Methods for treating SSTR-positive cancer

Abstract

Provided herein are methods of treating SSTR + cancer using radiopharmaceutical compositions. The radiopharmaceutical compositions may include one or more stabilizers, an aqueous vehicle, and a conjugate containing a targeting ligand and a radionuclide bound to a metal chelating agent. The targeting ligand may be a small molecule compound or peptide, such as a monocyclic peptide. The targeting ligand may be configured to bind to a tumor target. The stabilizers may include radiolytic stabilizers, free metal chelating agents, and / or pH stabilizers. Also provided herein are methods of making the radiopharmaceutical compositions and methods of treating cancer by administering the radiopharmaceutical compositions.

Description

Cross-reference to related applications

[0001] This application claims U.S. Provisional Application No. 63 / 504,696, filed May 26, 2023; International Application Serial No. PCT / US2023 / 024352, filed June 2, 2023; and U.S. Provisional Application No. 63 / 622,465, filed January 18, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] In the United States, cancer is the leading cause of death in people under 65, accounting for approximately 21% of all deaths in 2018. Neuroendocrine tumors (NETs) originate from neuroendocrine cells and are most commonly found in the lungs, digestive tract, and pancreas. NETs are among the cancers requiring systemic therapy because they are either inoperable or diagnosed at an advanced stage when tumor cells have spread to distant sites. For decades, traditional radiation therapies such as external beam radiation therapy have been used as standard care for patients with confirmed cancer. While some patients respond to external beam radiation therapy, many others do not. Furthermore, metastatic and circulating tumor cells can spread after standard care and remain in the bloodstream or body fluids, leading to resistance to therapy. The presence of cancer cells in various parts of the body reduces the effectiveness of traditional radiation therapy. Therefore, strategies for targeted radiation therapy are being developed to better treat and diagnose cancer. One of the major challenges in the production of radiopharmaceuticals is extending the shelf life of the product to allow for treatment of patients in locations far from the manufacturer's location. Compositions of radionuclides with improved stability and shelf life (e.g., radionuclides that emit alpha particles) remain in demand. Summary of the Invention

[0003] One of the major challenges in radiopharmaceutical production is extending the shelf life of the product to allow for patient treatment in locations far from the manufacturer's location. As radionuclides (such as actinium-225) decay, a range of highly reactive chemicals are produced. In some cases, these can react with pharmaceutical substances, for example, leading to degradation of the drug containing the radioisotope over time and increasing radioactive impurities. In one aspect, this article provides liquid radiopharmaceutical formulations that provide enhanced stability for alpha-emitting radionuclides such as actinium-225. In another aspect, this article provides formulations containing at least 120 hours of stability. 225 Ac-DOTA-TATE is a liquid radiopharmaceutical formulation.

[0004] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject at an amount equivalent to about 10.2 MBq per dose, and wherein the liquid radiopharmaceutical composition is administered at intervals of 7 to 9 weeks per cycle, with a maximum cumulative dose of about 40,800 kBq. In one aspect, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering an effective amount of the somatostatin receptor-positive (SSTR+) neuroendocrine tumor to the subject. 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, in which Lu-labeled somatostatin analogue (SSA) therapy is used. 225 Ac-DOTA-TATE was administered to the subjects at a dose equivalent to approximately 10.2 MBq per dose, and wherein... 225 Ac-DOTA-TATE is administered at intervals of 7 to 9 weeks per cycle, with a maximum cumulative dose of approximately 40,800 kBq.

[0005] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject as an initial dose equivalent to about 10.2 MBq per dose, and wherein at least one subsequent dose of the liquid radiopharmaceutical composition is administered to the subject at about 50% of the initial dose. In one aspect, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering an effective amount of the somatostatin receptor-positive (SSTR+) neuroendocrine tumor to the subject. 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, wherein the... 225 Ac-DOTA-TATE was administered to the subjects as an initial dose equivalent to approximately 10.2 MBq per dose, and wherein the... 225 At least one subsequent dose of Ac-DOTA-TATE was administered to the subject at approximately 50% of the initial dose.

[0006] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject as an initial dose equivalent to about 10.2 MBq per dose, and wherein if the subject has an adverse response to the initial dose, the liquid radiopharmaceutical composition is administered to the subject at a reduced dose of about 50% of the initial dose. In one aspect, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering an effective amount of... 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, wherein the... 225 Ac-DOTA-TATE is administered to the subject as an initial dose equivalent to approximately 10.2 MBq per dose, and wherein if the subject has an adverse reaction to the initial dose, the [unclear text - possibly a continuation of the previous sentence] is then [unclear text - possibly a continuation of the previous sentence]. 225 Ac-DOTA-TATE was administered to the subject at a reduced dose of approximately 50% of the initial dose.

[0007] In one aspect, this article provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering to the subject an effective amount of 225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition. In some embodiments, the 225Ac-DOTA-TATE is administered less than 150 hours after its manufacture. In some embodiments, the 225Ac-DOTA-TATE is administered less than 72 hours after its manufacture. In some embodiments, the... 225 Ac-DOTA-TATE is administered less than 120 hours but more than 24 hours after its manufacture. In some embodiments, the 225Ac-DOTA-TATE is administered less than 120 hours but more than 48 hours after its manufacture. In some embodiments, the 225Ac-DOTA-TATE is administered less than 120 hours but more than 72 hours after its manufacture. In some embodiments, the subject has not previously received [a specific treatment / treatment]. 177 Lu-labeled somatostatin analog (SSA) therapy. In some embodiments, the subject has previously received... 177Lu-labeled somatostatin analog (SSA) therapy. In some embodiments, the subject has previously received a treatment selected from... 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC and 177 Lu-HA-DOTA-TATE 177 Lu-SSA therapy. In some implementations, the... 177 Lu-SSA therapy is administered for a minimum of 2 cycles and a maximum of 4 cycles. In some embodiments, SSTR+ neuroendocrine tumors in the subjects are... 177 Progression has occurred following Lu-sostatin analogue (SSA) therapy. In some implementations, subjects with GEP-NETs are considered unresponsive to PRRT, where PRRT is defined as having previously... 177 Lu-DOTATATE / TOC or 177 Disease control (PR, CR, or SD) has not been achieved for at least 6 months following the last dose of Lu-HA-DOTATATE. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject has histologically confirmed, well-differentiated, inoperable advanced GEP-NET of grade 1-2.

[0008] In some embodiments, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering to the subject an effective amount of 225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has at least one characteristic selected from: (a) a Ki-67 index of up to 20%; (b) a creatinine clearance of at least 50 mL / min (or at least 60 mL / min); (c) a hemoglobin concentration of at least 5.0 mmol / L; (d) an absolute neutrophil count of at least 1000 cells / μL; (e) at least 100 x 10⁻⁶ cells / μL. 9 (f) a platelet count of at least 3 g / dL; (g) a total bilirubin level of at most three times the upper limit of normal; (h) a serum albumin level of at least 3.0 g / dL; (f) an SSTR+ neuroendocrine tumor with a Krenning score of 3 or 4; and (i) a combination thereof.

[0009] In some embodiments, this document provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of 225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject does not possess at least one characteristic selected from: (a) [missing information - likely related to...] 225 Actin68 gallium, 64 (a) Copper hypersensitivity; (b) Cardiovascular disease; (c) Refractory hypertension; (d) Uncontrolled diabetes; (e) In the application of the above-mentioned... 225 Ac-DOTA-TATE has a history of primary malignancy within the past 3 years, wherein the prior malignancy is not GEP-NET, treated skin carcinoma in situ or non-melanoma, cured malignancy or actively monitored untreated cancer; (f) brain, meninges or spinal cord metastases; (g) cirrhosis; and (h) combinations thereof.

[0010] In some embodiments, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering to the subject an effective amount of 225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has not received: (a) radioembolization; (b) prior to administration of the... 225 (c) Surgery within 12 weeks (84 days) prior to the administration of Ac-DOTA-TATE; 225 (d) Chemoembolization within 12 weeks (84 days) prior to the administration of Ac-DOTA-TATE; 225 (e) Radiofrequency ablation within 12 weeks (84 days) prior to the application of Ac-DOTA-TATE; 225 Ac-DOTA-TATE prior to peptide receptor radionuclide therapy (PRRT), but 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC and 177 Except for Lu-HA-DOTA-TATE; (f) when applying the above 225 Chemotherapy administered within 6 weeks (42 days) prior to the administration of Ac-DOTA-TATE; (g) during the administration of the aforementioned 225 Small molecule inhibitors within 4 weeks (28 days) prior to the administration of Ac-DOTA-TATE; (h) during the administration of the aforementioned 225 (i) investigational therapy within 4 weeks (30 days) prior to the administration of Ac-DOTA-TATE; 225 Biological agents administered within 7 days or 5 half-lives (whichever is longer) prior to the use of Ac-DOTA-TATE, or those administered as described above. 225 (j) Biological agents administered within 4 weeks prior to the application of Ac-DOTA-TATE; 225 Colony stimulating factors within 4 weeks (28 days) prior to the administration of Ac-DOTA-TATE; (k) during the administration of the aforementioned 225(l) Platelet production stimulants within 4 weeks (28 days) prior to the administration of Ac-DOTA-TATE; 225 Blood transfusion within 4 weeks (28 days) prior to Ac-DOTA-TATE; (m) external beam radiation therapy to more than 25% of the bone marrow; (n) during the administration of the aforementioned 225 (o) external beam radiation therapy of less than 25% within 6 weeks prior to Ac-DOTA-TATE; (p) liver transplantation; 225 High-dose glucocorticoids within 14 days prior to Ac-DOTA-TATE; or (q) combinations thereof.

[0011] In some embodiments, this document provides a method for treating a subject in need of a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an unresectable, advanced, somatostatin receptor-expressing (SSTR+), well-differentiated gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), which has been previously... 177 Lu-SSA therapy (such as) 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC or 177 Progress has been made since Lu-HA-DOTA-TATE.

[0012] In one aspect, this document provides a liquid radiopharmaceutical composition comprising: (i) a conjugate, wherein the conjugate is 225 Ac-DOTA-TATE; (ii) one or more stabilizers; and (iii) an aqueous medium. In one aspect, this document provides a liquid radiopharmaceutical composition comprising: (i) a conjugate, wherein the conjugate is 225Ac-DOTA-TOC; (ii) one or more stabilizers; and (iii) an aqueous medium. In one aspect, this disclosure relates to a liquid radiopharmaceutical composition comprising a conjugate, optionally one or more stabilizers, and an aqueous medium. The conjugate further comprises a targeting ligand, a metal chelator covalently attached to the targeting ligand, and a radionuclide bound to the metal chelator. In some embodiments, the targeting ligand binds to somatostatin receptors (SSRs), such as somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). In some embodiments, the targeting ligand binds to somatostatin receptor type 2 (SSTR2). In some embodiments, the targeting ligand is a binding peptide comprising 6 to 14 amino acid residues. In some embodiments, the targeting ligand is a tyr 3 -Octreotate, edolithotide, octreotate, or octreotide. In some embodiments, the targeting ligand is tyr. 3 - Octreotide. In some embodiments, the targeting ligand is an agonist of the SSR. In some embodiments, the targeting ligand is an antagonist of the SSR. In some embodiments, the binding affinity of the targeting ligand to human SSR is not greater than 250 nM, not greater than 100 nM, not greater than 50 nM, or not greater than 5 nM, as determined by half-maximal inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR is determined by [method / measurement]. In some embodiments, the binding affinity of the target ligand to human SSR is no greater than 250 nM, as determined by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the targeting ligand to human SSR is determined by [method / measurement]. In some embodiments, the binding affinity of the targeting ligand to human SSR is not greater than 100 nM, as determined by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR is determined by [method / measurement]. In some embodiments, the binding affinity of the target ligand to human SSR is not greater than 50 nM, such as by [method / measurement] at half-maximum inhibition concentration (IC50). 50 In some embodiments, the binding affinity of the targeting ligand to human SSR is no greater than 5 nM, such as by half-maximum inhibition concentration (IC50). 50 The binding affinity of the target ligand to human SSR is determined by [method / measurement]. In some embodiments, the binding affinity of the target ligand to human SSR is no greater than 2 nM, such as by [method / measurement] at half-maximum inhibition concentration (IC50). 50The determination is made by measuring the target ligand. In some embodiments, the human SSR is SSTR2. In some embodiments, the target ligand is covalently linked to the metal chelating agent via a linker. In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound material as part of the conjugate after 72 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound material as part of the conjugate after being subjected to temperatures of about 20ºC to about 25ºC for 120 hours. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 95% of the content bound as part of the conjugate after being subjected to temperatures of about 20ºC to about 25ºC for 120 hours. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound material as part of the conjugate after being subjected to temperatures of about 20ºC to about 25ºC for 120 hours. 225 The content of Ac is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after being kept at about 20ºC to about 25ºC for 72 hours. 225 The content of Ac can be determined by high performance liquid chromatography / fractional collection (HPLC-FC).

[0013] In one aspect, this document describes a radiopharmaceutical composition comprising a conjugate, said conjugate further comprising a targeting ligand covalently linked to a metal chelating agent via a linker. In some embodiments, the metal chelating agent is selected from AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2 A. NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH2-Bn-CHX-A″-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx -DTPA, 1B4M-DTPA-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA, l,4,8,11-tetraazacyclotetradecane-l,4,8,11-tetrapropionic acid (TETPA), DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L 1 H3L 4 H2azapa, H5decapa, bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa 2H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TRAP-Pr, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, thioctic acid, TGA, BAL, thiourea, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H2DEDPA , p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, motesafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE 3TA-NCS, NODASA, NETA-monoamide, C-NETA, TACN-HSB, NOPO, BPCA, p-SCN-Bn-DRO, DRO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L py L1, L2, L3, and EuK-106. In another embodiment, the metal chelating agent is the metal chelating agent disclosed in US Patent US11541134B1. In another embodiment, the metal chelating agent is... Figure 3 The metal chelating agent shown is, in some embodiments, DOTA, HEHA, or macropa. The metal chelating agent may be DOTA.

[0014] In one aspect, the disclosure herein refers to a radiopharmaceutical composition comprising one or more stabilizers. The stabilizer may include a radiolysis stabilizer, which may be an amino acid or peptide or a derivative thereof, a vitamin or a derivative thereof, a lipid or a derivative thereof, a carbohydrate or a derivative thereof, a bulking agent, or an antioxidant. In some embodiments, the amino acid or peptide is selected from N-acetyl-L-cysteine, glutathione, L-lysine, seleno-L-methionine, glutathione, albumin, melatonin, taurine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and derivatives thereof. In some embodiments, the amino acid is methionine. In some embodiments, the radiolysis stabilizer is an antioxidant, such as a flavonoid or a derivative thereof. In some embodiments, the flavonoids are (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate or CG), 3,3',4',5,5',7-hexahydroxyanthocyanin chloride, (-)-cis-3,3',4',5,7-pentahydroxyflavone (epicatechin or EC), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, 3,4,5-trihydroxybenzoic acid (gallic acid), 3,4',5,7-tetrahydroxyflavone (kaempferol), luteolin, 2-(3,4-dihydroxyphenyl)-5, 7-Dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]oxychromene-4-one (rutin), quercetin, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromene-3-yl] 3,4,5-Trihydroxybenzoate or epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin or EGC) or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC). In some embodiments, the flavonoid is a catechin or a derivative thereof, such as (2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate or CG), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin or EC), 3,4,5-trihydroxybenzoic acid (gallic acid), (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epicarcatechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromene-3-yl] 3,4,5-Trihydroxybenzoate or epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin or EGC) or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC). The antioxidant may also be a carotenoid or its derivative, such as all-trans-fucoxanthin, lycopene, etc. Lutein, beta-carotene, lycopene, or lutein. In some embodiments, the antioxidant is N-acetylcysteine, L-ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-acrylic acid (caffeic acid), beta-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate) ((-)catechin gallate or CG), 1,4,5-trihydroxycyclohexanecarboxylic acid, trans-4-hydroxycinnamic acid (p-coumaric acid), 3,3',4',5,5',7-hexahydroxyanthocyanin chloride, lipoic acid (dihydrolipoic acid, DHLA), 4,4',5,5',6,6'-hexahydroxybiphenyl dicarboxylic acid 2,6,2',6'-bis(ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavone (epicatechin or EC), 2-methoxy-4-(2-propenyl)phenol, trans-4-hydroxy-3 -Methoxycinnamic acid (ferulic acid), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, all-trans-fucoxanthin, 3,4,5-trihydroxybenzoic acid (gallic acid), (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((-)-gallicatechin), glutathione, 2-(3,4-dihydroxyphenyl)ethanol, 3,4',5,7-tetrahydroxyflavone (kaempferol), (±)-1,2-Dithiocyclopentane-3-pentanoic acid, luteolin, lycopene, L-lysine, neochlorogenic acid, oleic acid, trans-3,5,4'-trihydroxystilbene (resveratrol), 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5- Trihydroxy-6-methyltetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]oxychrome-4-one, Rutin, Selenol-L-methionine, Thiourea, (+)-α-tocopherol, Lutein, Citric Acid (CA), Gentian Acid (GA), Salicylic Acid (SA), Isoascorbic Acid (EA), Phenol, Sodium Bisulfite, Butylated Hydroxyanisole, Butylated Hydroxytoluene, Metabisulfite, Benzyl Alcohol, Thymol, Lipoic Acid (LA), Thioglycolic Acid (TGA), 2,3-Dimercaptoprop-1-ol (BAL), Zinc, Selenium, Aluminum, Ethanol, Mannitol, Sucrose, Melatonin, Ebuselenoline, Pyruvic Acid, Carboxy-PTIO, Trolox, Uric Acid, Edaravone, Beta-Carotene, NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol, Panthenol, Copper, Quercetin Cortisone, taurine, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromene-3-yl] 3,4,5-Trihydroxybenzoate or epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin or EGC), (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC), (-)-epigallocatechin-3-O-gallate, 5-aminolevulinic acid hydrate, polysorbate 80, allicin, sodium L-ascorbate, hyaluronic acid, dextran 60-90, selenool, and LysaKare. The radiolytic stabilizer may also be a vitamin or its derivative, such as L-ascorbic acid, β-carotene, provitamin A, (+)-α-tocopherol, isoascorbic acid (EA), Trolox, and lutein. In some embodiments, the radiolytic stabilizer is a lipid. The lipid may be a fatty acid, such as a saturated or unsaturated C6 to C2 fatty acid. 30Fatty acids. In some embodiments, the fatty acids are oleic acid, myristoleic acid, palmitoleic acid, sapienic acid, trans oleic acid, trans isoleic acid, linoleic acid, or alpha-linolenic acid. In another embodiment, the lipids are steroids or derivatives thereof, such as estrogen, estradiol, estriol, or cortisone. The radiolytic stabilizer may also be a carbohydrate or a derivative thereof, such as mannitol, sucrose, dextran (e.g., dextran 40, dextran 70), and cyclodextrins (e.g., alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin). In some embodiments, the radiolytic stabilizer is a volume-expanding agent. The volume-expanding agent may be a polymer or a mixture of polymers, such as PEG 3350, PEG 4000, polygelatin peptides, Haemaccel, Gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride, US FDA 2018 label). In some embodiments, the volume-expanding agent is selected from dextran, dextran 40, dextran 70, cyclodextrin, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, PEG 3350, PEG 4000, polygelatin peptides, Gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride, US FDA 2018 label). In some embodiments, the radiation stabilizer is selected from N-acetyl-L-cysteine, L-ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-acrylic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate or CG), 1,4,5-trihydroxycyclohexanecarboxylic acid, trans-4-hydroxycinnamic acid (p-coumaric acid), 3,3',4',5,5',7-hexahydroxyanthocyanin chloride, lipoic acid (dihydrolipoic acid, DHLA), 4,4 ',5,5',6,6'-Hexahydroxybiphenyl dicarboxylic acid 2,6,2',6'-bis(ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavone (epicatechin or EC), 2-methoxy-4-(2-propenyl)phenol, trans-4-hydroxy-3-methoxycinnamic acid (ferulic acid), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, all-trans-fucoxanthin, 3,4,5-trihydroxybenzoic acid (gallic acid), (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((-)-gallicatechin), glutathione, 2-(3,4-Dihydroxyphenyl)ethanol, 3,4',5,7-tetrahydroxyflavone (kaempferol), (±)-1,2-dithiacyclopentane-3-pentanoic acid, luteolin, lycopene, L-lysine, neochlorogenic acid, oleic acid, trans-3,5,4'-trihydroxystilbene (resveratrol), 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4, 5-Trihydroxy-6-methyltetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]oxychrome-4-one, rutin, selenoyl-L-methionine, thiourea, (+)-α-tocopherol, lutein, alanine and its derivatives, arginine and its derivatives, asparagine and its derivatives, aspartic acid and its derivatives, cysteine ​​and its derivatives, glutamine and its derivatives, glutamic acid and its derivatives, glycine and its derivatives, histidine and its derivatives, isoleucine and its derivatives, lysine and its derivatives Biological substances, methionine and its derivatives, phenylalanine and its derivatives, proline and its derivatives, serine and its derivatives, threonine and its derivatives, tryptophan and its derivatives, tyrosine and its derivatives, valine and its derivatives, citric acid (CA), gentian acid (GA), salicylic acid (SA), isoascorbic acid (EA), phenol, sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene, glutathione, metabisulfite, benzyl alcohol, thymol, lipoic acid (LA), thioglycolic acid (TGA), 2,3- Dimercaptopropane-1-ol (BAL), Zinc, Selenium, Aluminum, Ethanol, Mannitol, Sucrose, Melatonin, Ebuselenol, Pyruvic Acid, Carboxy-PTIO, Trolox, Uric Acid, Edaravone, Beta-Carotene, NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol, Panthenol, Copper, Quercetin, Cortisone, 2,3-Dimercaptosuccinic Acid (DMSA), Monoisopentyl Derivative (MiADMSA), Taurine, Dextran, Dextran 40, Dextran 70, PEG 3350, PEG 4000, Polygelatin Peptide, Glycerol, PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride, US FDA 2018 label), Cyclodextrin, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromene-3-yl] 3,4,5-Trihydroxybenzoate or epicatechin gallate (ECG), (2R,3R)-2-(3,4,(5-Trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin or EGC) and (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC).

[0015] In one aspect, this document discloses a radiopharmaceutical composition comprising one or more stabilizers, the stabilizers further comprising a first radiolytic stabilizer and a second radiolytic stabilizer. In some embodiments, the first radiolytic stabilizer and the second radiolytic stabilizer have a molar ratio of 1:5 to 5:1. In another aspect, this document discloses a radiopharmaceutical composition comprising a radiolytic stabilizer. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.01 mM to about 5 M. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at a concentration of about 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 500 mM. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.1 mM to about 500 mM. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at a concentration of about 10 mM to about 500 mM. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at a concentration of about 20 mM to about 100 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.0001 wt% to about 10 wt%. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.1 to 50 mg / mL.

[0016] In one aspect, this document discloses a radiopharmaceutical composition comprising one or more stabilizers, said stabilizers comprising a free metal chelating agent that is not attached to the targeting ligand. In some embodiments, the free metal chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 2-S-(4-benzyl isothiocyanate)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), 1,4,7,10,13-pentazacyclopentadecane-N,N',N",N"',N""-pentaacetic acid (PEPA), l 4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid (TETPA), triethylenetetraminepentaacetic acid, 2,2′,2"-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tetraacetic acid (DOTA-GA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphate) DOTP, deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid) (DOTP), 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))bis(pyridine-2-carboxylic acid) (Macropa), meso-2,3-dimercaptosuccinic acid (DMSA), dimercaptopropanesulfonate (DMPS), dihydrolipoic acid (DHLA), lipoic acid (LA), mercaptoglycolic acid (TGA), and 2,3-dimercaptoprop-1-ol (BAL). In some embodiments, the free metal chelating agent is EDTA, DTPA, or Macropa. In some embodiments, the free metal chelating agent is present at approximately 0.001... The free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 10 mM to about 500 mM.

[0017] In one aspect, this document discloses a radiopharmaceutical composition comprising one or more stabilizers, said one or more stabilizers comprising one or more pH stabilizers. In another aspect, this document discloses a radiopharmaceutical composition comprising a pH stabilizer. In some embodiments, the pH stabilizer is the same as the radiolysis stabilizer. The pH stabilizer can be used as a pH buffer. In some embodiments, the one or more pH stabilizers comprise an organic acid, such as acetic acid, fumaric acid, ascorbic acid, propionic acid, benzenesulfonic acid, carbonic acid, citric acid, aspartic acid, maleic acid, methanesulfonic acid, or tartaric acid. In some embodiments, the one or more pH stabilizers comprise an inorganic acid, such as hydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, or sulfuric acid. In some embodiments, the one or more pH stabilizers may comprise a base, such as tromethamine (Tris), ammonium hydroxide, diethanolamine, or sodium hydroxide. In some embodiments, the one or more pH stabilizers may also comprise an amino acid or a salt thereof. In some embodiments, the amino acid is glycine, lysine, arginine, histidine, or a salt thereof. In another embodiment, the one or more pH stabilizers comprise an alkaline salt, such as sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate. In some embodiments, the one or more pH stabilizers may comprise an acidic salt, such as ammonium sulfate. In some embodiments, the one or more pH stabilizers comprise sodium acetate, sodium ascorbate, ascorbic acid, acetic acid, fumaric acid, propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (l)-lysine, maleic acid, methanesulfonic acid, phosphoric acid, sodium dihydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, sodium hydroxide, sodium / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (tris), or combinations thereof. In some embodiments, the one or more pH stabilizers are present in the radiopharmaceutical composition at a concentration of about 0.001 wt% to about 10 wt%. In some embodiments, the one or more pH stabilizers are present in the radiopharmaceutical composition at a concentration of about 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%. In some embodiments, the one or more pH stabilizers are present in the radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL. In some embodiments, the one or more pH stabilizers are present in the radiopharmaceutical composition at a concentration of about 10 mM to about 500 mM. The one or more pH stabilizers may be configured to maintain the pH of the radiopharmaceutical composition at a concentration of about 4 to about 8.The one or more pH stabilizers can be configured to maintain the pH of the radiopharmaceutical composition at about 5 to about 7. In some embodiments, the pH of the radiopharmaceutical composition is in the range of about 4 to about 8. In some embodiments, the pH of the radiopharmaceutical composition is about 5.5 to about 6.0. The radiopharmaceutical composition may contain one or more radiolysis stabilizers, one or more free metal chelating agents, and / or one or more pH stabilizers.

[0018] In one aspect, this document discloses a radiopharmaceutical composition comprising an aqueous medium. The aqueous medium may include water (e.g., water for injection), saline solution, glucose solution, glucose saline solution, Ringer's solution, or lactated Ringer's solution. The radiopharmaceutical composition may be isotonic. The radiopharmaceutical composition may be a solution or a suspension. In some embodiments, the radiopharmaceutical composition is formulated for intravenous infusion or bolus injection. In some embodiments, the radiopharmaceutical composition further comprises one or more excipients selected from: tonic modifiers, preservatives, antimicrobial agents, solubilizers, suspending agents, and surfactants.

[0019] In one aspect, this document discloses a radiopharmaceutical composition comprising a conjugate, the conjugate further comprising a targeting ligand covalently linked to a metal chelating agent via a linker. In some embodiments, the targeting ligand is a binding peptide, and the linker is attached to the peptide via the N-terminus of the binding peptide. In some embodiments, the targeting ligand is a binding peptide, and the linker is attached to the peptide via the C-terminus of the binding peptide. In some embodiments, the targeting ligand is a binding peptide, and the linker is attached to the peptide via a non-terminal amino acid of the binding peptide. The linker may comprise one or more groups selected from: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0020] In one aspect, this document discloses a radiopharmaceutical composition comprising a conjugate, said conjugate further comprising a radionuclide. The radionuclide may be an alpha-emitting radionuclide, such as actinium-225, astatine-211, thorium-227, or radium-223. In some embodiments, the alpha-emitting radionuclide is actinium-225. In some embodiments, the actinium-225 is present in the radiopharmaceutical composition, providing a volumetric radioactivity of about 0.5 to 20 MBq / mL. In some embodiments, the conjugate is... 225 Ac-DOTATATE. In another embodiment, the conjugate is 225Ac-DOTATOC. In some embodiments, the radiopharmaceutical composition retains at least 90 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 95 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 98 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 120 hours at room temperature. In some embodiments, the composition retains 95 mol% or more of the initial conjugate after 48, 72, 96, 120, 148, 168, 192, or 216 hours at room temperature. In some embodiments, the radionuclide is actinium-225, and the composition contains no more than about 5% free actinium after 168 hours at room temperature, compared to the total amount of initially chelated actinium in the composition. In some embodiments, the radionuclide is actinium-225, and the composition contains no more than about 2% or about 1% free actinium after 168 hours at room temperature, compared to the total initial chelated actinium content in the composition. In some embodiments, the radionuclide is actinium-225, and the composition contains no more than a total of 5 mol% of free actinium-225 isotopes after 168 hours at room temperature, compared to the total initial chelated actinium content in the composition. In some embodiments, the radionuclide is actinium-225, and the composition contains no more than a total of 1 mol% of unchelated (free) actinium-225 isotopes after 168 hours at room temperature, compared to the total initial chelated actinium content in the composition. In some embodiments, the purity or molar percentage of the initial conjugate is determined by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the purity or molar percentage of the initial conjugate is determined by instantaneous thin-layer chromatography (iTLC).

[0021] In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) a conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 0.1 to about 100 mCi / L (e.g., about 10 to about 50 mCi / L, about 0.5 to about 100 mCi / L, 1 to about 50 mCi / L); (b) a radiolysis stabilizer, wherein the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 50 to about 200 mM (e.g., about 80 to about 120 mM); (c) an optional pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 10 wt%; (d) a free metal chelator, wherein the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL); and (e) an aqueous medium. In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) the conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 50 mCi / L (e.g., about 10 to 50 mCi / L); (b) a radiolysis stabilizer, wherein the radiolysis stabilizer is ascorbic acid or a salt thereof (e.g., sodium L-ascorbate) and is present in the radiopharmaceutical composition at a concentration of about 50 to about 200 mM (e.g., about 80 to about 120 mM); (c) a free metal chelating agent, wherein the free metal chelating agent is selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA or combinations thereof, and wherein the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 1 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous saline solution. In some embodiments, the radiopharmaceutical composition further comprises a pH stabilizer. In some embodiments, the radiopharmaceutical composition further comprises a second radiolysis stabilizer. In some embodiments, the second radiolysis stabilizer (e.g., dextran 40) is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10 wt%. In some embodiments, the second radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.05 wt% to about 5 wt%.In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) the conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 50 mCi / L (e.g., about 10 to 50 mCi / L); (b) a radiolysis stabilizer; (c) an optional pH stabilizer, wherein the pH stabilizer is configured to maintain the pH of the radiopharmaceutical composition at about 4 to 8; (d) a free metal chelating agent, wherein the free metal chelating agent is configured to maintain the level of free radionuclides in the radiopharmaceutical composition below about 0.05 mCi / L; and (e) an aqueous medium. In some embodiments, the radiolysis stabilizer (such as ascorbic acid or sodium ascorbate) may be used as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer are the same compound. In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) the conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 0.5 to 50 mCi / L; (b) a radiolysis stabilizer; and (c) optionally a pH stabilizer, wherein the pH stabilizer is configured to maintain the pH of the radiopharmaceutical composition at about 4 to 8; (d) a free metal chelating agent, wherein the free metal chelating agent is configured to maintain the level of free radionuclides in the radiopharmaceutical composition below about 0.05 mCi / L; and (e) an aqueous medium. In some embodiments, the radiolysis stabilizer (such as ascorbic acid or sodium ascorbate) may be used as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer are the same compound. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 2 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 100 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 50 mCi / L.

[0022] In one aspect, this disclosure relates to a method for preparing the radiopharmaceutical composition described herein. In some embodiments, the method for preparing the radiopharmaceutical composition includes reacting a radionuclide (such as...) with a radioactive nuclide. 225 Ac) is combined with an unlabeled conjugate (e.g., DOTATATE or DOTATOC) in the presence of one or more stabilizers, wherein the unlabeled conjugate comprises a targeting ligand and a metal chelating agent covalently attached to the targeting ligand, thereby producing a conjugate comprising a labeled conjugate.225 Ac-DOTATATE or 225 A mixture of Ac-DOTATOC; and optionally, one or more stabilizers are combined with the mixture. In some embodiments, the method for preparing the radiopharmaceutical composition includes reacting a radionuclide (such as...) with a radioactive nuclide. 225 Ac) is combined with an unlabeled conjugate (e.g., DOTATATE or DOTATOC), wherein the unlabeled conjugate comprises a targeting ligand and a metal chelating agent covalently attached to the targeting ligand, thereby producing a labeled conjugate; and the one or more stabilizers are combined with the labeled conjugate.

[0023] In one aspect, this disclosure relates to a method of treating a disease in a subject of need, the method comprising administering to the subject the radiopharmaceutical composition described herein. The disease may be cancer. In some embodiments, the cancer is an SSR-related cancer, such as an SSTR2-related cancer. The cancer may be a neuroendocrine carcinoma, lymphoma, pancreatic cancer, pituitary cancer, breast cancer, gastric cancer, lung cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine carcinoma, which may optionally be recurrent. In some embodiments, the neuroendocrine carcinoma is refractory to radiotherapy comprising a radionuclide emitting beta particles. In some embodiments, the subject has received radiotherapy comprising a radionuclide emitting beta particles prior to the administration of the radiopharmaceutical composition described herein. The neuroendocrine carcinoma may also be neuroendocrine lung cancer or neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine carcinoma is a carcinoid tumor in the lung, gastrointestinal tract, or thymus; a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, vasodilator, gastropancreatic neuroendocrine tumor); medullary thyroid carcinoma; Merkel cell carcinoma; pheochromocytoma of the adrenal gland; adrenal carcinoma; small cell carcinoma (e.g., in the lung); or large cell carcinoid tumor (e.g., in the lung). In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the lung cancer is extensive-stage small cell lung cancer. In some embodiments, the cancer is untreated. In some embodiments, the cancer is relapsed or refractory. In some embodiments, the small cell lung cancer is untreated. In some embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 1 kBq / kg to about 0.2 GBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 5 kBq / kg to about 50,000 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 20 kBq / kg to about 5,000 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 50 kBq / kg to about 500 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 50 kBq / kg to about 200 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 60 kBq / kg to about 150 kBq / kg body weight per dose.In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactivity dose of about 1 to 1,000 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactivity dose of about 10 to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactivity dose of about 100 to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactivity dose of about 100 to 300 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactivity dose of about 150 to 300 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactivity dose of about 175 to 275 μCi. In some embodiments, the radiopharmaceutical composition is administered at 8-week intervals. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose of about 10,000 kBq to about 100,000 kBq in the subject. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose of about 40,000 kBq to about 70,000 kBq in the subject. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose of about 40,800 kBq in the subject.

[0024] In one aspect, this article provides a diluted solution comprising one or more stabilizers and an aqueous medium.

[0025] In one aspect, this document provides a liquid radiopharmaceutical composition comprising: (a) 225 Ac-DOTA-TATE, wherein 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 80 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 90% of its saturation after 120 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In one aspect, this document provides a liquid radiopharmaceutical composition comprising essentially the following: (a) 225 Ac-DOTA-TATE, wherein 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 80 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 90% of its saturation after 120 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In one aspect, this document provides a liquid radiopharmaceutical composition comprising: (a) 225 Ac-DOTA-TATE, wherein 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 90% of its saturation after 120 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the... 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 25 mCi / L. In some embodiments, the... 225Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 12 mCi / L to 23 mCi / L. In some embodiments, the... 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 40 μg to about 120 μg of DOTA-TATE. In some embodiments, the... 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 25 μg to about 150 μg of DOTA-TATE. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 100 mM. In some embodiments, the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL. In some embodiments, the composition retains at least 90% of its styrene content after 168 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac. In some embodiments, the composition retains at least 90% of its content after being at about 20ºC to about 25ºC for 192 hours. 225 Ac-DOTA-TATE 225 The content of Ac. In some embodiments, the radiopharmaceutical composition is formulated into a unit dosage form containing about 12 mL of the solution, and wherein the liquid radiopharmaceutical composition comprises: (a) present in the radiopharmaceutical composition in an amount of 146-275 μCi in the about 12 mL solution. 225 (a) Ac-DOTA-TATE; (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 18.5 mg / mL; (c) DTPA present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL; and (d) an aqueous solution of sodium chloride at a concentration of about 0.9% w / w. In some embodiments, the liquid radiopharmaceutical composition has a pH of about 5.5 to about 7.0. In some embodiments, the radiopharmaceutical composition is formulated for intravenous infusion.

[0026] In one aspect, this document provides a liquid radiopharmaceutical composition, wherein... 225 Ac-DOTA-TATE has the following structure: .

[0027] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition comprises: (a) 225 Ac-DOTA-TATE, wherein 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 80%, at least 85%, or at least 90% of its saturation after 48 hours, 72 hours, or 120 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac can be determined by methods such as radiometric thin-layer chromatography (radio-TLC).

[0028] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition comprises essentially the following: (a) 225 Ac-DOTA-TATE, wherein 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 80%, at least 85%, or at least 90% of its saturation after 48 hours, 72 hours, or 120 hours at about 20ºC to about 25ºC.225 Ac-DOTA-TATE 225 The content of Ac can be determined by methods such as radiometric thin-layer chromatography (radio-TLC).

[0029] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition comprises: (a) 225 Ac-DOTA-TATE, wherein 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; (b) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 90% of its saturation after 120 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the subject has received treatment prior to the administration of the liquid radiopharmaceutical composition. 177 Lu-DOTA-TATE or 177 Lu-DOTA-TOC treatment. In some embodiments, the subject received [treatment / treatment] prior to the administration of the liquid radiopharmaceutical composition. 177 Lu-DOTA-TATE or 177Lu-DOTA-TOC treatment and tumor progression. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 60 kBq / kg body weight to 120 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 30 kBq / kg body weight to 240 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 15 kBq / kg body weight to 180 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 500 kBq / kg. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 1,000 kBq / kg. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 2,000 kBq / kg. In some embodiments, the radiopharmaceutical composition is administered at 8-week intervals. In some embodiments, the... 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 25 mCi / L.

[0030] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition comprises: (a) being present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 25 mCi / L. 25 (a) Ac-DOTA-TATE; (b) L-ascorbic acid sodium salt present in the radiopharmaceutical composition at a concentration of about 100 mM; (c) DTPA present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL; and (d) an aqueous solution of sodium chloride salt at a concentration of about 0.9% w / w.

[0031] In one aspect, this article provides a method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition is formulated in a unit dosage form having a solution of about 12 mL, and wherein the liquid radiopharmaceutical composition comprises: (a) being present in the radiopharmaceutical composition in an amount of 146-275 μCi in about 12 mL of solution. 225(a) Ac-DOTA-TATE; (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 18.5 mg / mL; (c) DTPA present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL; and (d) an aqueous solution of sodium chloride at a concentration of about 0.9% w / w. Incorporate by reference

[0032] For the specific purposes identified herein, all publications, patents and patent applications mentioned in this specification are incorporated herein by reference. Attached Figure Description

[0033] The novel features of this disclosure are set forth in the appended claims. The features and advantages of this disclosure will be better understood by referring to the following detailed description, which illustrates illustrative embodiments and drawings (also referred to herein as “figures” and “Figures (Illustrations)”) using the principles of this disclosure, and in the figures:

[0034] Figure 1 The structure of an exemplary stabilizer is shown.

[0035] Figure 2 The structure of an exemplary binding peptide is shown.

[0036] Figure 3 The structures of representative metal chelating agents were described.

[0037] Figure 4A and Figure 4B The abbreviations and modifications of amino acids are shown.

[0038] Figure 5 Depicting the use 225 The clinical treatment dosing schedule for Ac-DOTA-TATE is as follows: Patients receive a tapering dose regimen and will receive up to 4 cycles. 225 Ac-DOTA-TATE, once every 8 weeks.

[0039] Figure 6A The stained tissue samples with H scores of 281, 160, or 90 are shown. Figure 6B The images show stained tissue samples of normal lung or pancreas NET.

[0040] Figure 7 Depicting 225 The clinical treatment dosing schedule for Ac-DOTA-TATE is as follows: Patients receive an escalating dose structure and will receive 4-6 cycles. 225Ac-DOTA-TATE is administered every 6 weeks during standard of care (PD-L1i + CE) and every 4 weeks during the PD-L1 maintenance phase, for a maximum of 6 infusions. PD-L1i stands for PD-L1 inhibitor; C stands for carboplatin or cisplatin; E stands for etoposide. 225 Ac-DOTA-TATE is administered before or on the same day as PD-L1i, C, and E.

[0041] Figure 8 The Simon Phase 2 cohort expansion study of the clinical trial is described. The 1L-ES-SCLC cohort will receive... 225 Ac-DOTA-TATE in combination with standard care therapy (PD-L1i + CE). The 2L-ES-SCLC cohort will receive... 225 The combination of Ac-DOTA-TATE and CE. 1L-ES-SCLC represents first-line extensive-stage small cell lung cancer; 2L-ES-SCLC represents second-line extensive-stage small cell lung cancer; PD-L1i represents PD-L1 inhibitor; C represents carboplatin or cisplatin; E represents etoposide; DoR represents duration of response; CR represents complete response; PR represents partial response.

[0042] Figure 9A and Figure 9B The mean tumor volume and mean body weight are shown in mouse studies using [225Ac]Ac-DOTA-TATE and [225Ac]Ac-DOTA-JR-11, respectively.

[0043] Figure 10A and Figure 10B The treatment of SSTR2+ SCLC xenograft tumors with [225Ac]Ac-DOTA-TATE resulted in target-dependent, durable tumor suppression. [225Ac]Ac-DOTA-TATE was used as the formulation described in Example 24.

[0044] Figure 11A and Figure 11B Treatment of SSTR2+ SCLC xenograft tumors with [225Ac]Ac-DOTA-TATE resulted in durable tumor suppression superior to SOC. [225Ac]Ac-DOTA-TATE was used as the formulation described in Example 24. Detailed Implementation

[0045] The following description and examples illustrate embodiments of this disclosure in detail. It should be understood that this disclosure is not limited to the specific embodiments described herein and is therefore subject to change. Those skilled in the art will recognize that various variations and modifications of this disclosure are covered within its scope.

[0046] While the various features of this disclosure may be described in the context of a single embodiment, these features may also be provided individually or in any suitable combination. Conversely, although this disclosure may be described in the context of a single embodiment for clarity, this disclosure may also be implemented in a single embodiment.

[0047] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0048] All terms are intended to be understood in the manner of those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0049] The following definitions supplement those in this field and relate to this application, but are not to be categorized as relevant or irrelevant, such as any co-owned patents or applications. While any methods and materials similar to or equivalent to those described and used herein may be used in practice for testing the text of this disclosure, preferred materials and methods are described herein. Therefore, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. I. Definition

[0050] As used in the specification and appended claims, unless otherwise specified, the following terms shall have the meanings indicated below.

[0051] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly specifies otherwise. Thus, for example, reference to “an agent” includes multiple such agents, reference to “stabilizer” includes multiple such stabilizers, and reference to “the cell” includes reference to one or more cells and their equivalents known to those skilled in the art, and so on. When the scope is used herein with reference to physical properties (such as molecular weight) or chemical properties (such as chemical formula), it is intended to include all combinations and sub-combinations of the scope and specific embodiments thereof.

[0052] The term "about" or "approximately" can mean within an acceptable margin of error for a particular value, as determined by a person skilled in the art, depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, "about" can mean within one or more standard deviations. Alternatively, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within orders of magnitude of the value, within five times the value, or within twice the value.

[0053] The term “comprising” (and related terms such as “comprise”, “comprises”, or “having” or “including”) is not intended to exclude “consisting of the described features” or “consisting substantially of the described features” from certain other embodiments described herein (e.g., embodiments of any material composition, composition, method or process, etc.).

[0054] "Radiolysis" refers to the decay of radionuclides accompanied by the emission of energy in the form of alpha, beta, and / or gamma radiation. Energy entering a pharmaceutical preparation can break chemical bonds and generate reactive chemicals from solvent molecules, which can further decompose the radiopharmaceutical directly and / or indirectly.

[0055] "Amino" refers to the -NH2 group.

[0056] "Nitro" refers to the -NO2 group.

[0057] "Oxide group" refers to the =O group.

[0058] "Imine" refers to the =NH group.

[0059] "Hydroxyl" or "hydroxyl" refers to the -OH group.

[0060] "Alkyl" refers to a monovalent group of a straight-chain or branched saturated hydrocarbon that is optionally substituted. Alkyl groups can have one to about twenty carbon atoms, one to about ten carbon atoms, or one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups (such as heptyl, octyl, etc.). When used herein, numerical ranges such as “C1-C6 alkyl” mean that an alkyl group consists of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers instances where the term “alkyl” is not specified. In some embodiments, alkyl is C1-C6. 10Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with, for example, an oxo group, halogen, amino group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the alkyl group is optionally substituted with an oxo group, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -C≡CH. In some embodiments, the alkyl group is optionally substituted with an oxo group, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0061] The term "aryl" refers to a group comprising at least one aromatic ring, wherein each atom forming the ring is a carbon atom. The aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl group is phenyl. Depending on the structure, the aryl group may be a monovalent or divalent group (i.e., arylene). Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "aromatic-" (as in "arylalkyl") means to include optionally substituted aryl groups. In some embodiments, the aryl group comprises a partially reduced cycloalkyl group (e.g., 1,2-dihydronaphthalene) as defined herein. In some embodiments, the aryl group comprises a fully reduced cycloalkyl group (e.g., 1,2,3,4-tetrahydronaphthalene) as defined herein. When the aryl group comprises a cycloalkyl group, the aryl group is bonded to the remaining portion of the molecule via carbon atoms of the aromatic ring. The aryl group may be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused ring systems, spirocyclic systems, or bridged ring systems. Unless otherwise specifically stated in the specification, the aryl group may optionally be substituted with, for example, halogens, amino groups, alkylamino groups, aminoalkyl groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, heteroalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, -S(O)2NH-C1-C6 alkyl groups, etc. In some embodiments, the aryl group may optionally be substituted with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, -NO2 groups, -S(O)2NH2 groups, -S(O)2NHCH3 groups, -S(O)2NHCH2CH3 groups, -S(O)2NHCH (-CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3 are substituted. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen. In some embodiments, the aryl group is substituted with an alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group, wherein each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group is independently unsubstituted or substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0062] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, wherein each atom forming the ring (i.e., the skeleton atom) is a carbon atom. In some embodiments, the cycloalkyl group is saturated or partially unsaturated. In some embodiments, the cycloalkyl group is a spirocyclic compound or a bridging compound. In some embodiments, the cycloalkyl group is fused to an aromatic ring (in which case, the cycloalkyl group is bonded through non-aromatic carbon atoms). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrainyl, decahydronaphthyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise specifically stated in the specification, cycloalkyl groups may be optionally substituted. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (C3-C4). 15 cycloalkyl groups, having three to ten carbon atoms (C3-C4). 10Cycloalkyl groups are cycloalkyl groups having three to eight carbon atoms (C3-C8 cycloalkyl), three to six carbon atoms (C3-C6 cycloalkyl), three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). Cycloalkyl groups can comprise fused ring, spiro ring, or bridged ring systems. In some embodiments, the cycloalkyl group comprises a fused ring system. In some embodiments, the cycloalkyl group comprises a spiro ring system. In some embodiments, the cycloalkyl group comprises a bridged ring system. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic compounds include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl compounds include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyl compounds may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0063] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof). The heteroalkyl group is attached to the carbon atom of the heteroalkyl group to the rest of the molecule. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof), wherein the heteroalkyl group is attached to the carbon atom of the heteroalkyl group to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-. Unless otherwise specified in the specification, the heteroalkyl group is optionally substituted with, for example, an oxo group, halogen, amino group, nitrile group, nitro group, hydroxyl group, alkyl group, alkenyl group, alkynyl group, haloalkyl group, alkoxy group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the heteroalkyl group is optionally substituted with an oxo group, halogen, methyl group, ethyl group, -CN group, -CF3 group, -OH group, -OMe group, -NH2 group, or -NO2 group. In some embodiments, the heteroalkyl group is optionally substituted with an oxo group, halogen, methyl group, ethyl group, -CN group, -CF3 group, -OH group, or -OMe group. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0064] The term "heterocyclic alkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, a heterocyclic alkyl group can be a monocyclic or bicyclic system, which may include fused ring systems (where the heterocyclic alkyl group is bonded by non-aromatic atoms when fused with an aryl or heteroaryl ring) or bridged ring systems. The nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized. The nitrogen atom may optionally be quaternized. The heterocyclic alkyl group may be partially or fully saturated. Examples of heterocyclic alkyl groups include, but are not limited to, dioxolane, thienyl[1,3]dithiaalkyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocyclic alkyl groups have 2 to 12 carbons in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms and 1 or 2 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms and 3 or 4 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 12 carbon atoms, 0-2 nitrogen atoms, 0-2 oxygen atoms, 0-2 phosphorus atoms, and 0-1 sulfur atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 12 carbon atoms, 1-3 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (including heteroatoms) (i.e., the skeletal atoms of the heterocyclic alkyl ring). Unless otherwise specified in the specification, heterocyclic alkyl groups are optionally substituted with, for example, oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocyclic alkyl groups, heteroaryl groups, etc. In some embodiments, heterocyclic alkyl groups are optionally substituted with oxo groups, halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, heterocyclic alkyl groups are optionally substituted with oxo groups, halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, heterocyclic alkyl groups are optionally substituted with halogens.

[0065] "Heteroaryl" refers to a cyclic group comprising one or more carbon atoms and one or more cyclic heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group is monocyclic, bicyclic, or polycyclic. Illustrative examples of monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, furazolyl, indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, borazine, phthalazine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. Illustrative examples of monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, and furazonyl. Illustrative examples of bicyclic heteroaryl groups include indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, cinnamoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. In some embodiments, the heteroaryl group is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thiopheneyl, thiazolyl, or furanyl. In some embodiments, the heteroaryl group contains 0-6 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 4-6 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms, 0-1 oxygen atom, 0-1 phosphorus atom, and 0-1 sulfur atom in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms, 0-1 oxygen atom, and 0-1 sulfur atom in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group. In some embodiments, the heteroaryl group comprises a partially reduced cycloalkyl or heterocyclic alkyl group (e.g., 7,8-dihydroquinoline) as defined herein. In some embodiments, the heteroaryl group comprises a fully reduced cycloalkyl or heterocyclic alkyl group (e.g., 5,6,7,8-tetrahydroquinoline) as defined herein. When a heteroaryl group comprises a cycloalkyl or heterocyclic alkyl group, the heteroaryl group is bonded to the remainder of the molecule via a carbon atom or heteroatom in the heteroaryl ring. The heteroaryl group can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which can include fused ring systems, spirocyclic systems, or bridged ring systems. Unless otherwise specifically stated in the specification, the heteroaryl group may optionally be substituted, for example, with halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocyclic alkyl groups, heteroaryl groups, etc.In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0066] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally a recognized chemical entity that is embedded in or attached to a molecule.

[0067] As used herein, the terms “treatment,” “prevention,” “mitigation,” and “inhibition,” and those derived therefrom, do not necessarily imply 100% or complete treatment, prevention, mitigation, or inhibition. Rather, varying degrees of treatment, prevention, mitigation, and inhibition exist, which those skilled in the art will consider to have potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount and level of treatment, prevention, mitigation, or inhibition of disorders in mammals. For example, a disorder (including its symptoms or symptom) can be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, mitigation, or inhibition provided by the methods disclosed herein can include treatment, prevention, mitigation, or inhibition of one or more symptoms or symptom of a disorder (e.g., cancer or inflammatory disease). Additionally, for the purposes of this document, “treatment,” “prevention,” “mitigation,” or “inhibition” encompasses delaying the onset of a disorder or its symptoms or symptom. As used herein, “treatment” includes the concept of “remission,” which refers to reducing the frequency of occurrence or recurrence of any symptoms or other adverse effects associated with the disorder and / or related side effects, or reducing the severity of said symptoms or other adverse effects. The term “treatment” also encompasses the concept of “management,” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, such as prolonging the remission period for patients who already have the disease.

[0068] As used herein, the term "therapeutic effective amount" refers to an amount effective at the dose and duration required to achieve the desired therapeutic outcome. Therapeutic effective amounts of a composition can vary depending on factors such as an individual's condition, age, sex, weight, and the ability of the protein to elicit the desired response in an individual. Therapeutic effective amounts can also be amounts that exceed any toxic or harmful effects of the composition and have a beneficial therapeutic effect.

[0069] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the scenario in which the event or situation occurs and the scenario in which the event or situation does not occur. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0070] As used herein, the term "substituent" refers to a positional variable on an atom of the core molecule that is substituted at a specified atomic position, replacing one or more hydrogen atoms on the specified atom, provided that the substitution does not exceed the normal valence of the specified atom and the substitution produces a stable compound. Such combinations are permissible only when the combination of substituents and / or variables produces a stable compound. Those skilled in the art will note that any carbon and heteroatom having a valence that appears unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In some cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as an attachment point may be described, shown, or listed herein within the substituents section, where the structure may be shown only as a single bond as an attachment point to the core structure. Those skilled in the art will understand that while only single bonds are shown, double bonds are still intended to be used for those substituents.

[0071] The terms “optionally substituted” or “substituted” mean that the reference group is optionally substituted by one or more additional groups selected individually and independently from the following: D, halogen, -CN, oxo, -NH2, -NH (alkyl), -N (alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH (alkyl), -C(=O)N (alkyl)2, -S(=O)2NH2, -S(=O)2NH (alkyl), -S(=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, the optional substituents are independently selected from D, halogen, -CN, oxo, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from D, halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH (cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is replaced by one or two of the aforementioned groups. When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitutions, i.e., substituents replacing one hydrogen up to replacing all hydrogens.

[0072] The term "unsubstituted" means that a particular group does not have substituents.

[0073] Some of the compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure.

[0074] Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of said structures; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers and diastereomeric mixtures, are within the scope of this disclosure.

[0075] As used herein, the term "peptide" refers to a compound containing two or more amino acids. Peptides described herein may contain one or more non-natural amino acids. The term "peptide" also covers peptide analogs. In this disclosure, the term "amino acid" is used in its broadest sense and covers not only natural amino acids but also their derivatives and artificial amino acids. For example, the term "amino acid" covers non-natural amino acids.

[0076] As used in this article, the term "non-natural amino acid" refers to amino acids other than the 20 amino acids that are naturally present in proteins.

[0077] As used herein, the term "protein" refers to a polypeptide (i.e., a string of at least three amino acids linked together by peptide bonds). Proteins may include portions other than amino acids (e.g., glycoproteins, proteoglycans, etc.) and / or may be otherwise processed or modified. Proteins may be intact polypeptides (with or without a signaling sequence) produced by cells and / or active in cells. In some embodiments, a protein is or contains characteristic portions, such as polypeptides produced by cells and / or active in cells. Proteins may include more than one polypeptide chain.

[0078] The term "peptide mimic" or "mimic" refers to a bioactive compound that mimics the biological activity of a peptide or protein but is no longer entirely a peptide in its chemical properties; for example, it may contain non-peptide bonds (i.e., bonds other than amide bonds between amino acids). As used herein, the term peptide mimic is used in a broader sense to include molecules that are no longer essentially peptides, such as pseudopeptides, hemipeptides, and peptide-like molecules. Whether entirely or partially non-peptide, the peptide mimics described herein can provide a spatial arrangement of reactive chemical motifs that is very similar to the three-dimensional arrangement of the active groups in the subject amino acid sequence or subject molecule on which the peptide mimic is based. Due to this similar active site geometry, peptide mimics can exert biological activities on biological systems similar to those of the subject entity.

[0079] In some embodiments, peptide mimics are substantially similar to the subject amino acid sequence or subject molecule on which the peptide mimic is based, both in terms of three-dimensional shape and biological activity. Examples of methods for structurally modifying peptides to produce peptide mimics include inversions of the skeletal chiral centers of D-amino acid residue structures, which can (particularly at the N-terminus) result in enhanced stability against proteolytic degradation without adversely affecting activity. Examples are described in the article “Tritiated D-ala1-Peptide T Binding”, Smith CS et al., Drug Development Res., 15, pp. 371-379 (1988). A second approach is to modify the cyclic structure to obtain stability, such as N-to-C chain imides and lactams (Ede et al. in Smith and Rivier (ed.) “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp. 268-270). Examples of this are provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. The third method is to replace peptide bonds in the subject entity with pseudopeptide bonds that confer resistance to protein hydrolysis.

[0080] The ranges provided herein should be understood as abbreviations for all values ​​within the range. For example, the range 1 to 50 should be understood to include any number, combination of numbers, or subrange from any group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all intermediate decimal values ​​between the aforementioned integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. Regarding subranges, particular consideration is given to “nested subranges” extending from either endpoint of the range. For example, nested subranges of the exemplary range 1 to 50 may include 1 to 10, 1 to 20, 1 to 30 and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20 and 50 to 10 in another direction.

[0081] As used herein, C1-Cx (or C1-x) includes C1-C2, C1-C3…C1-Cx. By way of example only, a group designated as “C1-C4” indicates the presence of one to four carbon atoms in that moiety, i.e., a group containing one, two, three, or four carbon atoms. Therefore, by way of example only, “C1-C4 alkyl” indicates an alkyl group containing one to four carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Furthermore, by way of example only, C0-C2 alkylene groups include direct bonds, -CH2-, and -CH2CH2- linkages.

[0082] As used herein, the term "cyclized" or "cyclic" refers to the direct or indirect binding of two amino acids separated by at least one amino acid within a peptide to form a cyclic structure in the molecule. In some cases, the two amino acids bind via a linker or similar pathway.

[0083] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. On the one hand, mammals are companion animals, such as dogs or cats. On the other hand, a mammal is a human.

[0084] As used herein, the term "therapeutic effective amount" refers to the amount effective at achieving the desired therapeutic outcome. The therapeutic effective amount of a composition can vary depending on factors such as individual condition (e.g., age, sex, and weight), radiopharmaceutical conjugate, and method of administration (e.g., oral or parenteral). II. Technical Overview

[0085] Targeted radiopharmaceuticals (TRPs) are a new generation of nuclear medicine used for cancer treatment or diagnosis. TRPs selectively deliver high concentrations of molecules containing radionuclides to target cells, such as tumors, while delivering them at very low concentrations to unwanted cells present in normal, healthy tissues. The process can be achieved by engineering drug molecules with high-affinity binders (e.g., targeting ligands) and linking them to radioisotopes. The biological targets of these binders are highly expressed on tumor cells and have low or no expression in healthy tissues and organs. When the radioisotope decays, it emits high-energy ionizing radiation in the form of alpha, beta, and / or gamma particles. The energy released at the target site can cause damage or death of the target tissue or be visualized by an imaging scanner for therapeutic or diagnostic purposes.

[0086] In some traditional radiopharmaceutical formulations, stabilizers are used at very high concentrations relative to the radiopharmaceutical itself. These high concentrations can produce unknown biological effects and / or impair the therapeutic efficacy of the radiopharmaceutical. Because the stabilizers used in the past were inefficient, extensive dilution was required to slow decomposition. Therefore, in clinical settings, larger volumes of doses may need to be administered via infusion rather than bolus. This is less than ideal for patients due to prolonged stays at infusion centers and sometimes hospitalizations. One of the major challenges in radiopharmaceutical manufacturing is extending the product's shelf life to allow for patient treatment at locations far from the manufacturer's location. Increasing the stability of the radiopharmaceutical in its formulation solution can address this challenge.

[0087] In some cases, daughter isotopes can be released into solution as the parent isotope decays. These daughter isotopes can be non-radioactive or radioactive. When the daughter ions are radioactive, those unbonded ions can produce a non-specific distribution of radioactivity in the body and generate undesirable toxicity. Furthermore, even if they are not radioactive, they can still bind to the metal chelate portion of a radiopharmaceutical due to their higher affinity. Displacement of their parent ions can lead to the chemical decomposition of the drug substance. Over time, this process can also negatively affect radiochemical purity. When an actinium-225-DOTA-containing drug begins to decay, the isotope can first decay into francium-221(I). The recoil energy of the process can be approximately 10,000 times that of any known chemical bond energy. This can cause daughter ions to escape from their original chelating agent (e.g., DOTA). Due to the chemical properties of francium-221(I), in some cases, they cannot be recaptured by the free DOTA-containing drug. As decay continues, more free ions can enter the solution. Ultimately, most of the decayed daughter products can accumulate in the form of stable bismuth-209(III). Bismuth-209(III) can strongly chelate with DOTA and compete with Ac-225 for binding to the parent drug, causing Ac-225 to further dissociate from its chelating agent and produce additional radioactive free (unchelated) metal impurities.

[0088] The decay of radionuclides can be accompanied by energy emission in the form of alpha, beta, and / or gamma radiation. This energy can enter the solution containing the radiopharmaceutical and break chemical bonds, generating reactive chemicals from solvent molecules and further decomposing the radiopharmaceutical directly or indirectly. This process is called radiolysis. Radiolysis can be particularly severe when concentrated radioactive compounds are present in small volumes of solution. In the case of radiopharmaceuticals containing actinium-225-DOTA, actinium-225 can decay sequentially into francium-221, astatine-217, bismuth-213, thallium-209, polonium-213, lead-209, and bismuth-209. The decay chain can contain four alpha particle emissions and two beta particle emissions. Furthermore, francium-221 and bismuth-213 can release up to 25% of their decay energy through gamma emission. Ionizing radiation can cause radiolysis of surrounding water molecules, particularly producing H· atoms, ·OH radicals, and H3O. + Hydrogen peroxide, an ionic and oxidizing agent, is another component. These chemicals can be highly reactive. In some cases, over time, they can react with pharmaceutical substances, leading to the degradation of peptide drugs containing radioactive isotopes and increasing radioactive impurities.

[0089] Therefore, this article provides radiopharmaceutical compositions with improved stability, such as compositions containing actinium-225.

[0090] In one aspect, this disclosure relates to a radionuclide solution containing a radioisotope and its daughter ions. The solution composition may contain components that stabilize the radiopharmaceutical substance against radiolysis and chemical degradation. Increased stability of the pharmaceutical substance can extend the shelf life of the radiopharmaceutical, thereby enabling its widespread use as a pharmaceutical product for diagnostic and therapeutic purposes.

[0091] In one aspect, the compositions described herein have increased stability of the radiopharmaceutical conjugate. The radiopharmaceutical composition may contain components that stabilize the radiopharmaceutical substance against radiolysis and chemical decomposition, such as radiopharmaceutical stabilizers. Radiopharmaceutical stabilizers may contain reducing agents and / or free radical scavengers, such as ascorbic acid, to reduce radiolysis. The compositions of this disclosure may have an extended shelf life. The compositions described herein may contain one or more stabilizers. Stabilizers can prevent or delay radiolysis of the radiopharmaceutical conjugate. Stabilizers can prevent or delay the decomposition of the radiopharmaceutical conjugate. Stabilizers can prevent or delay the chemical decomposition of the radiopharmaceutical conjugate caused by daughter ions produced by radioactive decay. Stabilizers can prevent or delay the chemical decomposition of the radiopharmaceutical conjugate caused by pH changes. Stabilizers may be added to the composition at low concentrations. Stabilizers may optionally be added to the composition at low concentrations. The increased stability of the radiopharmaceutical conjugate enables one or more applications in the medical field. Applications may include pharmaceutical products used for one or more diagnostic purposes. Applications may include pharmaceutical products used for one or more therapeutic purposes. Treatment plans for patients or subjects receiving the radiopharmaceutical compositions described herein may include treatment at a remote location. Treatment plans for patients or subjects receiving the radiopharmaceutical compositions described herein may include shorter stays at infusion centers or hospitals.

[0092] Radiopharmaceutical conjugates may comprise a radionuclide and a metal chelating agent. The radionuclide and metal chelating agent may be linked by ionic and coordination bonds. Radionuclides for therapeutic purposes may include lutetium-177, actinium-225, yttrium-90, and bismuth-213. Radionuclides for diagnostic purposes may include gallium-68, copper-64, and indium-111. The chelating agent may further be covalently bound to a target binder, such as a target binder with high affinity for the target of the radiopharmaceutical conjugate, either directly or via a linker. Exemplary metal chelating agents may include azacrown ether polycarboxylic acids, such as 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Chelation prevents the release of the radionuclide into the environment in vitro and / or in vivo. III. Composition

[0093] In one aspect, this disclosure provides liquid radiopharmaceutical compositions comprising radiopharmaceutical conjugates. The conjugate may comprise a targeting ligand. The targeting ligand may be a binding peptide, chemical group, or small molecule. The conjugate may further comprise a chelating agent, such as a metal chelating agent. The chelating agent may be covalently attached to the targeting ligand. The conjugate may further comprise a radionuclide. In some embodiments, the radionuclide is bound to the chelating agent. The composition may further comprise one or more stabilizers. The one or more stabilizers are pharmaceutical agents capable of stabilizing the composition or formulation of the radiopharmaceutical conjugate. The one or more stabilizers can reduce or delay the decomposition of the radiopharmaceutical conjugate in the composition.

[0094] In one respect, this article provides [the following]: 225 Liquid radiopharmaceutical compositions containing Ac-DOTATATE. In one aspect, this document provides liquid radiopharmaceutical compositions containing Ac-DOTATATE. 225 Ac-DOTATOC liquid radiopharmaceutical compositions. In one aspect, this document provides compositions containing... 225 A liquid radiopharmaceutical composition comprising Ac-DOTA-JR-11. In one aspect, this document provides a liquid radiopharmaceutical composition comprising Ac-DOTA-JR-11. 225 Ac-HA-DOTA-TATE liquid radiopharmaceutical composition.

[0095] In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) a conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to about 100 mCi / L (e.g., about 10 to about 50 mCi / L, about 5 to about 50 mCi / L); (b) a pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at a concentration of about 50 to about 500 mM (e.g., about 80 to about 120 mM, about 50 to 200 mM); (c) an optional radiolysis stabilizer, wherein the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10 wt%; (d) a free metal chelator, wherein the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL); and (e) an aqueous medium.

[0096] In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) the conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 50 mCi / L; (b) a radiolysis stabilizer, wherein the radiolysis stabilizer is ascorbic acid or a salt thereof (e.g., sodium L-ascorbate) and is present in the radiopharmaceutical composition at a concentration of about 50 mM to about 1500 mM (e.g., about 80 to about 120 mM, about 80 to about 500 mM, about 50 mM to about 200 mM); and (c) a free metal chelating agent, wherein the free metal chelating agent is selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA or combinations thereof, and wherein the free metal chelating agent is present at a concentration of about 0.01 mg / mL to about 5 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 2.5 mg / mL). The radiopharmaceutical composition is present in a concentration of (mg / mL); and (d) an aqueous medium, wherein the aqueous medium is a saline solution. In some embodiments, the radiopharmaceutical composition further comprises a pH stabilizer. In some embodiments, a radiolysis stabilizer is used as a pH stabilizer. In some embodiments, the radiopharmaceutical composition further comprises a second radiolysis stabilizer. In some embodiments, the second radiolysis stabilizer (e.g., dextran 40) is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10 wt%. In some embodiments, the second radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.05 wt% to about 5 wt%. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 50 mCi / L. In some embodiments, the radiopharmaceutical composition comprises a pH stabilizer present in the preparation at a concentration of about 80 to about 500 mM. In some embodiments, the radiopharmaceutical composition comprises a pH stabilizer present in the preparation at a concentration of about 50 mM to about 200 mM. In some embodiments, the radiopharmaceutical composition comprises a pH stabilizer present in the preparation at a concentration of about 25 mM to about 300 mM. In some embodiments, the radiopharmaceutical composition comprises a free metal chelating agent present in the preparation at a concentration of about 0.01 mg / mL to about 1 mg / mL. In some embodiments, the radiopharmaceutical composition comprises a free metal chelating agent present in the preparation at a concentration of about 0.02 mg / mL to about 3 mg / mL.In some embodiments, the radiopharmaceutical composition comprises a free metal chelating agent present in the preparation at a concentration of about 0.02 mg / mL to about 2 mg / mL.

[0097] In one aspect, this document discloses a radiopharmaceutical composition comprising: (a) the conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 50 mCi / L; (b) optionally a pH stabilizer, wherein the pH stabilizer is configured to maintain the pH of the radiopharmaceutical composition at about 4 to 8; (c) a radiolysis stabilizer; (d) a free metal chelating agent, wherein the free metal chelating agent is configured to maintain the level of free radionuclides in the radiopharmaceutical composition below about 0.05 mCi / L; and (e) an aqueous medium. In some embodiments, the radiolysis stabilizer (such as ascorbic acid or sodium ascorbate) may be used as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer are the same compound. In some embodiments, the free metal chelating agent is configured to maintain the level of a free radionuclide in the radiopharmaceutical composition below about 0.05 mCi / L for at least 72 hours at about 20ºC to about 25ºC, as determined by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the free metal chelating agent is configured to maintain the level of a free radionuclide in the radiopharmaceutical composition below about 0.2, about 0.2, about 0.01, or about 0.001 mCi / L for at least 72 hours at about 20ºC to about 25ºC, as determined by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the free metal chelating agent is configured to maintain the level of a free radionuclide in the radiopharmaceutical composition below about 0.2, about 0.2, about 0.01, or about 0.001 mCi / L for at least 168 hours at about 20ºC to about 25ºC, as determined by radiometric thin-layer chromatography (radio-TLC). In some implementations, the free radionuclides are unbound or unchelated. 225 Ac. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to about 15 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L.

[0098] In some embodiments, the radiopharmaceutical composition described herein retains at least 80% of the components bound as part of the conjugate after 24 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein retains at least 80% of the bound material as part of the conjugate after being kept at about 20ºC to about 25ºC for 48 hours. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein retains at least 80% of the content bound as part of the conjugate after 72 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the bound material as part of the conjugate after 72 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the content bound as part of the conjugate after 120 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein retains at least 95% of the content bound as part of the conjugate after 120 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the content bound as part of the conjugate after 120 hours at about 20ºC to about 25ºC. 225 The Ac content is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the bound material as part of the conjugate after 72 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition described herein retains at least 95% of the bound material as part of the conjugate after 72 hours at about 20ºC to about 25ºC. 225 The Ac content is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the bound material as part of the conjugate after 168 hours at about 20ºC to about 25ºC.225 The Ac content is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition described herein retains at least 95% of the bound material as part of the conjugate after 168 hours at about 20ºC to about 25ºC. 225 The content of Ac can be determined by high performance liquid chromatography / fractional collection (HPLC-FC).

[0099] In one aspect, this document discloses a liquid radiopharmaceutical composition comprising: (a) a conjugate comprising (i) a targeting ligand, wherein the targeting ligand binds to a somatostatin receptor (SSR), (ii) a metal chelating agent covalently attached to the targeting ligand, and (iii) a radionuclide, wherein the radionuclide is 225 Ac; (b) means for maintaining the pH of the radiopharmaceutical composition, wherein the pH of the radiopharmaceutical composition is from about 4 to about 8; (c) means for removing free radionuclides from the radiopharmaceutical composition; and (d) an aqueous medium. In some embodiments, wherein the radiopharmaceutical composition retains at least 90% of the radionuclides as part of the composition after 120 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the means for removing free radionuclides is the free metal chelating agent described herein. In some embodiments, the means for maintaining the pH of the radiopharmaceutical composition is the pH stabilizer described herein. In some embodiments, the liquid radiopharmaceutical composition is a solution. In one aspect, a liquid radiopharmaceutical composition is disclosed herein comprising: (a) a conjugate comprising (i) a targeting ligand, wherein the targeting ligand binds to a somatostatin receptor (SSR), (ii) a metal chelating agent covalently attached to the targeting ligand, and (iii) a radionuclide, wherein the radionuclide is 225 Ac, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 0.1 mCi / L to about 50 mCi / L; (b) a pH stabilizer; (c) a free metal chelating agent; and (d) an aqueous medium. In some embodiments, the radiopharmaceutical composition retains at least 80%, at least 85%, or at least 90% of the radionuclide as part of the composition after 48 hours, 72 hours, or 120 hours at about 20ºC to about 25ºC. 225The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the liquid radiopharmaceutical composition is a solution. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 35 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 mCi / L to about 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 mCi / L to about 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 mCi / L to about 35 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 15 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 25 mCi / L. In some embodiments, the conjugate is 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC or 225 Ac-DOTA-JR-11. In some implementations, the conjugate is... 225 Ac-HA-DOTA-TATE. In some embodiments, the pH stabilizer is ascorbic acid, its salts, or combinations thereof. In some embodiments, the pH stabilizer is present in the radiopharmaceutical composition at a concentration of about 50 mM to about 200 mM. In some embodiments, the free metal chelating agent is selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or combinations thereof. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL. In some embodiments, the conjugate is... 225 Ac-DOTA-TATE and the composition retains at least 90% of its properties after 168 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac. In some implementations, the conjugate is 225 Ac-DOTA-TATE and the composition retains at least 95% of its properties after 168 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE225 The content of Ac. In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after 120 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition is formulated into unit dosage forms containing about 5 ml to about 50 ml (e.g., about 10-15 ml, about 12 mL) of solution. In some embodiments, the aqueous medium is a saline solution.

[0100] Liquid radiopharmaceutical compositions may contain pharmaceutically acceptable carriers or diluents. Exemplary pharmaceutically acceptable carriers include solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic agents, and absorption enhancers or delay agents compatible with drug administration. In some embodiments, the liquid radiopharmaceutical compositions described herein are formulated as solutions, emulsions, suspensions, syrups, elixirs, etc. The composition may be an aqueous radiopharmaceutical composition.

[0101] Liquid radiopharmaceutical compositions may contain an aqueous medium. For example, the aqueous medium may include water, saline solution, glucose solution, glucose saline solution, Ringer's solution, or lactated Ringer's solution. In some embodiments, the aqueous medium is water. In some embodiments, the aqueous medium is water for injection. In some embodiments, the aqueous medium is a 5.0% w / w sodium chloride solution. In some embodiments, the aqueous medium is a 4.0% w / w sodium chloride solution. In some embodiments, the aqueous medium is a 3.0% sodium chloride solution. In some embodiments, the aqueous medium is a 2.0% w / w sodium chloride solution. In some embodiments, the aqueous medium is a 1.5% w / w sodium chloride solution. In some embodiments, the aqueous medium is a 1.0% sodium chloride solution. In some embodiments, the aqueous medium is a 0.9% w / w sodium chloride saline solution. In some embodiments, the aqueous medium is a 0.5% w / w sodium chloride solution. In some embodiments, the aqueous medium is from 0.5% to 1.5% w / w sodium chloride solution. In some embodiments, the aqueous medium is a 0.7% to 1.1% w / w sodium chloride solution. In some embodiments, the aqueous medium is a saline solution. In some embodiments, the aqueous medium is a glucose solution. In some embodiments, the aqueous medium is a glucose saline solution. The composition may be isotonic. The composition may be a solution or a suspension. In some embodiments, the liquid radiopharmaceutical is formulated as a solution. The composition may be formulated to be compatible with a specific local or systemic route of administration. The composition may contain a carrier, diluent, or excipient suitable for administration via a specific route. The composition may be formulated for intravenous infusion or bolus injection. In some embodiments, the liquid radiopharmaceutical is formulated for intravenous administration.

[0102] In some implementations, the liquid radiopharmaceutical formulations described herein (e.g., formulations of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24) are administered to the subject via gravity infusion, infusion pump, or syringe pump.

[0103] In some implementations, the liquid radiopharmaceutical formulations described herein (e.g., formulations of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24) are administered to the subject via gravity infusion. In some implementations, the gravity infusion method includes one or more of the following steps: 1) confirming that the amino acid infusion has started at a constant rate before initiating the radiopharmaceutical preparation infusion; 2) connecting a sterile, non-ventilated short needle to the sterile sodium chloride solution via a catheter pre-filled with sterile sodium chloride solution; 3) pre-flushing the sterile short needle with sterile sodium chloride solution and clamping the tubing; 4) quickly and cleanly inserting the sterile short needle into the vial containing the radiopharmaceutical preparation, ensuring that the sterile short needle does not contact the radiopharmaceutical solution; 5) attaching a long needle to one end of the m / m tube and attaching a Luer lock to the other end of the m / m tube; 6) pre-flushing the m / m tube with sterile sodium chloride; 7) clamping the m / m tube; 8) inserting the long needle into the vial containing the radiopharmaceutical preparation, ensuring that the long needle contacts the radiopharmaceutical preparation; 9) removing the Luer lock; 10) connecting the m / m tube to the subject; and / or 11) releasing the m / m tube. An infusion pump or clamp is used to regulate the flow of sterile sodium chloride solution from a sterile short needle into the vial. The radiopharmaceutical preparation is administered at a rate of 100–200 mL / hr for 25–30 minutes. The infusion is stopped when the radiation level in the tube has stabilized for 5 minutes. Finally, the subject's intravenous line is flushed with 25 mL of sterile sodium chloride solution to remove any residual radiopharmaceutical preparation.

[0104] In some implementations, the liquid radiopharmaceutical formulations described herein (e.g., formulations of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24) are administered to the subject via infusion using an infusion pump. In some embodiments, the infusion pump method includes one or more of the following steps: 1) confirming that the amino acid infusion has started at a constant rate before initiating the radiopharmaceutical preparation infusion; 2) quickly and cleanly inserting a sterile venting needle into a vial containing the radiopharmaceutical preparation, ensuring that the sterile needle does not contact the radiopharmaceutical solution; 3) attaching a long needle to one end of an m / m tube and attaching a three-way stopcock with a valve to the other end of the m / m tube; 4) pre-flushing the m / m tube and long needle with sterile sodium chloride solution; 5) closing the clamp; 6) inserting the long needle into the vial containing the radiopharmaceutical preparation, ensuring that the long needle contacts the radiopharmaceutical preparation; 7) attaching the m / m tube with sterile sodium chloride solution to the three-way stopcock valve; 8) attaching a half-set infusion pump tubing to the three-way stopcock valve; 9) adjusting the stopcock valve to allow pre-flushing of the half-set infusion pump tubing with sterile saline solution; 10) inserting the half-set infusion pump tubing into the infusion pump; 11) ... Connect the pre-flushed intravenous catheter to the subject and set the three-way stopcock valve to connect the radiopharmaceutical preparation to the infusion pump, and / or 10) infuse the radiopharmaceutical preparation at a constant rate over 25 to 30 minutes. After the radiopharmaceutical preparation has been administered, shut off the infusion pump and position the three-way stopcock valve to connect the infusion pump to sterile sodium chloride solution. Finally, flush the subject's intravenous line with 25 mL of sterile sodium chloride solution to remove any residual radiopharmaceutical preparation from the line.

[0105] In some embodiments, the liquid radiopharmaceutical formulations described herein (e.g., formulations of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24) are administered to the subject via infusion using an infusion pump. In some embodiments, the infusion pump method includes one or more of the following steps: 1) confirming that the amino acid infusion has started at a constant rate before initiating the radiopharmaceutical formulation infusion; 2) quickly and cleanly inserting a sterile ventilated short needle into a vial containing the radiopharmaceutical formulation, ensuring that the sterile short needle does not contact the radiopharmaceutical solution; 3) drawing the radiopharmaceutical solution from the vial into a shielded sterile syringe with a needle; 4) removing and capping the needle; 5) connecting a tubing pre-flushed with sterile sodium chloride solution to the infusion pump; 6) placing the syringe containing the radiopharmaceutical solution into the infusion pump; 7) connecting the pre-flushed tubing to the infusion pump and the subject; and / or 8) infusing the radiopharmaceutical formulation at a constant rate over 25 to 30 minutes. Finally, the subject's intravenous line was flushed with 25 mL of sterile sodium chloride solution to remove any residual radiopharmaceutical preparations from the line.

[0106] Additional components or excipients may also be incorporated into the liquid radiopharmaceutical composition. The composition may further comprise one or more additional components or excipients. These additional components or excipients may be preservatives, antibacterial agents, antiviral agents, antimicrobial agents, and / or antifungal agents. They may also be tension modifiers, solubilizers, suspending agents, and / or surfactants.

[0107] The liquid radiopharmaceutical compositions described herein can be stored stably for a period of time. In some embodiments, the liquid radiopharmaceutical compositions described herein retain at least 80 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the liquid radiopharmaceutical compositions described herein retain at least 80 mol% of the initial conjugate after 24 or 48 hours at room temperature. In some embodiments, the composition retains at least 85 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 90 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 95 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 98 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 120 hours at room temperature. In some embodiments, the composition retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 96 hours at room temperature. In some embodiments, the composition retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 48 hours at room temperature. In some embodiments, the composition described herein retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 2 weeks under refrigerated conditions (about 4ºC). In some embodiments, the composition described herein retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 10 days under refrigerated conditions (about 4ºC). In some embodiments, the compositions described herein retain at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, at least 99 mol%, or at least 99.5 mol% of the initial conjugate after 168 hours of refrigeration (about 4ºC). In some embodiments, the compositions described herein retain at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, at least 99 mol%, or at least 99.5 mol% of the initial conjugate after 96 hours of refrigeration (about 4ºC).In some embodiments, the compositions described herein retain at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, at least 99 mol%, or at least 99.5 mol% of the initial conjugate after 48 hours of refrigeration (approximately 4ºC). In some embodiments, the purity or molar percentage of the conjugate is determined by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the purity or molar percentage of the conjugate is determined by instantaneous thin-layer chromatography (iTLC). In some embodiments, the purity or molar percentage of the conjugate is determined by measuring the relevant alpha particle emission using radiometric TLC.

[0108] The liquid radiopharmaceutical composition described herein can retain a certain amount of the initial conjugate (e.g., after being stored for a period of time) 225 (Ac-DOTA-TATE). In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 48, 72, 96, 120, 148, 168, 192, or 216 hours at room temperature. In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 96 hours at room temperature. In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 120 hours at room temperature. In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 148 hours at room temperature. In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 168 hours at room temperature. In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 192 hours at room temperature. In some embodiments, the purity or molar percentage of the conjugate is determined by instantaneous thin-layer chromatography (iTLC). In some embodiments, the purity or molar percentage of the conjugate is determined by radiometric thin-layer chromatography (radio-TLC). In some embodiments, room temperature may refer to a temperature of about 25ºC. In some embodiments, room temperature may refer to a temperature of 25ºC. In some embodiments, room temperature may refer to a temperature of about 22ºC to about 25ºC. In some embodiments, room temperature may refer to a temperature of about 20ºC to about 25ºC.

[0109] The liquid radiopharmaceutical compositions described herein may contain small amounts of unchelated and unconjugated radionuclides after a period of storage. In some embodiments, the liquid radiopharmaceutical compositions described herein contain small amounts of free actinium-225 and conjugated radionuclides after a period of storage. 225 Fragments of Ac-DOTA-TATE (e.g., as...) 225Actinium-225 present in the Ac-DOTA fragment. See, for example, Example 3. The total content of radionuclides such as actinium-225 in a radiopharmaceutical composition may also decrease over time due to radionuclide decay. In some embodiments, a radiopharmaceutical composition containing an actinium-225 conjugate contains no more than about 20% free actinium-225 (at the time of measurement) after 120 hours at about 20ºC to 25ºC, compared to the total amount of actinium-225 in the composition. In some embodiments, a radiopharmaceutical composition containing an actinium-225 conjugate contains no more than about 10% free actinium-225 after 120 hours at about 20ºC to 25ºC, compared to the total amount of actinium-225 in the composition. In some embodiments, the radiopharmaceutical composition containing an actinolite conjugate contains no more than about 5% free actinolite after 120 hours at about 20ºC to 25ºC, compared to the total amount of actinolite in the composition. In some embodiments, the radiopharmaceutical composition containing an actinolite conjugate contains no more than about 2% free actinolite after 120 hours at about 20ºC to 25ºC, compared to the total amount of actinolite in the composition. In some embodiments, the radiopharmaceutical composition containing an actinolite conjugate contains no more than about 1% free actinolite after 120 hours at about 20ºC to 25ºC, compared to the total amount of actinolite in the composition.

[0110] In some embodiments, after storage at about 20ºC to about 25ºC for 120 hours, at least 90 mol% of the liquid radiopharmaceutical composition... 225 Ac (i.e., Actinium-225) content (when measured) is expressed as... 225 Ac-DOTA-TATE is present. In some embodiments, after storage at about 20ºC to about 25ºC for 120 hours, at least 95 mol% of the liquid radiopharmaceutical composition is present. 225 Ac (i.e., actinium-225) content is expressed as follows: 225 Ac-DOTA-TATE is present. In some embodiments, after storage at about 20ºC to about 25ºC for 120 hours, at least 98 mol% of the liquid radiopharmaceutical composition is present. 225 Ac (i.e., actinium-225) content is expressed as follows: 225 Ac-DOTA-TATE is present. In some embodiments, after storage at about 20ºC to about 25ºC for 120 hours, at least 99 mol% of the liquid radiopharmaceutical composition is present. 225 Ac (i.e., actinium-225) content is expressed as follows: 225 Ac-DOTA-TATE is present. In some embodiments, after storage at about 20ºC to about 25ºC for 144 hours, at least 90 mol% of the liquid radiopharmaceutical composition is present.225 Ac (i.e., actinium-225) content (at that time) 225 Ac-DOTA-TATE is present. In some embodiments, after storage at about 20ºC to about 25ºC for 168 hours, at least 90 mol% of the liquid radiopharmaceutical composition is present. 225 Ac (i.e., actinium-225) content (at that time) 225 Ac-DOTA-TATE is present. In some embodiments, after storage at about 20ºC to about 25ºC for 192 hours, at least 90 mol% of the liquid radiopharmaceutical composition is present. 225 Ac (i.e., actinium-225) content (at that time) 225 Ac-DOTA-TATE exists.

[0111] In some embodiments, with the composition 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 20% of the total amount of free Ac after 120 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some embodiments, with the composition 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 15% of the total amount of free Ac after 120 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some embodiments, with the composition 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 10% of the total amount of free Ac after 120 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some embodiments, with the composition 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 10% of the total amount of free Ac after 120 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some embodiments, with the composition 225Compared to the total Ac content, radiopharmaceutical compositions containing actinium-225 conjugates contain no more than about 5% of the total amount of free Ac after 120 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. As the radioactive nuclide actinide-225 naturally decays, the composition... 225 The Ac content can decrease over time. In some embodiments, it is related to the composition... 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 10% of the total amount of free Ac after 144 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some embodiments, with the composition 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 10% of the total amount of free Ac after 168 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some embodiments, with the composition 225 Compared to the total Ac content, the radiopharmaceutical composition containing actinium-225 conjugates contains no more than about 10% of the total amount of free Ac after 192 hours at about 20ºC to 25ºC. 225 Ac and fragments of conjugates (e.g., as 225 Existing in the form of Ac-DOTA fragments 225 Ac. In some implementations, determination is performed by radiometric TLC. 225 The amount of Ac.

[0112] In some embodiments, the radiopharmaceutical composition described herein retains at least 80% of the liquid radiopharmaceutical composition as a byproduct after 24 or 48 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 80% of the liquid radiopharmaceutical composition as [missing information] after 96 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the liquid radiopharmaceutical composition as [missing information] after 120 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 95% of the liquid radiopharmaceutical composition as... 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 98% of the liquid radiopharmaceutical composition as a byproduct after 120 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 99% of the liquid radiopharmaceutical composition as... after 120 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the liquid radiopharmaceutical composition as [missing information] after 144 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the liquid radiopharmaceutical composition as [missing information] after 168 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225) is determined, for example, by radiometric TLC. In some embodiments, the radiopharmaceutical composition described herein retains at least 90% of the liquid radiopharmaceutical composition as [missing information] after 192 hours at about 20ºC to 25ºC. 225 Ac-DOTA-TATE 225 The content of Ac (i.e., actinium-225), such as that determined by radio-TLC.

[0113] In some embodiments, the liquid radiopharmaceutical composition comprises an actinide-225 conjugate. In some embodiments, the radiopharmaceutical composition comprising the actinide-225 conjugate contains no more than about 20% free actinide after 168 hours at room temperature, compared to the total initial amount of chelated actinide in the composition. In some embodiments, the radiopharmaceutical composition comprising the actinide-225 conjugate contains no more than about 10% free actinide after 168 hours at room temperature, compared to the total initial amount of chelated actinide in the composition. In some embodiments, the radiopharmaceutical composition comprising the actinide-225 conjugate contains no more than about 5% free actinide after 168 hours at room temperature, compared to the total initial amount of chelated actinide in the composition. In some embodiments, the radiopharmaceutical composition comprising the actinide-225 conjugate contains no more than about 3% free actinide after 168 hours at room temperature, compared to the total initial amount of chelated actinide in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than about 2% free actinium after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than about 1% free actinium after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than a total of 20 mol% of free actinium-225 isotopes after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than a total of 15 mol% of free actinium-225 isotopes after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than 10 mol% of the total actinium-225 free isotope after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than 5 mol% of the total actinium-225 free isotope after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than 3 mol% of the total actinium-225 free isotope after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than 2 mol% of the total actinium-225 free isotope after 168 hours at room temperature, compared to the total initial actinium content in the composition.In some embodiments, the radiopharmaceutical composition containing the actinium-225 conjugate contains no more than 1 mol% of the total free actinium-225 isotope after 168 hours at room temperature, compared to the total initial actinium content in the composition. In some embodiments, the purity or molar percentage of the conjugate is determined by radiometric thin-layer chromatography (radio-TLC).

[0114] In some embodiments, the radiopharmaceutical composition described herein is retained as part of a conjugate after 24 or 48 hours at about 20ºC to about 25ºC (e.g., as part of a conjugate). 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC 225 Ac-HA-DOTA-TATE or 225 At least 80% of the components of Ac-DOTA-JR-11 are combined. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition described herein is retained as part of the conjugate after being kept at about 20ºC to about 25ºC for 72 hours (e.g., as part of the conjugate). 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC 225 Ac-HA-DOTA-TATE or 225 At least 90% of the components of Ac-DOTA-JR-11 are combined. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after being kept at about 20ºC to about 25ºC for 120 hours. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after 168 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 95% of the bound material as part of the conjugate after being kept at about 20ºC to about 25ºC for 72 hours. 225 The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 95% of the bound material as part of the conjugate after being kept at about 20ºC to about 25ºC for 120 hours. 225The content of Ac is determined, for example, by radiometric thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after being kept at about 20ºC to about 25ºC for 120 hours. 225 The content of Ac is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after 168 hours at about 20ºC to about 25ºC. 225 The content of Ac is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 90% of the bound components as part of the conjugate after being kept at about 20ºC to about 25ºC for 72 hours. 225 The content of Ac is determined, for example, by high-performance liquid chromatography / fractional collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 95% of the bound components as part of the conjugate after being kept at about 20ºC to about 25ºC for 72 hours. 225 The content of Ac can be determined by high performance liquid chromatography / fractional collection (HPLC-FC). stabilizer

[0115] In one aspect, this document discloses radiopharmaceutical compositions with improved stability. The pharmaceutical compositions described herein may contain one or more stabilizers. In one aspect, this document provides solutions containing one or more stabilizers for use in radiopharmaceutical compositions. In some embodiments, the solution containing one or more stabilizers is a dilution solution. The one or more stabilizers may reduce, prevent, or delay the decomposition of the radiopharmaceutical. Decomposition may include radiopharmaceutical decomposition caused by radiolysis. The one or more stabilizers may reduce, prevent, or delay the decay of radionuclides. Radiation stabilizer

[0116] One or more stabilizers in the pharmaceutical compositions described herein may comprise radiolysis stabilizers. The one or more stabilizers may include two or more radiolysis stabilizers. The one or more stabilizers may comprise a first radiolysis stabilizer and a second radiolysis stabilizer. Radiolysis stabilizers may be amino acids or peptides or derivatives thereof, vitamins or derivatives thereof, lipids or derivatives thereof, carbohydrates or derivatives thereof, bulking agents, or antioxidants. Radiolysis stabilizers may include amino acids, peptides or derivatives thereof, vitamins or derivatives thereof, lipids or derivatives thereof, carbohydrates or derivatives thereof, bulking agents, antioxidants, or combinations thereof. In some embodiments, the radiopharmaceutical compositions described herein comprise means for stabilizing conjugates containing radionuclides. The means for stabilizing conjugates may be the radiolysis stabilizers described herein. In some embodiments, the radiopharmaceutical compositions described herein comprise means for scavenging free radicals in the composition. In some embodiments, the means for scavenging free radicals in the composition is a radiolysis stabilizer. In some embodiments, the radiopharmaceutical compositions described herein comprise means for reducing the concentration of free radicals in the composition. In some embodiments, the means for reducing the concentration of free radicals in the composition is a radiolysis stabilizer. In some embodiments, the reduction of free radicals in the composition reduces the radiolysis of the conjugate. In some implementations, the radiation stabilizer is an antioxidant.

[0117] The molar ratio of the first radiolytic stabilizer to the second radiolytic stabilizer can be 1:100,000 to 100,000:1, 1:1,000 to 1,000:1, 1:100 to 100:1, 1:20 to 20:1, 1:10 to 10:1, and 1:5 to 5:1. The molar ratio of the first radiolytic stabilizer to the second radiolytic stabilizer can also be 1:5 to 5:1. The radiodegradation stabilizer can be present in the radiopharmaceutical composition at concentrations of about 1 μM, 10 μM, 0.1 mM, 1 mM, 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, 500 mM, 1 M, 2 M, 3 M, 4 M, and 5 M. The radiodegradation stabilizer can be present in the radiopharmaceutical composition at concentrations of about 1 μM to 5 M. The radiodegradation stabilizer can be present in the radiopharmaceutical composition at concentrations of about 10 μM to 1 M. The radiodegradation stabilizer can be present in the radiopharmaceutical composition at concentrations of about 0.1 mM to 500 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 20 mM to 500 mM, about 50 mM to about 500 mM, about 75 mM to about 250 mM, or about 250 to about 500 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 50 mM to 200 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 75 mM to 150 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 25 mM to 250 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 10 mM to 500 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 20 mM to 100 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 25 mM to 75 mM. The radiodegradation stabilizer may be present in the radiopharmaceutical composition at concentrations of about 0.001 wt% to about 10 wt%. The radiolysis stabilizer may be present in the radiopharmaceutical composition in amounts of about 0.0001 wt% to about 20 wt%, 0.001 wt% to about 10 wt%, 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%. The radiolysis stabilizer may be present in the radiopharmaceutical composition in amounts of about 0.01 wt% to about 5 wt%. The radiolysis stabilizer may be present in the radiopharmaceutical composition in amounts of about 1 wt% to about 10 wt%, about 3 wt% to about 7 wt%, about 4 wt% to about 6 wt%, or about 2 wt% to about 15 wt%. The radiolysis stabilizer may be present in the radiopharmaceutical composition in amounts of about 5 wt%.The radiolysis stabilizer may be present in the radiopharmaceutical composition at a concentration of about 0.05 wt% to about 2 wt%. The radiolysis stabilizer may be present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 1 wt%. The radiolysis stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.0001 to 5,000 mg / mL. The radiolysis stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 500 mg / mL. The radiolysis stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. The radiolysis stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL. The radiolysis stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.5 to 2 mg / mL. In some embodiments, the radiolysis stabilizer is a dextran (such as dextran 40). In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 1 mM to 10 M. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 10 mM to 1 M. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 20 mM to 500 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 20 mM to 300 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 80 mM to 125 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of 100 mM. In some embodiments, the radiolysis stabilizer is ascorbic acid or a salt thereof (such as sodium ascorbate). In some embodiments, the radiolysis stabilizer is ascorbic acid. In some embodiments, the radiolysis stabilizer is sodium ascorbate. In some embodiments, the radiolysis stabilizer is ethanol. In some embodiments, the radiolysis stabilizer is gentianic acid. In some implementations, the radiation stabilizer is a salt of gentianic acid.

[0118] Radiolysis stabilizers may include amino acids or derivatives thereof. Radiolysis stabilizers may include peptides or derivatives thereof. Amino acids or derivatives thereof may be natural or non-natural amino acids. Amino acids can scavenge chemically active components generated by radiolysis. Amino acids may contain an amino group. Amino acids may optionally contain additional reducing heteroatoms, such as L-methionine, L-cysteine, or L-lysine. Peptides or derivatives thereof may contain two or more amino acids. Peptides may contain 2 to 50 amino acids. Peptides may contain 2 to 30 amino acids. Peptides may contain 2 to 15 amino acids. Peptides may contain 2 to 7 amino acids. Peptides may contain 2 to 4 amino acids. Peptides may contain 3 amino acids. Amino acids may be essential amino acids. Amino acids may be non-essential amino acids. Amino acids may be aliphatic amino acids. Amino acids may be aromatic amino acids. Amino acids may be acidic amino acids. Amino acids may be basic amino acids. Amino acids may be hydroxy amino acids. Amino acids may be sulfur-containing amino acids. Amino acids may be amide amino acids. Amino acids, their derivatives, or peptides can be N-acetyl-L-cysteine, glutathione, L-lysine, seleno-L-methionine, glutathione, albumin, melatonin, taurine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and / or their derivatives. Amino acids can be methionine. Amino acid derivatives such as N-acetyl-L-cysteine ​​may have higher solubility than the parent amino acid. Radiolytic stabilizers (such as thiourea, L-glutathione, and lipoic acid) may contain organic sulfur. Organic sulfur can optionally be oxidized to a higher oxidation state and coordinate with free heavy metal ions in solution.

[0119] Radiation stabilizers may include antioxidants (or reducing agents or free radical scavengers). Radiation stabilizers may include one or more antioxidants. Antioxidants may include flavonoids or derivatives thereof. Flavonoids may be polyphenolic compounds containing multiple phenolic moieties. Flavonoids may contain a 15-carbon structure. The 15-carbon structure may further contain two phenyl rings and one heterocycle. Flavonoids may include bioflavonoids, isoflavones, or novel flavonoids. Flavonoids may include catechins or derivatives thereof, such as... Figure 1The compounds shown are (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate or CG), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin or EC), 3,4,5-trihydroxybenzoic acid (gallic acid), and (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3 4-Dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate or EGCg), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol or epigallocatechin (EGC) or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC). Catechins can be administered to humans at doses of 1 mg / kg to 50 mg / kg, 5 mg / kg to 40 mg / kg, 10 mg / kg to 40 mg / kg, and 20 mg / kg to 35 mg / kg.Flavonoids may include (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate or CG), 3,3',4',5,5',7-hexahydroxyanthocyanin chloride, (-)-cis-3,3',4',5,7-pentahydroxyflavone (epicatechin or EC), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, 3,4,5-trihydroxybenzoic acid (gallic acid), 3,4',5,7-tetrahydroxyflavone (kaempferol), luteolin, 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy 3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]oxychromene-4-one (rutin), quercetin, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromene-3-yl] 3,4,5-Trihydroxybenzoate, epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin or EGC) or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC) or combinations thereof. In some embodiments, the antioxidant is a carotenoid or a derivative thereof. Carotenoids can be fat-soluble pigments, such as yellow, orange, or red pigments. Carotenoids can be all-trans-fucoxanthin, lycopene, lutein, β-carotene, lycopene, or lutein.

[0120] In some embodiments, the pharmaceutical compositions described herein comprise antioxidants, said antioxidants being N-acetylcysteine, L-ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-acrylic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate or CG), 1,4,5-trihydroxycyclohexanecarboxylic acid, trans-4-hydroxycinnamic acid (p-coumaric acid), 3,3',4',5,5',7-hexahydroxyanthocyanin chloride, lipoic acid (dihydrolipoic acid, D... HLA), 4,4',5,5',6,6'-hexahydroxybiphenyl dicarboxylic acid 2,6,2',6'-bis-lactone (ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavone (epicatechin or EC), 2-methoxy-4-(2-propenyl)phenol, trans-4-hydroxy-3-methoxycinnamic acid (ferulic acid), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, all-trans-fucoxanthin, 3,4,5-trihydroxybenzoic acid (gallic acid), (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((-)-gallicatechin), glutathione, 2-( 3,4-Dihydroxyphenyl)ethanol, 3,4',5,7-tetrahydroxyflavone (kaempferol), (±)-1,2-dithiacyclopentane-3-pentanoic acid, luteolin, lycopene, L-lysine, neochlorogenic acid, oleic acid, trans-3,5,4'-trihydroxystilbene (resveratrol), 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]oxychromene-4-one, rutin, selenoside-L-methionine, thiourea, (+)-α-tocopherol, leaf Flavonoids, Citric Acid (CA), Gentian Acid (GA), Salicylic Acid (SA), Isoascorbic Acid (EA), Phenol, Sodium Bisulfite, Butylated Hydroxyanisole, Butylated Hydroxytoluene, Metabisulfite, Benzyl Alcohol, Thymol, Alpha-Octobic Acid (LA), Thioglycolic Acid (TGA), 2,3-Dimercaptoprop-1-ol (BAL), Zinc, Selenium, Aluminum, Ethanol, Mannitol, Sucrose, Melatonin, Ebuselenium, Pyruvic Acid, Carboxy-PTIO, Trolox, Ebuselenium, Uric Acid, Edaravone, Beta-Carotene, NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol, Panthenol, Copper, Quercetin, Cortisone, Taurine, (2R,3R)-5,7-Dihydroxy-2-(3,4,(5-Trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate or EGC), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromene-3-yl] 3,4,5-trihydroxybenzoate or epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin or EGC), (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin or GC) (-)-cis-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-gallate ((-)-epigallocatechin-3-O-gallate), 5-aminolevulinic acid hydrate, polysorbate 80, allicin, sodium L-ascorbate, hyaluronic acid, dextran 60-90, selenool, LysaKare, or combinations thereof. Exemplary antioxidants in this disclosure are further described in Table 1. Table 1. Exemplary Antioxidants

[0121] In some embodiments, the radiolysis stabilizer comprises salts, esters, amides, enantiomers, or acetylated derivatives of the compounds listed in Table 1, or combinations thereof. In some embodiments, the radiolysis stabilizer is used as a pH stabilizer.

[0122] Radiation stabilizers may include vitamins or derivatives thereof. Radiation stabilizers may include one or more vitamins or derivatives thereof. In some embodiments, the vitamin or derivative thereof is L-ascorbic acid, β-carotene, provitamin A, (+)-α-tocopherol, isoascorbic acid (EA), Trolox, or lutein. In some embodiments, the radiation stabilizer is ascorbic acid or a salt thereof (such as sodium ascorbate). In some embodiments, the radiation stabilizer is ascorbic acid. In some embodiments, the radiation stabilizer is sodium ascorbate. In some embodiments, the radiation stabilizer is ethanol. In some embodiments, the radiation stabilizer is gentic acid. In some embodiments, the radiation stabilizer is a salt of gentic acid.

[0123] In some embodiments, the radioactive stabilizer comprises ascorbic acid or a salt thereof. In some embodiments, the radioactive stabilizer comprises sodium L-ascorbate. In some embodiments, the radioactive stabilizer comprises sodium ascorbate (e.g., sodium L-ascorbate) and is present in the radiopharmaceutical composition at a concentration of 1 mM to 10 M. In some embodiments, the radioactive stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 10 mM to 1 M. In some embodiments, the radioactive stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 20 mM to 500 mM. In some embodiments, the radioactive stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM. In some embodiments, the radioactive stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 80 mM to 125 mM. In some embodiments, the radiolysis stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, the radiolysis stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 100 mM. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof (e.g., sodium L-ascorbate) and is present in the radiopharmaceutical composition at a concentration of 1 mM to 10 M. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof and is present in the radiopharmaceutical composition at a concentration of 10 mM to 1 M. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof and is present in the radiopharmaceutical composition at a concentration of 20 mM to 500 mM. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof and is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof, and is present in the radiopharmaceutical composition at a concentration of 20 mM to 300 mM. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof, and is present in the radiopharmaceutical composition at a concentration of 80 mM to 125 mM. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof, and is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof, and is present in the radiopharmaceutical composition at a concentration of 100 mM.

[0124] In some embodiments, ascorbic acid or a salt thereof (such as sodium ascorbate) is present in the radiopharmaceutical composition at a concentration of 1 mM to 10 M. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 10 mM to 1 M. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 20 mM to 500 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 80 mM to 125 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 100 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 1 mg / mL to 100 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 5 mg / mL to 50 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 10 mg / mL to 30 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5 ± 4.63 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5 ± 5 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5 ± 10 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 18.5 mg / mL. In some embodiments, the sodium ascorbate is L-sodium ascorbate.

[0125] Radiation stabilizers may include fatty acids or derivatives thereof. Radiation stabilizers may include one or more lipids. Lipids may be fatty acids or derivatives thereof. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. Fatty acids may include monounsaturated fatty acids. Fatty acids may include polyunsaturated fatty acids. Fatty acids may include trans fats. Fatty acids may include C3 to C4 fats. 40 Fatty acids, C6 to C 30 Fatty acids, C6 to C 20 Fatty acids and C6 to C 10 Fatty acids. In some implementations, the fatty acids are C6 to C6. 30 Fatty acids. Fatty acids can include saturated or unsaturated C6 to C6 fatty acids. 30 Fatty acids. Fatty acids can include saturated or unsaturated C. 19 To C20 Fatty acids. Fatty acids can include saturated or unsaturated C. 12 To C 26 Fatty acids. In some embodiments, fatty acids include oleic acid, myristoleic acid, palmitoleic acid, oleic acid, trans oleic acid, trans isoleic acid or linoleic acid, α-linolenic acid or combinations thereof.

[0126] In some embodiments, the radiation stabilizer comprises a lipid that is a steroid or a derivative thereof. In some embodiments, the steroid may be a corticosteroid, such as estrogen, estradiol, estriol, or cortisone. The steroid may have four carbon rings. In some embodiments, the steroid may be estrogen, estradiol, estriol, or cortisone.

[0127] Radiation stabilizers may include volume expanders. In some embodiments, the volume expander is present in the radiopharmaceutical composition at a concentration of about 0.001 wt% to 80 wt%. In some embodiments, the volume expander can expand the volume of a liquid (such as human blood). The volume expander can be used as an absorbent radiation protectant. The volume expander can mimic human serum albumin. The volume expander may include human albumin. The volume expander may include polymers such as polyethylene glycol (PEG), glucose polymers, or mixtures of polymers. The glucose polymer may be a dextran or a sugar, such as an oligosaccharide. The glucose polymer may have a number average molecular weight of 1 kDa to 40,000,000 kDa, 5 kDa to 1,000,000 kDa, 10 kDa to 500,000 kDa, 15 kDa to 1,000 kDa, 20 kDa to 100 kDa, or 30 kDa to 50 kDa. The glucose polymer may have an average molecular weight of about 20-60 kDa, for example, about 40 kDa. Glucose polymers can be linear or cyclic. Cyclic glucose polymers can be cyclic oligosaccharides, such as cyclodextrins. Cyclodextrins can contain macrocycles of glucose subunits linked by α-1,4 glycosidic bonds. The macrocycle can contain 6 to 8 glucose subunits, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Polymer mixtures (such as artificial colloids) can contain 0.001 wt% to 80 wt% of glucose polymers. Polymer mixtures can contain 0.1 wt% to 50 wt% of glucose polymers. Polymer mixtures can contain 1 wt% to 20 wt% of glucose polymers. Polymer mixtures can be mixtures containing 5 wt% to 15 wt% of glucose polymers. Polymer mixtures can contain 0.1 wt% to 15 wt% of glucose polymers or 1 wt% to 10 wt% of glucose polymers. Dextran can be dextran 40 and dextran 70. Dextran can have a number-average molecular weight of about 5 to 100 kDa. Dextran can have a number-average molecular weight of about 40 to 70 kDa. Dextran can have a number-average molecular weight of 40, 60, or 70 kDa. Dextran 40 can be provided as a dextran 40 mixture, such as a 10% dextran 40 solution in 0.9% sodium chloride in an infusion bag. Dextran 40 mixtures can contain 0.1 wt% to 15 wt% dextran 40 or 1 wt% to 10% dextran 40. Dextran 40 mixtures can have a total osmolality of 300 mOsmol / L to 450 mOsmol / L. Dextran 40 mixtures can have a total osmolality of 350 mOsmol / L to 420 mOsmol / L. Dextran 40 mixtures can have a total osmolality of 380 mOsmol / L to 400 mOsmol / L.The dextran 40 mixture can have a total weight osmolality of 390 mOsmol / L. The polymer can be polyethylene glycol (PEG), such as PEG 4000 or PEG 3350. In some embodiments, the PEG has a number average molecular weight of about 200 to 20,000, 1,000 to 10,000, 2,000 to 8,000, 3,000 to about 5,000, or 3,000 to 4,000. The polymer mixture can contain a combination of PEG, such as PLENVU, PEG 3350, sodium ascorbate, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride. The polymer can be gelatin or modified gelatin, such as polygelatin peptides and succinyl gelatin. Polygelatin peptides can have a number average molecular weight of 5 kDa to 50 kDa, 10 kDa to 45 kDa, 20 kDa to 50 kDa, or 30 kDa to 40 kDa. Polygelatin peptides can have an average molecular weight of 35 kDa. The polymer mixture may be a mixture containing polygelatin peptides. Mixtures containing polygelatin peptides (such as hyaluronic acid) may also contain calcium chloride, potassium chloride, and / or sodium chloride. The polymer mixture may contain modified fluid gelatin, such as succinyl gelatin. The polymer mixture may be a solution, such as galactosyl gelatin. Galactosyl gelatin may contain 4% w / v succinyl gelatin.

[0128] Radiation stabilizers may include carbohydrates or derivatives thereof. Carbohydrates may be sugars. Sugars may be monosaccharides. Sugars may be disaccharides, oligosaccharides, or polysaccharides. Exemplary disaccharides include mannitol and sucrose. Polysaccharides may be dextrans, such as dextran 40 and dextran 70. Dextrans may have a molecular weight of about 10-200, 20-100, 30-50, or 40-70 kDa. Polysaccharides may have a number average molecular weight of 5 kDa to 1,000,000 kDa, 10 kDa to 500,000 kDa, 15 kDa to 1,000 kDa, 20 kDa to 100 kDa, or 30 kDa to 80 kDa. Oligosaccharides may be cyclic oligosaccharides, such as cyclodextrins. Cyclodextrins may contain a macrocycle of glucose subunits linked by α-1,4 glycosidic bonds. The macrocycle can contain 6 to 8 glucose subunits, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. The polysaccharide can be a dextran. The carbohydrate can be mannitol, sucrose, dextran (e.g., dextran 40, dextran 70), or cyclodextrin (α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin), such as 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl ether-β-cyclodextrin (SEB-β-CD). Free metal chelating agents

[0129] The one or more stabilizers may include free metal chelating agents. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more free metal chelating agents. In some embodiments, the radiopharmaceutical compositions described herein comprise means for removing free radionuclides from the radiopharmaceutical composition. The means for removing free radionuclides from the radiopharmaceutical composition may be the free metal chelating agents described herein. In some embodiments, the radiopharmaceutical compositions described herein comprise means for removing free radionuclides from the radiopharmaceutical composition and maintaining low levels of free radionuclides (such as free Ac-225). In some embodiments, the level of free radionuclides (such as free Ac-225) in the composition is maintained below about 0.05 mCi / L. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise free metal chelating agents configured to maintain low levels of free radionuclides in the composition. In some embodiments, the level of free radionuclides in the composition is maintained below about 0.01 mCi / L. In some embodiments, the level of free radionuclides in the composition is maintained below about 1 mCi / L. In some embodiments, the level of the free radionuclide in the composition is maintained below about 0.5 mCi / L. In some embodiments, the level of the free radionuclide in the composition is maintained below about 0.001 mCi / L. In some embodiments, the level of the free radionuclide in the composition is maintained below about 0.02 mCi / L. In some embodiments, the level of the free radionuclide is maintained for a period of time, such as 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, or 168 hours. In some embodiments, the level of the free radionuclide is maintained for a period of 72 hours. In some embodiments, the level of the free radionuclide is maintained for a period of 120 hours. In some embodiments, the level of the free radionuclide is maintained at a temperature of about 20ºC to about 25ºC.

[0130] In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more free metal chelators. The one or more stabilizers may comprise two or more free metal chelators. In some embodiments, the free metal chelators are not attached to a targeting ligand. The one or more stabilizers may comprise a first free metal chelator and a second free metal chelator. In some embodiments, the molar ratio of the first free metal chelator to the second free metal chelator is 1:100,000 to 100,000:1, 1:1,000 to 1,000:1, 1:100 to 100:1, 1:20 to 20:1, 1:10 to 10:1, and 1:5 to 5:1. In some embodiments, the molar ratio of the first free metal chelator to the second free metal chelator is 1:5 to 5:1. The free metal chelating agent may be present in the radiopharmaceutical composition at a concentration of about 0.001 wt% to about 10 wt%. The free metal chelating agent may be present in the radiopharmaceutical composition at concentrations of about 0.0001 wt% to about 20 wt%, 0.001 wt% to about 10 wt%, 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%. The free metal chelating agent may be present in the radiopharmaceutical composition at a concentration of about 0.01 wt% to about 5 wt%. The free metal chelating agent may be present in the radiopharmaceutical composition at a concentration of about 0.05 wt% to about 2 wt%. The free metal chelating agent may be present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 1 wt%. The free metal chelating agent may also be present in the radiopharmaceutical composition at a concentration of 0.0001 to 5,000 mg / mL. Free metal chelating agents may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 500 mg / mL. Free metal chelating agents may also be present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. Free metal chelating agents may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL. Free metal chelating agents may also be present in the radiopharmaceutical composition at a concentration of 0.5 to 2 mg / mL. In some embodiments, free metal chelating agents are present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 2 mg / mL. In some embodiments, free metal chelating agents are present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL. In some embodiments, free metal chelating agents are present in the radiopharmaceutical composition at a concentration of 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelating agents are selected from Table 2.

[0131] Free metal chelators can be linear or cyclic. Linear free metal chelators (such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA)) can be antidotes for heavy metal poisoning or scavengers of free heavy metals. DTPA can be present in the radiopharmaceutical composition at concentrations of 0.001 mg / mL to 2.5 mg / mL, 0.01 mg / mL to 5 mg / mL, 0.02 mg / mL to 3 mg / mL, 0.04 mg / mL to 1 mg / mL, or 0.05 mg / mL to 0.1 mg / mL. In some embodiments, the free metal chelator (such as DTPA) is present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL. In some embodiments, the free metal chelator (such as DTPA) is present in the radiopharmaceutical composition at a concentration of about 0.01 to 0.1 mg / mL. In some embodiments, a free metal chelating agent (such as DTPA) is present in the radiopharmaceutical composition at a concentration of about 0.02 to 0.07 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.02 mg / mL to 2.5 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.04 mg / mL to 1 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.01 to 0.25 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.02 to 0.125 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.04 to 0.06 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.05 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.05 mg / mL to 2 mg / mL. In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 0.5 mg / mL.In some embodiments, the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / mL.

[0132] In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more free metal chelating agents. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 to 0.1 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 to 2 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 to 3 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 to 4 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 to 5 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.02 to 0.07 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 10 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.02 mg / mL to 2.5 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.04 mg / mL to 1 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.01 to 0.25 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.02 to 0.125 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.04 to 0.06 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.05 mg / mL to 2 mg / mL. In some embodiments, the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 0.5 mg / mL.In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at concentrations of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / mL. The free metal chelator can also prevent potential hepatotoxicity caused by free radioactive metal ions when administered to subjects (e.g., human subjects). Cyclic free metal chelators can be macrocyclic free metal chelators, such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA). Macrocyclic free metal chelators can have strong chelating abilities and can be used at lower concentrations. Free metal chelating agents can include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 2-S-(4-benzyl isothiocyanate)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), 1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N"',N""-pentaacetic acid (PEPA), TETPA, 2,2′,2"-(10-( 2,6-Dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tetraacetic acid (DOTA-GA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphate) (DOTP), deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetraazacyclododecane-1, 4,7,10-Tetra(methylenephosphonic acid) (DOTP), 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))bis(pyridine-2-carboxylic acid) (Macropa), meso-2,3-dimercaptosuccinic acid (DMSA), dimercaptopropanesulfonate (DMPS), dihydrolipoic acid (DHLA), lipoic acid (LA), mercaptoglycolic acid (TGA), 2,3-dimercaptoprop-1-ol (BAL), or combinations thereof. The free metal chelating agent may include EDTA, DTPA, or Macropa. In some embodiments, the free metal chelating agent is EDTA. In some embodiments, the free metal chelating agent is DTPA. In some embodiments, the free metal chelating agent is Macropa. In some embodiments, the free metal chelating agent is TETA. In some embodiments, the free metal chelating agent is PEPA.In some embodiments, the free metal chelating agent is TETPA. In some embodiments, the free metal chelating agent comprises one or more compounds selected from Table 2. In some embodiments, the free metal chelating agent comprises two compounds selected from Table 2 or salts thereof. In some embodiments, the free metal chelating agent comprises three compounds selected from Table 2 or salts thereof. Exemplary free metal chelating agents of this disclosure are further described in Table 2. Table 2. Exemplary Free Metal Chelating Agents pH stabilizer

[0133] In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more pH stabilizers. In some embodiments, the radiopharmaceutical compositions described herein comprise means for maintaining the pH of the radiopharmaceutical composition. The means for maintaining the pH of the radiopharmaceutical composition may be the pH stabilizers described herein. In some embodiments, the radiopharmaceutical compositions described herein comprise means for maintaining the pH of the radiopharmaceutical composition at about 4-8. In some embodiments, the radiopharmaceutical compositions described herein comprise means for maintaining the pH of the radiopharmaceutical composition at about 5-7. In some embodiments, the radiopharmaceutical compositions described herein comprise means for maintaining the pH of the radiopharmaceutical composition at about 6-8. In some embodiments, the radiopharmaceutical compositions described herein comprise means for maintaining the pH of the radiopharmaceutical composition at about 5.5-6.5. In some embodiments, the radiopharmaceutical compositions described herein comprise means for maintaining the pH of the radiopharmaceutical composition at about 4-7. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain the pH of the composition at 4-8. In some embodiments, the radiopharmaceutical compositions disclosed herein include a pH stabilizer configured to maintain the pH of the composition at 5-7. In some embodiments, the radiopharmaceutical compositions disclosed herein include a pH stabilizer configured to maintain the pH of the composition at 6-8. In some embodiments, the radiopharmaceutical compositions disclosed herein include a pH stabilizer configured to maintain the pH of the composition at 5.5-6.5. In some embodiments, the radiopharmaceutical compositions disclosed herein include a pH stabilizer configured to maintain the pH of the composition at 4-7.

[0134] In some embodiments, the stability of the radiopharmaceutical composition can vary at different pH values. When the pH value exceeds a certain range, leakage of radioactive metals may also affect the radiochemical purity of the formulation and shorten its shelf life. Therefore, in some embodiments, in addition to radioprotective agents and / or free metal chelating agents, the one or more stabilizers may also include a pH stabilizing buffer. In some embodiments, the radiopharmaceutical compositions disclosed herein contain one or more pH stabilizers. Exemplary pH stabilizers include sodium acetate / acetic acid and sodium L-ascorbate / L-ascorbic acid aqueous buffers.

[0135] The one or more stabilizers may include one or more pH stabilizers. The one or more pH stabilizers may be used as pH buffers. The one or more pH stabilizers may be used as pH buffers. The one or more pH stabilizers may include organic acids. Organic acids may include acetic acid, fumaric acid, ascorbic acid, propionic acid, benzenesulfonic acid, carbonic acid, citric acid, aspartic acid, maleic acid, methanesulfonic acid, or tartaric acid. The one or more pH stabilizers may include inorganic acids. In some embodiments, the inorganic acid is hydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, sulfuric acid, or combinations thereof. The one or more pH stabilizers may include bases. Bases may include tromethamine (Tris), ammonium hydroxide, diethanolamine, sodium hydroxide, or combinations thereof. The one or more pH stabilizers may include amino acids or salts thereof. The one or more pH stabilizers may include glycine, lysine, arginine, histidine, or salts thereof. The one or more pH stabilizers may include basic salts. The basic salt may include sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate, or combinations thereof. Sodium ascorbate may be present in the radiopharmaceutical composition at a concentration of about 50 mM to 200 mM. The one or more pH stabilizers may include acid salts. The acid salt may be ammonium sulfate. In some implementations, the pH stabilizer is sodium acetate, sodium ascorbate, ascorbic acid, acetic acid, adipic acid, citric acid, bentonite, butane, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium hydroxide, calcium lactate, calcium oxide, calcium phosphate, fumaric acid, propionic acid, ascorbic acid, ammonium bicarbonate, ammonium carbonate, ammonium sulfate, ammonium hydroxide, aluminum sulfate, aluminum ammonium sulfate, potassium aluminum sulfate, sodium aluminum sulfate, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, sodium carboxymethyl cellulose, sodium caseinate, sodium citrate, sodium pectate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (l)-lysine, malic acid, maleic acid, lactic acid, methanesulfonic acid, phosphoric acid, phosphate. Sodium dihydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, sodium sesquicarbonate, potassium acid tartrate, potassium bicarbonate, potassium carbonate, potassium citrate, potassium hydroxide, potassium sulfate, sodium hydroxide, sodium succinate / disodium, potassium sodium tartrate, sodium tripolyphosphate, sodium tartrate, sodium acid pyrophosphate, tartaric acid, triacetin, tromethamine (tris), sulfuric acid or combinations thereof.The one or more pH stabilizers may comprise sodium acetate, sodium ascorbate, ascorbic acid, acetic acid, fumaric acid, propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (l)-lysine, maleic acid, methanesulfonic acid, phosphoric acid, sodium dihydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, sodium hydroxide, sodium / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (tris), or combinations thereof. Exemplary pH stabilizers of this disclosure are further described in Table 3. Table 3. Exemplary pH Stabilizers

[0136] In some embodiments, the pH stabilizer can reduce pH changes and maintain the purity of the radiopharmaceutical, which reduces the decomposition of the conjugate and thus extends the shelf life of the radiopharmaceutical composition described herein. The one or more stabilizers may include a pH stabilizer. The one or more stabilizers may include two or more pH stabilizers. The one or more stabilizers may include a first pH stabilizer and a second pH stabilizer. In some embodiments, the molar ratio of the first pH stabilizer to the second pH stabilizer is 1:100,000 to 100,000:1, 1:1,000 to 1,000:1, 1:100 to 100:1, 1:20 to 20:1, 1:10 to 10:1, and 1:5 to 5:1. In some embodiments, the molar ratio of the first pH stabilizer to the second pH stabilizer is 1:5 to 5:1. The pH stabilizer may be present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. A pH stabilizer may be present in the radiopharmaceutical composition in amounts of about 0.0001 wt% to about 20 wt%, 0.001 wt% to about 10 wt%, 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%. A pH stabilizer may be present in the radiopharmaceutical composition in amounts of about 0.01 wt% to about 5 wt%. A pH stabilizer may be present in the radiopharmaceutical composition in amounts of about 0.05 wt% to about 2 wt%. A pH stabilizer may be present in the radiopharmaceutical composition in amounts of about 0.1 wt% to about 1 wt%. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 1 μM, 10 μM, 0.1 mM, 1 mM, 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, 500 mM, 1 M, 2 M, 3 M, 4 M, or 5 M. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 1 μM to 5 M. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 10 μM to 1 M. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 0.1 mM to 500 mM. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 10 mM to 500 mM. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 50 mM to 250 mM. pH stabilizers can be present in radiopharmaceutical compositions at concentrations of about 25 mM to 350 mM. pH stabilizers can also be present in radiopharmaceutical compositions at concentrations of about 80 mM to 200 mM.pH stabilizers may be present in the radiopharmaceutical composition at a concentration of about 80 mM to 120 mM. pH stabilizers may also be present in the radiopharmaceutical composition at a concentration of 0.0001 to 5,000 mg / mL. pH stabilizers may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 500 mg / mL. pH stabilizers may also be present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. pH stabilizers may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL. pH stabilizers may also be present in the radiopharmaceutical composition at a concentration of 0.5 to 2 mg / mL. In some embodiments, the pH stabilizer comprises compounds selected from Table 3 or combinations thereof.

[0137] The radiopharmaceutical compositions described herein can have suitable pH values. The one or more pH stabilizers can be configured to maintain the pH of the radiopharmaceutical composition at about 3 to about 9, about 4 to about 8, or about 5 to about 7. The pH of the radiopharmaceutical composition can be in the range of about 3 to about 9. The pH of the radiopharmaceutical composition can be in the range of about 4 to about 8. The pH of the radiopharmaceutical composition can be in the range of about 5 to about 7. In some embodiments, the pH of the radiopharmaceutical composition is about 4.0 to about 9.0, about 4.5 to about 8.5, about 5.0 to about 8.0, about 5.5 to about 7.75, about 6.0 to about 7.5, about 6.5 to about 7.25, or 6.75 to about 7.25. The pH of the radiopharmaceutical composition can be about 4.0 to about 9.0. The pH of the radiopharmaceutical composition can be about 4.5 to about 8.5. The pH of the radiopharmaceutical composition can be about 5.0 to about 8.0. The pH of the radiopharmaceutical composition can be about 5.0 to about 7.0. The pH of the radiopharmaceutical composition can be about 5.5 to about 6.5. The pH of the radiopharmaceutical composition can be from about 5.5 to about 6. The pH of the radiopharmaceutical composition can be from about 5.6 to about 5.8. The pH of the radiopharmaceutical composition can be from about 5.75 to about 5.85. The pH of the radiopharmaceutical composition can be from about 5.5 to about 7.75. The pH of the radiopharmaceutical composition can be from about 6.0 to about 7.5. The pH of the radiopharmaceutical composition can be from about 6.5 to about 7.25. The pH of the radiopharmaceutical composition can be from about 6.75 to about 7.25. In some embodiments, the pH of the radiopharmaceutical composition is about 7. In some embodiments, the pH of the radiopharmaceutical composition is about 5.5. In some embodiments, the pH of the radiopharmaceutical composition is about 5.6. In some embodiments, the pH of the radiopharmaceutical composition is about 5.7. In some embodiments, the pH of the radiopharmaceutical composition is about 5.8. In some embodiments, the pH of the radiopharmaceutical composition is about 5.9. In some embodiments, the pH of the radiopharmaceutical composition is about 6. In some embodiments, the pH of the radiopharmaceutical composition is about 6.1. In some implementations, the pH of the radiopharmaceutical composition is about 6.2.

[0138] The radiopharmaceutical composition may contain one or more radiolysis stabilizers, one or more free metal chelators, and / or one or more pH stabilizers.

[0139] In some embodiments, the radiopharmaceutical composition described herein comprises: (a) a conjugate (e.g., 225 Ac-DOTA-TATE or225 (a) Ac-DOTA-TOC, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 45 mCi / L (e.g., 30 mCi / L); (b) pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at a concentration of about 80 to about 120 mM; (c) optional radiolysis stabilizer, wherein the radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10 wt%; (d) free metal chelating agent, wherein the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 1 mg / mL; and (e) an aqueous medium. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 15 to 45 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 150 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 35 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 25 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 12 to 23 mCi / L. In some embodiments, the radiopharmaceutical composition described herein comprises: (a) a conjugate (e.g., 225 Ac-DOTA-TATE or 225(a) an adjuvant (Ac-DOTA-TOC), wherein the adjuvant is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 45 mCi / L; (b) a pH stabilizer, wherein the pH stabilizer is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 80 to about 120 mM; (c) an optional radiolysis stabilizer, wherein the radiolysis stabilizer is dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10 wt%; (d) a free metal chelating agent, wherein the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 1 mg / mL; and (e) an aqueous medium, wherein the aqueous medium is a saline solution. In some embodiments, the adjuvant is present in the radiopharmaceutical composition at a concentration equivalent to about 15 to 45 mCi / L. In some embodiments, the radiopharmaceutical composition comprises (a) a conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 25 to 35 mCi / L; (b) a pH stabilizer, wherein the pH stabilizer is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a radiolysis stabilizer, wherein the radiolysis stabilizer is dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 4 wt%-6 wt%; (d) a free metal chelating agent, wherein the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.01-0.03 mg / mL; and (e) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride salt at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises (a) a conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 25 mCi / L; (b) a pH stabilizer, wherein the pH stabilizer is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a radiolysis stabilizer, wherein the radiolysis stabilizer is dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 4 wt%-6 wt%; (d) a free metal chelating agent, wherein the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.01-0.03 mg / mL; and (e) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride salt at a concentration of about 0.9% w / w.In some embodiments, the radiopharmaceutical composition comprises (a) a conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 25 to 35 mCi / L; (b) a pH stabilizer, wherein the pH stabilizer is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a free metal chelating agent, wherein the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.04-0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises (a) a conjugate, wherein the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 25 mCi / L; (b) a pH stabilizer, wherein the pH stabilizer is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a free metal chelating agent, wherein the free metal chelating agent is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.04-0.06 mg / mL; and (d) an aqueous medium, wherein the aqueous medium is an aqueous solution of sodium chloride at a concentration of about 0.9% w / w. Other excipients

[0140] The radiopharmaceutical compositions described herein may contain additional excipients. In some embodiments, the additional excipients include excipients suitable for preparing formulations for intravenous administration.

[0141] In some embodiments, the radiopharmaceutical compositions described herein comprise surfactants. A "surfactant" can be defined as a surface-active amphiphilic compound, such as a block copolymer. They can also be referred to as wetting agents. Non-limiting examples of surfactants include poloxamer (e.g., poloxamer 188), sodium lauryl sulfate, sodium deoxycholate, egg yolk lecithin, gelatin, hydrolyzed lecithin, polyoxyethylated fatty acids, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), PEG 40 castor oil (polyoxyethylene 40 castor oil, castor oil POE-40, Croduret 40, polyoxyethylene 40 castor oil, Protachem CA-40), PEG 60 castor oil (Cremophor RH 60, hydrogenated castor oil POE-60, Protachem CAH-60), poloxamer 188 (Pluronic F68), povidone (polyvinylpyrrolidone, crospovidone), sodium lauryl sulfate (sodium lauryl sulfate), aluminum monostearate, sorbitol, and Triton X-100 (octylphenyl ether-9).

[0142] Surfactants used in this disclosure may include nonionic surfactants. Nonionic surfactants do not have charged groups at their heads. Exemplary nonionic surfactants include, but are not limited to, fatty alcohols, cetyl alcohol, stearyl alcohol, cetearyl alcohol, and oleyl alcohol. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside), polyethylene glycol octylphenyl ether (such as Triton X-100), polyethylene glycol alkylphenyl ethers (such as nonylphenyl alcohol ether-9), glyceryl alkyl esters (such as glyceryl laurate), polyoxyethylene glycol dehydrated sorbitol alkyl esters (such as polysorbate), dehydrated sorbitol alkyl esters (such as Spans), cocoamide MEA, cocoamide DEA, dodecyl dimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamer), and polyoxyethylated tallow amine (POEA). In some embodiments, the surfactant is a nonionic surfactant comprising polyethylene glycol. In some embodiments, the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol.

[0143] In some embodiments, the nonionic surfactant has a number average molecular weight of about 1,000 to about 100,000 Da, 2,000 to about 20,000 Da, about 4,000 to about 15,000 Da, about 6,000 to about 12,000 Da, or about 7,000 to about 10,000 Da. In some embodiments, the nonionic surfactant has a number average molecular weight of about 7,000 to about 10,000 Da. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 30 wt% to about 99 wt%, about 50 wt% to about 95 wt%, about 60 wt% to about 95 wt%, about 75 wt% to about 90 wt%, or about 80 wt% to about 85 wt%. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 80 wt% to about 85 wt%.

[0144] Surfactants used in this disclosure may include cationic surfactants. Cationic surfactants include pH-dependent primary, secondary, or tertiary amines, such as oteninidine dihydrochloride; and permanently charged quaternary ammonium salts, such as cetrimonium bromide (CTAB), hexadecylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzyl chloride (BZT), dimethyl dioctadecyl ammonium chloride, and dioctadecyl dimethyl ammonium bromide (DODAB).

[0145] Surfactants used in this disclosure may include anionic surfactants. Anionic surfactants contain anionic functional groups at their heads, such as sulfates, sulfonates, phosphates, and carboxylates. Exemplary anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS), and related alkyl ether sulfates such as sodium laureth sulfate (sodium lauryl ether sulfate or SLES), sodium myristyl ether sulfate, sodium docusate (sodium succinate sulfonate), perfluorooctane sulfonic acid (PFOS), perfluorobutane sulfonic acid, alkyl aryl ether phosphates, and alkyl ether phosphates.

[0146] The surfactants used in this disclosure may be amphoteric surfactants. An amphoteric (ampholy) surfactant is a surfactant in which both a cationic and anionic centers are attached to the same molecule. Exemplary amphoteric surfactants include, but are not limited to, phospholipids, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin.

[0147] In some embodiments of this disclosure, the concentration of the surfactant described herein in the liquid pharmaceutical composition is 0.1% to 15% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.5% to 8% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.5% to 6% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.25% to 8% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 8% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.5% to 5% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 10% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 6% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 4% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 1% to 4% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 1% to 6% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 5% to 10% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 5% to 15% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 10% to 25% by weight.

[0148] In some embodiments, the radiopharmaceutical compositions described herein include a tension modifier. Exemplary tension modifiers include glucose, glycerol, mannitol, potassium chloride, and sodium chloride.

[0149] In some embodiments, the radiopharmaceutical compositions described herein contain specific additives. In some embodiments, these specific additives include acetyltryptophan, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, amino acids (leucine, isoleucine, lysine (acetate or HCl salt), valine, phenylalanine, threonine, tryptophan, alanine, aspartic acid, glutamic acid, proline, serine, tyrosine, taurine), ε-aminocaproic acid, calcium D-sucroseate, sodium caprylate, 8-chlorotheophylline, creatine, creatinine, cholesterol, sodium cholesterol sulfate, cyclohexanedione dioxime, diethanolamine, distearate phosphatidylcholine, distearate phosphatidylglycerol, L-α-dimyristoyl phosphatidylcholine, L-α-dimyristoyl phosphatidylglycerol, dioleoyl phosphatidylcholine (DOP) C), Dipalmitoylphosphatidylglycerol (DPPG), (R)-hexadecanoic acid, 1-[(phosphonooxy)methyl]-1,2-ethylenedimethyl ester monosodium salt (DPPA), (R)-4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1-oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphatidecane-1-ammonium inner salt 4-oxide (DPPC), (R)-[6-hydroxy-6-oxo-9-[(1-oxohexadecyl)oxy]-5,7,11-trioxa-2aza-6-phosphatidecane-1-yl]-ω-methoxy poly(oxy-1,2-ethylenedimethyl) monosodium salt (MPEG5000) DPPE), MPEG-distearate ethanolamine, ethyl lactate, ethylenediamine, sodium L-glutamate, sodium hyaluronate, hydrogenated soybean phosphatidylcholine, ferric ammonium citrate, lactic acid, D,L-lactic acid and glycolic acid copolymer, meglumine, methylboric acid, nicotinamide, methylparaben, egg phosphatidylglycerol (EPG), potassium sodium tartrate, protamine sulfate, dimethyl silicone oil, sodium saccharin, sodium D-gluconate, sodium hypochlorite, sodium sulfate, stannous chloride, disodium sulfosalicylate, stannous chloride (divalent and tetravalent tin), tributyl phosphate, tricaprylic acid glyceride, triolein, von Willebrand factor, zinc, zinc acetate, zinc carbonate, zinc oxide or combinations thereof.

[0150] In some embodiments, the radiopharmaceutical compositions described herein comprise a suspending agent. Non-limiting examples of suspending agents include carboxymethyl cellulose (CMC), croscarmellose sodium, sodium CMC, xanthan gum, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), and Avicel CL-611. Other exemplary suspending agents include carboxymethyl cellulose (sodium and other salts), carboxy-vinyl copolymers, carboxymethyl hydroxyethyl cellulose, cellulose (such as microcrystalline cellulose), combinations of microcrystalline cellulose and sodium carboxymethyl cellulose (such as Avicel RC-501, RC-581, RC-591 and CL-611), hydrophobically modified hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl guar gum, hydroxypropyl methyl cellulose (such as Benecel K750® or Benecel K1500®), hydroxypropyl cellulose, methyl cellulose, natural gums and their derivatives, xanthan gum, guar gum, gum arabic, partially and fully hydrolyzed polyvinyl alcohol, partially neutralized polyacrylic acid, polyalkylene glycols, polysaccharide gums, polyvinylpyrrolidone and its derivatives, starch and its derivatives, vinylpyrrolidone homopolymers and copolymers, water-soluble cellulose ethers and mixtures thereof.

[0151] These compositions can be sterilized using conventional sterilization techniques. The resulting aqueous solution can be packaged for use or filtered and lyophilized under aseptic conditions. The lyophilized formulation can be combined with the sterile aqueous solution before administration. The composition may contain pharmaceutically acceptable excipients suitable for near-physiological conditions, such as tonic modifiers, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, sorbitan monolaurate, triethanolamine oleate, etc. The pharmaceutical composition can be selected based on its physical characteristics, including but not limited to fluid volume, viscosity, and other parameters according to the selected specific method of administration. Conjugate

[0152] In one aspect, this document provides a radiopharmaceutical composition comprising the conjugate described herein or a pharmaceutically acceptable salt or solvate thereof. The radiopharmaceutical composition may further comprise a pharmaceutically acceptable carrier, such as an aqueous medium. Physiological saline may be used as a pharmaceutically acceptable carrier. Other suitable carriers or aqueous mediums may include, for example, water, buffered water, 0.9% isotonic saline, 0.4% saline, 0.3% glycine, etc., including glycoproteins for enhancing stability, such as albumin, lipoproteins, globulins, etc. In some embodiments, the aqueous medium is water for injection. In some embodiments, the aqueous medium is a 0.9% w / w sodium chloride aqueous solution. In some embodiments, the conjugate is... 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC 225 Ac-HA-DOTA-TATE or225 Ac-DOTA-JR-11.

[0153] The amount of conjugate applied can depend on the specific target portion used, the disease state being treated, the therapeutic agent being delivered, and the clinician's judgment.

[0154] The concentration of the conjugates or their pharmaceutically acceptable salts or solvates described herein in the pharmaceutical formulation may vary. In some embodiments, the conjugates are present in the pharmaceutical composition at about 0.05% to about 1% by weight, about 1% to about 2% by weight, about 2% to about 5% by weight, about 5% to about 10% by weight, about 10% to about 30% by weight, about 30% to about 50% by weight, about 50% to about 75% by weight, or about 75% to about 99% by weight. In some embodiments, the conjugates are present in the pharmaceutical composition at about 0.05% to about 1% by weight. In some embodiments, the conjugates are present in the pharmaceutical composition at about 0.1% to about 5% by weight.

[0155] In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing radioactivity of about 0.5 to about 1000 µCi / mL. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing radioactivity of about 1 to about 15 µCi / mL, about 2 to about 20 µCi / mL, about 5 to about 50 µCi / mL, about 10 to about 100 µCi / mL, about 20 to about 200 µCi / mL, about 50 to about 500 µCi / mL, about 100 to about 250 µCi / mL, about 5 to about 25 µCi / mL, about 10 to about 30 µCi / mL, or about 5 to about 15 µCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 20 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 45 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 100 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 15 to 45 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 35 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 25 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 12 to 23 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 200 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100 to 500 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100 to 1000 μCi / mL. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 5, 10, 15, 50, 75, 100, 200, or 500 µCi / ml of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 500, 600, 700, 800, 900, or 1000 µCi / ml of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 15 µCi / ml of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing about 1 to 15 µCi / ml of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 35 µCi / ml of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing about 1 to 35 µCi / ml of radioactivity.In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or 50 µCi / ml of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 50, 75, 100, 125, 150, or 200 µCi / ml of radioactivity.

[0156] In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing radioactivity of about 0.5 to about 1000 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing radioactivity of about 1 to about 15 mCi / L, about 2 to about 20 mCi / L, about 5 to about 50 mCi / L, about 10 to about 100 mCi / L, about 20 to about 200 mCi / L, about 50 to about 500 mCi / L, about 100 to about 250 mCi / L, about 5 to about 25 mCi / L, about 10 to about 30 mCi / L, or about 5 to about 15 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 20 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 45 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 100 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 15 to 45 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 35 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 25 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 12 to 23 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 200 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100 to 500 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100 to 1000 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 5, 10, 15, 50, 75, 100, 200, or 500 mCi / L of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 500, 600, 700, 800, 900, or 1000 mCi / L of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 15 mCi / L of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing about 1 to 15 mCi / L of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing up to about 35 mCi / L of radioactivity. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing about 1 to 35 mCi / L of radioactivity.In some embodiments, the conjugate is present in the pharmaceutical composition in an amount providing a radioactivity of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 or 50 mCi / L.

[0157] The compositions described herein may comprise conjugates containing actinium-225 or pharmaceutically acceptable salts or solvates thereof. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein, providing a volumetric radioactivity of about 0.005 to 1000 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein, providing a volumetric radioactivity of about 0.5 to 20 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein, providing a volumetric radioactivity of about 0.4 to 20 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein, providing a volumetric radioactivity of about 0.2 to 5 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein, providing a volumetric radioactivity of about 0.4 to 1 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical composition described herein, providing a volumetric radioactivity of about 0.1 to 100 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical composition described herein, providing a volumetric radioactivity of about 0.1 to 100, about 0.1 to 50, about 0.1 to 25, about 0.1 to 10, about 0.1 to 5, about 1 to 100, about 0.5 to 10, about 0.5 to 50, about 10 to 100, about 10 to 50, about 10 to 20, about 1 to 10, or about 1 to 20 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical composition described herein, providing a volumetric radioactivity of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical composition described herein, providing a volumetric radioactivity of at least about 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein, providing a volumetric radioactivity of up to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50 MBq / mL. In some embodiments, the compositions described herein have a total DOTA-TATE peptide (including, for example, unlabeled DOTA-TATE) of ≤ 11.5 μg / mL.225 (Ac-DOTATATE and metal-DOTATATE species) concentrations. In some embodiments, the compositions described herein have a total DOTA-TATE peptide concentration of up to about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 50 μg / mL. In some embodiments, the compositions described herein have a total DOTA-TATE peptide concentration of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 μg / mL.

[0158] The compositions described herein may comprise a conjugate or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. The conjugate may be substantially pure because it contains less than about 10%, less than about 5%, or less than about 1%, or less than about 0.1% by weight of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated, for example, in one or more steps of a synthetic method. The conjugate may be... 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC or 225 Ac-DOTA-JR-11. Conjugates can be... 225 Ac-DOTA-TATE. Conjugates can be... 225 Ac-DOTA-TOC. Conjugates can be... 225 Ac-DOTA-JR-11. In some implementations, the conjugate is... 225 Ac-high affinity DOTATATE (or 225 Ac-HA-DOTATATE). In some implementations, HA-DOTATATE is structured as follows: .

[0159] 225 Ac-DOTA-TATE can be defined as having the following structure: . 225The IUPAC name for Ac-DOTA-TATE is: (2,2',2''-(10-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4-hydroxy) Benzyl)-7-((R)-1-hydroxyethyl)-6,9,12,15,18-pentoxo-1,2-dithia-5,8,11,14,17-pentazacycloeicosano-19-yl)amino)-1-oxo-3-phenylprop-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; Actinide-225(3+)). 225 Ac-DOTA-TATE can also be called Actinide ( 225 Ac)Oxyoctreotide.

[0160] In some implementations, this document provides a method of including as A pharmaceutical composition of a conjugate and one or more stabilizers.

[0161] In some embodiments, this document provides a pharmaceutical composition comprising a conjugate having a structure and one or more stabilizers. In some embodiments, this document provides a pharmaceutical composition comprising a conjugate having a structure and one or more stabilizers. It should be understood that the above two structures do not show 225 The chelation between Ac and a metal chelating agent. In some embodiments, such as under acidic aqueous conditions, the radionuclide actinium-225 exists in the form of a salt, for example... 225 Ac 3+ In some embodiments, the conjugate is in the form of a salt. In some embodiments, the conjugate is an acetate. In some embodiments, this document provides a method comprising... A pharmaceutical composition comprising a conjugate and one or more stabilizers. In some embodiments, this document provides a composition comprising as... A pharmaceutical composition comprising a conjugate and one or more stabilizers. It should be understood that neither of the above two structures is shown. 225 The chelation between Ac and a metal chelating agent. In some embodiments, such as under acidic aqueous conditions, the radionuclide actinium-225 exists in the form of a salt, for example... 225 Ac 3+In some embodiments, the conjugate is in the form of a salt. In some embodiments, the conjugate is an acetate. Those skilled in the art will understand that the dissociation of an acid can depend on the pH and pK values ​​of the environment. Therefore, in some embodiments, the conjugate described herein can exist in a fully ionized, partially ionized, or non-ionized form. Targeted ligands

[0162] In one aspect, this document provides a radiopharmaceutical composition comprising a conjugate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the conjugate described herein comprises a targeting ligand and a metal chelating agent.

[0163] The targeting ligands described herein can bind to one or more targets within a subject system or in vitro system. The targeting ligands can target proteins, receptors on cells, or other chemical components that can perform signal transduction functions within the subject system. The targeting ligands can bind to receptors on the cell surface within the subject system. In some embodiments, the targeting ligand binds to somatostatin receptors (SSRs). SSRs can be mammalian SSRs. Mammal SSRs can be human SSRs. Human SSRs can include somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). SSRs can be human somatostatin receptor type 2 (SSTR2). In some embodiments, the targeting ligand binds to human somatostatin receptor type 2 (SSTR2). The targeting ligands can include peptides and / or small molecule compounds. The targeting ligands can include agonists of SSRs. The targeting ligands can include antagonists of SSRs. Agonists of SSRs can include partial agonists of SSRs. Agonists of SSRs can include complete agonists of SSRs. SSR agonists can include inverse SSR agonists. SSR antagonists can include competitive SSR antagonists. Targeting ligands can include SSR allosteric modulators. SSR allosteric modulators can be SSR allosteric agonists. SSR allosteric modulators can be SSR allosteric antagonists.

[0164] The targeting ligands described herein may comprise one or more peptides, which may be the same or different. Peptides may be linear or cyclic. Peptides may be monocyclic. Peptides may include binding peptides. Binding peptides may bind to one or more targets within a subject system or in vitro system. Binding peptides may bind to somatostatin receptors (SSRs). Binding peptides may bind to somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). Binding peptides may bind to somatostatin receptor type 2 (SSTR2). Binding peptides may bind to human somatostatin receptor type 2 (SSTR2).

[0165] Peptides can contain any suitable number of amino acid residues. Peptides can contain 4 to 50, 5 to 40, 6 to 30, 7 to 20, or 8 to 10 amino acid residues. Peptides can contain 6 to 14 amino acid residues. Peptides can contain 6 to 10 amino acid residues. Peptides can contain 7 to 9 amino acid residues. Peptides can contain 8 to 9 amino acid residues. Peptides can contain 14 amino acid residues. Peptides can contain 13 amino acid residues. Peptides can contain 12 amino acid residues. Peptides can contain 11 amino acid residues. Peptides can contain 10 amino acid residues. Peptides can contain 9 amino acid residues. Peptides can contain 8 amino acid residues. Peptides can contain 7 amino acid residues. Peptides can contain 6 amino acid residues. Peptides can consist of 10 amino acid residues. Peptides can consist of 14 amino acid residues. Peptides can consist of 13 amino acid residues. Peptides can consist of 12 amino acid residues. Peptides can consist of 11 amino acid residues. Peptides can consist of 10 amino acid residues. Peptides can consist of 9 amino acid residues. Peptides can consist of 8 amino acid residues. Peptides can consist of 7 amino acid residues. Peptides can consist of 6 amino acid residues. Conjugates can be monocyclic peptides containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 amino acid residues. The amino acid residues described herein can be modified to remove or add one or more functional groups.

[0166] The targeting ligands described herein can be cyclized peptides. Cyclization can be achieved via a single disulfide bond, or via peptide bonds, alkyl bonds, alkenyl bonds, ester bonds, thioester bonds, ether bonds, thioether bonds, phosphate ether bonds, azo bonds, C-S-C bonds, C-N-C bonds, C═N-C bonds, C═N-O bonds, amide bonds, lactam bridges, carbamoyl bonds, urea bonds, thiourea bonds, amine bonds, thioamide bonds, etc. (but not limited to these). Peptides can contain cyclic peptides cyclized via peptide bonds. Cyclization of peptides can stabilize the peptide structure, thereby enhancing affinity for the target. Cyclization can occur between the N-terminus and C-terminus, or it can occur between terminal amino acids and non-terminal amino acids. Cyclization can occur between two non-terminal amino acids. Peptides can be cyclized via one or more cysteine ​​residues. Peptides can contain cysteine ​​residues at the C-terminus. Peptides can contain cysteine ​​residues at the N-terminus. Cyclization can occur via disulfide bonds between cysteine ​​residues or between a cysteine ​​residue and another residue with a thiol group.

[0167] Exemplary targeting ligands include BMS-753493, somatostatin or growth hormone-releasing inhibitory factor (SRIF), SRIF-14, SRIF-28, octreotide, octreotate, lanreotide, Pasireotide, JR11, L-779,976, BIM-23120, satoreotide, depreotide, 18F-KYNDRLPLYISNP (SEQ ID NO: 103), CaIX-P1, and FAP-2286. Targeting ligands may include octreotide salt, octreotide, D-Phe1-cyclic (Cys2-Tyr3-D-Trp4-Lys5-Thr6-Cys7)Thr8 (tyr3-octreotide salt or TATE), D-Phe1-cyclic (Cys2-Tyr3-D-Trp4-Lys5-Thr6-Cys7)Thr(ol)8 (Phe1-Tyr3 octreotide, edotreotide or TOC), and D-Phe1-cyclic (Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys7). Thr(ol)8 (OC), D-Phe1-cyclic(Cys2-1-Nal-D-Trp4-Lys5-Thr6-Cys7)Thr(ol)8 (NOC), p-Cl-Phe-cyclic(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2) (JR11) or p-Cl-Phe-cyclic(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH2 (LM3). The targeting ligand can be tyr3-octreotide, edotreptide, octreotide, or octreotide. The targeting ligand can be tyr3-octreotide. In some embodiments, the targeting ligand is 3-iodo-Tyr3-octreotide. In some embodiments, the targeting ligand is TATE. In some embodiments, the targeting ligand is TOC. In some embodiments, the targeting ligand is NOC. In some embodiments, the targeting ligand is JR-11. In some embodiments, the targeting ligand is lanreotide. In some embodiments, the targeting ligand is parreotide. In some embodiments, the targeting ligand is OC. In some embodiments, the targeting ligand is NOC. In some embodiments, the targeting ligand is LM3. In some embodiments, the targeting ligand is sartoreotide. In some embodiments, the targeting ligand is deprilatide.

[0168] In some embodiments, the conjugates described herein comprise having a structure The targeting ligand (JR-11 or sartoretide). In some embodiments, the conjugates described herein comprise a structure having The targeting ligand (lanreotide).

[0169] Targeting ligands may include small molecule compounds. Such small molecule compounds may include L-797,591, L-779,976, L-796,778, L-803,087, or L-817,818.

[0170] The targeting ligand can have a binding affinity for human SSR of no more than about 1 mM, based on the half-maximum inhibitory concentration (IC50). 50 The target ligand can have a binding affinity to human SSR of no more than about 1000 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 500 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 250 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 200 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 150 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 100 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 75 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 50 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 25 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 10 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured as not exceeding approximately 5 nM, as indicated by the half-maximum inhibitory concentration (IC50). 50 The binding affinity of the target ligand to human SSR can be measured by means of a half-maximal inhibitory concentration (IC50). The target ligand can have a binding affinity to human SSR of no more than about 2 nM, as measured by means of a half-maximal inhibitory concentration (IC50). 50The measurement is performed using a specific method. Targeting ligands may include monocyclic peptides or peptide mimics or derivatives thereof. Radionuclides

[0171] In one aspect, this document describes conjugates containing radionuclides. Exemplary radionuclides include, but are not limited to: actinium-211, actinium-217, actinium-225, americium-243, radium-223, lead-212, lead-203, copper-64, copper-67, copper-60, copper-61, copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67, dysprosium-154, gadolinium-148, gadolinium-153, samarium-146, samarium-147, samarium-153, terbium-149, thorium-227, thorium-229, iron-59, yttrium-86, indium-111, holmium-166, technetium-94, and technetium-99. m Yttrium-90, lutetium-177, terbium-161, rhenium-186, rhenium-188, cobalt-55, scandium-43, scandium-44, scandium-47, dysprosium-166, fluorine-18, or iodine-131.

[0172] Typically, the type of radionuclide used in therapeutic radiopharmaceuticals can be customized based on the specific type of cancer, the type of target region, etc. Radionuclides undergoing alpha decay produce particles consisting of two neutrons and two protons, while those undergoing beta decay emit high-energy electrons from their nuclei. Some radionuclides may also emit Auger particles. In some embodiments, the conjugate contains a radionuclide that emits alpha particles. Alpha radiation can cause direct, irreparable double-strand DNA breaks, compared to gamma and beta radiation, which can cause single-strand breaks via indirect DNA damage. The extent of these particles in tissue and the half-life of the radionuclide can also be considered when designing radiopharmaceutical conjugates. Table 4 below illustrates some characteristics of exemplary radionuclides. Table 4. Exemplary Radionuclides

[0173] In some embodiments, the radiopharmaceutical conjugates described herein comprise radionuclides selected from Table 4.

[0174] In some embodiments, the radiopharmaceutical conjugates described herein comprise one or more independent radionuclides. In some embodiments, the radiopharmaceutical conjugate comprises two radionuclides. In some embodiments, each of the one or more radionuclides is bound to a metal chelating agent of the radiopharmaceutical conjugate. In some embodiments, both radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelating agent. In some embodiments, the two radionuclides of the radiopharmaceutical conjugate are bound to two separate metal chelating agents. In some embodiments, each of the one or more radionuclides is a radionuclide that emits alpha particles.

[0175] In some embodiments, the radiopharmaceutical conjugates described herein comprise a radionuclide that emits alpha particles. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide that emits alpha particles bound to a metal chelating agent. In some embodiments, the radionuclide that emits alpha particles is actinium-225 (Acrylonitrile-225). 225 Ac), Radium-223 ( 223 Ra), Radium-224 ( 224 Ra), Bismuth-209 ( 209 Bi), bismuth-213 ( 213 Bi), Gadolinium-148 ( 148 Gd), Terbium-149 ( 149 Tb), Polonium-213 ( 213 Po), Francium-223 223 Fr), Thorium-227 ( 227 Th), Thorium-229 ( 229 Th) or Lead-212 ( 212 Pb). In some embodiments, the radionuclide emitting alpha particles is selected from... 225 Ac、 223 Ra、 209 Bi、 213 Bi、 148 Gd, 149 Tb, 213 Po、 223 Fr、 227 Th、 229 Th and 212 Pb. In some implementations, the radionuclide that emits alpha particles is 225 Ac. In some implementations, the radionuclide that emits alpha particles is 213 Bi. In some implementations, the radionuclide that emits alpha particles is 212 Bi. In some implementations, the radionuclide that emits alpha particles is 212 Pb. In some implementations, the radionuclide that emits alpha particles is224 Ra. In some implementations, the radionuclide that emits alpha particles is... 223 Ra. In some implementations, the radionuclide that emits alpha particles is... 227 In some implementations, the radionuclide that emits alpha particles is... 149 Tb. In some implementations, the radionuclide is 225 The decay products of Ac, such as 221 Fr、 217 At、 213 Bi、 213 Po、 209 Tl、 209 Pb or 209 Bi. In some embodiments, the conjugate comprises two 225 Ac is a radioactive nuclide. In some implementations, the radioactive nuclide is... 177 Lu. In some implementations, the radionuclide is added without a carrier (i.e., without a carrier or NCA). 177 Lu. In some implementations, the radionuclide is added without a carrier (i.e., without a carrier or NCA). 225 Ac. In some implementations, the radionuclide is free of long-lived radioactive contaminants and byproducts. 177 Lu. In some implementations, the conjugate comprises two... 177 Lu is a radionuclide. In some embodiments, the radionuclide is a radionuclide added without a carrier.

[0176] In some embodiments, the radiopharmaceutical conjugates described herein comprise a radionuclide selected from the following: 62 Cu、 64 Cu、 67 Cu、 90 Y、 109 Pd, 111 Ag、 134 Ce、 149 Pm, 153 Sm、 166 Ho、 99m Tc, 67 Ga、 68 Ga、 111 In、 90 Y、 177 Lu、 186 Re、 188 Re、 197 Au、 198 Au、 199 Au、 105 Rh、 165 Ho、 161Tb, 149 Pm, 153 Pm, 44 Sc、 47 Sc、 213 Po、 212 Pb, 209 Bi、 212 Bi、 213 Bi、 225 Ac、 117m Sn、 67 Ga、 149 Tb, 152 Tb, 167 Tm、 175 Yb、 223 Ra、 223 Fr、 227 Th、 229 Th、 201 Tl、 148 Gd, 160 Gd, 148 Nd, 89 Sr and 89 Zr. In some embodiments, the radionuclide is selected from... 62 Cu、 64 Cu、 67 Cu、 68 Ga、 89 Zr、 90 Y、 99m Tc, 105 Rh、 111 In、 134 Ce、 148 Gd, 149 Tb, 152 Tb, 153 Pm, 167 Tm、 175 Yb、 177 Lu、 209 Bi、 212 Pb, 213 Po、 213 Bi、 223 Ra、 223 Fr、 227 Th、 225 Ac and 229 In some implementations, the radionuclide is... 225 Ac. In some implementations, the radionuclide is 225 The decay products of Ac, such as 221 Fr、 217 At、 213 Bi、 213 Po、 209 Tl、209 Pb or 209 Bi. In some embodiments, the radiopharmaceutical conjugate comprises two 225 Ac is a radioactive nuclide. In some implementations, the radioactive nuclide is... 177 Lu. In some embodiments, the radiopharmaceutical conjugate comprises two 177 Lu radionuclide.

[0177] In some embodiments, the radiopharmaceutical conjugates described herein comprise a radionuclide that emits beta particles. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide that emits beta particles bound to a metal chelating agent. In some embodiments, the radionuclide that emits beta particles is copper-67, rhodium-105, ytterbium-175, thulium-167, promethium-153, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the radionuclide that emits beta particles is copper-67, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the radionuclide that emits beta particles is lutetium-177.

[0178] In some embodiments, the radiopharmaceutical conjugates described herein comprise a radionuclide that emits gamma particles. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide that emits gamma particles bound to a metal chelating agent. In some embodiments, the radionuclide that emits gamma particles is indium-111 or tin-117m.

[0179] In some embodiments, the radiopharmaceutical conjugates described herein comprise a positron-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron-emitting radionuclide bound to a metal chelating agent. In some embodiments, the positron-emitting radionuclide is gallium-68, copper-61, copper-62, copper-64, zirconium-89, or terbium-152. In some embodiments, the radionuclide is zirconium-89. In some embodiments, the radionuclide is gallium-68.

[0180] In some embodiments, the conjugates described herein comprise radionuclides suitable for imaging or diagnostic purposes. In some embodiments, the radionuclides suitable for imaging are selected from... 62 Cu、 64 Cu、 89 Zr、 134 Ce、 152 Tb, 68 Ga、 111 In and 99m Tc. In some embodiments, the radionuclide is suitable for PET imaging. In some embodiments, the radionuclide suitable for PET imaging is selected from... 62 Cu、64 Cu、 89 Zr、 134 Ce、 152 Tb and 68 Ga. In some embodiments, the radionuclide is suitable for SPECT imaging. In some embodiments, the radionuclide suitable for SPECT imaging is selected from... 111 In and 99m Tc.

[0181] In some implementations, the radionuclide that emits alpha particles is 225 Ac. In some implementations, the radionuclide emitting alpha particles is unsupported (i.e., unsupported or nca). 225 Ac. In some implementation schemes, 225 Ac contains no long-lived radioactive contaminants or byproducts. In some embodiments, the radionuclide emitting alpha particles is added via a carrier. 225 Ac. In some implementation schemes, 225 Ac is produced from heavier radioactive nuclides. In some implementations, 225 Ac is generated using a thorium-229 generator. In some implementations, 225 Ac decays via 229Th. 225 Ra then 225 Ra and 225 Ac is produced by separation via ion exchange resin. In some embodiments, 229 Th is a legacy provided by government sources. 233 U-series reserves. In some implementation schemes, 225 Ac is generated using a linear electron accelerator (LINAC) with radium-226 as the target source. In some implementations, 225 Ac is generated using the following method: via an electron linear accelerator. 226 Ra(γ, n) 225 The Ra reaction, followed by separation using a series of ion exchange resins. 225 Ra and 225 Ac and purification. In some implementations, 225 Ac is produced using a cyclic proton accelerator with radium-226 as the target source. In some implementations, 225 Ac is a low-energy cyclic proton accelerator (also known as a cyclotron) that uses a low-energy cyclic proton accelerator to... 226 Ra(p, 2n) 225 Produced by the Ac reaction. In some implementations, 225 Ac is a low-energy cyclic proton accelerator (also known as a cyclotron) with an energy range of 10-20 MeV.226 Ra(p, 2n) 225 Produced by the Ac reaction. In some implementations, 225 Ac is generated using an electron beam accelerator (rhodotron) with radium-226 as the target source. In some implementations, 225 Ac is generated using the following method: accelerator via electron beam. 226 Ra(γ, n) 225 The Ra reaction, followed by separation using a series of ion exchange resins. 225 Ra and 225 Ac and purification. In some implementations, 225 Ac is generated using high-energy proton spallation with thorium-232 as the target source. In some implementations, 225 Ac uses a 70-100 MeV+ high-energy proton accelerator to... 232 Th(p, nxp) 225 Produced by the Ac reaction.

[0182] In some embodiments, the conjugates described herein do not contain any radionuclides, i.e., cold conjugates. For example, in some cases, the radionuclides may be replaced by substitutes (e.g., 225 Ac was replaced by lanthanum for testing and experimental purposes. Metal chelating agents

[0183] In one aspect, this document describes conjugates comprising a metal chelating agent configured to bind to a radionuclide. The metal chelating agent can refer to the portion of the conjugate configured to bind to a radionuclide. In some embodiments, the conjugates described herein comprise two or more independent metal chelating agents, such as 2, 3, 4, 5, or more metal chelating agents. In some embodiments, the conjugates described herein comprise two metal chelating agents, which may be the same or different. The metal chelating agent can be attached to a connector or targeting ligand via any suitable group / atom of the chelating agent.

[0184] In some embodiments, the metal chelating agent is capable of binding to radioactive atoms. Binding can be direct, for example, the metal chelating agent can form hydrogen bonds or electrostatic interactions with the radioactive atom. Binding can also be indirect, for example, the metal chelating agent binds to a molecule containing a radioactive atom. In some embodiments, the metal chelating agent comprises or is a macrocycle. In some embodiments, the metal chelating agent comprises or is DOTA or NOA. In some embodiments, the metal chelating agent comprises a macrocycle (e.g., a macrocycle containing O and / or N atoms), DOTA, NOA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or deferoxamine.

[0185] In some embodiments, the metal chelating agent comprises multiple amines. In some embodiments, the metal chelating agent comprises four or more nitrogen atoms, four or more carboxylic acid groups, or combinations thereof. In some embodiments, the metal chelating agent does not contain sulfur atoms. In some embodiments, the metal chelating agent comprises a ring. In some embodiments, the ring comprises oxygen and / or nitrogen atoms. In some embodiments, the metal chelating agent is a ring comprising three or more nitrogen atoms, three or more carboxylic acid groups, or combinations thereof. In some embodiments, the metal chelating agent is multidentate.

[0186] In some embodiments, the metal chelating agents described herein include cyclic chelating agents. Exemplary cyclic chelating agents include, but are not limited to, AAZTA, BAT, BAT-TM, crown ethers, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, oxo-DO3A, p-NH2-Bn-oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A″-EDTA, and MeO-DOTA-NCS. EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE 2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A″-DTPA, p-NH2-Bn-CHX-A″-DTPA, p-SC N-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A″-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L 1 H3L 4 H2azapa, H5decapa, bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa 2H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, alpha-lipoic acid, TGA, BAL, bis-thiocarbazone, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3P-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H2DED PA, p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, motesafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3T A, C-NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L py L1, L2, L3 and EuK-106.

[0187] In some embodiments, the metal chelating agent is DO3A. In some embodiments, the metal chelating agent is PEPA. In some embodiments, the metal chelating agent is EDTA. In some embodiments, the metal chelating agent is CHX-A″-DTPA. In some embodiments, the metal chelating agent is HEHA. In some embodiments, the metal chelating agent is DOTMP. In some embodiments, the metal chelating agent is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelating agent is macropa. In some embodiments, the metal chelating agent is macropa-NCS. In some embodiments, the metal chelating agent is H 4 py4pa. In some embodiments, the metal chelating agent is H4octapa. In some embodiments, the metal chelating agent is H4CHXoctapa. In some embodiments, the metal chelating agent is DOTP. In some embodiments, the metal chelating agent is a crown ether.

[0188] In some embodiments, the metal chelating agent is DOTA. In some embodiments, the metal chelating agent is a chiral derivative of DOTA. In some embodiments, the metal chelating agent is DOTA-GA. Exemplary chiral DOTA chelating agents are described in Dai et al., Nature Communications (2018) 9:857. In some embodiments, the metal chelating agent is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid. In some embodiments, the metal chelating agent has the following structure: In some embodiments, the metal chelating agent is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetraethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid. In some embodiments, the metal chelating agent has the following structure: In some embodiments of the conjugates described herein, the metal chelating agent has the following structure: , where each R e The metal chelating agent is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheteroalkyl, alkylaryl, alkylheteroaryl, or amino acid side chains. In some embodiments, the metal chelating agent has the following structure: , where each R e It is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheteroalkyl, alkylaryl, alkylheteroaryl, or amino acid side chains.

[0189] In some embodiments, the conjugate comprises DOTA. In some embodiments, the conjugate comprises a DOTA derivative, such as p-SCN-Bn-DOTA and MeO-DOTA-NCS. In some embodiments, the conjugate comprises two separate metal chelating agents, and at least one or both are DOTA. The structures of some exemplary metal chelating agents are shown in... Figure 3(Attachment not shown). Exemplary metal chelators are further described in WO2012 / 174136; US20130183235A1; US20120219495A1; Ramogidaand et al., EJNMMI radiopharm. chem. 4, 21 (2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018; Li et al., BioconjugateChem. 2019, 30, 5, 1539–1553; and Baranyai et al., Eur. J. Inorg. Chem. 36–56 (2020), each of which is incorporated herein by reference in its entirety. connector

[0190] In targeted radiopharmaceuticals, the chemical scaffold covalently linking the pharmacophore and metal chelator can be called a linker. Incorporating well-designed linkers into drug molecules can further enhance their affinity for their biological targets, accelerate internalization into target tissues, and optimize pharmacokinetic properties. Different chemical moieties can be used to construct linkers. By altering their physicochemical characteristics, desired in vivo characteristics (i.e., absorption, distribution, metabolism, and excretion of the drug molecule) can be achieved. In some embodiments, such as when it is difficult to modify the pharmacophore and metal chelating moieties without sacrificing biological affinity or metal-binding ability, the physicochemical characteristics of the conjugate can be tuned via linkers. The conjugates described herein may contain one or more linkers. The targeting ligand can be covalently linked to the metal chelator via a linker. The linker can covalently attach the targeting ligand to the metal chelator. The targeting ligand can also be directly attached to the metal chelator without a linker.

[0191] Linkers may contain one or more amino acid residues. Linkers may contain 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. Linkers may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. Linkers may contain 1 to 5 amino acid residues. For example, a linker may contain one or more lysine (K) residues, such as the K, KK, or KKK sequence. Linkers may contain lysine or its derivatives. Linkers may contain lysine. Linkers may contain one or more amino acids that are non-natural amino acids.

[0192] The connector can have a specified length to connect the metal chelating agent (and optionally a radionuclide) and the peptide, while allowing for an appropriate distance between them. In some embodiments, the connector length is 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5 atoms, or 2 to 20 atoms. In some embodiments, the connector length is 1 to 10 atoms. Isomers / stereoisomers

[0193] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include cis, trans, synonymous, antisense, isolateral (E), and homolateral (Z) isomers and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include diastereomers, enantiomers, and epimers, and corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are then recovered. tautomer

[0194] A "tautomer" is a molecule in which a proton can be transferred from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds provided herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibria include:

[0195] In some cases, the compounds disclosed herein exist in tautomer form. For clarity, the structures of the compounds are shown in one tautomer form. Alternative tautomer forms are explicitly included in this disclosure. Labeled compounds.

[0196] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those listed herein, but in fact, one or more atoms are replaced by atoms whose atomic mass or mass number differs from that found in nature. Examples of isotopes that may be incorporated into the compounds described herein or their solvates or stereoisomers include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl. Other isotopes of the compounds described herein containing the aforementioned isotopes and / or other atoms, and their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of this disclosure. Certain isotope-labeled compounds (e.g., those doped with radioactive isotopes, such as...) 3 H and 14 Those compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium-modified (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes have attracted attention due to their ease of preparation and detectability. Furthermore, the use of isotopes such as deuterium (i.e., 2 Substitution with heavy isotopes of H can produce certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In some embodiments, the isotopically labeled compound or its pharmaceutically acceptable salt, solvate, or stereoisomer is prepared by any suitable method.

[0197] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling. Pharmaceutically acceptable salt.

[0198] In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the compounds disclosed herein include pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salt" means any salt of a stabilizer that can be used to stabilize a radiopharmaceutical composition. As used herein, "pharmaceutical acceptable salt" means any salt of a stabilizer that can be used to prevent or delay the decomposition of a radiopharmaceutical within a composition.

[0199] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compounds in their free form with a suitable acid or base alone and isolating the resulting salts.

[0200] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases. These salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptates, glycerophosphates, glycolates, hemisulfates, heptanates, hexyn-1,6-dicitates, hydroxybenzoates, γ-hydroxybutyrates, and other salts. Salts, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0201] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid. Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucono-heptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, the compounds comprising free acid groups described herein react with a suitable base (such as a hydroxide, carbonate, bicarbonate, or sulfate) of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4, etc.

[0202] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization can yield water-soluble, oil-soluble, or dispersible products. Solvents.

[0203] In some embodiments, the compounds described herein are present as solvates. The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization in a pharmaceutically acceptable solvent (such as water, ethanol, etc.). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the methods described herein. Additionally, the compounds provided herein can exist in both non-solventized and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solventized form. Therefore, one aspect of this disclosure relates to hydrates and solvates of the compounds and / or their pharmaceutically acceptable salts as described herein, which can be separated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high-resolution X-ray diffraction, etc. Preparation of the composition

[0204] This disclosure provides methods for preparing and making the compositions described herein. In some embodiments, the method for preparing the radiopharmaceutical composition includes reacting a radionuclide (such as...) with a radioactive nuclide. 225 Ac) is combined with an unlabeled conjugate (e.g., DOTATATE or DOTATOC) in the presence of one or more stabilizers, wherein the unlabeled conjugate comprises a targeting ligand and a metal chelating agent covalently attached to the targeting ligand, thereby producing a conjugate comprising a labeled conjugate. 225 Ac-DOTATATE or 225 A mixture of Ac-DOTATOC; and optionally, one or more stabilizers are combined with the mixture. In some embodiments, the method of preparing the radiopharmaceutical composition includes combining a radionuclide with an unlabeled conjugate, wherein the unlabeled conjugate comprises a targeting ligand and a metal chelating agent covalently attached to the targeting ligand, thereby producing a labeled conjugate; and combining the one or more stabilizers with the labeled conjugate.

[0205] In some embodiments, the method of preparing the radiopharmaceutical composition includes combining a radionuclide with an unlabeled conjugate, the unlabeled conjugate comprising a targeting ligand and a metal chelating agent covalently attached to the targeting ligand, thereby producing a labeled conjugate; and optionally adding the one or more stabilizers to the labeled conjugate. In some embodiments, the method of preparing the radiopharmaceutical composition includes combining a radionuclide with an unlabeled conjugate in the presence of one or more stabilizers, the unlabeled conjugate comprising a targeting ligand and a metal chelating agent covalently attached to the targeting ligand, thereby producing a labeled conjugate; and optionally adding the one or more stabilizers to the labeled conjugate.

[0206] Methods for preparing the composition may include one or more steps. One or more such steps may include diluting a solution or mixture containing a radionuclide to a desired concentration (i.e., a dilution step). The solution or mixture containing the radionuclide may be diluted 2 to 1000 times, for example 10 to 50 times, 2 to 40 times, 25 to 75 times, or 50 to 100 times. One or more such steps may include adding one or more stabilizers during the dilution process. One or more such steps may include optionally adding one or more stabilizers during the dilution process. One or more such steps may include diluting an unlabeled conjugate solution or mixture to a desired concentration. One or more such steps may include adding one or more stabilizers prior to the dilution process. One or more such steps may include adding one or more stabilizers after the dilution process. The unlabeled conjugate may contain a targeting ligand and a metal chelating agent. The targeting ligand and the metal chelating agent may be covalently linked. One or more such steps may include dilution using a liquid solution or mixture.

[0207] Methods for preparing radiopharmaceutical compositions may include reacting or combining a radionuclide with an unlabeled conjugate solution or mixture to obtain a labeled conjugate solution or mixture (i.e., a labeling process). In some embodiments, the method includes maintaining a temperature during the labeling process. In some embodiments, the method includes maintaining a temperature within the following ranges: 0ºC to 100ºC, 10ºC to 100ºC, 20ºC to 100ºC, 30ºC to 100ºC, 40ºC to 100ºC, 50ºC to 100ºC, 60ºC to 100ºC, 70ºC to 100ºC, or 80ºC to 100ºC. In some embodiments, the method includes reacting the radionuclide with the unlabeled conjugate for a period of time. In some embodiments, the time period is about 1 minute to about 3 hours, about 2 minutes to about 2.5 hours, about 3 minutes to about 2 hours, about 5 minutes to about 1.5 hours, about 8 minutes to about 1 hour, or about 10 minutes to about 30 minutes. In some embodiments, the method includes mixing the radionuclide with the unlabeled conjugate during the labeling process. One or more of these steps may include mixing using laboratory mixing equipment such as a mixer, vortex mixer, stirrer, magnetic stirrer, vortex mixer, shaker, centrifuge, or homogenizer. One or more of these steps may include agitating the reaction solution or mixture. One or more of these steps may include agitating the reaction solution or mixture at speeds within the following ranges: about 10 rpm to about 5000 rpm, about 100 rpm to about 2500 rpm, about 200 rpm to about 1000 rpm, about 300 rpm to about 800 rpm, or about 400 rpm to about 600 rpm. One or more of these steps may include further diluting the labeled conjugate solution or mixture. One or more of these steps may include adding one or more stabilizers during the dilution process. One or more of these steps may optionally include adding one or more stabilizers after the dilution process.

[0208] In some implementations, it includes [ 225 Ac]Ac-DOTA-TATE (or 225 The radiopharmaceutical composition of Ac-DOTA-TATE can be obtained by reacting DOTA-TATE with a solution of HCl (e.g., 0.04 M, aqueous) 225 The reaction of Ac]AcCl3 is used to prepare it. Therefore, this article provides a method for preparing [Ac]AcCl3 containing... 225 A method for constructing a radiopharmaceutical composition of Ac-DOTA-TATE. In some embodiments, the method includes one or more of the following steps: diluting DOTA-TATE with sodium acetate / acetic acid buffer solution, adding [ 225The AcCl3 HCl solution was added to diluted DOTA-TATE, the mixture was mixed, heated, and then diluted to a preparation buffer containing one or more stabilizers as described herein. In some embodiments, [ 225 The concentration of AcCl3 in HCl solution is approximately 10 µCi / µl HCl. In some embodiments, [ 225 The concentration of Ac]AcCl3 in HCl solution is approximately 1 to 50 µCi / µl HCl. Accordingly, preparations containing [Ac]AcCl3 can be prepared. 225 Ac-HA-DOTA-TATE or 225 The radiopharmaceutical composition of Ac-DOTA-JR-11.

[0209] In some implementations, preparation includes [ 225 Ac]Ac-DOTA-TATE or [ 225 The method of producing a radiopharmaceutical composition of Ac-DOTA-TOC includes one or more of the following steps: providing [Ac]Ac-DOTA-TOC in a first vial 225 Ac]AcCl3 solution, this solution is transferred to a reactor, and then [...] 225 The first vial of AcCl3 solution provides a reaction buffer solution, and the reaction buffer solution and residual [ 225 The AcCl3 solution was transferred from the first vial to the reactor, and the DOTA-TATE or DOTA-TOC solution was then transferred to the reactor, so that the DOTA-TATE or DOTA-TOC solution reacted with […]. 225 Ac]AcCl3 solution reacts in a reactor to obtain [ 225 Ac]Ac-DOTA-TATE or [ 225 Ac]Ac-DOTA-TOC, and will [ 225 Ac]Ac-DOTA-TATE or [ 225 Ac]Ac-DOTA-TOC is diluted in a formulation buffer containing one or more stabilizers described herein to form a radiopharmaceutical composition. In some embodiments, 225 The molar ratio of Ac to DOTA-TATE or DOTA-TOC is 1:1 to 1:10, 1:1 to 1:8, 1:1 to 1:5, 1:1 to 1:3.5, 1:1 to 1:2, or 1:1 to 1.25. In some implementations, 225 The molar ratio of Ac to DOTA-TATE or DOTA-TOC is approximately 1:1, 1:2, 1:25, 1:3, 1:3.5, or 1:4. Accordingly, formulations containing [specific compounds] can be prepared. 225Ac-HA-DOTA-TATE or 225 The radiopharmaceutical composition of Ac-DOTA-JR-11.

[0210] Compounds used in the reactions and compositions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are those obtained from standard commercial sources, including ABX advanced biochemical compounds GmbH (Laderberg, Germany), Acros Organics (Pittsburgh, Pennsylvania), Aldrich Chemical (Milwaukee, Wisconsin, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avidity Science (USA), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (Westchester, Pennsylvania), Crescent Chemical Co. (Hopoa, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), ITM (Munich, Germany), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, New Hampshire), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Riedel de Haen AG (Hanover, Germany), Sigma-Aldrich (USA), Spectrum Quality Product, Inc. (New Brunswick, New Jersey), TCIAmerica (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), VWR (Radino, Pennsylvania, USA), Wako Chemicals USA, Inc. (Richmond, Virginia), and Wuxi-Apptech Inc. (Shanghai, China). Treatment

[0211] In one aspect, this disclosure provides methods for treating a disease or condition in a subject in need. The methods may include administering a radiopharmaceutical composition to the subject in need. The methods may provide therapeutic and / or preventative benefits to the subject in need, including administering the radiopharmaceutical composition described herein.

[0212] The method may include administering to a subject a radiopharmaceutical composition comprising a therapeutically effective amount of the conjugate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is SSR-related cancer. In some embodiments, the cancer is SSTR2-related cancer. In some embodiments, the cancer is somatostatin receptor-positive (SSTR+) cancer. In some embodiments, the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an unresectable, advanced, somatostatin receptor-expressing (SSTR+) well-differentiated gastrointestinal pancreatic neuroendocrine tumor (GEP-NET) that has been previously treated with 177Lu-SSA (such as...). 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC or 177 Progress has been made since Lu-HA-DOTA-TATE. In some embodiments, the SSTR+ neuroendocrine tumor is located in the middle / upper part of the pancreas or in the middle / upper part of the gastrointestinal tract. In some embodiments, the SSTR+ neuroendocrine tumor is located in the middle / upper part of the pancreas. In some embodiments, the SSTR+ neuroendocrine tumor is located in the middle / upper part of the gastrointestinal tract. In some embodiments, the neuroendocrine tumor is located in a gastrointestinal organ. In some embodiments, the gastrointestinal organ is the ileum, duodenum, or jejunum. In some embodiments, the gastrointestinal organ is the ileum. In some embodiments, the gastrointestinal organ is the duodenum. In some embodiments, the gastrointestinal organ is the jejunum. In some embodiments, the SSTR+ neuroendocrine tumor is located in the pancreas. In some embodiments, the SSTR+ neuroendocrine tumor is located in the ileum, duodenum, jejunum, or pancreas.

[0213] In some implementations, the cancer is a neuroendocrine carcinoma, lymphoma, pancreatic cancer, pituitary cancer, breast cancer, lung cancer, gastric cancer, medulloblastoma, or neuroblastoma. In some implementations, the cancer is a neuroendocrine carcinoma. In some implementations, the neuroendocrine carcinoma is recurrent or refractory. In some implementations, the neuroendocrine carcinoma is suitable for radiation therapy containing a radionuclide that emits beta particles (such as...). 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC or 177This is difficult to treat with Lu-HA-DOTA-TATE therapy. In some implementations, the subject has already received radiotherapy containing a radionuclide that emits beta particles (e.g., [unclear text - likely a continuation of the previous sentence]) prior to the administration of the radiopharmaceutical composition. 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC or 177 Lu-HA-DOTA-TATE therapy). In some implementations, subjects have received... 177 Lu-SSA therapy. In some implementations, subjects have received... 177 Prior treatment with Lu-DOTA-TATE. In some implementations, the subject has received... 177 Prior treatment with Lu-DOTA-TOC therapy. In some implementations, the subject has received... 177Prior treatment with Lu-HA-DOTA-TATE. In some embodiments, the neuroendocrine carcinoma is neuroendocrine lung cancer or neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine carcinoma is a carcinoid tumor in the lung, gastrointestinal tract, or thymus, a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, angiotensin-converting peptide tumor), medullary thyroid carcinoma, Merkel cell carcinoma, pheochromocytoma of the adrenal gland, adrenal carcinoma, small cell carcinoma (e.g., in the lung), or large cell carcinoid tumor (e.g., in the lung). In some embodiments, the cancer is an SSTR2+ pulmonary neuroendocrine tumor. In some embodiments, the cancer is a somatostatin receptor-positive (SSTR+) gastrointestinal pancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is extensive-stage small cell lung cancer (ES-SCLC) expressing somatostatin receptor (SSTR+). In some embodiments, the SCLC is untreated. In some embodiments, the SCLC is relapsed or refractory. In some embodiments, the subject has received up to one cycle of platinum-etoposide and PD-L1 inhibitor therapy. In some embodiments, the cancer is untreated. In some embodiments, the cancer is relapsed or refractory. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 1 kBq / kg to about 0.2 GBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 5 kBq / kg to about 50,000 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 20 kBq / kg to about 5,000 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 50 kBq / kg to about 500 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject at an amount equivalent to about 50 kBq / kg to about 200 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 60 kBq / kg to about 150 kBq / kg of body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject with a radioactivity of about 1 μCi to 1,000 μCi. In some embodiments, the radiopharmaceutical composition is administered to the subject with a radioactivity of about 10 μCi to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to the subject with a radioactivity of about 100 μCi to 500 μCi.In some embodiments, the radiopharmaceutical composition is administered to the subject at a radioactivity of about 100 μCi to 300 μCi. In some embodiments, the radiopharmaceutical composition is administered to the subject at a radioactivity of about 125 μCi to 275 μCi. In some embodiments, the radiopharmaceutical composition is administered to the subject at radioactivity of about 125 μCi, 175 μCi, 225 μCi, or 275 μCi. In some embodiments, the radiopharmaceutical composition is administered at 4 to 6-week intervals. In some embodiments, the radiopharmaceutical composition is administered at 4-12-week intervals. In some embodiments, the radiopharmaceutical composition is administered at 8-week intervals. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose of about 10,000 kBq to about 100,000 kBq in the subject. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose of about 40,000 kBq to about 70,000 kBq in the subject. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose of approximately 40,800 kBq in the subject. In some embodiments, the radiopharmaceutical composition comprises... 225 Ac-DOTA-TOC. In some embodiments, the radiopharmaceutical composition contains... 225 Ac-DOTA-TATE. In some embodiments, the radiopharmaceutical composition contains... 225 Ac-DOTA-JR-11. In some embodiments, the radiopharmaceutical composition contains... 225 Ac-HA-DOTA-TATE.

[0214] In some embodiments, the radiopharmaceutical formulations of Examples 9 (Formula B), 10, 11, 13, 19, or 24 are administered to the subject as part of first-line therapy. In some embodiments, the formulations are administered to the subject as part of second-line therapy. In some embodiments, the formulations are administered to the subject as part of third-line therapy. In some embodiments, a second therapeutic agent is administered to the subject in addition to the radiopharmaceutical formulation. In some embodiments, the second therapeutic agent includes everolimus, sunitinib, streptozotocin, temozolomide, capecitabine, or combinations thereof.

[0215] In some embodiments, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering an effective dose of... 225 Ac-DOTA-TATE, wherein the aforementioned 225Ac-DOTA-TATE is administered to the subject at an initial dose as described herein, wherein at least one subsequent dose of the liquid radiopharmaceutical composition is administered to the subject at approximately 50% of the initial dose. In some embodiments, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject at an initial dose as described herein, and wherein at least one subsequent dose of the liquid radiopharmaceutical composition is administered to the subject at approximately 50% of the initial dose. In some embodiments, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, wherein the subject had previously received 177 Lu-labeled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject as an initial dose equivalent to about 10.2 MBq per dose, and wherein at least one subsequent dose of the liquid radiopharmaceutical composition is administered to the subject at about 50% of the initial dose. In some embodiments, the at least one subsequent dose is an amount equivalent to about 5.1 MBq per dose. In some embodiments, the method includes administering about 75% of the initial dose. 225 Ac-DOTA-TATE (e.g., as a liquid radiopharmaceutical composition). In some embodiments, this document provides a method for treating a subject with a somatostatin receptor-positive (SSTR+) neuroendocrine tumor, the method comprising administering an effective amount of... 225 Ac-DOTA-TATE, wherein the aforementioned 225 Ac-DOTA-TATE is administered to the subject at an initial dose a...

Claims

1. A method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, The subject mentioned above had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, The liquid radiopharmaceutical composition was administered to the subject at a dose equivalent to approximately 10.2 MBq per dose, and The liquid radiopharmaceutical composition is administered at weekly intervals of 7 to 9 weeks, with a maximum cumulative dose of approximately 40,800 kBq.

2. A method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, The subject mentioned above had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, The liquid radiopharmaceutical composition was administered to the subject as an initial dose equivalent to approximately 10.2 MBq per dose, and At least one subsequent dose of the liquid radiopharmaceutical composition is administered to the subject at approximately 50% of the initial dose.

3. The method of claim 2, wherein the at least one subsequent dose is an amount equivalent to about 5.1 MBq per dose.

4. A method for treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject of need, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE, The subject mentioned above had previously received 177 Lu-labeled somatostatin analogue (SSA) therapy, The liquid radiopharmaceutical composition was administered to the subject as an initial dose equivalent to approximately 10.2 MBq per dose, and If the subject has an adverse reaction to the initial dose, the liquid radiopharmaceutical composition is administered to the subject at a reduced dose of approximately 50% of the initial dose.

5. The method of claim 4, wherein if the subject has an adverse reaction to the initial dose, the liquid radiopharmaceutical composition is discontinued for a period of time before the administration of the reduced dose.

6. The method of claim 5, wherein if the subject does not have an adverse reaction to a reduced dose of about 50% of the initial dose, the liquid radiopharmaceutical composition is administered at a second reduced dose of about 75% of the initial dose.

7. The method of claim 6, wherein if the subject does not have an adverse reaction to the second reduced dose, the liquid radiopharmaceutical composition is administered at the initial dose.

8. The method according to any one of claims 4 to 7, wherein the adverse reaction is selected from: i) NCI CTCAE (v5.0) Grade 2, 3 or 4 thrombocytopenia; ii) NCI CTCAE (v5.0) Grade 3 or 4 anemia or neutropenia; iii) Nephrotoxicity, including eGFR < 50 mL / min / 1.73m 2 A 40% increase in baseline serum creatinine or a 40% decrease in baseline eGFR; iv) Hepatotoxicity, including NCI CTCAE (v5) grade 3 or 4 bilirubinemia, or hypoalbuminemia < 3 g / dL with a reduced prothrombin ratio of less than 70%; and / or v) NCI CTCAE (v5.0) Grade 3 or 4 non-hematologic toxicity.

9. The method according to any one of claims 1 to 8, wherein the SSTR+ neuroendocrine tumor in the subject is... 177 Progress has been made following Lu-labeled somatostatin analog (SSA) therapy.

10. The method according to any one of claims 1 to 9, wherein the SSTR+ neuroendocrine tumor is an inoperable, advanced, well-differentiated SSTR+ gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), which is used in 177 Lu-labeled somatostatin analogs ( 177 Progress has been made following Lu-SSA therapy.

11. The method according to any one of claims 1 to 10, wherein the subject has previously received treatment selected from... 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC and / or 177 Lu-HA-DOTA-TATE 177 Lu-SSA therapy.

12. The method of claim 11, wherein the... 177 Lu-SSA therapy requires a minimum of two cycles.

13. The method according to any one of claims 1 to 12, wherein the... 177 Lu-SSA therapy can be administered for a maximum of four cycles.

14. The method according to any one of claims 11 to 13, wherein: Will 177 Lu-DOTA-TATE is administered at a dose of approximately 6.66 GBq to approximately 8.14 GBq per cycle; Will 177 Lu-DOTA-TOC is administered at a dose of approximately 6.75 GBq to approximately 8.25 GBq per cycle; or Will 177 Lu-HA-DOTA-TATE is administered at a dose of 6.66 GBq to approximately 8.14 GBq per cycle.

15. The method according to any one of claims 11 to 14, wherein: Will 177 Lu-DOTA-TATE is administered at a cumulative dose of approximately 26.64 GBq to approximately 32.56 GBq; Will 177 Lu-DOTA-TOC is administered at a cumulative dose of approximately 27 GBq to approximately 33 GBq; or Will 177 Lu-HA-DOTAT-ATE is administered at a cumulative dose of approximately 26.64 GBq to approximately 32.56 GBq.

16. The method according to any one of claims 1 to 15, wherein the liquid radiopharmaceutical composition is administered at 8-week intervals.

17. The method according to any one of claims 1 to 16, wherein the liquid radiopharmaceutical composition is administered at intervals of at least 7 weeks.

18. The method according to any one of claims 1 to 17, wherein the liquid radiopharmaceutical composition is administered for a maximum of four cycles.

19. The method according to any one of claims 2 to 18, wherein the liquid radiopharmaceutical composition is administered to the subject at a maximum cumulative dose of about 40,800 kBq.

20. The method according to any one of claims 1 to 19, wherein the liquid radiopharmaceutical composition is administered less than 150 hours after its manufacture.

21. The method according to any one of claims 1 to 19, wherein the liquid radiopharmaceutical composition is administered less than 72 hours after its manufacture.

22. The method according to any one of claims 1 to 21, wherein the subject has a Ki-67 index of up to 20%.

23. The method according to any one of claims 1 to 22, wherein the subject has a creatinine clearance rate of at least 50 or 60 mL / min.

24. The method according to any one of claims 1 to 23, wherein the subject meets one or more of the following criteria: (i) wherein the subject has at least 50 mL / min / 1.73m 2 eGFR; (ii) wherein the subject has a hemoglobin concentration of at least 5.0 mmol / L; (iii) wherein the subject has an absolute neutrophil count of at least 1000 cells / μL; (iv) wherein the subject has at least 75 x 10 9 Platelet count per L; (v) wherein the subject has at least 100 x 10 9 Platelet count per L; (vi) wherein the subject had a total bilirubin level at most three times the upper limit of normal; and / or (vii) wherein the subject has a serum albumin level of at least 3.0 g / dL.

25. The method according to any one of claims 1 to 24, wherein the subject has an SSTR+ neuroendocrine tumor with a Krenning score of 3 or 4.

26. The method according to any one of claims 1 to 25, wherein the subject... 225 Actin 68 Gallium or 64 Copper is not hypersensitive.

27. The method according to any one of claims 1 to 26, wherein the subject does not suffer from cirrhosis.

28. The method according to any one of claims 1 to 27, wherein the subject has not received radioembolism.

29. The method according to any one of claims 1 to 28, wherein the patient administers the... 225 Ac-DOTA-TATE has previously undergone at least one SSTR-PET test.

30. The method of claim 29, wherein the SSTR-PET comprises based on 68 Ga or 64 Cu is a developer.

31. The method of claim 29 or 30, wherein the patient has at least one SSTR-PET-positive measurable disease site and does not have SSTR-imaging-negative measurable metastatic lesions.

32. The method according to any one of claims 1 to 31, wherein the SSTR+ neuroendocrine tumor is a functional tumor, and the subject is administered a long-acting SSA, wherein the long-acting somatostatin analog (SSA) is administered before the treatment of the tumor. 225 Ac-DOTA-TATE should be administered at a stable dose for at least 12 weeks prior to administration.

33. The method according to any one of claims 1 to 31, wherein the SSTR+ neuroendocrine tumor is a functional or non-functional tumor, and wherein the subject administers the... 225 Ac-DOTA-TATE has not received a long-acting somatostatin analog (SSA) within the previous 4 weeks.

34. The method according to claim 32 or 33, wherein the long-acting SSA is octreotide long-acting release agent or lanreotide.

35. The method according to any one of claims 1 to 31, wherein the subject is receiving a short-acting somatostatin analog (SSA), wherein the short-acting SSA is administered during the administration of the... 225 Administer Ac-DOTA-TATE at least 24 hours before or at least 24 hours after.

36. The method according to any one of claims 1 to 35, wherein the application of the... 225 The subject was given an intravenous amino acid solution prior to the administration of Ac-DOTA-TATE.

37. The method of claim 36, wherein the amino acid solution comprises arginine and lysine.

38. The method according to claim 36, wherein the amino acid solution is a 1-2 liter solution containing 18-25 g of arginine and 18-25 g of lysine.

39. The method according to any one of claims 36 to 38, wherein the application of the method... 225 The amino acid solution was administered at least 30 minutes prior to Ac-DOTA-TATE.

40. The method according to any one of claims 36 to 39, wherein the amino acid solution is applied for a period of at least 4 hours.

41. The method according to any one of claims 1 to 40, the method further comprising administering an antiemetic to the subject.

42. The method of claim 41, wherein the antiemetic is selected from granisetron, ondansetron, and tropisetron.

43. The method according to claim 41 or 42, wherein the antiemetic is administered prior to the administration of the amino acid solution.

44. The method according to any one of claims 1 to 43, wherein the... 177 Lu-SSA therapy during the administration of the above 225 Ac-DOTA-TATE should be used at least one year prior to application.

45. The method according to any one of claims 1 to 43, wherein the... 177 Lu-SSA therapy during the administration of the above 225 Ac-DOTA-TATE should be used no more than one year prior.

46. ​​The method according to any one of claims 1 to 45, wherein the subject administers the... 225 Ac-DOTA-TATE had previously received a long-acting somatostatin analog (SSA).

47. The method of claim 46, wherein the long-acting SSA comprises octreotide or lanreotide.

48. The method according to any one of claims 1 to 47, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

49. The method according to any one of claims 1 to 48, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an unresectable, advanced, somatostatin receptor-expressing (SSTR+) well-differentiated gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), which has been previously... 177 Lu-SSA therapy (such as) 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC or 177 Progress has been made since Lu-HA-DOTA-TATE.

50. The method according to any one of claims 1 to 49, wherein the subject has elevated levels of chromogranin A.

51. The method according to any one of claims 1 to 50, wherein the subject has an elevated level of 5-hydroxyindoleacetic acid.

52. The method of claim 50 or 51, wherein the chromogranin A is detected in a urine sample from the subject.

53. The method according to claim 51 or 52, wherein the 5-hydroxyindoleacetic acid is detected in a urine sample from the subject.

54. The method according to any one of claims 1 to 53, wherein the SSTR+ neuroendocrine tumor is located in the gastrointestinal organs or pancreas.

55. The method of claim 54, wherein the SSTR+ neuroendocrine tumor is located in the gastrointestinal tract.

56. The method according to claim 54 or 55, wherein the gastrointestinal organ is the ileum, duodenum or jejunum.

57. The method according to any one of claims 1 to 52, wherein the SSTR+ neuroendocrine tumor is located in the ileum, duodenum, jejunum or pancreas.

58. The method according to any one of claims 1 to 57, wherein... 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 5 mCi / L to about 50 mCi / L.

59. A method for treating a subject with somatostatin receptor-positive (SSTR+) cancer, the method comprising administering to the subject an effective amount of a liquid radiopharmaceutical composition. 225 Ac-DOTA-TATE.

60. The method of claim 59, wherein the cancer is a neuroendocrine carcinoma, lymphoma, pancreatic cancer, pituitary cancer, breast cancer, lung cancer, gastric cancer, medulloblastoma, or neuroblastoma.

61. The method of claim 59, wherein the cancer is a neuroendocrine carcinoma.

62. The method according to any one of claims 59 to 61, wherein at least 20% of the measurable lesions in the subjects are SSTR+.

63. The method of claim 62, wherein at least 50% of the measurable lesions in the subject are SSTR+.

64. The method of claim 62, wherein at least 20%, at least 30%, at least 50%, at least 75%, or at least 99% of the measurable lesions in the subject are SSTR+.

65. The method of claim 62, wherein 20% to 100% of the measurable lesions in the subject are SSTR+.

66. The method according to any one of claims 59 to 61, wherein at least 20% of the lesions in the subject are SSTR+, as determined by imaging or immunohistochemistry.

67. The method of claim 66, wherein 20% to 100% of the lesions in the subject are SSTR+, as determined by imaging or immunohistochemistry.

68. The method according to any one of claims 59 to 67, wherein the subject has received radiotherapy comprising a radionuclide emitting beta particles prior to the administration of the radiopharmaceutical composition.

69. The method of claim 68, wherein radiotherapy comprising a radionuclide emitting beta particles includes... 177 Lu-DOTA-TATE, 177 Lu-DOTA-TOC or 77 Lu-HA-DOTA-TATE therapy.

70. The method according to any one of claims 61 to 69, wherein the neuroendocrine carcinoma is neuroendocrine lung cancer or neuroendocrine pancreatic cancer.

71. The method according to any one of claims 61 to 69, wherein the neuroendocrine carcinoma is a carcinoid tumor in the lung, gastrointestinal tract or thymus, a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, vasodilator), medullary thyroid carcinoma, Merkel cell carcinoma, pheochromocytoma of the adrenal gland, adrenal carcinoma, small cell carcinoma (e.g., in the lung) or large cell carcinoid tumor (e.g., in the lung).

72. The method according to any one of claims 59 to 69, wherein the cancer is an SSTR2+ pulmonary neuroendocrine tumor.

73. The method according to any one of claims 59 to 69, wherein the cancer is small cell lung cancer (SCLC).

74. The method according to any one of claims 59 to 69, wherein the cancer is extensive-stage small cell lung cancer (ES-SCLC) expressing somatostatin receptor (SSTR+).

75. The method of claim 73 or 74, wherein the SCLC is untreated, relapsed, or refractory.

76. The method of claim 73 or 74, wherein the subject has received up to one cycle of platinum-etoposide and PD-L1 inhibitor therapy.

77. The method according to any one of claims 59 to 76, wherein the cancer is untreated.

78. The method according to any one of claims 59 to 76, wherein the cancer is recurrent or refractory.

79. The method according to any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1 kBq / kg to about 0.2 GBq / kg body weight per dose.

80. The method according to any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 5 kBq / kg to about 50,000 kBq / kg body weight per dose, about 20 kBq / kg to about 5,000 kBq / kg body weight per dose, about 50 kBq / kg to about 500 kBq / kg body weight per dose, or about 50 kBq / kg to about 200 kBq / kg body weight per dose.

81. The method according to any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 60 kBq / kg to about 150 kBq / kg body weight per dose.

82. The method according to any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject at a radioactivity of about 1 µCi to 1,000 µCi, about 10 µCi to 500 µCi, about 100 µCi to 500 µCi, about 100 µCi to 300 µCi, about 125 µCi to 275 µCi, about 50 µCi to 125 µCi, or about 10 µCi to 50 µCi.

83. The method according to any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject at a radioactivity of about 125 µCi to 275 µCi (e.g., about 125 µCi, 175 µCi, 225 µCi, or 275 µCi).

84. The method according to any one of claims 59 to 83, wherein the radiopharmaceutical composition is administered at intervals of 4 to 6 weeks.

85. The method according to any one of claims 1 to 84, wherein the SSTR+ tumor or cancer is characterized by having an H score of at least 11.

86. A method for treating a disease in a subject in need, the method comprising: (a) Determine the SSTR expression level in the samples of the subjects; and (b) Administering an effective amount of the liquid radiopharmaceutical composition to the subject. 225 Ac-DOTA-TATE.

87. The method of claim 86, wherein the level of SSTR expression in the sample is determined by calculating an H score, and wherein the H score is between 11 and 300.

88. The method according to any one of claims 1 to 87, wherein the SSTR is somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4) and / or somatostatin receptor type 5 (SSTR5).

89. The method according to any one of claims 1 to 87, wherein the SSTR is somatostatin receptor type 2 (SSTR2).

90. The method according to any one of claims 1 to 89, wherein the liquid radiopharmaceutical composition comprises: (a) 225 Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein... 225 Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 50 mCi / L; (b) A pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at a concentration of 10 mM to 500 mM; (c) A free metal chelating agent, wherein the free metal chelating agent is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL; and (d) Water; The radiopharmaceutical composition is a solution, and The radiopharmaceutical composition retains at least 80% of its active ingredients after 48 hours. 225 Ac-DOTA-TATE or its pharmaceutically acceptable salts 225 Ac content.

91. The method of claim 90, wherein the pH of the liquid radiopharmaceutical composition is from about 4.0 to about 8.

0.

92. The method according to claim 90 or 91, wherein... 225 Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 25 mCi / L.

93. The method according to any one of claims 90 to 92, wherein the radiopharmaceutical composition retains at least 80% of its saturation after being kept at about 20°C to about 25°C for 48 hours. 225 Ac-DOTA-TATE or its pharmaceutically acceptable salts 225 Ac content.

94. The method according to any one of claims 1 to 90, wherein the liquid radiopharmaceutical composition comprises: (a) 225 Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein... 225 Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 5 mCi / L to 50 mCi / L; (b) Sodium ascorbate, wherein the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM; (c) Diethylenetriaminepentaacetic acid ester (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL; and (d) An aqueous medium, wherein the aqueous medium is a salt solution; The radiopharmaceutical composition is a solution, and The radiopharmaceutical composition retains at least 90% of its activity after 120 hours at about 20ºC to about 25ºC. 225 Ac-DOTA-TATE or its pharmaceutically acceptable salts 225 Ac content.

95. The method according to any one of claims 90 to 94, wherein the radiopharmaceutical composition is formulated into a unit dosage form containing about 5-25 mL of solution.

96. The method according to any one of claims 90 to 94, wherein the radiopharmaceutical composition is formulated into a unit dosage form containing about 12 mL of solution.

97. The method according to any one of claims 90 to 96, wherein the radiopharmaceutical composition is formulated for intravenous infusion.

98. The method according to any one of claims 90 to 97, wherein... 225 Ac-DOTA-TATE or its pharmaceutically acceptable salts have the following structures: .

99. The method according to any one of claims 1 to 98, wherein, compared to subjects receiving standard care (SoC) cancer therapy, the 225 The administration of Ac-DOTA-TATE (e.g., in the form of a liquid radiopharmaceutical composition) increased the progression-free survival of the subject by at least 2 months.

100. The method of claim 99, wherein the SoC cancer therapy is 177 Lu-SSA therapy or chemotherapy (such as streptozotocin, temozolomide or capecitabine).

101. The method of claim 99, wherein the SoC cancer therapy is everolimus, sunitinib, or a high-dose somatostatin analog (SSA) therapy.

102. The method according to any one of claims 99 to 101, wherein, compared to a subject receiving SoC cancer therapy, the 225 The administration of Ac-DOTA-TATE increased the progression-free survival of the subject by at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 36 months.

103. The method according to any one of claims 1 to 102, the method further comprising administering an additional anticancer agent to the subject. The other anticancer agent mentioned above is a local or regional cancer treatment.

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