A copper radiopharmaceutical composition for targeted molecular imaging

Abstract

The present disclosure provides a radiopharmaceutical composition containing copper-64 that functions as a target diagnostic PET agent. The radiopharmaceutical composition disclosed herein has a short physical half-life of about 12.7 hours. Included among the various aspects of the present disclosure is a radiopharmaceutical composition containing copper that functions as an oncologic agent for the diagnosis and staging of PC. Also disclosed herein is a PSMA-specific PET agent having a moderate half-life (e.g., copper-64( 64 Cu or Cu-64, t 1 / 2 = 12.7 hours)) that can be distributed nationwide from a central manufacturing facility as an immediately administrable dose.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Application No. 63 / 390,124, filed on July 18, 2022, which is hereby incorporated by reference in its entirety.

[0002] (Field of the Invention) The present disclosure relates to a radiopharmaceutical composition containing copper that functions as a target - molecule imaging agent for use in positron emission tomography (PET).

Background Art

[0003] (Background of the Invention) Prostate cancer (PC) is the second most common type of cancer in men worldwide and the fifth most common cause of cancer - related death in men. Determination of serum prostate - specific antigen (PSA) levels is the standard procedure for screening and early detection of PC, but it has shown sub - optimal diagnostic values. Although improving, non - invasive staging using standard imaging modalities (including computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy) provides unsatisfactory results with insufficient sensitivity in detecting distant metastases and lymph node metastases (LNM), resulting in significant under - evaluation of the disease.

[0004] Various positron emission tracers, such as C-11 (carbon-11) choline and F-18 (fluorine-18) choline, have been studied and found to be useful for the detection of lesions in PC patients using PET. C-11 choline PET / CT imaging or F-18 choline PET / CT imaging has been used to complement PSA levels for the early detection of prostate cancer; however, many clinical studies have reported low sensitivity and specificity, especially at low PSA levels and high Gleason scores. Furthermore, C-11 choline imaging procedures or F-18 choline imaging procedures are limited by blood flow and may result in higher uptake in patients with benign prostatic hyperplasia. C-11 choline PET / CT imaging or F-18 choline PET / CT imaging has good specificity for detecting LNM, but this imaging procedure also shows low sensitivity in the range of 10% - 73%.

[0005] Prostate-specific membrane antigen (PSMA) (a membrane-bound type II glycoprotein with a large extracellular domain (44 amino acids - 750 amino acids)) plays an important role in prostate carcinogenesis and progression. This transmembrane protein is overexpressed in androgen-dependent metastatic prostate cancer and androgen-independent metastatic prostate cancer, schwannoma, tumor neovasculature of many solid tumors, as well as specific subtypes of bladder cancer, but shows low levels of expression in normal prostate cells and in organs such as the brain, kidney, salivary gland, and small intestine. It is this combination of features that makes PSMA an ideal target for the diagnosis, treatment, and management of PC.

[0006] PSMA-targeted PET / CT imaging has emerged as a highly sensitive method for the detection of local recurrence lesions or metastatic lesions in the context of biochemical recurrence after primary prostate cancer treatment and for the localization of primary prostate cancer. Many gallium-68 (Ga-68) labeled PSMA ligands have been clinically evaluated and all appear to be equally beneficial in the staging and management of patients with PC.

[0007] To date, Ga-68 labeled PSMA ligands have received the most attention in assisting with the management of patients with PC. However, the short half-life of Ga-68 (67.7 minutes) presents logistical limitations. This short half-life restricts the application of Ga-68 PSMA to PET centers in the vicinity that have the preparation capacity using a germanium-68 / gallium-68 generator and an analytical group for quality control of the final product.

[0008] If there were a PET radionuclide with a longer half-life, it would provide an opportunity to utilize the diagnostic and patient management characteristics of PSMA imaging at PET diagnostic centers. An excellent candidate for this application is copper-64 (Cu-64), which has a longer half-life of 12.7 hours and emits positrons with a more favorable lower energy (Eβ + avg = 278 keV) compared to the average positron energy (Eβ + avg = 830 keV) emitted by Ga-68. The lower energy positrons travel a shorter distance before annihilation, which results in the annihilation photons detected by the scanner being generated closer to their point of origin, thus improving the resolution of the PET image. This longer half-life of Cu-64 improves logistical constraints in terms of both the acceptable distance between the Cu-64 radiopharmaceutical manufacturing site and the patient administration site and the improved flexibility of the patient administration schedule. Therefore, the use of Cu-64 as a diagnostic radionuclide can allow for a delayed imaging time point, provide sufficient time for clearance from background tissue, and result in increased image contrast and detection of smaller target regions.

[0009] Therefore, there is a clinical need for an effective diagnostic agent for PC that can overcome the logistical constraints of shorter-lived PET agents and provide improved sensitivity and resolution compared to similar Ga-68 labeled agents. Cu-64 PSMA I&T injection is a novel and promising diagnostic option for patients with PC.

Summary of the Invention

Means for Solving the Problems

[0010] (Summary of the Invention) Among various aspects of the present disclosure is a copper-containing radiopharmaceutical composition that functions as an oncologic agent for the diagnosis and staging of PC.

[0011] Also disclosed herein is a PSMA-specific PET agent with a moderate half-life (e.g., copper-64 ( 64 Cu or Cu-64, t 1 / 2 = 12.7 hours)) that can be distributed nationwide from a central manufacturing facility as an immediately administrable dose. An additional advantage of using these PSMA-specific PET agents is the improvement in the tumor-to-tissue ratio by allowing a longer time for the excretion of the drug from non-specific tissues, enabling an improvement in the quality and sensitivity of the images, as well as the ability to image a greater number of patients daily compared to shorter-lived agents.

[0012] Further disclosed herein is a radiopharmaceutical composition of Cu-64 PSMA I&T, which combines the PET imaging ability of Cu-64 with the PSMA targeting ability of PSMA I&T to form a diagnostic agent capable of monitoring PSMA expression in vivo.

[0013] Other features and aspects of the present disclosure are described in detail below.

Brief Description of the Drawings

[0014]

Figure 1

[0015]

Figure 2

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] (DETAILED DESCRIPTION OF THE INVENTION) Various aspects and embodiments will now be fully described herein. However, these aspects and embodiments may be embodied in many different forms and should not be construed as limited; rather, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the subject matter to those skilled in the art. Whether above or below, all publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0017] The headings included herein are for ease of reference only and are not intended to limit the disclosure in any way.

[0018] (I. DEFINITIONS) Unless otherwise defined, all terms and phrases used herein shall have the meaning ascribed to such terms and phrases within the context in which they are used, unless the contrary is clearly indicated or made obvious from the context, or is otherwise well understood by those skilled in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the particular methods and materials are now described.

[0019] Compounds useful in the present composition and method include the compounds described herein in any of their pharmaceutically acceptable forms (including isomers (e.g., diastereomers and enantiomers), salts, solvates, and polymorphs), and, where applicable, racemic mixtures and pure isomers of the compounds described herein.

[0020] When introducing elements of various embodiments of the present disclosure, the articles "a", "an", "the", and "said" are intended to mean that one or more of the elements are present. The terms "comprising", "including", and "having" are intended to be inclusive and to mean that additional elements other than the recited elements may exist.

[0021] The use of individual numerical values is described as approximate, as if the words "about" or "approximately" preceded each value. Similarly, numerical values within the various ranges specified in this application are described as approximate, as if the words "about" or "approximately" preceded both the minimum and maximum values within the recited range, unless otherwise expressly indicated. Thus, variations greater than and less than the recited range can be used to achieve substantially the same result as values within the range. As used herein, the terms "about" and "approximately" when referring to a numerical value shall have the meanings that are plain and ordinary to those of ordinary skill in the art in the field or fields to which the disclosed subject matter is most closely related. The amount of extension from a precise numerical boundary depends on many factors. For example, some of the factors that may be considered include the importance of the element and / or the effect that a given amount of variation has on the performance of the claimed subject matter, as well as other considerations known to those of ordinary skill in the art. As used herein, the use of significant digits for the various amounts for the various numerical values is not meant to limit how the use of the words "about" or "approximately" acts to extend a particular numerical value or range of numerical values. Thus, as a general matter, "about" or "approximately" extends a numerical value. Also, the disclosure of a range is intended as a continuous range, including any value between the minimum and maximum values, as well as the extension of the range given by the use of the terms "about" or "approximately". As a result, the recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein.

[0022] As used herein, the term "active agent" or "drug" refers to any chemical substance that induces a biochemical reaction when administered to a human or an animal. A drug can act as a substrate or product of a biochemical reaction, or a drug can interact with a cellular receptor to induce a physiological reaction, or a drug can bind to a receptor to block the receptor from inducing a physiological reaction.

[0023] As used herein, in the context of chemistry, the term "half-life" refers to the time it takes for half of the radioactive atoms of a particular radionuclide to decay.

[0024] The terms "subject" or "patient" are used interchangeably herein, and the terms "subject" or "patient" refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.

[0025] (II. Introduction) The present disclosure relates to a radiopharmaceutical composition comprising Cu-64 PSMA I&T, which combines the PET imaging ability of Cu-64 with the PSMA targeting ability of PSMA I&T to form a diagnostic agent capable of monitoring PSMA expression in vivo. Cu-64 PSMA I&T consists of a bioconjugate PSMA I&T radiolabeled with Cu-64, and this Cu-64 is bound to PSMA I&T via a bifunctional chelating agent, DOTAGA (Figure 1).

[0026] The Cu-64 PSMA I&T injection is provided as a sterile-filtered radiopharmaceutical solution. The chemical name of the Cu-64 PSMA I&T injection is 64Cu-(3S,7S,26R,29R,32R,37R)-29-benzyl-32(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazatriacontane-1,3,7,26,37-pentacarboxylic acid. It has the following chemical structure: [Chemical formula]

[0027] The invention disclosed herein provides several important advantages. The disclosed methods of preparation and formulations of Cu-64 PSMA I&T presented herein enable the preparation of higher activity batch sizes (e.g., up to 60 Ci or 2,220 GBq) and the formulation of the final product as a chemically stable and immediately administrable human dose. In another embodiment, the disclosed methods of preparation and formulations of Cu-64 PSMA I&T presented herein enable the preparation of higher activity batch sizes from about 15 Ci to about 60 Ci or 555 GBq to about 2,220 GBq and the formulation of the final product as a chemically stable and immediately administrable human dose. In yet another embodiment, the disclosed methods of preparation and formulations of Cu-64 PSMA I&T presented herein enable the preparation of higher activity batch sizes of about 15 Ci, about 20 Ci, about 25 Ci, about 30 Ci, about 35 Ci, about 40 Ci, about 45 Ci, about 50 Ci, about 55 Ci, and about 60 Ci and the formulation of the final product as a chemically stable and immediately administrable human dose.

[0028] An overview of the synthesis conditions and possible formulation generation conditions for one embodiment of the present invention is provided in Table 1. (Table 1. Overview of synthesis conditions and formulation generation conditions at controlled room temperature) [Table 1-1]

Table 1-2

[0029] Table 2 provides an overview of the synthesis conditions and possible formulation generation conditions for yet another embodiment of the present invention. (Table 2. Overview of synthesis conditions and formulation generation conditions at either elevated or reduced temperature)

Table 2

[0030] Cu-64 PSMA I&T injection is a PET drug that specifically targets prostate-specific membrane antigen expressed on metastatic prostate cancer cells. Specifically, Cu-64 PSMA I&T is required for the detection and localization of recurrent prostate cancer in men with biochemical recurrence based on elevated post-treatment serum prostate-specific antigen (PSA) levels. An embodiment of the pharmaceutical composition is presented in Table 3. (Table 3. Representative target composition of copper (Cu64) PSMA I&T pharmaceutical)

Table 3

Table 4-1

Table 4-2

[0031] In one embodiment, the pharmaceutical product comprises copper (Cu-64) PSMA I&T in an amount of about 1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi, about 7 mCi, about 8 mCi, about 9 mCi, or about 10 mCi per unit at the time of administration.

[0032] (III. Radioactive pharmaceutical composition containing copper) In one embodiment, the pharmaceutical product or radioactive pharmaceutical composition (or formulation) is a sterile filtered radioactive pharmaceutical solution containing a single dose of Cu-64 PSMA I&T in an aqueous solution of sodium acetate / gendronic acid containing sodium ascorbate / ascorbic acid. The product is diluted to a standard concentration, and thus the final volume of the bulk product varies depending on the introduced starting activity.

[0033] In another embodiment, the radioactive pharmaceutical composition or formulation comprises at least one stabilizer, pH adjuster, metal ion chelating agent, or a combination thereof.

[0034] In another embodiment, one or more stabilizers are selected from the list comprising ethanol, para-aminobenzoic acid (PABA), dihydroxybenzoic acid (gendronic acid compound), gendronic acid, cysteine, selenomethionine, ascorbic acid / sodium ascorbate, and methionine.

[0035] In another embodiment, the pH adjuster is selected from the group consisting of sodium acetate / acetic acid, gendronic acid, ascorbic acid / sodium ascorbate, ammonium acetate, citric acid, sodium citrate, sodium gendronic acid, and sodium carbonate / sodium bicarbonate.

[0036] In one embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 90%, at least about 95%, at least about 97%, or at least about 99% as measured by high performance liquid chromatography (HPLC), thin layer chromatography (TLC), instant thin layer chromatography (iTLC), or gas chromatography (GC). In another embodiment, the radiopharmaceutical composition or formulation has a purity of about 90%, about 90.5%, about 91%, about 91.5%, about 92%, about 92.5%, about 93%, about 93.5%, about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, or about 99.5% as measured by HPLC, TLC, iTLC, or GC.

[0037] In another embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC, or GC at any time after EOS (end of synthesis). In one embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC, or GC at about 0 hours, about 10 hours, about 15 hours, about 20 hours, about 25 hours, about 30 hours, about 35 hours, about 40 hours, about 45 hours, about 50 hours, about 55 hours, or about 60 hours after EOS. In a particular embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC, or GC at about 51 hours after EOS.

[0038] In certain embodiments, the radiopharmaceutical composition or formulation has a radiochemical purity of at least about 99% as measured by HPLC, TLC, iTLC, or GC 0 hours after EOS. In another particular embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 96.5% as measured by HPLC, TLC, or GC 24 hours after EOS, at least about 95% as measured by HPLC, LC, or GC 36 hours after EOS, at least about 93% as measured by HPLC, LC, or GC 48 hours after EOS, at least about 92.5% as measured by HPLC, LC, or GC 51 hours after EOS, and at least about 85% as measured by HPLC, LC, or GC 60 hours after EOS.

[0039] In one embodiment, the identity of the radionuclide is determined by gamma ray energy detection.

[0040] In another embodiment, radioactivity is measured in a dose calibrator. The chemistry amount of Cu-64 PSMA I&T in a single dose is calculated from the radioactivity measurement when a single dose is dispensed.

[0041] In one embodiment, the bacterial endotoxin content is determined for each batch prior to release using PTS equipment (USP <85>), and sterility is determined in accordance with USP <71>.

[0042] In one embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about 2°C to about 55°C, about 10°C to about 50°C, about 15°C to about 45°C, or about 20°C to about 40°C. In a particular embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about 10°C, about 12.5°C, about 15°C, about 17.5°C, about 20°C, about 20.5°C, about 21°C, about 21.5°C, about 22°C, about 22.5°C, about 23°C, about 23.5°C, about 24°C, about 24.5°C, about 25°C, about 25.5°C, about 26°C, about 26.5°C, about 27°C, about 27.5°C, about 28°C, about 28.5°C, about 29°C, about 29.5°C, about 30°C, about 32.5°C, about 35°C, about 37.5°C, about 40°C, about 42.5°C, about 45°C, about 47.5°C, about 50°C, about 52.5°C, or about 55°C.

[0043] In one embodiment, the unit dose is 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL. In a particular embodiment, the unit dose is 4 mL.

[0044] (i.Cu-64 PSMA I&T) The total amount of labeled Cu-64 PSMA I&T present in the radiopharmaceutical composition can be different, and it is different. In some embodiments, the total amount of Cu-64 PSMA I&T present in the radiopharmaceutical composition can be up to about 50 mCi / mL at EOS. In various embodiments, the total amount of Cu-64 PSMA I&T present in the radiopharmaceutical composition is about 5 mCi / mL, about 7.5 mCi / mL, about 10 mCi / mL, about 12.5 mCi / mL, about 15 mCi / mL, about 17.5, about 20 mCi / mL, about 22.5 mCi / mL, about 25 mCi / mL, about 27.5 mCi / mL, about 30 mCi / mL, about 32.5 mCi / mL, about 35 mCi / mL, about 37.5 mCi / mL, about 40 mCi / mL, about 42.5 mCi / mL, about 45 mCi / mL, about 47.5 mCi / mL, or about 50 mCi / mL at EOS. In still other embodiments, the total amount of Cu-64 PSMA I&T present in the radiopharmaceutical composition is about 30 mCi / mL, about 31 mCi / mL, about 32 mCi / mL, about 33 mCi / mL, about 34 mCi / mL, about 35, about 36 mCi / mL, about 37 mCi / mL, about 38 mCi / mL, about 39 mCi / mL, or about 40 mCi / mL. In another embodiment, the total amount of Cu-64 PSMA I&T present in the radiopharmaceutical composition is about 25 mCi / mL to about 50 mCi / mL at EOS. In yet another embodiment, the total amount of Cu-64 PSMA I&T present in the radiopharmaceutical composition is about 30 mCi / mL to about 45 mCi / mL at EOS. In yet another embodiment, the total amount of Cu-64 PSMA I&T present in the radiopharmaceutical composition is about 35 mCi / mL to about 40 mCi / mL at EOS.

[0045] In another embodiment, the total amount of labeled Cu-64 PSMA I&T present in the radiopharmaceutical composition can range from about 1 mCi / mL to about 3 mCi / mL at assay. In various embodiments, the total amount of labeled Cu-64 PSMA I&T present at assay can be about 1 mCi / mL, about 1.25 mCi / mL, about 1.5 mCi / mL, about 1.75 mCi / mL, about 2 mCi / mL, about 2.25 mCi / mL, about 2.5 mCi / mL, 2.75 mCi / mL, or about 3 mCi / mL.

[0046] The amount of PSMA I&T present in the radiopharmaceutical composition can also vary. In one embodiment, the amount of PSMA I&T present in the radiopharmaceutical composition can range from about 10 μg / mL to about 30 μg / mL of PSMA I&T. In various embodiments, the total amount of PSMA I&T can be about 1 μg / mL, about 1.25 μg / mL, about 1.5 μg / mL, about 1.75 μg / mL, about 2 μg / mL, about 2.25 μg / mL, or about 2.5 μg / mL. In another embodiment, the total amount of PSMA I&T can range from 1 μg / mL to about 30 μg / mL, about 10 μg / mL to about 30 μg / mL, about 15 μg / mL to about 27.5 μg / mL, or about 20 μg / mL to about 25 μg / mL. In another embodiment, the total amount of PSMA I&T can range from about 22.5 μg / mL to about 27.5 μg / mL.

[0047] In one embodiment, the radioactivity of Cu-64 PSMA I&T in the radiopharmaceutical composition is less than about 150 mCi, less than about 140 mCi, less than about 130 mCi, less than about 120 mCi, less than about 110 mCi, less than about 100 mCi, less than about 90 mCi, less than about 80 mCi, less than about 70 mCi, less than about 60 mCi, less than about 50 mCi, less than about 40 mCi, less than about 30 mCi, less than about 20 mCi, or less than about 10 mCi per unit dose. In another embodiment, the radioactivity of Cu-64 PSMA I&T in the radiopharmaceutical composition is from about 1 mCi to about 150 mCi, from about 1 mCi to about 125 mCi, from about 1 mCi to about 100 mCi, from about 1 mCi to about 75 mCi, from about 1 mCi to about 50 mCi, from about 1 mCi to about 40 mCi, from about 1 mCi to about 30 mCi, from about 1 mCi to about 20 mCi, from about 1 mCi to about 10 mCi, or from about 4 mCi to about 10 mCi, or from about 5 mCi to about 9 mCi per unit dose. In a particular embodiment, the radioactivity of Cu-64 PSMA I&T in the radiopharmaceutical composition is about 1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi, about 7 mCi, about 8 mCi, about 9 mCi, about 10 mCi, about 11 mCi, about 12 mCi, about 13 mCi, about 14 mCi, about 15 mCi, about 18 mCi, about 21 mCi, about 24 mCi, about 27 mCi, about 30 mCi, about 40 mCi, about 50 mCi, about 60 mCi, about 70 mCi, about 80 mCi, about 90 mCi, about 100 mCi, about 110 mCi, about 120 mCi, about 130 mCi, about 140 mCi, or about 150 mCi per unit dose.

[0048] In another embodiment, the radioactivity of Cu-64 PSMA I&T in the radiopharmaceutical composition is less than about 50 mCi per mL, less than about 40 mCi per mL, less than about 30 mCi per mL, less than about 20 mCi per mL, less than about 10 mCi per mL, less than about 5 mCi per mL, less than about 4 mCi per mL, less than about 3 mCi per mL, less than about 2.5 mCi per mL, less than about 2 mCi per mL, less than about 1.5 mCi per mL, or less than about 1 mCi per mL. In another embodiment, the radioactivity of Cu-64 PSMA I&T in the radiopharmaceutical composition is from about 1 mCi to about 100 mCi per mL, from about 1 mCi to about 50 mCi per mL, from about 1 mCi to about 20 mCi per mL, or from about 1 mCi to about 10 mCi per mL. In a particular embodiment, the radioactivity of Cu-64 PSMA I&T in the radiopharmaceutical composition is about 1 mCi, about 1.25 mCi, about 1.5 mCi, about 1.75 mCi, about 2 mCi, about 2.25 mCi, about 2.5 mCi, about 2.75 mCi, about 3 mCi, about 3.25 mCi, about 3.5 mCi, about 3.75 mCi, about 4 mCi, about 4.25 mCi, about 4.5 mCi, about 4.75 mCi, about 5 mCi, about 7 mCi, about 9 mCi, about 12 mCi, about 15 mCi, about 18 mCi, about 21 mCi, about 24 mCi, about 27 mCi, about 30 mCi, about 40 mCi, or about 50 mCi per mL.

[0049] In one embodiment, the RAC of Cu-64 PSMA I&T in the radiopharmaceutical composition is less than about 50 mCi / mL, less than about 45 mCi / mL, less than about 40 mCi / mL, less than about 35 mCi / mL, less than about 30 mCi / mL, less than about 25 mCi / mL, less than about 20 mCi / mL, less than about 15 mCi / mL, less than about 10 mCi / mL, less than about 5 mCi / mL, less than about 4 mCi / mL, less than about 3 mCi / mL, or less than about 2 mCi / mL.

[0050] In yet another embodiment, the RAC of Cu-64 PSMA I&T in the radiopharmaceutical composition is up to about 40 mCi / mL, up to about 39 mCi / mL, up to about 38 mCi / mL, up to about 37 mCi / mL, up to about 36 mCi / mL, up to about 35 mCi / mL, up to about 34 mCi / mL, up to about 33 mCi / mL, up to about 32 mCi / mL, up to about 31 mCi / mL, up to about 30 mCi / mL, up to about 29 mCi / mL, up to about 28 mCi / mL, up to about 27 mCi / mL, up to about 26 mCi / mL, up to about 25 mCi / mL, up to about 24 mCi / mL, up to about 23 mCi / mL, up to about 22 mCi / mL, up to about 21 mCi / mL, up to about 20 mCi / mL, up to about 19 mCi / mL, up to about 18 mCi / mL, up to about 17 mCi / mL, up to about 16 mCi / mL, up to about 15 mCi / mL, 14 mCi / mL, up to about 13 mCi / mL, up to about 12 mCi / mL, up to about 11 mCi / mL, up to about 10 mCi / mL, up to about 9 mCi / mL, up to about 8 mCi / mL, up to about 7 mCi / mL, up to about 6 mCi / mL, up to about 5 mCi / mL, up to about 4 mCi / mL, up to about 3 mCi / mL, up to about 2 mCi / mL, or up to about 1 mCi / mL.

[0051] In another embodiment, the RAC of Cu-64 PSMA I&T in the radiopharmaceutical composition is from about 1 mCi / mL to about 100 mCi / mL, from about 2 mCi / mL to about 90 mCi / mL, from about 3 mCi / mL to about 80 mCi / mL, from about 4 mCi / mL to about 60 mCi / mL, from about 5 mCi / mL to about 50 mCi / mL, from about 10 mCi / mL to about 40 mCi / mL, from about 1 mCi / mL to about 40 mCi / mL, from about 1 mCi / mL to about 36 mCi / mL, from about 1 mCi / mL to about 35 mCi / mL, or from about 20 mCi / mL to about 35 mCi / mL. In a particular embodiment, the RAC of Cu-64 PSMA I&T in the radiopharmaceutical composition is about 1 mCi / mL, about 10 mCi / mL, about 13.5 mCi / mL, about 15 mCi / mL, about 20 mCi / mL, about 27 mCi / mL, about 30 mCi / mL, about 33 mCi / mL, about 35 mCi / mL, about 40 mCi / mL, about 45 mCi / mL, or about 50 mCi / mL.

[0052] In yet another embodiment, the Cu-64 PSMA I&T pharmaceutical has an end-of-production standard concentration of from about 15 mCi / mL to about 40 mCi / mL at the end of production.

[0053] In one embodiment, the mass of the radiopharmaceutical component (Cu-64 PSMA I&T) and related non-radioactive substances in the pharmaceutical is less than about 200 μg, less than about 175 μg, less than about 150 μg, less than about 125 μg, less than about 120 μg, less than about 115 μg, less than about 110 μg, less than about 105 μg, less than about 100 μg, less than about 75 μg, or less than about 50 μg per vial.

[0054] (ii. Antioxidant) In one embodiment, the formulation contains an antioxidant. In another embodiment, the antioxidant is ascorbate / ascorbic acid. In another embodiment, the antioxidant is gentisic acid. In a particular embodiment, the antioxidant is a sodium acetate / gentisic acid solution.

[0055] In another embodiment, the total amount of the sodium acetate / gentisic acid solution in the radiopharmaceutical composition can vary and it does. In some embodiments, the sodium acetate / gentisic acid solution present in the radiopharmaceutical composition can range from about 0 μg / mL to about 600 μg / mL or from about 130 μg / mL to about 320 μg / mL of gentisic acid and from about 0 mg / mL to about 3.5 mg / mL or from about 1.3 mg / mL to about 3.3 mg / mL of sodium acetate.

[0056] In another embodiment, the concentration of sodium acetate in the final radiopharmaceutical composition can be from about 0.2 M to about 0.5 M, from about 0.25 M to about 0.4 M, or from about 0.3 M to about 0.35 M.

[0057] In yet another embodiment, the concentration of sodium acetate in the final radiopharmaceutical composition can be from about 1 mg / mL to about 5 mg / mL, from about 2 mg / mL to about 4 mg / mL, or from about 2.5 mg / mL to about 3.5 mg / mL.

[0058] In the dose of the final radiopharmaceutical composition, the concentration of ganciclovir acid can range from about 0 mg / mL to about 3.5 mg / mL. In another embodiment, the concentration of ganciclovir acid can range from about 1.3 mg / mL to about 3.3 μg / mL.

[0059] In the dose of the final radiopharmaceutical composition, the concentration of ganciclovir acid can range from about 0 mg / mL to about 600 μg / mL. In another embodiment, the concentration of ganciclovir acid can range from about 130 mg / mL to about 320 μg / mL.

[0060] (iii. Stabilizer) In one embodiment, the formulation contains a stabilizer.

[0061] In another embodiment, the stabilizer is sodium ascorbate. The total amount of sodium ascorbate in the radiopharmaceutical composition can vary and it is different. In some embodiments, the sodium ascorbate present in the radiopharmaceutical composition can range from about 5 mg to about 300 mg per unit dose. In one embodiment, sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 75 mg per mL. In yet another embodiment, sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg or about 40 mg per mL. In still another embodiment, sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 1 mg to about 500 mg, about 5 mg to about 300 mg, about 20 mg to about 80 mg, about 30 mg to about 60 mg, about 35 mg to about 50 mg, or about 40 mg to about 45 mg per mL.

[0062] One aspect of the present disclosure provides a radiopharmaceutical composition having a pH of from about 3 to about 9, from about 4 to about 9, from about 5 to about 9, from about 3 to about 8, from about 4 to about 8, from about 3 to about 7.5, from about 5 to about 7.5, or from about 5.5 to about 7.5. The pH of the radiopharmaceutical composition can be about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5.

[0063] (Preparation of IV.Cu-64 PSMA I&T Pharmaceutical) In certain embodiments, Cu-64 PSMA I&T is prepared using the general process described herein, and the general process can be carried out manually or by automated synthesis. Lyophilized PSMA I&T is reconstituted in a pH buffered solution of gentisic acid in sodium acetate. The reconstituted PSMA I&T solution is mixed with a solution of copper chloride 64 Cu, and the mixture is heated to 30 °C or held at ambient temperature for up to 30 minutes. The resulting Cu-64 PSMA I&T product can be purified by 18 solid phase extraction (SPE) or the reaction mixture can be used directly in the next process step (i.e., final formulation). For SPE purification, the drug substance is eluted in 50% aqueous ethanol and the eluate is passed through a 0.2 μm sterile filter and placed into a vial containing an aqueous solution of sodium ascorbate. The radioactivity concentration of the Cu-64 PSMA I&T solution is adjusted by dilution with additional sodium ascorbate if necessary, and then the bulk pharmaceutical solution can be aseptically dispensed.

[0064] (i. Ligand) The present invention includes a ligand capable of chelating Cu-64. In one embodiment, the ligand is PSMA I&T.

[0065] The amount of ligand added to the reaction mixture containing Cu-64 varies depending on the amount of active Cu-64 present. In one embodiment where the reaction mixture contains about 15 Ci of Cu-64, the ligand is added to the reaction mixture in an amount of about 8,000 μg to about 10,000 μg. In another embodiment, about 9,000 μg is added to the reaction mixture.

[0066] In another embodiment where the reaction mixture contains about 15 Ci of Cu-64, the ligand is added to the reaction mixture in an amount of about 7,000 μg to about 11,000 μg, about 8,000 μg to about 10,000 μg, or about 9,000 μg is added to the reaction mixture.

[0067] In another embodiment where the reaction mixture contains about 20 Ci of Cu-64, the ligand is added to the reaction mixture in an amount of about 8,000 μg to about 12,000 μg, about 9,000 μg to about 11,000 μg, or about 10,000 μg is added to the reaction mixture.

[0068] In another embodiment where the reaction mixture contains about 50 Ci of Cu-64, the ligand is added to the reaction mixture in an amount of about 20,000 μg to about 30,000 μg, about 22,000 μg to about 28,000 μg, about 24,000 μg to about 26,000 μg, or about 25,000 μg is added to the reaction mixture.

[0069] In yet another embodiment where the reaction mixture contains about 90 Ci of Cu-64, the ligand is added to the reaction mixture in an amount of about 36,000 μg to about 54,000 μg, about 40,000 μg to about 50,000 μg, or about 45,000 μg is added to the reaction mixture.

[0070] In another embodiment, PSMA I&T is added to the reaction mixture in an amount of from about 1,000 μg to about 60,000 μg, from about 5,000 μg to about 55,000 μg, from about 7,000 μg to about 11,000 μg, from about 8,000 μg to about 12,000 μg, from about 8,000 μg to about 10,000 μg, from about 9,000 μg to about 11,000 μg, from about 20,000 μg to about 30,000 μg, from about 22,000 μg to about 28,000 μg, from about 24,000 μg to about 26,000 μg, from about 36,000 μg to about 54,000 μg, or from about 40,000 μg to about 50,000 μg. In another embodiment, PSMA I&T is added to the reaction mixture in an amount of about 9,000 μg, about 10,000 μg, about 25,000 μg, or about 45,000 μg. In yet another embodiment, PSMA I&T is added to the reaction mixture in an amount less than about 11,000 μg, less than about 30,000 μg, or less than about 55,000 μg.

[0071] In a further embodiment, PSMA I&T is added to the reaction mixture in an amount of about 9,000 μg for a batch of about 15 Ci. In another embodiment, PSMA I&T is added to the reaction mixture in an amount of about 8,000 μg, about 9,000 μg, about 10,000 μg, or about 11,000 μg for a batch of about 20 Ci. In yet another embodiment, PSMA I&T is added to the reaction mixture in an amount of from about 8,000 μg to about 11,000 μg for a batch of about 20 Ci. In yet another embodiment, PSMA I&T is added to the reaction mixture in an amount of from about 20,000 μg to about 30,000 μg for a batch of about 50 Ci. In yet another embodiment, PSMA I&T is added to the reaction mixture in an amount of from about 36,000 μg to about 54,000 μg for a batch of about 90 Ci.

[0072] In another embodiment, PSMA I&T is used in an amount of from about 0.1 μg / mCi to about 20 μg / mCi, from about 0.5 μg / mCi to about 15 μg / mCi, from about 1 μg / mCi to about 11 μg / mCi, from about 1 μg / mCi to about 8 μg / mCi, from about 1 μg / mCi to about 5 μg / mCi, from about 1 μg / mCi to about 3 μg / mCi, or from about 0.1 μg / mCi to about 1.5 μg / mCi. In yet another embodiment, PSMA I&T is used in an amount of about 0.1 μg / mCi, about 0.25 μg / mCi, about 0.4 μg / mCi, about 0.5 μg / mCi, about 0.6 μg / mCi, about 0.75 μg / mCi, about 0.8 μg / mCi, about 1 μg / mCi, about 1.25 μg / mCi, about 1.5 μg / mCi, about 1.75 μg / mCi, about 2 μg / mCi, about 2.5 μg / mCi, about 3 μg / mCi, about 3.5, or about 4 μg / mCi.

[0073] In one embodiment, the concentration of PSMA I&T per mL in the radiolabeling step is greater than about 100 μg / mL, greater than about 150 μg / mL, greater than about 200 μg / mL, greater than about 250 μg / mL, greater than about 300 μg / mL, greater than about 333 μg / mL, or greater than about 400 μg / mL. In yet another embodiment, the concentration of PSMA I&T per mL in the radiolabeling step is greater than about 100 μg / mL, greater than about 110 μg / mL, greater than about 120 μg / mL, greater than about 130 μg / mL, greater than about 140 μg / mL, greater than about 150 μg / mL, greater than about 160 μg / mL, greater than about 170 μg / mL, greater than about 180 μg / mL, greater than about 190 μg / mL, or greater than about 200 μg / mL.

[0074] (ii. Radionuclide) In one embodiment, 64CuCl₂ is added to the reaction mixture in an amount of from about 100 mCi to about 5000 mCi, from about 200 mCi to about 4000 mCi, from about 300 mCi to about 3500 mCi, from about 400 mCi to about 3000 mCi, from about 500 mCi to about 2500 mCi, from about 500 mCi to about 15,000 mCi, from about 1,000 mCi to about 10,000 mCi, from about 1,000 mCi to about 15,000 mCi, or from about 7,500 mCi to about 15,000 mCi ( 64 as a source of Cu). In another embodiment, 64 CuCl₂ is added to the reaction mixture in an amount of up to about 10,000 mCi ( 64 as a source of Cu). In yet another embodiment, 64 CuCl₂ is added to the reaction mixture in an amount of up to about 15,000 mCi ( 64 as a source of Cu). In a further embodiment 64 CuCl₂ is added to the reaction mixture in an amount of about 100 mCi, about 200 mCi, about 300 mCi, about 400 mCi, about 500 mCi, about 600 mCi, about 700 mCi, about 800 mCi, about 900 mCi, about 1000 mCi, about 1500 mCi, about 2000 mCi, about 2500 mCi, about 3000 mCi, about 3500 mCi, about 4000 mCi, about 4500 mCi, about 5000 mCi, about 5500 mCi, about 6000 mCi, about 6500 mCi, about 7000 mCi, about 7500 mCi, about 8000 mCi, about 8500 mCi, about 9000 mCi, about 9500 mCi, about 10,000 mCi, about 15,000 mCi, about 20,000 mCi, about 30,000 mCi, about 40,000 mCi, about 50,000 mCi, about 60,000 mCi, about 70,000 mCi, about 80,000 mCi, about 90,000 mCi, or about 100,000 mCi ( 64 as a source of Cu). In yet another embodiment, 64CuCl2 is added to the reaction mixture in an amount of less than about 100 mCi, less than about 200 mCi, less than about 300 mCi, less than about 400 mCi, less than about 500 mCi, less than about 600 mCi, less than about 700 mCi, less than about 800 mCi, less than about 900 mCi, less than about 1000 mCi, less than about 1500 mCi, less than about 2000 mCi, less than about 2500 mCi, less than about 3000 mCi, less than about 3500 mCi, less than about 4000 mCi, less than about 4500 mCi, less than about 5000 mCi, less than about 5500 mCi, less than about 6000 mCi, less than about 6500 mCi, less than about 7000 mCi, less than about 7500 mCi, less than about 8000 mCi, less than about 8500 mCi, less than about 9000 mCi, less than about 9500 mCi, or less than about 10,000 mCi ( 64 as a source of Cu).

[0075] In another embodiment, carrier-free copper (e.g., CuCl2) is added to the reaction mixture to improve the consistency of the radiochemical purity of the precursor formulation. This process is referred to herein as "spiking". In one embodiment, at least about 5 ppm of carrier-free copper is present in the precursor formulation. In another embodiment, at least about 1 ppm, about 2 ppm, about 3 ppm, about 4 ppm, about 5 ppm, about 10 ppm, about 15 ppm, about 20 ppm, about 25 ppm, or about 30 ppm of carrier-free copper is present in the precursor formulation. In yet a further embodiment, the amount of carrier-free copper in the precursor formulation is from about 5 ppm to about 30 ppm. In yet a further embodiment, the amount of carrier-free copper in the precursor formulation is less than about 30 ppm.

[0076] (iii. Buffer solution) In one embodiment, the buffer solution used in the preparation of the bulk solution of the pharmaceutical is sodium acetate buffer, sodium acetate / gendronic acid buffer, sodium ascorbate buffer, sodium ascorbate / ethanol buffer, ammonium acetate buffer, ammonium acetate / gendronic acid buffer, ammonium ascorbate buffer, ammonium ascorbate / ethanol buffer, sodium phosphate / disodium phosphate, sodium citrate / citric acid, or any other suitable buffer. In one embodiment, the concentration of gendronic acid in the buffer is about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 10 mg / mL, or about 1 mg / mL to about 50 mg / mL. In yet another embodiment, the concentration of gendronic acid in the buffer is 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 20 mg / mL, about 30 mg / mL, about 40 mg / mL, or about 50 mg / mL.

[0077] In another embodiment, the concentration of sodium acetate in the buffer is about 10 mg / mL to about 100 mg / mL, about 20 mg / mL to about 80 mg / mL, about 30 mg / mL to about 60 mg / mL, or about 40 mg / mL to about 60 mg / mL. In yet another embodiment, the concentration of sodium acetate in the buffer is about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 54.8 mg / mL, about 55 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL.

[0078] In another embodiment, the buffer contains gentisic acid at about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 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, and sodium acetate at about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 54.8 mg / mL, about 55 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL.

[0079] In one embodiment, the buffer is a solution containing gentisic acid between about 2 mg / mL and about 4 mg / mL and sodium acetate between about 0.25 M and about 0.4 M. In another embodiment, the buffer is a solution containing about 4 mg / mL of gentisic acid and about 55 mg / mL of sodium acetate. In another embodiment, the buffer solution has a pH of about 4.5 to about 5.5.

[0080] (iv. Stabilizer) In one embodiment, the stabilizer is gentisic acid. In another embodiment, the stabilizer is ascorbate. However, any suitable stabilizer may be used.

[0081] In another embodiment, more than one stabilizer is used. In another embodiment, one stabilizer (e.g., gentisic acid) is used during the radiolabeling process and another stabilizer (e.g., sodium ascorbate or ascorbic acid) is used in the final formulated product.

[0082] In yet another embodiment, the stabilizer or combination thereof is added to the reaction mixture at a concentration of about 4 mg / mL, about 10 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 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.

[0083] In one embodiment, sodium ascorbate is added to the reaction mixture at a concentration of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 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.

[0084] In another embodiment, ascorbic acid is added to the reaction mixture at a concentration of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 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.

[0085] (v. radiolabeling conditions) In yet another embodiment, the radiolabeling reaction conditions are different. In one embodiment, the radiolabeling reaction is carried out at a temperature of about 20°C to about 95°C, about 20°C to about 90°C, about 20°C to about 40°C, about 20°C to about 35°C, about 35°C to about 50°C, about 50°C to about 70°C, about 70°C to about 95°C, or about 80°C to about 90°C. In a particular embodiment, the radiolabeling reaction is carried out at a temperature of about 10°C, about 12.5°C, about 15°C, about 17.5°C, about 20°C, about 20.5°C, about 21°C, about 21.5°C, about 22°C, about 22.5°C, about 23°C, about 23.5°C, about 24°C, about 24.5°C, about 25°C, about 25.5°C, about 26°C, about 26.5°C, about 27°C, about 27.5°C, about 28°C, about 28.5°C, about 29°C, about 29.5°C, about 30°C, about 32.5°C, about 35°C, about 37.5°C, about 40°C, about 42.5°C, about 45°C, about 47.5°C, about 50°C, about 52.5°C, about 55°C, about 57.5°C, about 60°C, about 62.5°C, about 65°C, about 67.5°C, about 70°C, about 72.5°C, about 75°C, about 77.5°C, about 80°C, about 82.5°C, about 85°C, about 87.5°C, or about 90°C.

[0086] In one embodiment, the radiolabeling reaction time is less than about 60 minutes, less than about 45 minutes, less than about 30 minutes, less than about 15 minutes, or less than about 5 minutes. In another embodiment, the radiolabeling reaction time is about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, or about 60 minutes. In yet another embodiment, the radiolabeling reaction time is about 1 minute to about 60 minutes, about 5 minutes to about 50 minutes, about 5 minutes to about 30 minutes, about 10 minutes to about 40 minutes, or about 20 minutes to about 30 minutes.

[0087] In another embodiment, the pH of the final product is about 4.0 to 8.5, about 4.5 to about 8.0, about 5.0 to about 7.5, or about 5.5 to about 7.5.

[0088] In one embodiment, at the end of production, the activity range for a unit dose containing the radiopharmaceutical composition is about 60 mCi / (per dose), about 70 mCi / (per dose), about 80 mCi / (per dose), about 90 mCi / (per dose), about 100 mCi / (per dose), about 110 mCi / (per dose), about 120 mCi / (per dose), about 130 mCi / (per dose), about 140 mCi / (per dose), about 150 mCi / (per dose), or about 160 mCi / (per dose). In yet another embodiment, the activity range for a unit dose containing the radiopharmaceutical composition is from about 130 mCi / (per dose) to about 150 mCi / (per dose). In still another embodiment, the activity range for a unit dose containing the radiopharmaceutical composition is about 146 mCi / (per dose).

[0089] In one embodiment, the radiopharmaceutical composition is prepared in bulk, and the radioactivity of the bulk solution is from about 1 mCi to about 100,000 mCi, from 1 mCi to about 90,000 mCi, from 1 mCi to about 80,000 mCi, from 1 mCi to about 70,000 mCi, from 1 mCi to about 60,000 mCi, from 1 mCi to about 50,000 mCi, from 1 mCi to about 40,000 mCi, from 1 mCi to about 10,000 mCi, from about 100 mCi to about 9,000 mCi, from about 1,000 mCi to about 8,000 mCi, from about 3,000 mCi to about 5,000 mCi, from about 1 mCi to about 5,000 mCi, from about 5,000 mCi to about 10,000 mCi, from about 1,000 mCi to about 30,000 mCi, from about 1,000 mCi to about 20,000 mCi, from about 10,000 mCi to about 40,000 mCi, from about 20 mCi to about 30,000 mCi, from about 5,000 mCi to about 30,000 mCi, or from about 10,000 mCi to about 15,000 mCi. In another embodiment, the radioactivity of the bulk solution is less than about 40,000 mCi, less than about 30,000 mCi, less than about 20,000 mCi, less than about 15,000 mCi, less than about 10,000 mCi, less than about 9,000 mCi, less than about 8,000 mCi, less than about 7,000 mCi, less than about 6,000 mCi, less than about 5,000 mCi, less than about 4,000 mCi, less than about 3,000 mCi, less than about 2,000 mCi, or less than about 1,000 mCi.

[0090] In yet another embodiment, the radiopharmaceutical composition is prepared with or without using a purification cartridge. In some embodiments, the radiopharmaceutical composition is obtained in high purity without purification.

[0091] In one embodiment, the radiopharmaceutical composition is chemically stable for up to about 40 hours, up to about 41 hours, up to about 42 hours, up to about 43 hours, up to about 44 hours, up to about 45 hours, up to about 46 hours, up to about 47 hours, up to about 48 hours, up to about 49 hours, up to about 50 hours, up to about 51 hours, up to about 52 hours, up to about 53 hours, up to about 54 hours, up to about 55 hours, up to about 56 hours, up to about 57 hours, up to about 58 hours, up to about 59 hours, or up to about 60 hours after formulation.

[0092] In one embodiment, the radiopharmaceutical composition is stored in a syringe. In yet another embodiment, the radiopharmaceutical composition is stored in a glass vial.

Examples

[0093] (Example) The following examples provide data on the manufacture, stability, and radiochemical purity for various formulations.

[0094] (Example 1) The pharmaceutical product is a sterile filtered radiopharmaceutical solution containing Cu-64 PSMA I&T injection. The pharmaceutical product is formulated in an ascorbic acid solution to target a maximum dose of 9 mCi (±10%) adjusted to a specific reference time.

[0095] Store the Cu-64 PSMA I&T injection at a controlled room temperature of 20°C to 25°C (68°F to 77°F) in the original package shield to protect humans from ionizing radiation. Temperature deviations between 15°C and 30°C (59°F and 86°F) are allowed during storage. The expiration date is approximately 1900 CT days from the assay, and the shelf life for the pharmaceutical product is approximately 49 hours to approximately 51 hours.

[0096] (Example 2 - Example of a Cu-64 PSMA I&T unit dose) Examples of Cu-64 PSMA I&T unit doses formulated at a dose of 9 mCi at the time of assay are presented in Table 4. (Table 4. Cu-64 PSMA I&T 9 mCi unit dose)

Table 5-1

Table 5-2

[0097] Examples of the formulated Cu-64 PSMA I&T unit doses at a dosage of 5 mCi to 9 mCi at the time of assay are presented in Table 5. (Table 5. Cu-64 PSMA I&T 5 mCi to 9 mCi unit doses)

Table 6

[0098] (Example 3 - Manufacture of copper (Cu-64) PSMA I&T injection using a purification cartridge) Radiolabeling: A buffered solution containing approximately 1 mg / mL of PSMA I&T, 54 mg / mL to 56 mg / mL of sodium acetate trihydrate, and 3 mg / mL to 5 mg / mL of gentisic acid was prepared (pH 4 to pH 5.5). For radiolabeling, the PSMA I&T solution was mixed with a 64 solution of Cu]CuCl2, and the mixture was held at ambient temperature or gently heated for 5 minutes to 30 minutes. After the reaction was complete, the crude reaction mixture was loaded onto a C 18 SPE cartridge, the cartridge was rinsed with water, 64 and the Cu]Cu-PSMA I&T drug substance was eluted in a 50% ethanol solution.

[0099] Final pharmaceutical formulation: The raw drug solution was passed through a sterile filter, collected in final multiple-dose vials, the radioactivity concentration was evaluated, and the radioactivity concentration was diluted with sodium ascorbate buffer to prepare a final pharmaceutical product with a concentration of 1.25 mCi / mL to 2.5 mCi / mL (at the time of assay). Before release, the pharmaceutical product was tested to ensure that it met the acceptable quality and safety requirements. The processes described herein can be carried out manually or using an automated synthesis unit.

[0100] (Example 4 - Removal of purification cartridge) Two 10 Ci batches of copper (Cu-64) PSMA I&T were prepared, and the main difference between these batches was the removal of the purification step. During purification, a solid-phase extraction cartridge was used to purify the product by removing the radiolabeled buffer and the remaining copper chloride ( 64 Cu) starting material; however, this step requires the concentration of batch activity in a small volume (i.e., <1 mL), which can promote radiolytic damage and have an adverse effect on the radiochemical purity (RCP). This phenomenon was experimentally observed when comparing the radiochemical purity of copper (Cu-64) PSMA I&T prepared with purification with that prepared without purification (Figure 2). The removal of the purification step resulted in a product with a higher RCP of 98.9% compared to 92.4% (Figure 2A) (Figure 2B). The difference between the two purity profiles was that the main radiolytic impurity (t R = 16.8’ - 17.2’) was mostly absent in the unpurified product. In both formulations, the RCP of the single-dose vials prepared was maintained over a period of 51 hours after formulation (i.e., 51 hours after the end of synthesis).

[0101] All references cited in this specification are hereby incorporated by reference herein. The foregoing is provided primarily for purposes of illustration. It will be readily apparent to those skilled in the art that additional drugs can be included and that the components, additives, ratios, methods of formulation, methods of use, and other parameters described herein can be further modified or substituted in various ways without departing from the spirit and scope of the invention.

Claims

**Claim 1** A radiopharmaceutical composition comprising a copper (Cu-64) PSMA I&T solution for injection, (a) an amount of copper (Cu-64) PSMA I&T of about 1 mCi to about 15 mCi per unit at the time of administration, (b) gentisic acid at a concentration of about 0 mg / mL to about 3.5 mg / mL, (c) sodium acetate at a concentration of about 1 mg / mL to about 5 mg / mL, comprising, wherein the radioactivity concentration of the radiopharmaceutical composition is about 1 mCi to about 36 mCi. A radiopharmaceutical composition. **Claim 2** The radiopharmaceutical composition according to claim 1, having a radioactivity of less than about 10 mCi. **Claim 3** The radiopharmaceutical composition according to claim 1, comprising an amount of copper (Cu-64) PSMA I&T of about 1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi, about 7 mCi, about 8 mCi, about 9 mCi, or about 10 mCi per unit at the time of administration. **Claim 4** The radiopharmaceutical composition according to claim 1, comprising gentisic acid at a concentration of about 1.3 mg / mL to about 3.3 mg / mL. **Claim 5** The radiopharmaceutical composition according to claim 1, comprising sodium acetate at a concentration of about 2 mg / mL to about 4 mg / mL. **Claim 6** The radiopharmaceutical composition according to claim 1, comprising sodium acetate at a concentration of about 2.5 mg / mL to about 3.5 mg / mL. **Claim 7** The radiopharmaceutical composition according to claim 1, which is in a sterile state. **Claim 8** The radiopharmaceutical composition according to claim 1, wherein the unit dose of the composition has a volume of about 1 mL to about 10 mL. **Claim 9** The radiopharmaceutical composition according to claim 1, wherein the unit dose of the composition has a volume of about 4 mL. **Claim 10** The radiopharmaceutical composition according to claim 1, having a radiochemical purity of at least 99% when measured by HPLC at 0 hours after EOS. **Claim 11** A radiopharmaceutical composition for use in the diagnosis of prostate cancer in a human subject, at the time of administration, (a) an amount of copper (Cu-64) PSMA I&T of about 5 mCi to about 9 mCi, (b) an amount of ascorbic acid of about 84 mg to about 148 mg, (c) an appropriate amount of water for injection into the human patient comprising. A radiopharmaceutical composition. **Claim 12** The radiopharmaceutical composition according to claim 11, having a radioactivity of less than about 10 mCi. **Claim 13** The radiopharmaceutical composition according to claim 11, wherein the pH of the composition is about 5.5 to about 7.

5. **Claim 14** The radiopharmaceutical composition according to claim 11, which is in a sterile state.

15. The radiopharmaceutical composition according to claim 11, having a volume of about 1 mL to about 10 mL.

16. The radiopharmaceutical composition according to claim 11, having a volume of about 4 mL.

17. The radiopharmaceutical composition according to claim 11, having a radiochemical purity of at least 95% when measured by HPLC.

18. The radiopharmaceutical composition according to claim 11, having a radiochemical purity of at least 96% when measured by HPLC.

19. The radiopharmaceutical composition according to claim 11, having a radiochemical purity of at least 97% when measured by HPLC.

20. The radiopharmaceutical composition according to claim 11, having a radiochemical purity of at least 98% when measured by HPLC.

21. The radiopharmaceutical composition according to claim 11, having a radiochemical purity of at least 99% when measured by HPLC.

22. A radiopharmaceutical solution for use in the diagnosis of prostate cancer in a human subject, (a) copper (Cu-64) PSMA I&T in an amount of about 1 mCi to about 15 mCi per unit at the time of administration, (b) gancididic acid at a concentration of about 0 mg / mL to about 3.5 mg / mL, and (c) sodium acetate at a concentration of about 1 mg / mL to about 5 mg / mL comprising the radiopharmaceutical solution.

23. The radioactive solution according to claim 22, wherein the radioactivity concentration of the radiopharmaceutical solution is up to 36 mCi.

24. The radiopharmaceutical solution according to claim 22, comprising copper (Cu-64) PSMA I&T in an amount of about 1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi, about 7 mCi, about 8 mCi, about 9 mCi, or about 10 mCi per unit at the time of administration.

25. The radiopharmaceutical solution according to claim 22, comprising gancididic acid at a concentration of about 1.3 mg / mL to about 3.3 mg / mL.

26. The radiopharmaceutical solution according to claim 22, comprising sodium acetate at a concentration of about 2 mg / mL to about 4 mg / mL.

27. The radiopharmaceutical solution according to claim 22, comprising sodium acetate at a concentration of about 2.5 mg / mL to about 3.5 mg / mL.

28. The radiopharmaceutical solution according to claim 22, wherein the pH of the solution is about 5.5 to about 7.

5.

29. The radiopharmaceutical solution according to claim 22, having at least 99% radiochemical purity when measured by HPLC 0 hours after EOS.

30. The radiopharmaceutical solution according to claim 22, having at least 99% radiochemical purity when measured by HPLC at the time of administration.

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