Methods for treating sstr positive cancer

Abstract

Provided herein are methods of treating SSTR+ cancers using radiopharmaceutical compositions. The radiopharmaceutical compositions can comprise one or more stabilizing agents, an aqueous vehicle, and a conjugate that comprises a targeting ligand and a radionuclide bound to a metal chelator. The targeting ligand can be a small molecule compound or a peptide such as a monocyclic peptide. The targeting ligand can be configured to bind with a tumor target. The stabilizing agent can comprise a radiolysis stabilizer, a free metal chelator, and / or a pH stabilizer. Further provided herein are methods of preparing the radiopharmaceutical compositions and methods of treating cancer by administering the described radiopharmaceutical compositions.

Description

[0001] WSGR Docket No.59541-743.602 METHODS FOR TREATING SSTR POSITIVE CANCER CROSS REFERENCE TO RELATED APPLICATIONS

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

[0002] In the United States, cancer is the leading cause of death for those under 65 years of age, and it accounted for about 21% of all deaths in 2018. Neuroendocrine tumors (NETs) arise from neuroendocrine cells and most commonly develop in the lung, digestive tract and pancreas. NETs are one of the cancers that need systemic therapies because either they are inoperable, or they are diagnosed at an advanced stage with distant spread of tumor cells. Traditional radiotherapies such as external beam radiation therapy have been used for decades as a standard-of-care treatment for diagnosed cancer patients. While some patients respond to external beam radiation therapy, many others do not. Further, metastasis and circulating tumor cells can spread and remain in the bloodstream or bodily fluids after standard-of-care treatment and lead to resistance to therapy. The presence of cancer cells in various parts of the body reduces the therapeutic efficacy of traditional radiotherapies. Accordingly, strategies for targeted radiotherapies are being developed for better cancer treatment and diagnosis. One of the major challenges in the production of radiopharmaceutical drugs is to extend the shelf-life of product to allow treatment of patients at remote locations from the manufacturer site. There remains a need for compositions of radionuclides, e.g., alpha- particle emitting radionuclides, that have improved stability and shelf lives. SUMMARY

[0003] One of the major challenges in the production of radiopharmaceutical drugs is to extend the shelf-life of product to allow treatment of patients at remote locations from the manufacturer site. As radionuclides, such as Actinium-225, decay, a series of highly reactive chemicals are generated. In some cases, they can react with the drug substance, e.g., causing degradation of the radioisotope-containing drug and increasing radioactive impurity overtime. In one aspect, provided herein are liquid radiopharmaceutical formulations that provide enhanced stability for alpha-emitting radionuclide such as Actinium-225. In one aspect, provided herein are liquid radiopharmaceutical formulations comprising225Ac-DOTA-TATE that are stable for at least 120 hours.

[0004] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose, and wherein the liquid radiopharmaceutical composition is administered at a 7- to 9-week interval per cycle with a maximum cumulative dose at about 40,800 kBq. In one aspect, provided herein WSGR Docket No.59541-743.602 is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the225Ac-DOTA-TATE is administered to the subject in an amount equivalent to about 10.2 MBq per dose, and wherein the225Ac-DOTA-TATE is administered at a 7- to 9-week interval per cycle with a maximum cumulative dose at about 40,800 kBq

[0005] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial 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, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the225Ac-DOTA-TATE is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial dose, and wherein at least one subsequent dose of the225Ac-DOTA- TATE is administered to the subject at about 50% of the initial dose.

[0006] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial dose, and wherein if the subject has an adverse reaction to the initial dose, the liquid radiopharmaceutical composition is administered to the subject at a reduced dose that is about 50% of the initial dose. In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the225Ac-DOTA-TATE is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial dose, and wherein if the subject has an adverse reaction to the initial dose, the225Ac-DOTA-TATE is administered to the subject at a reduced dose that is about 50% of the initial dose.

[0007] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, 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 from its manufacture. In some embodiments, the 225Ac-DOTA-TATE is administered less than 72 hours from its manufacture. WSGR Docket No.59541-743.602 In some embodiments, the225Ac-DOTA-TATE is administered less than 120 hours but more than 24 hours from its manufacture. In some embodiments, the 225Ac-DOTA-TATE is administered less than 120 hours but more than 48 hours from its manufacture. In some embodiments, the 225Ac-DOTA- TATE is administered less than 120 hours but more than 72 hours from its manufacture. In some embodiments, the subject has not previously received a177Lu-labelled somatostatin analog (SSA) therapy. In some embodiments, the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy. In some embodiments, the subject has previously received a177Lu-SSA therapy selected from177Lu-DOTA-TATE,177Lu-DOTA-TOC, and177Lu-HA-DOTA-TATE. In some embodiments, the177Lu-SSA therapy is administered for a minimum of 2 cycles and a maximum of 4 cycles. In some embodiments, SSTR+ neuroendocrine tumor in the subject has progressed following177Lu-somatostatin analog (SSA) therapy. In some embodiments, the subject^with a GEP-NET has been deemed nonresponsive to PRRT, wherein PRRT is defined as no disease control (PR, CR, or SD) achieved for at least 6 months following the last dose of prior177Lu-DOTATATE / TOC or177Lu-HA-DOTATATE treatment. In some embodiments, the subject is at least 18 years of old. In some embodiments, the subject has histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NET(s).

[0008] In some embodiments, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, 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 the group consisting of: (a) a Ki-67 index of at most 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) a platelet count of at least 100 x 109 / L; (f) a total bilirubin level of at most three times the upper limit of normal; (g) a serum albumin level of at least 3.0 g / dL; (h) a SSTR+ neuroendocrine tumor having a Krenning score of 3 or 4; and (i) a combination thereof.

[0009] In some embodiments, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, 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 have at least one characteristic selected from the group consisting of: (a) a hypersensitivity to225Actinium,68Gallium,64Copper; (b) a cardiovascular disease; (c) resistant hypertension; (d) uncontrolled diabetes mellitus; (e) a history of primary malignancy within the 3 years prior to administering the225Ac-DOTA-TATE, wherein the prior malignancy is other than GEP-NET, treated carcinoma in situ or non-melanoma carcinoma of the skin, curatively treated malignancy, or an untreated cancer on active surveillance; (f) a brain, meningeal or spinal cord metastases; (g) liver cirrhosis; and (h) a combination thereof.

[0010] In some embodiments, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of 225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject as not received: (a) a radioembolization; (b) a surgery within 12 weeks (84 days) WSGR Docket No.59541-743.602 prior to administering the225Ac-DOTA-TATE; (c) a chemoembolization within 12 weeks (84 days) prior to administering the225Ac-DOTA-TATE; (d) a radiofrequency ablation within 12 weeks (84 days) prior to administering the225Ac-DOTA-TATE; (e) a peptide receptor radionuclide therapy (PRRT) within 6 months (180 days), except for177Lu-DOTA-TATE,177Lu-DOTA-TOC, and177Lu-HA-DOTA-TATE, prior to administering the225Ac-DOTA-TATE; (f) a chemotherapeutic within 6 weeks (42 days) prior to administering the225Ac-DOTA-TATE; (g) a small molecule inhibitor within 4 weeks (28 days) prior to administering the225Ac-DOTA-TATE; (h) an investigational therapy within 4 weeks (30 days) prior to administering the225Ac-DOTA-TATE; (i) a biological agent within the greater of 7 days or 5 half-lives prior to administering the225Ac-DOTA-TATE, or a biological agent within 4 weeks prior to administering the225Ac-DOTA-TATE; (j) a colony-stimulating factor within 4 weeks (28 days) prior to administering the225Ac-DOTA-TATE; (k) a platelet-production stimulator within 4 weeks (28 days) prior to administering the225Ac-DOTA-TATE; (l) a transfusion within 4 weeks (28 days) prior to administering the225Ac-DOTA-TATE; (m) an external beam radiation therapy to more than 25% of the bone marrow (n) an external beam radiation therapy to less than 25% within 6 weeks prior to administering the225Ac-DOTA-TATE; (o) a liver transplant; (p) a high-dose glucocorticoid within 14 days prior to administering the225Ac-DOTA-TATE; or (q) a combination thereof.

[0011] In some embodiments, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an inoperable, advanced, somatostatin receptor expressing (SSTR+), well-differentiated gastro-enteropancreatic neuroendocrine tumor (GEP-NET) that has progressed following prior177Lu-SSA therapy (such as177Lu-DOTA-TATE,177Lu-DOTA-TOC, or177Lu-HA- DOTA-TATE).

[0012] In one aspect, provided herein is a liquid radiopharmaceutical composition comprising: (i) a conjugate, wherein the conjugate is225Ac-DOTA-TATE; (ii) one or more stabilizing agents; and (iii) an aqueous vehicle. In one aspect, provided herein is a liquid radiopharmaceutical composition comprising: (i) a conjugate, wherein the conjugate is225Ac-DOTA-TOC; (ii) one or more stabilizing agents; and (iii) an aqueous vehicle. In one aspect, the present disclosure relates to a liquid radiopharmaceutical composition comprising, a conjugate, optionally one or more stabilizing agents, and an aqueous vehicle. The conjugate further comprises a targeting ligand, a metal chelator covalently attached to the targeting ligand, and a radionuclide that is bound to the metal chelator. In some embodiments, the targeting ligand binds to a somatostatin receptor (SSR), such as a 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 a somatostatin receptor type 2 (SSTR2). In some embodiments, the targeting ligand is a binding peptide, which comprises 6 to 14 amino acid residues. In some embodiments, the targeting ligand is tyr3- octreotate, edotreotide, octreotate, or octreotide. In some embodiments, the targeting ligand is tyr3- octreotate. 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, a binding affinity of the targeting WSGR Docket No.59541-743.602 ligand to a human SSR is not more than 250 nM, not more than 100 nM, not more than 50 nM, or not more than 5 nM, as determined by half maximal inhibitory concentration (IC50). In some embodiments, the binding affinity of the targeting ligand to a human SSR is not more than 250 nM, as determined by half maximal inhibitory concentration (IC50). In some embodiments, the binding affinity of the targeting ligand to a human SSR is not more than 100 nM, as determined by half maximal inhibitory concentration (IC50). In some embodiments, the binding affinity of the targeting ligand to a human SSR is not more than 50 nM, as determined by half maximal inhibitory concentration (IC50). In some embodiments, the binding affinity of the targeting ligand to a human SSR is not more than 5 nM, as determined by half maximal inhibitory concentration (IC50). In some embodiments, the binding affinity of the targeting ligand to a human SSR is not more than 2 nM, as determined by half maximal inhibitory concentration (IC50). In some embodiments, the human SSR is SSTR2. In some embodiments, the targeting ligand is covalently linked to the metal chelator through a linker. In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 95 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC).

[0013] In one aspect, described herein is a radiopharmaceutical composition comprising a conjugate that further comprises a targeting ligand that covalently links to a metal chelator through a linker. In some embodiments, the metal chelator 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-AƎ-EDTA, MeO-DOTA- NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB- Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p- SCN-Bn-HEHA, DTPA, CHX-AƎ-DTPA, p-NH2-Bn-CHX-AƎ-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-AƎ- DTPA, PEPA, p-SCN-Bn-PEPA, l,4,8,11-tetraazacyclo tetradecane-l,4,8,11-tetrapropionic acid (TETPA), DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, H5decapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN- Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa2, H4phospa, H6phospa, p-SCN-Bn- WSGR Docket No.59541-743.602 H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TRAP-Pr, TPA, HBED, SHBED, HBED-CC, (HBED- CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, 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, motexafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-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, Lpy, L1, L2, L3, and EuK-106. In another embodiment, the metal chelator is a metal chelator is a chelator disclosed in U.S. Patent US11541134B1. In another embodiment, the metal chelator is a metal chelator illustrated in FIG.3. In some embodiments, the metal chelator is DOTA, HEHA, or macropa. The metal chelator can be DOTA.

[0014] In one aspect, the disclosure described herein is a radiopharmaceutical composition comprising one or more stabilizing agents. The stabilizing agent can comprise a radiolysis stabilizer, which can be an amino acid or a peptide or a derivative thereof, a vitamin or a derivative thereof, a lipid or a derivative thereof, a carbohydrate or a derivative thereof, a volume expander or an antioxidant. In some embodiments, the amino acid or peptide is selected from N-Acetyl-L-cysteine, Glutathione, L-Lysine, Selenol-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 flavonoid is (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-Hexahydroxyflavylium chloride, (-)-cis-3,3',4',5,7- Pentahydroxyflavane (Epi-Catechin 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-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one (Rutin hydrate), Quercetin, (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5- trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7- dihydroxy-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Epigallo-Catechin or EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo-Catechin or GC). In some embodiments, the flavonoid is a catechin or a derivative thereof, for example, (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-Pentahydroxyflavane (Epi-Catechin 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 (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7- dihydroxy-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG), WSGR Docket No.59541-743.602 (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Epigallo-Catechin or EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo-Catechin or GC). The antioxidant can also be a carotenoid or a derivative thereof, such as all-trans-Fucoxanthin, Lycopene, Xanthophyll, Beta carotene, Lycopene, or Lutein. In some embodiments, the antioxidant is N-acetyl cysteine, L-Ascorbic acid, N-tert-Butyl-Į-phenylnitrone, 3-(3,4-Dihydroxyphenyl)-2-propenoic acid (Caffeic Acid), ȕ-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- Hexahydroxyflavylium chloride, Thiocytic Acid (Dihydrolipoic Acid, DHLA), 4,4',5,5',6,6'- Hexahydroxydiphenic acid 2,6,2',6'-dilactone (Ellagic acid), (-)-cis-3,3',4',5,7-Pentahydroxyflavane (Epi- Catechin 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 ((-)-Gallocatechin), Glutathione, 2-(3,4-Dihydroxyphenyl)ethanol, 3,4',5,7- Tetrahydroxyflavone (Kaempferol), (±)-1,2-Dithiolane-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- methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one, Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-Į-Tocopherol, Xanthophyll, Citric acid (CA), Gentisic acid (GA), Salicylic acid (SA), Erythorbic acid (EA), Phenol, Sodium bisulfite, Butylated hydroxy anisole, Butylated hydroxy toluene, Metabisulfite, Benzyl alcohol, Thymol, Lipoic acid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Mannitol, Sucrose, Melatonin, Ebselen, Pyruvic acid, Carboxy-PTIO, Trolox, Uric acid, Edaravone, Beta carotene, NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol, Ubiquinol, 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 (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H- chromen-3-yl] 3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG), (2R,3R)-2-(3,4,5- trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Epigallo-Catechin or EGC), (2R,3S)-2-(3,4,5- trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo-Catechin or GC), (-)-Epigalocatechin-3- O-Gallate, 5-Aminolevulibic Acid hydrate, Ploysorbate 80, Garlic Acid, Sodium L-Ascorbate, Hyaluronic Acid, Dextran 60-90, Selenol, and LysaKare. The radiolysis stabilizer can also be a vitamin or a derivative thereof, for example, L-Ascorbic acid, ȕ-Carotene, Provitamin A, (+)-Į-Tocopherol, Erythorbic acid (EA), Trolox, and Lutein. In some embodiments, the radiolysis stabilizer is a lipid. The lipid can be a fatty acid, such as a saturated or unsaturated C6to C30fatty acid. In some embodiments, the fatty acid is oleic acid, Myristoleic acid, Palmitoleic acid, Sapienic acid, Elaidic acid, Vaccenic acid, or Linoleic acid, Į-Linolenic acid. In another embodiment, the lipid is a steroid or derivatives thereof, for example, Estrogen, Estradiol, Estriol, or Cortisone. The radiolysis stabilizer can also be a carbohydrate or a derivative thereof, such as Mannitol, Sucrose, Dextran (e.g., Dextran 40, Dextran 70), and Cyclodextrins, (e.g., Į (alpha)- WSGR Docket No.59541-743.602 cyclodextrin, ȕ (beta)-cyclodextrin, and Ȗ (gamma)-cyclodextrin). In some embodiments, the radiolysis stabilizer is a volume expander. The volume expander can be a polymer or a polymer mixture, such as PEG 3350, PEG 4000, Polygeline, 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 expander is selected from Dextran, Dextran 40, Dextran 70, Cyclodextrins, Į (alpha)-cyclodextrin, ȕ (beta)-cyclodextrin, and Ȗ (gamma)-cyclodextrin, PEG 3350, PEG 4000, Polygeline, Gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride US FDA 2018 Label). In some embodiments, radiolysis stabilizer is selected from N-Acetyl-L-cysteine, L-Ascorbic acid, N-tert-Butyl-Į-phenylnitrone, 3-(3,4- Dihydroxyphenyl)-2-propenoic acid (Caffeic Acid), ȕ-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-Hexahydroxyflavylium chloride, Thiocytic Acid (Dihydrolipoic Acid, DHLA), 4,4',5,5',6,6'-Hexahydroxydiphenic acid 2,6,2',6'-dilactone (Ellagic acid), (-)-cis-3,3',4',5,7- Pentahydroxyflavane (Epi-Catechin 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 ((-)-Gallocatechin), Glutathione, 2-(3,4-Dihydroxyphenyl)ethanol, 3,4',5,7-Tetrahydroxyflavone (Kaempferol), (±)-1,2-Dithiolane-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-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one, Rutin hydrate, Selenol-L- methionine, Thiourea, (+)-Į-Tocopherol, Xanthophyll, 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, 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), Gentisic acid (GA), Salicylic acid (SA), Erythorbic acid (EA), Phenol, Sodium bisulfite, Butylated hydroxy anisole, Butylated hydroxy toluene, Glutathione, Metabisulfite, Benzyl alcohol, Thymol, Lipoic acid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Mannitol, Sucrose, Melatonin, Ebselen, Pyruvic acid, Carboxy-PTIO, Trolox, Uric acid, Edaravone, Beta carotene, NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol, Ubiquinol, Copper, Quercetin, Cortisone, 2,3-dimercaptosuccinic acid (DMSA), monisoamyl derivative (MiADMSA), Taurine, Dextran, Dextran 40, Dextran 70, PEG 3350, PEG 4000, Polygeline, Gelofusine, PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride US FDA 2018 Label), Cyclodextrins, Į (alpha)-cyclodextrin, ȕ (beta)-cyclodextrin, and Ȗ (gamma)-cyclodextrin, (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1- WSGR Docket No.59541-743.602 benzopyran-3-yl 3,4,5-trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4- dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate or Epi- Catechin Gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Epigallo-Catechin or EGC), and (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7- triol (Gallo-Catechin or GC).

[0015] In one aspect, disclosed herein is a radiopharmaceutical composition comprising one or more stabilizing agents that further comprise a first and a second radiolysis stabilizer. In some embodiments, the first and the second radiolysis stabilizer has a molar ratio that is from 1:5 to 5:1. In one aspect, disclosed herein is a radiopharmaceutical composition comprising a radiolysis stabilizer. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at about 0.01 mM to about 5 M. In some embodiments, the stabilizing agent is present in the radiopharmaceutical composition from about 5 mM, 10 mM, 25 mM, 50 mM, or 75mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 500 mM. In some embodiments, the stabilizing agent is present in the radiopharmaceutical composition at about 0.1 mM to about 500 mM. In some embodiments, the stabilizing agent is present in the radiopharmaceutical composition at about 10 mM to about 500 mM. In some embodiments, the stabilizing agent is present in the radiopharmaceutical composition at about 20 mM to about 100 mM. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at about 0.0001 wt% to about 10 wt%. In some embodiments, the radiolysis stabilizer is present in the radiopharmaceutical composition at 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 from about 0.1 to 50 mg / mL.

[0016] In one aspect, disclosed herein is a radiopharmaceutical composition comprising one or more stabilizing agents that comprise a free metal chelator, which is not attached to the targeting ligand. In some embodiments, the free metal chelator is selected from Ethylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentaacetic acid (DTPA), 2-S-(4-Isothiocyanatobenzyl)-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), l,4,8,11-tetraazacyclo tetradecane-l,4,8,11-tetrapropionic acid (TETPA), triethylenetetraminepentaacetic acid, 2,2ƍ,2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-GA), 1,4,7,10-Tetraazacyclododecane- 1,4,7,10-tetra(methylene phosphonic acid (DOTP), Deferoxamine (DFO), N, N-bis(2- hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-Tetraazacyclododecane-1,4,7,10- tetra(methylene phosphonic acid) (DOTP), 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16- diyl)bis(methylene))dipicolinic acid (Macropa), Meso-2,3-dimercaptosuccinic acid (DMSA), Dimercaptopropane sulfonate (DMPS), Dihydrolipoic acid (DHLA), Lipoic acid (LA), Thioglycolic acid (TGA), and 2,3 Dimercaptopropan-1-ol (BAL). In some embodiments, the free metal chelator is EDTA, DTPA, or Macropa. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at about 0.01 wt% to about 5 wt%, about 0.05 wt% to about 2 wt%, WSGR Docket No.59541-743.602 or about 0.1 wt% to about 1 wt%. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of from 0.01 to 50 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at about 10 mM to about 500 mM.

[0017] In one aspect, disclosed herein is a radiopharmaceutical composition comprising one or more stabilizing agents that comprise one or more pH stabilizers. In one aspect, disclosed herein is a radiopharmaceutical composition comprising a pH stabilizer. In some embodiments, the pH stabilizer is the same as the radiolysis stabilizer. The pH stabilizers can function as a pH buffer. In some embodiments, the one or more pH stabilizers comprise an organic acid, such as an acetic acid, fumaric acid, ascorbic acid, propionic acid, benzene sulfonic acid, carbonic acid, citrate acid, aspartic acid, maleic acid, methane sulfonic acid, or tartaric acid. In some embodiments, the one or more pH stabilizers comprise an inorganic acid, for example, hydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, or sulfuric acid. In some embodiments, the one or more pH stabilizers can comprise a base, such as tromethamine (Tris), ammonium hydroxide, diethanolamine, or sodium hydroxide. In some embodiments, the one or more pH stabilizers can 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, for example, sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, tribasic sodium phosphate acid, dibasic sodium phosphate acid, monobasic sodium phosphate acid, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate. In some embodiments, the one or more pH stabilizers can comprise an acid 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, benzene sulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citrate acid, hydrobromic acid, glycine, histidine, sodium lactate, (l)-lysine, maleic acid, methane sulfonic acid, phosphate acid, monobasic sodium phosphate acid, tribasic sodium phosphate acid, dibasic sodium phosphate acid, sodium hydroxide, sodium / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (tris), or a combination thereof. In some embodiments, the one or more pH stabilizers are present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. In some embodiments, one or more pH stabilizers are present in the radiopharmaceutical composition at 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 from 0.1 to 5 mg / mL. In some embodiments, the one or more pH stabilizers are present in the radiopharmaceutical composition at about 10 mM to about 500 mM. The one or more pH stabilizers can be configured to maintain a pH of the radiopharmaceutical composition at about 4 to about 8. The one or more pH stabilizers can be configured to maintain a pH of the radiopharmaceutical composition at about 5 to about 7. In some embodiments, the pH of the radiopharmaceutical composition is within a 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 can comprise one or more radiolysis stabilizers, one or more free metal chelators, and / or one or more pH WSGR Docket No.59541-743.602 stabilizers.

[0018] In one aspect, disclosed herein is a radiopharmaceutical composition comprising an aqueous vehicle. The aqueous vehicle can comprise water (e.g., water for injection), saline solution, dextrose in water, dextrose in saline solution, Ringer's solution, or lactated Ringer's solution. The radiopharmaceutical composition can be isotonic. The radiopharmaceutical composition can be a solution or suspension. In some embodiments, the radiopharmaceutical composition is formulated for IV infusion or bolus injection. In some embodiments, the radiopharmaceutical composition further comprises one or more excipients selected from: a tonicity adjusting agent, a preservative, an antimicrobial agent, a solubilizing agent, a suspending agent, and a surfactant.

[0019] In one aspect, disclosed herein is a radiopharmaceutical composition comprising a conjugate that further comprises a targeting ligand that covalently links to a metal chelator through a linker. In some embodiments, the targeting ligand is a binding peptide, and the linker is attached to the binding peptide via the N terminus of the peptide. In some embodiments, the targeting ligand is a binding peptide, and the linker is attached to the binding peptide via the C terminus of the peptide. In some embodiments, the targeting ligand is a binding peptide, and the linker is attached to the binding peptide via a non-terminal amino acid of the peptide. The linker can 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, disclosed herein is a radiopharmaceutical composition comprising a conjugate that further comprises a radionuclide. The radionuclide can be an alpha particle-emitting radionuclide, such as actinium-225, astatine-211, thorium-227, or radium-223. In some embodiments, the alpha particle- emitting radionuclide is actinium-225. In some embodiments, the actinium-225 is present in the radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.5 to 20 MBq / mL. In some embodiments, the conjugate is225Ac-DOTATATE. In another embodiment, the conjugate is225Ac- 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 hours, 72 hours, 96 hours, 120 hours, 148 hours, 168 hours, 192 hours, or 216 hours at room temperature. In some embodiments, the radionuclide is actinium-225, and wherein the composition contains no more than about 5% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, the radionuclide is actinium-225, and wherein the composition contains no more than about 2% or about 1% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In WSGR Docket No.59541-743.602 some embodiments, the radionuclide is actinium-225, and wherein the composition contains no more than a total of 5 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, the radionuclide is actinium-225, and wherein the composition contains no more than a total of 1 mol% of un- chelated (free) daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, the purity or the molar percentage of the initial conjugate is determined by radio thin layer chromatography (radio- TLC). In some embodiments, the purity or the molar percentage of the initial conjugate is determined by instant thin layer chromatography (iTLC).

[0021] In one aspect, disclosed herein is a radiopharmaceutical composition, comprising: (a) the 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) optionally a pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at concentration of about 0.1 wt% to about 10wt%; (d) a free metal chelator, wherein the free metal chelator is present in the radiopharmaceutical composition at 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 vehicle. In one aspect, disclosed herein is 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 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 chelator, wherein the free metal chelator is selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or a combination thereof, and wherein the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 1 mg / mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is 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 10wt%. 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, disclosed herein is 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) optionally, a pH stabilizer, wherein the pH stabilizer is configured to maintain a pH of the radiopharmaceutical composition at about 4 to 8; (d) a free metal chelator, wherein the free metal chelator is configured to maintain a level of free radionuclide in the radiopharmaceutical composition below about 0.05 mCi / L; and (e) an aqueous vehicle. WSGR Docket No.59541-743.602 In some embodiments, the radiolysis stabilizer (such as ascorbic acid or sodium ascorbate) can function as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer is the same compound. In one aspect, disclosed herein is 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 a pH of the radiopharmaceutical composition at about 4 to 8; (d) a free metal chelator, wherein the free metal chelator is configured to maintain a level of free radionuclide in the radiopharmaceutical composition below about 0.05 mCi / L; and (e) an aqueous vehicle. In some embodiments, the radiolysis stabilizer (such as ascorbic acid or sodium ascorbate) can function as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer is 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, the present disclosure relates to a method of making a radiopharmaceutical composition described herein. In some embodiments, the method of making the radiopharmaceutical composition comprises combining a radionuclide (such as225Ac) with an -un-labeled conjugate (e.g., DOTATATE or DOTATOC) in the presence of one or more stabilizer agents, wherein the un-labeled conjugate comprises a targeting ligand and a metal chelator covalently attached to the targeting ligand, thereby producing a mixture comprising a labeled conjugate (e.g.,225Ac-DOTATATE or225Ac- DOTATOC), and optionally combining one or more stabilizing agents to the mixture. In some embodiments, the method of making the radiopharmaceutical composition comprises combining a radionuclide (such as225Ac) with an un-labeled conjugate (e.g., DOTATATE or DOTATOC), wherein the un-labeled conjugate comprises a targeting ligand and a metal chelator covalently attached to the targeting ligand, thereby producing a labeled conjugate, and combining the one or more stabilizing agents with the labeled conjugate.

[0023] In one aspect, the present disclosure relates to a method of treating a disease in a subject in need thereof comprising administering to the subject the radiopharmaceutical composition described herein. The disease can be a cancer. In some embodiments, the cancer is an SSR-associated cancer, such as an SSTR2-associated cancer. The cancer can be a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitary cancer, a breast cancer, a stomach cancer, a lung cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine cancer, which can optionally be recurrent. In some embodiments, the neuroendocrine cancer is refractory to a radiotherapy that comprises beta-particle emitting radionuclide. In some embodiments, the subject has received a radiotherapy that comprises beta-particle emitting radionuclide prior to the administering of the radiopharmaceutical composition described herein. The neuroendocrine cancer can also be a neuroendocrine lung cancer or a WSGR Docket No.59541-743.602 neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a Carcinoid tumor in the lungs, gastrointestinal tract or thymus, Pancreatic neuroendocrine tumor (e.g., Gastrinoma, Insulinoma, Glucagonoma, VIPoma, gastroenteropancreatic neuroendocrine tumor) Medullary thyroid carcinoma, Merkel cell carcinoma, Pheochromocytoma of the adrenal gland, Adrenal cancer, Small cell carcinoma (such as in the lungs), or Large cell carcinoid tumor (such as in the lungs). 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 recurrent or refractory. In some embodiments, the small-cell lung cancer is untreated. In some embodiments, the small-cell lung cancer is recurrent or refractory. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1kBq / kg to about 0.2GBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 5kBq / kg to about 50,000kBq / 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 5,000kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 50k Bq / 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 50k Bq / 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 300μCi. 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 an 8-week interval. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose in the subject of about 10,000 kBq to about 100,000 kBq. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose in the subject of about 40,000 kBq to about 70,000 kBq. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose in the subject of about 40,800 kBq.

[0024] In one aspect, provided herein is a dilution solution comprising one or more stabilizing agents and an aqueous vehicle.

[0025] In one aspect, provided herein is a liquid radiopharmaceutical composition comprising: (a)225Ac- DOTA-TATE, wherein the225Ac-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 WSGR Docket No.59541-743.602 sodium L-ascorbate is present in the radiopharmaceutical composition at a concentration of about 80 mM to about 110 mM; (c) diethylenetriamine pentaacetate (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 vehicle, wherein the aqueous vehicle is sodium chloride saline solution 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 the225Ac content as225Ac-DOTA-TATE after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In one aspect, provided herein is a liquid radiopharmaceutical composition consisting essentially of: (a)225Ac- DOTA-TATE, wherein the225Ac-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) diethylenetriamine pentaacetate (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 vehicle, wherein the aqueous vehicle is sodium chloride saline solution 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 the225Ac content as225Ac-DOTA-TATE after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In one aspect, provided herein is a liquid radiopharmaceutical composition consisting of: (a)225Ac-DOTA- TATE, wherein the225Ac-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) diethylenetriamine pentaacetate (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 vehicle, wherein the aqueous vehicle is sodium chloride saline solution 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 the225Ac content as225Ac-DOTA-TATE after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the225Ac-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, the225Ac-DOTA- TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 12 mCi / L to 23 mCi / L. In some embodiments, the225Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 40 μg to about 120 μg of the DOTA-TATE. In some embodiments, the225Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 25 μg to about 150 μg of the DOTA-TATE. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 100mM. In some embodiments, the DTPA is present in the radiopharmaceutical composition at a concentration of about 0.05mg / mL. In some embodiments, the composition retains at least 90 % of the225Ac content as225Ac-DOTA-TATE after 168 hours at about 20ºC to about 25°C. In some embodiments, the composition WSGR Docket No.59541-743.602 retains at least 90 % of the225Ac content as225Ac-DOTA-TATE after 192 hours at about 20ºC to about 25°C. In some embodiments, the radiopharmaceutical composition is formulated as a unit dose form that contains about 12mL of the solution, and wherein the liquid radiopharmaceutical composition consists of: (a)225Ac-DOTA-TATE present in the radiopharmaceutical composition in an amount of 146-275 μCi in the about 12 mL solution; (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) sodium chloride saline solution 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 IV infusion.

[0026] In one aspect, provided herein is a liquid radiopharmaceutical composition wherein the225Ac- DOTA-TATE has a structure illustrated as: .

[0027] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition comprises: (a)225Ac-DOTA-TATE, wherein the225Ac-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) diethylenetriamine pentaacetate (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 vehicle, wherein the aqueous vehicle is sodium chloride saline solution 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 the225Ac content as225Ac-DOTA-TATE after 48 hours, 72 hours, or 120 hours at about 20º to about 25°C as determined by radio thin-layer chromatography (radio-TLC).

[0028] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition consists essentially of: (a)225Ac-DOTA-TATE, wherein the225Ac-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 WSGR Docket No.59541-743.602 at a concentration of about 90 mM to about 110 mM; (c) diethylenetriamine pentaacetate (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 vehicle, wherein the aqueous vehicle is sodium chloride saline solution 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 the225Ac content as225Ac-DOTA-TATE after 48 hours, 72 uhours, or 120 hours at about 20º to about 25°C as determined by radio thin-layer chromatography (radio-TLC).

[0029] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition consists of: (a)225Ac-DOTA-TATE, wherein the225Ac-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) diethylenetriamine pentaacetate (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 vehicle, wherein the aqueous vehicle is sodium chloride saline solution 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 the225Ac content as225Ac- DOTA-TATE after 120 hours at about 20º to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the neuroendocrine tumor is gastroenteropancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the subject received177Lu-DOTA-TATE or177Lu-DOTA-TOC treatment prior to the administrating of the liquid radiopharmaceutical composition. In some embodiments, prior to the administrating of the liquid radiopharmaceutical composition, the subject received177Lu- DOTA-TATE or177Lu-DOTA-TOC treatment and the tumor has progressed. In some embodiments, the radiopharmaceutical composition is administered to the subject in 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 in 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 in 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 in an amount equivalent to about 500 kBq / kg. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1,000 kBq / kg. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 2,000 kBq / kg. In some embodiments, the radiopharmaceutical composition is administered at an 8-week interval. In some embodiments, the225Ac-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, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject a therapeutically WSGR Docket No.59541-743.602 effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition consists of: (a)25Ac- DOTA-TATE present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 25 mCi / L; (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 100mM; (c) DTPA, present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL; and (d) sodium chloride saline solution at a concentration of about 0.9% w / w.

[0031] In one aspect, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition is formulated as a unit dose form that has about 12mL of the solution, and wherein the liquid radiopharmaceutical composition consists of: (a)225Ac-DOTA-TATE present in the radiopharmaceutical composition in an amount of 146 – 275 μCi in about 12 mL solution; (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) sodium chloride saline solution at a concentration of about 0.9% w / w.^^ INCORPORATION BY REFERENCE

[0032] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing (also “figure” and “FIG.” herein), of which:

[0034] FIG.1 illustrates the structures of exemplary stabilizing agents.

[0035] FIG.2 illustrates the structures of exemplary binding peptide.

[0036] FIG.3 depicts the structures of representative metal chelators.

[0037] FIG.4A and FIG.4B illustrate the abbreviations and modification of amino acids.

[0038] FIG. 5 depicts a clinical treatment dosing schedule using225Ac-DOTA-TATE. Patients receive a de-escalating dose scheme and will receive up to 4 cycles of225Ac-DOTA-TATE every 8 weeks.

[0039] FIG.6A illustrates stained tissue samples having an H-score of 281, 160 or 90; FIG.6B illustrates stained tissue samples of normal lung or pancreatic NET.

[0040] FIG. 7 depicts a clinical treatment dosing schedule225Ac-DOTA-TATE. Patients receive an escalating dose structure and will receive 4-6 cycles of225Ac-DOTA-TATE once every 6 weeks during standard of care therapy (PD-L1i + CE) and once every 4 weeks during PD-L1 maintenance phase for a maximum of 6 infusions. PD-L1i represents a PD-L1 inhibitor; C represents carboplatin or cisplatin; E represents etoposide.225Ac-DOTA-TATE is administered earlier than or on the same day with PD-L1i, C, and E.

[0041] FIG.8 depicts a clinical trial Simon 2-stage cohort expansion study. The 1L-ES-SCLC cohort will WSGR Docket No.59541-743.602 receive225Ac-DOTA-TATE in combination with standard of care therapy (PD-L1i + CE). The 2L-ES- SCLC cohort will receive225Ac-DOTA-TATE in combination with 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 a 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] FIG. 9A and FIG. 9B illustrate the mean tumor volume and mean body weight respectively in a mouse study with [225Ac]Ac-DOTA-TATE and [225Ac]Ac-DOTA-JR-11.

[0043] FIG. 10A and FIG. 10B illustrate the treatment of SSTR2+ SCLC xenograft tumors with [225Ac]Ac-DOTA-TATE led to target-dependent, durable tumor inhibition. [225Ac]Ac-DOTA-TATE was used as a formulation described in Example 24.

[0044] FIG. 11A and FIG. 11B illustrate the treatment of SSTR2+ SCLC xenograft tumors with [225Ac]Ac-DOTA-TATE led to durable tumor inhibition superior to SOC. [225Ac]Ac-DOTA-TATE was used as a formulation described in Example 24. DETAILED DESCRIPTION

[0045] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0046] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0047] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

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

[0049] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. I. Definitions

[0050] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. WSGR Docket No.59541-743.602

[0051] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, reference to “a stabilizer” includes a plurality of such stabilizers, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0052] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. 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 an order of magnitude, within 5- fold, or within 2-fold, of a value.

[0053] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0054] “Radiolysis” refers to the decay of radionuclides accompanied by emission of energy in the form of alpha, beta and / or gamma radiations. The energy that goes into the drug-containing formulation can break chemical bonds and can generate reactive chemical species from solvent molecules, which may further decompose the radiopharmaceutical drug directly and / or indirectly.

[0055] "Amino" refers to the –NH2 radical.

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

[0057] "Oxo" refers to the =O radical.

[0058] "Imino" refers to the =N-H radical.

[0059] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0060] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from 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, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 WSGR Docket No.59541-743.602 alkyl, a C1-C9alkyl, a C1-C8alkyl, a C1-C7alkyl, a C1-C6alkyl, a C1-C5alkyl, a C1-C4alkyl, a C1-C3alkyl, a C1-C2alkyl, or a C1alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -CŁCH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0061] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4- tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3,-S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0062] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some WSGR Docket No.59541-743.602 embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15cycloalkyl), from three to ten carbon atoms (C3-C10cycloalkyl), from three to eight carbon atoms (C3-C8cycloalkyl), from three to six carbon atoms (C3-C6cycloalkyl), from three to five carbon atoms (C3-C5cycloalkyl), or three to four carbon atoms (C3-C4cycloalkyl). A cycloalkyl can comprise a fused, spiro or bridged ring system. In some embodiments, the cycloalkyl comprises a fused ring system. In some embodiments, the cycloalkyl comprises a spiro ring system. In some embodiments, the cycloalkyl comprises a bridged ring system. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, 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]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0063] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised 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 is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, –CH2-O-CH2-, –CH2-N(alkyl)-CH2-, –CH2- N(aryl)-CH2-, -OCH2CH2O-, –OCH2CH2OCH2CH2O-, or –OCH2CH2OCH2CH2OCH2CH2O-. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. WSGR Docket No.59541-743.602

[0064] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0065] “Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms that selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, WSGR Docket No.59541-743.602 thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1- C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0066] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0067] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, 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, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof. As used herein, “treating” includes the WSGR Docket No.59541-743.602 concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0068] The term "therapeutically effective amount" as used herein to refer to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0069] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, - CFHCHF2, etc.).

[0070] As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

[0071] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from 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, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are independently selected from D, halogen, -CN, oxo, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1- C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1- C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1- WSGR Docket No.59541-743.602 C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding 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. replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0072] The term “unsubstituted” means that the specified group bears no substituents.

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

[0074] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0075] The term “peptide” as used herein refers to a compound that includes two or more amino acids. A peptide described herein can comprise one or more unnatural amino acids. The term “peptide” also encompasses peptide mimetics. In the present disclosure, the term “amino acid” is used in its broadest meaning and it embraces not only natural amino acids but also derivatives thereof and artificial amino acids. For example, the term “amino acid” encompasses unnatural amino acids.

[0076] As used herein, the term “unnatural amino acid” refers to an amino acid other than the 20 amino acids that occur naturally in protein.

[0077] The term “protein” as used herein refers to a polypeptide (i.e., a string of at least 3 amino acids linked to one another by peptide bonds). Proteins can include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or can be otherwise processed or modified. A protein can be a complete polypeptide as produced by and / or active in a cell (with or without a signal sequence). In some embodiments, a protein is or comprises a characteristic portion such as a polypeptide as produced by and / or active in a cell. A protein can include more than one polypeptide chain.

[0078] The term “peptide mimetic” or “mimetic” refers to biologically active compounds that mimic the biological activity of a peptide or a protein but are no longer entirely peptidic in chemical nature, e.g., they can contain non-peptide bonds (that are, bonds other than amide bonds between amino acids). As used herein, the term peptide mimetic is used in a broader sense to include molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Whether completely or partially non-peptide, peptide mimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resemble the three-dimensional arrangement of active groups in the subject amino acid sequence or subject molecule on which the peptide mimetic is based. As a result of this similar active-site geometry, the peptide mimetic can have effects on biological systems that are similar to the biological activity of the subject entity.

[0079] In some embodiments, the peptide mimetics are substantially similar in both three-dimensional shape and biological activity to the subject amino acid sequence or subject molecule on which the peptide WSGR Docket No.59541-743.602 mimetic is based. Examples of methods of structurally modifying a peptide to create a peptide mimetic include the inversion of backbone chiral centers leading to D-amino acid residue structures that may, particularly at the N-terminus, lead to enhanced stability for proteolytical degradation without adversely affecting activity. An example is described in the paper “Tritiated D-ala1-Peptide T Binding”, Smith C. S. et al., Drug Development Res., 15, pp. 371-379 (1988). A second method is altering cyclic structure for stability, such as N to C interchain imides and lactames (Ede et al. in Smith and Rivier (Eds.) “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp. 268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third method is to substitute peptide bonds in the subject entity by pseudopeptide bonds that confer resistance to proteolysis.

[0080] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the 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, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 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 the other 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 that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0082] The term “cyclized” or “cyclization” as used herein means that two amino acids apart from each other by at least one amino acid bind directly or bind indirectly to each other in one peptide to form a cyclic structure in the molecule. In some cases, the two amino acids bind via a linker or the like.

[0083] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0084] The term "therapeutically effective amount" as used herein to refer to an amount effective at the dosage to achieve the desired therapeutic result. A therapeutically effective amount of a composition may vary depending on factors such as the individual's condition (e.g., age, sex, and weight), the radiopharmaceutical conjugate, and the method of administration (e.g., oral or parenteral). WSGR Docket No.59541-743.602 II. Technical Overview

[0085] Targeted Radiopharmaceuticals (TRP) are a new generation of nuclear medicine for cancer treatment or diagnosis. A TRP can selectively deliver high concentrations of radionuclide-containing molecules to the target cells such as a tumor, and no or very low concentrations to the undesired cells present in normal, healthy tissues. The process can be achieved by engineering the drug molecule with the high-affinity binder (e.g., targeting ligands) and linking it to the radioactive isotope. 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 highly energic ionizing radiation in form of alpha, beta, and / or gamma particles. The released energy at the target sites can cause damage or death of the target tissues or be visualized by imaging scanner to achieve therapeutic or diagnostic purposes.

[0086] In some traditional radiopharmaceutical formulations, a very high concentration of stabilizer as to radiopharmaceutical is used. The high concentration can produce unknown biological effects and / or compromise therapeutic efficacy of the radiopharmaceutical. Due to the low efficiency of those stabilizers used in the past, significant dilution was needed to slow down the decomposition. As a result, larger volume of dose can require treatment via infusion instead of bolus injection under clinical setting. This is less desired for patients due to the prolonged stay at the infusion center and sometimes hospitalization. One of the major challenges in the production of radiopharmaceutical drugs is to extend the shelf-life of product to allow treatment of patients at remote locations from the manufacturer site. Increasing stability of radiopharmaceutical drug in formulated solution can resolve this challenge.

[0087] In some cases, with decay of the parent isotopes, daughter isotopes can be released into the solution. They can be non-radioactive or radioactive. When the daughter ions are radioactive, those non- bonded ions can create non-specific distribution of radioactivity in vivo and generate undesired toxicities. In addition, even if they are not radioactive, they can still bind to the metal chelation moiety on the radiopharmaceutical drug due to their higher affinity. The replacement of their parent ions can cause chemical decomposition of the drug substance. This process can also negatively impact the radiochemical purities overtime. When decay of Actinium-225-DOTA-containing drug starts, the isotope can first decay into Francium-221(I). The recoil energy of the process can be approximately 10000 times higher than any known chemical bond energy. It can cause the daughter ions to escape from their original chelator (e.g., DOTA). Due to the chemical nature of Francium-221 (I), in some cases, they cannot be recaptured by free DOTA-containing drug. As decay continues, more free daughter ions can enter the solution. Eventually, the majority of the decayed daughters can accumulate in the form of stable Bismuth-209 (III). Bismuth- 209 (III) can be strongly chelated with DOTA and compete with Ac-225 for binding to the parent drug, leading to further dissociation of Ac-225 from its chelator and generating additional radioactive free (unchelated) metal impurities.

[0088] The decay of radionuclides can be accompanied by emission of energy in the form of alpha, beta and / or gamma radiations. The energy can go into the radiopharmaceutical-containing solution and can break chemical bonds, generate reactive chemical species from solvent molecules, and further decompose the radiopharmaceutical drug directly or indirectly. This process can be referred to as radiolysis. Radiolysis WSGR Docket No.59541-743.602 can be particularly severer when a concentrated radioactive compound is present in small volume of solution. In the case of Actinium-225-DOTA-containing radiopharmaceuticals, Actinium-225 can decay into Francium-221, Astatine-217, Bismuth-213, Thallium-209, Polonium-213, Lead-209, and Bismuth-209 in sequence. The decay chain can contain four alpha particle emissions and two beta particle emissions. In addition, Francium-221 and Bismuth-213 can release up to 25% of their decay energy through gamma emission. The ionizing radiation can cause radiolysis of surrounding water molecules particularly produce Hā atoms, āOH radicals, H3O+ions and oxidizing agent hydrogen peroxide. These chemical species can be highly reactive. In some cases. they can react with the drug substance, cause degradation of the radioisotope-containing peptide drug, and increase radioactive impurity overtime.

[0089] Accordingly, provided herein are radiopharmaceutical compositions with improved stability, for example, compositions containing Actinium-225.

[0090] In one aspect, the present disclosure relates to a radionuclide solution with radioisotopes and its daughter ions. The solution composition can comprise ingredients which stabilize the radioactive drug substance from radiolysis and chemical decomposition. The increased stability of the drug substance can extend shelf-life of radiopharmaceuticals, as such to achieve their wide applications as a drug product for their diagnostic and therapeutic purpose.

[0091] In one aspect, the compositions described herein have increased stability of the radiopharmaceutical conjugate. The radiopharmaceutical composition can contain ingredients, such as radiopharmaceutical stabilizers, which stabilize the radioactive drug substance from radiolysis and chemical decomposition. The radiopharmaceuticals stabilizers can comprise reducing agents and / or radical scavengers, such as ascorbic acid to reduce the radiolysis. The composition of the present disclosure can have extended shelf-life. The compositions described herein can comprise one or more stabilizing agents. The stabilizing agents can prevent or delay radiolysis of the radiopharmaceutical conjugate. The stabilizing agents can prevent or delay decomposition of the radiopharmaceutical conjugate. The stabilizing agents can prevent or delay chemical decomposition of the radiopharmaceutical conjugate caused by radioactive decay-generated daughter ions. The stabilizing agents can prevent or delay chemical decomposition of the radiopharmaceutical conjugate caused by pH changes. The stabilizing agents can be added into the composition at a low concentration. The stabilizing agents can be optionally added into the composition at a low concentration. The increased stability of the radiopharmaceutical conjugate can achieve one or more applications in the field of medicine. The applications can comprise acting as a drug product for one or more diagnostic purposes. The applications can comprise acting as a drug product for one or more therapeutic purposes. A treatment plan for a patient or subject receiving the radiopharmaceutical compositions described herein can include treatment at remote locations. A treatment plan for a patient or subject receiving the radiopharmaceutical compositions described herein can include a shorter stay at the infusion center or at the hospital.

[0092] A radiopharmaceutical conjugate can comprise a radionuclide and a metal chelator. The radionuclide and the metal chelator can be linked by ionic and coordinate bonding. The radionuclides for therapeutic purpose can include Lutetium-177, Actinium-225, Yttrium-90, and Bismuth-213. The WSGR Docket No.59541-743.602 radionuclides for diagnostic purpose can include Gallium-68, Copper-64, and Indium-111. The chelator can further bind to a target binder, such as one that has a high-affinity with the target of the radiopharmaceutical conjugate, directly or via a linker covalently. Exemplary metal chelators can include aza-crown ether-based polycarboxylic acid such as 2,2ƍ,2ƍƍ,2ƍƍƍ-(1,4,7,10-Tetraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid (DOTA), or 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA). The chelation can keep the radionuclide from releasing into surroundings in vitro and / or in vivo. III. Compositions

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

[0094] In one aspect, provided herein are liquid radiopharmaceutical compositions comprising225Ac- DOTATATE. In one aspect, provided herein are liquid radiopharmaceutical compositions comprising225Ac-DOTATOC. In one aspect, provided herein are liquid radiopharmaceutical compositions comprising225Ac-DOTA-JR-11. In one aspect, provided herein are liquid radiopharmaceutical compositions comprising225Ac-HA-DOTA-TATE.

[0095] In one aspect, disclosed herein is a radiopharmaceutical composition, comprising: (a) the 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) optionally a radiolysis stabilizer, wherein the radiolysis stabilizer is present in the radiopharmaceutical composition at concentration of about 1 wt% to about 10wt%; (d) a free metal chelator, wherein the free metal chelator is present in the radiopharmaceutical composition at 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 vehicle.

[0096] In one aspect, disclosed herein is 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); (c) a free metal chelator, wherein the free metal chelator is selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or a combination thereof, and wherein the free metal chelator is present in the radiopharmaceutical composition WSGR Docket No.59541-743.602 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); and (d) an aqueous vehicle, wherein the aqueous vehicle is saline solution. In some embodiments, the radiopharmaceutical composition further comprises a pH stabilizer. In some embodiments, the radiolysis stabilizer functions 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 10wt%. 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, a radiopharmaceutical composition comprise a pH stabilizer that is present in the formulation at about 80 to about 500 mM. In some embodiments, a radiopharmaceutical composition comprise a pH stabilizer that is present in the formulation at about 50 mM to about 200 mM.. In some embodiments, a radiopharmaceutical composition comprise a pH stabilizer that is present in the formulation at about 25 mM to about 300 mM. In some embodiments, a radiopharmaceutical composition comprise a fee metal chelator that is present in the formulation at about 0.01 mg / mL to about 1 mg / mL. In some embodiments, a radiopharmaceutical composition comprise a fee metal chelator that is present in the formulation at about 0.02 mg / mL to about 3 mg / mL. In some embodiments, a radiopharmaceutical composition comprise a fee metal chelator that is present in the formulation at about 0.02 mg / mL to about 2 mg / mL.

[0097] In one aspect, disclosed herein is 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 a pH of the radiopharmaceutical composition at about 4 to 8; (c) a radiolysis stabilizer; (d) a free metal chelator, wherein the free metal chelator is configured to maintain a level of free radionuclide in the radiopharmaceutical composition below about 0.05 mCi / L; and (e) an aqueous vehicle. In some embodiments, the radiolysis stabilizer (such as ascorbic acid or sodium ascorbate) can function as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer is the same compound. In some embodiments, the free metal chelator is configured to maintain a level of free radionuclide in the radiopharmaceutical composition below about 0.05 mCi / L for at least 72 hours at about at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the free metal chelator is configured to maintain a level of 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 at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the free metal chelator is configured to maintain a level of 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 at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the WSGR Docket No.59541-743.602 free radionuclide is unbound or unchelated225Ac. 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 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.

[0098] In some embodiments, a radiopharmaceutical composition described herein retains at least 80 % of the225Ac content bound as part of the conjugate after 24 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 80 % of the225Ac content bound as part of the conjugate after 48 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 80 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 90 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by radio thin- layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 95 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, a radiopharmaceutical composition described herein retains at least 90 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, a radiopharmaceutical composition described herein retains at least 95 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, a radiopharmaceutical composition described herein retains at least 90 % of the225Ac content bound as part of the conjugate after 168 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, a radiopharmaceutical composition described herein retains at least 95 % of the225Ac content bound as part of the conjugate after 168 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC).

[0099] In one aspect, disclosed herein is a liquid radiopharmaceutical composition comprising: (a) a conjugate that comprises (i) a targeting ligand, wherein the targeting ligand binds to a somatostatin receptor WSGR Docket No.59541-743.602 (SSR), (ii) a metal chelator covalently attached to the targeting ligand, and (iii) a radionuclide, wherein the radionuclide is225Ac, (b) a means for maintaining a pH of the radiopharmaceutical composition, wherein the pH of the radiopharmaceutical composition is about 4 to about 8; (c) a means for scavenging free radionuclide in the radiopharmaceutical composition; and (d) an aqueous vehicle. In some embodiments, wherein the radiopharmaceutical composition retains at least 90 % of the225Ac content as part of the radionuclide after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the means for scavenging free radionuclide is a free metal chelator described herein. In some embodiments, the means for maintaining a pH of the radiopharmaceutical composition is a pH stabilizer described herein. In some embodiments, the liquid radiopharmaceutical composition is a solution. In one aspect, disclosed herein is a liquid radiopharmaceutical composition comprising: (a) a conjugate that comprises (i) a targeting ligand, wherein the targeting ligand binds to a somatostatin receptor (SSR), (ii) a metal chelator covalently attached to the targeting ligand, and (iii) a radionuclide, wherein the radionuclide is225Ac, 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 chelator; and (d) an aqueous vehicle. In some embodiments, the radiopharmaceutical composition retains at least 80%, at least 85%, or at least 90 % of the225Ac content as part of the radionuclide after 48 hours, 72 hours, or 120 hours at about 20ºC to about 25°C as determined by radio 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 10 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 is225Ac-DOTA-TATE,225Ac-DOTA-TOC, or225Ac- DOTA-JR-11. In some embodiments, the conjugate is225Ac-HA-DOTA-TATE In some embodiments, the pH stabilizer is ascorbic acid, a salt thereof, or a combination 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 chelator is selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or a combination thereof. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01mg / mL to about 5 mg / mL. In some embodiments, the conjugate is225Ac-DOTA-TATE and the WSGR Docket No.59541-743.602 composition retains at least 90 % of the225Ac content as225Ac-DOTA-TATE after 168 hours at about 20ºC to about 25°C. In some embodiments, the conjugate is225Ac-DOTA-TATE and the composition retains at least 95 % of the225Ac content as225Ac-DOTA-TATE after 168 hours at about 20ºC to about 25°C. In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition is formulated as a unit dose form that contains about 5 ml to about 50 ml (e.g., about 10-15 ml, about 12mL) of the solution. In some embodiments, the aqueous vehicle is a saline solution.

[0100] The liquid radiopharmaceutical compositions can comprise pharmaceutically acceptable carriers or diluents. Exemplary pharmaceutically acceptable carriers include solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration. In some embodiments, the liquid radiopharmaceutical compositions described herein are formulated as a solution, emulsion, suspension, syrup, elixir, or the like. The compositions can be aqueous radiopharmaceutical compositions.

[0101] The liquid radiopharmaceutical composition can comprise an aqueous vehicle. For example, the aqueous vehicle can comprise water, saline solution, dextrose in water, dextrose in saline solution, Ringer's solution, or lactated Ringer's solution. In some embodiments, the aqueous vehicle is water. In some embodiments, the aqueous vehicle is water for injection. In some embodiments, the aqueous vehicle is 5.0% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is 4.0% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is 3.0% sodium chloride solution. In some embodiments, the aqueous vehicle is 2.0% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is 1.5% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is 1.0% sodium chloride solution. In some embodiments, the aqueous vehicle is 0.9% w / w sodium chloride saline solution. In some embodiments, the aqueous vehicle is 0.5% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is 0.5% to 1.5% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is 0.7% to 1.1% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is saline solution. In some embodiments, the aqueous vehicle is dextrose in water. In some embodiments, the aqueous vehicle is dextrose in saline solution. The compositions can be isotonic. The composition can be a solution or suspension. In some embodiments, the liquid radiopharmaceutical is formulated as a solution. The compositions can be formulated to be compatible with a particular local or systemic route of administration. The compositions can include carriers, diluents, or excipients suitable for administration by particular routes. The composition can be formulated for IV infusion or bolus injection. In some embodiments, the liquid radiopharmaceutical is formulated for intravenous administration.

[0102] In some embodiments, the liquid radiopharmaceutical formulation described herein, for example, of a formulation of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24, is administered to a subject via infusion using gravity, an infusion pump, or a syringe pump. WSGR Docket No.59541-743.602

[0103] In some embodiments, the liquid radiopharmaceutical formulation described herein, for example, of a formulation of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24, is administered to a subject via infusion using gravity. In some embodiments, the gravity infusion method comprises one or more of the following steps of 1) confirming the amino acid infusion has begun at a constant rate before beginning the radiopharmaceutical formulation infusion, 2) connecting a short sterile non-vented needle to a sterile sodium chloride solution via a catheter prefilled with sterile sodium chloride solution, 3) priming the short sterile needle with sterile sodium chloride solution and clamping the line, 4) inserting the short sterile needle into a vial containing the radiopharmaceutical formulation in a swift clean motion, ensuring the short sterile needle does not contact the radiopharmaceutical solution, 5) attaching a long needle to one end of the m / m tubing and a luer lock to the other end of the m / m tubing, 6) priming the m / m tubing with sterile sodium chloride, 7) clamping the m / m tubing, 8) inserting the long needle into the vial containing the radiopharmaceutical formulation, ensuring the long needle contacts the radiopharmaceutical formulation, 9) removing the luer lock, 10) connecting the m / m tubing to the subject, and / or 11) unclamping the m / m tubing. An infusion pump or clamp is used to regulate flow of sterile sodium chloride solution from the sterile short needle into the vial. Administration of the radiopharmaceutical formulation continues at a rate of 100-200 mL / hr for 25 to 30 minutes. The infusion is stopped when radiation levels in the m / m tubing have 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 formulation in the line.

[0104] In some embodiments, the liquid radiopharmaceutical formulation described herein, for example, of a formulation of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24, is administered to a subject via infusion using an infusion pump. In some embodiments, the infusion pump method comprises one or more of the following steps of 1) confirming the amino acid infusion has begun at a constant rate before beginning the radiopharmaceutical formulation infusion, 2) inserting a short sterile vented needle into a vial containing the radiopharmaceutical formulation in a swift clean motion, ensuring the short sterile needle does not contact the radiopharmaceutical solution, 3) attaching a long needle to one end of a m / m tube and a 3-way stopcock having a valve to the other end of the m / m tubing, 4) priming the m / m tubing and long needle with sterile sodium chloride solution, 5) closing the clamp, 5) inserting the long needle into the vial containing the radiopharmaceutical formulation, ensuring the long needle contacts the radiopharmaceutical formulation, 5) attaching the m / m tubing with sterile sodium chloride solution to the 3-way stopcock valve, 6) attaching the half-set infusion pump tubing to the 3-way stopcock, 7) adjusting the stopcock valve, allowing the sterile saline solution to prime the half-set infusion pump tubing, 8) inserting the half-set infusion pump tubing into the infusion pump, 9) connecting the primed IV catheter to the subject and setting the 3-way stopcock valve so that the radiopharmaceutical formulation is in line with the infusion pump, and / or 10) infusing the radiopharmaceutical formulation at a constant rate over 25 to 30 minutes. After the radiopharmaceutical formulation has been administered, the infusion pump is stopped and the 3-way stopcock valve is positioned so that the infusion pump is in line with the sterile sodium chloride solution. Finally, the WSGR Docket No.59541-743.602 subject’s intravenous line is flushed with 25 mL of sterile sodium chloride solution to remove any residual radiopharmaceutical formulation in the line.

[0105] In some embodiments, the liquid radiopharmaceutical formulation described herein, for example, of a formulation of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24, is administered to a subject via infusion using a syringe pump. In some embodiments, the syringe pump method comprises one or more of the following steps of 1) confirming the amino acid infusion has begun at a constant rate before beginning the radiopharmaceutical formulation infusion, 2) inserting a short sterile vented needle into a vial containing the radiopharmaceutical formulation in a swift clean motion, ensuring the short sterile needle does not contact the radiopharmaceutical solution, 3) withdrawing the radiopharmaceutical solution from the vial into a shielded sterile syringe having a needle, 4) remove and cap the needle, 5) connecting tubing primed with sterile sodium chloride solution to the syringe pump, 6) placing the syringe containing the radiopharmaceutical solution into the syringe pump, 7) connecting the primed tubing to the syringe 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 is flushed with 25 mL of sterile sodium chloride solution to remove any residual radiopharmaceutical formulation in the line.

[0106] Supplementary components or excipients can also be incorporated into the liquid radiopharmaceutical compositions. The composition can further comprise one or more supplementary components or excipients. The supplementary components or excipients can be preservatives, antibacterial, antiviral, antimicrobial and / or antifungal agents. The supplementary components or excipients can be a tonicity adjusting agent, a solubilizing agent, a suspending agent, and / or a surfactant.

[0107] The liquid radiopharmaceutical compositions described herein can be storage stable 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 compositions retain at least 85 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the compositions retain at least 90 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the compositions retain at least 95 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the compositions described retain 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 compositions described herein retain at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol% or at least WSGR Docket No.59541-743.602 99 mol% of the initial conjugate after 2 weeks at refrigerated condition (about 4°C). 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% or at least 99 mol% of the initial conjugate after 10 days at refrigerated condition (about 4°C). In some embodiments, the compositions described herein retain at least 85 mol%, 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 at refrigerated condition (about 4°C). 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 at refrigerated condition (about 4°C). 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 at refrigerated condition (about 4°C). In some embodiments, the purity or the molar percentage of the conjugate is determined by radio thin layer chromatography (radio-TLC). In some embodiments, the purity or the molar percentage of the conjugate is determined by instant thin layer chromatography (iTLC). In some embodiments, the purity or the molar percentage of the conjugate is determined by measuring the related Į-particle emission using radio-TLC.

[0108] The liquid radiopharmaceutical compositions described herein can retain an amount of the initial conjugate (such as225Ac-DOTA-TATE) after stored for a period of time. In some embodiments, the radiopharmaceutical composition retains 95 mol% or more of the initial conjugate after 48 hours, 72 hours, 96 hours, 120 hours, 148 hours, 168 hours, 192 hours, 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 the molar percentage of the conjugate is determined by instant thin-layer chromatography (iTLC). In some embodiments, the purity or the molar percentage of the conjugate is determined by radio thin-layer chromatography (radio-TLC). In some embodiments, room temperature can refer to a temperature of about 25°C. In some embodiments, room temperature can refer to a temperature of 25°C. In some embodiments, room temperature can refer to a temperature of about 22°C to about 25°C. In some embodiments, room temperature can refer to a temperature of about 20°C to about 25°C.

[0109] The liquid radiopharmaceutical compositions described herein can contain a small amount of the unchelated and un-conjugated radionuclide after stored for a period of time. In some embodiments, the liquid radiopharmaceutical compositions described herein contain a small amount of free actinium-225 and actinium-225 present in a fragment of the conjugate225Ac-DOTA-TATE (e.g., as225Ac-DOTA fragment) after being stored for a period of time. For example, see Example 3. The total content of the radionuclide such as actinium-225 in the radiopharmaceutical composition can also decrease over time due to the decay WSGR Docket No.59541-743.602 of the radionuclide. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 20% free actinium-225 after 120 hours at about 20°C to 25°C, compared to the total amount of the actinium-225 content in the composition (at that time of measurement). In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 10% free actinium-225 after 120 hours at about 20°C to 25°C, compared to the total amount of the actinium-225 content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 5% free actinium-225 after 120 hours at about 20°C to 25°C, compared to the total amount of the actinium-225 content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 2% free actinium-225 after 120 hours at about 20°C to 25°C, compared to the total amount of the actinium-225 content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 1% free actinium-225 after 120 hours at about 20°C to 25°C, compared to the total amount of the actinium- 225 content in the composition.

[0110] In some embodiments, after being stored for 120 hours at about 20ºC to about 25°C, at least 90 mol% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition (at that time of measurement) is present as225Ac-DOTA-TATE. In some embodiments, after being stored for 120 hours at about 20ºC to about 25°C, at least 95 mol% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition is present as225Ac-DOTA-TATE. In some embodiments, after being stored for 120 hours at about 20ºC to about 25°C, at least 98 mol% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition is present as225Ac-DOTA-TATE. In some embodiments, after being stored for 120 hours at about 20ºC to about 25°C, at least 99 mol% of the225Ac (i.e., actinium- 225) content in the liquid radiopharmaceutical composition is present as225Ac-DOTA-TATE. In some embodiments, after being stored for 144 hours at about 20ºC to about 25°C, at least 90 mol% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition (at that time) is present as225Ac-DOTA-TATE.In some embodiments, after being stored for 168 hours at about 20ºC to about 25°C, at least 90 mol% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition (at that time) is present as225Ac-DOTA-TATE. In some embodiments, after being stored for 192 hours at about 20ºC to about 25°C, at least 90 mol% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition (at that time) is present as225Ac-DOTA-TATE.

[0111] In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 20 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 120 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 15 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 120 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined WSGR Docket No.59541-743.602 amount of about 10 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 120 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 10 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 120 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 5 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 120 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. The total amount of the225Ac content in a composition can decrease overtime as the radionuclide actinium-225 naturally decays. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 10 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 144 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 10 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 168 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than a combined amount of about 10 % of free225Ac and225Ac present in a fragment of the conjugate (e.g., as225Ac-DOTA fragment) after 192 hours at about 20°C to 25°C, compared to the total amount of the225Ac content in the composition. In some embodiments, the amount of225Ac is determined by radio-TLC.

[0112] In some embodiments, a radiopharmaceutical composition described herein retains at least 80% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA- TATE after 24 or 48 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 80% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 96 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 90% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 120 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 95% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 120 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 98% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 120 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 99% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 120 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein WSGR Docket No.59541-743.602 retains at least 90% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 144 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 90% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 168 hours at about 20°C to 25°C as determined by radio-TLC. In some embodiments, a radiopharmaceutical composition described herein retains at least 90% of the225Ac (i.e., actinium-225) content in the liquid radiopharmaceutical composition as225Ac-DOTA-TATE after 192 hours at about 20°C to 25°C as determined by radio-TLC.

[0113] In some embodiments, the liquid radiopharmaceutical compositions comprise a conjugate that comprises actinium-225. In some embodiments, a radiopharmaceutical composition comprising actinium- 225 conjugates contains no more than about 20% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 10% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 5% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 3% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 2% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about 1% free actinium after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about a total of 20 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about a total of 15 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about a total of 10 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about a total of 5 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no WSGR Docket No.59541-743.602 more than about a total of 3 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about a total of 2 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, a radiopharmaceutical composition comprising actinium-225 conjugates contains no more than about a total of 1 mol% of free daughter isotopes of actinium-225 after 168 hours at room temperature, compared to the total amount of the initial chelated actinium content in the composition. In some embodiments, the purity or the molar percentage of the conjugate is determined by radio thin layer chromatography (radio-TLC).

[0114] In some embodiments, a radiopharmaceutical composition described herein retains at least 80 % of the225Ac content bound as part of the conjugate (e.g., as part of225Ac-DOTA-TATE,225Ac-DOTA- TOC,225Ac-HA-DOTA-TATE, or225Ac-DOTA-JR-11) after 24 or 48 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, a radiopharmaceutical composition described herein retains at least 90 % of the225Ac content bound as part of the conjugate (e.g., as part of225Ac-DOTA-TATE,225Ac-DOTA-TOC,225Ac-HA-DOTA-TATE, or225Ac-DOTA-JR-11) after 72 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 168 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio- TLC). In some embodiments, the radiopharmaceutical composition retains at least 95 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 95 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by radio thin-layer chromatography (radio-TLC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 120 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 168 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 90 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). In some embodiments, the radiopharmaceutical composition retains at least 95 % of the225Ac content bound as part of the conjugate after 72 hours at about 20ºC to about 25°C as determined by high performance liquid chromatography / fraction collection (HPLC-FC). WSGR Docket No.59541-743.602 Stabilizing agents

[0115] In one aspect, disclosed herein are radiopharmaceutical compositions with improved stability. Pharmaceutical compositions described herein can comprise one or more stabilizing agents. In one aspect, provided herein are solutions that comprise one or more stabilizing agents for use in a radiopharmaceutical composition. In some embodiments, the solutions that comprise one or more stabilizing agents are dilution solutions. The one or more stabilizing agents can reduce, prevent, or delay decomposition of the radiopharmaceutical. The decomposition can comprise radiolysis-caused decomposition of the radiopharmaceuticals. The one or more stabilizing agents can reduce, prevent, or delay the decay of radionuclides. Radiolysis Stabilizer

[0116] The one or more stabilizing agents of the herein described pharmaceutical composition can comprise a radiolysis stabilizer. The one or more stabilizing agents can comprise two or more radiolysis stabilizers. The one or more stabilizing agents can comprise a first and a second radiolysis stabilizer. The radiolysis stabilizer can be an amino acid or a peptide or a derivative thereof, a vitamin or a derivative thereof, a lipid or a derivative thereof, a carbohydrate or a derivative thereof, a volume expander or an antioxidant. The radiolysis stabilizer can comprise an amino acid, a peptide or a derivative thereof, a vitamin or a derivative thereof, a lipid or a derivative thereof, a carbohydrate or a derivative thereof, a volume expander, an antioxidant, or a combination thereof. In some embodiments, a radiopharmaceutical composition described herein comprises a means for stabilizing the conjugate comprising a radionuclide. The means for stabilizing the conjugate can be a radiolysis stabilizer described herein. In some embodiments, a radiopharmaceutical composition described herein comprises a 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, a radiopharmaceutical composition described herein comprises a means for reducing a free radical concentration in the composition. In some embodiments, the means for reducing a free radical concentration in the composition is a radiolysis stabilizer. In some embodiments, the reduction of free radicals in the composition reduces radiolysis of the conjugate. In some embodiments, the radiolysis stabilizer is an antioxidant.

[0117] The molar ratio of the first and the second radiolysis stabilizer can be from 1:100,000 to 100,000:1, from 1:1,000 to 1,000:1, from 1:100 to 100:1, from 1:20 to 20:1, from 1:10 to 10:1, and from 1:5 to 5:1. The molar ratio of the first and the second radiolysis stabilizer can be from 1:5 to 5:1. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 1 ^M, 10 ^M, 0.1mM, 1mM, 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, 5 M. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 1 ^M to 5 M. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 10 ^M to 1 M. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 0.1 mM to 500 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 20 mM to 500 mM, about 50 mM to WSGR Docket No.59541-743.602 about 500 mM, about 75mM to about 250 mM, or about 250 to about 500 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 50 mM to 200 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 75 mM to 150 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 25 mM to 250 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 10 mM to 500 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 20 mM to 100 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 25 mM to 75 mM. The radiolysis stabilizer can be present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. The radiolysis stabilizer can be present in the radiopharmaceutical composition at 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 can be present in the radiopharmaceutical composition at about 0.01 wt% to about 5 wt%. The radiolysis stabilizer can be present in the radiopharmaceutical composition at 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 can be present in the radiopharmaceutical composition at about 5 wt%. The radiolysis stabilizer can be present in the radiopharmaceutical composition at about 0.05 wt% to about 2 wt%. The radiolysis stabilizer can be present in the radiopharmaceutical composition at about 0.1 wt% to about 1 wt%. The radiolysis stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.0001 to 5,000 mg / mL. The radiolysis stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.1 to 500 mg / mL. The radiolysis stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.01 to 50 mg / mL. The radiolysis stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.1 to 5 mg / mL. The radiolysis stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.5 to 2 mg / mL. In some embodiments, the radiolysis stabilizer is 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 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 WSGR Docket No.59541-743.602 embodiments, the radiolysis stabilizer is ethanol. In some embodiments, the radiolysis stabilizer gentisic acid. In some embodiments, the radiolysis stabilizer is a salt of gentisic acid.

[0118] The radiolysis stabilizers can comprise an amino acid or a derivative thereof. The radiolysis stabilizers can comprise a peptide or a derivative thereof. The amino acid or a derivative thereof can be a natural amino acid or an unnatural amino acid. The amino acid can act to scavenge chemically active ingredients generated by radiolysis. The amino acid can contain an amino group. The amino acid can comprise optionally an extra reducing heteroatom, such as L-methionine, L-Cysteine, or L-Lysine. The peptide or a derivative thereof can comprise two or more amino acids. The peptide can comprise 2 to 50 amino acids. The peptide can comprise 2 to 30 amino acids. The peptide can comprise 2 to 15 amino acids. The peptide can comprise 2 to 7 amino acids. The peptide can comprise 2 to 4 amino acids. The peptide can comprise 3 amino acids. The amino acid can be an essential amino acid. The amino acid can be a nonessential amino acid. The amino acid can be an aliphatic amino acid. The amino acid can be an aromatic amino acid. The amino acid can be an acidic amino acid. The amino acid can be a basic amino acid. The amino acid can be a hydroxylic amino acid. The amino acid can be a sulfur-containing amino acid. The amino acid can be an amidic amino acid. The amino acid, its derivative, or peptide can be N- Acetyl-L-cysteine, Glutathione, L-Lysine, Selenol-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 derivatives thereof. The amino acid can be a methionine. The amino acid derivative, such as N-Acetyl-L-cysteine, can have higher solubilities compared to the parent amino acid. The radiolysis stabilizer, such as Thiourea, L-Glutathione, and Lipoic Acid, can comprise an organic sulfur. The organic sulfur can optionally be oxidized to a higher oxidation state and coordinate to free heavy metal ions in a solution.

[0119] The radiolysis stabilizers can comprise an antioxidant (or reducing agent or radical scavengers). The radiolysis stabilizers can comprise one or more antioxidants. The antioxidant can comprise a flavonoid or a derivative thereof. The flavonoid can be polyphenol compounds that comprise multiple phenol moieties. A flavonoid can comprise a 15-carbon structure. The 15-carbon structure can further comprise two phenyl rings and a heterocyclic ring. The flavonoid can comprise bioflavonoids, isoflavonoids, or neoflavonoids. The flavonoid can comprise a catechin or a derivative thereof, such as the compounds illustrated in FIG. 1, (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-Pentahydroxyflavane (Epi- Catechin 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 (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol or Epigallo- Catechin (EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo- Catechin or GC). The catechins can be administered to a human at a dose from 1mg / kg to 50mg / kg, from 5mg / kg to 40mg / kg, from 10mg / kg to 40mg / kg, from 20mg / kg to 35mg / kg. The flavonoid can comprise (2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate WSGR Docket No.59541-743.602 ((-) Catechin gallate or CG), 3,3',4',5,5',7-Hexahydroxyflavylium chloride, (-)-cis-3,3',4',5,7- Pentahydroxyflavane (Epi-Catechin 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-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one (Rutin hydrate), Quercetin, (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5- trihydroxybenzoate (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7- dihydroxy-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate, Epi-Catechin Gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Epigallo-Catechin or EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo-Catechin or GC), or a combination thereof. In some embodiments, the antioxidant is a carotenoid or a derivative thereof. The carotenoid can be a fat-soluble pigment, such as yellow, orange, or red pigments. The carotenoid can be all-trans-Fucoxanthin, Lycopene, Xanthophyll, Beta carotene, Lycopene, or Lutein.

[0120] In some embodiment, a herein described pharmaceutical composition comprises an antioxidant that is N-acetyl cysteine, L-Ascorbic acid, N-tert-Butyl-Į-phenylnitrone, 3-(3,4-Dihydroxyphenyl)-2- propenoic acid (Caffeic Acid), ȕ-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- Hexahydroxyflavylium chloride, Thiocytic Acid (Dihydrolipoic Acid, DHLA), 4,4',5,5',6,6'- Hexahydroxydiphenic acid 2,6,2',6'-dilactone (Ellagic acid), (-)-cis-3,3',4',5,7-Pentahydroxyflavane (Epi- Catechin 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 ((-)-Gallocatechin), Glutathione, 2-(3,4-Dihydroxyphenyl)ethanol, 3,4',5,7- Tetrahydroxyflavone (Kaempferol), (±)-1,2-Dithiolane-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- methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one, Rutin hydrate, Selenol-L-methionine, Thiourea, (+)-Į-Tocopherol, Xanthophyll, Citric acid (CA), Gentisic acid (GA), Salicylic acid (SA), Erythorbic acid (EA), Phenol, Sodium bisulfite, Butylated hydroxy anisole, Butylated hydroxy toluene, Metabisulfite, Benzyl alcohol, Thymol, Lipoic acid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Mannitol, Sucrose, Melatonin, Ebselen, Pyruvic acid, Carboxy-PTIO, Trolox, Ebselen, Uric acid, Edaravone, Beta carotene, NADPH, Lycopene, Lutein, Catalase, Estrogen, Estradiol, Estriol, Ubiquinol, 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 (EpiGallo-Catechin gallate or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7- dihydroxy-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate or Epi-Catechin Gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Epigallo-Catechin or EGC), WSGR Docket No.59541-743.602 (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo-Catechin or GC), (í)- cis-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-gallate ((-)-Epigalocatechin- 3-O-Gallate), 5-Aminolevulibic Acid hydrate, Ploysorbate 80, Garlic Acid, Sodium L-Ascorbate, Hyaluronic Acid, Dextran 60-90, Selenol, LysaKare, or a combination thereof. Exemplary antioxidants of the present disclosure are further described in Table 1. Table 1. Exemplary Antioxidants N-Acetyl-L-cysteine Benzyl alcohol L-Ascorbic acid Thymol N-tert-Butyl-Į-phenylnitrone Lipoic acid (LA) 3-(3,4-Dihydroxyphenyl)-2-propenoic acid (Caffeic Thioglycolic acid (TGA) Acid) ȕ-Carotene, Provitamin A 2,3 Dimercaptopropan-1-ol (BAL) (2S,3R)-2-(3,4-Dihydroxyphenyl)-3,4-dihydro-1(2H)- benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-) Zinc Catechin gallate) (from green tea) 1,4,5-Trihydroxycyclohexanecarboxylic acid Selenium trans-4-Hydroxycinnamic acid (p-Coumaric acid) Albumin 3,3ƍ,4ƍ,5,5ƍ,7-Hexahydroxyflavylium chloride Ethanol Thiocytic Acid (Dihydrolipoic Acid, DHLA) Mannitol 4,4ƍ,5,5ƍ,6,6ƍ-Hexahydroxydiphenic acid 2,6,2ƍ,6ƍ- Sucrose dilactone (Ellagic acid) (í)-cis-3,3ƍ,4ƍ,5,7-Pentahydroxyflavane (from green tea) Melatonin 2-Methoxy-4-(2-propenyl) phenol Ebselen trans-4-Hydroxy-3-methoxycinnamic acid (Ferulic acid) Pyruvic acid 2-(4-Carboxyphenyl)-4,5-dihydro-4,4,5,5- tetramethyl-1H-imidazol-1-yloxy-3-oxide 7-Hydroxy-3-(4^-methoxyphenyl)-4H-benzopyran-4-one potassium salt, 2-(4-Carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3- oxide (Carboxy-PTIO) Salt all-trans-Fucoxanthin Trolox 3,4,5-Trihydroxybenzoic acid (Gallic acid) Ebselen (2S,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)- benzopyran-3,5,7-triol ((-)-Gallocatechin)(from green Uric acid tea) Glutathione Edaravone 2-(3,4-Dihydroxyphenyl)ethanol Beta carotene WSGR Docket No.59541-743.602 Nicotinamide adenine dinucleotide 3,4ƍ,5,7-Tetrahydroxyflavone (Kaempferol) phosphate (NADPH) (±)-1,2-Dithiolane-3-pentanoic acid Lycopene Luteolin Lutein Lycopene (from tomato) Catalase Neochlorogenic acid Estrogen Oleic acid Estradiol trans-3,5,4ƍ-Trihydroxystilbene (Resveratrol) Estriol 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-methyloxan-2- Ubiquinol yl]oxymethyl]oxan-2-yl]oxychromen-4- one;hydrateRutin hydrate L-methionine Copper Thiourea Quercetin (+)-Į-Tocopherol Cortisone 2,3-dimercaptosuccinic acid (DMSA) or Xanthophyll monisoamyl derivative (MiADMSA) Natural L-amino acids: Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamine, Glutamic acid, Glycine, Histidine, Isoleucine, Lysine, Methionine, Taurine Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine, and their derivatives Citric acid (CA) Dextran 40 Gentisic acid (GA) Dextran 70 Salicylic acid (SA) PEG 3350 Erythorbic acid (EA) PEG 4000 Phenol Polygeline Sodium bisulfite Gelofusine PLENVU (polyethylene glycol 3350, Butylated hydroxy anisole sodium sulfate, ascorbic acid, sodium chloride and potassium chloride) Butylated hydroxy toluene Cyclodextrins Glutathione Metabisulfite PEG 400 PEG 1000 PEG (e.g., PEG having a number average molecular (-)-Epigallocatechin-3-O-Gallate weight of about 200-8000) WSGR Docket No.59541-743.602 5-Aminolevulibic Acid hydrate Ploysorbate 80 Garlic Acid Sodium L-Ascorbate Hyaluronic Acid Dextran 60-90 Selenol LysaKare

[0121] In some embodiments, the radiolysis stabilizers comprise a salt, an ester, an amide, an enantiomer, or an acetylation derivative of a compound of Table 1, or a combination thereof. In some embodiments, the radiolysis stabilizer functions as a pH stabilizer.

[0122] The radiolysis stabilizers can comprise a vitamin or a derivative thereof. The radiolysis stabilizers can comprise one or more vitamins or derivatives thereof. In some embodiments, the vitamin or a derivative thereof is L-Ascorbic acid, ȕ-Carotene, Provitamin A, (+)-Į-Tocopherol, Erythorbic acid (EA), Trolox, or Lutein. 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 gentisic acid. In some embodiments, the radiolysis stabilizer is a salt of gentisic acid.

[0123] In some embodiments, the radiolysis stabilizer comprises ascorbic acid or a salt thereof. In some embodiments, the radiolysis stabilizer comprises sodium L-ascorbate. In some embodiments, the radiolysis 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 radiolysis 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 radiolysis 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 radiolysis 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 radiolysis 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 WSGR Docket No.59541-743.602 acid or a salt thereof and is present in the radiopharmaceutical composition at a concentration of 20 mM to 300 mM. In 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, an 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, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 10 mM to 1 M. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 20 mM to 500 mM. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 80 mM to 125 mM. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 100 mM. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 1 mg / mL to 100 mg / mL. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 5 mg / mL to 50 mg / mL. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 10 mg / mL to 30 mg / mL. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5±4.63 mg / mL. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5±5 mg / mL. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5±10 mg / mL. In some embodiments, the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 18.5 mg / mL. In some embodiments, the sodium ascorbate is sodium L-ascorbate.

[0125] The radiolysis stabilizers can comprise a fatty acid or a derivative thereof. The radiolysis stabilizers can comprise one or more lipids. The lipids can 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. The fatty acid can comprise a mono-unsaturated fatty acid. The fatty acid can comprise a poly- unsaturated fatty acid. The fatty acid can comprise a trans-fat. The fatty acid can comprise a C3to C40fatty acid, C6to C30fatty acid, C6to C20fatty acid, and C6to C10fatty acid. In some embodiments, the fatty acid is a C6to C30fatty acid. The fatty acid can comprise a saturated or unsaturated C6to C30fatty acid. The fatty acid can comprise a saturated or unsaturated C19to C20fatty acid. The fatty acid can comprise a saturated or unsaturated C12to C26fatty acid. In some embodiments, the fatty acid comprises oleic acid, Myristoleic acid, Palmitoleic acid, Sapienic acid, Elaidic acid, Vaccenic acid, or Linoleic acid, Į-Linolenic acid, or a combination thereof. WSGR Docket No.59541-743.602

[0126] In some embodiments, the radiolysis stabilizers comprise a lipid that is a steroid or a derivative thereof. In some embodiments, the steroid can be a corticosteroid, such as Estrogen, Estradiol, Estriol, or Cortisone. The steroid can have four carbon rings. In some embodiments, the steroid can be Estrogen, Estradiol, Estriol, or Cortisone.

[0127] The radiolysis stabilizers can comprise a volume expander. In some embodiments, the volume expander is present in the radiopharmaceutical composition at a concentration of from about 0.001 wt% to 80% wt%. In some embodiments, the volume expander can expand the volume of a liquid, such as human blood volume. The volume expander can serve as an absorptive radio-protectant. The volume expander can mimic human serum albumin. The volume expander can comprise human albumin. The volume expander can comprise polymers, such as polyethylene glycol (PEG), a glucose polymer, or polymer mixtures. A glucose polymer can be a Dextran or a saccharide, such as an oligosaccharide. The glucose polymer can have a number average molecular weight from 1kDa to 40,000,000kDa, from 5kDa to 1,000,000kDa, from 10KDa to 500,000kDa, from 15kDa to 1,000kDa, from 20kDa to 100kDa, or from 30kDa to 50kDa. The glucose polymer can have an average molecular of about 20-60 kDa, e.g., about 40kDa. The glucose polymer can be linear or cyclic. The cyclic form glucose polymer can be cyclic oligosaccharides, such as cyclodextrins. The cyclodextrins can comprise a macrocyclic ring of glucose subunits joined by Į-1,4 glycosidic bonds. The macrocyclic ring can comprise 6 to 8 glucose subunits, such as, Į (alpha)-cyclodextrin, ȕ (beta)-cyclodextrin, and Ȗ (gamma)-cyclodextrin. The polymer mixture, such as an artificial colloid, can comprise the glucose polymer from 0.001 wt% to 80% wt%. The polymer mixture can comprise the glucose polymer from 0.1 wt% to 50% wt%. The polymer mixture can comprise the glucose polymer from 1 wt% to 20% wt%. The polymer mixture can be a mixture comprise the glucose polymer from 5 wt% to 15% wt%. The polymer mixture can comprise from 0.1%wt to 15%wt glucose polymer, or from 1%wt to 10% glucose polymer. The Dextran can be Dextran 40 and Dextran 70. The Dextran can have a number average molecular weight of about 5 to 100 kDa. The Dextran can have a number average molecular weight of about 40 to 70 kDa. The 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. The Dextran 40 mixture can comprise from 0.1%wt to 15%wt Dextran 40, or from 1%wt to 10% Dextran 40. The Dextran 40 mixture can have a total osmolality from 300 mOsmol / L to 450 mOsmol / L. The Dextran 40 mixture can have a total osmolality from 350 mOsmol / L to 420 mOsmol / L. The Dextran 40 mixture can have a total osmolality from 380 mOsmol / L to 400 mOsmol / L. The Dextran 40 mixture can have a total osmolality of 390 mOsmol / L. The polymer can be a Polyethylene glycol (PEG), such as PEG 4000, PEG 3350. In some embodiments, the PEG has a number average molecular weight of about 200 to 20,000, 1000 to 10,000, 2000 to 8000, 3000 to about 5000, or 3000 to 4000. The polymer mixture can comprise PEG, such as PLENVU, a combination of PEG 3350, sodium ascorbate, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride. The polymer can be a gelatin or a modified gelatin, such as polygeline and succinylated gelatin. The polygeline can have a number average molecular weight from 5kDa to 50kDa, from 10kDa to 45kDa, from 20KDa to 50kDa, from 30kDa to 40kDa. The polygeline can have an average WSGR Docket No.59541-743.602 molecular of 35kDa. The polymer mixture can be a mixture containing polygeline. A mixture comprising polygeline, such as Haemaccel, can also contain calcium chloride, potassium chloride and / or sodium chloride. The polymer mixture can comprise modified fluid gelatin, such as succinylated gelatin. The polymer mixture can be a solution, such as Gelofusine. Gelofusine can comprise 4%w / v succinylated gelatin.

[0128] The radiolysis stabilizers can comprise a carbohydrate or a derivative thereof. The carbohydrate can be a saccharide. The saccharide can be a monosaccharide. The saccharide can be a disaccharide, an oligosaccharide, or a polysaccharide. Exemplary disaccharides include a mannitol and a sucrose. The polysaccharide can be a Dextran such as Dextran 40 and Dextran 70. The Dextran can have a molecular weight of about 10-200, 20-100, 30-50, or 40-70 kDa. The polysaccharide can have a number average molecular weight from 5kDa to 1,000,000kDa, from 10KDa to 500,000kDa, from 15kDa to 1,000kDa, from 20kDa to 100kDa, or from 30kDa to 80kDa. The oligosaccharide can be a cyclic oligosaccharide, such as cyclodextrin. The cyclodextrin can comprise a macrocyclic ring of glucose subunits joined by Į- 1,4 glycosidic bonds. The macrocyclic ring can comprise 6 to 8 glucose subunits, such as, Į (alpha)- cyclodextrin, ȕ (beta)-cyclodextrin, and Ȗ (gamma)-cyclodextrin. The polysaccharide can be a Dextran. The carbohydrate can be Mannitol, Sucrose, Dextran (e.g., Dextran 40, Dextran 70), or Cyclodextrins (Į- cyclodextrin, ȕ-cyclodextrin, or Ȗ-cyclodextrin), such as 2-Hydroxypropyl-ȕ-cyclodextrin (HP-ȕ-CD) or sulfobutylether-ȕ-Cyclodextrin (SEB- ȕ-CD). Free metal chelator

[0129] The one or more stabilizing agents can comprise a free metal chelator. In some embodiments, a radiopharmaceutical composition disclosed herein comprises one or more free metal chelators. In some embodiments, a radiopharmaceutical composition described herein comprises a means for scavenging free radionuclide in the radiopharmaceutical composition. The means for scavenging free radionuclide in the radiopharmaceutical composition can be a free metal chelator described herein. In some embodiments, a radiopharmaceutical composition described herein comprises a means for scavenging free radionuclide in the radiopharmaceutical composition and maintaining a low level of free radionuclide (such as free Ac- 225). In some embodiments, the level of free radionuclide (such as free Ac-225) in the composition is maintained below about 0.05 mCi / L. In some embodiments, a radiopharmaceutical composition disclosed herein comprises a free metal chelator configured to maintain a low level of free radionuclide in the composition. In some embodiments, the level of free radionuclide in the composition is maintained below about 0.01 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained below about 1 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained below about 0.5 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained below about 0.001 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained below about 0.02 mCi / L. In some embodiments, the level of 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 free radionuclide is maintained for a period of 72 hours. In some WSGR Docket No.59541-743.602 embodiments, the level of free radionuclide is maintained for a period of 120 hours. In some embodiments, the level of free radionuclide is maintained at a temperature of about 20ºC to about 25°C.

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

[0131] The free metal chelator can be a linear or cyclic. The linear free metal chelator, such as Ethylenediaminetetraacetic acid (EDTA) and Diethylenetriaminepentaacetic acid (DTPA), can be a heavy metal poisoning antidote or a free heavy metal scavenger. The DTPA can be present in the radiopharmaceutical composition at a concentration from 0.001 mg / mL to 2.5 mg / mL, from 0.01 mg / mL to 5mg / mL, from 0.02 mg / mL to 3mg / mL, from 0.04mg / mL to 1 mg / mL, or from 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, the free metal chelator (such as DTPA) is present in the radiopharmaceutical composition at a concentration of about 0.02 to 0.07 mg / mL. In some embodiments, WSGR Docket No.59541-743.602 the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.01mg / mL to 10 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.01mg / mL to 5mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.02mg / mL to 2.5mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.04mg / mL to 1mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.01 to 0.25 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.02 to 0.125 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration from 0.04 to 0.06 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.05 mg / mL. In some embodiments, the free metal chelator 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 chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.01 mg / m to 0.5 mg / mL. In some embodiments, the free metal chelator 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, a radiopharmaceutical composition disclosed herein comprises one or more free metal chelators. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 to 0.1 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 to 2 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 to 3 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 to 4 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01 to 5 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.02 to 0.07 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.01mg / mL to 10 mL / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.01mg / mL to 5mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.02mg / mL to 2.5mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.04mg / mL to 1mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a WSGR Docket No.59541-743.602 concentration from 0.01 to 0.25 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.02 to 0.125 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration from 0.04 to 0.06 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.05 mg / mL to 2 mg / mL. In some embodiments, the free metal chelator 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 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. The free metal chelator can also prevent potential hepatoxicity caused by free radioactive metal ion when administered into a subject, such as a human subject. The cyclic free metal chelator can be a macrocyclic free metal chelator, such as 1,4,7- Triazacyclononane-1,4,7-triacetic acid (NOTA) 2,2ƍ,2ƍƍ,2ƍƍƍ-(1,4,7,10-Tetraazacyclododecane-1,4,7,10- tetrayl)tetraacetic acid (DOTA). The macrocyclic free metal chelator can have strong chelation ability and used in lower concentration. The free metal chelator can comprise Ethylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentaacetic acid (DTPA), 2-S-(4-Isothiocyanatobenzyl)-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, 2,2ƍ,2”-(10-(2,6- dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-GA), 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid (DOTP), Deferoxamine (DFO), N, N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10- Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (DOTP), 6,6'-((1,4,10,13-tetraoxa- 7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (Macropa), Meso-2,3- dimercaptosuccinic acid (DMSA), Dimercaptopropane sulfonate (DMPS), Dihydrolipoic acid (DHLA), Lipoic acid (LA), Thioglycolic acid (TGA), 2,3 Dimercaptopropan-1-ol (BAL), or a combination thereof. The free metal chelator can comprise EDTA, DTPA, or Macropa. In some embodiments, the free metal chelator is EDTA. In some embodiments, the free metal chelator is DTPA. In some embodiments, the free metal chelator is Macropa. In some embodiments, the free metal chelator is TETA. In some embodiments, the free metal chelator is PEPA. In some embodiments, the free metal chelator is TETPA. In some embodiments, the free metal chelator comprises one or more compounds selected from Table 2. In some embodiments, the free metal chelator comprises 2 compounds selected from Table 2, or salts thereof. In some embodiments, the free metal chelator comprises 3 compounds selected from Table 2, or salts thereof. Exemplary free metal chelators of the present disclosure are further described in Table 2. Table 2. Exemplary Free Metal Chelators N, N-bis(2-hydroxybenzyl)ethylenediamine-N, Ethylenediaminetetraacetic acid (EDTA) N-diacetic acid (HBED) 1,4,7,10-Tetraazacyclododecane-1,4,7,10- Diethylenetriaminepentaacetic acid (DTPA) tetra(methylene phosphonic acid) (DOTP) WSGR Docket No.59541-743.602 6,6'-((1,4,10,13-tetraoxa-7,16- 1,4,7-Triazacyclononane-1,4,7-triacetic acid diazacyclooctadecane-7,16- (NOTA) diyl)bis(methylene))dipicolinic acid (Macropa) 2,2ƍ,2ƍƍ,2ƍƍƍ-(1,4,7,10-Tetraazacyclododecane- Meso-2,3-dimercaptosuccinic acid (DMSA) 1,4,7,10-tetrayl)tetraacetic acid (DOTA) Triethylenetetramine (TETA) Dimercaptopropane sulfonate (DMPS) 1, 4, 7, 10, 13-pentaazacyclopentadecane-N, N', Dihydrolipoic acid (DHLA) N", N"', N""-pentaacetic acid (PEPA) triethylenetetraminepentaacetic acid (TETPA) Lipoic acid (LA) 2,2ƍ,2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)- 1,4,7,10-tetraazacyclododecane-1,4,7- Thioglycolic acid (TGA) triyl)triacetic acid (DOTA-GA) 1,4,7,10-Tetraazacyclododecane-1,4,7,10- 2,3 Dimercaptopropan-1-ol (BAL) tetra(methylene phosphonic acid (DOTP) Deferoxamine (DFO) pH Stabilizer

[0133] In some embodiments, a radiopharmaceutical composition disclosed herein comprises one or more pH stabilizers. In some embodiments, a radiopharmaceutical composition described herein comprises a means for maintaining a pH of the radiopharmaceutical composition. The means for maintaining a pH of the radiopharmaceutical composition can be a pH stabilizer described herein. In some embodiments, a radiopharmaceutical composition described herein comprises a means for maintaining a pH in the radiopharmaceutical composition at about 4-8. In some embodiments, a radiopharmaceutical composition described herein comprises a means for maintaining a pH in the radiopharmaceutical composition at about 5-7. In some embodiments, a radiopharmaceutical composition described herein comprises a means for maintaining a pH in the radiopharmaceutical composition at about 6-8. In some embodiments, a radiopharmaceutical composition described herein comprises a means for maintaining a pH in the radiopharmaceutical composition at about 5.5-6.5. In some embodiments, a radiopharmaceutical composition described herein comprises a means for maintaining a pH in the radiopharmaceutical composition at about 4-7. In some embodiments, a radiopharmaceutical composition disclosed herein comprises a pH stabilizer configured to maintain a pH in the composition. In some embodiments, a radiopharmaceutical composition disclosed herein comprises a pH stabilizer configured to maintain a pH of 4-8 in the composition. In some embodiments, a radiopharmaceutical composition disclosed herein comprises a pH stabilizer configured to maintain a pH of 5-7 in the composition. In some embodiments, a radiopharmaceutical composition disclosed herein comprises a pH stabilizer configured to maintain a pH of 6-8 in the composition. In some embodiments, a radiopharmaceutical composition disclosed herein comprises a pH stabilizer configured to maintain a pH of 5.5-6.5 in the composition. In some embodiments, WSGR Docket No.59541-743.602 a radiopharmaceutical composition disclosed herein comprises a pH stabilizer configured to maintain a pH of 4-7 in the composition.

[0134] In some embodiments, stabilities of the described radiopharmaceutical compositions can vary at different pH values. When pH falls out of certain range, leakage of the radioactive metal may also affect radiochemical purity of the formulated dose and shorten its shelf-life. Accordingly, in some embodiments, the one or more stabilizing agents can comprise pH stabling buffers in addition to the radiolysis protectants and / or free metal chelating agents. In some embodiments, a radiopharmaceutical composition disclosed herein comprises 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 stabilizing agents can comprise one or more pH stabilizers. The one or more pH stabilizers can function as a pH buffer. The one or more pH stabilizers can function as a pH buffer. The one or more pH stabilizers can comprise an organic acid. The organic acid can comprise an acetic acid, fumaric acid, ascorbic acid, propionic acid, benzene sulfonic acid, carbonic acid, citrate acid, aspartic acid, maleic acid, methane sulfonic acid, or tartaric acid. The one or more pH stabilizers can comprise an inorganic acid. In some embodiments, the inorganic acid is hydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, sulfuric acid, or a combination thereof. The one or more pH stabilizers can comprise a base. The base can comprise tromethamine (Tris), ammonium hydroxide, diethanolamine, sodium hydroxide, or a combination thereof. The one or more pH stabilizers can comprise an amino acid or a salt thereof. The one or more pH stabilizers can comprise glycine, lysine, arginine, histidine, or a salt thereof. The one or more pH stabilizers can comprise an alkaline salt. The alkaline salt can comprise sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, tribasic sodium phosphate acid, dibasic sodium phosphate acid, monobasic sodium phosphate acid, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate, or a combination thereof. The sodium ascorbate can be present in the radiopharmaceutical composition at a concentration of from about 50 mM to 200 mM. The one or more pH stabilizers can comprise an acid salt. The acid salt can be ammonium sulfate. In some embodiments, 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, aluminum potassium sulfate, aluminum sodium sulfate, arginine, aspartic acid, benzene sulfonic acid, sodium benzoate, sodium bicarbonate, sodium carboxymethylcellulose, sodium caseinate, sodium citrate, sodium pectinate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citrate acid, hydrobromic acid, glycine, histidine, sodium lactate, (l)-lysine, malic acid, maleic acid, lactic acid, methane sulfonic acid, phosphoric acid, phosphate acid, monobasic sodium phosphate acid, tribasic sodium phosphate acid, dibasic sodium phosphate acid, sodium sesquicarbonate, potassium acid tartrate, potassium bicarbonate, potassium carbonate, potassium citrate, potassium hydroxide, potassium sulfate, sodium hydroxide, sodium / disodium succinate, sodium potassium tartrate, sodium tripolyphosphate, sodium tartrate, sodium acid pyrophosphate, tartaric acid, triacetin, WSGR Docket No.59541-743.602 tromethamine (tris), sulfuric acid, or a combination thereof. The one or more pH stabilizers can comprise Sodium acetate, Sodium ascorbate, Ascorbic acid, Acetic acid, Fumaric acid propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzene sulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citrate acid, hydrobromic acid, glycine, histidine, sodium lactate, (l)-lysine, maleic acid, methane sulfonic acid, phosphate acid, monobasic sodium phosphate acid, tribasic sodium phosphate acid, dibasic sodium phosphate acid, sodium hydroxide, sodium / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (tris), or a combination thereof. Exemplary pH stabilizers of the present disclosure are further described in Table 3. Table 3. Exemplary pH Stabilizers Sodium acetate Citrate acid Acetic acid Hydrobromic acid Sodium L-ascorbate Glycine L-Ascorbic acid Histidine Fumaric acid Sodium lactate Propionic acid (L)-Lysine Ammonium sulfate Maleic acid Ammonium hydroxide Methane sulfonic acid Arginine Phosphate acid Aspartic acid Monobasic sodium phosphate acid Benzene sulfonic acid Tribasic sodium phosphate acid Sodium benzoate Dibasic sodium phosphate acid Sodium bicarbonate Sodium hydroxide Boric acid Sodium / disodium succinate Sodium carbonate, Sulfuric acid Carbon dioxide Sodium tartrate Diethanolamine Tartaric acid Tromethamine (Tris)

[0136] In some embodiments, the pH stabilizers can reduce the pH changes and maintain the radiopharmaceutical purity, which reduces the decomposition of the conjugate and thereby extending the shelf-life of the radiopharmaceutical compositions described herein. The one or more stabilizing agents can comprise a pH stabilizer. The one or more stabilizing agents can comprise two or more pH stabilizers. The one or more stabilizing agents can comprise a first and a second pH stabilizer. In some embodiments, the molar ratio of the first and the second pH stabilizer is from 1: 100,000 to 100,000:1, from 1:1,000 to 1,000:1, from 1:100 to 100:1, from 1:20 to 20:1, from 1:10 to 10:1, and from 1:5 to 5:1. In some embodiments, the molar ratio of the first and the second pH stabilizer is from 1:5 to 5:1. The pH stabilizer can be present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. The pH WSGR Docket No.59541-743.602 stabilizer can be present in the radiopharmaceutical composition at 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 pH stabilizer can be present in the radiopharmaceutical composition at about 0.01 wt% to about 5 wt%. The pH stabilizer can be present in the radiopharmaceutical composition at about 0.05 wt% to about 2 wt%. The pH stabilizer can be present in the radiopharmaceutical composition at about 0.1 wt% to about 1 wt%. The pH stabilizer can also be present in the radiopharmaceutical composition at a concentration of from about 1 ^M, 10 ^M, 0.1mM, 1mM, 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. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 1 ^M to 5 M. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 10 ^M to 1 M. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 0.1 mM to 500 mM. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 10 mM to 500 mM. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 50 mM to 250 mM. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 25 mM to 350 mM. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 80 mM to 200 mM. The pH stabilizer can be present in the radiopharmaceutical composition at a concentration of from about 80 mM to 120 mM. The pH stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.0001 to 5,000 mg / mL. The pH stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.1 to 500 mg / mL. The pH stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.01 to 50 mg / mL. The pH stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.1 to 5 mg / mL. The pH stabilizer can also be present in the radiopharmaceutical composition at a concentration of from 0.5 to 2 mg / mL. In some embodiments, the pH stabilizer comprises a compound selected from Table 3 or a combination thereof.

[0137] Radiopharmaceutical compositions described herein can have a suitable pH value. The one or more pH stabilizers can be configured to maintain a 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 within a range of about 3 to about 9. The pH of the radiopharmaceutical composition can be within a range of about 4 to about 8. The pH of the radiopharmaceutical composition can be within a range of about 5 to about 7. In some embodiments, the pH of the radiopharmaceutical composition is from about 4.0 to about 9.0, from about 4.5 to about 8.5, from about 5.0 to about 8.0, from about 5.5 to about 7.75, from about 6.0 to about 7.5, from about 6.5 to about 7.25, from 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 about 5.5 to about 6. The pH of the radiopharmaceutical composition can be about 5.6 WSGR Docket No.59541-743.602 to about 5.8. The pH of the radiopharmaceutical composition can be about 5.75 to about 5.85. The pH of the radiopharmaceutical composition can be about 5.5 to about 7.75. The pH of the radiopharmaceutical composition can be about 6.0 to about 7.5. The pH of the radiopharmaceutical composition can be about 6.5 to about 7.25. The pH of the radiopharmaceutical composition can be 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 embodiments, the pH of the radiopharmaceutical composition is about 6.2.

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

[0139] In some embodiments, a radiopharmaceutical composition described herein comprises: (a) a conjugate (e.g.,225Ac-DOTA-TATE or225Ac-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) a pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at a concentration of about 80 to about 120 mM; (c) optionally a radiolysis stabilizer, wherein the radiolysis stabilizer is present in the radiopharmaceutical composition at concentration of about 1 wt% to about 10wt%; (d) a free metal chelator, therein the free metal chelator is present in the radiopharmaceutical composition at concentration of about 0.01 mg / mL to about 1 mg / mL; and (e) an aqueous vehicle. 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, a radiopharmaceutical composition described herein comprises: (a) a conjugate (e.g.,225Ac- DOTA-TATE or225Ac-DOTA-TOC), wherein the conjugate 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) optionally a radiolysis stabilizer, wherein the radiolysis stabilizer is WSGR Docket No.59541-743.602 Dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10wt%; (d) a free metal chelator, wherein the free metal chelator 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 vehicle, wherein the aqueous vehicle is saline solution. 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 radiopharmaceutical composition comprises (a) the 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 4-6 wt%; (d) a free metal chelator, wherein the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.01-0.03 mg / mL; and (e) an aqueous vehicle, wherein the aqueous vehicle is sodium chloride saline solution at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises (a) the 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 4-6 wt%; (d) a free metal chelator, wherein the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.01-0.03 mg / mL; and (e) an aqueous vehicle, wherein the aqueous vehicle is sodium chloride saline solution at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises (a) the 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 chelator, wherein the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.04-0.06 mg / mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is sodium chloride saline solution at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises (a) the 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 chelator, wherein the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of about 0.04-0.06 mg / mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is sodium chloride saline solution at a concentration of about 0.9% w / w. Additional excipients WSGR Docket No.59541-743.602

[0140] Radiopharmaceutical compositions described herein can comprise additional excipients. In some embodiments, the additional excipients include excipients suitable for a formulation configured for intravenous administration.

[0141] In some embodiments, the radiopharmaceutical composition described herein comprises a surfactant. “Surfactants” can be defined as surface-active amphiphilic compounds such as block co- polymers. They can be referred to as wetting agents. Non-limiting examples of surfactants include a poloxamer (e.g., poloxamer 188), sodium lauryl sulfate, Desoxycholate sodium, Egg yolk phospholipid, Gelatin, Hydrolyzed Lecithin, Polyoxyethylated fatty acid, Polysorbate 80 (Tween 80), Polysorbate 20 (Tween 20), PEG 40 castor oil (polyoxyl 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 (Polyvinyl pyrrolidone, Crosspovidone), Sodium dodecyl sulfate (Na lauryl sulfate), Aluminum monostearate, Sorbitol, and Triton X-100 (Octoxynol-9).

[0142] The surfactant used in the present disclosure can comprise a non-ionic surfactant. A non-ionic surfactant has no charged groups in its head. Exemplary nonionic surfactants include, without limitation, fatty alcohols, cetyl alcohol, stearyl alcohol, cetostearyl 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 ethers (such as Triton X-100), polyethylene glycol alkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such as glyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such as polysorbate), sorbitan alkyl esters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers), and polyethoxylated tallow amine (POEA). In some embodiments, the surfactant is a non-ionic surfactant that comprises polyethylene glycol. In some embodiments, the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol.

[0143] In some embodiments, the non-ionic surfactant has a number average molecular weight of from about from about 1000 to about 100,000 Da, 2000 to about 20,000 Da, from about 4000 to about 15,000 Da, from about 6000 to about 12,000 Da, or from about 7000 to about 10,000 Da. In some embodiments, the non-ionic surfactant has a number average molecular weight of from about 7000 to about 10,000 Da. In some embodiments, the non-ionic surfactant has an ethylene glycol content of from about 30 wt% to about 99 wt%, from about 50 wt% to about 95 wt%, from about 60 wt% to about 95 wt%, from about 75 wt% to about 90 wt%, or from about 80 wt% to about 85 wt%. In some embodiments, the non-ionic surfactant has an ethylene glycol content of from about 80 wt% to about 85 wt%.

[0144] The surfactant used in the present disclosure can comprise a cationic surfactant. Cationic surfactants include pH-dependent primary, secondary, or tertiary amines such as octenidine dihydrochloride; and permanently charged quaternary ammonium salts such as cetrimonium bromide WSGR Docket No.59541-743.602 (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide (DODAB).

[0145] The surfactant used in the present disclosure can comprise an anionic surfactant. Anionic surfactants contain anionic functional groups at their head, such as sulfate, sulfonate, phosphate, and carboxylates. Exemplary anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS), and the related alkyl-ether sulfates sodium laureth sulfate (sodium lauryl ether sulfate or SLES), sodium myreth sulfate, docusate (dioctyl sodium sulfosuccinate), perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, alkyl-aryl ether phosphates, and alkyl ether phosphates.

[0146] The surfactant used in the present disclosure can be a zwitterionic surfactant. Zwitterionic (amphoteric) surfactants refer to those having cationic and anionic centers attached to the same molecule. Exemplary zwitterionic surfactants include, without limitation, phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.

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

[0148] In some embodiments, the radiopharmaceutical composition described herein comprises a tonicity adjusting agent. Exemplary tonicity adjusting agents include dextrose, glycerin, mannitol, potassium chloride and sodium chloride.

[0149] In some embodiments, the radiopharmaceutical composition described herein comprises a special additive. In some embodiments, the special additive comprises Acetyl tryptophan, Aluminum hydroxide, Aluminum phosphate, Aluminum potassium sulfate, Amino acids (leucine, isoleucine, lysine (as acetate or HCl salt), valine, phenylalanine, threonine, tryptophan, alanine, aspartic acid, glutamic WSGR Docket No.59541-743.602 acid, proline, serine, tyrosine, taurine), İ-Aminocaproic acid, Calcium D-saccharate, Caprylate sodium, 8-Chlorotheophylline, Creatine, Creatinine, Cholesterol, Cholesteryl sulfate sodium, Cyclohexanedione dioxime, Diethanolamine, Distearyl phosphatidylcholine, Distearyl phosphatidylglycerol, L-alpha- dimyristoylphosphatidylcholine, L-alpha-dimyristoylphosphatidylglycerol, Dioleoylphosphatidylcholine (DOPC), Dipalmitoylphosphatidylglycerol (DPPG), (R)-hexadecanoic acid, 1-[(phosphonoxy)methyl]- 1,2-ethanediyl ester, monosodium salt (DPPA), (R)-4-hydroxy-N,N,N-trimethyl-10-oxo-7- [(1oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphapentacosan-1-aminium, 4-oxide, inner salt (DPPC), (R)-[6- hydroxy-6-oxido-9-[(1-oxohexadecyl)oxy]-5,7,11-trioxa-2aza-6-phosphahexacos-1-yl]-^- methoxypoly(ox-1,2-ethanediyl), monosodium salt (MPEG5000 DPPE), MPEG-distearoyl phosphoethanolamine, Ethyl lactate, Ethylenediamine, L-Glutamate sodium, Hyaluronate sodium, Hydrogenated soy phosphatidylcholine, Iron ammonium citrate, Lactic acid, D,L-lactic and glycolic acid copolymer, Meglumine, Methyl boronic acid, Niacinamide, Paraben methyl, Phosphatidylglycerol, egg (EPG), Potassium sodium tartrate, Protamine (as sulfate), Simethicone, Saccharin sodium, Sodium D- gluconate, Sodium hypochlorite, Sodium sulfate, Stannous chloride, Sulfosalicylate disodium, Tin chloride (stannous and stannic), Tri-n-butyl phosphate, Tricaprylin, Triolein, von Willebrand factor, Zinc, Zinc acetate, Zinc carbonate, Zinc oxide, or a combination thereof.

[0150] In some embodiments, the radiopharmaceutical composition described herein comprises a suspending agent. Non-limiting examples of suspending agents include Carboxy methyl cellulose (CMC), Croscarmellose sodium, sodium CMC, xanthan gum, hydroxyl ethyl cellulose (HEC), hydroxyl propyl methyl cellulose (HPMC), and Avicel CL-611. Further exemplary suspending agents include carboxymethylcellulose (sodium and other salts), carboxy-vinyl copolymers, carboxymethyl hydroxyethylcellulose, cellulose, such as microcrystalline cellulose, combinations of microcrystalline cellulose with sodium carboxymethylcellulose (such as Avicel RC-501, RC-581, RC-591, and CL-611), hydrophobically modified hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl guar, hydroxypropyl methylcellulose (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 alcohols, partially neutralized polyacrylic acid, polyalkylene glycol, polysaccharide gums, polyvinylpyrrolidone and derivatives thereof, starch and its derivatives, vinylpyrrolidone homo- and copolymers, water-soluble cellulose ethers, and the mixtures thereof.

[0151] These compositions can be sterilized by conventional sterilization techniques. The resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized. The lyophilized preparation can be combined with a sterile aqueous solution prior to administration. The compositions can contain pharmaceutically acceptable auxiliary substances as appropriate to approximate physiological conditions, such as tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, sorbitan monolaurate, triethanolamine oleate, etc. Pharmaceutical compositions can be selected according to their physical characteristic, including, but not limited to fluid volumes, viscosities and other parameters in accordance with the particular mode of administration selected. WSGR Docket No.59541-743.602 Conjugate

[0152] In one aspect, provided herein is a radiopharmaceutical composition comprising a conjugate or pharmaceutically acceptable salts or solvates thereof described herein. The radiopharmaceutical composition can further comprise a pharmaceutically acceptable carrier such as an aqueous vehicle. Normal saline can be employed as the pharmaceutically acceptable carrier. Other suitable carriers or aqueous vehicles can include, e.g., water, buffered water, 0.9% isotonic saline, 0.4% saline, 0.3% glycine, and the like, including glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, etc. In some embodiments, the aqueous vehicle is water for injection. In some embodiments, the aqueous vehicle is 0.9% w / w sodium chloride saline solution. In some embodiments, the conjugate is225Ac-DOTA-TATE,225Ac-DOTA-TOC,225Ac-HA-DOTA-TATE, or225Ac-DOTA-JR-11.

[0153] The amount of conjugates administered can depend upon the particular targeting moiety used, the disease state being treated, the therapeutic agent being delivered, and the judgment of the clinician.

[0154] The concentration of the conjugates or pharmaceutically acceptable salts or solvates thereof described herein in the pharmaceutical formulations can vary. In some embodiments, the conjugate is present in the pharmaceutical composition from 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 conjugate is present in the pharmaceutical composition from about 0.05% to about 1% by weight. In some embodiments, the conjugate is present in the pharmaceutical composition from about 0.1% to about 5% by weight.

[0155] In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 0.5 to about 1000 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a 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 WSGR Docket No.59541-743.602 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 that provides a radioactivity of at most about 5, 10, 15, 50, 75, 100, 200, or 500 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most about 500, 600, 700, 800, 900, or 1000 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most about 15 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1 to 15 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most about 35 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1 to 35 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides 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 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most 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.

[0156] In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 0.5 to about 1000 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a 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 WSGR Docket No.59541-743.602 pharmaceutical composition in an amount that provides a radioactivity of at most about 5, 10, 15, 50, 75, 100, 200, or 500 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most about 500, 600, 700, 800, 900, or 1000 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most about 15 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1 to 15 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of at most about 35 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1 to 35 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides 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] A composition described herein can comprise a conjugate, or a pharmaceutically acceptable salt or solvate thereof, that comprises actinium-225. In some embodiments, actinium-225 is present in a herein- described radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.005 to 1000 MBq / mL. In some embodiments, the actinium-225 is present in a herein-described radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.5 to 20 MBq / mL. In some embodiments, the actinium-225 is present in a herein-described radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.4 to 20 MBq / mL. In some embodiments, the actinium- 225 is present in a herein-described radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.2 to 5 MBq / mL. In some embodiments, the actinium-225 is present in a herein- described radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.4 to 1 MBq / mL. In some embodiments, actinium-225 is present in a herein-described radiopharmaceutical composition that it provides a volumetric radioactivity of about 0.1 to 100 MBq / mL. In some embodiments, actinium-225 is present in a herein-described radiopharmaceutical composition that it provides 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 a herein-described radiopharmaceutical composition that it provides 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 a herein-described radiopharmaceutical composition that it provides 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 a herein-described radiopharmaceutical composition that it provides a volumetric radioactivity of at most 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, a composition described herein has a total DOTA-TATE peptide concentration of ^11.5 μg / mL (including e.g., unlabeled DOTATATE,225Ac-DOTATATE, and metal- DOTATATE species). In some embodiments, a composition described herein has a total DOTA-TATE WSGR Docket No.59541-743.602 peptide concentration of at most about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 50 μg / mL. In some embodiments, a composition described herein has 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 composition described herein can comprise a conjugate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. The conjugate as described can be substantially pure, in that 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 organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. The conjugate can be225Ac-DOTA-TATE,225Ac-DOTA-TOC, or225Ac-DOTA-JR-11. The conjugate can be225Ac-DOTA-TATE. The conjugate can be225Ac-DOTA-TOC. The conjugate can be225Ac-DOTA-JR- 11. In some embodiments, the conjugate is225Ac-high-affinity DOTATATE (or225Ac-HA-DOTATATE). In some embodiments, HA-DOTATATE is illustrated by the following structure .

[0002] WSGR Docket No.59541-743.602

[0159] 225Ac-DOTA-TATE can be illustrated as having the following structure: (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-hydroxybenzyl)-7-((R)-1-hydroxyethyl)- 6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19-yl)amino)-1-oxo-3- phenylpropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate;actinium- 225(3+)).225Ac-DOTA-TATE can also be referred as Actinium (225Ac) oxodotreotide.

[0160] In some embodiments, provided herein is a pharmaceutical composition comprising a conjugate that is , and one or more stabilizing agents.

[0003] WSGR Docket No.59541-743.602

[0161] In some embodiments, provided herein is a pharmaceutical composition comprising a conjugate that has a structure more stabilizing agents. In some embodiments, provided herein is a pharmaceutical composition comprising a conjugate that has a structure of one or more stabilizing agents. It is understood that the chelation between225Ac and the metal chelator is not shown in the above two structures. In some embodiments, for example in acidic aqueous conditions, the radionuclide actinium-225 exists in a salt form, e.g., as225Ac3+. In some embodiments, the conjugate is in a salt form. In some embodiments, the conjugate is an acetate salt. In some embodiments, provided herein is a pharmaceutical composition comprising conjugate that one or more stabilizing agents. WSGR Docket No.59541-743.602 In some embodiments, provided herein is a pharmaceutical composition comprising a conjugate that is agents. It is understood that the chelation between225Ac and the metal chelator is not shown in the above two structures. In some embodiments, for example in acidic aqueous conditions, the radionuclide actinium- 225 exists in a salt form, e.g., as225Ac3+. In some embodiments, the conjugate is in a salt form. In some embodiments, the conjugate is an acetate salt. A person of ordinary skill would appreciate that the dissociation of an acid can depend on the pH value of the environment and its pK value. Accordingly, in some embodiments, a conjugate described herein can exist in a completely ionized, partially ionized or non-ionized form. Targeting ligand

[0162] In one aspect, provided herein is a radiopharmaceutical composition comprising a conjugate or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the conjugate described herein comprises a targeting ligand and a metal chelator.

[0163] The targeting ligand described herein can bind to one or more target within a subject’s system or an in vitro system. The targeting ligand can target a protein, a receptor on a cell, or other chemical moiety that can perform signaling functions within the subject’s system. The targeting ligand can bind to a receptor on the surface of a cell within the subject’s system. In some embodiments, the targeting ligand binds to a somatostatin receptor (SSR). An SSR can be a mammalian SSR. A mammalian SSR can be a human SSR. A human SSR can comprise 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). An SSR can be a human somatostatin receptor type 2 (SSTR2). In some embodiments, the targeting ligand binds to a human somatostatin receptor type 2 (SSTR2). The targeting ligand can comprise a peptide and / or a small molecule compound. The targeting ligand can comprise an agonist of the SSR. The targeting ligand can comprise an antagonist of the SSR. The agonist of the SSR can comprise a partial agonist of the SSR. The agonist of the SSR can comprise a full agonist of the SSR. The agonist of the SSR can comprise an inverse agonist of the SSR. The antagonist of the SSR can comprise a competitive antagonist of the SSR. The targeting ligand can comprise an allosteric modulator of the SSR. The allosteric modulator of the SSR can be an allosteric agonist of SSR. The allosteric modulator of the SSR can be an allosteric antagonist of SSR. WSGR Docket No.59541-743.602

[0164] The targeting ligand described herein can comprise one or more peptides, which can be the same or different. The peptide can be linear or cyclic. The peptide can be monocyclic. The peptide can comprise a binding peptide. The binding peptide can bind to one or more target within a subject’s system or an in vitro system. The binding peptide can bind to a somatostatin receptor (SSR). The binding peptide can bind to a 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). The binding peptide can bind to a somatostatin receptor type 2 (SSTR2). The binding peptide can bind to a human somatostatin receptor type 2 (SSTR2).

[0165] The peptide can comprise any suitable number of amino acid residues. The peptide can comprise from 4 to 50, 5 to 40, 6 to 30, 7 to 20, or 8 to 10 amino acid residues. The peptide can comprise from 6 to 14 amino acid residues. The peptide can comprise from 6 to 10 amino acid residues. The peptide can comprise from 7 to 9 amino acid residues. The peptide can comprise 8 to 9 amino acid residues. The peptide can comprise 14 amino acid residues. The peptide can comprise 13 amino acid residues. The peptide can comprise 12 amino acid residues. The peptide can comprise 11 amino acid residues. The peptide can comprise 10 amino acid residues. The peptide can comprise 9 amino acid residues. The peptide can comprise 8 amino acid residues. The peptide can comprise 7 amino acid residues. The peptide can comprise 6 amino acid residues. The peptide can consist of 10 amino acid residues. The peptide can consist of 14 amino acid residues. The peptide can consist of 13 amino acid residues. The peptide can consist of 12 amino acid residues. The peptide can consist of 11 amino acid residues. The peptide can consist of 10 amino acid residues. The peptide can consist of 9 amino acid residues. The peptide can consist of 8 amino acid residues. The peptide can consist of 7 amino acid residues. The peptide can consist of 6 amino acid residues. The conjugate can comprise a monocyclic peptide of 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] A targeting ligand described herein can be a cyclized peptide. Cyclization can be achieved via a single disulfide bond or via a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, C—S—C bond, C—N—C bond, CőN—C bond, CőN—O bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, thioamide bond, or the like, but not limited to them. The peptide can comprise a cyclic peptide that is cyclized by a peptide bond. A cyclization of a peptide can stabilize the peptide structure and thereby enhance affinity for a target. The cyclization can occur between the N- and C-terminus, or it can occur between a terminal amino acid and a non-terminal amino acid. The cyclization can occur between two non- terminal amino acids. The peptide can be cyclized via one or more cysteines. The peptide can comprise a cysteine at the C-terminus. The peptide can comprise a cysteine at the N-terminus. The cyclization can occur via a disulfide bond between cysteines or between cysteine and another thiol group-bearing residue.

[0167] Exemplary targeting ligands include BMS-753493, Somatostatins or somatotropin release inhibiting 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 WSGR Docket No.59541-743.602 FAP-2286. The targeting ligand can comprise octreotate, octreotide, D-Phe1-cyclo(Cys2-Tyr3-D-Trp4- Lys5-Thr6-Cys7)Thr8 (tyr3-octreotate or TATE), D-Phe1-cyclo(Cys2-Tyr3-D-Trp4-Lys5-Thr6- Cys7)Thr(ol)8 (Phe1-Tyr3octreotide, edotreotide, or TOC), D-Phe1-cyclo(Cys2-Phe3-D-Trp4-Lys5-Thr6- Cys7)Thr(ol)8 (OC), D-Phe1-cyclo(Cys2-1-Nal-D-Trp4-Lys5-Thr6-Cys7)Thr(ol)8 (NOC), p-Cl-Phe- cyclo(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2) (JR11), or p-Cl-Phe-cyclo(D-Cys-Tyr- D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH2 (LM3). The targeting ligand can be tyr3-octreotate, edotreotide, octreotate, or octreotide. The targeting ligand can be tyr3-octreotate. In some embodiments, the targeting ligand is 3-iodo-Tyr3-octreotate. 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 Pasireotide. 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 satoreotide. In some embodiments, the targeting ligand is depreotide.

[0168] In some embodiments, a conjugate described herein comprises a targeting ligand that has a structure of (JR-11 or

[0004] WSGR Docket No.59541-743.602 Satoreotide). In some embodiments, a conjugate described herein comprises a targeting ligand that has a structure (Lanreotide).

[0169] The targeting ligands can comprise small molecule compounds. Such small molecule compounds can comprise 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 to a human SSR that is not more than about 1mM, by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 1000nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 500nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 250nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 200nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 150nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 100nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 75nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 50nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 25nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 10nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 5nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can have a binding affinity to a human SSR that is not more than about 2nM, as measured by half maximal inhibitory concentration (IC50). The targeting ligand can comprise a monocyclic peptide or peptide mimics or derivatives thereof. Radionuclide

[0171] In one aspect, described herein are conjugates that comprise a radionuclide. Exemplary radionuclides include, but are not limited to, astatine-211, astatine-217, actinium-225, americium-243, WSGR Docket No.59541-743.602 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, technetium-99m, 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] Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety, etc. Radionuclides that undergo Į-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo ȕ-decay emit energetic electrons from their nuclei. Some radionuclides can also emit Auger. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double- strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Table 4 below illustrates some properties of exemplary radionuclides. Table 4. Exemplary radionuclides Radionuclide Emission / Decay Exemplary Exemplary methods of binding the application-- radionuclide to a Therapeutics (Tx) radiopharmaceutical conjugate or Diagnostics (Dx) (e.g., through a Chelator or bound to the conjugate through a Covalent bond) Ac-225 Alpha Tx Chelator As-70 Positron Dx Covalent As-71 Positron Dx Covalent As-72 Positron Dx Covalent As-73 Electron Capture Dx Covalent As-74 Positron Dx Covalent As-76 Beta Tx Covalent As-77 Beta Tx Covalent At-211 Alpha Tx Covalent Bi-209 Alpha Tx Chelator Bi-212 Alpha Tx Chelator Bi-213 Alpha Tx Chelator Br-76 Positron Dx Covalent Ce-134 Electron Capture Dx Chelator Cu-61 Positron Dx Chelator Cu-62 Positron Dx Chelator Cu-64 Positron Dx Chelator WSGR Docket No.59541-743.602 Radionuclide Emission / Decay Exemplary Exemplary methods of binding the application-- radionuclide to a Therapeutics (Tx) radiopharmaceutical conjugate or Diagnostics (Dx) (e.g., through a Chelator or bound to the conjugate through a Covalent bond) Cu-67 Beta Tx Chelator Fr-223 Alpha Tx Chelator Ga-68 Positron Dx Chelator Gd-148 Alpha Tx Chelator Ho-166 Beta / gamma Tx / Dx Chelator I-123 Electron Capture Dx Covalent I-124 Positron Dx Covalent I-125 Electron Capture Dx Covalent I-131 Beta Tx Covalent In-111 Beta / Electron Tx / Dx Chelator Capture Lu-177 Beta Tx Chelator Pb-212 Alpha Tx Chelator Pm-153 Beta Tx Chelator Po-213 Alpha Tx Chelator Ra-223 Alpha Tx Chelator Ra-224 Alpha Tx Chelator Rh-105 Beta Tx Chelator Sm-153 Beta Tx Chelator Tb-149 Alpha Tx Chelator Tb-152 Positron Dx Chelator Tb-161 Beta Tx / Dx Chelator Tc-99m Gamma / Isomeric Dx Chelator Transition Th-227 Alpha Tx Chelator Th-229 Alpha Tx Chelator Tm-167 Beta / Electron Tx Chelator Capture Y-90 Beta Tx Chelator Yb-175 Beta Tx Chelator Zr-89 Positron Dx Chelator

[0173] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from Table 4.

[0174] In some embodiments, the radiopharmaceutical conjugate described herein comprises one or WSGR Docket No.59541-743.602 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 the metal chelator of the radiopharmaceutical conjugate. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelator. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0175] In some embodiments, the radiopharmaceutical conjugate described herein comprises an alpha particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises an alpha-particle emitting radionuclide bound to the metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 (225Ac), radium-223 (223Ra), radium-224 (224Ra), bismuth- 209 (209Bi), bismuth-213 (213Bi), gadolinium-148 (148Gd), terbium-149 (149Tb), polonium-213 (213Po), francium-223 (223Fr), thorium-227 (227Th), thorium-229 (229Th), or lead-212 (212Pb). In some embodiments, the alpha particle-emitting radionuclide is selected from225Ac,223Ra,209Bi,213Bi,148Gd,149Tb,213Po,223Fr,227Th,229Th, and212Pb. In some embodiments, the alpha particle-emitting radionuclide is225Ac. In some embodiments, the alpha particle-emitting radionuclide is213Bi. In some embodiments, the alpha particle-emitting radionuclide is212Bi. In some embodiments, the alpha particle-emitting radionuclide is212Pb. In some embodiments, the alpha particle-emitting radionuclide is224Ra. In some embodiments, the alpha particle-emitting radionuclide is223Ra. In some embodiments, the alpha particle- emitting radionuclide is227Th. In some embodiments, the alpha particle-emitting radionuclide is149Tb. In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,209Tl,209Pb, or209Bi. In some embodiments, the conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is177Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)177Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non- carrier-added or n.c.a.)225Ac. In some embodiments, the radionuclide is177Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the conjugate comprises two177Lu radionuclides. In some embodiments, the radionuclide is a non-carrier-added radionuclide.

[0176] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from62Cu,64Cu,67Cu,90Y,109Pd,111Ag,134Ce,149Pm,153Sm,166Ho,99mTc,67Ga,68Ga,111In,90Y,177Lu,186Re,188Re,197Au,198Au,199Au,105Rh,165Ho,161Tb,149Pm,153Pm,44Sc,47Sc,213Po,212Pb,209Bi,212Bi,213Bi,225Ac,117mSn,67Ga,149Tb,152Tb,167Tm,175Yb,223Ra,223Fr,227Th,229Th,201Tl,148Gd,160Gd,148Nd,89Sr, and89Zr. In some embodiments, the radionuclide is selected from62Cu,64Cu,67Cu,68Ga,89Zr,90Y,99mTc,105Rh,111In,134Ce,148Gd,149Tb,152Tb,153Pm,167Tm,175Yb,177Lu,209Bi,212Pb,213Po,213Bi,223Ra,223Fr,227Th,225Ac, and229Th. In some embodiments, the radionuclide is225Ac. In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,209Tl,209Pb, or209Bi. In some embodiments, the radiopharmaceutical conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is177Lu. In some embodiments, the radiopharmaceutical conjugate comprises two177Lu radionuclides.

[0177] In some embodiments, the radiopharmaceutical conjugate described herein comprises a beta WSGR Docket No.59541-743.602 particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a beta particle-emitting radionuclide bound to the metal chelator. In some embodiments, the beta particle- emitting radionuclide is copper-67, rhodium-105, ytterbium-175, thulium-167, promethium-153, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is copper-67, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is lutetium-177.

[0178] In some embodiments, the radiopharmaceutical conjugate described herein comprises a gamma particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a gamma particle-emitting radionuclide bound to the metal chelator. In some embodiments, the gamma particle-emitting radionuclide is indium-111 or tin-117m.

[0179] In some embodiments, the radiopharmaceutical conjugate described herein comprises a positron particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron particle-emitting radionuclide bound to the metal chelator. 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, a conjugate described herein comprises a radionuclide suitable for imaging or diagnostic purposes. In some embodiments, the radionuclide suitable for imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb,68Ga,111In, and99mTc. In some embodiments, the radionuclide is suitable PET imaging. In some embodiments, the radionuclide suitable for PET imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb, and68Ga. In some embodiments, the radionuclide is suitable for SPECT imaging. In some embodiments, the radionuclide suitable for SPECT imaging is selected from111In and99mTc.

[0181] In some embodiments, the alpha particle-emitting radionuclide is225Ac. In some embodiments, the alpha particle-emitting radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)225Ac. In some embodiments, the225Ac is free of long-lived radioactive contaminants and byproducts. In some embodiments, the alpha particle-emitting radionuclide is carrier added225Ac. In some embodiments,225Ac is generated from a heavier radionuclide. In some embodiments,225Ac is generated using a Thorium-229 generator. In some embodiments,225Ac is generated via 229Th decay to225Ra from which225Ra and225Ac are then separated via ionic exchange resins. In some embodiments,229Th is generated by legacy233U stock provided by government sources. In some embodiments,225Ac is generated using Electron Linear Accelerators (LINAC) with radium-226 as a target source. In some embodiments,225Ac is be generated by the226Ra(Ȗ, n)225Ra reaction using an electron linear accelerator, and subsequent separation and purification of225Ra and225Ac using a series of ionic exchange resins. In some embodiments,225Ac is generated using a cyclical proton accelerator using radium-226 as a target source. In some embodiments,225Ac is generated by the226Ra(p, 2n)225Ac reaction using a low energy cyclical proton accelerator (aka cyclotron). In some embodiments,225Ac is generated by the226Ra(p, 2n)225Ac reaction using a low energy cyclical proton accelerator (aka cyclotron) having an energy range between 10-20MeV. In some embodiments,225Ac is WSGR Docket No.59541-743.602 generated using electron beam accelerators (rhodotron) using radium-226 as a target source. In some embodiments,225Ac is generated by the226Ra(Ȗ, n)225Ra reaction using an electron beam accelerator, and subsequent separation and purification of225Ra and225Ac using a series of ionic exchange resins. In some embodiments,225Ac is generated using high energy proton spallation using thorium-232 as a target source. In some embodiments,225Ac is generated using by the232Th(p, nxp)225Ac reaction using a 70-100 MeV+ high energy proton accelerator.

[0182] In some embodiments, conjugates described herein do not contain any radionuclide, i.e., a cold conjugate. For example, in some cases, a radionuclide can be replaced with a surrogate (e.g.,225Ac replaced with lanthanum) for testing and experimental purposes. Metal Chelator

[0183] In one aspect, described herein are conjugates that comprise a metal chelator that is configured to bind with a radionuclide. The metal chelator can refer to a moiety of the conjugate that is configured to bind with a radionuclide. In some embodiments, a conjugate described herein comprises two or more independent metal chelators, e.g., 2, 3, 4, 5, or more metal chelators. In some embodiments, a conjugate described herein comprises two metal chelators, which can be the same or different. The metal chelator can be attached to the linker or the targeting ligand through any suitable group / atom of the chelator.

[0184] In some embodiments, the metal chelator is capable of binding a radioactive atom. The binding can be direct, e.g., the metal chelator can make hydrogen bonds or electrostatic interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, or is, DOTA or NOTA. In some embodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle comprising an O and / or an N atom, DOTA, NOTA, 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 chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more N atoms, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise an S atom. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an O and / or an N atom. In some embodiments, the metal chelator is a ring that includes 3 or more N atoms, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is poly polydentate.

[0186] In some embodiments, a metal chelator described herein comprises a cyclic chelating agent. Exemplary cyclic chelating agents include, but are not limited to, 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-AƎ- EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-AƎ-DTPA, p-NH2-Bn-CHX-AƎ-DTPA, p-SCN- DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn- WSGR Docket No.59541-743.602 CHX-AƎ-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, H5decapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa2, H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis- thioseminarabazones, 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, motexafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn- TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, 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, Lpy, L1, L2, L3, and EuK-106.

[0187] In some embodiments, the metal chelator is DO3A. In some embodiments, the metal chelator is PEPA. In some embodiments, the metal chelator is EDTA. In some embodiments, the metal chelator is CHX-AƎ-DTPA. In some embodiments, the metal chelator is HEHA. In some embodiments, the metal chelator is DOTMP. In some embodiments, the metal chelator is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelator is macropa. In some embodiments, the metal chelator is macropa- NCS. In some embodiments, the metal chelator is H4py4pa. In some embodiments, the metal chelator is H4octapa. In some embodiments, the metal chelator is H4CHXoctapa. In some embodiments, the metal chelator is DOTP. In some embodiments, the metal chelator is crown.

[0188] In some embodiments, the metal chelator is DOTA. In some embodiments, the metal chelator is a chiral derivative of DOTA. In some embodiments, the metal chelator is DOTA-GA. Exemplary chiral DOTA chelators are described in Dai et al., Nature Communications (2018) 9:857. In some embodiments, the metal chelator 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 chelator has a structure of . In some embodiments, the metal chelator 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 WSGR Docket No.59541-743.602 embodiments, the metal chelator has a structure some embodiments of a conjugate described herein, the metal chelator has a structure , wherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain. In some embodiments, the metal chelator has a wherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain.^

[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 independent metal chelators, and at least one or both are DOTA. The structures of some exemplary metal chelators are illustrated in FIG. 3 (without showing the attachment points). 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., Bioconjugate Chem. 2019, 30, 5, 1539–1553; and Baranyai et al., Eur. J. Inorg. Chem.36–56 (2020), each of which is incorporated by reference in its entirety. Linker

[0190] A chemical scaffold, covalently joining pharmacophore and metal-chelator in a targeted radiopharmaceutical, can be referred to as a linker. Incorporating a well-designed inker to a drug molecule can further boost affinity towards its biological target, accelerate internalization into the targeted tissues, WSGR Docket No.59541-743.602 and optimize the pharmacokinetic properties. Diverse chemical moieties can be used to construct the linkers. By changing their physio-chemical characters, the desired in vivo characters (i.e. absorption, distribution, metabolism, and excretion of the drug molecules) can be achieved. In some embodiments, physio-chemical characters of the conjugates can be adjusted by the linkers, for example, when it is difficult to change pharmacophore and metal-chelating portions without sacrificing the biological affinity or metal-binding ability. A conjugate described herein can comprise one or more linkers. The targeting ligand can be covalently linked to the metal chelator through a linker. The linker can covalently attach the targeting ligand with the metal chelator. The targeting ligand can also attach directly to the metal chelator without a linker.

[0191] A linker can comprise one or more amino acid residues. The linker can comprise 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. The linker can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. The linker can comprise 1 to 5 amino acid residues. For example, the linker can comprise one or more lysine (K) residues such as K, KK, or KKK sequences. The linker can comprise a lysine or a derivative thereof. The linker can comprise a lysine. The linker can comprise one or more amino acids that are unnatural amino acids.

[0192] The linker can have a prescribed length thereby linking the metal chelator (and optionally radionuclide) and the peptide while allowing an appropriate distance therebetween. In some embodiments, the linker has 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length. Isomers / Stereoisomers

[0193] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers WSGR Docket No.59541-743.602

[0194] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0195] In some instances, the compounds disclosed herein exist in tautomeric forms. The structures of said compounds are illustrated in the one tautomeric form for clarity. The alternative tautomeric forms are expressly included in this disclosure. Labeled compounds.

[0196] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are notable WSGR Docket No.59541-743.602 for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof 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 labels, or chemiluminescent labels. Pharmaceutically acceptable salts.

[0198] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the compounds disclosed herein include their pharmaceutically acceptable salts. As used herein, a “pharmaceutically acceptable salt” refers to any salt of a stabilizing agent that is useful for stabilizing the radiopharmaceutical compositions. As used herein, a “pharmaceutically acceptable salt” refers to any salt of a stabilizing agent that is useful for preventing or delaying the decomposition of the radiopharmaceutical within the compositions.

[0199] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0200] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, Ȗ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.

[0201] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as WSGR Docket No.59541-743.602 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-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0202] In some embodiments, the compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4alkyl)4, and the like.

[0203] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates.

[0204] In some embodiments, the compounds described herein exist as solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Accordingly, one aspect of the present disclosure pertains to hydrates and solvates of compounds of the present disclosure and / or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like. Preparation of the Compositions

[0205] The disclosure provides methods of preparing and making the compositions described herein. In some embodiments, the method of making the radiopharmaceutical composition comprises combining a radionuclide (such as225Ac) with an un-labeled conjugate (e.g., DOTATATE or DOTATOC) in the presence of one or more stabilizer agents, wherein the un-labeled conjugate comprises a targeting ligand WSGR Docket No.59541-743.602 and a metal chelator covalently attached to the targeting ligand, thereby producing a mixture comprising a labeled conjugate (e.g.,225Ac-DOTATATE or225Ac-DOTATOC), and optionally combining one or more stabilizing agents to the mixture. In some embodiments, the method of making the radiopharmaceutical composition comprises combining a radionuclide with an un-labeled conjugate, wherein the un-labeled conjugate comprises a targeting ligand and a metal chelator covalently attached to the targeting ligand, thereby producing a labeled conjugate, and combining the one or more stabilizing agents with the labeled conjugate.

[0206] In some embodiments, the method of making the radiopharmaceutical composition comprises combining a radionuclide with an un-labeled conjugate, which comprises a targeting ligand and a metal chelator covalently attached to the targeting ligand, thereby producing a labeled conjugate, and adding the one or more stabilizing agents to the labeled conjugate. In some embodiments, the method of making the radiopharmaceutical composition comprises combining a radionuclide with an un-labeled conjugate which comprises a targeting ligand and a metal chelator covalently attached to the targeting ligand, in the presence of one or more stabilizer agents, thereby producing a labeled conjugate, and optionally adding one or more stabilizing agents to the labeled conjugate.

[0207] The method of making the compositions can comprise one or multiple steps. One or more such steps can comprise diluting a radionuclide-containing solution or mixture to a desired concentration (i.e., a dilution step). The radionuclide-containing solution or mixture can be diluted by 2 to 1000 fold, e.g., 10- 50 fold, 2-40 fold, 25-75 fold, or 50-100 fold. One or more such steps can comprise adding one or more stabilizing agents during the process of dilution. One or more such steps can comprise optionally adding one or more stabilizing agents during the process of dilution. One or more such steps can comprise diluting an un-labeled conjugate solution or mixture to a desired concentration. One or more such steps can comprise adding one or more stabilizing agents before the process of dilution. One or more such steps can comprise adding one or more stabilizing agents after the process of dilution. The un-labeled conjugate can comprise a targeting ligand and a metal chelator. The targeting ligand and the metal chelator can be linked covalently. One or more such steps can comprise dilution using a liquid solution or mixture.

[0208] A method of making a radiopharmaceutical composition can comprise reacting or combining a radionuclide with an un-labeled conjugate solution or mixture to obtain a labeled conjugate solution or mixture (i.e., a labeling process). In some embodiments, the method comprises maintaining a temperature during the labeling process. In some embodiments, the method comprises maintaining a temperature ranging from 0°C to 100°C, from 10°C to 100°C, from 20°C to 100°C, from 30°C to 100°C, from 40°C to 100°C, from 50°C to 100°C, from 60°C to 100°C, from 70°C to 100°C, or from 80°C to 100°C. In some embodiments, the method comprises reacting the radionuclide with the un-labeled conjugate for a period of time. In some embodiments, the period of time is from about 1 minute to about 3 hours, from about 2 minutes to about 2.5 hours, from about 3 minutes to about 2 hours, from about 5 minutes to about 1.5 hours, from about 8 minutes to about 1 hours, or from about 10 minutes to about 30 minutes. In some embodiments, the method comprises mixing the radionuclide with the un-labeled conjugate during the labeling process. One or more such steps can comprise mixing using laboratory mixing equipment such as WSGR Docket No.59541-743.602 a mixer, a vortex mixer, a stirrer, a magnetic stirrer, a spinner, a shaker, a centrifuge, or a homogenizer. One or more such steps can comprise shaking the reaction solution or mixture. One or more such steps can comprise shaking the reaction solution or mixture at a speed ranging from about 10 rpm to about 5000 rpm, from about 100 rpm to about 2500 rpm, from about 200 rpm to about 1000 rpm, from about 300 rpm to about 800 rpm, or from about 400 rpm to about 600 rpm. One or more such steps can comprise further diluting the labeled conjugate solution or mixture. One or more such steps can comprise adding one or more stabilizing agents during the process of dilution. One or more such steps can comprise optionally adding one or more stabilizing agents after the process of dilution.

[0209] In some embodiments, a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE (or225Ac-DOTA-TATE) can be prepared by reacting DOTA-TATE with [225Ac]AcCl3from HCl (e.g., 0.04M, aqueous) solution. Accordingly, provide herein are methods of making a radiopharmaceutical composition comprising225Ac-DOTA-TATE. In some embodiments, the method comprises one or more of the following steps: diluting DOTA-TATE with sodium acetate / acetic acid buffer solution, adding [225Ac]AcCl3HCl solution to the diluted DOTA-TATE, mixing the mixture, heating the mixture, and diluting into a formulation buffer with one or more stabilizing agents described herein. In some embodiments, the concentration of [225Ac]AcCl3in the HCl solution is about 10 μCi / μl HCl. In some embodiments, the concentration of [225Ac]AcCl3in the HCl solution is about 1 to 50 μCi / μl HCl. A radiopharmaceutical composition comprising225Ac-HA-DOTA-TATE or225Ac-DOTA-JR-11 can be prepared accordingly.

[0210] In some embodiments, a method of making a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE or [225Ac]Ac-DOTA-TOC comprises one or more of the following steps: providing [225Ac]AcCl3solution in a first vial, transferring such solution into a reactor, providing a reaction buffer solution into the first vial containing [225Ac]AcCl3solution, transferring the reaction buffer solution and residual [225Ac]AcCl3solution from the first vial to the rector, transferring a DOTA-TATE or a DOTA- TOC solution into the reactor, reacting the DOTA-TATE or DOTA-TOC solution with [225Ac]AcCl3solution in the reactor to obtain [225Ac]Ac-DOTA-TATE or [225Ac]Ac-DOTA-TOC, and diluting the [225Ac]Ac-DOTA-TATE or [225Ac]Ac-DOTA-TOC in a formulation buffer comprising one or more stabilizing agents described herein to form the radiopharmaceutical composition. In some embodiments, the molar ratio of225Ac to DOTA-TATE or DOTA-TOC is from 1:1 to 1:10, from 1:1 to 1:8, from 1:1 to 1:5, from 1:1 to 1:3.5, from 1:1 to 1:2, or from 1:1 to 1.25. In some embodiments, the molar ratio of225Ac to DOTA-TATE or DOTA-TOC is about 1:1, 1:2, 1:25, 1:3, 1:3.5 or 1:4. A radiopharmaceutical composition comprising225Ac-HA-DOTA-TATE or225Ac-DOTA-JR-11 can be prepared accordingly.

[0211] The compounds used in the reactions and compositions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including ABX advanced biochemical compounds GmbH (Radeberg, Germany), Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avidity Science WSGR Docket No.59541-743.602 (U.S.A.), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), ITM (Munich, Germany), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Sigma-Aldrich (U.S.A.), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), VWR (Radnor, PA, USA), Wako Chemicals USA, Inc. (Richmond, VA), and Wuxi-Apptech Inc. (Shanghai, China). Method of Treatment

[0212] In one aspect, the disclosure provides methods of treating a disease or condition in a subject in need thereof. The methods can comprise administering a radiopharmaceutical composition to the subject in need thereof. The methods can provide a therapeutic and / or prophylactic benefit to a subject in need thereof comprising administering a radiopharmaceutical composition described herein.

[0213] The methods can comprise administering to a subject a radiopharmaceutical composition that comprise a therapeutically effective amount of a 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 an SSR-associated cancer. In some embodiments, the cancer is an SSTR2-associated cancer. In some embodiments, the cancer is a somatostatin receptor-positive (SSTR+) cancer. In some embodiments, the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an inoperable, advanced, somatostatin receptor expressing (SSTR+), well-differentiated gastro- enteropancreatic neuroendocrine tumor (GEP-NET) that has progressed following prior177Lu-SSA therapy (such as177Lu-DOTA-TATE,177Lu-DOTA-TOC, or177Lu-HA-DOTA-TATE). In some embodiments, the SSTR+ neuroendocrine tumor is located in / on the pancreas or in / on the gastrointestinal tract. In some embodiments, the SSTR+ neuroendocrine tumor is located in / on the pancreas. In some embodiments, the SSTR+ neuroendocrine tumor is located in / on the gastrointestinal tract. In some embodiments, the neuroendocrine tumor is located in a gastrointestinal organ. In some embodiments, the gastrointestinal organ is an ileum, a duodenum, or a jejunum. In some embodiments, the gastrointestinal organ is an ileum. In some embodiments, the gastrointestinal organ is a duodenum. In some embodiments, the gastrointestinal organ is a jejunum. In some embodiments, the SSTR+ neuroendocrine tumor is located in a pancreas. In some embodiments, the SSTR+ neuroendocrine tumor is located in an ileum, a duodenum, a jejunum, or a pancreas.

[0214] In some embodiments, the cancer is a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitary cancer, a breast cancer, a lung cancer, a stomach cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine cancer. In some embodiments, the neuroendocrine cancer is recurrent or refractory. In some embodiments, the neuroendocrine cancer is refractory to a radiotherapy that comprises beta-particle emitting radionuclide (such as177Lu-DOTA- WSGR Docket No.59541-743.602 TATE,177Lu-DOTA-TOC, or177Lu-HA-DOTA-TATE therapy). In some embodiments, the subject has received a radiotherapy that comprises beta-particle emitting radionuclide prior to the administering of the radiopharmaceutical composition (such as177Lu-DOTA-TATE,177Lu-DOTA-TOC, or177Lu-HA-DOTA- TATE therapy). In some embodiments, the subject has received a177Lu-SSA therapy. In some embodiments, the subject has received a prior treatment of177Lu-DOTA-TATE. In some embodiments, the subject has received a prior treatment of177Lu-DOTA-TOC therapy. In some embodiments, the subject has received a prior treatment of177Lu-HA-DOTA-TATE. In some embodiments, the neuroendocrine cancer is a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a Carcinoid tumor in the lungs, gastrointestinal tract or thymus, Pancreatic neuroendocrine tumor (e.g., Gastrinoma, Insulinoma, Glucagonoma, VIPoma) Medullary thyroid carcinoma, Merkel cell carcinoma, Pheochromocytoma of the adrenal gland, Adrenal cancer, Small cell carcinoma (such as in the lungs), or Large cell carcinoid tumor (such as in the lungs). In some embodiments, the cancer is a SSTR2+ lung neuroendocrine tumor. In some embodiments, the cancer is somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is somatostatin receptor expressing (SSTR+) extensive stage small cell lung cancer (ES-SCLC). In some embodiments, the SCLC is untreated. In some embodiments, the SCLC is recurrent or refractory. In some embodiments, the subject has received at most 1 cycle of platinum-^etoposide and PD-L1 inhibitor therapy. In some embodiments, the cancer is untreated. In some embodiments, the cancer is recurrent or refractory. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1kBq / kg to about 0.2GBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 5kBq / kg to about 50,000kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 20k Bq / kg to about 5,000kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 50k Bq / 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 50k Bq / 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 the subject at a radioactivity of about 1 μCi to 1,000 μCi. In some embodiments, the radiopharmaceutical composition is administered to the subject at a radioactivity of about 10 μCi to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to the subject at 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 a radioactivity of about 125 μCi, 175 μCi, 225 μCi, or 275 μCi. In some embodiments, the WSGR Docket No.59541-743.602 radiopharmaceutical composition is administered at a 4 to 6-week interval. In some embodiments, the radiopharmaceutical composition is administered at an 4-12-week interval. In some embodiments, the radiopharmaceutical composition is administered at an 8-week interval. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose in the subject of about 10,000 kBq to about 100,000 kBq. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose in the subject of about 40,000 kBq to about 70,000 kBq. In some embodiments, the radiopharmaceutical composition is administered to achieve a cumulative dose in the subject of about 40,800 kBq. In some embodiments, the radiopharmaceutical composition comprises225Ac- DOTA-TOC. In some embodiments, the radiopharmaceutical composition comprises225Ac-DOTA-TATE. In some embodiments, the radiopharmaceutical composition comprises225Ac-DOTA-JR-11. In some embodiments, the radiopharmaceutical composition comprises225Ac-HA-DOTA-TATE.

[0215] In some embodiments, a radiopharmaceutical formulation of Example 9 (Formula B), Example 10, Example 11, Example 13, Example 19, or Example 24 is administered to the subject as part of a first- line therapy. In some embodiments, the formulation is administered to the subject as part of a second-line therapy. In some embodiments, the formulation is administered to the subject as part of a third-line therapy. In some embodiments, a second therapeutic is administered to the subject in addition to the radiopharmaceutical formulation. In some embodiments, the second therapeutic comprises everolimus, sunitinib, streptozocin, temozolamide, capecitabine, or combinations thereof.

[0216] In some embodiments, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE, wherein the225Ac-DOTA-TATE 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 about 50% of the initial dose. In some embodiments, provided herein is a method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-l...

Claims

WSGR Docket No.59541-743.602 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose, and wherein the liquid radiopharmaceutical composition is administered at a 7- to 9-week interval per cycle with a maximum cumulative dose at about 40,800 kBq.

2. A method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial 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.

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 of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial dose, and wherein if the subject has an adverse reaction to the initial dose, the liquid radiopharmaceutical composition is administered to the subject at a reduced dose that is about 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 withheld for a period of time prior to the administering of the reduced dose.

6. The method of claim 5, wherein if the subject does not have an adverse reaction to the reduced dose that is about 50% of the initial dose, the liquid radiopharmaceutical composition is administered at a second reduced dose that is about 75% of the initial dose.WSGR Docket No.59541-743.602 7. The method of claim 6, wherein if the subject does not have an adverse reaction second reduced dose, the liquid radiopharmaceutical composition is administered at the initial dose.

8. The method of 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) renal toxicity comprising eGFR <50mL / min / 1.73m2, 40% increase in baseline serum creatinine, or 40% decrease in baseline eGFR; iv) hepatotoxicity comprising NCI CTCAE (v5) grade 3 or 4 bilirubinemia or hypoalbuminemia <3g / dL with a decreased prothrombin ratio less than 70%; and / or v) NCI CTCAE (v5.0) grade 3 or 4 non-hematologic toxicity.

9. The method of any one of claims 1 to 8, wherein the SSTR+ neuroendocrine tumor in the subject has progressed following the177Lu-labelled somatostatin analog (SSA) therapy.

10. The method of any one of claims 1 to 9, wherein the SSTR+ neuroendocrine tumor is an inoperable, advanced, well-differentiated, SSTR+ gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with177Lu-labelled somatostatin analogue (177Lu-SSA) therapy.

11. The method of any one of claims 1 to 10, wherein the subject has previously received a177Lu- SSA therapy selected from177Lu-DOTA-TATE,177Lu-DOTA-TOC, and / or177Lu-HA-DOTA- TATE.

12. The method of claim 11, wherein the177Lu-SSA therapy is administered for a minimum of two cycles.

13. The method of any one of claim 1 to 12, wherein the177Lu-SSA therapy is administered for a maximum of four cycles.

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

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

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

17. The method of any one of claims 1 to 16, wherein the liquid radiopharmaceutical composition is administered at least at a 7-week interval.WSGR Docket No.59541-743.602 18. The method of any one of claims 1 to 17, wherein the liquid radiopharmaceutical composition is administered for a maximum of 4 cycles.

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

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

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

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

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

24. The method of any one of claims 1 to 23, wherein the subject meets one or more of the following criteria: (i) wherein the subject has an eGFR of at least 50mL / min / 1.73m2; (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 a platelet count of at least 75 x 109 / L; (v) wherein the subject has a platelet count of at least 100 x 109 / L; (vi) wherein the subject has a total bilirubin level of 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 of any one of claims 1 to 24, wherein the subject has a SSTR+ neuroendocrine tumor having a Krenning score of 3 or 4.

26. The method of any one of claims 1 to 25, wherein the subject does not have a hypersensitivity to 225Actinium,68Gallium, or64Copper.

27. The method of any one of claims 1 to 26, wherein the subject does not have liver cirrhosis.

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

29. The method of any one of claims 1 to 28, wherein the patient has received at least one SSTR- PET prior to administering the225Ac-DOTA-TATE.

30. The method of claim 29, wherein the SSTR-PET comprises a68Ga or64Cu based imaging agent.

31. The method of claim 29 or 30, wherein the patient has at least one SSTR-PET positive measurable site of disease and no measurable metastatic lesions that are SSTR imaging-negative.

32. The method of 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 at a stable dose for at least 12 weeks prior to administering the225Ac-DOTA-TATE.WSGR Docket No.59541-743.602 33. The method of any one of claims 1 to 31, wherein the SSTR+ neuroendocrine tumor is a functional or a nonfunctional tumor, and wherein the subject has not received a long-acting somatostatin analog (SSA) within 4 weeks prior to administering the225Ac-DOTA-TATE.

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

35. The method of 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 at least 24 hours before or at least 24 hours after administering the225Ac-DOTA-TATE.

36. The method of any one of claims 1 to 35, wherein the subject is administered an intravenous amino acid solution prior to administering the225Ac-DOTA-TATE.

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

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

39. The method of any one of claims 36 to 38, wherein the amino acid solution is administered at least 30 minutes prior to administering the225Ac-DOTA-TATE.

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

41. The method of any one of claims 1 to 40, 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 of claim 41 or 42, wherein the antiemetic is administered prior to the administering of the amino acid solution.

44. The method of any one of claims 1 to 43, wherein the177Lu-SSA therapy is administered at least one year prior to administering the225Ac-DOTA-TATE.

45. The method of any one of claims 1 to 43, wherein the177Lu-SSA therapy is administered at most one year prior to administering the225Ac-DOTA-TATE.

46. The method of any one of claims 1 to 45, wherein the subject has received long acting somatostatin analogs (SSA) prior to administering the225Ac-DOTA-TATE.

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

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

49. The method of any one of claims 1 to 48, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an inoperable, advanced, somatostatin receptor expressing (SSTR+), well-differentiated gastro-enteropancreatic neuroendocrine tumor (GEP-NET) that has progressed following prior177Lu-SSA therapy (such as177Lu-DOTA-TATE,177Lu-DOTA-TOC, or177Lu-HA-DOTA-TATE).WSGR Docket No.59541-743.602 50. The method of any one of claims 1 to 49, wherein the subject has an elevated level of a chromogranin A.

51. The method of any one of claims 1 to 50, wherein the subject has an elevated level of a 5- hydroxyindole acetic 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 of claim 51 or 52, wherein the 5-hydroxyindole acetic acid is detected in a urine sample from the subject.

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

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

56. The method of claim 54 or 55, wherein the gastrointestinal organ is an ileum, a duodenum, or a jejunum.

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

58. The method of any one of claims 1 to 57, wherein the225Ac-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 of treating a somatostatin receptor-positive (SSTR+) cancer in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition.

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

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

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

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

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

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

67. The method of claim 66, wherein 20% to 100% of lesions in the subject are SSTR+ as determined by imaging or immunohistochemistry.WSGR Docket No.59541-743.602 68. The method of any one of claims 59 to 67, wherein the subject has received a radiotherapy that comprises beta-particle emitting radionuclide prior to the administering of the radiopharmaceutical composition.

69. The method of claim 68, wherein the radiotherapy that comprises beta-particle emitting radionuclide comprises177Lu-DOTA-TATE,177Lu-DOTA-TOC, or77Lu-HA-DOTA-TATE therapy.

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

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

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

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

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

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

76. The method of claim 73 or 74, wherein the subject has received at most 1 cycle of platinum- etoposide and PD-L1 inhibitor therapy.

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

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

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

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

81. The method of 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 of 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.WSGR Docket No.59541-743.602 83. The method of 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 of any one of claims 59 to 83, wherein the radiopharmaceutical composition is administered at a 4 to 6-week interval.

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

86. A method of treating a disease in a subject in need thereof, comprising (a) determining a level of SSTR expression in a sample of the subject; and (b) administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition.

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

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

90. The method of any one of claims 1 to 89, wherein the liquid radiopharmaceutical composition comprises: (a)225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein the225Ac- DOTA-TATE or the 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 chelator, wherein the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL; and (d) water; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 80 % of the225Ac content as225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after 48 hours.

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

0.

92. The method of claim 90 or 91, wherein the225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 25 mCi / L.WSGR Docket No.59541-743.602 93. The method of any one of claims 90 to 92, wherein the radiopharmaceutical composition retains at least 80 % of the225Ac content as225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after 48 hours at about 20ºC to about 25°C.

94. The method of any one of claims 1 to 90, wherein the liquid radiopharmaceutical composition comprises: (a)225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein the225Ac- DOTA-TATE or the 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) diethylenetriamine pentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of 0.01mg / mL to 5mg / mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is a saline solution; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 90 % of the225Ac content as225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after 120 hours at about 20ºC to about 25°C.

95. The method of any one of claims 90 to 94, wherein the radiopharmaceutical composition is formulated as a unit dose form that contains about 5-25 mL of the solution.

96. The method of any one of claims 90 to 94, wherein the radiopharmaceutical composition is formulated as a unit dose form that contains about 12 mL of the solution.

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

98. The method of any one of claims 90 to 97, wherein the225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof has a structure illustrated as.

99. The method of any one of claims 1 to 98, wherein the administering of the225Ac-DOTA-TATE (e.g., in the form of a liquid radiopharmaceutical composition) increases a progression freeWSGR Docket No.59541-743.602 survival in the subject of at least 2 months in comparision to a subject who receives a standard of care (SoC) cancer therapy.

100. The method of claim of 99, wherein the SoC cancer therapy is177Lu-SSA therapy, or chemotherapy (such as streptozocin, temozolamide, or capecitabine).

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

102. The method of any one of claims of 99 to 101, wherein the administering of the225Ac- DOTA-TATE increases a progression free survival in the subject of 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, in comparision to a subject who receives a SoC cancer therapy.

103. The method of any one of claims 1 to 102, further comprising administering to the subject an additional anti-cancer agent. wherein the additional anti-cancer agent is a local or regional cancer treatment.

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