invention, or a pharma- ceutically acceptable salt thereof, and having the following structure: [ka] {where, R 17 is aryl}, or a pharma- ceutically acceptable salt thereof.

[0097] An embodiment of the present invention relates to a complex according to the present invention, or a pharma- ceutically acceptable salt thereof, wherein the complex comprises four N-linked / chelated 212 The following PSMA-617 with radionuclides such as Pb: [ka] It is.

[0098] An embodiment of the invention relates to a complex according to the invention, wherein a DOTA unit, such as p-SCN-Bz-DOTA, is replaced with a TCMC unit, such as p-SCN-Bz-TCMC.

[0099] The linker of PSMA-617 may also be covalently linked to a C atom of the backbone instead of the N linkage shown in the diagram above.

[0100] Thus, the urea derivatives may have backbone C-linked or N-linked DOTA or TCMC linkages.

[0101] With respect to the backbone-C linked p-SCN-Bn-DOTA or p-SCN-Bn-TCMC linkages, the compounds have the following structure: [ka] wherein Z is one of the following: [ka] (wherein X is -OH or NH2). X is -OH for p-SCN-Bn-DOTA, and X is NH for p-SCN-Bn-TCMC.

[0102] This means that backbone-C linked p-SCN-Bn-DOTA or p-SCN-Bn-TCMC have the following structure: [ka] where X is -OH or NH2.

[0103] The backbone-C linked p-SCN-Bn-DOTA is as follows: [ka] It is.

[0104] Thus, an embodiment of the present invention relates to a compound that is p-SCN-Bn-DOTA-PSMA ligand 2.

[0105] The backbone-C linkage p-SCN-Bn-TCMC is as follows: [ka] It is.

[0106] Thus, an embodiment of the present invention relates to compounds which are p-SCN-Bn-TCMA-PSMA ligand 1 or p-SCN-Bn-DOTA-PSMA ligand 2 as disclosed above and in the Examples.

[0107] The p-SCN-Bn-TCMC-PSMA ligand (Ligand 1) and p-SCN-Bn-DOTA-PSMA ligand (Ligand 2) (shown in the Examples) are linked to the remainder of the compound via a carbon backbone (C backbone) and have an extended linker region that includes an isothiocyanato benzyl linker, and also use a carbon-substituted chelator that does not contain all four chelator arms and uses one of the chelator arms as the linker attachment, in contrast to PSMA-617, which has a shorter linker region. These differences result in significantly different biodistribution of the radiolabeled product and, as such, reduced kidney exposure compared to PSMA-617, which may be beneficial for PSMA-expressing tumors. 212 This makes it more suitable for targeting Pb as shown in the examples herein below.

[0108] In one embodiment of the invention, the compounds of the invention, such as p-SCN-Bn-TCMC-PSMA ligand 1 and p-SCN-Bn-DOTA-PSMA ligand 2, may be present in the form of a trifluoroacetate salt.

[0109] CTT1401 and CTT1403 with TCMC or DOTA variants and derivatives (Choy et al., 2017) were also used in the complexes of the present invention. 212 Can be used with Pb.

[0110] Following preparation of the PSMA-binding urea derivative according to the invention using a readily available amino group or another group suitable for conjugation, p-SCN-Bn-TCMC may be conjugated to a PSMA-binding compound. Subsequent purification allows the formation of a PSMA-binding compound in solution. 224 With and without Ra 212 This may be required prior to radiolabeling with Pb.

[0111] Thus, 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, in which the linker-chelator is p-SCN-Bn-TCMC. One embodiment of the present invention relates to a complex according to the present invention, in which the linker is p-SCN-Bn-DOTA. In other words, -p-SCN-Bn is the end of the linker region that is attached to the TCMC or DOTA chelator group via the carbon backbone.

[0112] Human serum albumin can be used to extend the half-life of a drug. Thus, in one embodiment, 212 The Pb-labeled PSMA-conjugated urea derivative further contains a group capable of binding to albumin to extend the circulatory half-life of the radiolabeled product.

[0113] A further embodiment of the present invention relates to a complex according to the present invention, wherein 212 The Pb-labeled PSMA-conjugated urea derivative further comprises human serum albumin either directly bound to the complex or bound to the complex through, for example, a liposome.

[0114] Pharmaceutical Compositions Typically, an important element of a pharmaceutical composition is a buffer solution which maintains to a substantial degree the chemical integrity of the radioimmunoconjugate and which is physiologically acceptable for injection into a patient.

[0115] In one embodiment of the invention, the pharmaceutical composition comprises one or more pharma- ceutically acceptable carriers and / or adjuvants.

[0116] Acceptable pharmaceutical carriers include, but are not limited to, non-toxic buffers, bulking agents, isotonic solutions, etc. More specifically, the pharmaceutical carrier can be, but is not limited to, standard saline (0.9%), half saline, lactated Ringer's solution, 5% dextrose, 3.3% dextrose / 0.3% saline. Physiologically acceptable carriers can contain radiolytic stabilizers, e.g., ascorbic acid, which protect the integrity of the radiopharmaceutical during storage and transportation.

[0117] An aspect of the present invention relates to a pharmaceutical composition comprising a complex according to the present invention, a diluent, carrier, surfactant, and / or excipient.

[0118] An embodiment of the present invention is a single agent 212 This concerns Pb-labeled ligands. 212 Pb is used, and 224 The compounds of the invention will be complexed without any additional radionuclide such as Ra.

[0119] An aspect of the present invention is 212 Pb-labeled ligands and cations or weak complexes 224 This concerns a dual targeting solution containing Ra. This is a cation or weakly complexed 224 Exists as Ra 224 With Ra 212 It would be a compound of the invention that is complexed with Pb.

[0120] Aspects of the invention include compounds and / or complexes according to the invention, further comprising 224 The present invention relates to a pharmaceutical composition comprising Ra. 224 Ra may be a cation. 224 The addition of Ra, for example, 212 When present together with Pb it allows for dual targeting.

[0121] An embodiment of the present invention relates to a pharmaceutical composition comprising a complex according to the present invention, wherein the radioactivity is between 100 kBq and 100 MBq per dose.

[0122] An aspect of the present invention relates to a pharmaceutical composition comprising a complex according to the present invention, wherein 224 Ra and 212 The amount of Pb is in radioactive equilibrium.

[0123] An aspect of the present invention relates to a pharmaceutical composition comprising a complex according to the present invention, wherein 212 Pb vs. 224 The radioactivity ratio (MBq) between Ra is 0.5 to 2, 0.8 to 1.5, etc., or 0.8 to 1.3, etc., or preferably 0.9 to 1.15, etc.

[0124] kit The solutions must be prepared physiologically suitable for injection, either at a centralized manufacturing site or by a kit system, typically consisting of 2-4 vials, which after combination of the kit vials is thereby rendered physiologically suitable for injection. An embodiment of the present invention relates to a kit comprising a first vial containing a radiopharmaceutical composition according to the present invention, and a second vial containing a neutralizing solution for adjusting the pH and / or isotonicity of the radiopharmaceutical composition prior to administration to a patient.

[0125] For example, with respect to monoclonal antibodies, it is usually desirable to keep the self-dose of alpha particles resulting in a radiopharmaceutical solution below 0.5 kGy to avoid reduced binding properties due to radiolysis. Thus, it is advisable to administer the chelator-bound ligand to the radiopharmaceutical solution for several hours to 10 minutes prior to injection. 224 A kit system added to the Ra (including daughter nuclide) solution is recommended for concentrated solutions intended for remote shipment and depends on the radiolysis resistance of the radioligand produced.

[0126] Aspects of the present invention include: 224a first vial containing a Ra solution; and 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 chelators, cyclic chelators, cryptands, crown ethers, porphyrins or cyclic or acyclic polyphosphonates, DOTMP, EDTMP, bisphosphonate derivatives, DOTA, DOTA derivatives, pamidronate bound to DOTA, TCMC, TCMC derivatives, pamidronate bound to TCMC, antibody-bound DOTA, antibody-bound TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, wherein the complexing agent is 212 Pb etc. 224 The complexing agent is capable of complexing the daughter nuclide of Ra in the drug solution. 224 does not complex Ra; and optionally, instructions for mixing the first vial with the second vial, thereby forming a pharmaceutical composition ready for administration to a patient 1 minute to 12 hours after mixing.

[0127] In one embodiment of the present invention, the kit is for use as a medicament. 224 The term "Ra solution" 224 It should be understood that Ra is advantageously in solution and is not tethered to a surface, such as, for example, a resin. In certain embodiments, the kit includes a third vial containing a neutralization solution for adjusting the pH and / or isotonicity of the radiopharmaceutical solution prior to administration to a patient.

[0128] In a further preferred embodiment, 224 Ra and 212 The amount of Pb is in radioactive equilibrium in the first vial.

[0129] In yet another preferred embodiment, in the first vial 212 Pb vs. 224The radioactivity ratios between Ra (MBq) are 0.5-2, 0.8-1.5, etc., 0.8-1.3, etc., or 0.9-1.15.

[0130] In yet another embodiment, the first vial has a radioactivity in the range of 100 kBq to 100 MBq.

[0131] In one embodiment of the invention, the chelator-binding ligand is administered 30 minutes to 5 hours prior to injection, such as 1 to 3 hours prior to injection. 224 Ra (including daughter nuclides) is added to the solution.

[0132] In one embodiment of the invention, the chelator-binding ligand is administered 1 to 20 minutes prior to injection. 224 Ra (including daughter nuclides) is added to the solution.

[0133] In one embodiment of the invention, the chelator-binding ligand is administered 1 to 10 minutes prior to injection. 224 Ra (including daughter nuclides) is added to the solution.

[0134] In one vial, the chelate-labeled protein or peptide and in another vial, 224 A kit also forms part of the invention, which includes a Ra solution, whereby the two contents are mixed 1 minute to 12 hours before administration. In one embodiment, the mixing is carried out in a manner that allows the chelate 212 Pb and / or 212 This is done several hours (e.g., 5 hours) to 30 minutes before administration to the patient to allow Bi to bind.

[0135] In one embodiment of the present invention, the two contents are mixed 30 minutes to 1 hour before injection.

[0136] In one embodiment of the present invention, the two contents are mixed 1 to 20 minutes prior to injection.

[0137] In an embodiment of the invention, the two contents are mixed 1 to 10 minutes prior to injection.

[0138] Optionally, a third vial may be used containing a liquid used for dilution and isotonicity adjustment prior to administration of the radiopharmaceutical solution. This third vial may contain, if necessary, 212 It may contain EDTMP, which can chelate Bi.

[0139] Medical Applications An aspect of the present invention relates to a radiopharmaceutical composition according to the present invention for use as a medicament.

[0140] In one embodiment of the invention, the disease is cancer.

[0141] An aspect of the invention relates to a radiopharmaceutical composition according to the invention for use in the treatment of soft tissue and / or bone diseases, the treatment being specific to PSMA-expressing diseases, including soft tissue and bone diseases.

[0142] In one embodiment of the invention, the bone disease is selected from the group consisting of soft tissue and / or skeletal metastases from cancer to the breast, prostate, kidney, lung, bone, or multiple myeloma.

[0143] In one embodiment of the present invention, the cancer is prostate cancer. The cancer may also be breast cancer. The cancer may also be renal 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.

[0144] In one embodiment of the invention, the solution is administered at a dose in the range of 50-150 kBq / kg body weight, such as 50-100 kBq / kg body weight.

[0145] An aspect of the present invention relates to a method of treating malignant or non-malignant disease by administration to an individual in need thereof of a radiopharmaceutical composition according to the present invention.

[0146] This is a refined 212Pb-labeled ligands or, accordingly, against cells expressing the PSMA antigen associated with the progression of metastatic prostate cancer. 224 Ra functions as a skeletal treatment and 212 The Pb urea derivative may be used in a dual-targeting solution, acting as a systemic therapy.

[0147] Thus, the complexes and solutions of the present invention can be used in the treatment of metastatic prostate cancer.

[0148] Another embodiment related to the present invention is accordingly 212 Pb is complexed by the urea-based PSMA targeting agent disclosed herein and the cation 224 Ra relates to a pharmaceutical solution with dual targeting properties, targeting bone metastases by calcium mimetic bone uptake.

[0149] Methods for preparation An aspect of the invention relates to a method for providing a radiopharmaceutical composition according to the invention, said method comprising: a first solution, wherein 224 Ra and 212 providing a first solution in which the amount of Pb is in radioactive equilibrium; and a second solution comprising a complexing agent selected from the group consisting of p-SCN-Bn-DOTA-PSMA ligand, p-SCN-Bn-TCMC-PSMA ligand, 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-bound DOTA, antibody-bound TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, wherein the complexing agent is 212 Pb etc. 224 A daughter nuclide of Ra can be complexed, and wherein the complexing agent is 224providing a second solution that does not complex Ra; and mixing the first composition with the second composition, thereby providing a pharmaceutical composition according to the invention.

[0150] PSMA derivatives PSMA (also called prostate-specific cancer antigen, PSM, FGCP, FOLH, GCP2, mGCP, GCPII, NAALAD1, NAALAidase, FOLH1, glutamate carboxypeptidase 2, glutamate carboxypeptidase II, membrane glutamate carboxypeptidase, N-acetylated-α-linked acid dipeptidase I, pteroyl poly-γ-glutamate carboxypeptidase, folyl poly-γ-glutamate carboxypeptidase, folate hydrolase 1, prostate-specific membrane antigen, and cell proliferation inhibitory protein 27) is a type II transmembrane protein and prostate epithelial cell membrane antigen, and consists of a short NH2-terminal cytoplasmic domain, a hydrophobic transmembrane region, and a large extracellular domain. In humans, PSMA is an enzyme encoded by the FOLH1 (folate hydrolase 1) gene. Human GCPII contains 750 amino acids and weighs approximately 84 kDa.

[0151] Expression of PSMA is restricted to a few healthy tissues, such as lacrimal and salivary glands, proximal tubules, epididymis, ovary, luminal side of ileum, and astrocytes in the central nervous system (CNS); healthy prostate expresses relatively little PSMA, and it is confined to the apical epithelium of secretory ducts. In these non-malignant tissues, uptake of PSMA-targeted probes may be limited by the intact blood-brain barrier, the healthy proximal small intestine lumen, and incomplete cytoplasmic expression of PSMA in normal prostate. PSMA is most relevant in advanced androgen independence, metastatic disease, and PSMA is expressed in most primary prostate tumors, regardless of androgen status.

[0152] Small molecule PSMA inhibitors are zinc-binding compounds and can be classified into three types: 1) phosphonates, phosphates, and phosphoramidates; 2) thiols; and 3) ureas. Urea derivatives appear to have particularly interesting properties as carriers for radionuclides for diagnostics and therapy.

[0153] The latest invention is 212 It concerns the use of Pb-urea derivatives, which may be combined with androgen deprivation therapy to enhance PSMA expression for better uptake of the radioligand (Bakht et al., 2017).

[0154] Radiation levels 212 When the Pb-labeled urea derivative is used alone, the radioactivity levels will typically be between 1 MBq and 500 MBq per patient, more typically between 10 and 100 MBq per patient.

[0155] 212 In equilibrium with Pb 224 When Ra is complexed with a PSMA-binding urea derivative, dosing 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 Th-labeled PSMA-targeting complex-based urea derivatives according to the present invention are useful for bone-targeting for dual targeting. 223 This results in Ra.

[0156] 227 Th can be present in pure form or in various amounts. 223 Ra, for example, 227 10%, 50%, 100%, or 250% compared to Th 223 It may also include Ra.

[0157] General rules It should be understood that any features and / or embodiments discussed above relating to the compounds according to the invention apply by analogy to the methods described herein.

[0158] The following figures and examples are provided below to illustrate the present invention, they are intended to be illustrative and should not be construed as limiting in any way. EXAMPLES

[0159] In the following examples, the xenograft models used are typically in contrast to the PC3 PIP model used by other investigators, which generally shows 30-40% ID / g uptake of mouse xenografts. 177 Lu-PSMA-617 is a tumor model with intermediate levels of PSMA-ligand uptake of 10-15% of the injected dose per gram (%ID / g) in mouse xenografts.

[0160] Example 1. Novel PSMA-binding chelator ligands compared to PSMA-617 Background: Several carrier molecules exist for radioligand targeting of prostate-specific membrane antigen (PSMA). Lutetium-177-labeled PSMA-617 ( 177 Lu-PSMA-617) is the compound in the most advanced stage of clinical development for use in radionuclide therapy. This molecule operates in a preferred manner: 177 Lu and 225 It provides relevant tumor-to-normal tissue ratios for longer-lived (i.e., half-lives of several days) radionuclides, including Ac, but exhibits high kidney uptake at early time points (typically several hours after injection). 212For shorter-lived radionuclides such as Pb (half-life of 10.6 hours), early kidney uptake represents a potential toxicity problem. Therefore, it would be advantageous to use a PSMA ligand with less kidney uptake, but this would not reduce tumor uptake. The PSMA ligand molecule is composed of (1) a PSMA binding domain, (2) a linker domain, and (3) a chelator, and accordingly, the linker domain connects (1) and (3). The linker domain is also used to adjust the molecular size, polarity, etc. to affect the in vivo distribution properties. PSMA-11 and PSMA I&T, and 131 I and 211 The PSMA-binding domain (motif) used in PSMA-617, including the At-labeled PSMA-binding ligand, is a structure found in several molecules of this class developed by several different inventors and researchers.

[0161] Thus, the p-SCN-Bn-TCMC-PSMA ligand has an extended linker region that includes an isothiocyanato 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 differences result in significantly different biodistribution of the radiolabeled product, which reduces renal exposure compared to PSMA-617, and therefore may be beneficial for PSMA-expressing tumors. 212 The greater suitability of p-SCN-Bn-TCMC-PSMA ligand 1 for targeting Pb is shown in the examples herein below.

[0162] Materials and Methods: PSMA ligand precursors for radiolabeling were synthesized by a contract commercial synthesis house.

[0163] PSMA-617 was synthesized according to literature procedures. p-SCN-Bn-TCMC precursor was synthesized according to literature procedures. In the final synthetic step, TCMC-PSMA ligand was synthesized by coupling p-SCN-Bn-TCMC to the amino group of PSMA-binding ligand intermediate. Both PSMA-617 and TCMC-Bn-PSMA ligand 1 were purified by HPLC to >98% purity, dried, and stored as trifluoroacetate salts. Structures and molecular weights were determined. 1 The results were determined by H-NMR and MS analysis.

[0164] The trifluoroacetate salt of 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.

[0165] 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-carboxamido)propanamido)pentyl)carbamoyl)-L-glutamic acid; Trifluoroacetic acid (1:4)

[0166] PSMA-617 trifluoroacetate has the chemical formula C 57 H 75 F 12 N9O 24 and has a molecular weight of 1498.25 g / mol. [ka] Trifluoroacetate salt of p-SCN-Bn-TCMC-PSMA ligand 1

[0167] [ka] Trifluoroacetate salt of PSMA-617

[0168] Thus, the p-SCN-Bn-TCMC-PSMA ligand has an extended linker region that includes 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 result in significantly different biodistribution of the radiolabeled product, which reduces renal exposure compared to PSMA-617, and therefore may be useful for targeting PSMA-expressing tumors. 212 What makes it even more suitable for targeting Pb is shown in the examples below.

[0169] In conclusion, we describe a novel molecule that has the same PSMA binding region but a different linker region and different chelating properties compared to PSMA-617.

[0170] Example 2. 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, 177 Carbon-substituted pSCN-Bn-DOTA-PSMA ligand for radiolabeling with Lu etc. Compared to PSMA-617, the ligand has a larger size and 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 to effect chelation of the radionuclide compared to PSMA-617.

[0171] p-SCN-Bn-DOTA-PSMA Ligand 2 is the DOTA analog of p-SCN-Bn-TCMC-PSMA Ligand 1 described in Example 1 and has a carbon linker to the chelator backbone with no remaining chelator groups for interaction with the radiolabel, and is therefore expected to improve the stability of the chelate after radiolabeling compared to radionuclide-labeled PSMA-617.

[0172] Due to the addition of a lipophilic benzyl unit in 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 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.

[0173] [ka] Trifluoroacetate salt of p-SCN-Bn-DOTA-PSMA ligand 2

[0174] 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.

[0175] With the carbon substituted for the attachment to DOTA, this molecule 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, moreover, 68 It has properties that make it highly suitable for radiolabeling with positron emission tomography (PET) compatible radionuclides such as Ga.

[0176] Thus, we describe a novel PSMA-binding molecule, p-SCN-Bn-DOTA-PSMA ligand 2, suitable for radioligand imaging and therapy.

[0177] In conclusion, we describe a carbon-substituted pSCN-Bn-DOTA-PSMA ligand 2 that has distinct properties in terms of size and chelating properties compared to PSMA-617.

[0178] Example 3. Radionuclides tested Lutetium-177 was dissolved in dilute HCl and used as a ready-to-use 177 It was purchased as LuCl3. Lead-212 224 Radium-224 was obtained from a Ra-based solution. 228 The actinide resin with Th was bound to the actinide resin (Eichrom Technologies, LLC) by eluting the column containing the actinide resin with 1 M HCl. 228 The eluate was made from Th. The eluate was purified by a second Ac-resin column and the eluate was evaporated to dryness using a distillation vial equipped with a gas inlet cap placed in a heating block at approximately 110°C and a gentle stream of nitrogen gas to remove the solvent. When the distillation vial was free of solvent, typically 200-400 μl of 0.1 M HCl was added to dissolve the residue.

[0179] Example 4. Radiolabeling of PSMA-binding ligands usually, 177 Lu and 224 Ra / 212 The Pb solution was adjusted to the desired volume and pH 5-6 with 10% 5M HCl with ammonium acetate. The PSMA binding ligand was dissolved in 0.1M HCl with 0.5M ammonium acetate to a concentration of 1mg / ml. A concentration of 20 micrograms per ml of radioactive solution was typically used. The reaction mixture was incubated on a shaker for 15-30 minutes and labeling was typically assessed by thin layer chromatography. Lead-212 labeling was performed at room temperature or 37°C with p-SCN-Bn-TCMC-PSMA ligand 1, while PSMA-617 was 177 Lu-labeled and 212Pb-labeling was carried out at 90 °C. Typical radiolabeling yields were in the range of 90-100% for the compounds and radionuclides tested, and those providing concentrations of >1 μg per 20 μl were used. In conclusion, radiolabeling of both ligands was successful. The novel p-SCN-Bn-TCMC-PSMA ligand 1 had to be labeled at high temperatures. 177 In contrast to Lu-PSMA-617, 212 Radiolabeling with Pb was possible at room temperature.

[0180] 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). 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 min before application to the strips to measure free radionuclides. A small beaker containing approximately 0.5 ml of 0.9% NaCl was used to place the sample-spotted strips. Typically, 1-4 μl of sample was added to the strips approximately 10% above the bottom of the strip. After the solvent front had migrated approximately 20% from the top of the strip, the strips were cut in half and each half was placed in a 5 ml test tube for counting. In this system, the radiolabeled ligand remained in the bottom half, whereas the EDTA-complexed radionuclides migrated to the top. 212 Pb and 177 It was confirmed that both Lu cations were complexed with EDTA and could not migrate to the top.

[0181] In conclusion, a TLC system is used that allows rapid measurement of radiolabeling yields that effectively distinguishes between radioligand and free radionuclide.

[0182] Example 6. 224 From Ra solution 212 Pb isolation The radiolabeled ligand is then reacted accordingly with 224 Ra targets bone disease and ligand targets systemic metastatic disease 224 It can be used as a component of the Ra dual targeting solution. 224 The Ra generating solution was labeled in situ 212 It can be used to prepare Pb-labeled ligands, i.e. 212 Pb is 224 Complexed by the ligand in the presence of Ra. 40 μl of radium-224 / in 0.5 M ammonium acetate, pH 5-6 212 To 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. 212 Pb-labeled ligands were produced. 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 applied to a Sephadex G-10 column PD MiniTrap G-10 (GE Healthcare Life Sciences) and eluted with 0.9% NaCl. 212 Fractions eluted after application of Pb-containing eluate, typically 0.7-1.5 ml, were collected and analyzed by gamma counter and TLC, and radioligand binding assays were performed. Product purification procedures have high radiochemical yields (usually >80%) and typically 212 Reaches less than 0.4% compared to Pb-labeled ligands 224 It had high radiochemical purity of Ra.

[0183] In conclusion, p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 224 In the presence of Ra 212 It can be radiolabeled with Pb and the incorporated 224 Targeting bone metastases with Ra and 212A dual targeting solution for systemic tumor cell targeting with Pb-labeled PSMA ligand was produced.

[0184] Both assays were performed using a Sephadex G-10 gel filtration column. 212 Pb-labeled PSMA ligand showed >80% recovery and <0.4% 224 Ra leakage in solution 224 Isolated from Ra and highly purified for standalone PSMA targeting 212 Pb-labeled PSMA radioligand was produced.

[0185] Example 7. 212 In vitro stability test of Pb-labeled ligands 224 Ra / 212 Radiolabeled ligand in Pb solution was mixed 1:1 with PBS or bovine serum albumin and incubated for up to 48 hours at 37° C. TLC analysis was performed at 1, 4, 24, and 48 hours of incubation.

[0186] The data are shown in Table 1, and 212 Pb is 224 After it is produced from Ra, it continues to react with the ligand and maintains a high percentage of radiochemical purity even after 48 hours. Thus, the PSMA ligand is an ideal candidate for in situ production of radioligands suitable for centralized production and shipment to end users. 224 Compatible with the use of Ra solutions.

[0187] Table 1. PBS and FBS 212 Pb-TCMC-PSMA Ligand 1 and 212 Radiochemical purity of Pb-PSMA-617 [Table 1]

[0188] Conclusion: The data shows that 212Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 were detected over a long period of time. 224 It has been shown to be stable in Ra solution and is amenable to centralized manufacturing and shipping of a ready-to-use product to end users, which may be used in the treatment of cancer.

[0189] Example 8. 212 Binding of Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 to prostate cancer cells The cell binding rate was determined by adding 0.2 ml of C4-2 cells (5 × 10 per ml) to a 5 ml test tube. 7 Approximately 1 ng of radioligand was added to the cells (cells) and incubated for 1 hour before measuring the applied radioactivity, which was measured by 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, the % binding was found to be in the range of 40-53% after subtracting nonspecific binding. Nonspecific binding was measured by blocking the cells with an excess of 10 μg / ml of unlabeled ligand before adding the radioligand. No significant difference in cell binding was found between radiolabeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617. In conclusion, we show that radiolabeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 radioligands have similar cell binding properties in vitro and that p-SCN-Bn-TCMC-PSMA ligand 1 has relevant antigen binding capacity.

[0190] Example 9. Radiolytic stability of p-SCN-Bn-TCMC-PSMA ligand 1 assessed by radioligand binding capacity and TLC analysis using prostate cancer cells Table 2 shows the results of incubation of 0.2 ml of C4-2 cells (5 × 10 per ml) in a 5 ml test tube. 7Figure 1 shows the percentage of cell binding measured by adding approximately 1 ng of radioactive ligand to 100 mM NaCl (10 mM NaCl) and 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, resulting in an absorbed radiation dose to the solution of approximately 1.8 Gy after 24 hours and 3.3 Gy after 48 hours. The data (Table 2) show a slight decrease at the longest exposure times, but in general a relatively strong radiolysis resistance of the ligand is observed, which is consistent with the results of the 100 mM NaCl concentration measured at 24 hours prior to administration of the product. 224 With or without Ra removal 224 The Company will accommodate centralized manufacturing and shipment of Ra-based generator solutions to end users.

[0191] Table 2. 224 When kept in Ra solution 212 Binding ability of Pb-p-SCN-Bn-TCMC-PSMA ligand 1 [Table 2]

[0192] Conclusion: The data shows that 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 for a long period of time 224 It is stable in Ra solution and that it is stable during storage. 224 Since it is produced from Ra, PSMA ligand 212 Having demonstrated the ability to complex Pb, such solutions may be used therapeutically against cancer, provided that the absorbed radiation dose is kept below about 2 kGy.

[0193] Example 10. C4-2 Biodistribution of Radiolabeled Ligand in Nude Mice Bearing PSMA-Positive Xenografts 212 Pb and 177 Lu-labeled p-SCN-Bn-TCMC-PSMA ligand 1 with PSMA-617 224 Ra / 212The biodistribution of Pb solutions was compared after intravenous injection in nude mice receiving C4-2 xenografts at various time points after injection. Each group usually consisted of 3 mice. 212 Pb labelling was greater than 92% for the product.

[0194] 177 Lu vs. 212 Since very high levels of radionuclides were used for Pb, the molar concentration of the ligand was 177 Lu-PSMA-617 was significantly lower. 224 Ra / 212 Each animal was injected with Pb, i.e., approximately 0.2 nmol of ligand per mouse. The animals were anesthetized by cervical dislocation and sacrificed, after which they were dissected and tissue, blood, and urine samples were collected. The samples were weighed and counted in a gamma counter.

[0195] Example 11. In mice 212 Comparison of tumor binding and renal uptake of Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and PSMA-617 212 Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 with PSMA-617 224 Ra / 212 The biodistribution of Pb solutions was compared after intravenous injection in nude mice that received C4-2 xenografts after injection; three mice in each group. 212 Pb labeling was greater than 92% for both products. The molar concentration of the ligand was the same for both products, i.e., 12.5 nmol per MBq. 224 Ra / 212 Each animal was injected with Pb, i.e., approximately 0.2 nmol of ligand per mouse. The animals were anesthetized by cervical dislocation and sacrificed, after which they were dissected and tissue, blood, and urine samples were taken. The samples were weighed and counted in a gamma counter. Results: 4 hours after injection, 212The ratios of Pb-p-SCN-Bn-TCMC-PSMA ligand 1 to PSMA-617 were as follows: tumor 1.35; kidney 0.20; blood 1.21; liver 2.67; spleen 0.71. 224 That Ra biodistribution was not significantly altered was confirmed by counting samples after 3 days of storage. 212 Pbp-SCN-Bn-TCMC-PSMA ligand 1 212 Compared to Pb-PSMA-617, it showed a significantly different biodistribution, which, most notably, was very low, and the favorable ratio of uptake in the kidneys as kidneys is expected to be the main dose limiting normal tissue for PSMA radioligand therapy with a relatively short-lived α-emitter (Figure 1). 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1, compared with PSMA-617, 212 It shows very promising biodistribution at early time points, which is important when using shorter-lived radionuclides such as Pb.

[0196] Example 12. In mice 212 Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and 177 Comparison of tumor binding and renal uptake of Lu-labeled PSMA-617 method: 212 Pb-labeled p-SCN-Bn-TCMC-PSMA ligand 1 and 177 Tumor and kidney uptake of Lu-labeled PSMA-617 was compared at 1 and 4 hours after administration of the product by intravenous injection into nude mice bearing C4-2 xenografts as described in Example 9. Results: Tumor and kidney were the tissues taking up the most radioactivity. For example: 212 Tumor and kidney uptake of Pb-p-SCN-Bn-TCMC-PSMA averaged 13.9 and 8.1 percent of the injected dose per gram (%ID / g), respectively, at 4 hours post-injection. 177Tumor and kidney uptake of Lu-PSMA-617 averaged 13.6 and 17.4%ID / g, respectively, 4 hours after injection. It is noteworthy that the molar amount of ligand injected was very low for PSMA-617, which is known to reduce kidney uptake, but is still a novel 212 The Pb-labeled compound showed less kidney uptake. At 4 hours, the tumor to kidney ratios were as follows: 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1, 1.7; 177 Lu-PSMA-617, 0.8.

[0197] The mean tumor-to-kidney ratio determined at 1 hour post-dose was: 212 0.40 for Pb-p-SCN-Bn-TCMC-PSMA ligand 1, and 177 The ratio for Lu-PSMA-617 was 0.17. 212 Despite the high molar ligand concentration for Pb-p-SCN-Bn-TCMC-PSMA ligand 1, 177 Lu-PSMA-617 showed a better tumor-to-kidney ratio, and 212 It has been shown to be highly suitable for Pb-based α-emitter radioligand therapy.

[0198] Example 13. In mice receiving PSMA-positive xenografts 212 Biodistribution of single-targeted solution containing Pb-p-SCN-Bn-TCMC-PSMA ligand 1 For reaction with p-SCN-Bn-TCMC-PSMA ligand 1 as described 212 Pb / 224 Purified using Ra solution 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 was purified using a Sephadex G-10 gel filtration column and approximately 30 kBq and 300 ng of purified radioligand product was injected per animal. The data are shown in Table 3. As can be seen, kidney radioactivity is reduced relatively rapidly whereas tumor uptake shows good retention. Tumor to tissue ratios (Table 4) are:212 The suitability for Pb-targeted radioligands is shown.

[0199] in conclusion, 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 exhibits relevant targeting properties for use in radioligand therapy against PSMA-expressing prostate cancer.

[0200] Table 3. At various time points postinjection 212 Biodistribution of Pb-p-SCN-Bn-TCMC-PSMA Ligand 1 [Table 3]

[0201] Table 4. At various time points 212 Tumor-to-tissue ratio of Pb-p-SCN-Bn-TCMC-PSMA ligand 1 [Table 4]

[0202] Example 14. Dosage The radiation energy produced for the two nuclides is primarily from alpha particles, therefore only alpha particles are considered in the following estimates.

[0203] 212 Pb and her short-lived daughter, 212 It produces alpha radiation with an average energy of 7.8 MeV per Pb atom. 212 The half-life of Pb is 10.6 hours. 213 Bi and her short-lived daughter, 213 This produces an average alpha energy of 8.4 MeV per Bi atom. 213 The half-life of Bi is 46 minutes. It was considered to be equivalent to an alpha particle dose of 5 Sv / Gy. Therefore, 1Bq 212 When Pb completely decays, it will have a mass of 1×(10.6×60 / 46)×7.8 / 8.4=12.6Bq. 213 It produces an equivalent alpha dose of Bi.

[0204] Salivary gland, kidney and red bone marrow were complexed to PSMA-617 213 Bi and 225 It has been reported to be the dose-limiting tissue for Ac (Kratochwil, et al, 2018). Based on imaging of PSMA-617 labeled with a radionuclide suitable for positron emission tomography detection, 90% of tumors 212 70% for Pb 213 The arrival and decay of Bi atoms (ie, the relative decay rate) is considered to be the maximum percentage incorporation that should be present at the 30 minute time point.

[0205] The relative destruction rate of the dose-limiting tissue is 213 It is estimated that 70% of all tissues were associated with Bi-PSMA-617. 212 With regard to Pb-PSMA-617 uptake, 50% is thought to be degraded in the salivary glands, 30% in the kidneys, and 20% in the bone marrow.

[0206] Energy per 1Bq and 212 Pb- and 213 According to the correction of the relative decay rate of Bi-labeled PSMA-617, 212 Dose evaluation of Pb-PSMA-617: 213 Bi- and 225 This is presented in Table 5 along with previously published data on Ac-labeled PSMA-617. 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 and 212 Using mouse data comparisons of Pb-PSMA-617 and assuming similar tissue uptake rates in humans, 212 Dose estimates for Pb-p-SCN-Bn-TCMC-PSMA Ligand 1 are presented in Table 5.

[0207] Table 5. Dose assessment assuming similar product stability and affinity regardless of radionuclide [Table 5]

[0208] 225 Ac- and 213 Both Bi-labeled PSMA-617 have been used clinically and have been reported to have demonstrated potent antitumor activity. Based on the estimates in this example, 212 Pb-labeled urea-based PSMA inhibitors represent a very promising therapeutic tool against PSMA-expressing cancers.

[0209] Example 15. Dual targeting 224 Ra cations and 212 Dosimetry of Pb-labeled PSMA-targeted urea derivatives 212 In equilibrium with Pb-labeled PSMA-conjugated urea derivative 224 Use Ra. 150kBq 224 For the dose of Ra, the total radioactivity administered is 10.5 MBq in a 70 kg human. 223 Using published dosimetry for Ra, and 224 Ra and 223 Correcting for half-life differences between Ra, assuming the same biodistribution, and taking into account 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 MBq administered, and the estimated dose to the tumor was 5 times the red bone marrow uptake, i.e., 1.3 Gy.

[0210] An equivalent dose of 5 Sv / Gy is assumed for the alpha particle dose, so in Table 6 the data are translated into Sv per injected dose (10.5 MBq / patient).

[0211] Table 6. 224 Ra cation + 212 Pb-labeled PSMA-conjugated urea derivative * Dose assessment of [Table 6]

[0212] Example 15. 227 Dose estimation of Th-labeled PSMA-conjugated urea derivative In this embodiment, 177 Lu is expected to be labeled to p-SCN-Bn-DOTA-PSMA ligand 2 or a HOPO-derived version of this molecule. 223 Ra test and prostate cancer patients 225 Based on adaptation of data from the Ac-PSMA-617 trial (Chittenden et al., 2015, Kratochwil et al., 2017, 2018).

[0213] For alpha particle radiation, 1 Gy is considered to be an equivalent dose of 5 Sv.

[0214] Produced in an organization 223 It is believed that Ra localizes and decays. 227 Produced from the systemic circulation of Th 223 It is believed that 40% of Ra is retained within the skeleton. Alpha particle doses alone account for more than 95% of the total radiant energy produced by this component.

[0215] In tissues with longer residence times for the radiolabeled PSMA urea derivative (salivary gland, kidney and tumor), 227 Arose from Th 223 The cumulative radioactivity of Ra is 227 It is thought that 20% of Th is expressed in the blood and 5% in red bone marrow. 227 It is assumed that 20% and 5% of the radium resulting from Th is in equilibrium with the alpha-emitting progeny radionuclides, so that essentially each radium decay produces an alpha emission of 26.4 MeV, whereas 227 Th produces the same α of 5.9 MeV.

[0216] 225 Ac and 227 Because the residence time is short compared to the half-life of Th, 227The cumulative radioactivity of Th was 225 Ac( 225 The α-radiation progeny decay from the parent nuclide and α-radiation progeny is considered to be 10% higher than that from the parent nuclide and α-radiation progeny decay. 225 This is thought to be a total alpha dose of 27.7 MeV per Ac atom.

[0217] In addition, red bone marrow dose and skeletal tumor dose were 227 Th-products are produced during systemic circulation etc. 223 There is a two-fold enhancement relative to the red bone marrow dose likely due to skeletal uptake of Ra.

[0218] The data are presented in Table 7. 227 Favourable tumor-to-tissue ratios for Th-labelled PSMA-conjugated urea derivatives are shown.

[0219] Table 7. 227 Dose estimation of equivalent doses for organs and tumors of interest for Th-labeled PSMA-conjugated urea derivatives (MBq / patient) [Table 7]

[0220] It is contemplated that the products described herein may be used in a single treatment or repeat treatment modality.

[0221] in conclusion, 212 Pb or 227 Dosimetry for the Th-labeled PSMA-targeted urea derivative shows promising tumor-to-tissue ratios indicating potential clinical benefit from its use.

[0222] Example 16. In nude mice receiving C4-2 xenografts 177 Lu-PSMA-617 and 212 Comparative treatment experiment using Pb-p-SCN-Bn-TCMC-PSMA ligand 1 Male nude mice were inoculated with C4-2-PSMA positive human prostate cells in the flank, and after 2 weeks, tumors had grown to 5-7 mm in diameter. Groups of eight animals each received either saline, 52 MBq of 177 Lu-PSMA-617 or 320 kBq 212 Pb-p-SCN-Bn-TCMC-PSMA ligand 1 was administered. When the tumor size reached 20 mm, the animals were sacrificed due to animal welfare requirements. Tumor dose was calculated based on the following assumptions: 177 With respect to Lu-PSMA-617 effective half-life, 10% of the injected dose per gram decays in the tumor, and 80% of the radiation from the decays in the tumor is absorbed in the tumor, resulting in 0.15 MeV of radiation energy per decay. 212 For Pb, the effective half-life is thought to be 10.6 hours, so 10% of the injected dose will decay in the tumor per gram, and 100% of the radiation will be absorbed in the tumor. 212 This results in 100% retention of Pb and its daughters and a radiation energy of 8 MeV per decay. The tumor dosimetry in terms of injected radioactivity is 177 Lu-PSMA-617 delivered an average of 35.9 Gy to the tumor and 212 The Pb-p-SCN-Bn-TCMC-PSMA ligand 1 group delivered 2.06 Gy to the tumor.

[0223] Results: 30 days after treatment, data were as follows: saline group, 177 Lu-PSMA-617 group and 212 The survival rates in the Pb-p-SCN-Bn-TCMC-PSMA ligand 1 group were 0%, 12.5%, and 75%, respectively (Figure 2). The median survival time was 0%, 12.5%, and 75%, respectively, in the saline group, 177 Lu-PSMA-617 group and 212 In the Pb-p-SCN-Bn-TCMC-PSMA ligand 1 group, the mean survival times were 15 days, 20 days, and >30 days (not reached), respectively.

[0224] In conclusion, the data show that radiation dose assessment is177 Despite being delivered with Lu-PSMA-617, which represented a 17-fold higher radiation dose in Gy, 212 Pb-p-SCN-Bn-TCMC-PSMA ligand pair 177 Lu-PSMA-617 shows strong tumor growth retardation. 212 Pb-p-SCN-Bn-TCMC-PSMA ligand pair 177 The relative radiobiological effectiveness (RBE) of Lu-PSMA-617 was at least 17. This high radiobiological effectiveness for therapeutic levels of α-emitters was hardly expected, since an RBE of 2-5 is typically expected for α-emitters versus β-emitters. and

[0225] References An effective chelator for the complexation of thorium-227. [ka]

[0226] matter 1. Compound X, a urea derivative suitable for targeting PSMA-expressing cells and tissues.

[0227] 2. 212 Pb, 177 Lu, 213 Bi, 225 Ac or 227 A complex comprising a compound X linked to Th, wherein said compound X is a urea derivative suitable for targeting PSMA-expressing cells and tissues.

[0228] 3. The compound X is reacted with a chelating molecule Z. 212 Pb or 227 Item 1. A compound according to item 1 or a complex according to item 2, linked to Th.

[0229] 4. 4. The compound or complex according to any one of claims 1 to 3, wherein 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-bound DOTA, antibody-bound TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A.

[0230] 4. 5. The compound or complex according to any one of items 1 to 4, wherein the linker is DOTA or a DOTA derivative.

[0231] 5. 5. The compound or complex according to any one of items 1 to 4, wherein the linker is a DOTA derivative, such as p-SCN-Bn-DOTA.

[0232] 6. 5. The compound or complex according to any one of items 1 to 4, wherein the linker is TCMC or a TCMC derivative.

[0233] 7. 7. The compound or complex according to any one of items 1 to 4 or 6, wherein the linker is a TCMC derivative, such as p-SCN-Bn-TCMC.

[0234] 8. 8. The compound or complex according to any one of items 1 to 7, wherein the linker is an octadentate hydroxypyridinone-containing ligand, such as 3,2-HOPO.

[0235] 9. The compound X linked to the chelating molecule Z has the following formula (I): [ka] {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 a bond or chain, where at least one carbon atom is optionally O, -NR 3 - or substituted with -C(O)-; G is C=O, C=S, C-NH2, or C-NR 3 and; 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 and R are the same or different; or a pharma- ceutical acceptable salt thereof, according to any one of items 1 to 8.

[0236] 10. The above 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}, or a medicamentically acceptable salt thereof, according to any one of items 1 to 9.

[0237] 11. The above A 4 is the bond, -(OCH2CH2) n - or -HC(0)CH2(OCH2CH2) n and L is a bond or -(OCH2CH2) n - {wherein n is independently 1 or 2}; or a medicamentically acceptable salt thereof, according to any one of items 1 to 10.

[0238] 12. The W has the following structure: [ka] {In the formula, R 20 and R 21 are each independently an amino acid residue linked via its amino group to the adjacent -C(O)- group;

[0239] 13. The W has the following structure: [ka] 13. The compound or complex according to any one of items 1 to 12, having the formula: {wherein R is hydrogen or a carboxylic acid protecting group}, or a pharma- ceutical acceptable salt thereof.

[0240] 14. The following structure: [ka] {where, R 17 is aryl}, or a pharma- ceutical acceptable salt thereof. The compound or complex according to any one of items 1 to 13, or a pharma- ceutical acceptable salt thereof.

[0241] 15. The complex is 212 A radionuclide such as Pb can be linked / chelated to the four N's ​​in PSMA-617: [ka] 15. The compound or complex according to any one of items 1 to 14, or a pharma- ceutical acceptable salt thereof,

[0242] 16. 16. The compound or complex according to item 15, wherein the DOTA unit is replaced by a TCMC unit.

[0243] 17. 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.

[0244] 18. 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 scaffold C-linked to a urea derivative (PSMA).

[0245] 19. The compound has the following backbone-C linkages: p-SCN-Bn-DOTA or p-SCN-Bn-TCMC: [ka] wherein Z is one of the following: [ka] (wherein X is -OH or NH2).

[0246] 20. The compound has the following backbone-C linkages: p-SCN-Bn-DOTA or p-SCN-Bn-TCMC: [ka] 20. The compound or complex according to any one of items 15 to 19, wherein X is -OH or NH2.

[0247] twenty one. The compound is the following backbone-C linked p-SCN-Bn-DOTA, i.e., p-SCN-Bn-DOTA-PSMA-Ligand 2: [ka] 21. The compound or complex according to any one of items 15 to 20,

[0248] twenty two. The compound is the following backbone-C linked p-SCN-Bn-TCMC, i.e., p-SCN-Bn-TCMC-PSMA Ligand 1: [ka] 21. The compound or complex according to any one of items 15 to 20,

[0249] twenty three. 212 A PSMA-targeted urea derivative containing a TCMC group for chelating Pb.

[0250] twenty four. 227 PSMA-targeted urea derivatives containing HOPO for chelating Th.

[0251] twenty five. 212 Pb or 227 PSMA-targeted urea derivatives containing DOTA labeled with either Th.

[0252] 26. A pharmaceutical composition comprising a compound or complex according to any one of claims 1 to 21 and / or a PSMA targeted urea derivative according to any one of claims 15 to 17, and a diluent, carrier, surfactant and / or excipient.

[0253] 27. 224 27. The radiopharmaceutical composition according to item 26, further comprising Ra.

[0254] 28. 28. The radiopharmaceutical composition according to any one of items 26 to 27, wherein the radioactivity is 100 kBq to 100 MBq per dose.

[0255] 29. The above 224 Ra and 212 29. The radiopharmaceutical composition according to any one of items 26 to 28, wherein the amount of Pb is in radioactive equilibrium.

[0256] 30. The above 212 Pb vs. 224 30. The radiopharmaceutical composition according to any one of items 26 to 29, wherein the 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 preferably such as 0.9 to 1.15.

[0257] 31. below: - a first vial containing a radiopharmaceutical composition according to any one of items 26 to 30, and - a second vial containing a neutralization solution for adjusting the pH and / or isotonicity of the radiopharmaceutical composition prior to administration to a patient, Kit including:

[0258] 32. below: - 224 Ra, 212 Pb, and / or 227 The 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 bound to DOTA, TCMC, TCMC derivatives, pamidronate bound to TCMC, antibody-bound DOTA, antibody-bound 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 is 212 Pb etc. 224 The complexing agent is capable of complexing the daughter nuclide of Ra in the drug solution. 224 Does not complex Ra; and - optionally, instructions for mixing the first vial with the second vial, thereby forming a pharmaceutical composition ready for administration to a patient between 1 minute and 12 hours after mixing; Kit including:

[0259] 33. 33. The kit according to any one of claims 31 to 32, wherein the kit is for use as a medicament.

[0260] 34. 23. The radiopharmaceutical composition according to any one of items 18 to 22 for use as a medicament.

[0261] 35. 23. The radiopharmaceutical composition according to any one of items 18 to 22 for use in the treatment of a bone disease.

[0262] 36. 36. The radiopharmaceutical composition for use according to item 35, wherein said bone disease is selected from the group consisting of skeletal metastases from cancer to the breast, prostate, kidney, lung, bone, or multiple myeloma, or non-cancerous diseases causing unwanted calcification, including ankylosing spondylitis.

[0263] 37. 37. The radiopharmaceutical composition for use according to any one of items 34 to 36, wherein the solution is administered at a dose in the range of 50 to 150 kBq per kg of body weight, such as 50 to 100 kBq per kg of body weight.

[0264] 38. A method for treating a malignant or non-malignant disease by administering to an individual in need thereof the radiopharmaceutical composition according to any one of items 26 to 30.

[0265] 39. A method for providing a radiopharmaceutical composition according to any one of items 26 to 30, the method comprising the steps of: a) a first solution, comprising: 224 Ra and 212 Prepare a first solution in which the amount of Pb is in radioactive equilibrium; b) a second solution comprising 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-bound DOTA, antibody-bound TCMC, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-Do3A, wherein the complexing agent is 212 Pb etc. 224 A daughter nuclide of Ra can be complexed, and wherein the complexing agent is 224 providing a second solution that does not complex Ra; and c) mixing the first composition with the second composition, thereby providing a pharmaceutical composition according to any one of items 26 to 30; The method includes:

Claims

1. Complexed with a radioactive nuclide 【Chemistry 1】 1. A complex comprising: wherein said radionuclide is selected from the group consisting of 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 227 Th, and 177 Lu.

2. The radioactive nuclide is ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac and ２２７ 2. The complex of claim 1, wherein said at least one of said aryl groups is selected from the group consisting of:

3. The radioactive nuclide is ２１２ 3. The complex of claim 2, wherein the metal is Pb.

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

5. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is administered at a radioactivity of 100 kBq to 100 MBq per dose.

6. The pharmaceutical composition of claim 4, wherein the composition is administered at a radioactivity of 1 MBq to 500 MBq per dose.

7. A complex described in any one of claims 1 to 3 for use in the manufacture of a medicament for the treatment or imaging of a PSMA-expressing tumor.

8. The complex for use according to claim 7, wherein the PSMA-expressing tumor is breast cancer, prostate cancer, renal cancer, lung cancer, bone cancer, or multiple myeloma.

9. The method of claim 7, wherein the PSMA-expressing tumor is prostate cancer.

10. The complex for use according to any one of claims 7 to 9, wherein the medicament has a radioactivity of between 1 MBq and 500 MBq.

11. A pharmaceutical composition comprising: 【Chemistry 2】 or a salt thereof, and Contains radionuclides, A pharmaceutical composition having a radioactivity of 100 kBq to 100 MBq.

12. The pharmaceutical composition of claim 11, wherein the radioactive nuclide is 68 Ga, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 227 Th, or 177 Lu.

13. The pharmaceutical composition of claim 11, wherein the radioactive nuclide is 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or 177 Lu.

14. The pharmaceutical composition described in any one of claims 11 to 13, having a radioactivity of 1 MBq to 20 MBq.

15. A complex for use in the manufacture of a medicament for inhibiting, treating or imaging a tumor, the complex comprising: 【Chemistry 3】 or a salt thereof, and Contains radionuclides, The pharmaceutical agent is a complex having a radioactivity of 1 MBq to 500 MBq.

16. A complex for use according to claim 15, wherein the radionuclide is 68 Ga, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 227 Th, or 177 Lu.

17. A complex for use according to claim 15, wherein the radionuclide is 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or 177 Lu.

18. A complex for use according to any one of claims 15 to 17, wherein the pharmaceutical has a radioactivity of between 1 MBq and 20 MBq.

19. The complex for use according to any one of claims 15 to 18, wherein the tumor is breast cancer, prostate cancer, renal cancer, lung cancer, bone cancer, or multiple myeloma.

20. The complex for use according to any one of claims 15 to 18, wherein the tumor is a PSMA-expressing tumor.

21. The complex for use according to any one of claims 15 to 20, wherein the tumor is prostate cancer.

22. A kit comprising: 【Chemistry 4】 or a vial containing a solution of said salt thereof; Radionuclides, and The kit further comprises a neutralizing solution for adjusting the pH and / or isotonicity of the solution.

23. The kit of claim 22, wherein the radioactive nuclide is 68 Ga, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 227 Th, or 177 Lu.

24. The kit of claim 22, wherein the radioactive nuclide is 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or 177 Lu.

25. The kit of any one of claims 22 to 24, wherein the vial has a radioactivity in the range of 1 MBq to 500 MBq.

26. The kit of claim 22, wherein the vial has a radioactivity of 100 kBq to 100 MBq.

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