PSMA-targeting radiopharmaceuticals for treatment of cancer

Abstract

Pharmaceutical compositions comprising the 225Ac-radioconjugates of Formula I and methods of their use in the treatment of PSMA-expressing cancers. Also disclosed herein are methods for preparing the pharmaceutical compositions.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 515,943, filed July 27, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] As a transmembrane glycoprotein, prostate-specific membrane antigen (PSMA) is significantly overexpressed in high-grade and advanced prostate cancer, making it an attractive target for diagnostic and therapeutic approaches.

[0003] PSMA has also become one of the most promising molecular targets in nuclear medicine. Various PSMA-targeting radiopharmaceuticals, such as radioligand imaging and radioligand therapy, have been developed and transferred to clinical applications. Among them, 177 Lu-PSMA-617 has recently been approved by the FDA for the treatment of progressive, PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). It is widely believed 225 Ac-labeled PSMA ligands exert better efficacy in the treatment of prostate cancer because alpha-emitters (e.g. 177 Lu) have higher energy, shorter range, and stronger killing effect on tumor cells compared to beta-emitters.

[0004] There is a need for improved treatments for PSMA-expressing cancers that exert superior therapeutic efficacy with an acceptable toxicity profile. SUMMARY

[0005] The present disclosure encompasses the insight that certain pharmaceutical compositions comprising 225 Ac-PSMA radioligands (i.e., 225 Ac-PSMA-I&T) can provide improved efficacy over beta-emitters. Radioactive decay causes direct physical damage (e.g., single- or double-stranded DNA breaks) or indirect damage (e.g., bystander or cross-fire effects) to biological molecules that make up cells. Radiopharmaceuticals (i.e., radiopharmaceuticals or radioconjugates) that deliver radionuclides to cancer cells provide a mechanism to generate DNA damage with anticancer therapeutic effects. The present disclosure provides pharmaceutical compositions comprising 225 Ac-radioconjugates that target PSMA-positive tumors and use actinium-225 to target cancer cells, thereby treating or ameliorating cancer, such as prostate cancer.

[0006] More specifically, pharmaceutical compositions for treating a patient having a PSMA-expressing cancer are provided, wherein the pharmaceutical compositions comprise: (a) 225 Ac-radioconjugate, or a pharmaceutically acceptable salt thereof, wherein the 225 Ac-radiolabeled conjugate comprises a chelate of a compound of Formula I or a prodrug thereof 225 Ac: (I), wherein 225 Ac-radiolabeled conjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or in an amount to provide a radioactive concentration of the pharmaceutical composition of about 10 µCi / mL to about 1000 µCi / mL; (b) sodium acetate, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL, (c) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) diethylenetriaminepentaacetic acid salt (DTPA), wherein the DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL, wherein the pharmaceutical composition is an aqueous formulation and does not contain a gentisate compound.

[0007] In certain embodiments, the pharmaceutical composition comprises: (a) 225 Ac-radiolabeled conjugate or a pharmaceutically acceptable salt thereof, wherein the 225 Ac-radiolabeled conjugate comprises a chelate of a compound of Formula I or a prodrug thereof 225 Ac: (I), wherein 225 Ac-radiolabeled conjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or in an amount to provide a radioactive concentration of the pharmaceutical composition of about 10 µCi / mL to about 1000 µCi / mL; (b) sodium acetate, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL, (c) sodium L-ascorbate, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) diethylenetriaminepentaacetic acid salt (DTPA), wherein the DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL, The pharmaceutical composition is an aqueous formulation and is substantially free of gentianate compounds.

[0008] In some implementations, the 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: .

[0009] In some embodiments, the pharmaceutical composition further comprises ethanol. In some embodiments, ethanol is present in the pharmaceutical composition at a concentration of about 20 mg / mL to about 100 mg / mL. In some embodiments, ethanol is present in the pharmaceutical composition at a concentration of about 20 µg / mL to about 20 mg / mL. In some embodiments, ethanol is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 20 µg / mL.

[0010] In some implementations, the pharmaceutical composition does not contain ethanol.

[0011] In some embodiments, the pharmaceutical composition comprises: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: , in 225 Ac- radioconjugates or their pharmaceutically acceptable salts are present in the pharmaceutical composition at a concentration of 7-9 µg / mL; (b) Sodium acetate present in the pharmaceutical composition at a concentration of 7-8 mg / mL. (c) Sodium L-ascorbate present in the pharmaceutical composition at a concentration of 51-54 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA) present in the pharmaceutical composition at a concentration of 51-54 µg / mL, wherein DTPA is the pentasodium diethylenetriaminepentaacetic acid.

[0012] In some embodiments, after 72 hours at about 2°C to about 25°C (room temperature), the pharmaceutical composition retains at least 90% (e.g., at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the integrity of the drug as determined by radiometric thin-layer chromatography (radio-TLC). 225Ac-radioconjugate or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition retains at least 95% of the intact components as determined by radiometric thin-layer chromatography (radio-TLC) after 72 hours at about 2°C to about 25°C (room temperature). 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0013] In some embodiments, after 7-10 days at about 2°C to about 25°C (room temperature), the pharmaceutical composition retains at least 90% (e.g., at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of its original integrity as determined by radiometric TLC. 225 Ac-radioconjugate or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition retains at least 95% of the complete contents as determined by radiometric thin-layer chromatography (radio-TLC) after 7-10 days at about 2°C to about 25°C (room temperature). 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0014] This disclosure also covers pharmaceutical compositions that are substantially composed of: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I), in 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL, which provides the pharmaceutical composition. (b) Sodium acetate, wherein sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and does not contain gentianate compounds.

[0015] In some embodiments, the pharmaceutical composition consists essentially of the following: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I), in 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL, which provides the pharmaceutical composition. (b) Sodium acetate, wherein sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and is substantially free of gentianate compounds.

[0016] In some embodiments, the pharmaceutical composition consisting essentially of the above-described components is characterized by: (a) The above 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: , in 225 Ac- radioconjugates or their pharmaceutically acceptable salts are present in the pharmaceutical composition at a concentration of 7-9 µg / mL; (b) The sodium acetate is present in the pharmaceutical composition at a concentration of 7-8 mg / mL. (c) The L-ascorbic acid sodium is present in the pharmaceutical composition at a concentration of 51-54 mg / mL; and (d) The DTPA is the pentasodium diethylenetriaminepentaacetate, present in the pharmaceutical composition at a concentration of 51-54 µg / mL.

[0017] Methods for treating patients with cancer expressing prostate-specific membrane antigen (PSMA) remain within the scope of this disclosure, wherein said methods include administering a therapeutically effective amount of one of the pharmaceutical compositions provided herein to a patient in need.

[0018] In some implementations, the cancers expressing PSMA are selected from the group consisting of: prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, testicular cancer, neuroendocrine carcinoma, and brain tumors. In some implementations, the cancer expressing PSMA is prostate cancer, such as metastatic castration-resistant prostate cancer (mCRPC).

[0019] This disclosure also covers the preparation of 225 A method for producing an Ac-PSMA I&T composition, the method comprising: (a) In the absence of gentianate compounds, in a reaction buffer solution, using 225 Ac radiolabeled PSMA I&T, wherein the reaction buffer solution contains sodium acetate and sodium L-ascorbate; (b) Heating the mixture from step (a) for a predetermined time to form a radiolabeled product; and (c) Mixing the radiolabeled product with a prepared buffer solution to form 225 Ac-PSMA I&T composition, wherein the prepared buffer solution comprises sodium L-ascorbate and pentasodium diethylenetriaminepentaacetate. Detailed Implementation

[0020] This disclosure relates to inclusion formula I. 225 Ac-radiocouplers (e.g., 225 Certain pharmaceutical compositions of Ac-PSMA-I&T are indicated for the treatment of PSMA-expressing cancers, with improved efficacy compared to existing therapies.

[0021] definition Chemical terms As used herein, the term "isomer" means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It is recognized that a compound of Formula I has one or more chiral centers and can therefore exist as a stereoisomer, such as a diastereomer (e.g., an enantiomer (i.e., (+) or (-))). Unless otherwise indicated, the chemical structures illustrated herein cover all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and mixtures of enantiomers and stereoisomers (e.g., racemic compounds). Mixtures of enantiomers and stereoisomers of a compound can typically be resolved into their constituent enantiomers or stereoisomers by well-known methods such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomer or enantiomeric pure intermediates, reagents and catalysts through well-known asymmetric synthesis methods.

[0022] As used herein, the term "stereoisomer" refers to all possible different isomers and conformations that a compound can possess (e.g., compounds of any formula described herein), particularly all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers, and / or conformational isomers. Some compounds may exist in different tautomer forms, all of which are included within the scope of this disclosure.

[0023] As used in this article, the term “diastereomer” means stereoisomers that are not mirror images of each other and do not overlap.

[0024] As used herein, the term “enantiomer” means each individual optically active form of a compound having an optical purity or enantiomer excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0025] Other terms As used herein, unless otherwise indicated or inferred from the context, the terms “about” or “approximately” mean a value of ±10% variation (and include the value itself). For example, unless otherwise stated or inferred from the context, a concentration of about 100 µg / mL indicates a concentration range of 100 ± 10% µg / mL, i.e., 90 µg / mL to 110 µg / mL, including 90 µg / mL and 110 µg / mL.

[0026] As used herein, “administering” an agent to a subject includes bringing the subject’s cells into contact with the agent.

[0027] The term "cancer" refers to any cancer caused by the proliferation of malignant tumorous cells, such as tumors, cysts, carcinomas, sarcomas, leukemia, and lymphomas. "Solid tumor cancer" is cancer that contains abnormal masses of tissue, such as sarcomas, carcinomas, and lymphomas. "Blood cancer" or "fluid cancer," used interchangeably as in this article, refers to cancers present in bodily fluids, such as lymphomas and leukemias.

[0028] As used herein, the term "chelate" refers to an organic compound or part thereof that can be bonded to a central metal or radioactive metal atom at two or more points.

[0029] As used herein, the term "coupler" refers to a molecule containing a chelating group or its metal complex, a linker group, and optionally a therapeutic or targeted portion.

[0030] As used herein, the term “compound” is intended to include all stereoisomers, geometric isomers and tautomers of the illustrated structure.

[0031] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as alkenes, C=N double bonds, etc., may also exist in the compounds described herein, and all such stable isomers are contemplated in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and can be isolated as mixtures of isomers or as individual isomers.

[0032] The disclosed compounds also include tautomer forms. Tautomer forms arise from the exchange of single bonds with adjacent double bonds and the resulting proton migration. Tautomer forms include proton-transfer tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-transfer tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms where the proton can occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomer forms can be in equilibrium or spatially locked into one form due to appropriate substitution.

[0033] As used herein, the terms “decrease,” “decreased,” “increase,” “increased,” or “reduction,” “reduced” (e.g., when referring to treatment outcomes or effects) have a meaning relative to a reference level. In some embodiments, the reference level is a level determined in an experimental animal model or clinical trial by using the method as a control. In some embodiments, the reference level is a level in the same subject before treatment or at the start of treatment. In some embodiments, the reference level is the average level in a group that has not been treated with the treatment method.

[0034] As used herein, the term "effective amount" of an agent (e.g., any of the aforementioned conjugates) is an amount sufficient to achieve a beneficial or desired outcome (e.g., clinical outcome), and thus "effective amount" depends on the context of its application.

[0035] As used herein, the term "pharmaceutical composition" means a composition comprising a compound described herein formulated together with pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is manufactured or sold as part of a treatment regimen for treating a mammalian disease, approved by a government regulatory authority. Pharmaceutical compositions may be formulated for oral administration, for example, in unit dosage forms (e.g., tablets, capsules, pouches, gel capsules, or syrups); for topical application (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system free of particulate emboli and suitable for intravenous use); or as any other formulation described herein.

[0036] As used herein, “pharmaceuticalally acceptable excipient” means any component other than the compounds described herein (for example, a medium that enables the active compound to be suspended or dissolved) and has non-toxic and non-inflammatory properties in patients. Pharmaceutically acceptable excipients are typically added to pharmaceutical products to help facilitate the formulation, stability, or delivery of the drug. Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow aids (flow enhancers), lubricants, preservatives, printing inks, radiation protectants, adsorbents, suspending or dispersing agents, sweeteners, or hydration. Exemplary excipients include (but are not limited to): ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dicalcium phosphate), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn starch), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds described herein that, to the extent of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or anaphylactic reactions. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use (Edited by PH Stahl and CG Wermuth), Wiley-VCH, 2008. The salts may be prepared in situ during the final isolation and purification of the compounds described herein, or solely by reacting the free base group with a suitable organic acid.

[0038] Compounds may have ionizable groups to enable the preparation of pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or, in the case of the acidic form of the compound, the salts may be prepared from inorganic or organic bases. Typically, compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, and various amines for forming basic salts. Methods for preparing suitable salts are well-established in the art.

[0039] Representative acid addition salts include, in particular, acetates, adipates, alginates, ascorbic acid salts, aspartates, benzenesulfonates, benzoates, hydrogen sulfates, borates, butates, camphorates, camphor sulfonates, citrates, cyclopentanepropionates, digluconate, dodecyl sulfates, ethanesulfonates, fumarates, gluconate, glyceryl phosphates, hemisulfates, heptanates, hexanoates, hydrobromide, hydrochloride, hydroiodates, 2-hydroxy-ethanesulfonate, lactose, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalate, pectates, persulfates, 3-phenylpropionate, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and valerates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including (but not limited to) ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0040] As used herein, the terms “radiopharmaceutical” or “radioconjugate” refer to any compound or conjugate that includes a radioisotope or radionuclide (such as the radioisotope or radionuclide described herein).

[0041] As used herein, the term "prodrug" refers to a pharmacologically inactive compound or agent administered in an inactive form, which is converted into a pharmacologically active drug in vivo through metabolism or other chemical reactions.

[0042] As used herein, the term "aqueous formulation" refers to a liquid or semi-solid dosage form containing water as the primary solvent or medium. Examples of aqueous formulations include solutions, suspensions, emulsions, and gels. In a solution, the drug or active ingredient is dissolved in water; in a suspension, the drug is suspended in water with the aid of a stabilizer. In an emulsion, the drug is dispersed in water using surfactants and emulsifiers. A gel is a semi-solid aqueous formulation containing a gelling agent to provide a thickening consistency.

[0043] As used herein, the term “substantially free” when used in conjunction with a given component of a composition (e.g., a pharmaceutical composition substantially free of gentianate compounds) means that said component is substantially not added to the composition. When a composition is “substantially free” of a given component, the composition suitably contains no more than 0.001 wt%, suitably no more than 0.0001 wt%, suitably no more than 0.00001 wt%, suitably no more than 0.000001 wt%, and most suitably no more than 0.0001 parts per billion (by weight).

[0044] As used herein, and as understood in the art, “treating” a disease or “treatment” of a disease (e.g., a disease described herein, such as cancer) is a method of achieving a beneficial or desired outcome (e.g., clinical outcome). A beneficial or desired outcome may include (but is not limited to) reducing or improving one or more symptoms or conditions; weakening the severity of a disease, symptom, or condition; stabilizing the state of a disease, symptom, or condition (i.e., preventing its worsening); preventing the spread of a disease, symptom, or condition; delaying or slowing the progression of a disease, symptom, or condition; improving or alleviating a disease, symptom, or condition; and alleviating (whether partial or overall), whether detectable or undetectable. In the context of cancer treatment, “improvement” may include, for example, reducing the incidence of metastasis, reducing tumor volume, reducing tumor angiogenesis, and / or reducing the rate of tumor growth. “Alleviating” a disease, symptom, or condition means a reduction in the severity and / or undesirable clinical manifestations of the disease, symptom, or condition, and / or a slowing or prolonging of the course of progression, compared to the severity or duration without treatment.

[0045] Pharmaceutical compositions This disclosure provides for inclusion of formula I 225 A pharmaceutical composition comprising an Ac-radiocoupler and free of gentianate compounds. This pharmaceutical composition may be used to treat patients with cancers expressing PSMA.

[0046] The pharmaceutical compositions disclosed herein include: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I), in 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL, which provides the pharmaceutical composition. (b) Sodium acetate, wherein sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and does not contain gentianate compounds.

[0047] In some embodiments, the pharmaceutical composition disclosed herein comprises: (b) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I), in 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL, which provides the pharmaceutical composition. (b) Sodium acetate, wherein sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and is substantially free of gentianate compounds.

[0048] Compounds of Formula I include various stereoisomers, such as diastereomers or enantiomers of the Formula I structure.

[0049] In some implementations, the 225 Ac-radiocouplers contain structures chelated with PSMA I&T. 225 Ac: .

[0050] In some implementations, the 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac, the structure is that of a stereocenter on the carbon adjacent to DOTA. R - PSMA I&T in enantiomer form: .

[0051] In some implementations, the 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac, the structure is that of a stereocenter on the carbon adjacent to DOTA. S - PSMA I&T in enantiomer form: .

[0052] In some implementation schemes, 225Ac- radioconjugates or their pharmaceutically acceptable salts at concentrations of about 1 µg / mL to about 100 µg / mL, for example, about 2 µg / mL to about 90 µg / mL, about 3 µg / mL to about 80 µg / mL, about 4 µg / mL to about 60 µg / mL, about 5 µg / mL to about 50 µg / mL, about 6 µg / mL to about 40 µg / mL, about 7 µg / mL to about 30 µg / mL, about 8 µg / mL to about 20 µg / mL, about 8 µg / mL to about 10 µg / mL, about 7 µg / mL to about 10 µg / mL, about 6 µg / mL to about 10 µg / mL, about 5 µg / mL to about 10 µg / mL, about 4 µg / mL to about 10 µg / mL, about 3 µg / mL to about 10 µg / mL, about 2 µg / mL to about 10 µg / mL, about 1 ... µg / mL to about 15 µg / mL, about 15 µg / mL to about 20 µg / mL, about 20 µg / mL to about 25 µg / mL, about 25 µg / mL to about 30 µg / mL, about 30 µg / mL to about 35 µg / mL, about 35 µg / mL to about 40 µg / mL, about 40 µg / mL to about 45 µg / mL, about 45 µg / mL to about 50 µg / mL, about 50 µg / mL to about 55 µg / mL, about 55 µg / mL to about 60 µg / mL, about 60 µg / mL to about 65 µg / mL, about 65 µg / mL to about 70 µg / mL, about 70 µg / mL to about 75 µg / mL, about 75 µg / mL to about 80 µg / mL, about 80 µg / mL to about 85 µg / mL, about 85 µg / mL to about 90 µg / mL, about 90 µg / mL The concentrations of about µg / mL to about 95 µg / mL, about 95 µg / mL to about 100 µg / mL, about 10 µg / mL to about 20 µg / mL, about 20 µg / mL to about 30 µg / mL, about 30 µg / mL to about 40 µg / mL, about 40 µg / mL to about 50 µg / mL, about 50 µg / mL to about 60 µg / mL, about 60 µg / mL to about 70 µg / mL, about 70 µg / mL to about 80 µg / mL, about 80 µg / mL to about 90 µg / mL, or about 90 µg / mL to about 100 µg / mL are present in the pharmaceutical composition.

[0053] In some implementations, 225Ac- radioconjugate or its pharmaceutically acceptable salt is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 50 µg / mL (e.g., about 5 µg / mL to about 45 µg / mL, about 5 µg / mL to about 40 µg / mL, about 5 µg / mL to about 35 µg / mL, about 5 µg / mL to about 30 µg / mL, about 5 µg / mL to about 25 µg / mL, about 5 µg / mL to about 20 µg / mL).

[0054] In some implementations, 225 Ac- radiocoupled substances or their pharmaceutically acceptable salts are present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 20 µg / mL (e.g., about 5 µg / mL to about 10 µg / mL).

[0055] In some implementations, 225 Ac-radiocouplers or their pharmaceutically acceptable salts are present in the pharmaceutical composition at a concentration of about 7 µg / mL to about 9 µg / mL. In some embodiments, 225 The Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 7 µg / mL to about 8 µg / mL (e.g., 7.0 µg / mL, 7.1 µg / mL, 7.2 µg / mL, 7.3 µg / mL, 7.4 µg / mL, 7.5 µg / mL, 7.6 µg / mL, 7.7 µg / mL, 7.8 µg / mL, 7.9 µg / mL, or 8.0 µg / mL). In some embodiments, 225 Ac- radioconjugates or their pharmaceutically acceptable salts are present in the pharmaceutical composition at concentrations of about 8 µg / mL to about 9 µg / mL (e.g., 8.1 µg / mL, 8.2 µg / mL, 8.3 µg / mL, 8.4 µg / mL, 8.5 µg / mL, 8.6 µg / mL, 8.7 µg / mL, 8.8 µg / mL, 8.9 µg / mL, or 9.0 µg / mL).

[0056] In some implementation schemes, 225Ac- radiocoupled compounds or their pharmaceutically acceptable salts to provide approximately 10 µCi / mL to approximately 1000 µCi / mL, for example, approximately 10 µCi / mL to approximately 50 µCi / mL, approximately 50 µCi / mL to approximately 100 µCi / mL, approximately 100 µCi / mL to approximately 150 µCi / mL, approximately 150 µCi / mL to approximately 200 µCi / mL, approximately 200 µCi / mL to approximately 250 µCi / mL, approximately 250 µCi / mL to approximately 300 µCi / mL, approximately 300 µCi / mL to approximately 350 µCi / mL, approximately 350 µCi / mL to approximately 400 µCi / mL, approximately 400 µCi / mL to approximately 450 µCi / mL, approximately 450 µCi / mL to approximately 500 µCi / mL, approximately 500 µCi / mL to approximately 550 µCi / mL, ... The presence of radioactive concentrations of approximately 600 µCi / mL to about 600 µCi / mL, approximately 600 µCi / mL to about 650 µCi / mL, approximately 650 µCi / mL to about 700 µCi / mL, approximately 700 µCi / mL to about 750 µCi / mL, approximately 750 µCi / mL to about 800 µCi / mL, approximately 800 µCi / mL to about 850 µCi / mL, approximately 850 µCi / mL to about 900 µCi / mL, approximately 900 µCi / mL to about 950 µCi / mL, or approximately 950 µCi / mL to about 1000 µCi / mL.

[0057] In the pharmaceutical compositions disclosed herein, sodium acetate is present as a buffer or pH stabilizer. Other equivalent excipients that can be used as buffers or pH stabilizers include (but are not limited to) acetic acid, sodium ascorbate, ascorbic acid, fumaric acid, propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citric acid, hydrobromic acid, glycine, histidine, sodium lactate, (L)-lysine, maleic acid, methanesulfonic acid, phosphoric acid, sodium dihydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, sodium hydroxide, sodium succinate / disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, and tromethamine (tris).

[0058] In some embodiments, sodium acetate is used at a concentration of about 5 mg / mL to about 200 mg / mL, for example, about 5 mg / mL to about 15 mg / mL, about 15 mg / mL to about 25 mg / mL, about 25 mg / mL to about 35 mg / mL, about 35 mg / mL to about 45 mg / mL, about 45 mg / mL to about 55 mg / mL, about 55 mg / mL to about 65 mg / mL, about 65 mg / mL to about 75 mg / mL, about 75 mg / mL to about 85 mg / mL, about 85 mg / mL to about 95 mg / mL, about 95 mg / mL to about 100 mg / mL, about 100 mg / mL to about 110 mg / mL, about 110 mg / mL to about 120 mg / mL, about 120 mg / mL to about 130 mg / mL, about 130 mg / mL to about 140 mg / mL, about 140 mg / mL to about 150 mg / mL, about 150 mg / mL to about 160 mg / mL, about 160 mg / mL to about 160 mg / mL. The pharmaceutical composition is present at concentrations of about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, or about 200 mg / mL.

[0059] In some embodiments, sodium acetate is present in the pharmaceutical composition at a concentration of about 6 mg / mL to about 10 mg / mL.

[0060] In some embodiments, sodium acetate is present in the pharmaceutical composition at a concentration of about 9 mg / mL.

[0061] In the pharmaceutical compositions disclosed herein, sodium L-ascorbate is present as a buffer or radioprotective agent. Other excipients equivalent to sodium L-ascorbate include (but are not limited to) ascorbic acid, sodium acetate, sodium benzoate, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium tartrate, sodium lactate, sodium succinate, and disodium succinate.

[0062] In some embodiments, sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 45 mg / mL to about 100 mg / mL, such as about 45 mg / mL to about 50 mg / mL, about 50 mg / mL to about 55 mg / mL, about 55 mg / mL to about 60 mg / mL, about 60 mg / mL to about 65 mg / mL, about 65 mg / mL to about 70 mg / mL, about 70 mg / mL to about 75 mg / mL, about 75 mg / mL to about 80 mg / mL, about 80 mg / mL to about 85 mg / mL, about 85 mg / mL to about 90 mg / mL, about 90 mg / mL to about 95 mg / mL, or about 95 mg / mL to about 100 mg / mL.

[0063] In some embodiments, sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 45 mg / mL to about 60 mg / mL.

[0064] In some embodiments, sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 50 mg / mL.

[0065] In the pharmaceutical compositions disclosed herein, diethylenetriaminepentaacetic acid (DTPA) is present as a metal chelating agent. Other metal chelating agents equivalent to DTPA include (but are not limited to) diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid (EDTA), and 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipyridinic acid (Macropa) or any pharmaceutically acceptable salt thereof.

[0066] In some embodiments, DTPA is calcium trisodium diethylenetriaminepentaacetate hydrate (DTPA-CTSH) or pentasodium diethylenetriaminepentaacetate (DTPA-PS). In some embodiments, DTPA is DTPA-PS.

[0067] In some embodiments, DTPA (e.g., DTPA-PS) is present in the pharmaceutical composition at a concentration of about 20 µg / mL to about 55 µg / mL, such as about 20 µg / mL to about 25 µg / mL, about 25 µg / mL to about 30 µg / mL, about 30 µg / mL to about 35 µg / mL, about 35 µg / mL to about 40 µg / mL, about 40 µg / mL to about 45 µg / mL, about 45 µg / mL to about 50 µg / mL, or about 50 µg / mL to about 55 µg / mL.

[0068] In some embodiments, DTPA (e.g., DTPA-PS) is present in the pharmaceutical composition at a concentration of about 45 µg / mL to about 52 µg / mL.

[0069] In some embodiments, DTPA (e.g., DTPA-PS) is present in the pharmaceutical composition at a concentration of about 50 µg / mL.

[0070] The pharmaceutical compositions disclosed herein may contain ethanol. In some embodiments, the pharmaceutical compositions do not contain ethanol.

[0071] In some embodiments, the pharmaceutical composition further comprises ethanol, wherein the ethanol is present in the pharmaceutical composition at a concentration of about 20 mg / mL to about 100 mg / mL, such as about 40 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, about 20 mg / mL to about 40 mg / mL, about 40 mg / mL to about 60 mg / mL, about 60 mg / mL to about 80 mg / mL, about 80 mg / mL to about 100 mg / mL, about 20 mg / mL to about 30 mg / mL, about 30 mg / mL to about 40 mg / mL, about 40 mg / mL to about 50 mg / mL, about 50 mg / mL to about 60 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 90 mg / mL, or about 90 mg / mL to about 100 mg / mL.

[0072] In some embodiments, ethanol is optionally present in the pharmaceutical composition at a concentration of about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL.

[0073] In some embodiments, ethanol is optionally present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 100 mg / mL or about 20 mg / mL to about 40 mg / mL.

[0074] In some embodiments, ethanol is optionally present in the pharmaceutical composition at a concentration of less than 40 mg / mL.

[0075] In some embodiments, ethanol is used at a concentration of about 20 µg / mL to about 20 mg / mL, for example, about 20 µg / mL to about 200 µg / mL, about 200 µg / mL to about 500 µg / mL, about 500 µg / mL to about 1 mg / mL, about 1 mg / mL to about 10 mg / mL, about 10 mg / mL to about 20 mg / mL, about 20 µg / mL, about 100 µg / mL, about 200 µg / mL, about 400 µg / mL, about 600 µg / mL, about 800 µg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 16 mg / mL, about 18 mg / mL, or about 20. The concentration of mg / mL is present in the pharmaceutical composition.

[0076] In some embodiments, ethanol is optionally used at a concentration of about 1 µg / mL to about 20 µg / mL, for example, about 1 µg / mL to about 5 µg / mL, about 5 µg / mL to about 10 µg / mL, about 10 µg / mL to about 15 µg / mL, about 15 µg / mL to about 20 µg / mL, about 5 µg / mL to about 10 µg / mL, about 1 µg / mL, about 2 µg / mL, about 3 µg / mL, about 4 µg / mL, about 5 µg / mL, about 6 µg / mL, about 7 µg / mL, about 8 µg / mL, about 9 µg / mL, about 10 µg / mL, about 11 µg / mL, about 12 µg / mL, about 13 µg / mL, about 14 µg / mL, about 15 µg / mL, about 16 µg / mL, about 17 µg / mL, about 18 µg / mL, about 19 µg / mL, or about 20 µg / mL. The concentration of µg / mL is present in the pharmaceutical composition.

[0077] In some embodiments, ethanol is optionally present in the pharmaceutical composition at a concentration of about 2 µg / mL to about 10 µg / mL.

[0078] In some embodiments, ethanol is optionally present in the pharmaceutical composition at a concentration of about 5 µg / mL.

[0079] In the pharmaceutical compositions disclosed herein, the aqueous formulation is typically formed in an aqueous solution of sodium chloride, the concentration of which may be from about 0.1% w / w to about 5% w / w (e.g., from about 0.1% w / w to about 0.5% w / w, from about 0.5% w / w to about 1% w / w, from about 1% w / w to about 2% w / w, from about 2% w / w to about 3% w / w, from about 3% w / w to about 4% w / w, or from about 4% w / w to about 5% w / w). In some embodiments, the concentration of the aqueous solution of sodium chloride is from about 0.5% w / w to about 1% w / w (e.g., from about 0.6% w / w, from about 0.7% w / w, from about 0.8% w / w, from about 0.9% w / w).

[0080] In some embodiments, the pharmaceutical compositions disclosed herein comprise: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: , in 225 Ac- radioconjugates or their pharmaceutically acceptable salts are present in the pharmaceutical composition at a concentration of 7-9 µg / mL; (b) Sodium acetate present in the pharmaceutical composition at a concentration of 7-8 mg / mL. (c) Sodium L-ascorbate present in the pharmaceutical composition at a concentration of 51-54 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA) present in the pharmaceutical composition at a concentration of 51-54 µg / mL, wherein DTPA is the pentasodium diethylenetriaminepentaacetic acid.

[0081] In some embodiments, the pH of the pharmaceutical composition is from about 3 to about 9 (e.g., 4 to 9, 5 to 9, 3 to 8, 4 to 8, or 5 to 8). The pH of the pharmaceutical composition can be about 3.5, 4.0, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.0, or any range therebetween. In some embodiments, the pH of the pharmaceutical composition is from about 5 to about 8.

[0082] In some embodiments, after 72 hours (e.g., after 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours, or 240 hours) at about 2°C to about 25°C (e.g., about 2°C to about 5°C, about 2°C to about 8°C, about 2°C to about 10°C, about 10°C to about 15°C, about 15°C to about 20°C, or about 20°C to about 25°C), as determined by radiometric thin-layer chromatography (radio-TLC), the pharmaceutical composition retains at least 90% (e.g., at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the integrity of the pharmaceutical composition as determined by radiometric thin-layer chromatography (radio-TLC). 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0083] In some embodiments, after 7-10 days (e.g., after 7 days, 8 days, 9 days, or 10 days) at about 2°C to about 25°C (e.g., about 2°C to about 5°C, about 2°C to about 8°C, about 2°C to about 10°C, about 10°C to about 15°C, about 15°C to about 20°C, or about 20°C to about 25°C), as determined by radiometric TLC, the pharmaceutical composition retains at least 90% (e.g., at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the integrity of the pharmaceutical composition. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0084] In some embodiments, after 7-10 days (e.g., after 7, 8, 9, or 10 days) at about 2°C to about 8°C, the pharmaceutical composition retains at least 90% (e.g., at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of its original integrity as determined by radiometric TLC. 225Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0085] In some embodiments, after 7-10 days (e.g., after 7, 8, 9, or 10 days) at about 20°C to about 25°C, the pharmaceutical composition retains at least 90% (e.g., at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of its original integrity as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0086] In some embodiments, the pharmaceutical composition retains at least 95% of its integrity after 3 days at approximately 2°C to approximately 8°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0087] In some embodiments, the pharmaceutical composition retains at least 95% of its integrity after 3 days at approximately 20°C to approximately 25°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0088] In some embodiments, the pharmaceutical composition retains at least 95% of its integrity after 7-10 days at about 2°C to about 8°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0089] In some embodiments, the pharmaceutical composition retains at least 95% of its integrity after 7-10 days at approximately 20°C to approximately 25°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0090] In some embodiments, the pharmaceutical composition retains at least 99% of its integrity after 3 days (or 72 hours) at about 2°C to about 8°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0091] In some embodiments, the pharmaceutical composition retains at least 98% of its integrity after 7 days (or 168 hours) at about 2°C to about 8°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0092] In some embodiments, the pharmaceutical composition retains at least 90% of its integrity after 10 days (or 240 hours) at about 2°C to about 8°C, as determined by radiometric TLC.225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0093] In some embodiments, the pharmaceutical composition retains at least 99% of its integrity after 3 days (or 72 hours) at approximately 20°C to approximately 25°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0094] In some embodiments, the pharmaceutical composition retains at least 98% of its integrity after 7 days (or 168 hours) at approximately 20°C to approximately 25°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0095] In some embodiments, the pharmaceutical composition retains at least 90% of its integrity after 10 days (or 240 hours) at about 20°C to about 25°C, as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

[0096] This disclosure also covers the preparation of the above-described [materials / methods]. 225 A method for producing an Ac-PSMA I&T composition, wherein the method comprises: (a) In the absence of gentianate compounds, in a reaction buffer solution, using 225 Ac radiolabeled PSMA I&T, wherein the reaction buffer solution contains sodium acetate and sodium L-ascorbate; (b) Heating the mixture from step (a) for a predetermined time to form a radiolabeled product; and (c) Mixing the radiolabeled product with a prepared buffer solution to form 225 Ac-PSMA I&T composition, wherein the buffer solution is prepared by comprising sodium L-ascorbate and pentasodium diethylenetriaminepentaacetate.

[0097] In some embodiments, the radiolabeling step (a) uses 225 Ac is reduced in HCl solutions with concentrations less than 0.05 M (e.g., 0.04 M, 0.03 M, 0.02 M, 0.01 M, 0.005 M, 0.004 M, 0.003 M, 0.002 M, or 0.001 M).

[0098] In some embodiments, the gentianate compound is gentianic acid, so step (a) is carried out in the absence of gentianic acid.

[0099] In some implementations, the predetermined heating time in step (b) is less than 25 minutes (e.g., 20 minutes, 15 minutes, or 10 minutes).

[0100] Subject In the method disclosed in this paper, the inclusion formula I is... 225 The pharmaceutical composition of Ac-radiocoupler is administered to patients with cancer expressing PSMA or at risk of developing said cancer.

[0101] In some implementations, the patient may have already been diagnosed with cancer. The cancer can be primary or metastatic. The patient may have cancer at any stage, such as stage I, II, III, or IV, with or without lymph node involvement and with or without metastasis. The methods provided may prevent or reduce further growth of the cancer and / or otherwise improve the cancer (e.g., prevent or reduce metastasis). In some implementations, the patient may be identified as being at risk of developing a PSMA-expressing cancer, for example, due to the presence of one or more risk factors (e.g., environmental exposure), the presence of one or more gene mutations or variants, family history, etc., even if they do not have cancer.

[0102] In some implementations, cancers expressing PSMA are selected from the group consisting of: prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, testicular cancer, neuroendocrine carcinoma, and brain tumors.

[0103] In some implementations, the cancer is prostate cancer, such as metastatic castration-resistant prostate cancer (mCRPC).

[0104] Administration and dosage Effective or therapeutically effective dose In some embodiments, a therapeutic agent or pharmaceutical composition comprising a therapeutic agent, as disclosed herein, is administered to a subject in a manner sufficient to cure or at least partially prevent symptoms of the disease and its complications (e.g., dosage and timing selection). In the context of monotherapy (“monotherapy”), an amount sufficient to achieve this purpose is defined as a “therapeutic effective amount”, which is an amount of compound sufficient to substantially improve at least one symptom associated with the disease or medical condition. The “therapeutic effective amount” typically varies depending on the therapeutic agent. For known therapeutic agents, the relevant therapeutic effective amount is known or readily determined by those skilled in the art.

[0105] For example, in cancer treatment, an agent or compound that reduces, prevents, delays, inhibits, or stops any symptoms of the disease or condition will be therapeutically effective. A therapeutically effective amount of the agent or compound is not required to cure the disease or condition, but rather to provide treatment that delays, inhibits, or prevents the onset of the disease or condition, or improves the symptoms, or alters the duration of the disease or condition, or (for example) makes it less severe, or accelerates recovery in an individual. For example, if a treatment causes cancer to regress or slows cancer growth, it can be considered therapeutically effective.

[0106] Effective dosing regimens for these uses (e.g., the amount of each therapeutic agent, the relative timing of the therapy, etc.) may depend on the severity of the disease or ailment and the subject's weight and general condition. For example, the therapeutically effective amount of a particular composition containing a therapeutic agent administered to a mammal (e.g., a human) can be determined by those skilled in the art taking into account individual differences in the mammal's age, weight, and ailment. Because some conjugates of this disclosure exhibit enhanced targeting and persistence of cancer cells, the dosage of these compounds may be lower than (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%) the equivalent dose required for the therapeutic effect of the unconjugate. The therapeutically effective and / or optimal amount can also be determined empirically by those skilled in the art.

[0107] Single or multiple administrations of radiopharmaceuticals or compositions (e.g., pharmaceutical compositions comprising therapeutic agents or radiocouples disclosed herein) can be administered at dose levels and in modes selected by the treating physician. Dosage and administration schedules can be determined and adjusted based on the severity of the subject's disease or condition, and the severity of the disease or condition can be monitored throughout the course of treatment according to methods typically practiced by clinicians or methods described herein.

[0108] In some implementations, the radiopharmaceutical is administered in a single dose. In other implementations, the radiopharmaceutical is administered more than once, i.e., multiple doses. When the radiopharmaceutical is administered more than once, the dose administered each time may be the same or different.

[0109] In some embodiments, a composition (e.g., a composition comprising a radioconjugate) is administered for radiotherapy planning or diagnostic purposes. When administered for radiotherapy planning or diagnostic purposes, the composition may be administered to the subject at a diagnostically effective dose and / or an amount that effectively determines a therapeutically effective dose. In some embodiments, a first dose of the disclosed conjugate or a composition thereof (e.g., a pharmaceutical composition) is administered at an amount effective for radiotherapy planning, followed by a second dose of the disclosed conjugate or a composition thereof (e.g., a pharmaceutical composition) at an amount effective for therapeutic treatment.

[0110] Contains one or more agents (e.g., 225 Pharmaceutical compositions of Ac-radiocouplers can be formulated for use in various drug delivery systems according to the disclosed methods and systems. The compositions may also include one or more physiologically acceptable excipients or carriers for appropriate formulation. Examples of suitable formulations can be found in […]. Remington’s Pharmaceutical Sciences Mack Publishing Company, Philadelphia, PA, 17th edition, 1985. For a brief overview of drug delivery methods, see, for example, Langer (…). Science 249:1527-1533, 1990).

[0111] Formulation Pharmaceutical compositions can be formulated for non-enteral, intranasal, topical, oral, or local application, such as percutaneously, for prophylactic and / or therapeutic treatment. Pharmaceutical compositions can be administered non-enterally (e.g., via intravenous, intramuscular, or subcutaneous injection), or orally, or via topical or intra-articular injection to areas affected by vascular or cancerous conditions. Examples of additional routes of administration include intravascular, intra-arterial, intratumoral, intraperitoneal, intraventricular, intradural, and intranasal, ocular, intrascleral, intraorbital, rectal, topical, or aerosol inhalation. Sustained-release administration via methods such as accumulation injection or erosive implants or components is also particularly contemplated. Suitable compositions include those comprising an agent (e.g., compounds disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier (e.g., especially water, buffered water, saline, or PBS) for example, non-enteral administration. Compositions may contain pharmaceutically acceptable excipients that approximate physiological conditions, such as, in particular, pH adjusters and buffers, tonic modifiers, wetting agents, or cleansing agents. In some embodiments, the composition is formulated for oral delivery; for example, the composition may contain inert ingredients such as binders or fillers for formulation of unit dosage forms, such as tablets or capsules. In some embodiments, the composition is formulated for topical application; for example, the composition may contain inert ingredients such as solvents or emulsifiers for formulation of creams, ointments, gels, pastes, or eye drops.

[0112] The composition can be sterilized, for example, by conventional sterilization techniques or by aseptic filtration. The aqueous solution can be used as is, or lyophilized, with the lyophilized formulation combined with a sterile aqueous carrier prior to application. The pH of the formulation is typically between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7 (e.g., 6 to 6.5).

[0113] Action Therapeutic effect refers to the expected or beneficial effect of a drug or medical treatment in the treatment of a disease, ailment, or symptom. It is the intended effect that a drug or treatment aims to produce in order to improve the patient's health or well-being.

[0114] The therapeutic effects of the drugs or drug compositions disclosed herein may include relieving symptoms, treating or curing a disease, preventing the disease from worsening, or improving overall health and quality of life.

[0115] The therapeutic effects on cancer patients depend on the type and stage of the cancer. The goal of cancer treatment is to eliminate or control cancer cells while minimizing damage to normal healthy cells in the body. In some implementations, therapeutic effects include reducing tumor volume, stabilizing tumor volume, or slowing the rate of tumor growth. In some implementations, therapeutic effects include reducing the incidence of recurrence or metastasis.

[0116] Example Material: The compounds used in the pharmaceutical compositions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature using standard organic synthesis techniques known to those skilled in the art."Commercially available chemicals" can be obtained from standard commercial sources, including (but not limited to): ABX advanced biochemical compounds LLC (Radeberg, Germany), Acros Organics (Pittsburgh, Pa.), Apin Chemicals Ltd. (Milton Park, UK), Avidity Science (USA), Avocado Research (Lancashire, UK), BDH Ltd. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Ltd. (WestChester, Pa.), Crescent Chemical Ltd. (Hauppauge, NY), Eastman Organic Chemicals Ltd. of Eastman Kodak (Rochester, NY), Fisher Scientific Ltd. (Pittsburgh, Pa.), Frontier Scientific (Logan, Utah), ICN Biomedicals Ltd. (Costa Mesa, Calif.), ITM (Munich, Germany), Key Organics (Cornwall, UK), LancasterSynthesis (Windham, NH), Parish Chemical Ltd. (Orem, Utah), Pfaltz & Bauer (Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical (Rockford, Ill.), Sigma-Aldrich (USA), Spectrum Quality Products (New Brunswick, NJ), TCI America (Portland, Oreg.), Trans World Chemicals (Rockville, Md.), VWR (Radnor, Pa., USA), Wako Chemicals USA (Richmond, Va.), and Wuxi-Apptech (Shanghai, China).

[0117] Example 1. Preparation of the pharmaceutical composition Compound I is a small molecule antagonist targeting PSMA, which can be, for example, actinium-225 ( 225 Radiolabeling of a radionuclide with an Ac) to form a radiopharmaceutical chelated with a radionuclide. The synthesis of compounds of Formula I or corresponding radiopharmaceutical chelates can be found in the following documents: Weinesen M et al. EJNMMI Research , 2014,4:63;Weineisen M et al., J Nucl Med 2015, 56:1169-1176; US 11,129,912 B1; and WO2018 / 108287 A1.

[0118] Formula I can be prepared by following or referring to the scheme described below. 225 Pharmaceutical compositions of Ac-chelated radiocoupled substances.

[0119] Preparation of 0.001 M HCl solution: Add 4.2 µL of concentrated hydrochloric acid (TraceSelect or equivalent) to 37 mL of water (W8-1), and then mix the solution until completely homogenized. Confirm the pH of the buffer solution is 3.0 ± 0.5 using a pH meter.

[0120] Preparation of 0.05 M HCl solution: Add 220 µL of concentrated hydrochloric acid (TraceSelect or equivalent) to 40 mL of water (W8-1), and then mix the solution until completely homogeneous.

[0121] Preparation of sodium acetate-dissolution buffer: Transfer 3.9–4.3 g of sodium acetate to a 150 mL biotainer. Using an appropriately sized disposable serum pipette, add 50 mL of water (W8-1) to the biotainer, followed by 68 µL of concentrated hydrochloric acid (TraceSelect or equivalent). Mix the solution until completely homogenized. Confirm the pH of the buffer solution is 6.5 ± 0.3 using a pH meter.

[0122] Preparation of sodium acetate-sodium ascorbate reaction buffer: Transfer 0.25–0.27 g of L-ascorbate and 3.9–4.3 g of sodium acetate to a 50 mL conical tube. Using an appropriately sized disposable serum pipette, add 50 mL of water (W8-1) to the biotainer, followed by 65 µL of concentrated hydrochloric acid (TraceSelect or equivalent). Mix the solution until completely homogenized. Confirm the pH of the buffer solution is 6.5 ± 0.3 using a pH meter.

[0123] Preparation of the ascorbate-DTPA buffer solution: Transfer 17.9–18.1 g of L-ascorbate sodium to a 500 mL receiving bottle. Add 300 mL of water (W8-1) to the receiving bottle using an appropriately sized serum pipette, followed by 45 µL of pentasodium-DTPA solution (approximately 40% in H2O) using an appropriately sized calibrated pipette. Add 7.5 mL of 0.05 M hydrochloric acid to the receiving bottle using an appropriately sized disposable serum pipette. Seal the receiving bottle and vortex the resulting solution until completely homogenized. Confirm the pH of the buffer solution is 6.5 ± 0.3 using a pH meter.

[0124] Ac-225 Reduction Vial: Using a calibrated pipette, transfer 0.001 M HCl solution to a v-vial containing [Ac-225] ([Ac-225] source vial) to achieve a radioactivity concentration of 2.04 µCi / µL in the [Ac-225] source vial. Allow at least 14 hours before proceeding to the next step. Transfer the entire solution from the [Ac-225] source vial to the "Reaction" tube. Allow at least 2 hours before measuring the radioactivity in the "Reaction" tube and recording the value in µCi.

[0125] Preparation of PSMA I&T buffer solution: Add sodium acetate-dissolution buffer (DB) to the PSMA I&T precursor vial to obtain a 1 mg / mL solution. Rotate the vial for 30 seconds and invert it several times until all contents are dissolved and a homogeneous solution is obtained.

[0126] Radiolabeling: Transfer the PSMA I&T buffer solution described above to the "intermediate" vial such that the ratio of the transferred volume to the radioactivity in the "reaction" tube is 4.2 µCi / µL. Add sodium acetate-dissolving buffer (DB) and sodium acetate-ascorbate reaction buffer (RB) to the "intermediate" vial to obtain a mixture containing equal volumes of DB and RB, wherein the ratio of the total volume in the "intermediate" vial to the radioactivity in the "reaction" tube is 2.8 µL / µCi. Transfer the entire solution from the "intermediate" vial to the "reaction" tube. Gently swirl the contents of the "reaction" tube to ensure thorough mixing, and then heat on a heated mixer at 90°C for 15 minutes. After this, transfer the "reaction" tube to a lead ingot and allow it to stand at room temperature for 5–10 minutes.

[0127] Final Product Formulation: Using an appropriately sized syringe, transfer the entire contents of the "Reaction" tube to a final product vial labeled "Ac-225-PSMA-I&T Bulk Product". Using an appropriately sized syringe, add ascorbate-DTPA formulation buffer to the final product vial, making it 10 times the volume of RB and DB added in the previous step. Slowly and carefully swirl the solution for 30 seconds to ensure complete mixing of the solution in the "Ac-225-PSMA-I&T Bulk Product" vial.

[0128] Store the “Ac-225-PSMA-I&T Bulk Product” vial in lead ingots labeled “Ac-225-PSMA-I&T Bulk Product Vial” at 2-8°C for at least 14 hours. Measure the radioactivity of the “Ac-225-PSMA-I&T Bulk Product” vial using a dosimeter and record the final product’s radioactivity value in µCi.

[0129] Table 1 below provides pharmaceutical compositions prepared according to the schemes described above.

[0130] Table 1. Exemplary Formulations of Pharmaceutical Compositions

[0131] Example 2. Evaluation of the stability of the composition The stability of the pharmaceutical composition was assessed according to the protocol described below.

[0132] In glass containers, use the components described above. 225 Stability testing was conducted on the bulk final products of Ac-PSMA-I&T.

[0133] The stability of the test samples was evaluated by storing them upright in a shielded container at an appropriate storage temperature.

[0134] Record the storage location, date, and time corresponding to the batch number.

[0135] Before the expiry date and time (7 days from the manufacturing date), remove the test sample from its storage location for testing and allow it to reach room temperature for at least 30 minutes. Record the sample removal date and time corresponding to the batch number.

[0136] Temperature monitoring data from the storage location of the test samples over a relevant period of time was used to verify that there was no temperature deviation.

[0137] The stability of the test samples is evaluated based on the quality attributes shown in Table 2 below.

[0138] Table 2. Quality attributes of drug composition stability

[0139] To assess stability, a pharmaceutical composition was prepared having a radioactivity of 1.26 mCi, a radioactivity concentration of 28 μCi / mL, a molar radioactivity of 5.24 μCi / nmol, and a radiochemical purity of 99.5%. Following the stability protocol provided above, the pharmaceutical composition demonstrated stability, as determined below by radiometric thin-layer chromatography (radio-TLC): After 7 days at 2-8°C, the pharmaceutical composition retained 99.0% of its integrity. 225 Ac-PSMA-I&T.

[0140] Tables 3-6 below provide information on certain pharmaceutical compositions that include this disclosure and their stability tests. Table 3 covers the composition of the formulation batches stated in Tables 4-6.

[0141] Table 3. Exemplary Formulations of Pharmaceutical Compositions

[0142] Table 4. Exemplary Formulation Batches

[0143] Table 4A. Exemplary formulation batches

[0144] Table 4B. Exemplary Formulation Batches

[0145] Table 4C. Exemplary Formulation Batches

[0146] Table 4D. Exemplary formulation batches

[0147] Table 5. 225 Stability results of process performance verification batch [225Ac]-FPI-2265-24024-ST (PPQ5)

[0148] Table 6. Stability tests after 7 and 14 days of storage at 2-8℃

[0149] Example 3. Application of the composition in cancer treatment The scheme described below will include 225 The pharmaceutical composition of Ac-radiocoupler is administered to patients with cancers expressing PSMA.

[0150] Dosage preparation Each dose should be prepared individually prior to administration. The dose calibrator used for participant administration measurements should be the same machine used during dose calibrator calibration at the start of the study.

[0151] Prepare the dose aseptically for administration under standard environmental conditions and standard operating procedures (SOPS) at the site. Follow the procedure below to prepare for administration: Thaw the vial containing the test drug (IMP) in lead ingots on a workbench at room temperature. The thawing time is estimated to take 1 hour, but the site may determine this during thawing to ensure the IMP reaches room temperature before administration.

[0152] Ensure the preparation area is clean before dispensing. Wash or disinfect the operator's hands with an alcohol-based hand sanitizer before putting on gloves. Once gloves are on, spray with 70% isopropyl alcohol (IPA). Wipe the vial septum with a sterile IPA pad. Dry the wiped septum before puncturing.

[0153] Sterile, disposable syringes and needles should be used for injection preparation and should be assembled just before injection. The syringe should be assembled with the needle in a clean environment (or a sterile environment, if possible). Sterile connections should not be handled directly.

[0154] The radioactivity concentration of the product at the Time of Calibration (TOC). TOC is the date and time corresponding to the specified activity of the supplied radionuclide. After TOC, radioactivity decreases. The radioactivity concentration and the time and date of calibration are stated on the Certificate of Analysis (CoA). A decay correction factor is used. 225 Ac corrects the physical decay to the closest possible hour.

[0155] For the administration of [225Ac]-PSMA-I&T, the dose of [225Ac]-PSMA-I&T should be calculated using the actual body weight obtained from the participant’s general screening visit.

[0156] The estimated volume of [225Ac]-PSMA-I&T administered to participants in need is calculated as follows: Dosage administration The administration of the pharmaceutical composition followed the procedure described below to administer [225Ac]-PSMA-I&T to the participants.

[0157] IMP should not be diluted or administered with any other IV fluid, in combination with other drugs, or through an infusion set used concurrently for any purpose other than the current IMP administration.

[0158] IMP is administered via slow intravenous injection (IV, 2–5 minutes). For [225Ac]-PSMA-I&T, the desired dose depends on the participant's weight and the study group assignment.

[0159] The injection can be administered via a peripheral vein (preferably) or a central vein. A three-way stopcock is recommended during injection to ensure intravenous delivery of the product and to ensure proper pre-filling and flushing. After administration, thoroughly flush the tubing with normal saline to ensure full dose delivery.

[0160] After administration, the injection tubing should be removed from the participant and must not be used for any other procedures. The syringe and all contaminated tubing should be tested using the same dosing calibrator to determine the net dose administered. Injection volume, time of administration, and the participant's net dose should be recorded.

[0161] Other implementation plans Those skilled in the art will recognize, or can determine, many equivalents of the specific embodiments described herein using only conventional experiments. Such equivalents are intended to be covered by the preceding claims.

Claims

1. A pharmaceutical composition comprising: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I)， The above 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL that provides the pharmaceutical composition. (b) Sodium acetate, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein the DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and does not contain gentianate compounds.

2. The pharmaceutical composition of claim 1, wherein... 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: 。 3. The pharmaceutical composition of claim 1, wherein... 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 7 µg / mL to about 9 µg / mL.

4. The pharmaceutical composition of claim 1, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 6 mg / mL to about 10 mg / mL.

5. The pharmaceutical composition of claim 1, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 50 mg / mL.

6. The pharmaceutical composition of claim 1, wherein the DTPA is present in the pharmaceutical composition at a concentration of about 50 µg / mL.

7. The pharmaceutical composition of claim 1, wherein the pH value of the composition is between 3 and 9.

8. The pharmaceutical composition of claim 1, wherein the composition further comprises ethanol, wherein the ethanol is present in the pharmaceutical composition at a concentration of less than 40 mg / mL or about 40 mg / mL to about 100 mg / mL.

9. The pharmaceutical composition of claim 1, wherein the composition is free of ethanol.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: ， The above 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of 7-9 µg / mL; (b) Sodium acetate present in the pharmaceutical composition at a concentration of 7-8 mg / mL. (c) Sodium L-ascorbate present in the pharmaceutical composition at a concentration of 51-54 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA) present in the pharmaceutical composition at a concentration of 51-54 µg / mL, wherein the DTPA is the pentasodium diethylenetriaminepentaacetic acid.

11. The pharmaceutical composition of claim 1, wherein, after 72 hours at about 2°C to about 25°C, the pharmaceutical composition retains at least 95% of the [specific ingredient] as determined by radiometric thin-layer chromatography (radio-TLC). 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

12. The pharmaceutical composition of claim 11, wherein, after 7-10 days at about 2°C to about 25°C, the pharmaceutical composition retains at least 95% of the [specific properties] as determined by radiometric TLC. 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts.

13. The pharmaceutical composition of claim 1, wherein... 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: 。 14. A pharmaceutical composition comprising essentially the following: (a) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I)， The above 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL that provides the pharmaceutical composition. (b) Sodium acetate, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein the DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and does not contain gentianate compounds.

15. The pharmaceutical composition of claim 14, wherein: (a) The above 225 Ac-radiocouplers contain structures chelated with the following structures 225 Ac: ， The above 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of 7-9 µg / mL; (b) The sodium acetate is present in the pharmaceutical composition at a concentration of 7-8 mg / mL. (c) The L-ascorbic acid sodium is present in the pharmaceutical composition at a concentration of 51-54 mg / mL; and (d) The DTPA is the pentasodium diethylenetriaminepentaacetate, present in the pharmaceutical composition at a concentration of 51-54 µg / mL.

16. A method for treating a patient with cancer expressing prostate-specific membrane antigen (PSMA), wherein the method comprises administering to the patient in need a therapeutically effective amount of the pharmaceutical composition of claim 1 or 14.

17. The method of claim 16, wherein the cancer expressing PSMA is selected from the group consisting of: prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, testicular cancer, neuroendocrine carcinoma, and brain tumor.

18. A method for preparing 225 A method for producing an Ac-PSMA I&T composition, the method comprising: (a) In the absence of gentianate compounds, in a reaction buffer solution, using 225 Ac radiolabeled PSMA I&T, wherein the reaction buffer solution contains sodium acetate and sodium L-ascorbate; (b) The mixture from step (a) is heated for a predetermined time to form a radiolabeled product; as well as (c) Mixing the radiolabeled product with a prepared buffer solution to form 225 Ac-PSMA I&T composition, wherein the prepared buffer solution comprises sodium L-ascorbate and pentasodium diethylenetriaminepentaacetate.

19. The method of claim 18, wherein the gentianate compound is gentianic acid.

20. The method of claim 18, wherein the predetermined time is less than 25 minutes.

21. The method of claim 18, wherein... 225 Ac is reduced in HCl solution with a concentration of less than 0.05 M.

22. The method of claim 18, wherein... 225 The Ac-PSMA I&T composition is free of gentianate compounds and retains at least 99% of its integrity, as determined by radiometric TLC, after 7 days or longer at approximately 2°C to approximately 8°C. 225 Ac-PSMA I&T.

23. A pharmaceutical composition comprising: (b) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I)， The above 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL that provides the pharmaceutical composition. (b) Sodium acetate, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein the DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and is substantially free of gentianate compounds.

24. A pharmaceutical composition comprising essentially the following: (b) 225 Ac- radiocoupled compounds or their pharmaceutically acceptable salts. The above 225 Ac-radiocouplers comprise compounds chelated with Formula I or their prodrugs. 225 Ac: (I)， The above 225 Ac- radioconjugate or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 1 µg / mL to about 100 µg / mL or at a radioactive concentration of about 10 µCi / mL to about 1000 µCi / mL that provides the pharmaceutical composition. (b) Sodium acetate, wherein the sodium acetate is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 400 mg / mL. (c) Sodium L-ascorbate, wherein the sodium L-ascorbate is present in the pharmaceutical composition at a concentration of about 40 mg / mL to about 150 mg / mL; and (d) Diethylenetriaminepentaacetic acid (DTPA), wherein the DTPA is present in the pharmaceutical composition at a concentration of about 5 µg / mL to about 60 µg / mL. The pharmaceutical composition is an aqueous formulation and is substantially free of gentianate compounds.

25. The method of claim 18, wherein... 225 Ac-PSMA I&T compositions are essentially free of gentianate compounds and retain at least 99% of their integrity, as determined by radiometric TLC, after being subjected to temperatures ranging from approximately 2°C to approximately 8°C for 7 days or longer. 225 Ac-PSMA I&T.

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