Radiolabeling and formulation of 64Cu-DOTATATE for scale-up

Abstract

Providing radiolabeling and formulations for the scale-up of 64Cu-DOTATATE. [Solution] This specification provides the following: 64 Cu-DOTATATE preparation, final formulation parameters and 64 Design of Experiments (DOE) to monitor the effect of Cu-DOTATATE on stability, 500mCi~2000mCi 64 Scaled-up experiments for preparing Cu-DOTATATE, and its final formulation 64 The stability of Cu-DOTATATE, optimization of the amount of DOTATATE used relative to the total activity used for radiolabeling, and 64 Cu-DOTATATE purity 64 The effect of the specific activity of copper chloride solution.

Description

[Technical Field]

[0001] Related projects This application claims priority to U.S. Provisional Application No. 63 / 074,451, filed on 3 September 2020, which is incorporated herein by reference in its entirety to the maximum extent legally permitted.

[0002] Technical field This disclosure relates to a bioconjugate compound containing a positron-emitting radionuclide. 64 This invention relates to compositions and methods for radiolabeling and purification of Cu-DOTATATE. [Background technology]

[0003] background The most important known imaging techniques in medical diagnosis are positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), single-photon computed tomography (SPECT), and ultrasound (US). Although today's imaging techniques are well-developed, most rely on nonspecific macroscopic, physical, physiological, or metabolic changes that distinguish normal tissue from pathological tissue.

[0004] Targeting molecular imaging (MI) has the potential to reach a new dimension in medical diagnosis. The term "targeting" refers to the selective and highly specific binding of a natural or synthetic ligand (binding agent) to a target molecule (molecular target) in vitro or in vivo.

[0005] MI is a rapidly emerging field of biomedical research that can be defined as the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. It is a novel interdisciplinary field where the resulting images reflect the cellular and molecular pathways, as well as the in vivo mechanisms, of disease as it exists in a physiologically authentic environment, rather than identifying the molecular events that cause the disease.

[0006] Several different contrast enhancers are known today. They can be used in functional imaging, primarily developed for PET and SPECT. The application of radiolabeled bioactive peptides for diagnostic imaging is gaining importance in nuclear medicine. Bioactive molecules that selectively interact with specific cell types are useful for delivering radioactivity to target tissues. For example, radiolabeled peptides have significant potential for the delivery of radionuclides to tumors, infarcts, and infected tissues for diagnostic imaging and radiotherapy.

[0007] DOTA(1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) and its derivatives constitute an important type of chelator for biomedical applications because they stably accommodate a variety of divalent and trivalent metal ions. One of its derivatives, which can be used as a targeting agent, is DOTATATE, [(4,7,10-tricarboxymethyl-1,4,7,10-tetrazacyclododeca-1-yl)acetyl]-(D)-phenylalanyl-(L)-cysteinyl-(L)-tyrosyl-(D)-tryptophanyl-(L)-lysyl-(L)-threoninyl-(L)-cysteinyl-(L)-threonine-cyclic (2-7) disulfide. The chemical structure of DOTATATE is shown below. [ka]

[0008] A newly emerging area is the use of chelators and conjugated bioactive peptides for labeling with radioactive metals in various fields of diagnostic and therapeutic nuclear oncology. Several reports have recently been published regarding targeted radiotherapy with radiolabeled somatostatin analogs. 68 Ga-DOTATATE (Dedden SA, et al.; J Nucl Med; 2016 vol. 57 no. 6 872-878), 68Ga-DOTATOC (Nicolas, GP, et al.; J Nucl Med; 2018 vol. 59 no. 6 915-921), 68 Ga-DOTANOC (Amdrosini V., et al.; J Nucl Med; 2010 vol. 51 no. 5 669-673) is a well-known PET tracer used to visualize NETs. 177 Lu-DOTATATE is used in radionuclide therapy (Strosberg, J. et al.; N Engl (J Med 2017; 376:125-135). However, there is a need for further peptide-based compounds that have utility in diagnostic imaging techniques such as PET.

[0009] Copper-64( 64 Cu) is a positron-emitting radionuclide that is well suitable for use as a diagnostic agent for positron emission tomography (PET). Its half-life of 12.7 hours is long enough to allow for post-production processing, labeling, and transport, and its average positron energy of 0.28 MeV provides high-resolution images. Importantly, 64 Ni(p,n) 64 The broad scope of the Cu reaction allows for the production of commercial quantities. The PET radioisotope copper-64 (Cu-64) is radiolabeled with DOTATATE, a chelate-peptide conjugate, for diagnostic imaging of human neuroendocrine tumors.

[0010] While the complete chemical structure of the Cu-DOTATATE complex has not been determined by X-ray crystallography, the Cu-DOTA complex has been structurally determined by X-ray crystallography. In its crystalline form, the Cu-DOTA complex has been shown to be 6-coordinate, utilizing four amino nitrogen atoms and two carboxylate oxygen atoms, as described below. [ka]

[0011] Two of the carboxylic acid groups remain free and are not coordinated to the copper metal ion. Therefore, even if a peptide binds via one of the carboxylic acids to form a linking amide bond, it is not predicted that the coordination of copper to the DOTATATE peptide will change.

[0012] 64 Cu-DOTATATE binds to somatostatin receptors with the highest affinity for subtype 2 receptor (SSTR2). It binds to cells expressing somatostatin receptors, including malignant neuroendocrine cells that overexpress the SSTR2 receptor. 64 Cu is a positron (β + ) emitting radionuclide with a decay yield that enables positron emission tomography (PET) imaging. 64 When the imaging ability of Cu is combined with the receptor targeting ability of DOTATATE, the result is Cu-DOTATATE, a radiopharmaceutical capable of imaging somatostatin receptor-expressing neuroendocrine tumors (NETs). 64 Cu-DOTATATE, a radiopharmaceutical. Today, 64 Cu-DOTATATE is prepared for use at a low total radioactivity preparation site for a very limited number of patients. Therefore, there is still a need to provide an improved process for making high purity 64 Cu-DOTATATE, scale up the production of radiolabeled Cu-DOTATATE and maintain sufficient stability to transport the drug product to patients in the hospital. 64 Cu-DOTATATE remains unmet.

Prior Art Documents

Non-Patent Documents

[0013]

Non-Patent Document 1

Non-Patent Document 2

[0014] overview This disclosure satisfies the above needs and provides copper-labeled drug products. 64 This relates to a method for providing a useful process that can supply commercial quantities of cu-DOTATATE.

[0015] The object of the present invention is to demonstrate and confirm the finding that labeling copper at lower temperatures (≤30°C) has the advantage of improving the purity of drug products, because many other common metal impurities actually label chelates such as dotate much more slowly than copper does. Copper radioisotopes (i.e., 64 Cu, 67 Previous studies on the radiative labeling of copper (Cu) have typically been conducted at high temperatures, such as 40°C–95°C. High temperatures were used to increase the rate of the labeling process and to ensure maximum radiative labeling of copper to the chelate. Some literature reviews have shown that labeling at room temperature can achieve sufficient labeling. This disclosure teaches that the faster labeling kinetics of copper can be used to obtain purer products compared to the slower labeling kinetics of other metals.

[0016] This specification provides the following: 64 Cu-DOTATATE preparation, final formulation parameters and 64Design of Experiments (DOE) to monitor the effect of Cu-DOTATATE on stability, 500mCi~2000mCi 64 Scaled-up experiments for preparing Cu-DOTATATE, and its final formulation 64 The stability of Cu-DOTATATE, optimization of the amount of DOTATATE used relative to the total activity used for radiolabeling, and 64 Cu-DOTATATE purity 64 The effect of the specific activity of copper chloride solution.

[0017] For example, this specification provides a method for radiolabeling dotatate, comprising the step of reacting copper-64 with a buffered solution containing dotatate, wherein the reaction occurs at a temperature below or equal to 30°C in less than 15 minutes, and the molar ratio of dotatate to copper-64 in the reaction solution is about 110:1 to about 90:1.

[0018] This specification further states, 64 A method is provided for preparing a drug product containing Cu-DOTATATE, wherein the drug product is prepared by radiolabeling DOTATATE with copper-64 at a concentration of about 0.6 μg / mL (μg of DOTATATE per mCi of copper-64), and the radionuclide purity of copper-64 in the drug product is about 99%.

[0019] In this specification, 64 A drug product containing Cu-DOTATATE for use in positron emission tomography, 64 Cu-DOTATATE is 148MBq 64 A drug product is also provided that is stored in a single-dose vial containing Cu-DOTATATE, has a radioactivity concentration of approximately 5-15 mCi / mL, and has a radiochemical purity of ≥96% after dilution.

[0020] The aforementioned features of the embodiment will be more readily understood by referring to the following detailed description, which will be interpreted with reference to the attached drawings. [Brief explanation of the drawing]

[0021] [Figure 1A] Figure 1(A) shows a schematic radiolabeling and formulation scheme. [Figure 1B] Figure 1(B) shows a schematic radiolabeling and formulation scheme relating to the present invention.

[0022] [Figure 2] Figure 2 shows typical HPLC chromatograms of gentisic acid standard solutions and dotatate.

[0023] [Figure 3] Figure 3 presets a typical HPLC chromatogram of the crude Cu-DOTATATE reaction mixture after mixing equimolar amounts of DOTATATE and Cu at room temperature for 5 minutes.

[0024] [Figure 4] Figure 4 shows the recovery of dotate at a flow rate of 12 mL / min in the fractionated loading solution (total 12 mL) and the final 50% ethyl eluate.

[0025] [Figure 5] Figure 5 shows the recovery of dotate at a flow rate of 18 mL / min in the fractionated loading solution (total 18 mL) and the final 50% ethyl eluate. [Modes for carrying out the invention]

[0026] Detailed explanation Various aspects and embodiments are described in detail herein. However, these aspects and embodiments may be embodied in many different forms and should not be construed as limiting; rather, these embodiments are provided so as to make this disclosure sufficient and complete and to fully convey the scope of the subject matter to those skilled in the art. All publications, patents, and patent applications referenced herein, whether above or below, are incorporated herein by reference in their entirety. A.Definition

[0027] Unless otherwise defined, all terms and phrases used herein have the meanings derived in the art unless explicitly stated otherwise or the context in which the term or phrase is used. Any methods and materials similar to or equivalent to those described herein may be used in carrying out or testing the present invention, but specific methods and materials are described below.

[0028] Unless otherwise specified, the use of individual numerical values ​​is stated as approximations, as if preceded by the word “about” or “approximately.” Similarly, numerical values ​​within various ranges specified herein are stated as approximations, as if preceded by the word “about” or “approximately,” as if preceded by the word “about” or “approximately,” both the minimum and maximum values ​​within the ranges referred to, unless otherwise explicitly stated. Thus, the variation above and below the ranges referred to can be used to achieve practically the same results as the values ​​within that range. Where used herein, the terms “about” and “approximately,” when referring to numerical values, have their plain and ordinary meanings to those skilled in the art of the art relating to the art most closely relating to the disclosed subject matter or to the range or element in question. The amount of deviation from the exact 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 of variation of a given amount on the performance of the claimed subject matter, as well as other considerations known to those skilled in the art. Where used herein, the use of different amounts of significant figures for different numerical values ​​is not intended to limit how the use of the word “about” or “approximately” works to broaden a particular numerical value or range. Therefore, as a general rule, “about” or “approximately” broadens the range of values. Furthermore, the disclosure of a range is intended to be a continuous range that includes all values ​​between the minimum and maximum values, plus the broader range obtained by the use of the terms “about” or “approximately.” Consequently, the enumeration of ranges of values ​​herein is merely intended and shall function as a concise way of referring individually to each individual value within the range, and each individual value is incorporated herein as if it were individually enumerated herein.

[0029] "Drug products" or " 64 The term "Cu-DOTATATE injection" is used herein synonymously with the final formulation used as a radiodiagnostic agent. 64 This refers to Cu-DOTATATE.

[0030] "As needed" or "as required" means that the elements, components, or circumstances described thereafter may or may not occur, and therefore the description includes both cases in which they occur and cases in which they do not.

[0031] The terms “subject” or “patient” are used synonymously in this specification and refer to humans or other mammals. B. Introduction

[0032] This disclosure is, 64 Improved radiolabeling and formulation for scaling up Cu-DOTATATE preparation; Figure 1(A).

[0033] High-resolution imaging techniques such as positron emission tomography (PET) can be used in oncology to help clinicians gain a better understanding of a patient's disease state, monitor the effectiveness of treatments, and provide more effective and personalized care. One such PET agent targets and images neuroendocrine tumors (NETs) that overexpress somatostatin receptor subtype 2 (SSTR2). 64 It is Cu-DOTATATE, which can help identify patients who may benefit from receptor-targeted therapy. Its imaging capability is due to its positron-emitting radionuclide properties. 64 (t) 1 / 2 = 12.7 hours, β + avg =0.28MeV, I=17.6% [sometimes reported as branching ratio (BR), representing intensity (I)], this can be imaged using PET, but the targeting portion of the molecule is a modified version of octreotate (DOTA- D -Phe-Cys-Tyr- D -Trp-Lys-Thr-Cys-Thr (disulfide cyclized Cys2-Cys7) is a cyclic peptide that mimics the natural SSTR2-ligand somatostatin. The functions of these two are simultaneously 64 The difunctional chelator DOTA, which captures Cu while remaining bound to the N-terminus of the peptide, binds to it together (forming DOTATATE).64 The structure of Cu-DOTATATE (copper Cu64 DOTATATE) is shown below. [ka]

[0034] radioactive isotope 64 The radioactive labeling of dotate with copper was initially performed several decades ago. In previous studies, small amounts of copper were used. 64 Cu-DOTATATE was prepared for use only at the preparation site, with low total radioactivity, for very limited use and a small number of patients. Recently, radiolabeling has been improved with higher radioactivity for scale-up to commercial production. The final purified product is produced at a much higher initial total radioactivity level, and radiolysis is prevented by improved formulation and purification methods.

[0035] The scaling up and formulation of large quantities of radiolabeled drugs was necessary to enable the distribution of drugs throughout the country. The scaling up led to new problems and challenges, as well as new discoveries and solutions, in order to achieve large batches of drugs. This disclosure (i) describes improvements and changes to previous research and results, and (ii) teaches the research conducted and teaches scaling up to large, high-activity batches.

[0036] A general overview of the radiolabeling and formulation schemes used is shown in Figure 1(B).

[0037] Specifically, this disclosure is: 64 Cu-DOTATATE can be radiolabeled and purified for use in injectable drug products. 64 I will explain how to significantly scale up the total radioactivity of Cu.

[0038] Previous research showed that 64 The radioactivity (mCi) of Cu was low to moderate. This disclosure scales up the total radioactivity to >5,400 mCi with radiolabeling. The challenges are due to radiolysis and DOTATATE. 64The objective is to achieve radiolabeling without decomposition due to competition with other metals besides Cu. The radiolabeled product must then be rapidly purified and immediately diluted in a stabilizing solution to prevent decomposition from radiolysis, so as to maintain the required high radiochemical purity (RCP).

[0039] The final formulation (45 mg / mL sodium ascorbate in 5% ethanol) contains purified 64 The stability of Cu-DOTATATE was evaluated for up to 48 hours after labeling, and the stability of the complex was assessed. 64 This indicates that there is no significant decomposition or loss of Cu.

[0040] 64 To prepare Cu-DOTATATE, in dilute HCl 64 CuCl2 is reacted with dotate in sodium acetate buffer containing gentisic acid at a ratio of 2 μg dotate / mCi. The reaction mixture is incubated and then purified in sodium ascorbate (NaOAsc) buffer. 64 The Cu-DOTATE solution was sterile filtered to obtain the final formulation. The development efforts disclosed herein aim to improve the production design space and ≥2Ci 64 The focus is on scaling up a radiolabeling reaction to prepare Cu-DOTATATE. Radiolabeling was also demonstrated at 15°C for 5 minutes. The purified product yielded up to 10,000 mCi. 64 This was achieved using Cu-DOTATATE. The purified product was obtained using 50% ethanol in water (previous literature indicated only pure ethanol). In fact, the use of 50% ethanol in water improved the yield of the purified product compared to the use of 100% ethanol.

[0041] The purified drug product (2 mL) was immediately diluted to a large volume (>20 mL; however, typically >100 mL for products with 2000-10,000 mCi) to prevent degradation (radiolysis) and maintain the required RCP >95%. Previous literature diluted the purified product to <20 mL.

[0042] The final drug product was purified and stabilized for up to 48 hours using 28–122 mg / mL sodium ascorbate with 1–5% ethanol, achieving an RCP > 95%. Prior 48-hour RCP stabilization was only achieved with 45 mg / mL sodium ascorbate / 5% ethanol.

[0043] The initial labeling (radiation labeling step) can be achieved in the presence of sodium ascorbate.

[0044] Surprisingly, it was found that when dotate was labeled at lower temperatures, i.e., ≤30°C, chelation of copper by dotate occurred more rapidly than with other metals. This phenomenon can be used to reduce the amount of metallic impurities present in the final drug product. C. 64 Preparation of Cu-DOTATATE bulk solution i. Ligand

[0045] In one embodiment, the ligand is DOTATATE; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA); 1,4,7-triazacidonanane-1,4,7-triyltriacetic acid (NOTA), or a derivative thereof.

[0046] In one embodiment, the ligand is added to the reaction mixture in amounts of approximately 1 μg to 6000 μg, 50 μg to 5000 μg, 100 μg to 4500 μg, 200 μg to 4000 μg, 300 μg to 3000 μg, 400 μg to 2000 μg, and 500 μg to 1000 μg. In another embodiment, the ligand is approximately 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1000 μg, 1100 μg, 1200 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg, 1700 μg, 1800 μg, 1900 μg, and 2000 μg. It is added to the reaction mixture in amounts of μg, 2100 μg, approximately 2200 μg, approximately 2300 μg, approximately 2400 μg, approximately 2500 μg, approximately 2600 μg, approximately 2700 μg, approximately 2800 μg, approximately 2900 μg, approximately 3000 μg, approximately 3100 μg, approximately 3200 μg, approximately 3300 μg, approximately 4400 μg, approximately 4500 μg, approximately 5000 μg, approximately 5500 μg, or approximately 6000 μg. In yet another embodiment, the ligand is less than approximately 100 μg, less than approximately 200 μg, less than approximately 300 μg, less than approximately 400 μg, less than approximately 500 μg, less than approximately 600 μg, less than approximately 700 μg, less than approximately 800 μg, less than approximately 900 μg, less than approximately 1000 μg, less than approximately 1100 μg, less than approximately 1200 μg, less than approximately 1300 μg, less than approximately 1400 μg, less than approximately 1500 μg, less than approximately 1600 μg, less than approximately 1700 μg, less than approximately 1800 μg, less than approximately 1900 μg, and about 200 μg. It is added to the reaction mixture in amounts less than 0 μg, less than 2100 μg, less than approximately 2200 μg, less than approximately 2300 μg, less than approximately 2400 μg, less than approximately 2500 μg, less than approximately 2600 μg, less than approximately 2700 μg, less than approximately 2800 μg, less than approximately 2900 μg, less than approximately 3000 μg, less than approximately 3100 μg, less than approximately 3200 μg, less than approximately 3300 μg, less than approximately 4400 μg, less than approximately 4500 μg, less than approximately 5000 μg, less than approximately 5500 μg, or less than approximately 6000 μg.

[0047] In another embodiment, the ligand is used in amounts of approximately 0.1 ug / mCi to approximately 20 ug / mCi, approximately 0.5 ug / mCi to approximately 15 ug / mCi, approximately 1 ug / mCi to approximately 11 ug / mCi, approximately 1 ug / mCi to approximately 8 ug / mCi, approximately 1 ug / mCi to approximately 5 ug / mCi, approximately 1 ug / mCi to approximately 3 ug / mCi, or approximately 0.1 ug / mCi to approximately 1.5 ug / mCi. In yet another embodiment, the ligand is used in amounts of about 0.1 ug / mCi, about 0.25 ug / mCi, about 0.4 ug / mCi, about 0.5 ug / mCi, about 0.6 ug / mCi, about 0.75 ug / mCi, about 0.8 ug / mCi, about 1 ug / mCi, about 1.25 ug / mCi, about 1.5 ug / mCi, about 1.75 ug / mCi, about 2 ug / mCi, about 2.5 ug / mCi, about 3 ug / mCi, about 3.5, or about 4 ug / mCi.

[0048] In one embodiment, the ligand / mL concentration in the radiolabeling step is greater than approximately 200 ug / mL, greater than approximately 250 ug / mL, greater than approximately 300 ug / mL, greater than approximately 333 ug / mL, or greater than approximately 400 ug / mL.

[0049] In yet another embodiment, the labeled total ligand amounts to approximately 200 μg to 6000 μg, 500 μg to 5000 μg, 1000 μg to 4000 μg, 1500 μg to 3000 μg, 2000 μg to 25000 μg, 2000 μg to 4000 μg, and 3000 μg to 4000 μg. In another embodiment, the total labeled ligand is approximately 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1000 μg, 1100 μg, 1200 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg, 1700 μg, 1800 μg, 1900 μg, These amounts are approximately 2000 μg, 2100 μg, 2200 μg, 2300 μg, 2400 μg, 2500 μg, 2600 μg, 2700 μg, 2800 μg, 2900 μg, 3000 μg, 3100 μg, 3200 μg, 3300 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, or 6000 μg. In yet another embodiment, the total labeled ligand is less than about 500 μg, less than about 1000 μg, less than about 1500 μg, less than about 2000 μg, less than about 2500 μg, less than about 3000 μg, less than about 3500 μg, less than about 4000 μg, less than about 45000 μg, less than about 5000 μg, less than about 5500 μg, less than about 6000 μg, less than about 6500 μg, less than about 7000 μg, less than about 8000 μg, less than about 9000 μg, or less than about 10000 μg. ii. Radionuclides

[0050] In another embodiment, the radionuclides are bismuth-213, chromium-51, cobalt-60, dysprosium-165, erbium-169, holmium-166, iridium-192, iron-59, lead-212, lutetium-177, molybdenum-99, palladium-103, rhenium-186, rhenium-188, samarium-153, strontium-89, tetra These include knetium-99m, xenon-133, ytterbium-169, ytterbium-177, yttrium-90, carbon-11, cobalt-57, copper-64, copper-67, fluorine-18, gallium-67, gallium-68, germanium-68, indium-111, rubidium-81, rubidium-82, strontium-82, thallium-201, and others.

[0051] In another embodiment, 64 CuCl2 is added to the reaction mixture in amounts of approximately 100 mCi to 5000 mCi, 200 mCi to 4000 mCi, 300 mCi to 3500 mCi, 400 mCi to 3000 mCi, 500 mCi to 2500 mCi, or up to approximately 10,000 mCi. 64 (As a source of Cu). In one embodiment, 64 CuCl2 is found in amounts of approximately 100 mCi, 200 mCi, 300 mCi, 400 mCi, 500 mCi, 600 mCi, 700 mCi, 800 mCi, 900 mCi, 1000 mCi, 1500 mCi, 2000 mCi, 2500 mCi, 3000 mCi, 3500 mCi, and 4 mCi. It is added to the reaction mixture in amounts of approximately 000mCi, 4500mCi, 5000mCi, 5500mCi, 6000mCi, 6500mCi, 7000mCi, 7500mCi, 8000mCi, 8500mCi, 9000mCi, 9500mCi, or 10,000mCi. 64 (As a source of Cu). In yet another embodiment, 64CuCl2 is present in amounts less than approximately 100 mCi, less than approximately 200 mCi, less than approximately 300 mCi, less than approximately 400 mCi, less than approximately 500 mCi, less than approximately 600 mCi, less than approximately 700 mCi, less than approximately 800 mCi, less than approximately 900 mCi, less than approximately 1000 mCi, less than approximately 1500 mCi, less than approximately 2000 mCi, less than approximately 2500 mCi, less than approximately 3000 mCi, less than approximately 3500 mCi, It is added to the reaction mixture in amounts less than approximately 4000 mCi, less than approximately 4500 mCi, less than approximately 5000 mCi, less than approximately 5500 mCi, less than approximately 6000 mCi, less than approximately 6500 mCi, less than approximately 7000 mCi, less than approximately 7500 mCi, less than approximately 8000 mCi, less than approximately 8500 mCi, less than approximately 9000 mCi, less than approximately 9500 mCi, or less than approximately 10,000 mCi. 64 (As a source of Cu)

[0052] In one embodiment, the radionuclide is added to the reaction mixture in amounts of approximately 0.1 μg, 0.2 μg, 0.3 μg, 0.39 μg, 0.4 μg, 0.44 μg, 0.5 μg, 0.6 μg, 0.7 μg, 0.8 μg, 0.9 μg, 1 μg, 1.12 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg.

[0053] In yet another embodiment, 64 Cu is added to the reaction mixture in amounts of approximately 0.1 μg, 0.2 μg, 0.3 μg, 0.4 μg, 0.44 μg, 0.5 μg, 0.6 μg, 0.7 μg, 0.8 μg, 0.9 μg, 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg. iii.Buffer solution

[0054] In one embodiment, the buffer solution used in the preparation of the bulk solution of the drug product is sodium acetate buffer, sodium acetate / gentisic acid buffer, sodium ascorbate buffer, sodium ascorbate / ethanol buffer, ammonium acetate buffer, ammonium acetate / gentisic acid buffer, ammonium ascorbate buffer, ammonium ascorbate / ethanol buffer, or any other suitable buffer.

[0055] In one embodiment, the concentration of the buffer solution is approximately 0.1 M, approximately 0.2 M, approximately 0.3 M, approximately 0.4 M, approximately 0.5 M, approximately 0.6 M, approximately 0.7 M, approximately 0.8 M, approximately 0.9 M, or approximately 1.0 M. In yet another embodiment, the concentration of the buffer solution is approximately 20 mg / mL to approximately 200 mg / mL, approximately 25 mg / mL to approximately 190 mg / mL, approximately 30 mg / mL to approximately 170 mg / mL, approximately 35 mg / mL to approximately 160 mg / mL, approximately 40 mg / mL to approximately 150 mg / mL, approximately 45 mg / mL to approximately 140 mg / mL, approximately 45 mg / mL to approximately 122 mg / mL, approximately 50 mg / mL to approximately 130 mg / mL, approximately 60 mg / mL to approximately 120 mg / mL, or approximately 70 mg / mL to approximately 100 mg / mL. In yet another embodiment, the concentration of the buffer solution is approximately 4 mg / mL, approximately 10 mg / mL, approximately 20 mg / mL, approximately 25 mg / mL, approximately 30 mg / mL, approximately 35 mg / mL, approximately 40 mg / mL, approximately 45 mg / mL, approximately 50 mg / mL, approximately 60 mg / mL, approximately 65% ​​mg / mL, approximately 66% mg / mL, approximately 70 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, approximately 95%, approximately 100 mg / mL, approximately 110 mg / mL, approximately 120 mg / mL, approximately 122 mg / mL, approximately 130 mg / mL, approximately 132 mg / mL, approximately 140 mg / mL, approximately 150 mg / mL, approximately 160 mg / mL, approximately 170 mg / mL, approximately 180 mg / mL, approximately 190 mg / mL, or approximately 200 mg / mL.

[0056] In another embodiment, the buffer solution contains approximately 4 mg / mL, approximately 10 mg / mL, approximately 15 mg / mL, approximately 20 mg / mL, approximately 25 mg / mL, approximately 30 mg / mL, approximately 35 mg / mL, approximately 40 mg / mL, approximately 45 mg / mL, approximately 50 mg / mL, approximately 60 mg / mL, approximately 70 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, or approximately 100 mg / mL of gentisic acid, and approximately 0.1 M, approximately 0.2 M, approximately 0.3 M, approximately 0.33 M, approximately 0.4 M, approximately 0.5 M, approximately 0.6 M, approximately 0.7 M, approximately 0.8 M, approximately 0.9 M, or approximately 1.0 M of sodium acetate.

[0057] In one specific embodiment, the buffer solution is a solution containing gentisic acid at 4 mg / mL and sodium acetate at 0.4 M.

[0058] In yet another embodiment, the buffer contains sodium ascorbate in amounts of approximately 4 mg / mL, approximately 10 mg / mL, approximately 20 mg / mL, approximately 25 mg / mL, approximately 30 mg / mL, approximately 35 mg / mL, approximately 40 mg / mL, approximately 45 mg / mL, approximately 46% mg / mL, approximately 50 mg / mL, approximately 60 mg / mL, approximately 64.8 mg / mL, approximately 66% mg / mL, approximately 70 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, and approximately 100 mg / mL of EtOH. In one specific embodiment, the buffer is a solution having 45 mg / mL of sodium ascorbate and 5% EtOH.

[0059] In another embodiment, the buffer solution comprises approximately 4 mg / mL, approximately 10 mg / mL, approximately 15 mg / mL, approximately 20 mg / mL, approximately 25 mg / mL, approximately 30 mg / mL, approximately 35 mg / mL, approximately 40 mg / mL, approximately 45 mg / mL, approximately 50 mg / mL, approximately 60 mg / mL, approximately 70 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, or approximately 100 mg / mL of gentisic acid, and approximately 0.1 M, approximately 0.2 M, approximately 0.3 M, approximately 0.33 M, approximately 0.4 M, approximately 0.5 M, approximately 0.6 M, approximately 0.7 M, approximately 0.8 M, approximately 0.9 M, or approximately 1.0 M of sodium ascorbate. iv. Stabilizers

[0060] In one embodiment, the stabilizer is gentisic acid. In another embodiment, the stabilizer is sodium ascorbate. However, any suitable stabilizer may be used.

[0061] In another embodiment, more than one stabilizer is used. In another embodiment, one stabilizer, such as gentisic acid, is used during the radiolabeling process, and another stabilizer, such as sodium ascorbate, is used in the final formulation.

[0062] In one embodiment, the stabilizer is added in an amount of about 1.0 g to about 9.0 g. In another embodiment, the stabilizer is added in an amount of about 2.0 mg to about 8.0 mg. In yet another embodiment, the stabilizer is added in an amount of about 3.0 mg to about 7.0 mg. In yet another embodiment, the stabilizer is added in an amount of about 3.0 mg to about 5.0 mg. In yet another embodiment, the stabilizer is added in an amount of about 4.0 mg to about 6.0 mg. In one specific embodiment, the stabilizer is added to the reaction mixture in an amount of about 4.0 mg.

[0063] In yet another embodiment, the stabilizer is added in an amount of about 1.0 g to about 9.0 g. In another embodiment, gentisic acid is added in an amount of about 2.0 mg to about 8.0 mg. In another embodiment, gentisic acid is added in an amount of about 3.0 mg to about 7.0 mg. In another embodiment, gentisic acid is added in an amount of about 3.0 mg to about 5.0 mg. In another embodiment, gentisic acid is added in an amount of about 4.0 mg to about 6.0 mg. In one specific embodiment, gentisic acid is added to the reaction mixture in an amount of about 4.0 mg.

[0064] In another embodiment, sodium ascorbate is added in an amount of about 2.0 mg to about 8.0 mg. In another embodiment, sodium ascorbate is added in an amount of about 3.0 mg to about 7.0 mg. In another embodiment, sodium ascorbate is added in an amount of about 3.0 mg to about 5.0 mg. In another embodiment, sodium ascorbate is added in an amount of about 4.0 mg to about 6.0 mg. In one specific embodiment, sodium ascorbate is added to the reaction mixture in an amount of about 4.0 mg. v. Radiation labeling conditions

[0065] In one embodiment, radiolabeling is performed with radionuclides at concentrations of 500 mCi to 15,000 mCi. The radioactivity concentrations at the time of radiolabeling are ≥250 mCi / mL, ≥300 ug / mL, ≥333 mCi / mL, ≥350 mCi / mL, ≥400 mCi / mL, ≥421 mCi / mL, or ≥460 mCi / mL. The total labeled ligand concentration is 1000 to 4000 ug, or ≥333 ug / mL.

[0066] In one embodiment, radiolabeling is performed with radionuclides ranging from 500 mCi to 10,000 mCi. The radioactivity concentration at the time of radiolabeling is ≥333 mCi / mL. The total labeled ligand concentration is 1,000 to 4,000 ug, or ≥333 ug / mL.

[0067] In another embodiment, radiolabeling is performed with radionuclides at concentrations of 500 mCi to 2,500 mCi. The radioactivity concentrations at radiolabeling are ≥250 mCi / mL, ≥300 ug / mL, ≥333 mCi / mL, ≥350 mCi / mL, ≥400 mCi / mL, ≥421 mCi / mL, or ≥460 mCi / mL. The total labeled ligand concentration is 1000 to 4000 μg, or ≥333 μm / mL.

[0068] In one embodiment, the radiant label is 500 mCi to 15,000 mCi 64This is performed using Cu. The radioactivity concentrations at the radiolabeled stage are ≥250 mCi / mL, ≥300 mL, ≥333 mCi / mL, ≥350 ug / mL, ≥400 mCi / mL, ≥421 mCi / mL, or ≥460 mCi / mL. The total labeled dotate concentration is 1000-4000 ug, or ≥333 ug / mL.

[0069] In one embodiment, radioactive labeling is performed using 64Cu with a concentration of 500 mCi to 10,000 mCi. The radioactivity concentration at the radioactive label is ≥333 mCi / mL. The total labeled dotate concentration is 1000 to 4000 ug, or ≥333 ug / mL.

[0070] In another embodiment, the radiant label is 500 mCi to 2,500 mCi 64 This is performed using Cu. The radioactivity concentrations with radiolabeling are ≥250 mCi / mL, ≥300 ug / mL, ≥333 mCi / mL, ≥350 ug / mL, ≥400 mCi / mL, ≥421 mCi / mL, or ≥460 mCi / mL. The total labeled dotate concentration is 1000-4000 μg, or ≥333 μg / mL.

[0071] In another embodiment, the pH of the reaction mixture is 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, or 7.0. In yet another embodiment, the pH of the reaction mixture is about 4.5 to about 7.0, about 4.6 to about 6.9, about 4.7 to about 6.8, about 4.8 to about 6.7, about 4.9 to about 6.6, about 5.0 to about 6.6, about 5.1 to about 6.5, about 5.2 to about 6.3, about 5.3 to about 6.2, about 5.4 to about 6.1, or about 5.5 to about 6.0. In one specific embodiment, the pH of the reaction mixture is approximately 5 to 6.

[0072] Bioconjugate chelates such as DOTA-TATE generally complex at temperatures of 50-95°C to ensure high radiochemical labeling and radiolabeling yield. However, this disclosure describes how copper can be labeled at lower temperatures, i.e., room temperature or lower. 64 This study teaches that the purity of Cu-DOTATATE is improved due to the faster labeling of copper(2+) ions to DOTATATE compared to other common metal impurities.

[0073] In another embodiment, the temperature of the reaction mixture is about 10°C to about 50°C, about 15°C to about 45°C, about 20°C to about 40°C, about 10°C to about 30°C, about 10°C to about 20°C, about 20°C to about 50°C, about 20°C to about 40°C, or about 20°C to about 30°C. In one embodiment, the temperature of the reaction mixture is about 10°C, about 15°C, about 20°C, about 22°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C. In another embodiment, the temperature of the reaction mixture is the ambient temperature.

[0074] In yet another embodiment, the temperature of the reaction mixture is less than or equal to 50°C, less than 50°C, less than or equal to 45°C, less than 40°C, less than 40°C, less than 35°C, less than 30°C, less than 30°C, less than 25°C, less than 25°C, less than 20°C, less than 20°C, less than 15°C, less than 15°C, less than 10°C, or less than 10°C.

[0075] In one embodiment, the molar ratio of ligand to radionuclide in the reaction mixture is approximately 125:1, 120:1, 115:1, 110:1, 105:1, 100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 4:1, 3:1, 2:1, 2.5:1, or 1:1. In another embodiment, the molar ratio of ligand to radionuclide in the reaction mixture is approximately 125:1 to approximately 75:1. In yet another embodiment, the molar ratio of ligand to radionuclide in the reaction mixture is approximately 105:1 to approximately 95:1. In yet another embodiment, the molar ratio of ligand to radionuclide in the reaction mixture is about 110:1 to about 90:1. In yet another embodiment, the molar ratio of ligand to radionuclide in the reaction mixture is about 102:1 to about 99:1. In yet another embodiment, the molar ratio of ligand to radionuclide in the reaction mixture is about 125:1 to about 1:1, about 105:1 to about 10:1, about 102:1 to about 10:1, about 110:1 to about 50:1, about 90:1 to about 70:1, or about 60:1 to about 1:1, or about 110:1 to about 90:1.

[0076] In one specific embodiment, DOTATATE 64 The molar ratio to Cu is approximately 125:1, 120:1, 115:1, 110:1, 105:1, 100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 4:1, 3:1, 2:1, 2.5:1, or 1:1. In another embodiment, the amount of DOTATATE in the reaction mixture is 64 The molar ratio to Cu is approximately 105:1 to approximately 95:1. In yet another embodiment, the dotate in the reaction mixture 64 The molar ratio to Cu is approximately 102:1 to approximately 99:1. In yet another embodiment, the dotate in the reaction mixture 64The molar ratios to Cu are approximately 125:1 to 1:1, 105:1 to 10:1, 102:1 to 10:1, 110:1 to 50:1, 90:1 to 70:1, 60:1 to 1:1, or 110:1 to 90:1.

[0077] In one embodiment, the ratio of ligand mass (μg) to radioactivity (mCi) of the radionuclide is approximately 5:1, 4:1, 3:1, 2:1, or 1:1. In yet another embodiment, the concentration of ligand mass (μg) relative to radioactivity (mCi) of the radionuclide is approximately 1.0 μg / mCi, 0.9 μg / mCi, 0.8 μg / mCi, 0.7 μg / mCi, 0.6 μg / mCi, 0.5 μg / mCi, 0.4 μg / mCi, 0.3 μg / mCi, 0.2 μg / mCi, or 0.1 μg / mCi for each reaction. In yet another embodiment, the concentration of ligand mass (μg) relative to radioactivity (mCi) of the radionuclide was approximately 0.6 μg / mCi for each reaction.

[0078] In one embodiment, the mass of the ligand (μg): 64 The ratio of the radioactivity (mCi) of Cu is approximately 5:1, 4:1, 3:1, 2:1, or 1:1. In yet another embodiment, 64 The concentration of ligand mass (μg) relative to the radioactivity (mCi) of Cu is approximately 1.0 μg / mCi, 0.9 μg / mCi, 0.8 μg / mCi, 0.7 μg / mCi, 0.6 μg / mCi, 0.5 μg / mCi, 0.4 μg / mCi, 0.3 μg / mCi, 0.2 μg / mCi, or 0.1 μg / mCi for each reaction. In yet another embodiment, 64 The concentration of ligand mass (μg) relative to the radioactivity (mCi) of Cu was approximately 0.6 μg / mCi for each reaction.

[0079] In one embodiment, the mass of DOTATATE (μg): 64 The ratio of the radioactivity (mCi) of Cu is approximately 5:1, 4:1, 3:1, 2:1, or 1:1. In yet another embodiment, 64The concentration of DOTATATE by mass (μg) relative to the radioactivity (mCi) of Cu is approximately 1.0 μg / mCi, 0.9 μg / mCi, 0.8 μg / mCi, 0.7 μg / mCi, 0.6 μg / mCi, 0.5 μg / mCi, 0.4 μg / mCi, 0.3 μg / mCi, 0.2 μg / mCi, or 0.1 μg / mCi for each reaction. In yet another embodiment, DOTATATE, 64 The concentration of DOTATATE (in μg) relative to the radioactivity of Cu (mCi) was approximately 0.6 μg / mCi for each reaction.

[0080] In one embodiment, the radioactivity of the bulk solution of the active pharmaceutical ingredient is approximately 1 mCi to 10,000 mCi, approximately 1 mCi to 9,900 mCi, approximately 1 mCi to 9,800 mCi, approximately 1 mCi to 9,700 mCi, approximately 1 mCi to 9,600 mCi, approximately 1 mCi to 9,500 mCi, approximately 1 mCi to 9,400 mCi, approximately 1 mCi to 9,300 mCi, approximately 1 mCi to 9,200 mCi, approximately 1 mCi to 9,100 mCi, approximately 1 mCi to 9,000 mCi, approximately 1 mCi to 8,900 mCi, approximately 1 mCi to 8,800 mCi, approximately 1 mCi to 8,700 mCi, and approximately 1mCi ~ approx. 8,600mCi, approx. 1mCi ~ approx. 8,500mCi, approx. 1mCi ~ approx. 8,400mCi, approx. 1mCi ~ approx. 8,300mCi , about 1mCi to about 8,200mCi, about 1mCi to about 8,100mCi, about 1mCi to about 8,000mCi, about 1mCi to about 7,900m Ci, about 1mCi to about 7,800mCi, about 1mCi to about 7,700mCi, about 1mCi to about 7,600mCi, about 1mCi to about 7,50 0mCi, about 1mCi to about 7,400mCi, about 1mCi to about 7,300mCi, about 1mCi to about 7,200mCi, about 1mCi to about 7, 100mCi, about 1mCi to about 7,000mCi, about 1mCi to about 6,900mCi, about 1mCi to about 6,800mCi, about 1mCi to about 6,700mCi, approximately 1mCi to approximately 6,600mCi, approximately 1mCi to approximately 6,500mCi, approximately 1mCi to approximately 6,400mCi, approximately 1mCi ~6,300mCi, approximately 1mCi~6,200mCi, approximately 1mCi~6,100mCi, approximately 1mCi~6,000mCi, approximately 1m Ci ~ approx. 5,900mCi, approx. 1mCi ~ approx. 5,800mCi, approx. 1mCi ~ approx. 5,700mCi, approx. 1mCi ~ approx. 5,600mCi, approx. 1mCi ~ approx. 5,500mCi, approx. 1mCi ~ approx. 5,400mCi, approx. 1mCi ~ approx. 5,300mCi, approx. 1mCi ~ approx. 5,200mCi , about 1mCi to about 5,100mCi, about 1mCi to about 5,000mCi, about 1mCi to about 4,900mCi, about 1mCi to about 4,800m Ci, approximately 1mCi to approximately 4,700mCi, approximately 1mCi to approximately 4,600mCi, approximately 1mCi to approximately 4,500mCi, approximately 1mCi to approximately 4,40 0mCi, about 1mCi to about 4,300mCi, about 1mCi to about 4,200mCi, about 1mCi to about 4,100mCi, about 1mCi to about 4,000mCi, approximately 1mCi to approximately 3,900mCi, approximately 1mCi to approximately 3,800mCi, approximately 1mCi to approximately 3,700mCi, approximately 1mCi to approximately 3,600mCi, approximately 1mCi to approximately 3,500mCi, approximately 1mCi to approximately 3,400mCi, approximately 1mCi to approximately 3 ,300mCi, about 1mCi to about 3,200mCi, about 1mCi to about 3,100mCi, about 1mCi to about 3000mCi, about 10mCi to about 2900mCi, about 20mCi to about 2,800mCi, about 30mCi to about 2,700mCi, about 40mCi The ranges are approximately 2,600 mCi, 2,500 mCi, 2,400 mCi, 2,300 mCi, 2,200 mCi, 2,100 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,500 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 2,000 mCi, 1,500 mCi, 1,000 mCi, or 750 mCi.

[0081] In another embodiment, the radioactivity of the bulk solution of the active pharmaceutical ingredient is approximately 1 mCi, approximately 20 mCi, approximately 40 mCi, approximately 60 mCi, approximately 80 mCi, approximately 100 mCi, approximately 120 mCi, approximately 140 mCi, approximately 160 mCi, approximately 200 mCi, approximately 220 mCi, approximately 240 mCi, approximately 260 mCi, approximately 280 mCi, approximately 300 mCi, approximately 320 mCi, approximately 340 mCi, approximately 360 mCi, approximately 380 mCi, approximately 400 mCi, approximately 420 mCi, approximately 440 mCi, approximately 460 mCi, approximately 480 mCi, approximately 500 mCi, approximately 550 mCi, approximately 600 mCi, approximately 650 mCi, and approximately 700 mCi. , about 750mCi, about 800mCi, about 850mCi, about 900mCi, about 950mCi, about 1,000mCi, about 1,100mCi, about 1,200mCi, approx. 1,300mCi, approx. 1,400mCi, approx. 1,500mCi, approx. 1,600mCi, approx. 1,700mCi, approx. 1, 800mCi, approx. 1,900mCi, approx. 2,000mCi, approx. 2,100mCi, approx. 2,200mCi, approx. 2,300mCi, approx. 2,40 0mCi, approx. 2,500mCi, approx. 2,600mCi, approx. 2,700mCi, approx. 2,800mCi, approx. 2,900mCi, approx. 3,000m Ci, approx. 3,100mCi, approx. 3,200mCi, approx. 3,300mCi, approx. 3,400mCi, approx. 3,500mCi, approx. 3,600mCi , approx. 3,700mCi, approx. 3,800mCi, approx. 3,900mCi, approx. 4,000mCi, approx. 4,100mCi, approx. 4,200mCi, approx. 4,300mCi, approx. 4,400mCi, approx. 4,500mCi, approx. 4,600mCi, approx. 4,700mCi, approx. 4,800mCi, approx. 4, 900mCi, approx. 5,000mCi, approx. 5,100mCi, approx. 5,200mCi, approx. 5,300mCi, approx. 5,400mCi, approx. 5,50 0mCi, approx. 5,600mCi, approx. 5,700mCi, approx. 5,800mCi, approx. 5,900mCi, approx. 6,000mCi, approx. 6,100m Ci, approx. 6,200mCi, approx. 6,300mCi, approx. 6,400mCi, approx. 6,500mCi, approx. 6,600mCi, approx. 6,700mCi , approx. 6,800mCi, approx. 6,900mCi, approx. 7,000mCi, approx. 7,100mCi, approx. 7,200mCi, approx. 7,300mCi, approx. 7,400mCi, approximately 7,500mCi, approximately 7,600mCi, approximately 7,700mCi, approximately 7,800mCi, approximately 7,900mCi, approximately 8,These values ​​are approximately 000mCi, 8,100mCi, 8,200mCi, 8,300mCi, 8,400mCi, 8,500mCi, 8,600mCi, 8,700mCi, 8,800mCi, 8,900mCi, 9,000mCi, 9,100mCi, 9,200mCi, 9,300mCi, 9,400mCi, 9,500mCi, 9,600mCi, 9,700mCi, 9,800mCi, 9,900mCi, or 10,000mCi. In one specific embodiment, the radioactivity of the bulk solution of the active pharmaceutical ingredient is approximately 100 mCi, 500 mCi, 1000 mCi, 2000 mCi, 3,000 mCi, 4,000 mCi, 5,000 mCi, 6,000 mCi, 7,000 mCi, 8,000 mCi, 9,000 mCi, or 10,000 mCi.

[0082] In one embodiment, the volume of the radionuclide solution is approximately 0.1 mL to 10 mL, approximately 0.2 mL to 9 mL, approximately 0.3 mL to 8 mL, approximately 0.4 mL to 7 mL, approximately 0.5 mL to 6 mL, approximately 1 mL to 5 mL, or approximately 2 mL to 4 mL. In another embodiment, the volume of the radionuclide solution is approximately 0.1 mL, approximately 0.2 mL, approximately 0.3 mL, approximately 0.4 mL, approximately 0.5 mL, approximately 1 mL, approximately 2 mL, approximately 3 mL, approximately 4 mL, approximately 5 mL, approximately 6 mL, approximately 7 mL, approximately 8 mL, approximately 9 mL, or approximately 10 mL. In one embodiment, 64 The volumes of the Cu solution are approximately 0.1 mL to 10 mL, 0.2 mL to 9 mL, 0.3 mL to 8 mL, 0.4 mL to 7 mL, 0.5 mL to 6 mL, 1 mL to 5 mL, and 2 mL to 4 mL. In another embodiment, 64 The volumes of the Cu solution are approximately 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL.

[0083] In yet another embodiment, the volume of the radioactively labeled solution is approximately 0.1 mL to 10 mL, approximately 0.5 mL to 9 mL, approximately 1 mL to 7 mL, approximately 1.5 mL to 6 mL, approximately 0.5 mL to 6 mL, approximately 1 mL to 5 mL, and approximately 2 mL to 4 mL. In yet another embodiment, the volume of the radioactively labeled solution is approximately 0.1 mL, approximately 0.2 mL, approximately 0.3 mL, approximately 0.4 mL, approximately 0.5 mL, approximately 1 mL, approximately 1.5 mL, approximately 2 mL, approximately 3 mL, approximately 4 mL, approximately 5 mL, approximately 6 mL, approximately 7 mL, approximately 8 mL, approximately 9 mL, or approximately 10 mL.

[0084] In another embodiment, the reaction time is approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours. In one embodiment, the reaction time is approximately 1 minute to 24 hours, 1 minute to 18 hours, 1 minute to 12 hours, or 1 minute to 6 hours. In yet another embodiment, the reaction time is approximately 1 minute to 60 minutes, 2 minutes to 45 minutes, or 5 minutes to 30 minutes.

[0085] In yet another embodiment, the concentration of the anti-radiolytic agent in the final formulation is 29-122 mg / mL + 1-5% ethanol.

[0086] In yet another embodiment, the amount of non-radioactive copper added to the reaction mixture is 0 to 30 μg / mL (ppm). In yet another embodiment, the amount of non-radioactive copper added to the reaction mixture is 0.1 to 30 μg / mL (ppm). D. 64 Purification of Cu-DOTATATE bulk solution

[0087] In yet another embodiment, the bulk metal-ligand solution is purified using a C-18 Light Sep Pak or any suitable purification system / column.

[0088] In one embodiment, the elution solvent in purification is ethanol, 5% ethanol (95% water), 10% ethanol (90% water), 15% ethanol (85% water), 20% ethanol (80% water), 25% ethanol (75% water), 30% ethanol (70% water), 35% ethanol (65% water), 40% ethanol (60% water), 45% ethanol (55% water), 50% ethanol (50% water), 55% ethanol (45% water), 60% ethanol (40% water), 65% ethanol (35% water), 70% ethanol (30% water), 75% ethanol (25% water), 80% ethanol (20% water), 85% ethanol (15% water), 90% ethanol (10% water), 95% ethanol (5% water), or 100% ethanol.

[0089] In yet another embodiment, the volume of solvent from the purification step is about 0.1 mL to about 10 mL, about 0.5 mL to about 9 mL, about 1 mL to about 7 mL, about 1.5 mL to about 6 mL, about 0.5 mL to about 6 mL, about 1 mL to about 5 mL, or about 2 mL to about 4 mL. In yet another embodiment, the volume of solvent from the purification step is about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 1 mL, about 1.5 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL.

[0090] In another embodiment, in the drug product 64 The radionuclide purity of Cu is ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, or ≥99.9%.

[0091] In yet another embodiment, the amount of radionuclide impurities in the drug product is ≤1%, ≤0.9%, ≤0.8%, ≤0.7%, ≤0.6%, ≤0.5%, ≤0.4%, ≤0.3%, ≤0.2%, or ≤0.1%. In yet another embodiment, the amount of a single radionuclide impurity in the drug product is ≤0.1%, ≤0.09%, ≤0.08%, ≤0.07%, ≤0.06%, ≤0.05%, ≤0.04%, ≤0.03%, ≤0.02%, or ≤0.01%.

[0092] In one embodiment, the radiochemical purity of the drug product is ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, or ≥99.9% as copper Cu64 dotate.

[0093] In one embodiment, purity is measured using high-performance liquid chromatography (HPLC) or any other acceptable or suitable technique.

[0094] In another embodiment, gentisic acid is present in the drug product in amounts of ≤50 ppm, ≤40 ppm, ≤30 ppm, ≤20 ppm, ≤10 ppm, ≤5 ppm, or ≤1 ppm.

[0095] In one embodiment, a single impurity is present in the drug product in an amount of ≤1%, ≤0.9%, ≤0.8%, ≤0.7%, ≤0.6%, ≤0.5%, ≤0.4%, ≤0.3%, ≤0.2%, or ≤0.1% of DOTATATE and related substances.

[0096] In another embodiment, the total impurities are present in amounts of ≤10%, ≤9%, ≤8%, ≤7%, ≤6%, ≤5%, ≤4%, ≤3%, ≤2%, ≤1%, ≤0.9%, ≤0.8%, ≤0.7%, ≤0.6%, ≤0.5%, ≤0.4%, ≤0.3%, ≤0.2%, or ≤0.1% of the dotatate and related substances in the drug product.

[0097] In another embodiment, the bacterial endotoxin is present in the drug product in amounts of ≤100 EU / mL, ≤90 EU / mL, ≤80 EU / mL, ≤70 EU / mL, ≤60 EU / mL, ≤50 EU / mL, ≤40 EU / mL, ≤39 EU / mL, ≤30 EU / mL, ≤20 EU / mL, ≤10 EU / mL, ≤9 EU / mL, ≤8 EU / mL, ≤7 EU / mL, ≤6 EU / mL, ≤5 EU / mL, ≤4 EU / mL, ≤3 EU / mL, ≤2 EU / mL, or ≤1 EU / mL. F. Drug products (64 Cu-DOTATATE injection)

[0098] The drug products disclosed herein are indicated for use with positron emission tomography (PET) for the localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in adult patients. i. Chemical characteristics

[0099] The drug products described herein are radiodiagnostic agents for use in PET imaging, and are copper 64 It contains Cu-DOTATATE. Chemically, 64 Cu-DOTATATE is described as copper(Cu64)-N-[(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododeca-1-yl)acetyl]-diphenylalanyl-L-cysteinyl-L-tyrosyl-D-tripprophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7) disulfide. Its molecular weight is 1497.2 daltons, and the following is the structural formula of one isomer: [ka]

[0100] The drug product is a sterile, clear, colorless to yellow solution for intravenous use. Each 10 mL single-dose vial contains 148 MBq (4 mCi) 64 Cu-DOTATATE is contained in a 4 mL solution volume at the calibration date. Furthermore, each mL of the solution contains 40 mg of ascorbic acid, 0.05 mL of anhydrous alcohol, and USP (ethanol) in sterile water for injection. The pH is adjusted with sodium hydroxide and hydrochloric acid to approximately 5.5 to 7.5. ii. Physical characteristics

[0101] Tables 1 and 2 are, 64 This provides key radiation emission data and physical decay data for Cu. 64 Cu has a half-life t 1 / 2 =12.7 hours: (a) 17.6% 64Positron emission to Ni, which results in the emission of two 511 keV annihilation photons (35.7%), (b) 64 38.5% by beta decay to Zn, and (c) 64 43.8% by electron capture to Ni, and decays via this combination. The decay of Cu-64 also results in the emission of characteristic 1346 keV gamma rays with an intensity of approximately 0.48%.

[0102] The gamma emission spectrum of the pharmaceutical product shows peaks at approximately 511 keV and approximately 1346 keV.

Table 1

Table 2

[0103] Gamma constant: 3.6×10 -5 mSv / h per MBq at 1 meter (0.133 mrem / h per mCi at 1 meter). Table 3 shows the 64 radiation attenuation by lead shielding of Cu.

Table 3

[0104] In one embodiment, the pharmaceutical product is stored at a temperature of about 15°C to about 30°C, about 15°C to about 25°C, about 15°C to about 20°C, or about 20°C to about 30°C. In another embodiment, the pharmaceutical product is stored at a temperature of about 10°C, about 15°C, about 20°C, about 22°C, about 25°C, or about 30°C. In yet another embodiment, the pharmaceutical product is stored at a controlled room temperature of about 20°C to about 25°C.

[0105] In another embodiment, the drug product is stored at a temperature of approximately 30°C to 60°C, approximately 35°C to 55°C, approximately 40°C to 50°C, or approximately 50°C to 60°C. In yet another embodiment, the drug product is stored at a temperature of approximately 30°C, approximately 35°C, approximately 40°C, approximately 45°C, approximately 50°C, approximately 55°C, or approximately 60°C. In yet another embodiment, the drug product is stored at a temperature of approximately 50°C to 55°C.

[0106] Radiochemical identity can be confirmed using HPLC. 64 The HPLC relative retention time (RRT) of Cu-DOTATATE correlates with that of the DOTATATE standard. In one embodiment, 64 The HPLC RRT of Cu-DOTATATE is approximately 1 to 2, or approximately 1.15 to 1.25.

[0107] Radionuclide identity can be confirmed using gamma emission spectroscopy. The gamma emission spectra of drug products show peaks at approximately 511 keV and 1346 keV.

[0108] In one embodiment, the solution volume of the drug product is approximately 1 mL to 10 mL, approximately 2 mL to 9 mL, approximately 3 mL to 7 mL, approximately 4 mL to 6 mL, or approximately 3 mL to 6 mL. In yet another embodiment, the solution volume of the drug product is approximately 1 mL, approximately 2 mL, approximately 3 mL, approximately 4 mL, approximately 5 mL, approximately 6 mL, approximately 7 mL, approximately 8 mL, approximately 9 mL, or approximately 10 mL.

[0109] In yet another embodiment, the drug product has 148 MBq (4 mCi) (37 MBq (1 mCi) per mL) at the calibration date and time. 64 This is a sterile, clear, colorless to yellow solution containing Cu-DOTATATE in a single-dose vial. The sealed vial is placed in a shielded (lead) container for radiation protection. The drug product is transported in Type A packaging.

[0110] In one embodiment, the total vial radioactivity (assay) is approximately 1.0 mCi / vial to approximately 10 mCi / vial, approximately 1.5 mCi / vial to approximately 9 mCi / vial, approximately 2.0 mCi / vial to approximately 8 mCi / vial, approximately 2.5 mCi / vial to approximately 7 mCi / vial, approximately 3.0 mCi / vial to approximately 6 mCi / vial, or approximately 3.6 mCi / vial to approximately 4.4 mCi / vial. In another embodiment, the total vial radioactivity (assay) is approximately 1.0 mCi / vial, approximately 1.5 mCi / vial, approximately 2.0 mCi / vial, approximately 2.5 mCi / vial, approximately 3.0 mCi / vial, approximately 3.5 mCi / vial, approximately 3.6 mCi / vial, approximately 4.0 mCi / vial, approximately 4.4 mCi / vial, approximately 4.5 mCi / vial, approximately 5.0 mCi / vial, approximately 5.5 mCi / vial, approximately 6 mCi / vial, approximately 7 mCi / vial, approximately 8 mCi / vial, approximately 9 mCi / vial, or approximately 10 mCi / vial.

[0111] In yet another embodiment, the radioactivity concentration of the drug product is approximately 0.5 mCi / mL to approximately 15 mCi / mL, approximately 0.5 mCi / mL to approximately 12.5 mCi / mL, approximately 0.5 mCi / mL to approximately 10 mCi / mL, approximately 0.5 mCi / mL to approximately 7.5 mCi / mL, approximately 0.5 mCi / mL to approximately 5 mCi / mL, approximately 0.5 mCi / mL to approximately 3 mCi / mL, approximately 0.6 mCi / mL to approximately 2.5 mCi / mL, approximately 0.7 mCi / mL to approximately 2.0 mCi / mL, approximately 0.8 mCi / mL to approximately 1.5 mCi / mL, or approximately 0.9 mCi / mL to approximately 1.1 mCi / mL. In yet another embodiment, the radioactivity concentration of the drug product is approximately 15 mCi / mL, approximately 14 mCi / mL, approximately 13 mCi / mL, approximately 12 mCi / mL, approximately 11 mCi / mL, approximately 10 mCi / mL, approximately 9 mCi / mL, approximately 8 mCi / mL, approximately 7 mCi / mL, approximately 6 mCi / mL, or approximately 5 mCi / mL. In yet another embodiment, the radioactivity concentration of the drug product is approximately 5–15 mCi / mL. In yet another embodiment, the radioactivity concentration of the drug product is approximately 9–14 mCi / mL. In yet another embodiment, the radioactivity concentration of the drug product is approximately 10–11 mCi / mL. In yet another embodiment, the radioactivity concentration of the drug product is approximately 11–12 mCi / mL. In an additional embodiment, the radioactivity concentration of the drug product is approximately 12–13 mCi / mL.

[0112] In another embodiment, DOTATATE and related substances are present in the drug product in amounts of ≤50 ppm, ≤40 ppm, ≤30 ppm, ≤27 ppm, ≤22.7 ppm, ≤20 ppm, or ≤10 ppm.

[0113] In one embodiment, the apparent specific activity of the drug product is DOTATATE and related substances with a calibrated value of ≥10 mCi / mg, ≥20 mCi / mg, ≥30 mCi / mg, ≥40 mCi / mg, ≥50 mCi / mg, ≥60 mCi / mg, ≥70 mCi / mg, ≥80 mCi / mg, or ≥90 mCi / mg.

[0114] In another embodiment, the average specific radioactivity of the drug product is approximately 2.96 MBq / μg. In another embodiment, the average specific radioactivity of the drug product is approximately 1.0 to approximately 5.0 MBq / μg. In another embodiment, the average specific radioactivity of the drug product is approximately 2.0 to approximately 4.0 MBq / μg. In another embodiment, the average specific radioactivity of the drug product is approximately 2.5 to approximately 3.5 MBq / μg. In yet another embodiment, the average specific radioactivity of the drug product is approximately 0.5 MBq / μg, 1.0 MBq / μg, 1.5 MBq / μg, 2.0 MBq / μg, 2.5 MBq / μg, 3.0 MBq / μg, 3.5 MBq / μg, 4.0 MBq / μg, 4.5 MBq / μg, 5.0 MBq / μg, 6.0 MBq / μg, 7.0 MBq / μg, 8.0 MBq / μg, 9.0 MBq / μg, or 10.0 MBq / μg at calibration.

[0115] In yet another embodiment, the filling volume of the drug product in the vial is approximately 1 mL to approximately 10 mL, approximately 2 mL to approximately 8 mL, approximately 3 mL to approximately 6 mL, or approximately 3.6 mL to approximately 4.4 mL. In yet another embodiment, the filling volume of the drug product in the vial is approximately 1 mL, approximately 2 mL, approximately 3 mL, approximately 3.6 mL, approximately 4 mL, approximately 4.4 mL, approximately 5 mL, approximately 6 mL, approximately 7 mL, approximately 8 mL, approximately 9 mL, or approximately 10 mL.

[0116] In another embodiment, the pH of the drug product is approximately 4.5 to approximately 8.0, approximately 4.6 to approximately 7.9, approximately 4.7 to approximately 7.8, approximately 4.8 to approximately 7.7, approximately 4.9 to approximately 7.6, approximately 5.0 to approximately 7.5, or approximately 5.5 to approximately 7.5. In another embodiment, the pH of the drug product is 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, or 7.5.

[0117] In one embodiment, the uniformity of the content of the drug product is ≤10%, ≤9%, ≤8%, ≤7%, ≤6%, ≤5%, ≤4%, ≤3%, ≤2%, ≤1%, ≤0.9%, ≤0.8%, ≤0.7%, ≤0.6%, ≤0.5%, ≤0.4%, ≤0.3%, ≤0.2%, or ≤0.1%.

[0118] In another embodiment, ethanol is present in the drug product in amounts of about 1% to about 10%, about 2% to about 9%, about 3% to about 8%, about 4% to about 7%, or about 4% to about 6%. In yet another embodiment, ethanol is present in the drug product in amounts of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.

[0119] In one embodiment, the ascorbic acid content in the drug product is approximately 1 mg / mL to approximately 100 mg / mL, approximately 10 mg / mL to approximately 90 mg / mL, approximately 20 mg / mL to approximately 80 mg / mL, approximately 3 mg / mL to approximately 70 mg / mL, approximately 40 mg / mL to approximately 60 mg / mL, approximately 30 mg / mL to approximately 60 mg / mL, or approximately 36 mg / mL to approximately 44 mg / mL. In another embodiment, the ascorbic acid content in the drug product is approximately 1 mg / mL, approximately 10 mg / mL, approximately 15 mg / mL, approximately 20 mg / mL, approximately 30 mg / mL, approximately 36 mg / mL, approximately 40 mg / mL, approximately 44 mg / mL, approximately 50 mg / mL, approximately 60 mg / mL, approximately 70 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, or approximately 100 mg / mL.

[0120] In one embodiment, the RCP of the drug product is ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%.

[0121] In another embodiment, the drug product has a separation radiochemical yield (RCY) of about 50%, about 55%, about 56%, about 60%, about 65%, about 68%, about 70%, about 75%, about 80%, about 83%, about 85%, about 90%, or about 95% (attenuation corrected).

[0122] In one embodiment, a filter integrity test is performed on the drug product. In another embodiment, the sterility of the drug product is tested.

[0123] iv. Dosage of drug products

[0124] With respect to drug product doses used herein, this disclosure is sufficient to enable positron emission tomography (PET) imaging in subjects requiring it. 64 Provides an effective amount of cu-DOTATATE.

[0125] In one embodiment, the dose of the drug product administered to a subject requiring it is approximately 20 MBq to 350 MBq, 30 MBq to 340 MBq, 40 MBq to 330 MBq, 50 MBq to 320 MBq, 60 MBq to 310 MBq, 70 MBq to 300 MBq, 80 MBq to 290 MBq, 90 MBq to 280 MBq, 100 MBq to 270 MBq, 110 MBq to 260 MBq, 132 MBq to 163 MBq, or 111 MBq to 185 MBq, or 120 MBq to 250 MBq at the calibration date and time.

[0126] In another embodiment, the dose of the drug product administered to a subject requiring it is approximately 20 MBq, 30 MBq, 37 MBq, 40 MBq, 50 MBq, 60 MBq, 70 MBq, 80 MBq, 90 MBq, 100 MBq, 110 MBq, 111 MBq, 120 MBq, 130 MBq, 140 MBq, 148 MBq, 150 MBq, and 160 MBq at the calibration date and time. These are MBq, approximately 170 MBq, approximately 180 MBq, approximately 185 MBq, approximately 190 MBq, approximately 200 MBq, approximately 210 MBq, approximately 220 MBq, approximately 230 MBq, approximately 240 MBq, approximately 250 MBq, approximately 260 MBq, approximately 270 MBq, approximately 280 MBq, approximately 290 MBq, approximately 300 MBq, approximately 310 MBq, approximately 320 MBq, approximately 330 MBq, approximately 340 MBq, or approximately 350 MBq.

[0127] In one embodiment, the dose of the drug product administered to a subject requiring it is approximately 0.5 mCi to 9.5 mCi, approximately 0.54 mCi to 9.0 mCi, approximately 0.6 mCi to 8.5 mCi, approximately 0.7 mCi to 8 mCi, approximately 0.8 mCi to 7.5 mCi, approximately 0.9 mCi to 7 mCi, approximately 1.0 mCi to 6.5 mCi, and approximately The ranges are approximately 1.1 mCi to 6 mCi, approximately 1.2 mCi to 5.5 mCi, approximately 1.3 mCi to 5.0 mCi, approximately 1.4 mCi to 4.5 mCi, approximately 1.5 mCi to 4.0 mCi, approximately 2 mCi to 3 mCi, approximately 0.1 mCi to 10 mCi, approximately 0.5 mCi to 5 mCi, approximately 1 mCi to 5 mCi, or approximately 1 mCi to 4 mCi.

[0128] In yet another embodiment, the dose of the drug product administered to a subject requiring it is approximately 0.1 mCi, 0.5 mCi, 0.54 mCi, 0.6 mCi, 0.7 mCi, 0.8 mCi, 0.9 mCi, 1.0 mCi, 1.1 mCi, 1.2 mCi, 1.3 mCi, 1.4 mCi, 1.5 mCi, 2.0 mCi, 2.5 mCi, 3.0 mCi, 3.1 mCi, 3.2 mCi, 3.3 mCi, 3.4 mCi, and 3.5 mCi at the calibration date and time. i is approximately 3.6 mCi, 3.7 mCi, 3.8 mCi, 3.9 mCi, 4.0 mCi, 4.1 mCi, 4.2 mCi, 4.3 mCi, 4.4 mCi, 4.5 mCi, 4.6 mCi, 4.7 mCi, 4.8 mCi, 4.9 mCi, 5.0 mCi, 5.5 mCi, 6.0 mCi, 6.5 mCi, 7.0 mCi, 7.5 mCi, 8.0 mCi, 8.5 mCi, 9.0 mCi, 9.5 mCi, or 10.0 mCi.

[0129] In one embodiment, the drug product is administered intravenously. In another embodiment, the drug product is delivered intravenously to the subject requiring it, in single, double, triple, or multiple doses.

[0130] In one particular embodiment, the pharmaceutical product is administered to the subject as an intravenous bolus injection at a dose of approximately 148 MBq (or approximately 4 mCi), and the images are acquired approximately 45 to approximately 90 minutes after drug administration.

[0131] Dose selection for elderly patients should be done carefully and usually starts at the lower end of the dosing range, reflecting reduced liver, kidney, or heart function as well as a greater frequency of complications or other drug therapies.

[0132] In one embodiment, the pharmaceutical product is administered to the subject over a period of approximately 15 minutes, approximately 10 minutes, approximately 5 minutes, approximately 4 minutes, approximately 3 minutes, approximately 2 minutes, or approximately 1 minute.

[0133] In one particular embodiment, the amount of radioactivity to be administered for PET imaging in adults is 148 MBq (4 mCi) administered as an intravenous injection over a period of approximately 1 minute.

[0134] In one specific embodiment, the pharmaceutical product is in a single-dose vial at calibration 64 contains 148 MBq (4 mCi) at a concentration of 37 MBq (1 mCi) per mL of Cu-DOTATATE. v. Imaging

[0135] The somatostatin analog 64 competitively binds to the same somatostatin receptors as Cu-DOTATATE and can affect imaging. Patients are imaged immediately before the somatostatin analog is dosed. For patients dosed with a long-acting somatostatin analog, a washout period of 28 days is recommended before imaging. For patients dosed with a short-acting somatostatin analog, a washout period of 2 days is recommended before imaging.

[0136] For pharmaceutical product PET imaging, whole-body acquisition from the head to the mid-thigh is recommended. Image acquisition starts between approximately 45 and approximately 90 minutes after intravenous administration of the pharmaceutical product. The uptake time and scan duration of the pharmaceutical product are adapted according to the equipment used as well as the patient and tumor characteristics to obtain optimal image quality. G. Method of administering drug products

[0137] 64 Cu-DOTATATE binds to somatostatin receptors. Based on the signal intensity, 64 PET images obtained using Cu-DOTATATE injection show the presence and density of somatostatin receptors in tissue. Uptake can also be seen in various non-NET tumors containing somatostatin receptors, or as normal physiological mutations. NET tumors lacking somatostatin receptors are not visualized.

[0138] The method of administering drug products to patients is: (a) 64 Steps for calibrating Cu-DOTATATE injection, (b) Within approximately 2 hours after calibration 64 Steps using Cu-DOTATATE injection, (c) 64 When discontinuing and re-administering Cu-DOTATATE injection, the steps involve using sterile techniques and radiation shielding. (d) Visually inspect for particulate matter and discoloration before administration. 64 The step of testing the Cu-DOTATATE injection and using it only if the solution does not contain particulate matter and does not change color. (e) A step of calculating the volume to be administered based on the measured radioactivity, volume, calibration time, and date. (f) A step of measuring the patient's dose immediately before administering the drug product using a dose calibrator. (g) 64 The steps include: administering Cu-DOTATATE injection, intravenous flushing with 0.9% sodium chloride injection, administering USP to the patient, and (h) The step of disposing of any unused drugs in a safe manner in accordance with applicable rules.

[0139] 64Table 4 shows the estimated absorbed radiation dose per unit of injected radioactivity in the organs and tissues of adult patients after intravenous administration of Cu-DOTATATE. [Table 4]

[0140] The effective radiation dose obtained from an administration of 148 MBq (4 mCi) to an adult is approximately 4.7 mSv. With an administered radioactivity of 148 MBq (4 mCi), typical radiation doses to the determinant organs—the liver, kidneys / adrenal glands, and spleen—are approximately 24 mGy, 21 mGy, and 17 mGy, respectively. Since the spleen has one of the highest physiological uptake rates, higher uptake and radiation doses to other organs or pathological tissues may occur in patients who have undergone splenectomy.

[0141] Non-radioactive somatostatin analogs and 64 Cu-DOTATATE competitively binds to the somatostatin receptor (SSTR2). Patients are imaged immediately before administration of a somatostatin analog. For patients administered a long-acting somatostatin analog, a 28-day drug-free period before imaging is recommended. For patients administered a short-acting somatostatin analog, a 2-day drug-free period before imaging is recommended.

[0142] 64 Cu-DOTATATE uptake reflects the level of somatostatin receptor density in NETs, ​​but uptake can also be seen in various other tumors that express somatostatin receptors. Increased uptake may be seen in other non-cancerous pathological conditions that express somatostatin receptors, including thyroid diseases, or in subacute inflammation, or may occur as a normal physiological variation (e.g., the uncinate process of the pancreas).

[0143] Negative scanning after administration of a drug product in patients without a history of NET disease does not rule out the disease.

[0144] 64Maximum radioactivity is observed in the adrenal glands, kidneys, pituitary gland, spleen, and liver 1 to 3 hours after a single dose of Cu-DOTATATE injection.

[0145] 64 Following a single intravenous dose of Cu-DOTATATE injection (4.15 ± 0.13 mCi) (n=6), radioactivity between 16% and 40% of the injection dose was recovered in urine over a 6-hour collection period.

[0146] In one embodiment, 64 Following a single intravenous injection of Cu-DOTATATE, approximately 5%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the injected dose of radioactivity is recovered in the urine over a 6-hour collection period.

[0147] In another embodiment, 64 Following a single intravenous injection of Cu-DOTATATE, approximately 5%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the radioactivity of the injection dose is recovered in the urine over a 5-hour collection period.

[0148] In yet another embodiment, 64 Following a single intravenous dose of Cu-DOTATATE injection, approximately 5%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the radioactivity of the injected dose is recovered in the urine over a 4-hour collection period.

[0149] In one embodiment, 64 Following a single intravenous injection of Cu-DOTATATE, approximately 5%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the injected dose of radioactivity is recovered in the urine over a 3-hour collection period.

[0150] In another embodiment, 64Following a single intravenous injection of Cu-DOTATATE, approximately 5%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the injected dose of radioactivity is recovered in the urine over a 2-hour collection period.

[0151] In yet another embodiment, 64 Following a single intravenous injection of Cu-DOTATATE, approximately 5%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the injected dose of radioactivity is recovered in the urine over a 1-hour collection period. [Examples]

[0152] The following examples demonstrate high purity 64 This invention provides an improved process for producing copper-labeled dotate. By labeling dotate with copper at low temperatures (i.e., ≤30°C), chelation of other metals by dotate can be reduced, thereby providing a drug product of higher purity. Furthermore, these examples maintain sufficient chemical stability for dispensing the drug product to a patient. 64 This provides a useful process for scaling up the production of Cu-DOTATATE. The following buffer solutions were prepared for use in Examples 1-5 described below.

[0153] Sodium acetate / gentisic acid buffer: Gentisic acid (GA) and sodium acetate (NaOAc) were dissolved in high-resistance water (HRW), and the pH of the resulting solution was adjusted using glacial acetic acid or 1M sodium hydroxide. The solution was further diluted with HRW to obtain the desired concentrations of NaOAc and GA.

[0154] Sodium ascorbate buffer: Sodium ascorbate was dissolved in HRW. The pH of the solution was adjusted to 6.5–7.5 using 1M HCl or 1M NaOH. The solution was further diluted with HRW to achieve the desired concentration of sodium ascorbate.

[0155] Sodium ascorbate / ethanol buffer: Sodium ascorbate was dissolved in HRW and anhydrous ethanol. The pH was adjusted to 6.5–7.5 with either 1M HCl or 1M NaOH, and then further diluted with HRW to achieve the desired final concentrations of both sodium ascorbate and ethanol.

[0156] HPLC was performed using an Agilent 1200 series system equipped with a variable wavelength UV-Vis detector followed inline by a sodium iodide detector (Bioscan B-FC-200P). A Phenomenex Luna C18 column (150 mm × 4.6 mm, 5 μm) was used. Mobile phases were prepared with solvent A and solvent B. Solvent A was 0.1% trifluoroacetic acid (TFA) in HRW, and solvent B was 0.1% TFA acid in acetonitrile (ACN). The gradients were (i) 15–40% solvent B in solvent A for 10 minutes, 40% solvent B in solvent A for 10–15 minutes, 15% solvent B in solvent A for 15–16 minutes, and 15% solvent B in solvent A for 16–19 minutes. The flow rate was 1.2 mL / min, and UV detection was monitored at 220 nm.

[0157] (Example 1) Preparation of non-radioactive Cu-DOTATATE

[0158] An initial non-radioactive reaction was performed to prepare Cu-DOTATATE by mixing a 0.05 M HCl solution of CuCl2 with a DOTATATE peptide solution in a gentisic acid / sodium acetate buffer solution. The pH of the buffer solution was 6 unless otherwise specified. The formation of Cu-DOTATATE was confirmed by HPLC. The relative retention times of the DOTATATE starting materials, the Cu-DOTATATE product peak, and other reaction components were established. Representative chromatograms for standard solutions containing gentisic acid / and DOTATATE are shown in Figure 2.

[0159] In the initial experiment, nearly equimolar amounts of dotate (0.035 μmol) in NaOAc / GA buffer and copper metal cations (0.039 μmol) in 0.05 M HCl were mixed in a vial at room temperature. The reaction mixture was analyzed by HPLC at numerous time intervals. The HPLC chromatogram for the sample collected at 5 minutes, shown in Figure 3, showed a new product peak identified as Cu-DOTATATE at approximately 7.2 minutes, which corresponded to a reduction in the dotate precursor peak (retention time approximately 6 minutes). The data suggest that Cu-DOTATATE formation is rapid and quantitative at ambient temperature in a reaction mixture containing equimolar amounts of starting materials.

[0160] (Example 2) The formation of metal dotate complexes prefers copper over other common metals.

[0161] Due to the high specific activity of Cu-64, a typical [ 64 Cu]Cu 2+ In solution, the amount of Cu is nano to micrograms. 2+ [ 64 Cu]Cu 2+ Other trace metals that may be present in the solution are typically environmental impurities introduced by the manufacturing process. Common transition metals that may be present include iron, lead, zinc, and nickel. These experiments were conducted because the effect that metallic impurities have on the preparation of copper Cu64 dotatate is chemically identical. 64 Instead of Cu nat The evaluation was performed using a non-radioactive solution of Cu.

[0162] A 0.05 M HCl solution containing 0.44 μg (0.00692 μmol) of Cu was mixed with 100 μg (0.0693 μmol) of dotatate in sodium acetate / gentisic acid buffer at room temperature (approximately 22°C) to obtain a molar ratio of dotatate to Cu of 10:1. The reaction was monitored by HPLC. As shown in Table 5, the HPLC peak areas of dotatate and the Cu-dotate compound showed essentially no change in the peak areas obtained at 5 minutes and 7 hours, indicating that the formation of Cu-dotatate was rapid at room temperature and completed after 5 minutes. [Table 5]

[0163] isotope-enriched 64 Ni is typically 64 Ni is another possible metallic impurity because it is used in the production of Cu. However, since achieving HPLC baseline separation between Ni-DOTATATE and Cu-DOATATE is difficult, similar competitive experiments were performed using Ni instead of Cu to evaluate the reaction kinetics of Ni. The non-radiolabeled reaction was performed by mixing a solution of Ni (0.0063 μmol), Fe (0.0069 μmol), Zn (0.0067 μmol), and Co (0.0068 μmol) in 0.05 M HCl with a solution of DOTATATE (0.0693 μmol) in gentisic acid / sodium acetate buffer at room temperature (approximately 22°C). To better evaluate the chelation behavior of Ni in the presence of Fe, Zn, and Co, copper was not added to the solution.

[0164] The reaction mixture was analyzed by HPLC at both 5 minutes and 6 hours. The peak area results are summarized in Table 6. 2+ The reaction dynamics of with DOTATATE are Cu 2+ This demonstrates that it is much slower than in the case of [another metal]. Therefore, it appears that Cu chelation by dotate, like with other transition metals (e.g., Fe, Co, Zn), occurs faster than Ni at ambient temperature. [Table 6]

[0165] (Example 3) Formation of Cu-DOTATATE at lower temperatures

[0166] Experiments similar to those described in Example 2 were conducted to determine whether Cu-DOTATATE formation occurred similarly at reduced temperatures (i.e., 15°C to 18°C). The reaction mixture was prepared as described in Example 2, but adjusted as necessary to meet the conditions outlined in Table 7. [Table 7]

[0167] Each reaction mixture was sampled for HPLC analysis approximately 5 minutes later. The reaction mixture containing only Cu was also sampled after approximately 2 hours. The results are summarized in Table 8. These data confirm that DOTATATE labeling is largely complete after 5 minutes, even at reduced temperatures and in the presence of Fe. [Table 8]

[0168] (Example 4) Up to 2,000 mCi in a single reaction 64 Preparation of Cu-DOTATATE

[0169] The radiolabeling reaction was carried out according to the general procedure described herein. 64 Cu 0.05M The solution in HCl was mixed with the sodium acetate / gentisic acid buffer solution of DOTATATE. The reaction mixture was heated at 30°C for 5 minutes and then purified via a C-18 solid-phase extraction cartridge. 64Cu-DOTATATE was collected in 2 mL of 50% EtOH and then diluted with ascorbic acid solution. The final product was assayed for radioactivity, and radiochemical purity (RCP) was assessed by radio-HPLC analysis. Characterization was performed on non-radioactive DOTATATE(t R =6.3 min) and Cu-DOTATATE(t R (7.3 minutes) Performed against the standard.

[0170] In general, we achieved a single-reaction scale-up of Cu-64 from 100 mCi to approximately 7,000 mCi. Table 9 outlines representative reactions and results for batch sizes from 100 mCi to 7,000 mCi. HPLC analysis showed that the main product peak had a retention time of approximately 7.4 minutes (t). R This indicates that it possesses non-radioactive Cu-DOTATATE(t R It was eluted simultaneously with (7.3 minutes). Eluted radioactivity (t R The remaining time (6.2-7.2 minutes) is due to degradation products resulting from radiolysis. The chemical stability of the purified reaction solution was monitored by HPLC, as shown in Table 9. 64 Cu-DOTATATE was demonstrated to be stable for a period of at least 47 hours. [Table 9]

[0171] (Example 5) Larger than 7,500 mCi 64 Preparation of Cu-DOTATATE

[0172] Higher batch size 64 Cu-DOTATATE can be prepared by combining two sub-batches. For example, 5,250 mCi 64 Cu(R1) and 4,800mCi 64Two radiolabeling reactions consisting of Cu(R2) were performed to prepare copper Cu64 dotatate totaling approximately 9Ci (attenuation is not corrected for during synthesis). Two separate 5Ci 64 The Cu radiolabeling reaction is performed in 0.05 M HCl 64 Cu is mixed with a solution of DOTATATE gentisic acid / sodium ascorbate buffer, 64 The synthesis was carried out by mixing DOTATATE at a ratio of 0.6 μg per mCi of Cu. The purified drug product solutions from each radiolabeling reaction were combined and diluted to a total of approximately 9 Ci. 64 Cu-DOTATATE was obtained during purification. The process yield was ≥95%. The RCP of the final drug product solution at release was ≥96%.

[0173] (Example 6) Maximum prepared with reduced DOTATATE concentration 64 Cu-DOTATATE batch

[0174] 64 Before preparing Cu-DOTATATE, add the DOTATATE ligand to the reaction mixture. 64 DOTATATE was added at a ratio of 1 μg per 1 mCi of Cu (i.e., a molar ratio of approximately 170:1 during synthesis). 64 To improve the molar activity of Cu-DOTATATE, process improvements were initiated to reduce the amount of DOTATATE in the radiolabeling reaction. Two radiolabeling reactions, reaction 1 (R1) and reaction 2 (R2), were performed with a maximum of 5,250 mCi each. 64 Cu and up to 4,800 mCi 64 The reaction was carried out with Cu. In the case of R1, the total labeled dotate was approximately 3,125 μg or ≥276 μg / mL. In the case of R2, the total labeled dotate was approximately 3,018 μg or ≥265 μg / mL. The reaction mixture contained the ligand (i.e., moles of dotate) and the radionuclide (i.e., 64 The molar ratios of Cu to R1 were approximately 102:1 (R1) and approximately 99:1 (R2). 64The concentration of ligand mass (μg) relative to the radioactivity (mCi) of Cu was approximately 0.6 μg / mCi for each reaction. 64 The Cu solution was combined with a DOTATATE solution in sodium acetate / gentisic acid buffer. The radioactivity concentrations (RAC) of R1 and R2 during radiosynthesis were ≥460 mCi / mL and ≥421 mCi / mL, respectively. The reaction was maintained at 30°C for 5 minutes, followed by 5 minutes at ambient temperature, and then purified.

[0175] The crude reaction mixtures for R1 and R2 were purified using a C-18 solid-phase extraction (SPE) cartridge, and the eluates containing the purified products were combined to obtain a total volume of approximately 8.7 Ci. 64 A bulk solution containing Cu-DOTATATE was prepared (attenuation was not corrected during synthesis). The process yield was ≥95%, and the radiochemical purity (RCP) of the final drug product solution after dilution was ≥96%.

[0176] In another experiment, approximately 7 Ci 64 Cu-DOTATATE was prepared in a single reaction using a DOTATATE ratio of 0.6 μg per mCi of Cu-64 (see Table 9).

[0177] (Example 7) 64 Effects of gentisic acid and ethanol on Cu-DOTATATE product stability

[0178] 64 The effects of ethanol (EtOH) and gentisic acid (GA) content in the final dose matrix on the chemical stability of Cu-dotatate were evaluated. In these experiments, the 500 mCi reaction was performed using the general procedure outlined in Example 2. 64 The Cu-DOTATATE product was eluted from Sep-Pak with 2 mL of 50% EtOH(aq) into 5 mL of 50 mg / mL NaOAsc buffer and purified. 64 This was used as a Cu-DOTATATE stock solution. 64A 1 mL aliquot was transferred from the Cu-DOTATATE stock to a vial containing the following solution: [Table 1A]

[0179] Each vial was analyzed for stability by HPLC, and the results are summarized in Table 10. Surprisingly, the highest degradation rate (24% to 38%) was observed in samples containing high amounts of GA, which is generally considered to be a radioprotective agent. In those samples, 64 The decrease in Cu-DOTATATE is due to t R = Free at 6.6 minutes and 7.1 minutes 64 This correlated with an increase in Cu and two unknown radioactive impurities. Since vials with similar radioactivity concentrations showed little to no decomposition, it is unlikely that the decomposition was due to radiolysis, and therefore the mechanism resulting in chemical instability remains unknown. 64 The only other condition that resulted in a loss of more than 2% of Cu-DOTATATE was vial 3, which differed from the control (vial 1) in that it contained approximately 10% EtOH. [Table 10]

[0180] The results showed that in a solution containing sodium ascorbate at concentrations ranging from 45 to 122 mg / mL, ethanol at concentrations of 1.6% to 5.2%, and radioactivity at concentrations of 3.6 to 16 mCi / mL (at the time of preparation), purity was higher than 95%. 64 This study demonstrated that Cu-DOTATATE remained chemically stable for two days. 64 The cu-dotatate product remained stable with a purity of more than 90% in a solution containing sodium ascorbate at a maximum concentration of 98 mg / mL and ethanol at a maximum concentration of 9.7%, and with a radioactivity concentration of approximately 18 mCi / mL (at the time of preparation).

[0181] (Example 8) Preparation of Cu-DOTATATE in the presence of increased gentisic acid or sodium ascorbate

[0182] The general reaction scheme used in previous experiments was repeated, except that the concentration of gentisic acid in the reaction mixture was increased fourfold. After the reaction, samples were taken from the mixture and purified via a C-18 solid-phase extraction (SPE) cartridge. The purified product was analyzed by HPLC to determine the reaction yield. The results of the HPLC analysis are summarized in Table 11. Nearly quantitative recovery of dotatate and cu-dotatate was achieved, and neither the labeling efficiency nor the purification was affected by the excessively high concentration of gentisic acid in the reaction mixture. [Table 11]

[0183] The gentisic acid in the reaction mixture acts as a radioprotective agent, helping to reduce decomposition by radiolysis. To evaluate the possibility of using another radioprotective agent, a reaction was performed in which sodium ascorbate was added to the reaction mixture (pH=6.8). DOTATATE (0.0693 μmol) in sodium acetate / gentisic acid buffer was added to Cu 2+ Mix with a solution in 0.05 M HCl (0.0069 μmol), dilute with sodium ascorbate, and then add Cu DOTATATE. 2+ The ratio was set to 10:1. The reaction mixture was mixed at room temperature, and samples were taken at 5 minutes and 51 minutes to monitor the formation of Cu-DOTATATE via HPLC analysis. The HPLC peak areas for Cu-DOTATATE were 2.33 mV / min at 5 minutes and 2.36 mV / min at 51 minutes, indicating that the reaction was completed in 5 minutes.

[0184] (Example 9) 64 Effect of non-radioactive copper on the radiochemical purity of cu-DOTATATE

[0185] Three reactions were conducted, each using approximately 5 Ci. R1 was a control reaction without the addition of non-radioactive copper. No copper was detected in R1. Non-radioactive copper was added to R2 and R3 to investigate its effect on RCP. R2 had a total copper content of approximately 139 μg (11.0 μg / mL) in 12.6 mL. R3 had a total copper content of approximately 476 μg (31.1 μg / mL) in 15.3 mL. The total DOTATATE labeled in each reaction was approximately 3000 μg (R1), approximately 3000 μg (R2), and approximately 3600 μg (R3), or concentrations of ≥250 μg / mL, ≥238 μg / mL, and ≥235 μg / mL, respectively. The reaction time for each reaction was approximately 5 minutes. After heating, each reaction was cooled at room temperature for approximately 5 minutes, and the mixture was subsequently purified and diluted to its final bulk solution.

[0186] The final drug product solutions of R1, R2, and R3 had RACs of approximately 11.7 mCi / mL (R1), approximately 10.3 mCi / mL (R2), and approximately 12.4 mCi / mL (R3), respectively. The decay correction process yields of R1, R2, and R3 were approximately 95.4%, approximately 98.7%, and approximately 95.6%, respectively. The RCPs of each final drug product solution after dilution were ≥95.5% (R1), ≥97.3% (R2), and ≥97.9% (R3).

[0187] (Example 10) Recovery of DOTATATE from SPE Cartridges at Higher Flow Rates

[0188] Typically, the flow rate through the SPE cartridge is carried out at a low flow rate (i.e., 1 - 5 mL / min) to ensure an appropriate loading of the desired product onto the cartridge and a high recovery rate of the purified product eluate. 64In the case of Cu-DOTATATE, concentrating the product on the SPE cartridge can lead to greater radiolysis damage, especially in high-radioactivity batches. Therefore, to shorten the purification time, the recovery of DOTATATE was evaluated at higher flow rates. Since C-18 SPE chemistry is primarily driven by DOTATATE interaction with the cartridge, the experiments were conducted using a non-radioactive solution of DOTATATE, as the behavior of Cu-DOTATATE or other metal-DOTATATE species is very similar.

[0189] A solution of dotate in sodium acetate / gentisic acid buffer was prepared and loaded into a C-18 SPE cartridge at a flow rate of either 12 mL / min or 18 mL / min. The cartridge was rinsed with water, and dotate was eluted in 50% ethyl ethanol. The amount of dotate in the loading solution and the purified product eluate was evaluated by HPLC. At a flow rate of 12 mL / min, 5.3% of dotate passed through the SPE cartridge during loading, while 97.1% was recovered in the eluate (total recovery rate 102%). When purification was performed at 18 mL / min, 28.4% of dotate passed through during loading, and 68.7% was recovered in the eluate (total recovery rate 97%). The results indicate that a flow rate of at least up to 12 mL / min is required while maintaining a nearly quantitative recovery yield. 64 This demonstrates that it can be used for the purification of Cu-DOTATATE. The loaded solution was collected by fractionation, and the DOTATATE recovery results for each fraction are shown in Figures 4 and 5. (Example 11) Improved purification yield of Cu-DOTATATE using 50% ethanol eluent.

[0190] Typically, radiolabeled copper Cu-64 dotatate is purified using C-18 SPE. In this procedure, the crude radiolabeled solution is loaded into a C-18 SPE cartridge, the cartridge is rinsed with water to remove hydrophilic impurities, and then the purified copper is removed. 64Cu-DOTATATE compounds are typically eluted from cartridges using 100% ethanol. The inventors found that the purification yield of Cu-DOTATATE could be improved by using 50% EtOH. Several experiments were performed to support this observation.

[0191] Reaction mixtures containing copper(2+) ions, transition metal ion impurities, and a bioconjugate chelator (DOTATATE) were prepared in triplicate under each condition. The reaction mixtures were held at room temperature (approximately 20°C) for 5 minutes, then purified using a C-18 SPE cartridge and eluted with either 100% EtOH (n=3) or 50% EtOH (n=3). The ratio of DOTATATE to metal in the reaction mixtures is shown in Table 12. [Table 12]

[0192] Approximately 10 minutes after mixing, a sample of the crude reaction mixture was analyzed by HPLC to obtain the in situ reaction yield. Each reaction mixture was then purified via a C-18 SPE cartridge, and the product was eluted with either 100% EtOH or 50% EtOH. The separation yield of the purified product solution was determined by HPLC analysis. The results are shown in Table 13. The reaction yield was determined by comparison with the DOTATATE standard. [Table 13]

[0193] (Example 12) Effectiveness of drug products

[0194] The efficacy of the drug product was established in two single-center, open-label studies. Study 1 prospectively evaluated a total of 63 subjects, including 42 patients with known or suspected NETs based on histology, conventional imaging, or clinical assessment, and 21 healthy volunteers. Of the 42 patients, 37 (88%) had a history of NETs at the time of drug product imaging. In the entire study population of 63 subjects, 28 (44%) were male and 35 (56%) were female, and the majority of subjects were Caucasian (86%). The mean age of the subjects was 54 years (ranging from 25 to 82 years).

[0195] Drug product images from each subject were interpreted as either positive or negative for NET by three independent readers who were unaware of clinical information and other imaging results. PET imaging results were evaluated by a single oncologist-blinded assessment of the subject's diagnosis based on available histopathological results, and reports of previous imaging performed within 8 weeks prior to drug product imaging (MRI, contrast-enhanced CT, bone scintigraphy, [ 18 F]Fluorodeoxyglucose PET / CT, 18 F] Sodium fluoride PET / CT, 111 Indium pentetreotide SPECT / CT, 68 The drug product was compared to a composite reference standard consisting of clinical and laboratory data, including chromogranin A and serotonin levels, as well as [Ga]Ga-doatate PET / CT. The positive agreement rate was quantified using the proportion of disease-positive subjects for each composite reference identified as positive by drug product imaging. The negative agreement rate was quantified using the proportion of disease-free subjects for each composite reference identified as negative by drug product imaging. Table 14 shows the performance of the drug product in detecting NETs for Study 1. [Table 14]

[0196] Study 2 demonstrated similar performance through a retrospective analysis of publicly available data collected from 112 patients (63 male and 49 female; mean age 62 years, range 30 - 84 years) with a known history of NET.

[0197] (Example 13) Safety and efficacy of pharmaceutical products

[0198] In the safety and efficacy study, 71 subjects received a single - dose pharmaceutical product. Of these 71 subjects, 21 were healthy volunteers and the remainder were patients with known or suspected NET. The following adverse reactions occurred at a rate of < 2%: (a) gastrointestinal disorders: nausea, vomiting; and (b) vascular disorders: flushing.

[0199] 126 patients with a known history of NET were 64 administered a single dose of Cu - DOTATATE. Four patients reported experiencing nausea immediately after the injection.

[0200] The embodiments described herein are intended to be merely illustrative. It will be understood by those skilled in the art that modifications and variations may be made without departing from the scope of the invention as encompassed by the following claims. In one embodiment, for example, the following items are provided. (Item 1) A method for radiolabeling DOTATATE, comprising reacting copper - 64 with a buffered solution containing DOTATATE ​​​​​​​​​​​​A method for radiolabeling DOTATATE as described in item 1, wherein the reaction occurs in approximately 5 minutes. (Item 4) The method for radiolabeling dotate according to item 1, wherein the molar ratio of dotate to copper-64 in the reaction solution is approximately 100:1. (Item 5) A method for radiolabeling the DOTATATE described in item 1, wherein the reaction occurs at a temperature below 25°C. (Item 6) A method for radiolabeling the DOTATATE described in item 1, wherein the reaction occurs at a temperature below 20°C. (Item 7) A method for radiolabeling the DOTATATE described in item 1, wherein the reaction occurs at a temperature below 15°C. (Item 8) Prepared by the method described in item 1 64 A drug product containing Cu-DOTATATE. (Item 9) 64 A method for preparing a drug product containing Cu-DOTATATE, A method wherein the drug product is prepared by (i) radiolabeling copper-64 with dotate at a concentration of approximately 0.6 μg / mL (μg of dotate per mCi of copper-64), and the radionuclide purity of copper-64 in the drug product is approximately 99%. (Item 10) Prepared by the method described in item 9 64 A drug product containing Cu-DOTATATE. (Item 11) The aforementioned DOTATATE 64 The method described in item 9, wherein the molar ratio to Cu is approximately 125:1, 120:1, 115:1, 110:1, 105:1, 100:1, 95:1, 90:1, 85:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 4:1, 3:1, 2:1, 2.5:1, or 1:1. (Item 12) The method according to item 9, wherein the drug product has a separation radiochemical yield (RCY) of approximately 50%, approximately 55%, approximately 56%, approximately 60%, approximately 65%, approximately 68%, approximately 70%, approximately 75%, approximately 80%, approximately 83%, approximately 85%, approximately 90%, or approximately 95% (attenuation corrected). (Item 13) The method according to item 9, wherein the radiant light is realized in approximately 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 15 hours, 20 hours, or 22 hours. (Item 14) The method according to item 9, wherein the aforementioned radiant labeling is achieved in less than 15 minutes. (Item 15) The method according to item 9, wherein the radiative labeling is carried out at a reaction temperature of approximately 10°C to 50°C, approximately 15°C to 45°C, approximately 20°C to 40°C, approximately 10°C to 30°C, approximately 10°C to 20°C, approximately 20°C to 50°C, approximately 20°C to 40°C, or approximately 20°C to 30°C. (Item 16) The method according to item 9, wherein the radioactive labeling is performed at pH levels of approximately 4.5 to 7.0, 4.6 to 6.9, 4.7 to 6.8, 4.8 to 6.7, 4.9 to 6.6, 5.0 to 6.6, 5.1 to 6.5, 5.2 to 6.3, 5.3 to 6.2, 5.4 to 6.1, or 5.5 to 6.0. (Item 17) A method for radially labeling DOTATATE, Steps to react copper-64 with a buffered solution containing dotate. Includes; The above reaction occurs at a temperature below or equal to 30°C in less than 15 minutes; and DOTATATE at a concentration of approximately 0.6 μg / mL ( 64 A method for radioactive labeling of copper-64 with dotate (μg per mCi) of copper. (Item 18) Prepared by the method described in item 17. 64 A drug product containing Cu-DOTATATE. (Item 19) The method according to item 17, wherein non-radioactive copper is added to the reaction mixture. (Item 20) The method according to item 19, wherein 0.1 to 30 μg / mL (ppm) of non-radioactive copper is added to the reaction mixture. (Item 21) 64 A drug product for use in positron emission tomography, comprising Cu-DOTATATE, 64 Cu-DOTATATE is 148MBq 64 A drug product stored in a single-dose vial containing Cu-DOTATATE, having a radioactivity concentration of approximately 5-15 mCi / mL, and having a radiochemical purity of ≥96% after dilution. (Item 22) The drug product according to item 21, wherein the radiochemical purity of the drug product after dilution is ≥97%. (Item 23) The drug product according to item 21, wherein the radiochemical purity of the drug product after dilution is ≥98%. (Item 24) The drug product according to item 21, wherein the radiochemical purity of the drug product after dilution is ≥99%. (Item 25) The drug product described in item 21, wherein the drug product is stable for 48 hours after formulation. (Item 26) The drug product described in item 21, wherein the drug product is stable for 24 hours after formulation. (Item 27) The drug product described in item 21 has a radioactivity concentration of approximately 9-14 mCi / mL. Physical products. (Item 28) The drug product described in item 21, wherein the radioactivity concentration of the drug product is approximately 10-11 mCi / mL.

Claims

[Claim 1] The invention described in the specification.

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