Stabilized formulations of radionuclides and uses thereof

Abstract

Provided herein are radiopharmaceutical compositions and their uses. The radiopharmaceutical compositions may include one or more stabilizers, an aqueous vehicle, a conjugate including a targeting ligand and a radionuclide bound to a metal chelator. The targeting ligand may be a small molecule compound or a peptide, such as a monocyclic peptide. The targeting ligand may be configured to bind to a tumor target. The stabilizer may include 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

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 228,535, filed August 2, 2021, and U.S. Provisional Application No. 63 / 329,306, filed April 8, 2022, and is a continuation-in-part of U.S. Application No. 17 / 665,202, filed February 4, 2022, each of which is incorporated by reference herein in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, and is incorporated herein by reference in its entirety. The above XML file, created on August 1, 2022, is named 59541-718_601_SL.xml and is 155,726 bytes in size. [Background technology]

[0003] In the United States, cancer is the leading cause of death in people under 65, accounting for approximately 21% of all deaths in 2018. Neuroendocrine tumors (NETs) arise from neuroendocrine cells and most commonly affect the lungs, gastrointestinal tract, and pancreas. NETs are a type of cancer that require systemic therapy; they are either inoperable or diagnosed at an advanced stage, meaning tumor cells have metastasized to distant sites. Conventional radiation therapy, such as external beam radiation therapy, has been used for decades as the standard treatment for patients diagnosed with cancer. While some patients respond favorably to external beam radiation therapy, many others do not. Furthermore, metastatic and circulating tumor cells can spread and persist in the bloodstream or body fluids after standard treatment, potentially leading to treatment resistance. The presence of cancer cells in various parts of the body reduces the therapeutic effectiveness of conventional radiation therapy. Therefore, strategies for targeted radiation therapy have been developed to better treat and diagnose cancer. One of the main challenges in radiopharmaceutical manufacturing is extending the product's shelf life and treating patients at locations far from the manufacturer's site. For example, there remains a need for compositions of radionuclides, such as alpha particle-emitting radionuclides, that have improved stability and shelf life. Summary of the Invention

[0004] One of the major challenges in radiopharmaceutical manufacturing is extending the shelf life of the product to treat patients at locations away from the manufacturer's site. The decay of radionuclides, such as actinium-225, produces a series of highly reactive chemicals. In some cases, these chemicals can react with the drug substance, for example, causing degradation of the radioisotope-containing drug and increasing radioactive impurities over time. In one aspect, provided herein is a liquid radiopharmaceutical formulation that provides improved stability for alpha-emitting radionuclides, such as actinium-225. In one aspect, 225 Provided herein is a liquid radiopharmaceutical formulation comprising Ac-DOTA-TATE that is stable for at least 120 hours.

[0005] In one aspect, (i) 225Provided herein is a liquid radiopharmaceutical composition comprising a conjugate that is Ac-DOTA-TATE, (ii) one or more stabilizers, and (iii) an aqueous vehicle. In one aspect, (i) 225 Provided herein is a liquid radiopharmaceutical composition comprising a conjugate that is Ac-DOTA-TOC; (ii) one or more stabilizers; and (iii) an aqueous vehicle. In one aspect, the disclosure relates to a liquid radiopharmaceutical composition comprising the conjugate, optionally one or more stabilizers, and an aqueous vehicle. The conjugate further comprises a targeting ligand, a metal chelator covalently bound to the targeting ligand, and a radionuclide bound to the metal chelator. In some embodiments, the targeting ligand binds to a somatostatin receptor (SSR), such as somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). In some embodiments, the targeting ligand binds to somatostatin receptor type 2 (SSTR2). In some embodiments, the targeting ligand is a binding peptide comprising 6-14 amino acid residues. In some embodiments, the binding peptide comprises an amino acid sequence having at least 90% identity to a sequence selected from SEQ ID NOs: 1-96. In some embodiments, the binding peptide comprises an amino acid sequence selected from SEQ ID NOs: 1-96. In some embodiments, the targeting ligand is selected from octreotate, octreotide, D-Phe 1 -cyclo(Cys 2 -Tyr 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr 8 (SEQ ID NO: 97) (tyr 3 -octreotate, i.e., TATE), D-Phe 1 -cyclo(Cys 2 -Tyr 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys7 )Thr(ol) 8 (SEQ ID NO: 98) (Phe 1 -Tyr 3 Octreotide, edotreotide (i.e., TOC), D-Phe 1 -cyclo(Cys 2 -Phe 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr(ol) 8 (SEQ ID NO: 99) (OC), D-Phe 1 -cyclo(Cys 2 -1-Nal-D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr(ol) 8 (SEQ ID NO: 100) (NOC), p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2) (SEQ ID NO: 101) (JR11), or p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH2 (SEQ ID NO: 102) (LM3). In some embodiments, the targeting ligand is tyr 3 In some embodiments, the targeting ligand is tyrosine triphosphate, ... 3 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 another embodiment, the targeting ligand is a small molecule compound such as L-797,591, L-779,976, L-796,778, L-803,087, or L-817,818. In some embodiments, the binding affinity of the targeting ligand to the human SSR is greater than or equal to the 50% inhibitory concentration (IC 50 In some embodiments, the binding affinity of the targeting ligand for a human SSR is 250 nM or less, 100 nM or less, 50 nM or less, or 5 nM or less, as measured by a 50% inhibitory concentration (IC50 In some embodiments, the binding affinity of the targeting ligand for a human SSR is 250 nM or less as measured by 50% inhibitory concentration (IC 50 In some embodiments, the binding affinity of the targeting ligand for a human SSR is 100 nM or less as measured by a 50% inhibitory concentration (IC 50 In some embodiments, the binding affinity of the targeting ligand for a human SSR is 50 nM or less as measured by a 50% inhibitory concentration (IC 50 In some embodiments, the binding affinity of the targeting ligand for a human SSR is 5 nM or less as measured by a 50% inhibitory concentration (IC 50 In some embodiments, the human SSR is SSTR2. In some embodiments, the targeting ligand is covalently attached to the metal chelator via a linker. In some embodiments, the radiopharmaceutical composition has a binding activity as part of the conjugate of 2 nM or less after 72 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 95% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225Retain at least 90% of the Ac content.

[0006] In one aspect, described herein are radiopharmaceutical compositions comprising a conjugate further comprising a targeting ligand covalently attached to the metal chelator via a linker. In some embodiments, the metal chelator is selected from the group consisting of AAZTA, BAT, BAT-™, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOT A, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A”-DTPA, p-NH2-Bn-CHX-A”-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M- DTPA-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A"-DTPA, PEPA, p-SCN-Bn-PEPA, l,4,8,11-tetraazacyclotetradecane-l,4,8,11-tetrapropionic acid (TETPA), DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L 1 , H3L 4 , H2azapa, H5decapa, bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa 2, H4phospa, H6phospa, p-SCN-Bn-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(thiose micarbazone), 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, H2DEDP A, 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-N E3TA-NCS, NODASA, NETA-monoamide, C-NETA, TACN-HSB, NOPO, BPCA, p-SCN-Bn-DRO, DRO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L py , L1, L2, L3, and EuK-106. In another embodiment, the metal chelator is a metal chelator shown in Figures 3-17. In some embodiments, the metal chelator is DOTA, HEHA, or macropa. The metal chelator may be DOTA.

[0007] In one aspect, the disclosure described herein is a radiopharmaceutical composition comprising one or more stabilizers. The stabilizer may include a radiolytic stabilizer, which may be an amino acid or peptide or derivative thereof, a vitamin or derivative thereof, a lipid or derivative thereof, a carbohydrate or derivative thereof, a bulking agent, or an antioxidant. In some embodiments, the amino acid or peptide is selected from N-acetyl-L-cysteine, glutathione, L-lysine, 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 radiolytic stabilizer is an antioxidant, such as a flavonoid or 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, i.e., CG), 3,3',4',5,5',7-hexahydroxyflavylium chloride, (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin, i.e., EC), 7-hydroxy-3-(4'-methoxyphenyl)-4H- Benzopyran-4-one, 3,4,5-trihydroxybenzoate (gallate), 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 (epigallocatechin gallate, or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl],3,4,5-trihydroxybenzoate zoates, i.e., epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin gallate, i.e., EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, i.e., GC). In some embodiments, the flavonoid is catechin or a derivative thereof, such as (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e., CG), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin, i.e., EC), 3,4,5-trihydroxybenzoate (gallate), (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4- Dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate, i.e., EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate, i.e., epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxybenzoate) (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin, or EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, or GC). Antioxidants include carotenoids or derivatives thereof, such as all-trans-fucoxanthin,In some embodiments, the antioxidant may be lycopene, xanthophyll, beta-carotene, lycopene, or lutein. In some embodiments, the antioxidant is N-acetylcysteine, L-ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-propenoic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e., 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'-hexahydroxydiphenolic acid 2,6,2',6'-dilactone (ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epi-catechin, i.e., 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-trihydroxybenzoate (gallate), (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-pentane 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,(+)-α-Tocopherol, Xanthophyll, Citric Acid (CA), Gentisic Acid (GA), Salicylic Acid (SA), Erythorbic Acid (EA), Phenol, Sodium Bisulfite, Butylated Hydroxyanisole, Butylated Hydroxytoluene, Metabisulfite, Benzyl Alcohol, Thymol, Lipoic Acid (LA), Thioglycolic Acid (TGA), 2,3-Dimercaptopropan-1-ol (BAL), Zinc, Selenium, Albumin, Ethanol, Manganese Nititol, sucrose, melatonin, ebselen, pyruvate, 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 (epigallocatechin gallate, i.e., EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate, i.e., epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3,5,7-triol ( Examples of suitable stabilizers include epigallocatechin (EGC), (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin (GC)), (-)-epigallocatechin-3-O-gallate, 5-aminolevurivic acid hydrate, proisolbate 80, gallic acid, sodium L-ascorbate, hyaluronic acid, dextran 60-90, selenol, and LysaKare. The radiolytic stabilizer may also be a vitamin or a derivative thereof, such as L-ascorbic acid, β-carotene, provitamin A, (+)-α-tocopherol, erythorbic acid (EA), trolox, and lutein. In some embodiments, the radiolytic stabilizer is a lipid. The lipid may be a fatty acid, such as a saturated or unsaturated C6-C30 fatty acid. In some embodiments, the fatty acid may be oleic acid,The lipid may be myristoleic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, or linoleic acid, α-linolenic acid. In another embodiment, the lipid is a steroid or a derivative thereof, such as estrogen, estradiol, estriol, or cortisone. The radiolytic stabilizer may also be a carbohydrate or a derivative thereof, such as mannitol, sucrose, dextran (e.g., dextran 40, dextran 70), and cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin). In some embodiments, the radiolytic stabilizer is a bulking agent. The bulking agent may be a polymer or a mixture of polymers, such as PEG3350, PEG4000, polygeline, Haemaccel, Gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride, U.S. FDA 2018 label). In some embodiments, the bulking agent is selected from dextran, dextran 40, dextran 70, cyclodextrin, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, PEG3350, PEG4000, polygeline, Gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride, U.S. FDA 2018 label). In some embodiments, the radiolytic stabilizer is selected from the group consisting of N-acetyl-L-cysteine, L-ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-propenoic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e., 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-pentahydroxyflavan (epicatechin, or EC), 2-methoxy-4-(2-propenyl)phenol, trans-4-hydroxy-3-methoxycinnamic acid (ferulic acid), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, all-trans-fucoxa, Catechin, 3,4,5-trihydroxybenzoate (gallate), (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, ( +)-α-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 hydroxyanisole, Butylated hydroxytoluene, 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, pyruvate, carboxy-PTIO, trolox, uric acid, edaravone, beta-carotene, NADPH, lycopene, lutein, catalase, estrogen, estradiol, estriol, ubiquinol, copper, quercetin, cortisone, 2,3-dimercaptosuccinic acid (DMSA), monoisoamyl 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 U.S. FDA 2018 label), cyclodextrin, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate, or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydro

[0023] 2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl)-3,4,5-trihydroxybenzoate, i.e., epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3,5,7-triol (epigallocatechin, i.e., EGC), and (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3,5,7-triol (gallocatechin, i.e., GC).

[0008] In one aspect, disclosed herein are radiopharmaceutical compositions comprising one or more stabilizers, further comprising a first radiolytic stabilizer and a second radiolytic stabilizer. In some embodiments, the first radiolytic stabilizer and the second radiolytic stabilizer have a molar ratio of 1:5 to 5:1. In one aspect, disclosed herein are radiopharmaceutical compositions comprising a radiolytic stabilizer. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at about 0.01 mM to about 5 M. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at about 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 500 mM. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at about 0.1 mM to about 500 mM. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at about 10 mM to about 500 mM. In some embodiments, the stabilizer is present in the radiopharmaceutical composition at about 20 mM to about 100 mM. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at about 0.0001 wt% to about 10 wt%. In some embodiments, the radiolytic 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 radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.1 to 50 mg / mL.

[0009] In one aspect, disclosed herein are radiopharmaceutical compositions comprising one or more stabilizers comprising a free metal chelator that is not bound to a targeting ligand. In some embodiments, the free metal chelator is selected from the group consisting of 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), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid (TETP), and 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid (TETP). A), triethylenetetraminepentaacetic acid, 2,2',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(methylenephosphonic acid (DOTP)), deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetraazacyclododecane The esters of the 2,3-dimercaptopropanesulfonic acid (DMSA), 2,3-dimercaptopropanesulfonic acid (DMPS), 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%, 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 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.

[0010] In one aspect, radiopharmaceutical compositions are disclosed herein that include one or more stabilizers, including one or more pH stabilizers. In one aspect, radiopharmaceutical compositions are disclosed herein that include a pH stabilizer. In some embodiments, the pH stabilizer is the same as the radiolysis stabilizer. The pH stabilizer can function as a pH buffer. In some embodiments, the one or more pH stabilizers include an organic acid, such as acetic acid, fumaric acid, ascorbic acid, propionic acid, benzenesulfonic acid, carbonic acid, citric acid, aspartic acid, maleic acid, methanesulfonic acid, or tartaric acid. In some embodiments, the one or more pH stabilizers include an inorganic acid, such as hydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, or sulfuric acid. In some embodiments, the one or more pH stabilizers may include a base, such as tromethamine (Tris), ammonium hydroxide, diethanolamine, or sodium hydroxide. In some embodiments, the one or more pH stabilizers may also include 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 include an alkali salt, such as sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium phosphate, monosodium phosphate, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate. In some embodiments, the one or more pH stabilizers may include 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, fumarate propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (1)-lysine, maleic acid, methanesulfonic acid, phosphoric acid, monosodium phosphate, trisodium phosphate, disodium phosphate, sodium hydroxide, sodium succinate / 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, the 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 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 may be configured to maintain the pH of the radiopharmaceutical composition at about 4 to about 8. The one or more pH stabilizers may be configured to maintain the pH of the radiopharmaceutical composition at about 5 to about 7. In some embodiments, the pH of the radiopharmaceutical composition is in the range of about 4 to about 8. In some embodiments, the pH of the radiopharmaceutical composition is about 5.5 to about 6.0. The radiopharmaceutical composition may include one or more radiolysis stabilizers, one or more free metal chelators, and / or one or more pH stabilizers.

[0011] In one aspect, disclosed herein is a radiopharmaceutical composition comprising an aqueous vehicle. The aqueous vehicle may comprise water (e.g., water for injection), saline, dextrose solution, dextrose saline, Ringer's solution, or lactated Ringer's solution. The radiopharmaceutical composition may be isotonic. The radiopharmaceutical composition may be a solution or a suspension. In some embodiments, the radiopharmaceutical composition is formulated for IV infusion or bolus injection. In some embodiments, the radiopharmaceutical composition further comprises one or more excipients selected from a tonicity adjuster, a preservative, an antibacterial agent, a solubilizing agent, a suspending agent, and a surfactant.

[0012] In one aspect, disclosed herein is a radiopharmaceutical composition comprising a conjugate further comprising a targeting ligand covalently bound to a metal chelator via 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 comprises 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.

[0013] In one aspect, disclosed herein is a radiopharmaceutical composition comprising a conjugate further comprising a radionuclide. The radionuclide may 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, actinium-225 is present in the radiopharmaceutical composition to provide a radioactivity per volume of about 0.5 to 20 MBq / mL. In some embodiments, the conjugate is225 In another embodiment, the conjugate is: 225Ac-DOTATOC. In some embodiments, the radiopharmaceutical composition retains at least 90 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 95 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 98 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 85 mol%, at least 90 mol%, at least 92 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the initial conjugate after 120 hours at room temperature. In some embodiments, the composition retains 95 mol% or more of the initial conjugate after 48 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 the composition contains about 5% or less free actinium compared to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the radionuclide is actinium-225, and the composition contains about 2% or about 1% or less of free actinium relative to the total amount of initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the radionuclide is actinium-225, and the composition contains a total of 5 mol% or less of free daughter isotopes of actinium-225 relative to the total amount of initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the radionuclide is actinium-225, and the composition contains a total of 1 mol% or less of unchelated (free) daughter isotopes of actinium-225 relative to the total amount of initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the purity or molar percentage of the initial conjugate is measured by radio thin layer chromatography (radio-TLC). In some embodiments, the purity or molar percentage of the initial conjugate is measured by instant thin layer chromatography (iTLC).

[0014]

[0010] In one aspect, disclosed herein is a radiopharmaceutical composition comprising: (a) a conjugate 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 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 present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 10 wt%; (d) a free metal chelator present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL); and (e) an aqueous vehicle. In one aspect, disclosed herein is a radiopharmaceutical composition comprising: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 50 mCi / L (e.g., about 10 to about 50 mCi / L); (b) a radiolysis stabilizer, the radiolysis stabilizer being ascorbic acid or a salt thereof (e.g., sodium L-ascorbate), and 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 selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or a combination thereof, and present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 1 mg / mL; and (d) an aqueous vehicle that is saline. In some embodiments, the radiopharmaceutical composition further comprises a pH stabilizer. In some embodiments, the radiopharmaceutical composition further comprises a second radiolytic stabilizer. In some embodiments, the second radiolytic stabilizer (e.g., dextran 40) is present in the radiopharmaceutical composition at a concentration of about 1 wt% to about 10 wt%. In some embodiments, the second radiolytic 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) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 1-50 mCi / L (e.g., about 10-50 mCi / L); (b) a radiolytic stabilizer; (c) optionally, a pH stabilizer configured to maintain the pH of the radiopharmaceutical composition at about 4-8; (d) a free metal chelator configured to maintain the level of free radionuclide in the radiopharmaceutical composition at less than about 0.05 mCi / L; and (e) an aqueous vehicle. In some embodiments, the radiolytic stabilizer (such as ascorbic acid or sodium ascorbate) can function as a pH stabilizer. In some embodiments, the radiolytic stabilizer and the pH stabilizer are the same compound. In one aspect, disclosed herein is a radiopharmaceutical composition comprising: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 0.5-50 mCi / L; (b) a radiolytic stabilizer; (c) optionally, a pH stabilizer configured to maintain the pH of the radiopharmaceutical composition at about 4-8; (d) a free metal chelator configured to maintain the level of free radionuclide in the radiopharmaceutical composition at less than about 0.05 mCi / L; and (e) an aqueous vehicle. In some embodiments, the radiolytic stabilizer (e.g., ascorbic acid or sodium ascorbate) can function as a pH stabilizer. In some embodiments, the radiolytic stabilizer and the pH stabilizer are the same compound. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 2-50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5-50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 1-100 mCi / L, hi some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-50 mCi / L.

[0015] In one aspect, the present disclosure relates to methods of making the radiopharmaceutical compositions described herein. In some embodiments, the method of making the radiopharmaceutical composition comprises reacting a radionuclide ( 225Ac) with an unlabeled conjugate (e.g., DOTATATE or DOTATOC), where the unlabeled conjugate comprises a targeting ligand and a metal chelator covalently bound to the targeting ligand, thereby combining the labeled conjugate (e.g., 225 Ac-DOTATATE or 225 In some embodiments, the method for producing a radiopharmaceutical composition includes the steps of: forming a mixture containing a radionuclide ( 225 Ac) with an unlabeled conjugate (e.g., DOTATATE or DOTATOC), where the unlabeled conjugate comprises a targeting ligand and a metal chelator covalently bound to the targeting ligand, thereby producing a labeled conjugate; and combining the labeled conjugate with one or more stabilizers.

[0016] In one aspect, the present disclosure relates to a method for treating a disease in a subject in need thereof, comprising administering to the subject a radiopharmaceutical composition described herein. The disease may be cancer. In some embodiments, the cancer is an SSR-associated cancer, such as an SSTR2-associated cancer. The cancer may be neuroendocrine cancer, lymphatic cancer, pancreatic cancer, pituitary cancer, breast cancer, gastric cancer, lung cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine cancer, which may optionally be recurrent. In some embodiments, the neuroendocrine cancer is refractory to radiation therapy comprising a beta-particle-emitting radionuclide. In some embodiments, the subject has received radiation therapy comprising a beta-particle-emitting radionuclide prior to administering the radiopharmaceutical composition described herein. The neuroendocrine cancer may also be neuroendocrine lung cancer or neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a carcinoid tumor of the lung, gastrointestinal tract, or thymus, a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, vipoma, pancreatic-gastrointestinal neuroendocrine tumor), medullary thyroid carcinoma, Merkel cell carcinoma, adrenal pheochromocytoma, adrenal carcinoma, small cell carcinoma (e.g., in the lung), or large cell carcinoid tumor (e.g., in the lung). In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the lung cancer is extensive-stage small cell lung cancer. In some embodiments, the cancer is untreated. In some embodiments, the cancer is relapsed or refractory. In some embodiments, the small cell lung cancer is untreated. In some embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1 kBq to about 0.2 GBq per kg of body weight per dose. In some embodiments, the radiopharmaceutical composition is administered to a subject in an amount equivalent to about 5 kBq to about 50,000 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to a subject in an amount equivalent to about 20 kBq to about 5,000 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to a subject in an amount equivalent to about 50 kBq to about 500 kBq per kg of body weight per administration.In some embodiments, the radiopharmaceutical composition is administered to a subject at a dose equivalent to about 50 kBq to about 200 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to a subject at a dose equivalent to about 60 kBq to about 150 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactive dose of about 1 to 1,000 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactive dose of about 10 to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactive dose of about 100 to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactive dose of about 100 to 300 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactive dose of about 150 to 300 μCi. In some embodiments, the radiopharmaceutical composition is administered to deliver a radioactive dose of about 175-275 μCi. In some embodiments, the radiopharmaceutical composition is administered at 8-week intervals. In some embodiments, the radiopharmaceutical composition is administered to reach 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 reach a cumulative dose in the subject of about 40,000 kBq to about 70,000 kBq.

[0017] In one aspect, provided herein is a diluent comprising one or more stabilizers and an aqueous vehicle.

[0018] In one embodiment, (a) is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L. 225Provided herein is a liquid radiopharmaceutical composition comprising Ac-DOTA-TATE; (b) sodium L-ascorbate, present in the radiopharmaceutical composition at a concentration of about 80 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), 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 which is sodium chloride saline at a concentration of about 0.9% w / w, wherein the radiopharmaceutical composition is a solution and exhibits, after 120 hours at about 20° C. to about 25° C., 225 As Ac-DOTA-TATE 225 In one embodiment, (a) the radiopharmaceutical composition contains at least 90% of the Ac content. 225 Provided herein is a liquid radiopharmaceutical composition consisting essentially of Ac-DOTA-TATE, (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 80 mM to about 110 mM, (c) diethylenetriaminepentaacetate (DTPA) 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 which is sodium chloride saline at a concentration of about 0.9% w / w, wherein the radiopharmaceutical composition is a solution and exhibits, after 120 hours at about 20° C. to about 25° C., 225 As Ac-DOTA-TATE 225 In one embodiment, (a) the radiopharmaceutical composition contains at least 90% of the Ac content. 225Provided herein is a liquid radiopharmaceutical composition comprising: (b) Ac-DOTA-TATE; (b) sodium L-ascorbate, present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA), 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 which is sodium chloride saline at a concentration of about 0.9% w / w, wherein the radiopharmaceutical composition is a solution and exhibits, after 120 hours at about 20° C. to about 25° C., 225 As Ac-DOTA-TATE 225 Retains at least 90% of the Ac content. In some embodiments, 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 25 mCi / L. 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 12 mCi / L to 23 mCi / L. 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 40 μg to about 120 μg of DOTA-TATE. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 100 mM. In some embodiments, DTPA is present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL. In some embodiments, the composition is incubated at about 20° C. to about 25° C. for 168 hours, at which time the radiopharmaceutical composition is heated to about 20° C. and then cooled to about 25° C. for 168 hours. 225 As Ac-DOTA-TATE 225 In some embodiments, the composition retains at least 90% of its Ac content after 192 hours at about 20° C. to about 25° C. 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical composition is formulated as a unit dose form containing about 12 mL of solution, and the liquid radiopharmaceutical composition is (a) present in the radiopharmaceutical composition in an amount that provides 146 to 275 μCi in about 12 mL of solution. 225(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 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.

[0019] In one aspect, 225 Ac-DOTA-TATE

[0020] [ka] Provided herein are radiopharmaceutical compositions having the structure shown below:

[0021]

[0013] In one aspect, provided herein is a method of treating a somatostatin receptor positive (SSTR+) neuroendocrine tumor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition (a) is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L. 225 (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA) 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 which is sodium chloride saline at a concentration of about 0.9% w / w, wherein the radiopharmaceutical composition is a solution and exhibits, after 120 hours at about 20° to about 25° C., 225 As Ac-DOTA-TATE 225 Retain at least 90% of the Ac content.

[0022]

[0013] In one aspect, provided herein is a method of treating a somatostatin receptor positive (SSTR+) neuroendocrine tumor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition (a) is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L. 225 (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA) 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 which is sodium chloride saline at a concentration of about 0.9% w / w, wherein the radiopharmaceutical composition is a solution that exhibits, after 120 hours at about 20° to about 25° C., 225 As Ac-DOTA-TATE 225 Retain at least 90% of the Ac content.

[0023]

[0013] In one aspect, provided herein is a method of treating a somatostatin receptor positive (SSTR+) neuroendocrine tumor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition, wherein the liquid radiopharmaceutical composition (a) is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L. 225 (b) sodium L-ascorbate present in the radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA) 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 which is sodium chloride saline at a concentration of about 0.9% w / w, wherein the radiopharmaceutical composition is a solution that exhibits, after 120 hours at about 20° to about 25° C., 225 As Ac-DOTA-TATE 225In some embodiments, the neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the subject receives 177 Lu-DOTA-TATE or 177 In some embodiments, prior to administration of the liquid radiopharmaceutical composition, the subject received treatment with Lu-DOTA-TOC. 177 Lu-DOTA-TATE or 177 The subject is undergoing treatment with Lu-DOTA-TOC and the tumor is progressing. In some embodiments, the radiopharmaceutical composition is administered to the subject at a dose equivalent to about 60 kBq / kg to about 120 kBq / kg of body weight per dose. In some embodiments, the radiopharmaceutical composition is administered at 8-week intervals. In some embodiments, 225 Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 25 mCi / L.

[0024] In one aspect, provided herein is a method of treating somatostatin receptor positive (SSTR+) neuroendocrine tumors in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a liquid radiopharmaceutical composition consisting 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 100 mM; (c) DTPA, present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL; and (d) sodium chloride saline at a concentration of about 0.9% w / w.

[0025] In one aspect, provided herein is a method of treating somatostatin receptor positive (SSTR+) neuroendocrine tumors in a subject in need thereof, the method 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 having about 12 mL of solution, and wherein the liquid radiopharmaceutical composition is (a) present in the radiopharmaceutical composition in an amount that provides 146 to 275 μCi in about 12 mL of solution.225 (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 at a concentration of about 0.9% w / w.

[0026] Citation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. [Brief explanation of the drawings]

[0027] The novel features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also referred to as "figures" and "FIGs."). [Figure 1A] FIG. 1 shows the structures of exemplary radiolytic stabilizers, catechins and their derivatives. [Figure 1B] FIG. 1 shows the structure of an exemplary stabilizer, cyclodextrin. [Figure 1C] FIG. 1 shows structures of exemplary stabilizers (antioxidants). [Figure 1D] FIG. 1 shows structures of exemplary stabilizers (amino acids). [Figure 1E] FIG. 1 shows structures of exemplary stabilizers. [Figure 2A] FIG. 1 shows the structures of exemplary small molecule targeting ligands. [Figure 2B] FIG. 1 shows the structure of an exemplary binding peptide. [Figure 3] FIG. 1 shows the structures of representative metal chelating agents. [Figure 4-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 4-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 5-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 5-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 6-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 6-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 7-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 7-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 8-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 8-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 9-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 9-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 10] FIG. 1 shows the structures of representative metal chelating agents. [Figure 11-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 11-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 11-3] FIG. 1 shows the structures of representative metal chelating agents. [Figure 12-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 12-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 13] FIG. 1 shows the structures of representative metal chelating agents. [Figure 14-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 14-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 15-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 15-2]FIG. 1 shows the structures of representative metal chelating agents. [Figure 16-1] FIG. 1 shows the structures of representative metal chelating agents. [Figure 16-2] FIG. 1 shows the structures of representative metal chelating agents. [Figure 17] FIG. 1 shows the structures of representative metal chelating agents. [Figure 18A] FIG. 1 shows amino acid abbreviations and modifications. [Figure 18B] FIG. 1 shows amino acid abbreviations and modifications. [Figure 19] 1 shows a clinical treatment regimen using 225Ac-DOTA-TATE. Patients are administered 225Ac-DOTA-TATE every 8 weeks for up to 4 cycles on a tapering dose scheme. [Figure 20A] FIG. 1 shows stained tissue samples with H-scores of 281, 160, or 90. [Figure 20B] FIG. 1 shows stained tissue samples of normal lung or pancreatic NETs. [Figure 21] Figure 1 shows the clinical treatment dosing schedule for 225Ac-DOTA-TATE. Patients receive an escalating dose structure, receiving 225Ac-DOTA-TATE once every 6 weeks during standard of care therapy (PD-L1 CE) and once every 4 weeks during the PD-L1 maintenance phase, for a maximum of 6 infusions, for 4 to 6 cycles. PD-L1i represents PD-L1 inhibitor, C represents carboplatin or cisplatin, and E represents etoposide. 225Ac-DOTA-TATE is administered before or on the same day as PD-L1i, C, and E. [Figure 22]Figure 1 shows the Simon two-cohort expansion study. The 1L-ES-SCLC cohort receives 225Ac-DOTA-TATE in combination with standard of care (PD-L1i + CE). The 2L-ES-SCLC cohort receives 225Ac-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 PD-L1 inhibitor, C represents carboplatin or cisplatin, E represents etoposide, DoR represents duration of response, CR represents complete response, and PR represents partial response. [Figure 23A] FIG. 1 shows the mean tumor volume and mean body weight in a mouse study using [225Ac]Ac-DOTA-JR-11. [Figure 23B] FIG. 1 shows the mean tumor volume and mean body weight in a mouse study using [225Ac]Ac-DOTA-JR-11. DETAILED DESCRIPTION OF THE INVENTION

[0028] The following description and examples will explain the embodiments of the present disclosure in detail. It should be understood that the present disclosure is not limited to the specific embodiments described herein and can therefore be modified. Those skilled in the art will recognize that the present disclosure has many variations and modifications, which are included within the scope of the present disclosure.

[0029] While various features of the present disclosure may be described in the context of a single embodiment, those features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may for clarity be described herein in the context of separate embodiments, the present disclosure may also be implemented in a single embodiment.

[0030] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0031] All terms are intended to be understood as understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0032] The following definitions supplement those in the art and are intended for this application and are not to be construed as belonging to any related or unrelated case, such as a jointly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used to carry out the tests of the present disclosure, the preferred materials and methods are described herein. Therefore, the terminology used herein is intended only to describe specific embodiments and is not intended to be limiting.

[0033] I. Definition As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings specified below.

[0034] 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, a reference to "an agent" includes a plurality of such agents, a reference to "a stabilizer" includes a plurality of such stabilizers, a reference to "the cell" includes a reference to one or more cells (or 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 formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0035] The term "about" or "approximately" can mean within an acceptable error range of a particular value as determined by one skilled in the art, which will vary depending 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 standard deviations, in accordance with the practice in the art. Alternatively, "about" can mean within 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 a certain multiple, within 5-fold, or within 2-fold of a value.

[0036] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude other specific embodiments, e.g., any composition of matter, composition of matter, method, process, etc., although "consist of" or "consist essentially of" stated features does intend such exclusion.

[0037] "Radiolysis" refers to the decay of a radionuclide with the release of energy in the form of alpha, beta, and / or gamma radiation. When energy enters a drug-containing formulation, it can break chemical bonds and generate reactive chemical species from solvent molecules, which can further degrade the radiopharmaceutical directly and / or indirectly.

[0038] "Amino" refers to the -NH2 radical.

[0039] "Nitro" refers to the -NO2 radical.

[0040] "Oxo" refers to the =O radical.

[0041] "Imino" refers to the =NH radical.

[0042] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0043] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have 1 to about 20 carbon atoms, 1 to about 10 carbon atoms, or 1 to 6 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, as well as longer chain alkyl groups such as heptyl, octyl, and the like. Whenever a numerical range appears herein, such as "C1-C6 alkyl," the C1-C6 alkyl means that the alkyl group is composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of C1-C6 alkyl, ... 10The alkyl group may be alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless stated otherwise in the specification, an alkyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or C≡CH. In some embodiments, an alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or OMe. In some embodiments, an alkyl is optionally substituted with halogen.

[0044] The term "aryl" refers to a radical containing at least one aromatic ring, where each atom forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise stated herein, the term "aryl" or the prefix "ar-" (as in "aralkyl") is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group includes a partially reduced cycloalkyl group as defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group includes a fully reduced cycloalkyl group as defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When an aryl includes a cycloalkyl group, the aryl is attached to the remainder of the molecule via an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic ring system (e.g., bicyclic, tricyclic, or tetracyclic), which can include fused, spiro, or bridged ring systems. Unless stated otherwise in the specification, an aryl can be optionally substituted with, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)NH-C1-C6 alkyl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, -NO, -S(O)NH, -S(O)NHCH, -S(O)NHCHCH, -S(O)NHCH(CH), -S(O)N(CH), or S(O)NHC(CH). In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or OMe. In some embodiments, aryl is optionally substituted with halogen.In some embodiments, the aryl is substituted with an alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, and each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl is independently unsubstituted or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0045] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 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 embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. Unless stated otherwise in the specification, cycloalkyl groups may be optionally substituted. Representative cycloalkyls include cycloalkyls having 3 to 15 carbon atoms (C3-C6). 15cycloalkyl), cycloalkyl having 3 to 10 carbon atoms (C3-C 10Cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl), cycloalkyls having 3 to 6 carbon atoms (C3-C6 cycloalkyl), cycloalkyls having 3 to 5 carbon atoms (C3-C5 cycloalkyl), or cycloalkyls having 3 to 4 carbon atoms (C3-C4 cycloalkyl). Cycloalkyls can include fused ring systems, spiro ring systems, or bridged ring systems. In some embodiments, cycloalkyls include fused ring systems. In some embodiments, cycloalkyls include spiro ring systems. In some embodiments, cycloalkyls include bridged ring systems. In some embodiments, cycloalkyls are 3 to 6-membered cycloalkyls. In some embodiments, cycloalkyls are 5 to 6-membered cycloalkyls. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl 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 otherwise specified herein, cycloalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or NO2.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0046] "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 a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed 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 a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CHO-, -OCH2CHOCH2CHO-, or OCH2CHOCH2CHOCH2CHO-. Unless stated otherwise in the specification, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or NO. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0047] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified specifically in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. The nitrogen, carbon, or sulfur atom in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be 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 specified, heterocycloalkyls have 2-12 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 1 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms within the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise in the specification, a heterocycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or NO. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0048] "Heteroaryl" refers to a ring system radical containing carbon atom(s), one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic, or polycyclic. Specific 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. Specific examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Specific 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, heteroaryls contain 0 to 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, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, the heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group, as defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, the heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group, as defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When the heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is attached to the remainder of the molecule through a carbon atom or heteroatom of the heteroaromatic ring. The heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which can include fused, spiro, or bridged ring systems. Unless stated otherwise in the specification, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0049] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0050] As used herein, the terms "treat," "prevent," "ameliorate," and "inhibit," as well as terms derived therefrom, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition that one of ordinary skill in the art would recognize as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount and level of treatment, prevention, amelioration, or inhibition of a disorder in a mammal. For example, a disorder (including its symptoms or pathology) can be alleviated 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 pathology or symptoms of a disorder, e.g., cancer or inflammatory disease. For purposes herein, "treatment," "prevention," "amelioration," or "inhibition" also encompasses delaying the onset of a disorder, or its symptoms or conditions. As used herein, "treating" encompasses the concept of "alleviating," which refers to reducing the frequency or severity of the occurrence or recurrence of any symptoms or other adverse effects associated with a disorder, and / or 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., extending the period of remission in a patient afflicted with a disease.

[0051] The term "therapeutically effective amount" as used herein refers to an amount effective at a dosage and for a period of time necessary to achieve a desired therapeutic result. The therapeutically effective amount of a composition may vary depending on factors such as the individual's condition, age, sex, weight, and the ability of the protein to elicit a desired response in the individual. A therapeutically effective amount may also be an amount that exceeds the toxic or harmful effects of the composition, which would have a beneficial effect on treatment.

[0052] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0053] As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that is substituted at the designated atomic position, replacing one or more hydrogens on the designated atom, provided that the substitution does not exceed the normal valence of the designated atom and results in a stable compound. Combinations of substituents and / or variables are permissible only if the combination results in a stable compound. Those of skill in the art should note that any carbon and heteroatom having valences that appear unsatisfied as described or depicted herein are assumed to have a sufficient number of hydrogen atoms to satisfy the valences depicted or depicted. In certain cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as a point of attachment may be described, displayed, or listed herein within a substituent group, although the structure may show only a single bond as the point of attachment to the core structure. Those of skill in the art will understand that although only a single bond is depicted, a double bond is intended for those substituents.

[0054] 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, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), 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, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -NH(cyclopropyl), -CH, -CHCH, -CF, -OCH, and OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. When referring to the number of substituents, the term "one or more" refers to the maximum possible number of substitutions, i.e., from one substituent to the replacement of all hydrogens with substituents.

[0055] The term "unsubstituted" means that the specified group bears no substituents.

[0056] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0057] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0058] The term "peptide" as used herein refers to a compound containing two or more amino acids. The peptides described herein may contain one or more unnatural amino acids. The term "peptide" also encompasses peptidomimetics. In the present invention, the term "amino acid" is used in the broadest sense and includes not only natural amino acids but also their derivatives and artificial amino acids. For example, the term "amino acid" encompasses unnatural amino acids.

[0059] As used herein, the term "unnatural amino acid" refers to an amino acid other than the 20 amino acids that naturally occur in proteins.

[0060] As used herein, the term "protein" refers to a polypeptide (i.e., a string of at least three amino acids linked together by peptide bonds). A protein can include moieties other than amino acids (e.g., it can be a glycoprotein, proteoglycan, etc.) and / or can be otherwise processed or modified. A protein can be an entire polypeptide (with or without a signal sequence) produced by and / or active within a cell. In some embodiments, a protein is or includes a characteristic portion, such as a polypeptide produced by and / or active within a cell. A protein can include multiple polypeptide chains.

[0061] The term "peptidomimetic" or "mimetic" refers to a biologically active compound that mimics the biological activity of a peptide or protein but is no longer entirely peptidic in chemical nature; for example, it may contain non-peptide bonds (i.e., bonds other than amide bonds between amino acids). As used herein, the term peptidomimetic is used broadly to include molecules that are no longer entirely peptidic in nature, such as pseudopeptides, semi-peptides, and peptoids. Although completely or partially non-peptidic, the peptidomimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resembles the three-dimensional arrangement of active groups in the target amino acid sequence or target molecule on which the peptidomimetic is based. As a result of this similar geometric arrangement of the active site, peptidomimetics can affect biological systems in a manner similar to the biological activity of the target entity.

[0062] In some embodiments, peptide mimetics are substantially similar in both three-dimensional shape and biological activity to the target amino acid sequence or target molecule on which they are based. Examples of methods for structurally modifying peptides to create peptide mimetics include inverting the backbone chiral center, particularly at the N-terminus, resulting in a D-amino acid residue structure that can improve proteolytic stability without adversely affecting activity. One example is described in the paper "Tritiated D-ala-Peptide T Binding", Smith CSet et al., Drug Development Res., 15, pp. 371-379 (1988). A second method is to modify the cyclic structure for stability, such as N-to-C interchain imides and lactams (Ede et al. in Smith and Rivier (Eds.) "Peptides: Chemistry and Biology", Escom, Leiden (1991), pp. 268-270). An example of this is provided by conformationally restricted thymopentin-like compounds such as those disclosed in U.S. Patent No. 4,457,489. A third approach is to replace peptide bonds in the target entity with pseudopeptide bonds that confer resistance to proteolysis.

[0063] Ranges provided herein are understood to be abbreviations for all values ​​within that range. For example, the range 1 to 50 is understood to include any number, combination of numbers, or subrange 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, and all fractional values ​​between the aforementioned integers, e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, etc. With respect to subranges, "nested subranges" extending from either end of the range are specifically contemplated. For example, nested subranges of the exemplary range of 1 to 50 could include, in one direction, 1 to 10, 1 to 20, 1 to 30, and 1 to 40, or in the opposite direction, 50 to 40, 50 to 30, 50 to 20, and 50 to 10.

[0064] 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 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Also by way of example, C0-C2 alkylene includes a direct bond, a -CH2- bond, and a CH2CH2- bond.

[0065] As used herein, the term "cyclized" or "cyclization" means that two amino acids separated by at least one amino acid in a peptide are directly or indirectly linked to each other to form a ring structure within the molecule. Optionally, the two amino acids are linked via a linker or the like.

[0066] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian genus, e.g., humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a companion animal, such as a dog or cat. In one aspect, the mammal is a human.

[0067] The term "therapeutically effective amount" as used herein refers to an amount effective at a dosage required to achieve a desired therapeutic result. The therapeutically effective amount of a composition may vary depending on factors such as the condition of the individual (e.g., age, sex, and weight), the radiopharmaceutical conjugate, and the method of administration (e.g., oral or parenteral).

[0068] II.Technology overview Targeted radiopharmaceuticals (TRPs) are a new generation of nuclear medicine for cancer treatment and diagnosis. TRPs selectively deliver radionuclide-containing molecules at high concentrations to target cells, such as tumors, while delivering none or very low concentrations to undesired cells in normal, healthy tissues. This process is achieved by engineering drug molecules with high-affinity conjugates (e.g., targeting ligands) and linking them to radioisotopes. The biological targets of these conjugates are highly expressed in tumor cells and low or absent in healthy tissues and organs. Upon decay, the radioisotope emits high-energy ionizing radiation in the form of alpha, beta, and / or gamma particles. The energy released at the target site can damage or kill the target tissue or be visualized by an imaging scanner for therapeutic or diagnostic purposes.

[0069] Some conventional radiopharmaceutical formulations use extremely high concentrations of stabilizers in the radiopharmaceutical. High concentrations can result in unknown biological effects and / or impair the therapeutic efficacy of the radiopharmaceutical. The low efficacy of traditionally used stabilizers necessitates significant dilution to slow degradation. As a result, large dose volumes may require infusion treatment instead of bolus injection in clinical settings. This is undesirable because it requires prolonged patient stays at infusion centers or, in some cases, hospitalization. One of the main challenges in radiopharmaceutical manufacturing is extending the product's shelf life to treat patients at locations far from the manufacturer's site. Increasing the stability of the radiopharmaceutical in the formulation solution can address this challenge.

[0070] In some cases, daughter isotopes may be released into solution as the parent isotope decays. Daughter isotopes can be nonradioactive or radioactive. If the daughter ion is radioactive, the unbound ion can produce nonspecific distribution of radioactivity in vivo, potentially resulting in undesirable toxicity. Additionally, even if the daughter ion is not radioactive, its high affinity can still bind to the metal chelating moiety of the radiopharmaceutical. Displacement of the parent ion can result in chemical degradation of the drug substance. This process can also adversely affect radiochemical purity over time. When actinium-225-DOTA-containing drugs begin to decay, the isotope may first decay to francium-221(I). The recoil energy of this process can be approximately 10,000 times higher than any known chemical bond energy, resulting in the daughter ion's departure from the original chelating agent (e.g., DOTA). Due to the chemical properties of francium-221(I), in some cases it cannot be recaptured by the free DOTA-containing drug. As decay continues, more free daughter ions may elute into solution. Eventually, most of the decayed daughter ions may accumulate in the stable form of bismuth-209(III). Bismuth-209(III) tightly chelates with DOTA and may compete with Ac-225 for binding to the parent drug, further dissociating Ac-225 from the chelator and generating additional radioactive free (unchelated) metal impurities.

[0071] The decay of radionuclides can involve the release of energy in the form of alpha, beta, and / or gamma radiation. Energy enters the radiopharmaceutical-containing solution and can break chemical bonds, generate reactive species from solvent molecules, or directly or indirectly further decompose the radiopharmaceutical. This process can also be referred to as radiolysis. Radiolysis can be particularly severe when concentrated radioactive compounds are present in small volumes of solution. In the case of actinium-225-DOTA-containing radiopharmaceuticals, actinium-225 can decay sequentially into francium-221, astatine-217, bismuth-213, thallium-209, polonium-213, lead-209, and bismuth-209. The decay chain can include the emission of four alpha particles and two beta particles. In addition, francium-221 and bismuth-213 can release up to 25% of their decay energy through gamma radiation. Ionizing radiation causes radiolysis of surrounding water molecules, particularly H atoms, OH radicals, and HO. + The radioisotope-containing peptide drug is degraded by the generation of radioactive impurities over time.

[0072] Accordingly, provided herein are radiopharmaceutical compositions, eg, actinium-225-containing compositions, with improved stability.

[0073] In one aspect, the present disclosure relates to a radionuclide solution having a radioisotope and its daughter ion. The solution composition may include components that stabilize the radiopharmaceutical substance after radiolysis or chemical degradation. Increasing the stability of the drug substance can extend the shelf life of the radiopharmaceutical, thereby achieving a wider range of uses as a drug product for diagnostic and therapeutic purposes.

[0074] In one aspect, the compositions described herein have increased stability of the radiopharmaceutical conjugate. The radiopharmaceutical composition may include components, such as radiopharmaceutical stabilizers, that stabilize the radiopharmaceutical substance from radiolysis or chemical degradation. The radiopharmaceutical stabilizers may include reducing agents and / or radical scavengers, such as ascorbic acid, to reduce radiolysis. The compositions of the present disclosure may have a longer shelf life. The compositions described herein may include one or more stabilizers. The stabilizers can prevent or delay radiolysis of the radiopharmaceutical conjugate. The stabilizers can prevent or delay degradation of the radiopharmaceutical conjugate. The stabilizers can prevent or delay chemical degradation of the radiopharmaceutical conjugate due to daughter ions generated by radioactive decay. The stabilizers can prevent or delay chemical degradation of the radiopharmaceutical conjugate due to changes in pH. The stabilizers may be added to the composition at low concentrations. The stabilizers may optionally be added to the composition at low concentrations. By increasing the stability of the radiopharmaceutical conjugate, one or more uses in the pharmaceutical field can be achieved. Uses may include serving as a drug product for one or more diagnostic purposes. Uses may include serving as a drug product for one or more therapeutic purposes. Treatment regimens for patients or subjects administered with the radiopharmaceutical compositions described herein may include treating at a remote location. Treatment regimens for patients or subjects administered with the radiopharmaceutical compositions described herein may include shortening the stay at an infusion center or hospital.

[0075] The radiopharmaceutical conjugate may comprise a radionuclide and a metal chelator. The radionuclide and metal chelator can be linked by ionic or coordinate bonds. Radionuclides for therapeutic purposes may include lutetium-177, actinium-225, yttrium-90, and bismuth-213. Radionuclides for diagnostic purposes may include gallium-68, copper-64, and indium-111. The chelator can be further covalently bound, directly or via a linker, to a targeting agent, such as one with high affinity for the target of the radiopharmaceutical conjugate. Exemplary metal chelators may include azacrown ether polycarboxylic acids, such as 2,2',2'',2''''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Chelation can prevent the radionuclide from being released into the environment in vitro and / or in vivo.

[0076] III. Composition In one aspect, the present disclosure provides a liquid radiopharmaceutical composition comprising a radiopharmaceutical conjugate. The conjugate may comprise a targeting ligand. The targeting ligand may be a binding peptide or a chemical group or a small molecule. The conjugate may further comprise a chelating agent, such as a metal chelator. The chelating agent may be covalently bound to the targeting ligand. The conjugate may further comprise a radionuclide. In some embodiments, the radionuclide is bound to the chelating agent. The composition may further comprise one or more stabilizers. The one or more stabilizers are agents capable of stabilizing a composition or formulation of the radiopharmaceutical conjugate. The one or more stabilizers may reduce or delay degradation of the radiopharmaceutical conjugate in the composition.

[0077] In one aspect, 225 Provided herein is a liquid radiopharmaceutical composition comprising Ac-DOTATATE. 225Provided herein is a liquid radiopharmaceutical composition comprising Ac-DOTATOC. 225 Provided herein is a liquid radiopharmaceutical composition comprising Ac-DOTA-JR-11. 225 Provided herein is a liquid radiopharmaceutical composition comprising Ac-HA-DOTA-TATE.

[0078]

[0010] In one aspect, disclosed herein is a radiopharmaceutical composition comprising: (a) a conjugate 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 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 present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 10 wt%; (d) a free metal chelator present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL); and (e) an aqueous vehicle.

[0079] In one embodiment, the radiopharmaceutical composition comprises: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 1 to 50 mCi / L; (b) a radiolysis stabilizer, which is ascorbic acid or a salt thereof (e.g., sodium L-ascorbate) and which is present in the radiopharmaceutical composition at a concentration of about 50 mM to about 1500 mM (e.g., about 80 to about 120 mM, about 80 to about 500 mM, about 50 mM to about 200 mM); and (c) a free metal chelator, which is EDTA Disclosed herein are radiopharmaceutical compositions comprising: (a) a free metal chelator selected from , macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or a combination thereof, present in the radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL (e.g., about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 2.5 mg / mL); and (d) an aqueous vehicle that is saline. In some embodiments, the radiopharmaceutical composition further comprises a pH stabilizer. In some embodiments, the radiolytic stabilizer functions as a pH stabilizer. In some embodiments, the radiopharmaceutical composition further comprises a second radiolytic stabilizer. In some embodiments, the second radiolytic stabilizer (e.g., dextran 40) is present in the radiopharmaceutical composition at a concentration of about 1 wt % to about 10 wt %. In some embodiments, the second radiolysis stabilizer is present in the radiopharmaceutical composition at a concentration of about 0.05 wt% to about 5 wt%. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 5 to 50 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10 to 50 mCi / L. In some embodiments, the radiopharmaceutical composition comprises a pH stabilizer present in the formulation at about 80 to about 500 mM. In some embodiments, the radiopharmaceutical composition comprises a pH stabilizer present in the formulation at about 50 mM to about 200 mM. In some embodiments, the radiopharmaceutical composition comprises a pH stabilizer present in the formulation at about 25 mM to about 300 mM. In some embodiments, the radiopharmaceutical composition comprises a free metal chelator present in the formulation at about 0.01 mg / mL to about 1 mg / mL.In some embodiments, the radiopharmaceutical composition comprises a free metal chelator present in the formulation at about 0.02 mg / mL to about 3 mg / mL, hi some embodiments, the radiopharmaceutical composition comprises a free metal chelator present in the formulation at about 0.02 mg / mL to about 2 mg / mL.

[0080] In one aspect, disclosed herein is a radiopharmaceutical composition comprising: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 1-50 mCi / L; (b) optionally, a pH stabilizer configured to maintain the pH of the radiopharmaceutical composition at about 4-8; (c) a radiolysis stabilizer; (d) a free metal chelator configured to maintain the level of free radionuclide in the radiopharmaceutical composition at less than about 0.05 mCi / L; and (e) an aqueous vehicle. In some embodiments, the radiolysis stabilizer (e.g., ascorbic acid or sodium ascorbate) can function as a pH stabilizer. In some embodiments, the radiolysis stabilizer and the pH stabilizer are the same compound. In some embodiments, the free metal chelator is configured to maintain the level of free radionuclide in the radiopharmaceutical composition at less than about 0.05 mCi / L for at least 72 hours at about 20°C to about 25°C, as measured by radio-thin layer chromatography (radio-TLC). In some embodiments, the free metal chelator is configured to maintain the level of free radionuclide in the radiopharmaceutical composition at less than about 0.2, about 0.2, about 0.01, or about 0.001 mCi / L for at least 72 hours at about 20° C. to about 25° C., as measured by radio-thin layer chromatography (radio-TLC). In some embodiments, the free metal chelator is configured to maintain the level of free radionuclide in the radiopharmaceutical composition at less than about 0.2, about 0.2, about 0.01, or about 0.001 mCi / L for at least 168 hours at about 20° C. to about 25° C., as measured by radio-thin layer chromatography (radio-TLC). In some embodiments, the free radionuclide is unbound or unchelated. 225Ac. 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.

[0081] In some embodiments, the radiopharmaceutical compositions described herein contain 100% or more of the 20% to 25% hydroxybenzoates bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 95% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac content bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac content bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 95% of the Ac content bound as part of the conjugate after 168 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac content bound as part of the conjugate after 168 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 Retain at least 95% of the Ac content.

[0082] In one embodiment, (a) a conjugate comprising: (i) a targeting ligand that binds to a somatostatin receptor (SSR); (ii) a metal chelator covalently attached to the targeting ligand; and (iii) 225 Disclosed herein is a liquid radiopharmaceutical composition comprising: (a) a conjugate comprising a radionuclide, wherein the conjugate is Ac; (b) a means for maintaining the pH of the radiopharmaceutical composition, wherein the pH of the radiopharmaceutical composition is from about 4 to about 8; (c) a means for collecting free radionuclide in the radiopharmaceutical composition; and (d) an aqueous vehicle. In some embodiments, the radiopharmaceutical composition has a pH of from about 20° C. to about 25° C. after 120 hours, as measured by radio thin layer chromatography (radio-TLC), of at least 100% of the radionuclide. 225In some embodiments, the means for scavenging free radionuclides is a free metal chelator described herein. In some embodiments, the means for maintaining the pH of the radiopharmaceutical composition is a pH stabilizer described herein. In some embodiments, the liquid radiopharmaceutical composition is a solution. In one aspect, (a) a conjugate comprising: (i) a targeting ligand that binds to a somatostatin receptor (SSR); (ii) a metal chelator covalently bound to the targeting ligand; and (iii) 225 Disclosed herein is a liquid radiopharmaceutical composition comprising: (a) a conjugate comprising a radionuclide, Ac, 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 has a pH of 0.1 mCi / L as a fraction of the radionuclide after 120 hours at about 20° C. to about 25° C., as measured by radio thin layer chromatography (radio-TLC). 225 The liquid radiopharmaceutical composition retains at least 90% of its Ac content. 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 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. 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC, or225 In some embodiments, the conjugate is: 225 Ac-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 0.01 mg / mL to about 5 mg / mL. In some embodiments, the conjugate is 225 Ac-DOTA-TATE, and the composition is 225 As Ac-DOTA-TATE 225 In some embodiments, the conjugate retains at least 90% of the Ac content. 225 Ac-DOTA-TATE, and the composition is 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical composition retains at least 95% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 Retains at least 90% of the Ac content. In some embodiments, the radiopharmaceutical composition is formulated as a unit dose form containing about 5 ml to about 50 ml (e.g., about 10-15 ml, about 12 mL) of solution. In some embodiments, the aqueous vehicle is saline.

[0083] Liquid radiopharmaceutical compositions may include a pharmaceutically acceptable carrier or diluent. Exemplary pharmaceutically acceptable carriers include solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic agents, and absorption enhancers or delayers that are compatible with the method of administration of the drug. In some embodiments, the liquid radiopharmaceutical compositions described herein are formulated as solutions, emulsions, suspensions, syrups, elixirs, and the like. The composition may be an aqueous radiopharmaceutical composition.

[0084] The liquid radiopharmaceutical composition may comprise an aqueous vehicle. For example, the aqueous vehicle may comprise water, saline, dextrose solution, dextrose saline, 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 a 5.0% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a 4.0% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a 3.0% sodium chloride solution. In some embodiments, the aqueous vehicle is a 2.0% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a 1.5% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a 1.0% sodium chloride solution. In some embodiments, the aqueous vehicle is a 0.9% w / w sodium chloride saline solution. In some embodiments, the aqueous vehicle is a 0.5% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a 0.5%-1.5% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a 0.7%-1.1% w / w sodium chloride solution. In some embodiments, the aqueous vehicle is a saline solution. In some embodiments, the aqueous vehicle is a dextrose solution. In some embodiments, the aqueous vehicle is a dextrose-saline solution. The composition may be isotonic. The composition may be a solution or a suspension. In some embodiments, the liquid radiopharmaceutical composition is formulated as a solution. The composition may be formulated to be compatible with a particular local or systemic route of administration. The composition may include a carrier, diluent, or excipient suitable for administration by a particular route. The composition may be formulated for IV infusion or bolus injection. In some embodiments, the liquid radiopharmaceutical is formulated for intravenous administration.

[0085] Auxiliary ingredients or excipients may also be incorporated into the liquid radiopharmaceutical composition. The composition may further comprise one or more auxiliary ingredients or excipients. The auxiliary ingredient or excipient may be a preservative, an antibacterial agent, an antiviral agent, an antimicrobial agent, and / or an antifungal agent. The auxiliary ingredient or excipient may be a tonicity adjusting agent, a solubilizing agent, a suspending agent, and / or a surfactant.

[0086] The liquid radiopharmaceutical compositions described herein may be storage stable over 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 composition retains at least 85 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 90 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the composition retains at least 95 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the described compositions retain at least 98 mol% of the initial conjugate after 168 hours at room temperature. In some embodiments, the compositions 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 120 hours at room temperature. In some embodiments, the compositions 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 96 hours at room temperature. In some embodiments, the compositions 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 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 99 mol% of the initial conjugate after 2 weeks at refrigerated conditions (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 conditions (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 168 hours at refrigerated conditions (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 conditions (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 conditions (about 4° C.). In some embodiments, the purity or molar percentage of the conjugate is measured by radio thin layer chromatography (radio-TLC). In some embodiments, the purity or molar percentage of the conjugate is measured by instant thin layer chromatography (iTLC). In some embodiments, the purity or molar percentage of the conjugate is measured by measuring the associated alpha particle emission using radio-TLC.

[0087] The liquid radiopharmaceutical compositions described herein may be stored for a period of time after which the initial conjugate (e.g., 225In 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 molar percentage of the conjugate is measured by instant thin layer chromatography (iTLC). In some embodiments, the purity or molar percentage of the conjugate is measured by radio thin layer chromatography (radio-TLC). In some embodiments, room temperature may refer to a temperature of about 25°C. In some embodiments, room temperature may refer to a temperature of 25°C. In some embodiments, room temperature may refer to a temperature of about 22°C to about 25°C. In some embodiments, room temperature may refer to a temperature of about 20°C to about 25°C.

[0088] The liquid radiopharmaceutical compositions described herein may contain small amounts of unchelated, unconjugated radionuclides after being stored for a period of time. In some embodiments, the liquid radiopharmaceutical compositions described herein contain small amounts of free actinium-225 and conjugated radionuclides after being stored for a period of time. 225 In the fragments of Ac-DOTA-TATE (e.g., 225Actinium-225 conjugates contain actinium-225 present in the radiopharmaceutical composition (as the Ac-DOTA fragment). See, e.g., Example 3. The total content of radionuclides, such as actinium-225, in the radiopharmaceutical composition may also decrease over time due to radionuclide decay. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain about 20% or less free actinium-225 relative to the total actinium-225 content in the composition (as measured) after 120 hours at about 20°C-25°C. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain about 10% or less free actinium-225 relative to the total actinium-225 content in the composition after 120 hours at about 20°C-25°C. In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 5% or less free actinium-225 relative to the total amount of actinium-225 in the composition after 120 hours at about 20° C. to 25° C. In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 2% or less free actinium-225 relative to the total amount of actinium-225 in the composition after 120 hours at about 20° C. to 25° C. In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 1% or less free actinium-225 relative to the total amount of actinium-225 in the composition after 120 hours at about 20° C. to 25° C.

[0089] In some embodiments, the liquid radiopharmaceutical composition (at the time of measurement) contains 120 hours of storage at about 20°C to about 25°C. 225 At least 90 mol% of the Ac (i.e., actinium-225) content 225 In some embodiments, the liquid radiopharmaceutical composition is present as Ac-DOTA-TATE after storage at about 20°C to about 25°C for 120 hours. 225 At least 95 mol% of the Ac (i.e., actinium-225) content 225In some embodiments, the liquid radiopharmaceutical composition is present as Ac-DOTA-TATE after storage at about 20°C to about 25°C for 120 hours. 225 At least 98 mol% of the Ac (i.e., actinium-225) content 225 In some embodiments, the liquid radiopharmaceutical composition is present as Ac-DOTA-TATE after storage at about 20°C to about 25°C for 120 hours. 225 At least 99 mol% of the Ac (i.e., actinium-225) content 225 In some embodiments, the liquid radiopharmaceutical composition is present as Ac-DOTA-TATE after 144 hours of storage at about 20°C to about 25°C. 225 At least 90 mol% of the Ac (i.e., actinium-225) content 225 In some embodiments, the liquid radiopharmaceutical composition is present as Ac-DOTA-TATE after 168 hours of storage at about 20°C to about 25°C. 225 At least 90 mol% of the Ac (i.e., actinium-225) content 225 In some embodiments, the liquid radiopharmaceutical composition is present as Ac-DOTA-TATE after 192 hours of storage at about 20°C to about 25°C. 225 At least 90 mol% of the Ac (i.e., actinium-225) content 225 It exists as Ac-DOTA-TATE.

[0090] In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate is maintained at about 20° C. to 25° C. for 120 hours, and the composition 225 Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 20% or less of the total amount of actinium-225 conjugate in the composition after 120 hours at about 20°C to 25°C. 225 Compared with the total Ac content, free 225Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 15% or less of the total amount of actinium-225 conjugate in the composition after 120 hours at about 20°C to 25°C. 225 Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 10% or less of the total amount of actinium-225 conjugate in the composition after 120 hours at about 20°C to 25°C. 225 Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 10% or less of the total amount of actinium-225 conjugate in the composition after 120 hours at about 20°C to 25°C. 225 Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 The total amount of Ac and the composition is about 5% or less. 225 The total Ac content may decrease over time as the radionuclide actinium-225 naturally decays. In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate exhibits a 50% or greater increase in the Ac content of the composition after 144 hours at about 20° C. to 25° C. 225 Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 10% or less of the total amount of actinium-225 conjugate in the composition after 168 hours at about 20°C to 25°C. 225Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains about 10% or less of the total amount of actinium-225 conjugate in the composition after 192 hours at about 20°C to 25°C. 225 Compared with the total Ac content, free 225 Ac and in the conjugate fragments (e.g., 225 free (as Ac-DOTA fragment) 225 In some embodiments, the total amount of Ac is about 10% or less. 225 The amount of Ac is determined by radio-TLC.

[0091] In some embodiments, the radiopharmaceutical compositions described herein have a radioactivity of about 1000 kJ / cm2, as measured by radio-TLC, after 120 hours at about 20° C. to 25° C., and the radioactivity of the liquid radiopharmaceutical composition is about 1000 kJ / cm2, as measured by radio-TLC. 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac (i.e., actinium-225) content of the liquid radiopharmaceutical composition after 120 hours at about 20° C. to 25° C., as measured by radio-TLC. 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 95% of the Ac (i.e., actinium-225) content of the liquid radiopharmaceutical composition after 120 hours at about 20° C. to 25° C., as measured by radio-TLC. 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 98% of the Ac (i.e., actinium-225) content of the liquid radiopharmaceutical composition after 120 hours at about 20° C. to 25° C., as measured by radio-TLC. 225 As Ac-DOTA-TATE 225In some embodiments, the radiopharmaceutical compositions described herein retain at least 99% of the Ac (i.e., actinium-225) content of the liquid radiopharmaceutical composition after 144 hours at about 20° C. to 25° C., as determined by radio-TLC. 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac (i.e., actinium-225) content of the liquid radiopharmaceutical composition after 168 hours at about 20° C. to 25° C. as determined by radio-TLC. 225 As Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical compositions described herein retain at least 90% of the Ac (i.e., actinium-225) content of the liquid radiopharmaceutical composition after 192 hours at about 20° C. to 25° C., as determined by radio-TLC. 225 As Ac-DOTA-TATE 225 Retain at least 90% of the Ac (i.e., actinium-225) content.

[0092] In some embodiments, the liquid radiopharmaceutical composition comprises a conjugate comprising actinium-225. In some embodiments, the radiopharmaceutical composition comprising the actinium-225 conjugate contains about 20% or less free actinium relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the radiopharmaceutical composition comprising the actinium-225 conjugate contains about 10% or less free actinium relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the radiopharmaceutical composition comprising the actinium-225 conjugate contains about 5% or less free actinium relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the radiopharmaceutical composition comprising the actinium-225 conjugate contains about 3% or less free actinium relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain about 2% or less free actinium relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain about 1% or less free actinium relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain about 20 mol% or less total free actinium daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain about 15 mol% or less total free actinium daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature.In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain a total of about 10 mol % or less of free daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain a total of about 5 mol % or less of free daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain a total of about 3 mol % or less of free daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, radiopharmaceutical compositions comprising actinium-225 conjugates contain a total of about 2 mol % or less of free daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, a radiopharmaceutical composition comprising an actinium-225 conjugate contains less than about 1 mol % total free daughter isotopes of actinium-225 relative to the total initial chelated actinium content in the composition after 168 hours at room temperature. In some embodiments, the purity or molar percentage of the conjugate is measured by radio thin layer chromatography (radio-TLC).

[0093] In some embodiments, the radiopharmaceutical compositions described herein exhibit, as part of a conjugate (e.g., 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC, 225 Ac-HA-DOTA-TATE, or 225 As part of Ac-DOTA-JR-11 225In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 168 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as determined by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 95% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as determined by radio-thin layer chromatography (radio-TLC). 225 In some embodiments, the radiopharmaceutical composition retains at least 95% of the Ac content bound as part of the conjugate after 120 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 168 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225 In some embodiments, the radiopharmaceutical composition retains at least 90% of the Ac content bound as part of the conjugate after 72 hours at about 20° C. to about 25° C. as measured by high performance liquid chromatography / fraction preparative (HPLC-FC). 225Retain at least 95% of the Ac content.

[0094] stabilizers In one aspect, radiopharmaceutical compositions with improved stability are disclosed herein. The pharmaceutical compositions described herein may include one or more stabilizers. In one aspect, a solution comprising one or more stabilizers for use in a radiopharmaceutical composition is provided herein. In some embodiments, the solution comprising one or more stabilizers is a diluent. The one or more stabilizers can reduce, prevent, or delay degradation of the radiopharmaceutical. Degradation can include radiolytic degradation of the radiopharmaceutical. The one or more stabilizers can reduce, prevent, or delay decay of the radionuclide.

[0095] Radiolytic stabilizer One or more stabilizers of the pharmaceutical compositions described herein may comprise a radiolytic stabilizer. The one or more stabilizers may comprise two or more radiolytic stabilizers. The one or more stabilizers may comprise a first radiolytic stabilizer and a second radiolytic stabilizer. The radiolytic stabilizer may be an amino acid or peptide or derivative thereof, a vitamin or derivative thereof, a lipid or derivative thereof, a carbohydrate or derivative thereof, a bulking agent, or an antioxidant. The radiolytic stabilizer may comprise an amino acid, a peptide or derivative thereof, a vitamin or derivative thereof, a lipid or derivative thereof, a carbohydrate or derivative thereof, a bulking agent, an antioxidant, or a combination thereof. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for stabilizing a conjugate comprising a radionuclide. The means for stabilizing the conjugate may be a radiolytic stabilizer described herein. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for scavenging free radicals in the composition. In some embodiments, the means for scavenging free radicals in the composition is a radiolytic stabilizer. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for reducing the concentration of free radicals in the composition. In some embodiments, the means for reducing the concentration of free radicals in the composition is a radiolytic stabilizer. In some embodiments, reducing the free radicals in the composition reduces the radiolytic degradation of the conjugate. In some embodiments, the radiolytic stabilizer is an antioxidant.

[0096] The molar ratio of the first radiolytic stabilizer to the second radiolytic stabilizer may be 1:100,000-100,000:1, 1:1,000-1,000:1, 1:100-100:1, 1:20-20:1, 1:10-10:1, and 1:5-5:1. The molar ratio of the first radiolytic stabilizer to the second radiolytic stabilizer may be 1:5-5:1. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 1 μM, 10 μM, 0.1 mM, 1 mM, 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, 500 mM, 1 M, 2 M, 3 M, 4 M, 5 M. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 1 μM to 5 M. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 10 μM to 1 M. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 0.1 mM to 500 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 20 mM to 500 mM, about 50 mM to about 500 mM, about 75 mM to about 250 mM, or about 250 to about 500 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 50 mM to 200 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 75 mM to 150 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 25 mM to 250 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 10 mM to 500 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 20 mM to 100 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at a concentration of about 25 mM to 75 mM. The radiolytic stabilizer may be present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. The radiolytic stabilizer may 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 radiolytic stabilizer may be present in the radiopharmaceutical composition at about 0.01 wt% to about 5 wt%.The radiolytic stabilizer may 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 radiolytic stabilizer may be present in the radiopharmaceutical composition at about 5 wt%. The radiolytic stabilizer may be present in the radiopharmaceutical composition at about 0.05 wt% to about 2 wt%. The radiolytic stabilizer may be present in the radiopharmaceutical composition at about 0.1 wt% to about 1 wt%. The radiolytic stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.0001 to 5,000 mg / mL. The radiolytic stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 500 mg / mL. The radiolytic stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. The radiolytic stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.1-5 mg / mL. The radiolytic stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.5-2 mg / mL. In some embodiments, the radiolytic stabilizer is dextran (e.g., Dextran 40). In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 1 mM-10 M. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 10 mM-1 M. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 20 mM-500 mM. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 40 mM-250 mM. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 20 mM-300 mM. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 80 mM-125 mM. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, the radiolytic stabilizer is present in the radiopharmaceutical composition at a concentration of 100 mM. In some embodiments, the radiolytic stabilizer is ascorbic acid or a salt thereof (such as sodium ascorbate). In some embodiments, the radiolytic stabilizer is ascorbic acid. In some embodiments, the radiolytic stabilizer is sodium ascorbate.In some embodiments, the radiolytic stabilizer is ethanol. In some embodiments, the radiolytic stabilizer is gentisic acid. In some embodiments, the radiolytic stabilizer is a salt of gentisic acid.

[0097] The radiolytic stabilizer may include an amino acid or a derivative thereof. The radiolytic stabilizer may include a peptide or a derivative thereof. The amino acid or a derivative thereof may be a natural amino acid or a non-natural amino acid. The amino acid may act to capture chemically active moieties generated by radiolysis. The amino acid may include an amino group. The amino acid may optionally include an additional reduced heteroatom such as L-methionine, L-cysteine, or L-lysine. The peptide or derivative thereof may include two or more amino acids. The peptide may include 2 to 50 amino acids. The peptide may include 2 to 30 amino acids. The peptide may include 2 to 15 amino acids. The peptide may include 2 to 7 amino acids. The peptide may include 2 to 4 amino acids. The peptide may include 3 amino acids. The amino acid may be an essential amino acid. The amino acid may be a non-essential amino acid. The amino acid may be an aliphatic amino acid. The amino acid may be an aromatic amino acid. The amino acid may be an acidic amino acid. The amino acid may be a basic amino acid. The amino acid may be a hydroxyl amino acid. The amino acid may be a sulfur-containing amino acid. The amino acid may be an amino acid amide. The amino acid, its derivative, or peptide may 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 their derivatives. The amino acid may be methionine. Amino acid derivatives such as N-acetyl-L-cysteine ​​may have higher solubility than the parent amino acid. Radiolytic stabilizers such as thiourea, L-glutathione, and lipoic acid may contain organic sulfur. The organic sulfur may optionally be oxidized to a higher oxidation state and coordinated to free heavy metal ions in solution.

[0098] The radiolytic stabilizer may include an antioxidant (or reducing agent or radical scavenger). The radiolytic stabilizer may include one or more antioxidants. The antioxidant may include a flavonoid or a derivative thereof. The flavonoid may be a polyphenolic compound containing multiple phenolic moieties. The flavonoid may include a 15-carbon structure. The 15-carbon structure may further include two phenyl rings and one heterocyclic ring. The flavonoid may include a bioflavonoid, isoflavonoid, or neoflavonoid. Flavonoids include catechin or its derivatives, such as the compounds shown in Figure 1, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e., CG), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin, i.e., EC), 3,4,5-trihydroxybenzoate (gallate), (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4, The formulation may include 5-trihydroxybenzoate (epigallocatechin gallate, or EGCg), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol or epigallocatechin (EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, or GC). The catechin may be administered to humans at a dose of 1 mg / kg to 50 mg / kg, 5 mg / kg to 40 mg / kg, 10 mg / kg to 40 mg / kg, or 20 mg / kg to 35 mg / kg.The flavonoids are (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate) ((-)catechin gallate, i.e., CG), 3,3',4',5,5',7-hexahydroxyflavylium chloride, (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin, i.e., EC), 7-hydroxy-3-(4'-methoxyphenyl)-4H-benzopyran-4-one, and 3,4,5-trihydroxybenzoate. Hydroxybenzoate (gallate), 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-trihydroxybenzoate (gallate), 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-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one (rutin hydrate), quercetin, (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl],3,4,5-trihydroxybenzoate (epigallocatechin gallate, i.e., EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl],3,4,5-trihydroxybenzoate, i.e., epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3,5,7-triol (gallate epigallocatechin, or EGC), or (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, or GC). In some embodiments, the antioxidant is a carotenoid or a derivative thereof. The carotenoid may be a fat-soluble pigment, such as a yellow, orange, or red pigment. The carotenoid may be all-trans-fucoxanthin, lycopene, xanthophyll, beta-carotene, lycopene, or lutein.

[0099] In some embodiments, the pharmaceutical compositions described herein comprise N-acetylcysteine, L-ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-propenoic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e. CG), 1,4,5-trihydroxycyclohexanecarboxylic acid, trans-4-hydroxycinnamic acid (p-coumaric acid), 3,3',4',5,5',7-hexahydroxyflavylium chloride, thiocyanic acid (dihydrolipoic acid, DHLA), 4,4',5,5',6,6'-hexahydroxydiphenolic acid 2,6,2',6'-dilactone (ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epi-catechin, i.e., 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-trihydroxybenzoate (gallate), (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((-)-gallocatechin), glutathione, 2-(3,4-dihydro (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, (+)-α-tocopherol, xanthophyll, citric acid (CA), gentisic acid (GA), salicylic acid (SA), erythorbic acid (EA), phenol, sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene, metabisulfite, benzyl alcohol, thiamine mononitrate, thiazolinone ... Mol, lipoic acid (LA), thioglycolic acid (TGA), 2,3-dimercaptopropan-1-ol (BAL), zinc, selenium, albumin, ethanol, mannitol, sucrose, melatonin, ebselen, pyruvate, carboxy-PTIO, trolox, ebselen, uric acid, edaravone, beta-carotene, NADPH, lycopene, lutein, catalase, estrogen, estradiol, estriol, ubiquinol, copper, quercetin, cortisone, Urine, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate, i.e., EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate, i.e., epicatechin gallate (EC G), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin, or EGC), (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, or GC), (-)-cis-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,Antioxidants include 7-triol 3-gallate ((-)-epigallocatechin-3-O-gallate), 5-aminolevurivic acid hydrate, proisolbate 80, gallic acid, sodium L-ascorbate, hyaluronic acid, dextran 60-90, selenol, LysaKare, or combinations thereof. Exemplary antioxidants of the present disclosure are further described in Table 1.

[0100] [Table 1-1]

[0101] [Table 1-2]

[0102] In some embodiments, the radiolytic stabilizer comprises a salt, ester, amide, enantiomer, or acetylated derivative, or a combination thereof, of a compound in Table 1. In some embodiments, the radiolytic stabilizer functions as a pH stabilizer.

[0103] The radiolytic stabilizer may include a vitamin or derivative thereof. The radiolytic stabilizer may include one or more vitamins or derivatives thereof. In some embodiments, the vitamin or derivative thereof is L-ascorbic acid, β-carotene, provitamin A, (+)-α-tocopherol, erythorbic acid (EA), trolox, or lutein. In some embodiments, the radiolytic stabilizer is ascorbic acid or a salt thereof (such as sodium ascorbate). In some embodiments, the radiolytic stabilizer is ascorbic acid. In some embodiments, the radiolytic stabilizer is sodium ascorbate. In some embodiments, the radiolytic stabilizer is ethanol. In some embodiments, the radiolytic stabilizer is gentisic acid. In some embodiments, the radiolytic stabilizer is a salt of gentisic acid.

[0104] In some embodiments, the radiolytic stabilizer comprises ascorbic acid or a salt thereof. In some embodiments, the radiolytic stabilizer comprises sodium L-ascorbate. In some embodiments, the radiolytic 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 radiolytic 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 radiolytic 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 radiolytic 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 radiolytic 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 radiolytic 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 radiolytic stabilizer comprises sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of 100 mM. In some embodiments, the radiolytic stabilizer comprises ascorbic acid or a salt thereof. In some embodiments, the radiolytic 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 radiolytic 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 radiolytic 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 radiolytic 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 radiolytic stabilizer comprises ascorbic acid or a salt thereof and is present in the radiopharmaceutical composition at a concentration of 20 mM to 300 mM.In some embodiments, the radiolytic 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 radiolytic 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 radiolytic stabilizer comprises ascorbic acid or a salt thereof and is present in the radiopharmaceutical composition at a concentration of 100 mM.

[0105] In some embodiments, ascorbic acid or a salt thereof (e.g., sodium ascorbate) is present in the radiopharmaceutical composition at a concentration of 1 mM to 10 M. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 10 mM to 1 M. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 20 mM to 500 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 80 mM to 125 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 90 mM to 110 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 100 mM. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 1 mg / mL to 100 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 5 mg / mL to 50 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 10 mg / mL to 30 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5±4.63 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5±5 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 18.5±10 mg / mL. In some embodiments, sodium ascorbate is present in the radiopharmaceutical composition at a concentration of about 18.5 mg / mL. In some embodiments, sodium L-ascorbate is sodium L-ascorbate.

[0106] The radiolytic stabilizer may comprise a fatty acid or a derivative thereof. The radiolytic stabilizer may comprise one or more lipids. The lipid may be a fatty acid or a derivative 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 may comprise a monounsaturated fatty acid. The fatty acid may comprise a polyunsaturated fatty acid. The fatty acid may comprise a trans fat. The fatty acid may comprise a C3-C 40 fatty acids, C6-C 30 fatty acids, C6-C 20 Fatty acids, and C6-C 10 In some embodiments, the fatty acid may be C6-C 30 Fatty acids are saturated or unsaturated C6-C 30 The fatty acid may be saturated or unsaturated C 19 -C 20 The fatty acid may be saturated or unsaturated C 12 -C 26 Fatty acids may be included, in some embodiments, the fatty acids include oleic acid, myristoleic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, or linoleic acid, alpha-linolenic acid, or combinations thereof.

[0107] In some embodiments, the radiolytic stabilizer comprises a lipid that is a steroid or a derivative thereof. In some embodiments, the steroid may be a corticosteroid, such as estrogen, estradiol, estriol, or cortisone. The steroid may have a four-carbon ring. In some embodiments, the steroid may be estrogen, estradiol, estriol, or cortisone.

[0108] The radiolytic stabilizer may include a bulking agent. In some embodiments, the bulking agent is present in the radiopharmaceutical composition at a concentration of about 0.001 wt% to about 80 wt%. In some embodiments, the bulking agent can increase the volume of a fluid, such as human blood volume. The bulking agent can act as an absorbable radioprotector. The bulking agent can mimic human serum albumin. The bulking agent may include human albumin. The bulking agent may include a polymer, such as polyethylene glycol (PEG), a glucose polymer, or a polymer mixture. The glucose polymer may be a sugar, such as dextran or an oligosaccharide. The glucose polymer may have a number average molecular weight of 1 kDa to 40,000,000 kDa, 5 kDa to 1,000,000 kDa, 10 kDa to 500,000 kDa, 15 kDa to 1,000 kDa, 20 kDa to 100 kDa, or 30 kDa to 50 kDa. The glucose polymer may have an average molecular weight of about 20 to 60 kDa, for example, about 40 kDa. The glucose polymer may be linear or cyclic. The cyclic glucose polymer may be a cyclic oligosaccharide such as cyclodextrin. The cyclodextrin may include a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. The macrocyclic ring may include 6 to 8 glucose subunits, such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. The polymer mixture, such as an artificial colloid, may include 0.001 wt% to 80 wt% glucose polymer. The polymer mixture may include 0.1 wt% to 50 wt% glucose polymer. The polymer mixture may include 1 wt% to 20 wt% glucose polymer. The polymer mixture may include 5 wt% to 15 wt% glucose polymer. The polymer mixture may contain 0.1 wt% to 15 wt% glucose polymers, or 1 wt% to 10 wt% glucose polymers. The dextran may be dextran 40 and dextran 70. The dextran may have a number average molecular weight of about 5 to 100 kDa. The dextran may have a number average molecular weight of about 40 to 70 kDa.The dextran may have a number-average molecular weight of 40, 60, or 70 kDa. Dextran 40 may be provided as a dextran 40 mixture, such as a 10% dextran 40 in 0.9% sodium chloride solution in an infusion bag. The dextran 40 may contain 0.1 wt% to 15 wt% dextran 40, or 1 wt% to 10 wt% dextran 40. The dextran 40 mixture may have a total osmolality of 300 mOsmol / L to 450 mOsmol / L. The dextran 40 mixture may have a total osmolality of 350 mOsmol / L to 420 mOsmol / L. The dextran 40 mixture may have a total osmolality of 380 mOsmol / L to 400 mOsmol / L. The dextran 40 mixture may have a total osmolality of 390 mOsmol / L. The polymer may be polyethylene glycol (PEG), such as PEG 4000 or PEG 3350. In some embodiments, the PEG has a number-average molecular weight of about 200 to 20,000, 1000 to 10,000, 2000 to 8000, 3000 to about 5000, or 3000 to 4000. The polymer mixture may include a combination of PEG, PEG 3350, such as PLENVU, sodium ascorbate, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride. The polymer may be gelatin or a modified gelatin, such as polygeline and succinylated gelatin. The polygeline may have a number-average molecular weight of 5 kDa to 50 kDa, 10 kDa to 45 kDa, 20 kDa to 50 kDa, or 30 kDa to 40 kDa. The polygeline may have an average molecular weight of 35 kDa. The polymer mixture may also contain polygeline. Mixtures containing polygeline, such as Haemaccel, may also contain calcium chloride, potassium chloride, and / or sodium chloride. The polymer mixture may also contain a modified fluid gelatin, such as succinated gelatin. The polymer mixture may also be a solution, such as Gelofusine, which may contain 4% w / v succinated gelatin.

[0109] The radiolytic stabilizer may include a carbohydrate or derivative thereof. The carbohydrate may be a sugar. The sugar may be a monosaccharide. The sugar may be a disaccharide, oligosaccharide, or polysaccharide. Exemplary disaccharides include mannitol and sucrose. The polysaccharide may be a dextran, such as dextran 40 and dextran 70. The dextran may have a molecular weight of about 10 to 200, 20 to 100, 30 to 50, or 40 to 70 kDa. The polysaccharide may have a number average molecular weight of 5 kDa to 1,000,000 kDa, 10 kDa to 500,000 kDa, 15 kDa to 1,000 kDa, 20 kDa to 100 kDa, or 30 kDa to 80 kDa. The oligosaccharide may be a cyclic oligosaccharide, such as a cyclodextrin. Cyclodextrins may contain a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. The macrocyclic ring may contain six to eight glucose subunits, such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. The polysaccharide may be dextran. The carbohydrate may be mannitol, sucrose, dextran (e.g., dextran 40, dextran 70), or a cyclodextrin (α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin), such as 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutylether-β-cyclodextrin (SEB-β-CD).

[0110] Free metal chelators The one or more stabilizers may comprise a free metal chelator. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more free metal chelators. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for capturing free radionuclides in the radiopharmaceutical composition. The means for capturing free radionuclides in the radiopharmaceutical composition may be a free metal chelator described herein. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for capturing free radionuclides in the radiopharmaceutical composition to maintain low levels of free radionuclides (such as free Ac-225). In some embodiments, the level of free radionuclide (such as free Ac-225) in the composition is maintained at less than about 0.05 mCi / L. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a free metal chelator configured to maintain low levels of free radionuclides in the composition. In some embodiments, the level of free radionuclide in the composition is maintained at less than about 0.01 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained at less than about 1 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained at less than about 0.5 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained at less than about 0.001 mCi / L. In some embodiments, the level of free radionuclide in the composition is maintained at less than 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 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 20° C. to about 25° C.

[0111] In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more free metal chelators. The one or more stabilizers may comprise two or more free metal chelators. In some embodiments, the free metal chelators are not bound to a targeting ligand. The one or more stabilizers may comprise a first free metal chelator and a second free metal chelator. In some embodiments, the molar ratio of the first free metal chelator to the second free metal chelator is 1:100,000-100,000:1, 1:1,000-1,000:1, 1:100-100:1, 1:20-20:1, 1:10-10:1, and 1:5-5:1. In some embodiments, the molar ratio of the first free metal chelator to the second free metal chelator is 1:5-5:1. The free metal chelating agent may be present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. The free metal chelating agent may 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 chelating agent may be present in the radiopharmaceutical composition at about 0.01 wt% to about 5 wt%. The free metal chelating agent may be present in the radiopharmaceutical composition at about 0.05 wt% to about 2 wt%. The free metal chelating agent may be present in the radiopharmaceutical composition at about 0.1 wt% to about 1 wt%. The free metal chelator may also be present in the radiopharmaceutical composition at a concentration of 0.0001 to 5,000 mg / mL. The free metal chelator may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 500 mg / mL. The free metal chelator may also be present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. The free metal chelator may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL. The free metal chelator may also be present in the radiopharmaceutical composition at a concentration of 0.5 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 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 5 mg / mL.In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelator is selected from Table 2.

[0112] The free metal chelator may be linear or cyclic. Linear free metal chelators, such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), may be used as heavy metal poisoning antidotes or free heavy metal scavengers. DTPA may be present in the radiopharmaceutical composition at a concentration of 0.001 mg / mL to 2.5 mg / mL, 0.01 mg / mL to 5 mg / mL, 0.02 mg / mL to 3 mg / mL, 0.04 mg / mL to 1 mg / mL, or 0.05 mg / mL to 0.1 mg / mL. In some embodiments, the free metal chelator (e.g., DTPA) is present in the radiopharmaceutical composition at a concentration of about 0.05 mg / mL. In some embodiments, the free metal chelator (e.g., 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 (e.g., DTPA) is present in the radiopharmaceutical composition at a concentration of about 0.02-0.07 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.001 mg / mL-10 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 / mL-10 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 / mL-5 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.02 mg / mL-2.5 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.04 mg / mL-1 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 / mL to 0.25 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.02 mg / mL to 0.125 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.04 mg / mL 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 / mL 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.

[0113] In some embodiments, the radiopharmaceutical compositions disclosed herein comprise 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 0.01-0.1 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01-2 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01-3 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01-4 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.01-5 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of about 0.02-0.07 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 10 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 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 0.001 mg / mL to 10 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.02 mg / mL to 2.5 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.04 mg / mL to 1 mg / mL. In some embodiments, the free metal chelator is present in the radiopharmaceutical composition at a concentration of 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 of 0.02 mg / mL to 0.125 mg / mL. In some embodiments, the free metal chelator is DTPA and is present in the radiopharmaceutical composition at a concentration of 0.04 mg / mL to 0.06 mg / mL, hi 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 liver toxicity caused by free radioactive metal ions when administered to a subject, such as a human subject. The cyclic free metal chelator may be a macrocyclic free metal chelator such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA). Macrocyclic free metal chelators have strong chelating ability and may be used at low concentrations.The free metal chelators were 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, 2,2',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(methylenephosphonic 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(methylenephosphonic acid) (DOTP), 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (Macro The free metal chelator may include 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 two compounds selected from Table 2 or salts thereof. In some embodiments, the free metal chelator comprises three compounds selected from Table 2 or salts thereof.Exemplary free metal chelators of the present disclosure are further described in Table 2.

[0114] [Table 2]

[0115] pH stabilizer In some embodiments, the radiopharmaceutical compositions disclosed herein comprise one or more pH stabilizers. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for maintaining the pH of the radiopharmaceutical composition. The means for maintaining the pH of the radiopharmaceutical composition may be a pH stabilizer described herein. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for maintaining the pH of the radiopharmaceutical composition at about 4 to 8. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for maintaining the pH of the radiopharmaceutical composition at about 5 to 7. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for maintaining the pH of the radiopharmaceutical composition at about 6 to 8. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for maintaining the pH of the radiopharmaceutical composition at about 5.5 to 6.5. In some embodiments, the radiopharmaceutical compositions described herein comprise a means for maintaining the pH of the radiopharmaceutical composition at about 4 to 7. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain the pH of the composition. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain a pH of 4 to 8 in the composition. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain a pH of 5 to 7 in the composition. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain a pH of 6 to 8 in the composition. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain a pH of 5.5 to 6.5 in the composition. In some embodiments, the radiopharmaceutical compositions disclosed herein comprise a pH stabilizer configured to maintain a pH of 4 to 7 in the composition.

[0116] In some embodiments, the stability of the described radiopharmaceutical compositions may vary at various pH values. If the pH is outside a certain range, leakage of the radiometal may also affect the radiochemical purity of the formulated dose and shorten its shelf life. Therefore, in some embodiments, one or more stabilizers may include a pH-stabilizing buffer in addition to a radiolysis protectant and / or a free metal chelator. In some embodiments, the radiopharmaceutical compositions disclosed herein include one or more pH stabilizers. Exemplary pH stabilizers include aqueous buffers of sodium acetate / acetic acid and sodium L-ascorbate / L-ascorbic acid.

[0117] The one or more stabilizers may include one or more pH stabilizers. The one or more pH stabilizers may function as a pH buffer. The one or more pH stabilizers may function as a pH buffer. The one or more pH stabilizers may include an organic acid. The organic acid may include acetic acid, fumaric acid, ascorbic acid, propionic acid, benzenesulfonic acid, carbonic acid, citric acid, aspartic acid, maleic acid, methanesulfonic acid, or tartaric acid. The one or more pH stabilizers may include 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 may include a base. The base may include tromethamine (Tris), ammonium hydroxide, diethanolamine, sodium hydroxide, or a combination thereof. The one or more pH stabilizers may include an amino acid or a salt thereof. The one or more pH stabilizers may include glycine, lysine, arginine, histidine, or a salt thereof. The one or more pH stabilizers may include an alkali salt. The alkali salt may include sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium phosphate, monosodium phosphate, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate, or a combination thereof. The sodium ascorbate may be present in the radiopharmaceutical composition at a concentration of about 50 mM to 200 mM. The one or more pH stabilizers may include an acid salt. The acid salt may be ammonium sulfate.The one or more pH stabilizers may include sodium acetate, sodium ascorbate, ascorbic acid, acetic acid, fumaric acid propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (1)-lysine, maleic acid, methanesulfonic acid, phosphoric acid, monosodium phosphate, trisodium phosphate, disodium phosphate, sodium hydroxide, sodium succinate / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (Tris), or combinations thereof. Exemplary pH stabilizers of the present disclosure are further described in Table 3.

[0118] [Table 3]

[0119] In some embodiments, the pH stabilizer can attenuate pH changes to maintain radiopharmaceutical purity, thereby reducing conjugate degradation and thereby extending the shelf life of the radiopharmaceutical compositions described herein. The one or more stabilizers may comprise a pH stabilizer. The one or more stabilizers may comprise two or more pH stabilizers. The one or more stabilizers may comprise a first pH stabilizer and a second pH stabilizer. In some embodiments, the molar ratio of the first pH stabilizer to the second pH stabilizer is 1:100,000-100,000:1, 1:1,000-1,000:1, 1:100-100:1, 1:20-20:1, 1:10-10:1, and 1:5-5:1. In some embodiments, the molar ratio of the first pH stabilizer to the second pH stabilizer is 1:5-5:1. The pH stabilizer may be present in the radiopharmaceutical composition at about 0.001 wt% to about 10 wt%. The pH stabilizer may 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 may be present in the radiopharmaceutical composition at about 0.01 wt% to about 5 wt%. The pH stabilizer may be present in the radiopharmaceutical composition at about 0.05 wt% to about 2 wt%. The pH stabilizer may be present in the radiopharmaceutical composition at about 0.1 wt% to about 1 wt%. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of about 1 μM, 10 μM, 0.1 mM, 1 mM, 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, 500 mM, 1 M, 2 M, 3 M, 4 M, or 5 M. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of about 1 μM to 5 M. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of about 10 μM to 1 M. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of about 0.1 mM to 500 mM. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of about 10 mM to 500 mM. The pH stabilizer may be present in the radiopharmaceutical composition at a concentration of about 50 mM to 250 mM.The pH stabilizer may be present in the radiopharmaceutical composition at a concentration of about 25 mM to 350 mM.The pH stabilizer may be present in the radiopharmaceutical composition at a concentration of about 80 mM to 200 mM. The pH stabilizer may be present in the radiopharmaceutical composition at a concentration of about 80 mM to 120 mM. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.0001 to 5,000 mg / mL. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 500 mg / mL. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.01 to 50 mg / mL. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL. The pH stabilizer may also be present in the radiopharmaceutical composition at a concentration of 0.5 to 2 mg / mL. In some embodiments, the pH stabilizer comprises a compound selected from Table 3 or a combination thereof.

[0120] The radiopharmaceutical compositions described herein may have a suitable pH value. One or more pH stabilizers may be configured to maintain the pH of the radiopharmaceutical composition at about 3 to about 9, about 4 to about 8, or about 5 to about 7. The pH of the radiopharmaceutical composition may be within the range of about 3 to about 9. The pH of the radiopharmaceutical composition may be within the range of about 4 to about 8. The pH of the radiopharmaceutical composition may be within the range of about 5 to about 7. In some embodiments, the pH of the radiopharmaceutical composition is about 4.0 to about 9.0, about 4.5 to about 8.5, about 5.0 to about 8.0, about 5.5 to about 7.75, about 6.0 to about 7.5, about 6.5 to about 7.25, or 6.75 to about 7.25. The pH of the radiopharmaceutical composition may be about 4.0 to about 9.0. The pH of the radiopharmaceutical composition may be about 4.5 to about 8.5. The pH of the radiopharmaceutical composition may be about 5.0 to about 8.0. The pH of the radiopharmaceutical composition may be about 5.0 to about 7.0. The pH of the radiopharmaceutical composition may be about 5.5 to about 6.5. The pH of the radiopharmaceutical composition may be about 5.5 to about 6. The pH of the radiopharmaceutical composition may be about 5.6 to about 5.8. The pH of the radiopharmaceutical composition may be about 5.75 to about 5.85. The pH of the radiopharmaceutical composition may be about 5.5 to about 7.75. The pH of the radiopharmaceutical composition may be about 6.0 to about 7.5. The pH of the radiopharmaceutical composition may be about 6.5 to about 7.25. The pH of the radiopharmaceutical composition may 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.

[0121] The radiopharmaceutical composition may comprise one or more radiolysis stabilizers, one or more free metal chelators, and / or one or more pH stabilizers. The radiopharmaceutical composition may comprise one or more radiolysis stabilizers. The radiopharmaceutical composition may comprise one or more free metal chelators. The radiopharmaceutical composition may comprise one or more pH stabilizers.

[0122] In some embodiments, the radiopharmaceutical compositions described herein comprise (a) a conjugate (e.g., 225 Ac-DOTA-TATE or 225 (Ac-DOTA-TOC), (b) a pH stabilizer present in the radiopharmaceutical composition at a concentration of about 80 to about 120 mM, (c) optionally a radiolysis stabilizer present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 10 wt%, (d) a free metal chelator present in the radiopharmaceutical composition at a 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 10-25 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 12-23 mCi / L. In some embodiments, the radiopharmaceutical compositions described herein comprise (a) a conjugate (e.g., 225 Ac-DOTA-TATE or 225(Ac-DOTA-TOC), (b) a pH stabilizer, which 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, which is dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 0.1 wt% to about 10 wt%; (d) a free metal chelator, which 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, which is saline. 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) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 25-35 mCi / L; (b) a pH stabilizer, which is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a radiolysis stabilizer, which is dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 4-6 wt%; (d) a free metal chelator, which 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, which is sodium chloride saline at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 10-25 mCi / L; (b) a pH stabilizer, which is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a radiolysis stabilizer, which is dextran 40 and is present in the radiopharmaceutical composition at a concentration of about 4-6 wt%; (d) a free metal chelator, which 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, which is sodium chloride saline at a concentration of about 0.9% w / w.In some embodiments, the radiopharmaceutical composition comprises: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 25-35 mCi / L; (b) a pH stabilizer, which is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a free metal chelator, which 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, which is sodium chloride saline at a concentration of about 0.9% w / w. In some embodiments, the radiopharmaceutical composition comprises: (a) a conjugate present in the radiopharmaceutical composition at a concentration equivalent to about 10-25 mCi / L; (b) a pH stabilizer, which is sodium L-ascorbate and is present in the radiopharmaceutical composition at a concentration of about 90-110 mM; (c) a free metal chelator, which 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, which is sodium chloride saline at a concentration of about 0.9% w / w.

[0123] Additional excipients The radiopharmaceutical compositions described herein may include additional excipients, hi some embodiments, the additional excipients include excipients suitable for formulations adapted for intravenous administration.

[0124] In some embodiments, the radiopharmaceutical compositions described herein comprise a surfactant. A "surfactant" may be defined as a surface-active amphiphilic compound, such as a block copolymer. Surfactants may also be referred to as wetting agents. Non-limiting examples of surfactants include poloxamers (e.g., poloxamer 188), sodium lauryl sulfate, sodium deoxycholate, egg yolk phospholipids, gelatin, hydrolyzed lecithin, polyoxyethylated fatty acids, 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 RH60, hydrogenated castor oil POE-60, Protachem CAH-60), poloxamer 188 (Pluronic F68), povidone (polyvinylpyrrolidone, crospovidone), sodium dodecyl sulfate (sodium lauryl sulfate), aluminum monostearate, sorbitol, and Triton X-100 (Octoxynol-9).

[0125] The surfactant used in the present disclosure may include a nonionic surfactant. A nonionic surfactant does not have a charged group at its head. Exemplary nonionic surfactants include, but are not limited to, 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 and pentaethylene glycol monododecyl ether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, and 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 polysorbates), sorbitan alkyl esters (such as Span), cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers), and polyethoxylated tallow amine (POEA). In some embodiments, the surfactant is a nonionic surfactant comprising polyethylene glycol. In some embodiments, the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol.

[0126] In some embodiments, the nonionic surfactant has a number average molecular weight of about 1000 to about 100,000 Da, 2000 to about 20,000 Da, about 4000 to about 15,000 Da, about 6000 to about 12,000 Da, or about 7000 to about 10,000 Da. In some embodiments, the nonionic surfactant has a number average molecular weight of about 7000 to about 10,000 Da. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 30 wt% to about 99 wt%, about 50 wt% to about 95 wt%, about 60 wt% to about 95 wt%, about 75 wt% to about 90 wt%, or about 80 wt% to about 85 wt%. In some embodiments, the nonionic surfactant has an ethylene glycol content of about 80 wt% to about 85 wt%.

[0127] The surfactant used in the present disclosure may include cationic surfactants, such as pH-dependent primary, secondary, or tertiary amines, such as octenidine dihydrochloride, and permanently charged quaternary ammonium salts, such as cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide (DODAB).

[0128] The surfactant used in the present disclosure may include anionic surfactants. Anionic surfactants contain anionic functional groups in their head groups, such as sulfate, sulfonate, phosphate, and carboxylic acid. Exemplary anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, i.e., SLS or SDS), and related alkyl ether sulfates, sodium laureth sulfate (sodium lauryl ether sulfate, i.e., SLES), sodium myreth sulfate, docusate (sodium dioctyl sulfosuccinate), perfluorooctane sulfonic acid (PFOS), perfluorobutane sulfonic acid, alkyl-aryl ether phosphate, and alkyl ether phosphate.

[0129] The surfactant used in the present disclosure may be a zwitterionic surfactant. Zwitterionic (amphoteric) surfactant refers to a surfactant that has a cationic center and an anionic center attached to the same molecule. Exemplary zwitterionic surfactants include, but are not limited to, the phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin.

[0130] In some embodiments of the present disclosure, the concentration of the surfactant described herein in the liquid pharmaceutical composition is 0.1% to 15% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.5% to 8% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.5% to 6% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.25% to 8% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 8% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.5% to 5% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 10% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 6% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 0.75% to 4% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 1% to 4% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 1% to 6% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 5% to 10% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 5% to 15% by weight. In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is 10% to 25% by weight.

[0131] In some embodiments, the radiopharmaceutical compositions described herein comprise a tonicity adjusting agent. Exemplary tonicity adjusting agents include dextrose, glycerin, mannitol, potassium chloride, and sodium chloride.

[0132] In some embodiments, the radiopharmaceutical compositions described herein comprise a special additive. In some embodiments, the special additive is acetyltryptophan, aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate, amino acids (leucine, isoleucine, lysine (as acetate or HCl salt), valine, phenylalanine, threonine, tryptophan, alanine, aspartic acid, glutamic acid, proline, serine, tyrosine, taurine), ε-aminocaproic acid, D-calcium saccharinate, sodium caprylate, 8-chlorotheophylline, creatine, creatinine, cholesterol, sodium cholesteryl sulfate, cyclohexanedione dioxime, diethanolamine, distearylphosphatidylcholine, distearylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine ... Myristoyl phosphatidylglycerol, dioleoyl phosphatidylcholine (DOPC), dipalmitoyl phosphatidylglycerol (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-phosphapentacosane-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]-ω-methoxypoly(ox-1,2-ethanediyl), monosodium salt (MPEG5000 DPPE), MPEG-distearoylphosphoethanolamine, ethyl lactate, ethylenediamine, sodium L-glutamate, sodium hyaluronate, hydrogenated soy phosphatidylcholine, ammonium ferric citrate, lactic acid, D,Contains: L-lactic and glycolic acid copolymer, meglumine, methylboronic acid, niacinamide, paraben methyl, phosphatidylglycerol, egg (EPG), potassium sodium tartrate, protamine (as sulfate), simethicone, sodium saccharin, sodium D-gluconate, sodium hypochlorite, sodium sulfate, stannous chloride, disodium sulfosalicylate, stannous chloride (stannous oxide and stannic oxide), tri-n-butyl phosphate, tricaprylin, triolein, von Willebrand factor, zinc, zinc acetate, zinc carbonate, zinc oxide, or combinations thereof.

[0133] In some embodiments, the radiopharmaceutical compositions described herein comprise a suspending agent, non-limiting examples of which include carboxymethylcellulose (CMC), croscarmellose sodium, CMC sodium, xanthan gum, hydroxylethylcellulose (HEC), hydroxylpropylmethylcellulose (HPMC), and Avicel CL-611. Further exemplary suspending agents include celluloses such as carboxymethylcellulose (sodium and other salts), carboxy-vinyl copolymers, carboxymethylhydroxyethylcellulose, microcrystalline cellulose, mixtures of microcrystalline cellulose and sodium carboxymethylcellulose (such as Avicel RC-501, RC-581, RC-591, and CL-611), hydrophobically modified hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropyl guar, hydroxypropylmethylcellulose (such as Benecel K750® or Benecel K1500®), hydroxypropylcellulose, methylcellulose, natural gums and their derivatives, xanthan gum, guar gum, gum arabic, partial and complete hydrolyzates of polyvinyl alcohol, partially neutralized polyacrylic acid, polyalkylene glycols, polysaccharide gums, polyvinylpyrrolidone and its derivatives, starch and its derivatives, homopolymers and copolymers of vinylpyrrolidone, water-soluble cellulose ethers, and mixtures thereof.

[0134] These compositions can be sterilized by conventional sterilization techniques. The resulting aqueous solution can be packaged for use or filtered under aseptic conditions and then lyophilized. The lyophilized preparation can be mixed with a sterile aqueous solution before administration. The composition can contain pharmaceutically acceptable auxiliary substances as needed to approximate physiological conditions, including tonicity adjusters, such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, sorbitan monolaurate, triethanolamine oleate, etc. Pharmaceutical compositions can be selected according to physical characteristics, including, but not limited to, fluid volume, viscosity, and other parameters depending on the particular mode of administration selected.

[0135] Conjugates In one aspect, provided herein is a radiopharmaceutical composition comprising a conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof. The radiopharmaceutical composition may further comprise a pharmaceutically acceptable carrier, such as an aqueous vehicle. Physiological saline can be used as a pharmaceutically acceptable carrier. Other suitable carriers or aqueous vehicles include, for example, water, buffered water, 0.9% isotonic saline, 0.4% saline, 0.3% glycine, etc., which may include glycoproteins to enhance stability, such as albumin, lipoproteins, globulins, 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. In some embodiments, the conjugate is 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC, 225 Ac-HA-DOTA-TATE, or 225 Ac-DOTA-JR-11.

[0136] The amount of conjugate administered will depend on the particular targeting moiety used, the disease state being treated, the therapeutic agent being delivered, and the judgment of the clinician.

[0137] The concentration of the conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutical formulation can vary. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount of 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%, 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 in an amount of about 0.05% to about 1% by weight. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount of about 0.1% to about 5% by weight.

[0138] 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 1-100 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 15-45 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-35 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-25 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 12-23 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-200 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100-500 μCi / mL. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100-1000 μCi / mL. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of up to about 5, 10, 15, 50, 75, 100, 200, or 500 μCi / ml, hi some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of up to 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 up to about 15 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1-15 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of up to about 35 μCi / ml. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1-35 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 up to about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 50, 75, 100, 125, 150, or 200 μCi / ml.

[0139] 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 1-100 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 15-45 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-35 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-25 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 12-23 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 10-200 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100-500 mCi / L. In some embodiments, the conjugate is present in the radiopharmaceutical composition at a concentration equivalent to about 100-1000 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of up to 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 up to 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 up to about 15 mCi / L.In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1-15 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of up to about 35 mCi / L. In some embodiments, the conjugate is present in the pharmaceutical composition in an amount that provides a radioactivity of about 1-35 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.

[0140] The compositions described herein may include a conjugate comprising actinium-225, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity of about 0.005 to 1000 MBq / mL per volume. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity of about 0.5 to 20 MBq / mL per volume. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity of about 0.4 to 20 MBq / mL per volume. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity of about 0.2 to 5 MBq / mL per volume. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity of about 0.4 to 1 MBq / mL per volume. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity per volume of about 0.1 to 100 MBq / mL, hi some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity per volume of about 0.1 to 100, about 0.1 to 50, about 0.1 to 25, about 0.1 to 10, about 0.1 to 5, about 1 to 100, about 0.5 to 10, about 0.5 to 50, about 10 to 100, about 10 to 50, about 10 to 20, about 1 to 10, or about 1 to 20 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity per volume of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30 MBq / mL.In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity per volume of at least about 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 MBq / mL. In some embodiments, actinium-225 is present in the radiopharmaceutical compositions described herein to provide a radioactivity per volume of up to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50 MBq / mL. In some embodiments, the compositions described herein contain a total DOTA-TATE peptide concentration (e.g., unlabeled DOTATATE) of 11.5 μg / mL or less. 225 In some embodiments, the compositions described herein have a total DOTA-TATE peptide concentration of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 50 μg / mL. In some embodiments, the compositions described herein have a total DOTA-TATE peptide concentration of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 μg / mL.

[0141] The compositions described herein may comprise a conjugate or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient or carrier. The conjugates described may be substantially pure in that they contain, for example, less than about 10% by weight, less than about 5% by weight, or less than about 1% by weight, or less than about 0.1% by weight of other small organic molecules, such as unreacted intermediates or synthetic by-products produced in one or more steps of the synthesis method. The conjugates may be 225 Ac-DOTA-TATE, 225 Ac-DOTA-TOC, or 225The conjugate may be Ac-DOTA-JR-11. 225 The conjugate may be Ac-DOTA-TATE. 225 The conjugate may be Ac-DOTA-TOC. 225 In some embodiments, the conjugate may be: Ac-DOTA-JR-11. 225 Ac-DOTATATE with high affinity (or 225 In some embodiments, HA-DOTATATE has the following structure:

[0142] [ka] It is shown as follows.

[0143] 225 Ac-DOTA-TATE has the following structure:

[0144] [ka] can be shown as having 225 The IUPAC name for Ac-DOTA-TATE is (2,2',2''-(10-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4-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)triacetic acid; Actinium-225(3+)).

[0145] In some embodiments,

[0146] [ka] Provided herein are pharmaceutical compositions comprising a conjugate wherein:

[0147] In some embodiments, the structure

[0148] [ka] Provided herein are pharmaceutical compositions comprising a conjugate having the structure

[0149] [ka] Provided herein are pharmaceutical compositions comprising a conjugate having the formula: and one or more stabilizers. 225 It is understood that the chelating bond between Ac and the metal chelator is not shown. In some embodiments, for example, under acidic aqueous conditions, the radionuclide actinium-225 is in salt form, e.g., 225 Ac3 + In some embodiments, the conjugate is in a salt form. In some embodiments, the conjugate is an acetate salt. In some embodiments,

[0150] [ka] Provided herein are pharmaceutical compositions comprising a conjugate of the formula:

[0151] [ka] Provided herein is a pharmaceutical composition comprising a conjugate of the formula: and one or more stabilizers. 225It is understood that the chelating bond between Ac and the metal chelator is not shown. In some embodiments, for example, under acidic aqueous conditions, the radionuclide actinium-225 is in salt form, e.g., 225 Ac3 + In some embodiments, the conjugate is in a salt form. In some embodiments, the conjugate is an acetate salt. One of ordinary skill in the art will appreciate that acid dissociation may depend on the pH value of the environment and its pK value. Thus, in some embodiments, the conjugates described herein may exist in a fully ionized, partially ionized, or non-ionized form.

[0152] Targeting Ligands In one aspect, provided herein is a radiopharmaceutical composition comprising a conjugate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the conjugates described herein comprise a targeting ligand and a metal chelator.

[0153] The targeting ligands described herein can bind to one or more targets in a system of interest or in an in vitro system. The targeting ligand can target a protein, a receptor on a cell, or other chemical moiety capable of performing a signaling function in a system of interest. The targeting ligand can bind to a receptor on the surface of a cell in a system of interest. In some embodiments, the targeting ligand binds to a somatostatin receptor (SSR). The SSR can be a mammalian SSR. The mammalian SSR can be a human SSR. The human SSR can include somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). The SSR can be human somatostatin receptor type 2 (SSTR2). In some embodiments, the targeting ligand binds to human somatostatin receptor type 2 (SSTR2). The targeting ligand may comprise a peptide and / or a small molecule compound. The targeting ligand may comprise an agonist of the SSR. The targeting ligand may comprise an antagonist of the SSR. The agonist of the SSR may comprise a partial agonist of the SSR. The agonist of the SSR may comprise a full agonist of the SSR. The agonist of the SSR may comprise an inverse agonist of the SSR. The antagonist of the SSR may comprise a competitive antagonist of the SSR. The targeting ligand may comprise an allosteric modulator of the SSR. The allosteric modulator of the SSR may be an allosteric agonist of the SSR. The allosteric modulator of the SSR may be an allosteric antagonist of the SSR.

[0154] The targeting ligands described herein may comprise one or more peptides, which may be the same or different. The peptides may be linear or cyclic. The peptides may be monocyclic. The peptides may comprise a binding peptide. The binding peptides may bind to one or more targets in a subject's system or in an in vitro system. The binding peptides may bind to somatostatin receptors (SSRs). The binding peptides may bind to somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). The binding peptides may bind to somatostatin receptor type 2 (SSTR2). The binding peptides may bind to human somatostatin receptor type 2 (SSTR2).

[0155] A peptide can contain any suitable number of amino acid residues. A peptide may contain 4 to 50, 5 to 40, 6 to 30, 7 to 20, or 8 to 10 amino acid residues. A peptide may contain 6 to 14 amino acid residues. A peptide may contain 6 to 10 amino acid residues. A peptide may contain 7 to 9 amino acid residues. A peptide may contain 8 to 9 amino acid residues. A peptide may contain 14 amino acid residues. A peptide may contain 13 amino acid residues. A peptide may contain 12 amino acid residues. A peptide may contain 11 amino acid residues. A peptide may contain 10 amino acid residues. A peptide may contain 9 amino acid residues. A peptide may contain 8 amino acid residues. A peptide may contain 7 amino acid residues. A peptide may contain 6 amino acid residues. A peptide may consist of 10 amino acid residues. A peptide may consist of 14 amino acid residues. The peptide may consist of 13 amino acid residues. The peptide may consist of 12 amino acid residues. The peptide may consist of 11 amino acid residues. The peptide may consist of 10 amino acid residues. The peptide may consist of 9 amino acid residues. The peptide may consist of 8 amino acid residues. The peptide may consist of 7 amino acid residues. The peptide may consist of 6 amino acid residues. The conjugate may comprise a monocyclic peptide of 6, 7, 8, 9, 10, 11, 12, 13, or 14 amino acid residues. The amino acid residues described herein may be modified to remove or add one or more functional groups.

[0156] The targeting ligand described herein may be a cyclized peptide. Cyclization can be achieved through a single disulfide bond or through a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, CSC bond, CNC bond, C=NC bond, C=NO bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, thioamide bond, etc., but is not limited thereto. The peptide may include a cyclic peptide cyclized by a peptide bond. Peptide cyclization stabilizes the peptide structure, thereby increasing affinity for the target. Cyclization can occur between the N-terminus and C-terminus, or between a terminal amino acid and a non-terminal amino acid. Cyclization can occur between two non-terminal amino acids. The peptide may be cyclized through one or more cysteines. The peptide may include a cysteine ​​at the C-terminus. The peptide may include a cysteine ​​at the N-terminus. Cyclization can occur through disulfide bonds between cysteines or through disulfide bonds between cysteines and thiol-bearing residues.

[0157] Exemplary targeting ligands include BMS-753493, somatostatin or somatotropin-releasing inhibitory factor (SRIF), SRIF-14, SRIF-28, octreotide, octreotate, lanreotide, pasireotide, JR11, L-779,976, BIM-23120, satreotide, depreotide, 18F-KYNDRLPLYISNP (SEQ ID NO: 103), CaIX-P1, and FAP-2286. Targeting ligands include octreotate, octreotide, D-Phe 1 -cyclo(Cys 2 -Tyr 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr 8 (SEQ ID NO: 97) (tyr 3 -octreotate, i.e., TATE), D-Phe 1-cyclo(Cys 2 -Tyr 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr(ol) 8 (SEQ ID NO: 98) (Phe 1 -Tyr 3 Octreotide, edotreotide (i.e., TOC), D-Phe 1 -cyclo(Cys 2 -Phe 3 -D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr(ol) 8 (SEQ ID NO: 99) (OC), D-Phe 1 -cyclo(Cys 2 -1-Nal-D-Trp 4 -Lys 5 -Thr 6 -Cys 7 )Thr(ol) 8 (SEQ ID NO: 100) (NOC), p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2) (SEQ ID NO: 101) (JR11), or p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)-D-Tyr-NH2 (SEQ ID NO: 102) (LM3). 3 -octreotate, edotreotide, octreotide, or octreotide. The targeting ligand may be tyrosine 3 In some embodiments, the targeting ligand may be 3-iodo-tyrosine. 3In some embodiments, the targeting ligand is -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 satreotide. In some embodiments, the targeting ligand is depriotide.

[0158] In some embodiments, the conjugates described herein have the structure:

[0159] [ka] In some embodiments, the conjugates described herein comprise a targeting ligand (JR-11 or satreotide) having the following structure:

[0160] [ka] The compound comprises a targeting ligand (lanreotide) having the formula:

[0161] In some embodiments, the conjugates described herein comprise a targeting ligand that is a binding peptide (e.g., a peptide selected from Table 4). The binding peptide may comprise an amino acid sequence having at least 70% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 75% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 80% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 85% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 85% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 90% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 95% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 98% identity to a sequence selected from SEQ ID NOs: 1-96. The binding peptide may comprise an amino acid sequence having at least 99% identity to a sequence selected from SEQ ID NOs: 1 to 96. The binding peptide may comprise an amino acid sequence selected from SEQ ID NOs: 1 to 96 listed in Table 4.

[0162] [Table 4-1]

[0163] [Table 4-2]

[0164] [Table 4-3]

[0165] Exemplary abbreviations and modifications of Table 4 are shown in Figures 18A and 18B.

[0166] The targeting ligand may include a small molecule compound, such as L-797,591, L-779,976, L-796,778, L-803,087, or L-817,818, the structures of which are shown in Figure 2A.

[0167] The targeting ligand was measured at a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 1 mM or less at a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 1000 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 500 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 250 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 200 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 150 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 100 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 75 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 50 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 25 nM or less, as measured by a 50% inhibitory concentration (IC 50 The targeting ligand may have a binding affinity for the human SSR of about 10 nM or less, as measured by a 50% inhibitory concentration (IC 50The targeting ligand may have a binding affinity for the human SSR of about 5 nM or less, as measured by a 50% inhibitory concentration (IC 50 ) may have a binding affinity for the human SSR of about 2 nM or less. The targeting ligand may comprise a monocyclic peptide or a peptidomimetic or derivative thereof.

[0168] radionuclides In one aspect, conjugates comprising radionuclides are described herein. Exemplary radionuclides include astatine-211, astatine-217, actinium-225, americium-243, radium-223, lead-212, lead-203, copper-64, copper-67, copper-60, copper-61, copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67, dysprosium-154, gadolinium-148, gadolinium-153, samarium-146, samarium-147, samarium-153, terbium-149, thorium-227, thorium-229, iron-59, yttrium-86, indium-111, holmium-166, technetium-94, and technetium-99. m , yttrium-90, lutetium-177, terbium-161, rhenium-186, rhenium-188, cobalt-55, scandium-43, scandium-44, scandium-47, dysprosium-166, fluorine-18, or iodine-131.

[0169] In general, the type of radionuclide used in therapeutic radiopharmaceuticals can be tailored to the specific type of cancer, the type of target moiety, and the like. Radionuclides that undergo α decay produce particles consisting of two neutrons and two protons, while radionuclides that undergo β decay release high-energy electrons from their nuclei. Some radionuclides may also emit Auger. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-stranded DNA breaks, compared to gamma and beta radiation, which cause single-strand breaks through indirect DNA damage. The design of radiopharmaceutical conjugates can also take into account the range of these particles in tissues and the half-life of the radionuclide. Tables 5A and 5B below show some properties of exemplary radionuclides.

[0170] [Table 5-1]

[0171] [Table 5-2]

[0172] In some embodiments, the conjugates described herein comprise one or more independent radionuclides. In some embodiments, the conjugates comprise two radionuclides. In some embodiments, each of the one or more radionuclides is bound to a metal chelator of the conjugate. In some embodiments, the two radionuclides of the conjugate are bound to the same metal chelator. In some embodiments, the two radionuclides of the conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0173] In some embodiments, the conjugates described herein comprise an alpha particle-emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 (225 Ac), astatine-211( 211 At), radium-223( 223 Ra), radium-224 ( 224 Ra), Bismuth-213( 213 Bi), terbium-149( 149 Tb), or thorium-227 ( 227 In some embodiments, the alpha particle-emitting radionuclide is 225 In some embodiments, the alpha particle-emitting radionuclide is 213 In some embodiments, the alpha particle-emitting radionuclide is Bi. 212 In some embodiments, the alpha particle-emitting radionuclide is Bi. 212 In some embodiments, the alpha particle-emitting radionuclide is 224 In some embodiments, the alpha particle-emitting radionuclide is 223 In some embodiments, the alpha particle-emitting radionuclide is 227 In some embodiments, the alpha particle-emitting radionuclide is 211 In some embodiments, the alpha particle-emitting radionuclide is 149 In some embodiments, the radionuclide is zirconium-89 ( 89 In some embodiments, the conjugates described herein are 67 Cu, 64 Cu, 89 Zr, 90 Y, 109 Pd, 111 Ag, 149 Pm, 153 Sm, 166 Ho, 99m Tc, 67 Ga, 68 Ga, 111 In, 90 Y, 177 Lu, 186 Re, 188 Re, 197 Au, 198 Au, 199 Au,105 Rh, 165 Ho, 161 Tb, 149 Pm, 44 Sc, 47 Sc, 70 As, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 117m Sn, 67 Ga, 201 Tl, 123 I, 131 I, 160 Gd, 148 Nd, 89 Sr, and 211 In some embodiments, the radionuclide is selected from: 225 In some embodiments, the radionuclide is 221 Fr, 217 At, 213 Bi, 213 Po, 209 Tl, 209 Pb, or 209 Bi et al. 225 In some embodiments, the conjugate is a decay daughter of Ac. 225 In some embodiments, the radionuclide is 177 In some embodiments, the radionuclide is no carrier added (i.e., no carrier added, or nca). 177 In some embodiments, the radionuclide is no carrier added (i.e., no carrier added, or nca). 225 In some embodiments, the radionuclide is free of long-lived radioactive contaminants and by-products. 177 In some embodiments, the conjugate is two 177In some embodiments, the radionuclide is a carrier-free radionuclide.

[0174] In some embodiments, the alpha particle-emitting radionuclide is 225 In some embodiments, the alpha particle-emitting radionuclide is no added carrier (i.e., no added carrier, or nca). 225 In some embodiments, 225 Ac is free of long-lived radioactive contaminants and by-products. In some embodiments, the alpha particle-emitting radionuclide is 225 In some embodiments, 225 Ac is generated from a heavier radionuclide. 225 Ac is generated using a thorium-229 generating agent. In some embodiments, 229 Th 225 By collapsing into Ra 225 Ac is generated, and then 225 Ra and 225 Ac is separated via ion exchange resin. In some embodiments, 229 The previous information provided by government sources 233 In some embodiments, 225 Ac is generated using an electron linear accelerator (LINAC) that uses radium-226 as the target source. In some embodiments, 225 Ac uses an electron linear accelerator 226 Ra(γ,n) 225 Ra reaction, followed by the use of a series of ion exchange resins 225 Ra and 225 In some embodiments, Ac is produced by isolating and purifying 225 Ac is generated using a circular proton accelerator using radium-226 as the target source. In some embodiments, 225 Ac is generated using a low-energy circular proton accelerator (also known as a cyclotron). 226 Ra(p,2n)225 In some embodiments, the compound is produced by the Ac reaction. 225 Ac is generated using a low-energy circular proton accelerator (also known as a cyclotron) in the energy range of 10-20 MeV. 226 Ra(p,2n) 225 In some embodiments, the compound is produced by the Ac reaction. 225 Ac is generated using an electron beam accelerator (roadtron) using radium-226 as the target source. In some embodiments, 225 Ac uses an electron beam accelerator 226 Ra(γ,n) 225 Ra reaction, followed by the use of a series of ion exchange resins 225 Ra and 225 In some embodiments, Ac is produced by isolating and purifying 225 Ac is produced using high energy proton spallation using thorium-232 as the target material. In some embodiments, 225 Ac uses a high-energy proton accelerator of 70-100MeV+. 232 Th(p,nxp) 225 It is produced by the Ac reaction.

[0175] In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide bound to a metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225, astatine-211, thorium-227, or radium-223. In some embodiments, the alpha particle-emitting radionuclide is actinium-225.

[0176] In some embodiments, the conjugate comprises a beta particle-emitting radionuclide bound to a metal chelator, hi some embodiments, the beta particle-emitting radionuclide is zirconium-89, yttrium-90, iodine-131, samarium-153, lutetium-177, or lead-212.

[0177] In some embodiments, the conjugate comprises a gamma particle-emitting radionuclide. In some embodiments, the gamma particle-emitting radionuclide is indium-111.

[0178] In some embodiments, the conjugates described herein do not contain any radionuclides, i.e., are non-radioactive conjugates. For example, in some cases, for testing and experimental purposes, the radionuclide is replaced with a substitute (e.g., 225 (Replace Ac with Lantern).

[0179] Metal chelating agents In one aspect, conjugates are described herein that include a metal chelator configured to bind to a radionuclide. A metal chelator may refer to the portion of a conjugate configured to bind to a radionuclide. In some embodiments, the conjugates described herein include two or more independent metal chelators, for example, two, three, four, five, or more metal chelators. In some embodiments, the conjugates described herein include two metal chelators, which may be the same or different. The metal chelator can be attached to a linker or targeting ligand via any suitable group / atom of the chelator.

[0180] In some embodiments, the metal chelator can bind to a radioactive atom. The binding can be direct, for example, the metal chelator can form a hydrogen bond or electrostatic interaction with the radioactive atom. The binding can be indirect, for example, the metal chelator binds to a molecule containing the 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, for example, the macrocycle comprises an O atom 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 desferrioxamine.

[0181] In some embodiments, the metal chelator comprises multiple amines. In some embodiments, the metal chelator comprises four or more N atoms, or four or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not contain any S atoms. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises O atoms and / or N atoms. In some embodiments, the metal chelator is a ring containing three or more N atoms, or three or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is multidentate.

[0182] In some embodiments, the metal chelators described herein comprise cyclic chelators. Exemplary cyclic chelators include AAZTA, BAT, BAT-™, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, oxo-DO3A, p-NH2-Bn-oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A"-EDTA, and 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-A”-DTPA, p-NH2-Bn-CHX-A”-DTPA, p-SCN-DTP A, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A”-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L 1 , H3L 4 , H2azapa, H5decapa, bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa 2, 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-thioseminara Bazon, 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, H2DEDP A, 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-NE3T A, C-NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L py , L1, L2, L3, and EuK-106.

[0183] 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-A″-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 H 4In some embodiments, the metal chelator is py4pa. 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.

[0184] 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 the structure

[0185] [ka] 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 embodiments, the metal chelator has the structure

[0186] [ka] In some embodiments of the conjugates described herein, the metal chelator has the structure

[0187] [ka] wherein each R eis 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 the structure

[0188] [ka] wherein each R e are 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, at least one or both of which is DOTA. The structures of some exemplary metal chelators are shown in Figures 3-17 (connection points not shown). Exemplary metal chelators are further described in WO 2012 / 174136; U.S. Patent Application Nos. 20130183235(A1); 20120219495(A1); 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.

[0190] Linker The chemical scaffold that covalently links the pharmacophore and metal chelator in a targeted radiopharmaceutical can also be referred to as a linker. Incorporating a properly designed linker into a drug molecule can further enhance its affinity for its biological target, accelerate internalization into target tissues, and optimize its pharmacokinetic properties. Various chemical moieties can be used to construct the linker. By altering its physiochemical properties, desired in vivo properties (i.e., absorption, distribution, metabolism, and excretion of the drug molecule) can be achieved. In some embodiments, for example, when it is difficult to alter the pharmacophore and metal chelator moieties without sacrificing biological affinity or metal binding capacity, the linker can adjust the physiochemical properties of the conjugate. The conjugates described herein may contain one or more linkers. The targeting ligand may be covalently attached to the metal chelator via a linker. The linker can covalently attach the targeting ligand to the metal chelator. The targeting ligand can also be directly attached to the metal chelator without a linker.

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

[0192] The linkers described herein can be attached to the N-terminus of the peptide, the C-terminus of the peptide, or a non-terminal amino acid of the peptide, or the linker can be attached to the peptide through a combination of the above. In some embodiments, the linker is attached to the peptide via its N-terminus. In some embodiments, the linker is attached to the peptide via its C-terminus. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid. The linker can be attached to the peptide, the metal chelator, or both, for example, via a chemically reactive group. Exemplary chemically reactive groups include, but are not limited to, a free amino, imino, hydroxyl, thiol, or carboxyl group (e.g., at the N-terminus or C-terminus, the epsilon amino group of one or more lysine residues, the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or the sulfhydryl group of one or more cysteinyl residues). The site at which the linker is attached to the peptide may be a natural or unnatural amino acid of the peptide and / or may be introduced into the peptide, for example, by recombinant DNA techniques (e.g., by introducing a cysteine ​​or protease cleavage site into the amino acid sequence) or by protein biochemistry (e.g., reduction, pH adjustment, or proteolysis). Exemplary methods for attaching linkers include carbodiimide reactions, reactions using bifunctional reagents such as dialdehydes or imidoesters, Schiff base reactions, Suzuki-Miyaura cross-coupling reactions, isothiocyanates as coupling agents, and click chemistry.

[0193] The linker can have a predetermined length, thereby linking the metal chelator (and optionally the radionuclide) and the peptide while maintaining an appropriate distance therebetween. In some embodiments, the linker has a length of 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5 atoms, or 2 to 20 atoms. In some embodiments, the linker has a length of 1 to 10 atoms.

[0194] A linker can comprise a flexible region and / or a rigid region. Exemplary flexible linker regions include those containing Gly and Ser residues ("GS" linkers), glycine residues, alkylene chains, PEG chains, etc. Exemplary rigid linker regions include alpha-helix-forming sequences (e.g., EAAAK (SEQ ID NO: 104)), proline-rich sequences, and double- and / or triple-bond-rich regions.

[0195] In some embodiments, the linker comprises a click chemistry residue. The linker may be coupled to the peptide, the metal chelator, or both via click chemistry, thereby forming the click chemistry residue. For example, the peptide may comprise an azide group (at the N-terminus or C-terminus, or at a non-terminal amino acid) that reacts with the alkyne moiety of the linker. As another example, the peptide may comprise an alkyne group (at the N-terminus or C-terminus, or at a non-terminal amino acid) that reacts with the azide of the linker. The metal chelator and the linker can be similarly coupled. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both.

[0196] The linkers described herein may contain one or more motifs. One or more of the motifs may be attached via click chemistry and clicked into or out of the linker. Each motif within a linker may have an independent function. For example, a linker may contain a motif that functions to modulate plasma half-life and / or a motif that functions as a spacer between the peptide and the metal chelator.

[0197] In some embodiments, the linker has the structure

[0198] [ka] (wherein each L is independently —O—, —NR L-, -N(R L )2 + -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, substituted or unsubstituted C1-C 30 Alkylene, substituted or unsubstituted C2-C 30 Alkenylene, substituted or unsubstituted C2-C 30 Alkynylene, substituted or unsubstituted C1-C 30 Heteroalkylene, -(C1-C 30 alkylene)-O-, -O-(C1-C 30 alkylene)-, -(C1-C 30 (Alkylene)-NR L -, -NR L -(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-N(R L )2 + -, -N(R L )2 + -(C1-C 30 alkylene)-, or click chemistry residue, and each R Lare independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0199] Isomers / stereoisomers 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 their corresponding mixtures. In some cases, the compounds described herein possess one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation 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 conjugates are preferred. In some embodiments, 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 enantiomers are then recovered along with the resolving agent.

[0200] tautomers "Tautomer" refers to a molecule capable of transferring a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein, in certain embodiments, exist as tautomers. In situations where tautomerism is possible, a chemical equilibrium of the tautomers will exist. The exact ratio between the tautomers will vary depending on several factors, including physical conditions, temperature, solvent, and pH. Examples of tautomeric equilibrium include the following:

[0201] [ka]

[0202] In some cases, the compounds disclosed herein exist in tautomeric forms. The structures of the compounds shown above are shown in one tautomeric form for clarity. Alternative tautomeric forms are expressly included in the present disclosure.

[0203] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, but in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or their solvates, or their stereoisomers, include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P,35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride ions, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, 3 H and 14 Compounds incorporating radioactive isotopes, such as C, are useful in drug and / or substrate tissue distribution assays. Tritium-labeled isotopes, i.e. 3 H isotopes, and carbon-14, i.e. 14 The C isotope is notable for its ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavy isotopes, such as H, may produce certain therapeutic advantages due to increased metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements. In some embodiments, isotopically labeled compounds or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are prepared by any suitable method.

[0204] 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.

[0205] pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the compounds disclosed herein include their pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refers to any salt of a stabilizer useful for stabilizing a radiopharmaceutical composition. As used herein, "pharmaceutically acceptable salts" refers to any salt of a stabilizer useful for preventing or retarding degradation of a radiopharmaceutical within a composition.

[0206] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt so formed.

[0207] Examples of pharmaceutically acceptable salts include salts prepared by reaction of a compound described herein with a mineral acid, an organic acid, or an inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, and hydrochloride. , hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propionate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0208] Additionally, 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 hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids, including 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, and the like. , 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0209] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, or with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N(C1-4 alkyl)4, and the like.

[0210] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is 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.

[0211] solvate 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 crystallization process using pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Advantageously, solvates of the compounds described herein can be prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. Thus, one aspect of the present disclosure pertains to hydrates and solvates of the compounds of the present disclosure and / or their pharmaceutically acceptable salts as described herein, which can be isolated and characterized by methods known in the art, such as, for example, thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fischer titration, and high-resolution X-ray diffraction.

[0212] Preparation of the Composition The present disclosure provides methods for preparing and manufacturing the compositions described herein. In some embodiments, the method for manufacturing a radiopharmaceutical composition comprises mixing a radionuclide (e.g., 225Ac) with an unlabeled conjugate (e.g., DOTATATE or DOTATOC), where the unlabeled conjugate comprises a targeting ligand and a metal chelator covalently bound to the targeting ligand, thereby combining the labeled conjugate (e.g., 225 Ac-DOTATATE or 225 In some embodiments, a method of producing a radiopharmaceutical composition includes combining a radionuclide with an unlabeled conjugate, the unlabeled conjugate comprising a targeting ligand and a metal chelator covalently bound to the targeting ligand, thereby producing a labeled conjugate, and combining the labeled conjugate with one or more stabilizers.

[0213] In some embodiments, a method of making a radiopharmaceutical composition comprises combining a radionuclide with an unlabeled conjugate comprising a targeting ligand and a metal chelator covalently bound to the targeting ligand, thereby producing a labeled conjugate, and adding one or more stabilizers to the labeled conjugate. In some embodiments, a method of making a radiopharmaceutical composition comprises combining a radionuclide with an unlabeled conjugate comprising a targeting ligand and a metal chelator covalently bound to the targeting ligand in the presence of one or more stabilizers, thereby producing a labeled conjugate, and optionally adding one or more stabilizers to the labeled conjugate.

[0214] The method for producing a composition may include one or more steps. One or more such steps may include diluting a radionuclide-containing solution or mixture to a desired concentration (i.e., a dilution step). The radionuclide-containing solution or mixture may be diluted 2 to 1000 times, for example, 10 to 50 times, 2 to 40 times, 25 to 75 times, or 50 to 100 times. One or more such steps may include adding one or more stabilizers during the dilution process. One or more such steps may optionally include adding one or more stabilizers during the dilution process. One or more such steps may include diluting an unlabeled conjugate solution or mixture to a desired concentration. One or more such steps may include adding one or more stabilizers before the dilution process. One or more such steps may include adding one or more stabilizers after the dilution process. The unlabeled conjugate may include a targeting ligand and a metal chelator. The targeting ligand and the metal chelator may be covalently bonded. One or more such steps may include diluting with a liquid solution or mixture.

[0215] Methods for preparing a radiopharmaceutical composition may include reacting or combining a radionuclide with an unlabeled conjugate solution or mixture to obtain a labeled conjugate solution or mixture (i.e., a labeling process). In some embodiments, the method includes maintaining a temperature during the labeling process. In some embodiments, the method includes maintaining a temperature in the range of 0°C to 100°C, 10°C to 100°C, 20°C to 100°C, 30°C to 100°C, 40°C to 100°C, 50°C to 100°C, 60°C to 100°C, 70°C to 100°C, or 80°C to 100°C. In some embodiments, the method includes reacting the radionuclide with the unlabeled conjugate for a period of time. In some embodiments, the period of time is about 1 minute to about 3 hours, about 2 minutes to about 2.5 hours, about 3 minutes to about 2 hours, about 5 minutes to about 1.5 hours, about 8 minutes to about 1 hour, or about 10 minutes to about 30 minutes. In some embodiments, the method includes mixing the radionuclide and the unlabeled conjugate during the labeling process. One or more such steps may include mixing using a laboratory mixing device such as a mixer, vortex mixer, stirrer, magnetic stirrer, spinner, shaker, centrifuge, or homogenizer. One or more such steps may include shaking the reaction solution or mixture. One or more such steps may include shaking the reaction solution or mixture at a speed ranging from about 10 rpm to about 5000 rpm, about 100 rpm to about 2500 rpm, about 200 rpm to about 1000 rpm, about 300 rpm to about 800 rpm, or about 400 rpm to about 600 rpm. One or more such steps may further include diluting the labeled conjugate solution or mixture. One or more such steps may include adding one or more stabilizers during the dilution process. One or more such steps may optionally include adding one or more stabilizers after the dilution process.

[0216] In some embodiments, 225 Ac]Ac-DOTA-TATE (or 225Radiopharmaceutical compositions containing DOTA-TATE (Ac-DOTA-TATE) can be prepared by combining DOTA-TATE with [[[(D-DOTA-TATE)-2-yl]-2-hydroxybenzoate]] from a HCl (e.g., 0.04 M, aqueous) solution. 225 Ac]AcCl3. 225 Provided herein are methods for producing a radiopharmaceutical composition comprising Ac-DOTA-TATE. In some embodiments, the method comprises the steps of diluting DOTA-TATE with a sodium acetate / acetic acid buffer solution, and adding [ 225 In some embodiments, the method comprises one or more of the steps of adding [Ac]AcCl3HCl solution to the formulation buffer, mixing the mixture, heating the mixture, and diluting with one or more stabilizers described herein. 225 The concentration of [Ac]AcCl3 is about 10 μCi / μl HCl. In some embodiments, the concentration of [Ac]AcCl3 in the HCl solution is about 10 μCi / μl HCl. 225 The concentration of Ac]AcCl3 is approximately 1-50 μCi / μl HCl. 225 Ac-HA-DOTA-TATE or 225 A radiopharmaceutical composition containing Ac-DOTA-JR-11 may be prepared.

[0217] In some embodiments, 225 Ac]Ac-DOTA-TATE or [ 225 The method for preparing a radiopharmaceutical composition comprising [Ac]Ac-DOTA-TOC includes adding [Ac]Ac-DOTA-TOC to a first vial. 225 providing an Ac]AcCl3 solution and transferring the solution to a reactor; 225 Provide the reaction buffer solution to the first vial containing the [Ac]AcCl solution, and add the reaction buffer solution and residual [ 225 transferring the DOTA-TATE or DOTA-TOC solution to the reactor; and mixing the DOTA-TATE or DOTA-TOC solution and the [Ac]AcCl3 solution in the reactor. 225 Ac]AcCl3 solution, and [ 225 Ac]Ac-DOTA-TATE or [ 225 Ac]Ac-DOTA-TOC;225 Ac]Ac-DOTA-TATE or [ 225 and diluting [Ac]Ac-DOTA-TOC with a formulation buffer containing one or more stabilizers as described herein to form a radiopharmaceutical composition. 225 The molar ratio of Ac to DOTA-TATE or DOTA-TOC is 1:1 to 1:10, 1:1 to 1:8, 1:1 to 1:5, 1:1 to 1:3.5, 1:1 to 1:2, or 1:1 to 1.25. 225 The molar ratio of Ac to DOTA-TATE or DOTA-TOC is about 1:1, 1:2, 1:25, 1:3, 1:3.5, or 1:4. 225 Ac-HA-DOTA-TATE or 225 A radiopharmaceutical composition containing Ac-DOTA-JR-11 may be prepared.

[0218] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" include, for example, 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 (USA), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), 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, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), 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 (USA), 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).

[0219] Treatment method In one aspect, the present disclosure provides a method of treating a disease or condition in a subject in need thereof. The method may comprise administering to the subject in need thereof a radiopharmaceutical composition. Methods comprising administering the radiopharmaceutical compositions described herein can provide therapeutic and / or prophylactic benefit to the subject in need thereof.

[0220] The method may include administering to the subject a radiopharmaceutical composition comprising a therapeutically effective amount of the conjugate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is 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.

[0221] In some embodiments, the cancer may be a neuroendocrine cancer, lymphatic cancer, pancreatic cancer, pituitary cancer, breast cancer, lung cancer, gastric cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine cancer. In some embodiments, the neuroendocrine cancer is relapsed or refractory. In some embodiments, the neuroendocrine cancer is treated with radiation therapy including beta particle-emitting radionuclides (e.g., 177 Lu-DOTA-TATE or 177 In some embodiments, the subject is refractory to radiation therapy (e.g., Lu-DOTA-TOC therapy) comprising a beta particle-emitting radionuclide prior to administration of the radiopharmaceutical composition. 177 Lu-DOTA-TATE or177 In some embodiments, the subject is receiving: 177 In some embodiments, the subject has received prior treatment with Lu-DOTA-TATE. 177The patient has been previously treated with Lu-DOTA-TOC therapy. In some embodiments, the neuroendocrine cancer is neuroendocrine lung cancer or neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a carcinoid tumor in the lung, gastrointestinal tract, or thymus, a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, vipoma), medullary thyroid carcinoma, Merkel cell carcinoma, adrenal pheochromocytoma, adrenal carcinoma, small cell carcinoma (such as in the lung), or large cell carcinoid tumor (such as in the lung). In some embodiments, the cancer is an SSTR2+ lung neuroendocrine tumor. In some embodiments, the cancer is a somatostatin receptor-positive (SSTR+) gastrointestinal pancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is 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 relapsed or refractory. In some embodiments, the subject has received up to one cycle of platinum-etoposide and a PD-L1 inhibitor therapy. In some embodiments, the cancer is untreated. In some embodiments, the cancer is relapsed or refractory. In some embodiments, the radiopharmaceutical composition is administered to the subject at a dose equivalent to about 1 kBq to about 0.2 GBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to the subject at a dose equivalent to about 5 kBq to about 50,000 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to the subject at a dose equivalent to about 20 kBq to about 5,000 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to the subject at a dose equivalent to about 50 kBq to about 500 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to a subject at a dose equivalent to about 50 kBq to about 200 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to a subject at a dose equivalent to about 60 kBq to about 150 kBq per kg of body weight per administration. In some embodiments, the radiopharmaceutical composition is administered to a subject at a radioactivity of about 1 μCi to 1,000 μCi.In some embodiments, the radiopharmaceutical composition is administered to a subject at a radioactivity of about 10 μCi to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to a subject at a radioactivity of about 100 μCi to 500 μCi. In some embodiments, the radiopharmaceutical composition is administered to a subject at a radioactivity of about 100 μCi to 300 μCi. In some embodiments, the radiopharmaceutical composition is administered to a subject at a radioactivity of about 125 μCi to 275 μCi. In some embodiments, the radiopharmaceutical composition is administered to a subject at a radioactivity of about 125 μCi, 175 μCi, 225 μCi, or 275 μCi. In some embodiments, the radiopharmaceutical composition is administered at 4-6 week intervals. In some embodiments, the radiopharmaceutical composition is administered at 4-12 week intervals. In some embodiments, the radiopharmaceutical composition is administered at 8 week intervals. In some embodiments, the radiopharmaceutical composition is administered to reach 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 reach a cumulative dose in the subject of about 40,000 kBq to about 70,000 kBq. In some embodiments, the radiopharmaceutical composition is 225 In some embodiments, the radiopharmaceutical composition comprises: Ac-DOTA-TOC. 225 In some embodiments, the radiopharmaceutical composition comprises: Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical composition comprises Ac-DOTA-JR-11. 225 Ac-HA-DOTA-TATE.

[0222] In some embodiments, provided herein are methods for killing cells, comprising contacting the cells with a conjugate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cells express a receptor described herein. In some embodiments, the conjugate, or a pharmaceutically acceptable salt or solvate thereof, binds to a structure on the cell. In some embodiments, the conjugate, or a pharmaceutically acceptable salt or solvate thereof, emits a large number of alpha particles by spontaneous radioactive decay. In some embodiments, the conjugate, or a pharmaceutically acceptable salt or solvate thereof, emits a large number of beta particles, gamma rays, and / or Auger electrons by spontaneous radioactive decay. The conjugates described herein can kill cells by radiation. In some embodiments, the conjugates directly kill cells by radiation. In some embodiments, the radiation generates oxidized bases, abasic sites, single-strand breaks, double-strand breaks, DNA crosslinks, chromosomal rearrangements, or a combination thereof, within the cells. The conjugates can kill cells by inducing double-strand DNA breaks. The emitted alpha particles may be sufficient to kill cells. The emitted alpha particles may be sufficient to halt cell proliferation. The conjugate also indirectly kills cells through the generation of reactive oxygen species (ROS), such as free hydroxyl radicals. In some embodiments, the conjugate indirectly kills cells by releasing tumor antigens from one or more different cells, thereby exerting a vaccine effect. The conjugate kills cells by the abscopal effect. The cells may be cancer cells. In some embodiments, the method includes killing cells using an alpha particle-emitting radionuclide.

[0223] The described conjugates can be internalized by cells after contact with the cells. The internalization can be mediated by cell receptors, cell membrane endocytosis, etc. In some embodiments, a rapid internalization rate into cancer cells can provide a therapeutic benefit when accompanied by a slow excretion rate.

[0224] In one embodiment, the disclosed conjugate or its pharmaceutically acceptable salt or solvate is configured to treat cancer by ablating tumor cells. The conjugate or its pharmaceutically acceptable salt or solvate may not regulate the biological properties of tumor cells and / or surrounding stroma. The conjugate or its pharmaceutically acceptable salt or solvate may not regulate immune cells. Ablation of tumor cells may result in downstream immunological cascades.

[0225] Non-limiting examples of cancers treatable by the methods of the present disclosure include melanoma (e.g., metastatic malignant melanoma), kidney cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), esophageal cancer, head and neck squamous cell carcinoma, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other malignant neoplasms. In some embodiments, the subject or population of subjects treated with the pharmaceutical compositions of the present disclosure has a solid tumor. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, gastroenterological or pancreatic neuroendocrine tumor, or Merkel cell carcinoma. In some embodiments, the subject or population of subjects treated with the radiopharmaceutical compositions of the present disclosure has a hematological cancer. In some embodiments, the subject has a hematological cancer such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin's lymphoma ("HL"), non-Hodgkin's lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML"), or multiple myeloma ("MM"). In some embodiments, the subject or population of subjects treated has a cancer selected from the group consisting of ovarian cancer, lung cancer, and melanoma. The cancer may be an SSTR1-associated cancer. The cancer may be an SSTR2-associated cancer. The cancer may be an SSTR3-associated cancer. The cancer may be an SSTR4-associated cancer. The cancer may be an SSTR5-associated cancer. The cancer may be a neuroendocrine cancer, lymphatic cancer, pancreatic cancer, pituitary cancer, breast cancer, gastric cancer, medulloblastoma, or neuroblastoma. The cancer may be a neuroendocrine cancer. The neuroendocrine cancer may be recurrent. The neuroendocrine cancer may be refractory to radiation therapy including beta-particle-emitting radionuclides. The neuroendocrine cancer may be neuroendocrine lung cancer or neuroendocrine pancreatic cancer. The neuroendocrine cancer may be a carcinoid tumor in the lung, gastrointestinal tract, or thymus, a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, vipoma), medullary thyroid carcinoma, Merkel cell carcinoma, adrenal pheochromocytoma, adrenal carcinoma, small cell carcinoma (such as in the lung), or large cell carcinoid tumor (such as in the lung).In some embodiments, the neuroendocrine cancer may be a pancreatic neuroendocrine tumor (e.g., a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET)). In some embodiments, the neuroendocrine cancer may be a gastrointestinal neuroendocrine tumor (GI-NET). In some embodiments, the neuroendocrine cancer may be a gastroesophageal pancreatic neuroendocrine tumor.

[0226] Gastrointestinal and pancreatic neuroendocrine tumors, or GEP-NETs, ​​are rare, with an incidence rate of 5.45 cases per 100,000 people in the United States. Despite this low incidence, many GEP-NETs have a more indolent disease course than other epithelial malignancies, resulting in a prevalence of approximately 100,000 cases in the United States. GEP-NET tumors can be aggressive and resistant to treatment, with metastatic disease present at the time of diagnosis in 40–76% of cases, according to the Surveillance, Epidemiology, and End Results database. Depending on their morphology and proliferative activity, GEP-NETs can be classified as well-differentiated tumors or poorly differentiated carcinomas. Well-differentiated GEP-NETs can include low-grade (defined as tumors with 0-1 mitosis per 10 high-power photons (HPFs) or a Ki67 index of 0-2%, Grade 1) and intermediate-grade (defined as tumors with 2-20 mitosis per 10 HPFs or a Ki67 index of 3-20%, Grade 2) tumors, while poorly differentiated GEP-NETs can be high-grade (defined as tumors with >20 mitosis per 10 HPFs or a Ki67 index of >20%, Grade 3).

[0227] In some embodiments, the primary site of gastrointestinal NETs is the rectum, small intestine, pancreas, stomach, colon, and / or appendix. In some embodiments, GEP-NETs are classified as hormone-functioning tumors (those associated with signs and symptoms consistent with excessive hormone secretion). In some embodiments, GEP-NETs are classified as non-functioning tumors, and clinical characteristics and aggressiveness vary depending on the primary tumor site. In some embodiments, the cancer is a pancreatic neuroendocrine tumor (pNET).

[0228] In some embodiments, the subject with GEP-NETs has been treated with surgery. In some embodiments, the subject with GEP-NETs is not suitable for surgical treatment. In some embodiments, the subject with GEP-NETs has developed metastatic disease. In some embodiments, the GEP-NETs overexpress somatostatin receptor 2, i.e., SSTR2, on the cell surface. In some embodiments, the subject has been previously treated with a somatostatin analog, i.e., SSA. In some embodiments, the SSA is administered in combination with a conjugate described herein. In some embodiments, the subject has been previously treated with chemotherapy and a molecularly targeted therapy, such as everolimus or sunitinib. In some embodiments, chemotherapy and a molecularly targeted therapy, such as everolimus or sunitinib, are administered in combination with a conjugate described herein.

[0229] In some embodiments, methods and compositions for treating a disease or condition are provided herein. Exemplary diseases or conditions include refractory or recurrent malignant tumors whose growth may be inhibited using the therapeutic methods of the present disclosure. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, extensive small cell lung cancer, hepatocellular carcinoma, colorectal cancer, gastric adenocarcinoma, pancreatic neuroendocrine tumor (e.g., pancreatic-gastrointestinal neuroendocrine tumor), melanoma, or advanced cancer. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, small cell lung cancer, extensive small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, pancreatic neuroendocrine tumor, pancreatic-enterological neuroendocrine tumor, mesothelioma, sarcoma, blood cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, cancers treated by the methods of the present disclosure include, for example, carcinoma, squamous cell carcinoma (e.g., of the cervix, eyelid, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, and esophagus), and adenocarcinoma (e.g., of the prostate, small intestine, endometrium, cervix, colon, lung, pancreas, esophagus, rectum, uterus, stomach, breast, and ovary). In some embodiments, the cancer is a hypoxic tumor. In some embodiments, the cancer is GEP-NET. In some embodiments, the cancer is small cell lung cancer. In some embodiments, cancers treated by the methods of the present disclosure further include sarcoma (e.g., myogenic sarcoma), leukemia, neuroma, melanoma, and lymphoma. In some embodiments, the cancer treated by the methods of the present disclosure is lung cancer. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is small cell lung cancer (SCLC). In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is extensive-stage small cell lung cancer (ES-SCLC). In some embodiments, the cancer, such as ES-SCLC, has progressed at least 90 days after completion of first-line therapy.In some embodiments, the cancer has progressed at least 90 days after completion of first-line therapy, including a platinum-based therapy. In some embodiments, the cancer has progressed at least 6 months after completion of first-line therapy. In some embodiments, the cancer has progressed at least 6 months after completion of first-line therapy, including a platinum-based therapy. In some embodiments, the cancer has progressed at least 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, or 2 years later. In some embodiments, the cancer has not progressed. In some embodiments, the cancer treated by the methods of the present disclosure is breast cancer. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is triple-negative breast cancer (TNBC). In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is pancreatic cancer. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is pancreatic neuroendocrine tumor. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is gastrointestinal pancreatic neuroendocrine tumor. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is GEP-NET. In some embodiments, the cancer treated by the therapeutic methods of the present disclosure is a gastroesophageal pancreatic neuroendocrine tumor.

[0230] In some embodiments, the cancers described herein are untreated, and therefore the compositions described herein can be used as first-line therapy.

[0231] In some embodiments, the cancer described herein is recurrent or refractory. For example, the subject with cancer may have undergone one or more rounds of standard treatment therapy. In some embodiments, the subject has undergone radiation therapy (including beta particle-emitting radionuclides) prior to administration of the radiopharmaceutical composition. 177 Lu-DOTA-TATE or 177In some embodiments, the subject is receiving platinum-etoposide and PD-L1 inhibitor therapy (e.g., Lu-DOTA-TOC therapy). In some embodiments, the subject is receiving no more than one cycle of platinum-etoposide and PD-L1 inhibitor therapy.

[0232] In addition to the above-mentioned therapeutic methods, the radioactive compositions described herein can be used for imaging and / or as part of the treatment of a disease. Conjugates used in imaging applications, such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can contain radionuclides suitable for use as imaging isotopes, such as the isotopes in Table 5B. Thus, the conjugates can be administered as companion diagnostics.

[0233] In one aspect, provided herein is a method for diagnosing a patient having an SSR-expressing cancer or tumor, the method comprising administering to the patient a radiopharmaceutical described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising same. In one aspect, provided herein is a method for imaging a patient having an SSR-expressing cancer or tumor, the method comprising administering to the patient a radiopharmaceutical described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising same. In some embodiments, the method further comprises selecting or confirming that a tumor in the patient expresses an SSR. In some embodiments, the SSR-expressing cancer is an SSTR2-expressing cancer. In some embodiments, the method further comprises measuring the concentration of the radiopharmaceutical accumulated in the patient. In some embodiments, the method further comprises measuring the amount of radiation emitted from the radionuclide. In some embodiments, the method further comprises analyzing the elimination or clearance profile of the radiopharmaceutical in the patient. In some embodiments, the method further comprises measuring the elimination half-life of the radiopharmaceutical in the patient. In some embodiments, the method further comprises analyzing the clearance profile of the radiopharmaceutical in the patient. 68 The method includes administering a radiopharmaceutical comprising a radionuclide from Table 5B, such as Ga. For example, a radiopharmaceutical of the present disclosure may be administered for patient selection purposes, such as to ensure that a tumor has adequate expression of an SSR target (e.g., SSTR2). As another example, a radiopharmaceutical of the present disclosure may be administered to a patient to ensure that the patient's care team is able to ensure that the radiopharmaceutical is cleared from the body in a suitable time frame to minimize undesired irradiation of other tissues.

[0234] In some embodiments, the methods described herein comprise administering to a patient two radiopharmaceuticals of the present disclosure. In some embodiments, the two radiopharmaceuticals may have the same targeting ligand. In some embodiments, the methods described herein comprise administering (i) a radiopharmaceutical of the present disclosure comprising a radionuclide of Table 5B, followed by (i) a radiopharmaceutical of the present disclosure comprising a radionuclide of Table 5A. In some embodiments, the methods comprise: 68 administering Ga-DOTA-TATE, followed by 225 In some embodiments, the method comprises administering Ac-DOTA-TATE. 68 administering Ga-DOTA-JR-11, followed by 225 In some embodiments, the method comprises administering Ac-DOTA-JR-11. 68 administering Ga-HA-DOTA-TATE, followed by 225 The method includes administering Ac-HA-DOTA-TATE.

[0235] The subject may be between 4 and 120 years old. The subject may be between 5 and 10, 5 and 15, 5 and 18, 5 and 25, 5 and 35, 5 and 45, 5 and 55, 5 and 65, 5 and 75, 10 and 15, 10 and 18, 10 and 25, 10 and 35, 10 and 45, 10 and 55, 10 and 65, 10 and 75, 15 and 18, 15 and 25, 15 and 35, 15 and 45, 15 and 55, 15 and 65, 15 and 75 The subject may be 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to 35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to 65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to 75 years of age. The subject may be at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years of age. The subject may be at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years of age. In some embodiments, the subject has not received radiation therapy comprising a beta-particle-emitting radionuclide prior to administering the radiopharmaceutical composition. In some embodiments, the subject has not received radiation therapy comprising an alpha particle-emitting radionuclide prior to administering the radiopharmaceutical composition. In some embodiments, the subject has received radiation therapy comprising an alpha particle-emitting radionuclide prior to administering the radiopharmaceutical composition. In some embodiments, the subject has received radiation therapy comprising a beta particle-emitting radionuclide prior to administering the radiopharmaceutical composition. In some embodiments, the subject has received radiation therapy comprising a beta particle-emitting radionuclide (e.g., 177 In some embodiments, the subject has progressive disease after treatment with radiation therapy including a Lu-labeled somatostatin analog. 177 In some embodiments, the subject has previously received treatment with Lu-DOTA-TATE. 177The subject has previously received treatment with Lu-DOTA-TOC. In some embodiments, the subject has not received radiation therapy including a platinum-based therapy prior to administration of the radiopharmaceutical composition. In some embodiments, the subject has not received radiation therapy including an immune checkpoint inhibitor prior to administration of the radiopharmaceutical composition. In some embodiments, the subject has not received radiation therapy including a topoisomerase II inhibitor prior to administration of the radiopharmaceutical composition. In some embodiments, the subject has received no more than one cycle of therapy including a platinum-based compound (e.g., cisplatin), an immune checkpoint inhibitor (e.g., PD-L1 inhibitor), and a topoisomerase II inhibitor (e.g., etoposide) prior to administration of the radiopharmaceutical composition.

[0236] In some embodiments, a subject has been diagnosed with an SSR-expressing lesion, neoplasm, cancer, or tumor. In some embodiments, the SSR-expressing lesion, neoplasm, cancer, or tumor is characterized by quantifying SSR expression and calculating an H-score. In some embodiments, the H-score is obtained by a) staining a tissue biopsy for SSR expression (e.g., SSTR2), b) assigning cells a staining intensity of 0, 1, 2, or 3, and c) multiplying the percentage of cells by that staining intensity level. H-scores range from 0 to 300. In some embodiments, an SSR-expressing lesion, neoplasm, cancer, or tumor has an H-score greater than 10. In some embodiments, an SSR-expressing lesion, neoplasm, cancer, or tumor has an H-score greater than 100. In some embodiments, an SSR-expressing lesion, neoplasm, cancer, or tumor has an H-score between 11 and 300. In some embodiments, an SSR-expressing lesion, neoplasm, cancer, or tumor has an H-score greater than 200. In some embodiments, the H-score is between 11 and 100. In some embodiments, the H-score is between 50 and 150. In some embodiments, the H-score is between 100 and 200. In some embodiments, the H-score is between 150 and 250. In some embodiments, the H-score is between 200 and 300.

[0237] Accordingly, provided herein is a method of treating cancer in a subject in need thereof, the method comprising determining an H-score of a tissue sample of the subject's lesion, neoplasm, cancer, or tumor; administering to the subject a radiopharmaceutical composition (e.g., a radiopharmaceutical composition) as described herein (e.g., a radiopharmaceutical composition), 225 In one aspect, provided herein is a method of treating a subject having an SSTR+ cancer, the method comprising administering to the subject a radiopharmaceutical composition (such as Ac-DOTA-TATE) described herein. 225 In some embodiments, the method comprises administering a conjugate disclosed herein (e.g., Ac-DOTA-TATE) to a subject having a cancer sample that has had an H-score determined prior to administration of the conjugate disclosed herein. In some embodiments, the method comprises administering an H-score to a subject having a tumor cancer. In some embodiments, the H-score is between 0 and 300. In some embodiments, the H-score is greater than 10. In some embodiments, the H-score is greater than 50. In some embodiments, the H-score is greater than 100. In some embodiments, the H-score is greater than 150. In some embodiments, the H-score is greater than 100. In some embodiments, the H-score is greater than 200. In some embodiments, the H-score is between about 120 and 300. In some embodiments, the H-score is between about 40 and 300. In some embodiments, the H-score is between about 50 and 300. In some embodiments, the H-score is between about 100 and 300. In some embodiments, the H score is between 200 and 300. The H score can be calculated according to the method of Example 15.

[0238] In one aspect, described herein is a method of treating an SSTR+ cancer in a subject in need thereof, the method comprising administering to the subject a radiopharmaceutical composition disclosed herein, wherein the H-score of the cancer sample from the subject is at least 11. In one aspect, described herein is a method of treating a disease in a subject in need thereof, the method comprising (a) determining the level of SSTR expression in a sample from the subject; and (b) administering to the subject a radiopharmaceutical composition disclosed herein. In some embodiments, the level of SSTR expression in the sample is determined by calculating an H-score. In some embodiments, the H-score is between 11 and 300. In some embodiments, the H-score is between 11 and 200. In some embodiments, the H-score is between 11 and 100. In some embodiments, the H-score is between 101 and 300. In some embodiments, the H-score is between 101 and 201. In some embodiments, the H-score is between 201 and 300. In some embodiments, the radiopharmaceutical composition comprises: 225 In some embodiments, the radiopharmaceutical composition comprises: Ac-DOTA-TOC. 225 In some embodiments, the radiopharmaceutical composition comprises: Ac-DOTA-TATE 225 In some embodiments, the radiopharmaceutical composition comprises Ac-HA-DOTA-TATE. 225 Includes Ac-DOTA-JR-11.

[0239] In some embodiments, the radiopharmaceutical compositions described herein can be administered alone or in combination with one or more additional therapeutic agents. For example, combination therapy can include a composition comprising the radiopharmaceutical composition described herein co-formulated and / or co-administered with one or more additional therapeutic agents, e.g., one or more anti-cancer agents, e.g., cytotoxic or cytostatic agents, immune checkpoint inhibitors, hormonal therapy, vaccines, and / or immunotherapy. In some embodiments, the radiopharmaceutical composition is administered in combination with other therapies, including surgery, cryosurgery, and / or chemotherapy. Such combination therapy can advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding potential toxicities or complications associated with various monotherapies.

[0240] When administered in combination, two (or more) different therapies can be delivered to a subject during the course of the subject's illness. For example, two or more therapies are delivered after the subject is diagnosed with the disorder but before the disorder is cured or resolved. In some embodiments, overlap exists because delivery of one treatment is still occurring when delivery of the second treatment begins. This is sometimes referred to herein as "simultaneous delivery" or "concurrent delivery." In some embodiments, delivery of one treatment ends before delivery of the other treatment begins. In some embodiments, the treatments are more effective when administered in combination. For example, a second treatment is more effective when, for example, a lower amount of the second treatment is significantly more effective, or the second treatment alleviates symptoms to a greater extent than would be observed if administered in the absence of the first treatment, or a similar situation occurs with the first treatment. In some embodiments, delivery is such that the alleviation of symptoms or other parameters associated with the disorder is greater than that observed when one treatment is administered in the absence of the other. The effects of the two treatments may be partially additive, fully additive, or greater than additive. Delivery may be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0241] In some embodiments, the conjugates described herein are used in combination with a chemotherapeutic agent, such as a DNA-damaging chemotherapeutic agent. Non-limiting examples of DNA-damaging chemotherapeutic agents include topoisomerase I inhibitors, topoisomerase II inhibitors (e.g., etoposide), alkylating agents, DNA intercalators, DNA intercalators and free radical generators such as bleomycin, and nucleoside mimetics. In some embodiments, the conjugates described herein are used in combination with a platinum-based DNA-damaging agent. In some embodiments, the conjugates described herein are used in combination with carboplatin or cisplatin. In some embodiments, the conjugates described herein are used in combination with a topoisomerase II inhibitor, such as etoposide. In some embodiments, the conjugates described herein are used in combination with a radiosensitizer that sensitizes tumor cells to radiation therapy. In some embodiments, the conjugates described herein are used in combination with a DNA damage repair inhibitor (or DNA damage response (DDR) inhibitor). In some embodiments, the conjugates described herein are used in combination with an immune checkpoint inhibitor. Non-limiting examples of immune checkpoint inhibitors include PD-1 inhibitors (e.g., pembrolizumab, sold under the trade name Keytruda, nivolumab, sold under the trade name Opdivo, cemiplimab, sold under the trade name Libtayo, or dostarlimab, sold under the trade name Jemperli), PD-L1 inhibitors (e.g., atezolizumab, sold under the trade name Tecentriq, avelumab, sold under the trade name Bavencio, or durvalumab, sold under the trade name Imfinzi), and CTLA-4 inhibitors (e.g., ipilimumab, sold under the trade name Yervoy). In some embodiments, the conjugates described herein are used in combination with a PD-1 inhibitor. In some embodiments, the conjugates described herein are used in combination with a PD-L1 inhibitor.In some embodiments, the conjugates described herein are used in combination with durvalumab or atezolizumab. In some embodiments, the conjugates described herein are used in combination with durvalumab. In some embodiments, the conjugates described herein are used in combination with atezolizumab. In some embodiments, the conjugates described herein are used in combination with a CTLA-4 inhibitor.

[0242] Durvalumab may be administered in the form of an injectable solution, for example, at either 500 mg / 10 mL or 120 mg / 2.4 mL strength in a single-dose vial. In some embodiments, durvalumab is administered as an intravenous infusion. In some embodiments, for subjects weighing 30 kg or greater with ES-SCLC, durvalumab is administered at 1500 mg (fixed dose) with platinum-based chemotherapy and etoposide on day 1 of every 3-week (21-day) cycle during the induction phase (i.e., SoC of 4 x 12-day cycles) for a total of 4 cycles. In some embodiments, for subjects weighing 30 kg or greater, durvalumab is administered at 1500 mg (fixed dose) once every 4 weeks during the maintenance phase until disease progression or unacceptable toxicity. In some embodiments, for subjects weighing 30 kg or more, durvalumab is administered in combina...

Claims

1. 1. A liquid radiopharmaceutical composition comprising: (a) ２２５ a conjugate which is Ac-DOTA-TATE, said conjugate being present in said liquid radiopharmaceutical composition at a concentration equivalent to about 10 to about 35 mCi / L; (b) a radiolytic stabilizer; and (c) a free metal chelator; and (d) an aqueous vehicle; 1. A liquid radiopharmaceutical composition comprising:

2. 10. The liquid radiopharmaceutical composition of claim 1, wherein the pH of said liquid radiopharmaceutical composition is in the range of about 4 to about 8, or the pH of said liquid radiopharmaceutical composition is about 5.5 to about 6.

0.

3. (i) (a) the liquid radiopharmaceutical composition contains, after 72 hours at about 20° C. to about 25° C., bound as part of the conjugate, as determined by radio-thin layer chromatography (radio-TLC); ２２５ retaining at least 90% of the Ac content; or (b) the liquid radiopharmaceutical composition contains, after 120 hours at about 20° C. to about 25° C., bound as part of the conjugate, as determined by radio-thin layer chromatography (radio-TLC). ２２５ retaining at least 90% of the Ac content; or (c) the liquid radiopharmaceutical composition retains at least 90% of its radionuclide content as part of the conjugate after 168 hours at about 20°C to about 25°C as measured by radio-thin layer chromatography (radio-TLC); and / or (ii) (a) the liquid radiopharmaceutical composition contains, after 120 hours at about 20° C. to about 25° C., bound as part of the conjugate, as determined by radio-thin layer chromatography (radio-TLC); ２２５ retains at least 95% of its Ac content; or (b) the liquid radiopharmaceutical composition retains at least 95% of its radionuclide content as part of the conjugate after 168 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC); and / or (iii) the liquid radiopharmaceutical composition retains at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% of its radionuclide content as part of the conjugate after 120 hours at room temperature (about 20° C. to about 25° C.) as measured by radio-thin layer chromatography (radio-TLC); and / or (iv) the liquid radiopharmaceutical composition retains 95% or more of its radionuclide content as part of the conjugate after 48 hours, 72 hours, 96 hours, 120 hours, 148 hours, 168 hours, 192 hours, or 216 hours at about 20° C. to about 25° C. as measured by radio-thin layer chromatography (radio-TLC); and / or (v) the liquid radiopharmaceutical composition contains about 5% or less free actinium-225 relative to the total amount of actinium-225 in the liquid radiopharmaceutical composition after 168 hours at about 20° C. to about 25° C., as measured by radio-thin layer chromatography (radio-TLC); and / or (vi) the liquid radiopharmaceutical composition contains about 2% or about 1% or less of free actinium-225 relative to the total amount of actinium-225 in the liquid radiopharmaceutical composition after 168 hours at about 20°C to about 25°C as measured by radio-thin layer chromatography (radio-TLC); and / or (vii) the liquid radiopharmaceutical composition contains a total of 5% or less of unchelated daughter isotopes of actinium-225 relative to the total amount of actinium-225 in the liquid radiopharmaceutical composition after 168 hours at about 20° C. to about 25° C., as measured by radio-thin layer chromatography (radio-TLC); and / or (viii) (a) the liquid radiopharmaceutical composition contains, after 120 hours at about 20° C. to about 25° C., a fraction of the radiopharmaceutical composition bound as part of the conjugate, as determined by high performance liquid chromatography / fraction preparative (HPLC-FC). ２２５ retaining at least 90% of the Ac content; or (b) the liquid radiopharmaceutical composition contains, after 72 hours at about 20° C. to about 25° C., a fraction of the radiopharmaceutical composition bound as part of the conjugate, as determined by high performance liquid chromatography / fraction preparative (HPLC-FC). ２２５ retaining at least 90% of the Ac content; 3. A liquid radiopharmaceutical composition according to claim 1 or 2.

4. The radiolytic stabilizer is a) an amino acid, peptide, or derivative thereof 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; b) a vitamin or a derivative thereof selected from L-ascorbic acid, β-carotene, provitamin A, (+)-α-tocopherol, erythorbic acid (EA), trolox, and lutein, or a salt thereof; c) lipids or derivatives thereof; d) a carbohydrate or a derivative thereof, wherein the carbohydrate is mannitol, sucrose, dextran, or cyclodextrin; e) a bulking agent, wherein the bulking agent is a polymer or a mixture of polymers including PEG, polygeline, Haemaccel, Gelofusine, PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride U.S. FDA 2018 labeling), or a combination thereof; f) an antioxidant, (i) an antioxidant, wherein the antioxidant is a flavonoid or a derivative thereof, and optionally the flavonoid is a catechin or a derivative thereof; or (ii) The antioxidant is selected from the group consisting of N-acetylcysteine, ascorbic acid, N-tert-butyl-α-phenylnitrone, 3-(3,4-dihydroxyphenyl)-2-propenoic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e., CG), 1,4,5-trihydroxybenzoate, ... Hydroxycyclohexanecarboxylic acid, trans-4-hydroxycinnamic acid (p-coumaric acid), 3,3',4',5,5',7-hexahydroxyflavylium chloride, thiocyanic acid (dihydrolipoic acid, DHLA), 4,4',5,5',6,6'-hexahydroxydiphenolic acid 2,6,2',6'-dilactone (ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epi-catechin, or EC), 2-methoxy-4-(2-propenyl)-2-hydroxybenzoate (2-propenyl) (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol ((-)-gallocatechin), glutathione, 2-(3,4-dihydroxyphenyl)-1(2H)-benzopyran-3,5,7-triol, 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)-1(2H)-benzopyran-3,5,7-triol, diphenyl)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, (+)-α-tocopherol, xanthophyll, citric acid (CA), gentisic acid (GA), salicylic acid (SA), erythorbic acid (EA), phenol, sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene, metabisulfite, benzyl alcohol, thymol, lipoic acid (LA), thioglycolic acid (TGA), 2,3 dimercaptopropan-1-ol (BAL), zinc, selenium, albumin, ethanol, mannitol, sucrose, Melatonin, Ebselen, Pyruvate, 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 (Epigallocatechin gallate, or EGCg), (2R,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoates, i.e., epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin, i.e., EGC), (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, i.e., GC) an antioxidant selected from the group consisting of (-)-cis-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-gallate ((-)-epigallocatechin-3-O-gallate), 5-aminolevurivic acid hydrate, proisolbate 80, garlic acid, sodium L-ascorbate, hyaluronic acid, dextran 60-90, selenol, and LysaKare; or g) combinations thereof 3. The liquid radiopharmaceutical composition of claim 1 or 2, wherein

5. The radiolytic stabilizer may be selected from the group consisting of N-acetyl-L-cysteine, L-ascorbic acid, N-tert-butyl-α-phenyl nitrone, 3-(3,4-dihydroxyphenyl)-2-propenoic acid (caffeic acid), β-carotene, provitamin A, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate ((-)catechin gallate, i.e., 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, and the like. 2,6,2',6'-dilactone (ellagic acid), (-)-cis-3,3',4',5,7-pentahydroxyflavan (epicatechin, i.e., 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, (+)-α-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 Hydroxyanisole, butylated hydroxytoluene, 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, e Stradiol, estriol, ubiquinol, copper, quercetin, cortisone, 2,3-dimercaptosuccinic acid (DMSA), monisoamyl derivative (MiADMSA), taurine, dextran (e.g., dextran 40, dextran 70), PEG (e.g., PEG 3350 and PEG 4000), Polygeline, Gelofusine, PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride, U.S. FDA 2018 label), cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin), (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate (epigallocatechin gallate, or EGCg), (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate, or epicatechin gallate (ECG), (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (epigallocatechin, or EGC), (2R,3S)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (gallocatechin, or GC), or a combination thereof; or The radiation degradation stabilizer is ascorbic acid or a salt thereof, ethanol, gentisic acid or a salt thereof.

5. The liquid radiopharmaceutical composition of claim 4.

6. 5. The liquid radiopharmaceutical composition of claim 4, wherein said radiolytic stabilizer is present in said liquid radiopharmaceutical composition at about 0.01 mM to about 5 M.

7. (i) the radiolysis stabilizer is present in the liquid radiopharmaceutical composition at about 5 mM, 10 mM, 25 mM, 50 mM, or 75 mM to about 80 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 500 mM; or (ii) the radiolysis stabilizer is present in the liquid radiopharmaceutical composition at about 10 mM to about 500 mM; or (iii) the radiolysis stabilizer is present in the liquid radiopharmaceutical composition at about 50 mM to about 200 mM; or (iv) the radiolytic stabilizer is present in the liquid radiopharmaceutical composition at about 0.0001 wt % to about 10 wt %, or (iii) the radiolytic stabilizer is present in the liquid 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 %, or (v) said radiolysis stabilizer is present in said liquid radiopharmaceutical composition at a concentration of about 0.1 to 50 mg / mL; 7. The liquid radiopharmaceutical composition of claim 6.

8. 3. The liquid radiopharmaceutical composition of claim 1 or 2, wherein the free metal chelator is ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), or 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (Macropa).

9. (i) the free metal chelator is present in the liquid radiopharmaceutical composition at about 0.001 wt % to about 10 wt %; or (ii) the free metal chelator is present in the liquid 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 %, or (iii) the free metal chelator is present in the liquid radiopharmaceutical composition at a concentration of 0.001 to 50 mg / mL (e.g., 0.01 to 5 mg / mL, 0.01 to 1 mg / mL, 0.01 to 0.5 mg / mL, or 0.01 to 1 mg / mL); or (iv) the free metal chelator is present in the liquid radiopharmaceutical composition at about 10 mM to about 500 mM; or (v) the free metal chelator is present in the liquid radiopharmaceutical composition at about 5 mM to 10 mM, 10 mM to 25 mM, 25 mM to 50 mM, 50 mM to 75 mM, 75 mM to 100 mM, or 100 mM to 200 mM; 9. The liquid radiopharmaceutical composition of claim 8.

10. said liquid radiopharmaceutical composition further comprising one or more pH stabilizers; (i) the one or more pH stabilizers comprise an organic acid or a salt thereof; and / or (ii) the one or more pH stabilizers comprise an inorganic acid or a salt thereof; and / or (iii) the one or more pH stabilizers comprise a base or a salt thereof; and / or (iv) the one or more pH stabilizers comprise an amino acid or a salt thereof, wherein the amino acid is glycine, lysine, arginine, histidine, or a combination thereof; and / or (v) the one or more pH stabilizers comprise an alkali salt, an acid salt, or both; 3. A liquid radiopharmaceutical composition according to claim 1 or 2.

11. 11. The liquid radiopharmaceutical composition of claim 10, wherein the one or more pH stabilizers comprise an organic acid or a salt thereof, wherein the organic acid is acetic acid, fumaric acid, ascorbic acid, propionic acid, benzenesulfonic acid, carbonic acid, citric acid, aspartic acid, maleic acid, methanesulfonic acid, or tartaric acid.

12. 11. The liquid radiopharmaceutical composition of claim 10, wherein the one or more pH stabilizers comprise an alkaline salt, an acid salt, or both, and the alkaline salt is sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium phosphate, monosodium phosphate, sodium tartrate, sodium lactate, sodium succinate, or disodium succinate.

13. 11. The liquid radiopharmaceutical composition of claim 10, wherein the one or more pH stabilizers comprise sodium acetate, sodium ascorbate, ascorbic acid, acetic acid, fumarate propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (1)-lysine, maleic acid, methanesulfonic acid, phosphoric acid, monosodium phosphate, trisodium phosphate, disodium phosphate, sodium hydroxide, sodium succinate / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (Tris), or a combination thereof.

14. (i) the one or more pH stabilizers are present in the liquid radiopharmaceutical composition at about 0.001 wt % to about 10 wt %; or (ii) the one or more pH stabilizers are present in the liquid 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 %, or (iii) the one or more pH stabilizers are present in the liquid radiopharmaceutical composition at a concentration of 0.1 to 5 mg / mL; or (iv) the one or more pH stabilizers are present in the liquid radiopharmaceutical composition at about 10 mM to about 500 mM; or (v) the one or more pH stabilizers are present in the liquid radiopharmaceutical composition at about 0.1 mM to 2 mM, 1 mM to 2 mM, 1 mM to 10 mM, 5 mM to 10 mM, 5 mM to 15 mM, 1 mM to 15 mM, or 1 mM to 25 mM; 11. The liquid radiopharmaceutical composition of claim 10.

15. (i) the one or more pH stabilizers are configured to maintain the pH of the liquid radiopharmaceutical composition at about 4 to about 8; or (ii) the one or more pH stabilizers are configured to maintain the pH of the liquid radiopharmaceutical composition at about 5 to about 7; 11. The liquid radiopharmaceutical composition of claim 10.

16. 3. The liquid radiopharmaceutical composition of claim 1 or 2, wherein the aqueous vehicle comprises water, saline, dextrose, dextrose saline, Ringer's solution, or lactated Ringer's solution.

17. 17. The liquid radiopharmaceutical composition of claim 16, wherein the aqueous vehicle is saline.

18. 3. The liquid radiopharmaceutical composition of claim 1 or 2, formulated for IV infusion or bolus injection.

19. 3. The liquid radiopharmaceutical composition of claim 1, wherein actinium-225 is present in said liquid radiopharmaceutical composition at a concentration equivalent to about 440 to 851 kBq / mL (about 10 to 30 μCi / mL).

20. 1. A liquid radiopharmaceutical composition comprising: (a) ２２５ a conjugate which is Ac-DOTA-TATE, said conjugate being present in said liquid radiopharmaceutical composition at a concentration equivalent to about 10 to about 50 mCi / L; (b) a radiolysis stabilizer present in said liquid radiopharmaceutical composition at a concentration of about 50 to about 500 mM; (c) optionally a pH stabilizer, optionally a second radiolysis stabilizer, or both, wherein the second radiolysis stabilizer is optionally present in said liquid radiopharmaceutical composition at a concentration of from about 1 wt % to about 10 wt %; and (d) a free metal chelator present in said liquid radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL; (e) an aqueous vehicle; 1. A liquid radiopharmaceutical composition comprising:

21. (a) a conjugate present in said liquid radiopharmaceutical composition at a concentration equivalent to about 10-50 mCi / L; (b) a radiolysis stabilizer, the radiolysis stabilizer being ascorbic acid or a salt thereof, ethanol, or gentisic acid or a salt thereof, and present in said liquid radiopharmaceutical composition at a concentration of about 50 mM to about 500 mM; (c) a free metal chelator selected from EDTA, macropa, TETA, PEPA, TETPA, DFO, DOPT, DHLA, TGA, LA, and DTPA, or a combination thereof, present in said liquid radiopharmaceutical composition at a concentration of about 0.01 mg / mL to about 5 mg / mL; (d) an aqueous vehicle that is saline; 21. The liquid radiopharmaceutical composition of claim 20, comprising:

22. (a) present in said liquid radiopharmaceutical composition at a concentration equivalent to about 10 mCi / L to about 30 mCi / L; ２２５ Ac-DOTA-TATE, (b) sodium L-ascorbate present in said liquid radiopharmaceutical composition at a concentration of about 90 mM to about 110 mM; (c) diethylenetriaminepentaacetate (DTPA) present in said liquid radiopharmaceutical composition at a concentration of about 0.04 mg / mL to about 0.06 mg / mL; (d) an aqueous vehicle which is sodium chloride saline at a concentration of about 0.9% w / w; 10. The liquid radiopharmaceutical composition of claim 1, comprising: the liquid radiopharmaceutical composition is a solution; The liquid radiopharmaceutical composition has, after 120 hours at about 20° C. to about 25° C., a molecular weight of: ２２５ As Ac-DOTA-TATE ２２５ A liquid radiopharmaceutical composition that retains at least 90% of its Ac content.

23. 23. The liquid radiopharmaceutical composition of claim 22, formulated as a unit dose form containing about 12 mL of solution.

24. 23. The liquid radiopharmaceutical composition of claim 22, wherein the pH of said liquid radiopharmaceutical composition is from about 5.5 to about 7.

0.

25. 23. The liquid radiopharmaceutical composition of claim 22, formulated for IV infusion.

26. 26. A liquid radiopharmaceutical composition according to any one of claims 1, 2 and 20 to 25 for treating somatostatin receptor positive (SSTR+) neuroendocrine tumors in a subject in need thereof.

27. 27. The liquid radiopharmaceutical composition of claim 26, wherein said neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

28. for treating somatostatin receptor positive (SSTR+) neuroendocrine tumors ２２５ Ac or a pharmaceutically acceptable salt thereof, wherein the liquid radiopharmaceutical composition of any one of claims 1, 2, and 20-25 is prepared by reacting, in the presence of one or more stabilizers, ２２５ Ac or a pharmaceutically acceptable salt thereof and DOTA-TATE or a pharmaceutically acceptable salt thereof, ２２５ producing a mixture comprising Ac-DOTA-TATE, wherein the liquid radiopharmaceutical composition is administered to a subject in need of treatment, and optionally the neuroendocrine tumor is a gastroenteric-pancreatic neuroendocrine tumor (GEP-NET); ２２５ Ac or a pharmaceutically acceptable salt thereof.

29. 26. A liquid radiopharmaceutical composition comprising DOTA-TATE or a pharmaceutically acceptable salt thereof for treating somatostatin receptor positive (SSTR+) neuroendocrine tumors, the composition comprising the liquid radiopharmaceutical composition of any one of claims 1, 2, and 20-25, in the presence of one or more stabilizers: ２２５ Ac or a pharmaceutically acceptable salt thereof and DOTA-TATE or a pharmaceutically acceptable salt thereof, ２２５ 1. A method for treating gastroenteric pancreatic neuroendocrine tumor (GEP-NET), comprising the steps of: forming a mixture comprising Ac-DOTA-TATE; and administering the liquid radiopharmaceutical composition to a subject in need of treatment; wherein the neuroendocrine tumor is a gastroenteric pancreatic neuroendocrine tumor (GEP-NET).

30. (i) prior to administration of the liquid radiopharmaceutical composition, the subject: １７７ Lu-DOTA-TATE or １７７ have been treated with Lu-DOTA-TOC and the tumor has progressed; and / or (ii) the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 60 kBq / kg body weight to about 120 kBq / kg body weight per dose; and / or (iii) the liquid radiopharmaceutical composition is administered at 8 week intervals; 28. A liquid radiopharmaceutical composition according to claim 27.

31. 26. A liquid radiopharmaceutical composition according to any one of claims 1, 2 and 20-25 for treating a disease in a subject in need thereof, wherein the disease is cancer, and the cancer is a somatostatin receptor positive (SSTR+) cancer.

32. For treating a disease in a subject in need thereof ２２５ Ac or a pharmaceutically acceptable salt thereof, wherein the liquid radiopharmaceutical composition of any one of claims 1, 2, and 20-25 is prepared by reacting, in the presence of one or more stabilizers, ２２５ Ac or a pharmaceutically acceptable salt thereof and DOTA-TATE or a pharmaceutically acceptable salt thereof, ２２５ a liquid radiopharmaceutical composition produced by a method comprising the step of: producing a mixture containing Ac-DOTA-TATE; and administering the liquid radiopharmaceutical composition to a subject in need of treatment, the disease being cancer, the cancer being somatostatin receptor positive (SSTR+) cancer. ２２５ Ac or a pharmaceutically acceptable salt thereof.

33. 26. A liquid radiopharmaceutical composition comprising DOTA-TATE or a pharmaceutically acceptable salt thereof for treating somatostatin receptor positive (SSTR+) cancer, the composition comprising the liquid radiopharmaceutical composition of any one of claims 1, 2, and 20-25, in the presence of one or more stabilizers: ２２５ Ac or a pharmaceutically acceptable salt thereof and DOTA-TATE or a pharmaceutically acceptable salt thereof, ２２５ 1. A method for treating a cancer disease comprising administering to a subject in need of treatment a liquid radiopharmaceutical composition comprising: producing a mixture containing Ac-DOTA-TATE; and administering to a subject in need of treatment a liquid radiopharmaceutical composition comprising Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein the disease is cancer, and the cancer is a somatostatin receptor positive (SSTR+) cancer.

34. 32. The liquid radiopharmaceutical composition of claim 31, wherein the cancer is a neuroendocrine cancer, lymphatic cancer, pancreatic cancer, pituitary cancer, breast cancer, lung cancer, gastric cancer, medulloblastoma, or neuroblastoma.

35. 35. The liquid radiopharmaceutical composition of claim 34, wherein the cancer is a neuroendocrine cancer.

36. (i) the neuroendocrine cancer is neuroendocrine lung cancer or neuroendocrine pancreatic cancer; or (ii) the neuroendocrine cancer is a carcinoid tumor of the lung, gastrointestinal tract, or thymus, a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, VIPomas), medullary thyroid carcinoma, Merkel cell carcinoma, adrenal pheochromocytoma, adrenal carcinoma, small cell carcinoma (such as in the lung), or a large cell carcinoid tumor (such as in the lung); 36. A liquid radiopharmaceutical composition according to claim 35.

37. (i) the cancer is an SSTR2+ lung neuroendocrine tumor; or (ii) the cancer is small cell lung cancer (SCLC); (iii) the cancer is somatostatin receptor-expressing (SSTR+) extensive-stage small cell lung cancer (ES-SCLC); 32. The liquid radiopharmaceutical composition of claim 31.

38. (i) the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1 kBq / kg to about 0.2 GBq / kg of body weight per dose; or (ii) the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 5 kBq / kg to about 50,000 kBq / kg of body weight per dose, about 20 kBq / kg to about 5,000 kBq / kg of body weight per dose, about 50 kBq / kg to about 500 kBq / kg of body weight per dose, or about 50 kBq / kg to about 200 kBq / kg of body weight per dose; or (iii) the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 60 kBq per kg to about 150 kBq per kg of body weight per dose; 32. The liquid radiopharmaceutical composition of claim 31.

39. 39. The liquid radiopharmaceutical composition of claim 38, wherein said liquid radiopharmaceutical composition is administered at 4 to 6 week intervals.

40. 26. A method for producing a liquid radiopharmaceutical composition according to any one of claims 1, 2 and 20 to 25, comprising, in the presence of one or more stabilizers: ２２５ Ac or a pharmaceutically acceptable salt thereof and DOTA-TATE or a pharmaceutically acceptable salt thereof, ２２５ A method comprising the step of forming a mixture comprising Ac-DOTA-TATE.

41. A method for producing a liquid radiopharmaceutical composition according to any one of claims 1, 2 and 20 to 25, ２２５ 2. Use of Ac or a pharmaceutically acceptable salt thereof, ２２５ Ac, or a pharmaceutically acceptable salt thereof, is combined with DOTA-TATE, or a pharmaceutically acceptable salt thereof, in the presence of one or more stabilizers, to form ２２５ Use to produce a mixture containing Ac-DOTA-TATE.

42. 26. Use of DOTA-TATE or a pharmaceutically acceptable salt thereof in a method for producing a liquid radiopharmaceutical composition according to any one of claims 1, 2 and 20 to 25, wherein said DOTA-TATE or a pharmaceutically acceptable salt thereof is dissolved in water in the presence of one or more stabilizers: ２２５ Ac or a pharmaceutically acceptable salt thereof, ２２５ Use to produce a mixture containing Ac-DOTA-TATE.

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