Formulations for radiotherapy and diagnostic imaging and their use in disease treatment, diagnosis and imaging - Patent Application 20070122997

Abstract

The present invention relates to formulations of radiolabeled compounds for use in radiotherapy and diagnostic imaging. Specifically, the present invention relates to an aqueous formulation of a Cu-radiolabelled compound of formula (I) for use in radiotherapy and diagnostic imaging, further comprising a buffer, gentisic acid, ethanol, and ascorbic acid. [Formula 1] TIFF2025529820000060.tif42170

Description

[Technical Field]

[0001] The present invention relates to formulations of radiolabeled compounds useful in radiotherapy and diagnostic imaging. [Background technology]

[0002] Radiolabeled compounds or ligands can be used as radiopharmaceuticals in applications such as radiotherapy or diagnostic imaging. Particularly useful are radiolabeled compounds that exhibit some tendency to selectively target specific sites in vivo (e.g., specific receptors), and then deliver radioisotopes to desired sites of action. This requires that the ligand contains a component for forming a complex with the radioisotope and another component for targeting the desired site.

[0003] One known problem associated with such ligands is the premature dissociation of the radioisotope before the ligand-radioisotope conjugate reaches the site of action. Not only does this reduce the efficacy of the conjugate, but loss of the radioisotope to areas where the radiotherapeutic effect is not intended can have deleterious consequences.

[0004] Dissociation of the radioisotope from the ligand can occur as a result of transchelation, in which the radioisotope is transferred to another biological ligand in vivo. Again, this results in reduced therapeutic efficacy and delivery of the radioisotope to areas where treatment is not required.

[0005] Radiolabeled ligands and radioisotopes are usually stored and transported to patients in separate containers to minimize the above-mentioned problems related to dissociation before administration. The ligand can be transported as a lyophilized powder at low temperature to extend the stability of the compound. The radioisotope can then be combined with the ligand to form a radiopharmaceutical just before administration, which can help minimize dissociation of the radioisotope before the complex reaches the site of action.

[0006] Another problem associated with radiolabeled compounds is that the use of radioisotopes can result in radiolysis, i.e., the destruction or partial destruction of the ligand. When a radioisotope undergoes spontaneous decay and subsequent radiation emission, this energy can be sufficient to induce bond cleavage and subsequent destruction of the ligand. In addition to a decrease in the effectiveness of the radiopharmaceutical, the release of the radioisotope or fragments of the original pharmaceutical also occurs, resulting in the delivery of radiation to undesired sites.

[0007] Since many radiopharmaceuticals are designed to be administered parenterally, i.e., parenterally, usually as a solution, the ligand itself must be soluble in a pharmaceutically acceptable solvent or carrier. As is known in the art, the solubility of a particular compound in any given solvent can be unpredictable. While the solubility of a particular compound in a particular solvent may be known, the solubility of an analog of the compound in a different solvent system may be quite different. This therefore poses a challenge to those seeking to develop formulations of the compound, particularly pharmaceutically acceptable injectable formulations.

[0008] Pharmaceutical formulations typically contain one or more excipients that affect the compound in some way, such as improving the solubility of the compound or increasing the stability of the compound in solution. Alternatively, additional excipients may be used to provide other characteristics to the formulation, such as preservatives, buffers, etc.

[0009] Although thousands of formulations of ligand-radioisotope conjugates have been documented, it is not expected that the excipients used in such formulations will provide the required solubility, stability, and bioavailability of any newly developed conjugate. Furthermore, it is not possible to predict that a particular combination of excipients will further prevent or minimize dissociation of the radioisotope or minimize the occurrence of radiolysis. For example, a formulation containing a particular combination of excipients may provide the required solubility, stability, and bioavailability of a particular conjugate, but may be completely inappropriate for another conjugate. Furthermore, where stability may be observed at low levels of radioactivity, it may not be observed at higher levels of radioactivity. This may be, for example, the difference in activity levels used for diagnostic doses on the order of hundreds of megabecquerels compared to higher therapeutic doses of radioactivity on the order of several gigabecquerels. Alternatively, this difference may be in the radioactivity levels when large multidose batches are prepared and then divided into smaller radioactivity doses. Differences in stability can also result from the type of radioactivity, such as gamma, beta, or alpha emission, of one isotope versus another, even when used in the same drug substance, in some instances used for diagnostic imaging and in other instances delivering a therapeutic cell-killing dose.

[0010] The extent of radiolysis of a ligand-radioisotope complex depends on the level of radioactivity, the level of specific activity, and the structure of the ligand. A formulation may provide the necessary stability for a complex with one radionuclide that may not be found with another radionuclide. A good example is positron-emitting copper-64 ( 64 Cu, t 1 / 2 =12.7 hours) and beta particle-emitting copper-67 ( 67 Cu, t 1 / 2 = 2.58 days). Beta-emission often results in complexes that are less stable than their stably labeled counterparts, and therefore 67Cu-labeled complexes are prone to radiolysis. Taking this into account, formulations can vary significantly depending on the radionuclide used, for example, by adding or increasing the amount of stabilizers. In addition to cost, increasing the level of additional agents in the formulation can introduce new problems, such as precipitation or pH imbalance in the formulation. Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, there is a need to tailor desirable formulations of ligand-radioisotope conjugates to exhibit the necessary stability with respect to radiolysis and dissociation of the radioisotope while also being pharmaceutically acceptable. The present invention seeks to address these issues with respect to certain ligand conjugates. [Means for solving the problem]

[0012] In one aspect of the present invention, 67 1. An aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions: [ka] During the ceremony, X is [ka] where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 A group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): [ka] Buffer: about 0.01% to about 0.1% (w / v) gentisic acid or a salt thereof; about 1% to about 7% (v / v) ethanol; and About 4% to about 10% (w / v) ascorbic acid or its salt An aqueous formulation is provided, further comprising: In certain embodiments of the first aspect, R is a group of formula (A): [ka] wherein X is as defined above, for example with the following stereochemistry: [ka]

[0013] In certain embodiments of the first aspect, R is an optionally substituted C1-C 12 It is alkyl.

[0014] In a further embodiment, R is methyl.

[0015] In certain embodiments of the first aspect, X is [ka] In the formula, n is an integer of 1 to 10.

[0016] In a further embodiment, X is [ka] and n is 4.

[0017] In certain embodiments, the radiochemical purity of the formulation is greater than about 90% for a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation is greater than about 92% for a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation is greater than about 94% for a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation is greater than about 96% for a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation is greater than about 98% for a period of at least 96 hours.

[0018] In some embodiments, the free radicals present in the formulation 67 In some embodiments, the amount of Cu present in the formulation is about 5% or less. 67 In another embodiment, the amount of free Cu present in the formulation is about 4% or less. 67 In other embodiments, the amount of free Cu present in the formulation is less than about 1%. 67 The amount of Cu is less than about 2%.

[0019] In certain embodiments, the pH of the formulation is about 4 to about 8. In other embodiments, the pH of the formulation is about 4, about 5, about 6, about 7, or about 8. In some embodiments, the pH of the formulation is about 6.

[0020] According to a further aspect of the present invention, 67 1. A process for preparing an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions, comprising: i) dissolving a compound of formula (I) or a salt thereof in a buffer solution containing gentisic acid or a salt thereof; ii) 67 adding a solution of Cu ions to the solution of step i); iii) filtering the solution obtained from step ii); iv) diluting the reaction by addition of aqueous ethanol and ascorbic acid; 67and recovering the aqueous formulation comprising the compound of formula (I) or a salt thereof complexed with Cu ions.

[0021] According to another aspect of the present invention there is provided an aqueous formulation prepared by the process defined above.

[0022] The aqueous formulations of the present invention may also be prepared by providing certain components of the formulation as a kit of parts, the kit comprising at least the compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof that is intended to be complexed with the compound of formula (I) or a salt thereof. 67 Cu ions, wherein a compound of formula (I) or a salt thereof, and 67 The Cu ions may be provided separately in the kit and combined to form the complexes described above prior to administration.

[0023] Thus, in another aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: 67 1. A kit for preparing an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions, comprising: a container containing a lyophilized compound of formula (I) or a salt thereof; [ka] During the ceremony, X is [ka] where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 is a group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): [ka] 67 a container containing a solution of Cu ions; and instructions for preparing the aqueous formulation defined in the above embodiment, comprising the addition of sodium phosphate buffer, gentisic acid or a salt thereof, ethanol, and ascorbic acid or a salt thereof.

[0024] A further aspect of the present invention is a kit for making an aqueous formulation as defined in the above aspect for parenteral administration, comprising: a container containing a lyophilized compound of formula (I) or a salt thereof; [ka] During the ceremony, X is [ka] where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 is a group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): [ka] 67 a container containing a solution of Cu ions; a container comprising a sodium phosphate buffer solution and gentisic acid or a salt thereof; a container comprising aqueous ethanol and ascorbic acid or a salt thereof; and instructions for preparing the aqueous formulation defined in the above aspect.

[0025] The radioactivity of the formulations disclosed herein is 67 This is due to the presence of a Cu radioisotope. In certain embodiments of the formulations disclosed herein, 67The radioactivity concentration of the formulation as a result of the Cu radioisotope is about 1.0 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.95 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.90 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.85 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.80 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.75 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.70 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.65 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.60 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.55 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.50 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.45 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.40 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.35 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.30 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.25 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.20 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.15 GBq / mL. In other embodiments, the radioactivity concentration of the formulation is about 0.10 GBq / mL. Concentrations within the above values ​​are also contemplated as part of this invention.

[0026] Another aspect of the present invention provides a method for radioimaging, diagnosis or treatment of cancer comprising administering to a subject in need thereof the aqueous formulation according to the first aspect.

[0027] According to another aspect, the present invention provides a method of treating cancer in a subject, the method comprising administering to a subject in need thereof the aqueous formulation according to the first aspect.

[0028] According to a further aspect, the present invention provides a method of radioimaging a subject, the method comprising administering to a subject in need thereof the aqueous formulation according to the first aspect.

[0029] The methods disclosed herein include administering a formulation of the invention, the formulation comprising: 67 Includes compounds of formula (I) complexed with a Cu radioisotope. 67 Administration of a complex of Cu and a compound of Formula (I) localizes the compound to sites expressing GRP receptors, resulting in the decay of the radioisotope and a therapeutic effect in the region of the subject to which the complex is bound. In some embodiments, the methods disclosed herein comprise administering a dose of a formulation of the invention having a radioactivity of about 1 GBq to about 20 GBq.

[0030] In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 20 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 19 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 18 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 17 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 16 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 15 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 14 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 13 GBq. In other embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 12 GBq. In other embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 11 GBq. In other embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 10 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 9 GBq. In other embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 8 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 7 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 6 GBq. In other embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 5 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the invention having a radioactivity of about 4 GBq.In other embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 3 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 2 GBq. In certain embodiments, the methods disclosed herein comprise administering a dose of a formulation of the present invention having a radioactivity of about 1 GBq. Doses within the above ranges are also contemplated as part of the present invention.

[0031] The present inventors 67 It has been found that the formulations disclosed herein containing a compound of formula (I) complexed with Cu allow for the delivery of high doses of radioactivity to a subject, and that the formulations and complexed compounds are stable and radiologically pure for at least 96 hours. Furthermore, the formulations disclosed herein allow for the delivery of high concentrations of the compound of formula (I). 67 As a result of forming a complex with Cu, 67 The present inventors have found that even when high concentrations of radiolabeled compound are incorporated into the formulation, the compound of Formula (I) does not degrade by radiolysis in the presence of the radioisotope in the formulation, even at increasing concentrations. Without wishing to be bound by theory, the present inventors believe that the formulations disclosed herein allow for the administration of high doses of radiation delivered as part of a complex with the compound of Formula (I), and that the formulations also prevent the degradation of the compound of Formula (I) by radiolysis, even at such high concentrations and radioactivities. This is illustrated in Figures 1-4, which show the stability of the formulations for up to 96 hours.

[0032] In certain embodiments, the methods disclosed herein relate to cancers associated with the expression of gastrin-releasing peptide (GRP) receptors. In certain embodiments, the cancer is a tumor. In other embodiments, the tumor is associated with prostate cancer, breast cancer, ovarian cancer, urinary tract cancer, small cell lung cancer, glioblastoma, and gastrointestinal stromal tumor.

[0033] In certain methods for treating cancer disclosed herein, the method further comprises radiological imaging of the subject after administration of the formulation of the present invention. In certain embodiments, the radiological imaging of the subject is by PET-CT or SPECT-CT.

[0034] The present invention is herein described, by way of example only, with reference to the following non-limiting figures. [Brief explanation of the drawings]

[0035] [Figure 1] Figure 1 shows a chromatogram from a radio-HPLC analysis of a formulation containing [Cu]Sar-BBN 12 hours after preparation. The chromatogram shows that the radiochemical purity of the formulation is 97.68%, indicating that the Cu radioisotope present in the formulation is complexed with the compound of formula (I). [Figure 2] Figure 2 shows a chromatogram from a radio-HPLC analysis of a formulation containing [Cu]Sar-BBN 96 hours after preparation of the formulation. The chromatogram shows a radiochemical purity of the formulation of 93.96%, indicating that the Cu radioisotope present in the formulation is complexed with the compound of formula (I). [Figure 3] Figure 3 shows a chromatogram from radio-TLC analysis of a formulation containing [Cu]Sar-BBN 12 hours after preparation. The chromatogram shows that the majority of the Cu radioisotope present in the formulation is complexed with the compound of formula (I), with very little Cu being detectable. [Figure 4] Figure 4 shows a chromatogram from a radio-TLC analysis of a formulation containing [Cu]Sar-BBN 96 hours after preparation. The chromatogram shows that the majority of the Cu radioisotope present in the formulation is complexed with the compound of formula (I), with very little free Cu being detectable. DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention relates to stable formulations of certain radioisotope-ligand conjugates. The inventors have discovered that formulations of the conjugates disclosed herein minimize dissociation of the radioisotope from the ligand and / or minimize radiolysis of the ligand resulting from the radioisotope.

[0037] The radioisotope-ligand conjugate formulations referred to herein are stable in solution and under physiological conditions for a period of time. The stability of the formulation relates to the stability of the conjugate when the radioisotope undergoes dissociation or when the conjugate undergoes radiolysis. The stability of the conjugate can be measured by considering the radiochemical purity of the formulation. Radiochemical purity is defined as the amount of radioisotope complexed by the sarcofazine ligand, expressed as a percentage of the total amount of radioisotope present in the formulation. The radioisotope may be present in the formulation as a complex with the sarcofazine ligand, as a free radioisotope, or as part of a radiolysis product. In certain embodiments, the radiochemical purity of the formulation is greater than about 90% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 91% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 92% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 93% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 94% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 95% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 96% for a period of at least 96 hours. In other embodiments, the radiochemical purity of the formulation is greater than about 97% for a period of at least 96 hours. In embodiments described herein, radiochemical purity can be determined by techniques such as radio-HPLC, in which the amount of radioisotope, either complexed or free, is determined and compared to the amount of radioisotope incorporated into the formulation. Those skilled in the art will understand the conditions necessary for the separation, analysis, and quantitation of formulations by radio-HPLC. Nevertheless, in certain embodiments, the mobile phase used to analyze the formulations disclosed herein by radio-HPLC comprises about 0.1% trifluoroacetic acid (TFA) in water.In certain embodiments, the mobile phase used for analyzing the formulations disclosed herein by radio-HPLC comprises about 0.1% trifluoroacetic acid (TFA) in acetonitrile.

[0038] The stability of the complex can also be measured by considering the amount of free copper, i.e., the amount of free copper radioisotope present in the formulation that is intended to form a complex with the sarcofazine ligand. In certain embodiments, the amount of free copper radioisotope present in the formulation is about 5% or less. In other embodiments, the amount of free copper radioisotope present in the formulation is about 4% or less. In other embodiments, the amount of free copper present in the formulation is about 3% or less. In other embodiments, the amount of free copper present in the formulation is about 2% or less. In other embodiments, the amount of free copper present in the formulation is about 1% or less. In other embodiments, the amount of free copper present in the formulation is about 1% or less. 67 In other embodiments, the amount of free Cu present in the formulation is less than about 1%. 67 The amount of Cu is less than about 2%.

[0039] The stable formulations of the present invention comprise a compound of formula (I) or a salt thereof: [ka] During the ceremony, X is [ka] where n is an integer from 1 to 10; R is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 A group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): [ka] wherein X is as defined above.

[0040] The compound of formula (I) or a salt thereof comprises a peptide having the sequence D-Pro-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH and has the following structure: [ka]

[0041] The peptide fragments are related to a family of bombesin receptor peptides that exhibit antagonist (or agonist) activity at the gastrin-releasing peptide (GRP) receptor. GRP receptors are known to be expressed or overexpressed on the membranes of various cancers and may be targets for diagnostic or therapeutic purposes. Compounds containing the bombesin-like peptides described herein can bind to sites expressing GRP receptors, and if a suitable radionuclide is also delivered as part of the compound, a localized diagnostic or therapeutic effect can be achieved. The amino acids of bombesin-like peptides, as used herein, may have the specific stereochemistry shown below: [ka] The compound of formula (I) or a salt thereof also contains a nitrogen-containing macrocycle capable of chelating a metal ion. The macrocycle of formula (I) is 3,6,10,13,16,19-hexazabicyclo[6.6.0]icosane, which may be referred to as a "sarcofazine." The sarcofazine of formula (I) contains six nitrogen atoms, one or more of which may be protected with a suitable protecting group.

[0042] The compound of formula (I) or a salt thereof comprises sarcofazine and a bombesin-like peptide, wherein the peptide is attached to the terminal position of sarcofazine via a linker group. As shown herein, the linker group comprises a propylamide group attached directly to the terminal position of sarcofazine. The propylamide group is then attached to a linker comprising a polyethylene glycol (PEG) group having 1 to 10 repeating units. The PEG group has the following structure: [ka] In the formula, n is an integer of 1 to 10.

[0043] The present inventors have discovered a compound of formula (I) or a salt thereof that contains a combination of sarcofazine and a bombesin-like peptide, or a peptide that functions as either an agonist or antagonist of the gastrin-releasing peptide receptor, for example, a compound of formula (I) or a salt thereof, in which the sarcofazine and the bombesin-like peptide are linked via a propylamide group (adjacent to the sarcofazine), and a linker containing a PEG group is capable of chelating metal ions and binding to target receptors. Without wishing to be bound by theory, the present inventors believe that the combination of sarcofazine, a bombesin-like peptide, a propylamide group, and a linker containing a PEG group provides certain advantages, as observed and discussed below. While the properties of the compounds of the present invention are a result of the individual components of the compounds, the present inventors believe that the presence of a linker containing a PEG group to modify the biodistribution, metabolism, and excretion profile of the compounds increases the overall biocompatibility of the compounds and may be responsible for the observed advantages.

[0044] In certain embodiments, the group R in the compound of formula (I) or salt thereof is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 Alkyl, optionally substituted amino, optionally substituted C1-C 12 Amides, optionally substituted C-C 10 aryl, and a group of formula (A): [ka] wherein X is as defined above.

[0045] In certain embodiments, R is a group of formula (A) having the stereochemistry defined below: [ka]

[0046] In certain embodiments, R is an optionally substituted C1-C 12 In one embodiment, R is an optionally substituted C1 alkyl group. In another embodiment, R is an optionally substituted methyl group. In another embodiment, R is an unsubstituted C1-C 12 In another embodiment, R is an unsubstituted C alkyl group. In another embodiment, R is an unsubstituted methyl group.

[0047] In certain embodiments, the compound of Formula (I) or salt thereof has the following structure: [ka] In the formula, n is an integer of 1 to 10.

[0048] In a specific embodiment, the compound of formula (I) or salt thereof has the following structure: [ka]

[0049] In certain embodiments, R is an optionally substituted C1-C 12 In certain embodiments, R is an optionally substituted C1 amide group. In certain embodiments, R is a C1 amide group further substituted with one or more groups.

[0050] In certain embodiments, R is a group of formula (A): [ka] wherein X is as defined above.

[0051] In one embodiment, R is a group of formula (A) and X is a group of formula [ka] where n is an integer of 1 to 10.

[0052] In one embodiment, R is a group of formula (A) and X is a group of formula [ka] where n is 4.

[0053] In one embodiment, R is an unsubstituted methyl group and X is a group of formula [ka] where n is an integer of 1 to 10.

[0054] In one embodiment, R is an unsubstituted methyl group and X is a group of formula [ka] where n is 4.

[0055] In certain embodiments, the compound of formula (I) has the following structure of formula (Ia): [ka]

[0056] In other embodiments, the compound of Formula (I) or a salt thereof has the structure of Formula (Ia), wherein the stereochemistry is defined as follows: [ka]

[0057] In a further embodiment, the compound of formula (I) or salt thereof has the structure of formula (Ib): [ka]

[0058] In other embodiments, the compound of Formula (I) or a salt thereof has the structure of Formula (Ib), wherein the stereochemistry is defined as follows: [ka]

[0059] As used herein, unless otherwise specified, the term "alkyl" refers to a straight-chain or branched aliphatic hydrocarbon group, preferably C1 to C6. 12 Alkyl, more preferably C1-C 10 "C1-C6 alkyl" refers to a group or part of a group that is an alkyl, most preferably C1-C6. Examples of suitable straight and branched C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.

[0060] As used herein, the term "amide" refers to a functional group consisting of a carbonyl group attached to a nitrogen atom. Thus, the term "optionally substituted amide" refers to an amide functional group with further substitution.

[0061] As used herein, the term "aryl" refers to (i) a group or portion of a group representing an optionally substituted monocyclic or fused polycyclic aromatic carbocyclic ring (a ring structure having all carbon ring atoms), preferably having 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, etc.; (ii) phenyl and C 5~7 Cycloalkyl or C 5~7 Cycloalkenyl groups are optionally substituted partially saturated bicyclic aromatic carbocyclic moieties fused together to form a ring structure, such as tetrahydronaphthyl, indenyl, or indanyl. Typically, aryl groups are C6-C 18 It is an aryl group.

[0062] As used herein, unless otherwise specified, the term "cycloalkyl" refers to a saturated monocyclic or fused or spiropolycyclic carbocyclic ring, preferably containing 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. Cycloalkyl groups are typically C3 to C9 cycloalkyl groups.

[0063] As used herein, the term "halogen" refers to chlorine, fluorine, bromine or iodine.

[0064] As used herein, the term "heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 12 carbons, more preferably 2 to 6 carbons, in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with a heteroatom group selected from S, O, P, and NR', where R' is H, optionally substituted C1-C 12 Alkyl, optionally substituted C-C 12 Cycloalkyl, optionally substituted C-C 18 Aryl and optionally substituted C1-C 18 Heteroaryl is selected from the group consisting of: alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyC1-C6 alkyl, C1-C6 alkyloxyC1-C6 alkyl, aminoC1-C6 alkyl, C1-C6 alkylaminoC1-C6 alkyl, and di(C1-C6 alkyl)aminoC1-C6 alkyl.

[0065] As used herein, the term "heteroaryl," alone or as part of a group, refers to a group containing an aromatic ring (preferably a 5- or 6-membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring, with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen, and sulfur. Examples of heteroaryls include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xanthrene, phenoxathine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoxazolone, benzophenone, benzoisothiazole, naphtho[2,3-b]thiophene, furan, isoindol ...isothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xanthrene, phenoxathine, pyrrole, imidazole, pyrazole, Heteroaryl groups typically include C1-C6 alkyl, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl, 1-, 2-, or 3-indolyl, and 2- or 3-thienyl. 18 It is a heteroaryl group.

[0066] As used herein, "C1-C 12 The term "alkylene" refers to a divalent straight or branched chain aliphatic hydrocarbon group having 1 to 12 carbon atoms in the chain.

[0067] As used herein, the term "optionally substituted" when used in connection with a particular group indicates that the group may or may not be further substituted or fused (so as to form a fused polycyclic ring system) with one or more non-hydrogen substituents. In certain embodiments, the substituents are selected from the group consisting of halogen, ═O, ═S, —CN, —NO 2 , —CF 3 , —OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyl. C(=O)OH, C(=O)R, alkylsulfonylamino, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=O)OH, -C(=O)R a , -C(=O)OR a , C(=O)NR a R b , C(=NOH)R a , C(=NR a )NR b R c , N.R. a R b , N.R. aC(=O)R b , N.R. a C(=O)OR b , N.R. a C(=O)NR b R c , N.R. a C(=NR b )NR c R d , N.R. a SO2R b , -SR a , SO2NR a R b , -OR a , OC(=O)NR a R b , OC(=O)R a and acyl, and R a , R b , R c and R d H, C1~C 12 Alkyl, C1-C 12 Haloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C2-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C2-C 12 Heterocycloalkyl, C2-C 12 Heterocycloalkenyl, C6-C 18 Aryl, C1-C 18 heteroaryl, and acyl, or R a , R b , R c and R d Any two or more of, taken together with the atoms to which they are attached, form a heterocyclic ring system having from 3 to 12 ring atoms.

[0068] In some embodiments, each optional substituent is independently selected from the group consisting of halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH, and acyl.

[0069] Examples of particularly suitable optional substituents include F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, COOH, COOCH3, and CN.

[0070] As used herein, the term "salt" refers to acid addition and base addition salts of compounds, where the salts are prepared from inorganic or organic acids or inorganic or organic bases. In some embodiments, the salts of the compounds of the present invention may be pharmaceutically acceptable salts.

[0071] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and may be an acid addition salt or a base addition salt. Suitable pharmaceutically acceptable acid addition salts of compounds of formula (I) can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Further information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of drugs that are solid, it will be understood by those of skill in the art that the compounds, drugs and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specific formula.

[0072] As used herein, the term "complex" means 67 It refers to a compound coordinated by a metal ion, such as the compound of formula (I) or a salt thereof coordinated with Cu.

[0073] The administrable formulation of the present invention comprises a compound of formula (I) or a salt thereof and a radioisotope 67 The ligands herein include complexes with copper ions, particularly Cu. Radioisotopes are sometimes referred to as radionuclides. 2+It has been found that the complexation of ions is particularly successful. Those skilled in the art will also understand that the complexation of a compound of formula (I) or a salt thereof with a radioisotope can be achieved by contacting a compound of formula (I) or a salt thereof with the radioisotope to be complexed, such that the compound of formula (I) or a salt thereof forms a complex with the radioisotope. This can include mixing the compound of formula (I) or a salt thereof and the radioisotope in a suitable solvent system (such as those specifically described herein).

[0074] In certain embodiments, the formulations disclosed herein include a buffer solution. In some embodiments, the buffer solution is a phosphate buffer solution, meaning that the formulation contains both phosphate ions and copper ions in solution. The inventors have recognized that copper phosphate salts readily form and subsequently precipitate, which is undesirable for any pharmaceutically acceptable formulation and product. The formulations disclosed herein include a copper radioisotope that provides a radiotherapeutic effect. In certain embodiments, the formulations disclosed herein include a buffer solution, and in specific embodiments, the buffer solution is a phosphate buffer solution, which is known to be a physiologically acceptable component. While formulations containing both copper ions and phosphate ions have a known potential for forming insoluble precipitates, the inventors have unexpectedly found that formulations containing both of these components disclosed herein do not result in the undesirable (and harmful) precipitation of copper salts. The inventors have also recognized that the formation of metal salts, such as copper phosphate salts, is also dependent on the pH of the formulation, and that factors such as pH, temperature, and ion concentration in the solution must be carefully considered to avoid or prevent the undesirable formation of metal salts. With the knowledge that copper phosphate salts can form in the physiologically relevant pH range, the inventors have unexpectedly found that the formulations disclosed herein, which contain both copper ions and phosphate ions in solution at physiological pH, do not form copper phosphate salts and are therefore pharmaceutically acceptable for administration to a subject.

[0075] In some embodiments, the formulation is an aqueous formulation and the pharmaceutically acceptable carrier is saline containing a phosphate buffer, hi a preferred embodiment, the pharmaceutically acceptable carrier is sodium phosphate buffer.

[0076] The formulations of the present invention are intended for administration to a subject in need thereof and therefore have a pharmaceutically and physiologically acceptable pH to ensure the stability of the formulation's components and the safety of the subject. In certain embodiments, the formulations of the present invention have a pH of about 4 to about 8. In some embodiments, the pH of the formulation is about 4. In other embodiments, the pH of the formulation is about 5. In other embodiments, the pH of the formulation is about 6. In other embodiments, the pH of the formulation is about 7. In other embodiments, the pH of the formulation is about 8. In some embodiments, the pH of the formulation can range between the pH values ​​disclosed herein. In some embodiments, the pH of the formulation is due to the chemical properties of the components present in the formulation. In other embodiments, the pH of the formulation is due to the use of one or more buffers present in the formulation. In certain embodiments, the formulations disclosed herein include a buffer solution that maintains the formulation at a specific pH or range. In some embodiments, the buffer solution present in the formulation not only contributes to determining and maintaining the pH of the formulation, but also helps ensure the stability of one or more components of the formulation. In some embodiments, one or more components involved in ensuring the pH of the formulation may also stabilize the formulation and prevent radiolysis of a conjugate containing a radioisotope.

[0077] In one embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 4% to about 12% (w / v). In one embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 4% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 4.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 5.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 6% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 6.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 7% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 7.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 8% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 8.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 9% (w / v). In another embodiment, a formulation of the present invention comprises one or more stabilizers in a total amount of about 9.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 10% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 10.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 11% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 11.5% (w / v). In another embodiment, an aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 12% (w / v). In other embodiments, the present invention also contemplates one or more stabilizers being present in amounts ranging between those stated above.

[0078] In one embodiment, 67Aqueous formulations containing a compound of Formula (I) or its salt complexed with Cu contain gentisic acid or its salt as a stabilizer. Gentisic acid is also known as 2,5-dihydroxybenzoic acid, 5-hydroxysalicylic acid, or hydroquinonecarboxylic acid. Salts of gentisic acid can include the sodium salt and sodium salt hydrate. Any reference to gentisic acid can also include a reference to its salts, if relevant. As noted above, the pH of the formulations disclosed herein is about 4 to about 8. Because the pKa (i.e., acid dissociation constant) of gentisic acid is about 2.5, the gentisic acid present in the formulations disclosed herein is in its dissociated form, i.e., as gentisate. While not wishing to be bound by theory, the inventors believe that the use of either the free acid (i.e., gentisic acid) or the corresponding acid does not result in any difference in the materials in the formulation.

[0079] In some embodiments, gentisic acid or its salt is present in the formulation in an amount of about 0.01% to about 0.1% (w / v). In some embodiments, gentisic acid or its salt is present in the formulation in an amount of about 0.01% (w / v). In some embodiments, gentisic acid or its salt is present in the formulation in an amount of about 0.015% (w / v). In some embodiments, gentisic acid or its salt is present in the formulation in an amount of about 0.02% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.025% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.03% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.035% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.04% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.045% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.05% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.055% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.6% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.065% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.07% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.075% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.08% (w / v). In another embodiment, gentisic acid or a salt thereof is present in the formulation in an amount of about 0.085% (w / v). In another embodiment, gentisic acid or a salt thereof is present in the formulation in an amount of about 0.09% (w / v). In another embodiment, gentisic acid or a salt thereof is present in the formulation in an amount of about 0.095% (w / v). In another embodiment, gentisic acid or a salt thereof is present in the formulation in an amount of about 0.1% (w / v). In other embodiments, the present invention also contemplates gentisic acid or a salt thereof within the ranges between the aforementioned amounts.In a preferred embodiment, gentisic acid or a salt thereof is present in the formulation in an amount of about 0.03% to about 0.04% (w / v).

[0080] Ascorbic acid or its salts are also present in aqueous formulations as a stabilizer. Ascorbic acid is also known as L-ascorbic acid or vitamin C. Salts of ascorbic acid include sodium ascorbate, calcium ascorbate, potassium ascorbate, and sodium ascorbyl phosphate. Derivatives of ascorbic acid are also contemplated. These include fatty acid esters of ascorbic acid, such as palmitic acid esters of ascorbic acid, i.e., ascorbyl palmitate.

[0081] In one embodiment, ascorbic acid or its salt is present in an amount of about 4.0% to about 10.0% (w / v). In one embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 4.0% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 4.5% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 5.0% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 5.5% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 6.0% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 6.5% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 7.0% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 7.5% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 8.0% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 8.5% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 9.0% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 9.5% (w / v). In another embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 10.0% (w / v). In other embodiments, the present invention also contemplates ascorbic acid or its salt within the above-mentioned amounts. In a preferred embodiment, ascorbic acid or its salt is present in the formulation in an amount of about 6.5% to about 8% (w / v).

[0082] L-methionine or its salts can also be used as a stabilizer. As used herein, the term L-methionine refers to an amino acid having an S-methylthioether side chain. The addition of L-methionine to the formulations of the present invention can further improve the stability of the formulation by preventing or minimizing the radiolysis of the radiolabeled complex of Formula (I), thereby increasing the radiochemical purity of the formulation.

[0083] The aqueous formulation of the present invention also contains ethanol as a component. The ethanol used in the formulation may be absolute ethanol. Alternatively, the ethanol used in the aqueous formulation may not have undergone a drying process and may be hydrated. In certain embodiments, the ethanol is aqueous ethanol. The ethanol is preferably pharmaceutical-grade ethanol. The ethanol present in the formulation may further help prevent radiolysis of the radiolabeled complex of formula (I).

[0084] In one embodiment, ethanol is present in the aqueous formulation in an amount of about 1% to about 7% (v / v). In one embodiment, ethanol is present in the formulation in an amount of about 1% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 1.5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 2% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 2.5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 3% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 3.5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 4% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 4.5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 5.5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 6% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 6.5% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 7% (v / v). In a preferred embodiment, ethanol is present in the formulation in an amount of about 4% (v / v). In other embodiments, the present invention also contemplates ethanol in ranges between the aforementioned amounts.

[0085] The formulation of the present invention may also contain sodium chloride as a component. The sodium chloride in the formulation of the present invention may be provided as saline. Saline is defined as an aqueous solution of sodium chloride. For example, normal saline is defined as an aqueous solution of sodium chloride at a concentration of 0.9% (w / v). In some embodiments of the present invention, the sodium chloride in the formulation is provided by saline.

[0086] The formulations of the present invention have a pH of about 4 to about 8. One skilled in the art will appreciate that the pH of the formulation is an inherent characteristic of the formulation resulting from the combination of the compound of formula (I) or its conjugate with the remaining excipients of the formulation. The inventors have found that this pH range results in optimal radiolabeling efficiency.

[0087] In one embodiment, the pH of the formulation is about 4 to about 8. In one embodiment, the pH of the formulation is about 4. In another embodiment, the pH of the formulation is about 4.5. In another embodiment, the pH of the formulation is about 5.0. In one embodiment, the pH of the formulation is about 5.5. In another embodiment, the pH of the formulation is about 5.6. In another embodiment, the pH of the formulation is about 5.7. In another embodiment, the pH of the formulation is about 5.8. In another embodiment, the pH of the formulation is about 5.9. In another embodiment, the pH of the formulation is about 6.0. In another embodiment, the pH of the formulation is about 6.1. In another embodiment, the pH of the formulation is about 6.2. In another embodiment, the pH of the formulation is about 6.3. In another embodiment, the pH of the formulation is about 6.4. In another embodiment, the pH of the formulation is about 6.5. In another embodiment, the pH of the formulation is about 7.0. In another embodiment, the pH of the formulation is about 7.5. In another embodiment, the pH of the formulation is about 8.0. In a preferred embodiment, the pH of the formulation is about 6.0.

[0088] Without wishing to be bound by theory, the inventors believe that the stability of the formulations disclosed herein comprising a radiolabeled conjugate of a compound of formula (I), gentisic acid or a salt thereof, ethanol, and ascorbic acid or a salt thereof is a result of the combination of these components, and that omission of one or more of these components results in a formulation with much lower stability. Furthermore, the inventors also believe that the use of each listed component results in the prevention and minimization of any radiolysis of the radiolabeled conjugate, and that the components of the formulation 67 It is believed that this prevents the decay of the ligand containing the Cu radioisotope, allowing the radiotherapeutic compound, i.e., to remain intact and therefore therapeutically effective for a longer period of time. 67 The compound of formula (I) is provided in a complex with Cu, thereby increasing the efficiency of a given dose administered to a subject. This also means that the costs involved in preparing and treating a subject with the formulations disclosed herein are reduced, as more of the therapeutically active compound is available for treatment over a longer period of time.

[0089] In one embodiment, the aqueous formulation of the present invention comprises: 67 In one embodiment, the aqueous formulation of the present invention comprises a compound of formula (I) or a salt thereof complexed with Cu ions, about 4% (v / v) ethanol, about 6.5 to about 8% (w / v) ascorbic acid, and about 0.03 to about 0.04% (w / v) gentisic acid or a salt thereof, and has a pH of about 6.0. 67 In a further embodiment, the aqueous formulation of the present invention comprises a compound of formula (I) or a salt thereof complexed with Cu ions, about 4% (v / v) ethanol, about 6.5 to about 8% (w / v) ascorbic acid, and about 0.06% (w / v) or less of gentisic acid or a salt thereof, wherein the formulation has a pH of about 6.0. 67 The formulation comprises a compound of formula (I) or a salt thereof complexed with Cu ions, about 4% ethanol, about 6.5 to about 8% ascorbic acid, and about 0.035% gentisic acid or a salt thereof, and has a pH of about 6.0.

[0090] Therefore, the present invention provides 67 1. An aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions: [ka] During the ceremony, X is [ka] where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 A radical of a group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and formula (A): [ka] Buffer solution and: about 1% to about 7% (v / v) ethanol; about 4% to about 10% (w / v) ascorbic acid or a salt thereof; and About 0.01% to about 0.1% (w / v) of gentisic acid or a salt thereof further including; An aqueous formulation having a pH of about 4 to about 8 is provided.

[0091] According to the present invention, 67 The preparation of the complex of Cu and the compound of formula (I) or a salt thereof may have a radiochemical purity of at least 90% for a period of at least 96 hours. 67 This means that at least about 90% of the Cu radioisotope is complexed with the compound of formula (I) or a salt thereof for at least 96 hours after preparation of the formulation. 67 When the Cu radioisotope is not complexed with the compound of formula (I) or a salt thereof, 67 The Cu radioisotope is free 67 It may be present as Cu ions or as part of the radiolysis products.

[0092] In one embodiment, 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 90% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 91% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 92% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 93% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 94% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 95% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 96% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 97% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 98% at about 96 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 99% at about 96 hours after preparation of the formulation.

[0093] In one embodiment, 67The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% immediately after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 94% about 1 hour after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 3 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 6 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 9 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 94% about 12 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 15 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 94% about 18 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 21 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 24 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of Formula (I) or a salt thereof is about 94% about 48 hours after preparation of the formulation. 67 The radiochemical purity of a formulation of the present invention comprising a complex of Cu and a compound of formula (I) or a salt thereof is about 94% about 72 hours after preparation of the formulation.

[0094] Preparation of aqueous formulations of the present invention 67 The compound of formula (I) or a salt thereof complexed with Cu ions can be prepared by reacting the compound of formula (I) or a salt thereof in the presence of a buffer and one or more stabilizers. 67 This can be achieved by mixing the solution with a solution of Cu ions, then filtering the solution, followed by diluting the reactants to give: 67 A formulation may be provided comprising a compound of formula (I) or a salt thereof complexed with Cu ions. In one embodiment, the stabilizer is gentisic acid or a salt thereof. In one embodiment, a formulation comprising a compound of formula (I) and a salt thereof complexed with Cu ions may be provided. 67 The reaction between Cu ions is diluted in an aqueous ethanol solution containing ascorbic acid or its salts.

[0095] Therefore, the present invention provides 67 1. A process for preparing an aqueous formulation comprising a compound of formula (I) complexed with Cu ions, comprising: i) dissolving a compound of formula (I) or a salt thereof in a buffer solution containing gentisic acid or a salt thereof; ii) 67 adding a solution of Cu ions to the solution of step i); iii) filtering the solution obtained from step ii); iv) diluting the reaction by addition of aqueous ethanol and ascorbic acid; 67 and recovering the aqueous formulation comprising the compound of formula (I) or a salt thereof complexed with Cu ions.

[0096] The buffer solution may be a solution of ammonium acetate. Alternatively, the buffer solution may be a solution of sodium acetate. In a preferred embodiment, the buffer solution is a sodium phosphate buffer.

[0097] In certain embodiments, the buffer solution comprises phosphate ions. In some embodiments, the buffer solution comprises a sodium phosphate salt. In other embodiments, the buffer solution comprises one or more sodium phosphate salts. In some embodiments, the buffer solution comprises two or more sodium phosphate salts. In some embodiments, the buffer solution comprises dibasic sodium phosphate. In other embodiments, the buffer solution comprises monobasic sodium phosphate. In some embodiments, the buffer solution comprises dibasic sodium phosphate and another phosphate salt. In some embodiments, the buffer solution comprises monobasic sodium phosphate and another phosphate salt. In other embodiments, the buffer solution comprises dibasic sodium phosphate and monobasic sodium phosphate. In some embodiments, the pH of the buffer solution is about 6. In other embodiments, the pH of the buffer solution is about 6.5. In other embodiments, the pH of the buffer solution is about 7.

[0098] The inventors understand that the combination of copper cations with phosphate anions typically results in the formation of an insoluble phosphate salt of copper. The inventors have unexpectedly found that in the process for preparing the formulations defined herein, 67 Cu radioisotope (Cu 2+ It has been shown that when a compound of formula (I) (present as a cation) is introduced into a solution containing a phosphate buffer, insolubility and salt formation are not observed. Without wishing to be bound by theory, the present inventors believe that the 67 It is believed that at least some combination of characteristics (eg, temperature, concentration, etc.) have been found that allow for successful incorporation of Cu radioisotopes.

[0099] The buffer solution also contains gentisic acid or a salt thereof as a component. As mentioned above, the salt of gentisic acid can include the sodium salt or sodium salt hydrate. Other salts of gentisic acid are also contemplated. The buffer solution can contain sodium gentisate at a concentration of about 0.01 to about 0.1% (w / v). In one embodiment, the buffer solution contains sodium gentisate at a concentration of about 0.01% (w / v). In another embodiment, the buffer solution contains sodium gentisate at a concentration of about 0.015% (w / v). In another embodiment, the buffer solution contains sodium gentisate at a concentration of about 0.02% (w / v). In another embodiment, the buffer solution contains sodium gentisate at a concentration of about 0.025% (w / v). In another embodiment, the buffer solution contains sodium gentisate at a concentration of about 0.03% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.035% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.04% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.045% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.05% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.055% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.06% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.065% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.07% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.075% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.08% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.085% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.095% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.1% (w / v).In a preferred embodiment, the buffer solution contains sodium gentisate at a concentration of about 0.035% to 0.04% (w / v).

[0100] Then, a compound of formula (I) 67 The reactant between Cu ions is diluted in an aqueous ethanol solution. As previously mentioned, the ethanol may be anhydrous or may have been previously subjected to drying procedures known in the art. The solution may contain ethanol at a concentration of about 1 to about 7% (v / v). In one embodiment, the solution contains ethanol at a concentration of about 1% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 1.5% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 2% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 2.5% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 3% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 3.5% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 4% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 4.5% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 5% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 5.5% (v / v). In another embodiment, the solution contains ethanol at a concentration of about 6% (v / v). In another embodiment, the buffer solution contains ethanol at a concentration of about 6.5% (v / v). In another embodiment, the buffer solution contains ethanol at a concentration of about 7% (v / v). In a preferred embodiment, the buffer solution contains ethanol at a concentration of about 4% (v / v).

[0101] As described above, the aqueous ethanol solution further comprises ascorbic acid or a salt thereof. Ascorbic acid is also known as L-ascorbic acid or vitamin C. Salts of ascorbic acid include sodium ascorbate, calcium ascorbate, potassium ascorbate, and sodium ascorbyl phosphate. Derivatives of ascorbic acid are also contemplated. These include fatty acid esters of ascorbic acid, such as palmitate esters of ascorbic acid, i.e., ascorbyl palmitate. In one embodiment, the ascorbic acid or a salt thereof is present in an amount of about 4.0% to about 10.0% (w / v). In one embodiment, the ascorbic acid or a salt thereof is present in the solution in an amount of about 4.0% (w / v). In another embodiment, the ascorbic acid or a salt thereof is present in the solution in an amount of about 4.5% (w / v). In another embodiment, the ascorbic acid or a salt thereof is present in the solution in an amount of about 5.0% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 5.5% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 6.0% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 6.5% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 7.0% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 7.5% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 8.0% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 8.5% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 9.0% (w / v). In another embodiment, the ascorbic acid or its salt is present in the solution in an amount of about 9.5% (w / v). In another embodiment, the ascorbic acid or salt thereof is present in the solution in an amount of about 10.0% (w / v). In a preferred embodiment, the ascorbic acid or salt thereof is present in the solution in an amount of about 6.5% to about 8% (w / v).

[0102] According to one embodiment of the present invention, the compound of formula (I) or its salt is mixed in a sodium phosphate buffer solution containing gentisic acid or its salt. The compound of formula (I) or its salt may be obtained as a solid. In one embodiment, the compound of formula (I) or its salt is obtained as a lyophilized powder. In one embodiment, the compound of formula (I) or its salt obtained as a lyophilized powder is mixed with a sodium phosphate buffer solution containing gentisic acid or its salt. In one embodiment, about 80 μg to about 160 μg of the compound of formula (I) or its salt as a lyophilized powder is mixed with a sodium phosphate buffer solution containing gentisic acid or its salt.

[0103] A mixture of a compound of formula (I) or a salt thereof and a sodium phosphate buffer solution containing gentisic acid or a salt thereof 67 A Cu ion solution is added and allowed to stand for a period of time.

[0104] In one embodiment, 67 A solution of Cu ions is 67 In another embodiment, the solution is a solution of Cu salt. 67 The solution of Cu ions is a solution of a chloride salt containing copper. 67 The solution of Cu ions is 67 Cu]CuCl2 solution.

[0105] 67 The solution of Cu ions is provided as an aqueous solution. 67 The Cu ions may be provided in an aqueous hydrochloric acid solution. 67 The Cu ions are provided in a solution of about 0.01 to about 0.1 mol / L hydrochloric acid. 67 The Cu ions are provided in a solution of about 0.01 mol / L hydrochloric acid. 67 The Cu ions are provided in a solution of about 0.02 mol / L hydrochloric acid. 67 The Cu ions are provided in a solution of about 0.05 mol / L hydrochloric acid. 67The Cu ions are provided in a solution of about 0.075 mol / L hydrochloric acid. 67 The Cu ions are provided in a solution of about 0.1 mol / L hydrochloric acid. 67 Cu ions are dissolved in a solution of approximately 0.05 mol / L hydrochloric acid [ 67 Cu]CuCl2.

[0106] 67 The solution of Cu radioisotope is provided as an aqueous solution having a radioactivity of about 1,000 to about 100,000 MBq. 67 The radioactivity of the Cu radioisotope is about 1,000 MBq. 67 The radioactivity of the Cu radioisotope is about 5,000 MBq. 67 The radioactivity of the Cu radioisotope is about 10,000 MBq. 67 The radioactivity of the Cu radioisotope is about 15,000 MBq. 67 The radioactivity of the Cu radioisotope is about 20,000 MBq. 67 The radioactivity of the Cu radioisotope is about 25,000 MBq. 67 The radioactivity of the Cu radioisotope is about 30,000 MBq. 67 The radioactivity of the Cu radioisotope is about 35,000 MBq. 67 The radioactivity of the Cu radioisotope is about 40,000 MBq. 67 The radioactivity of the Cu radioisotope is about 45,000 MBq. 67 The radioactivity of the Cu radioisotope is about 50,000 MBq. 67 The radioactivity of the Cu radioisotope is about 55,000 MBq. 67 The radioactivity of the Cu radioisotope is about 60,000 MBq. 67 The radioactivity of the Cu radioisotope is about 65,000 MBq. 67The radioactivity of the Cu radioisotope is about 70,000 MBq. 67 The radioactivity of the Cu radioisotope is about 75,000 MBq. 67 The radioactivity of the Cu radioisotope is about 80,000 MBq. 67 The radioactivity of the Cu radioisotope is about 85,000 MBq. 67 The radioactivity of the Cu radioisotope is about 90,000 MBq. 67 The radioactivity of the Cu radioisotope is about 95,000 MBq. 67 The radioactivity of the Cu radioisotope is approximately 100,000 MBq.

[0107] 67 A mixture of Cu ions, a compound of formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof may be allowed to stand at room temperature. The mixture may be allowed to stand with or without stirring. The mixture may be allowed to stand for about 5 to about 25 minutes. In one embodiment, 67 A mixture of Cu ions, a compound of formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for about 5 minutes without stirring. 67 A mixture of Cu ions, a compound of formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for about 10 minutes without stirring. 67 A mixture of Cu ions, a compound of formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for about 15 minutes without stirring. 67 A mixture of Cu ions, a compound of formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for about 20 minutes without stirring. 67 A mixture of Cu ions, a compound of formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for about 25 minutes without stirring. 67In another preferred embodiment, the mixture of Cu ions, the compound of formula (I) or a salt thereof, and the sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for less than 25 minutes without stirring. 67 A mixture of a Cu radioisotope, a compound of Formula (I) or a salt thereof, and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is allowed to stand for about 25 minutes without stirring. 67 The mixture of Cu ions and a compound of Formula (I) or a salt thereof is allowed to stand at room temperature, which is defined as ambient temperature according to the USP. In certain embodiments, the ambient temperature is about 15°C to about 25°C.

[0108] According to another embodiment of the present invention, 67 A mixture of Cu ions, a compound of formula (I) or its salt, and a sodium phosphate buffer solution containing gentisic acid or its salt is filtered. The mixture can be filtered by a solid-phase extraction process. The mixture can be filtered through a solid-phase extraction process, with the stationary phase of the solid-phase extraction cartridge retaining the compound of formula (I) or its salt complexed with Cu ions, any uncomplexed compound of formula (I) or its salt, and any gentisic acid present in salt form, such as sodium gentisate. As used herein, the term "stationary phase" refers to a resin-like material retained within the solid-phase extraction cartridge and enabling separation of compounds based on their polarity.

[0109] The solid-phase extraction process described herein may use a reversed-phase stationary phase. As used herein, the term "reverse-phase" in relation to a stationary phase refers to a stationary phase that is hydrophobic in nature, such that the stationary phase has an affinity for hydrophobic or uncharged molecules. Examples of reversed-phase stationary phases may include Phenomenex Strata-X 33u Polymeric Reversed Phase, Waters tC18, or Waters C18. Other similar stationary phases may also be used. Because the solid-phase extraction process uses a reversed-phase stationary phase, free 67The Cu ions and remaining gentisic acid or its salts are not retained by the stationary phase and these components are discarded.

[0110] In one embodiment, 67 A mixture of Cu ions, a compound of formula (I), and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is filtered through a solid-phase extraction cartridge. In one embodiment, a mixture of Cu ions, a compound of formula (I), and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is filtered through a solid-phase extraction cartridge having a reversed-phase stationary phase. In one embodiment, 67 The compound of formula (I) complexed with Cu ions is retained by a solid phase extraction cartridge having a reversed phase stationary phase. In a preferred embodiment, 67 A mixture of Cu radioisotope, the compound of formula (I), and a sodium phosphate buffer solution containing gentisic acid or a salt thereof is filtered through a solid phase extraction cartridge having a reversed phase stationary phase. 67 The compound of formula (I) complexed with Cu ions is retained by a solid phase extraction cartridge having a reversed phase stationary phase.

[0111] 67 The compound of formula (I) complexed with Cu ions is eluted from the solid phase extraction cartridge containing the stationary phase by washing with a solvent. Since the solid phase extraction cartridge contains a reversed phase stationary phase, 67 To elute the compound of formula (I) complexed with Cu ions, the stationary phase must be washed with ethanol, saline, and / or another solvent. In one embodiment, the solid phase extraction cartridge is washed with ethanol, 67 The compound of formula (I) complexed with Cu ions is eluted. In another embodiment, the solid phase extraction cartridge is washed with saline; 67 The compound of formula (I) complexed with Cu ions is eluted. In another embodiment, the solid phase extraction cartridge is washed with ethanol and saline; 67The compound of formula (I) complexed with Cu ions is eluted. In a preferred embodiment, the solid phase extraction cartridge is washed with ethanol and contains ascorbic acid. 67 The compound of formula (I) complexed with Cu ions is eluted. In a preferred embodiment, the solid phase extraction cartridge is washed with ethanol containing ascorbic acid to provide the formulation of the present invention.

[0112] Those skilled in the art will appreciate that formulation excipients may be used to 67 It will be understood that this includes the solvents used to elute the compound of formula (I) complexed with Cu ions, and that the amount of each solvent used is related to the amount of each excipient in the formulation of the present invention.

[0113] Those skilled in the art will appreciate that the present disclosure provides a manual process for producing formulations according to the present invention. Those skilled in the art will appreciate that the steps described herein can be automated by using a suitable automated radiosynthesis module to obtain formulations according to the present invention.

[0114] The inventors have found that the formulations disclosed herein have greater stability and exhibit reduced radiolysis in light of higher starting radioactivity. This improved stability can be attributed to increased radiochemical purity of the formulation at a given radioactivity. The stability of the formulations of the present invention can be observed for up to 96 hours after manufacture. When the formulations of the present invention are used for treatment or therapy, the greater stability can mean that doses for multiple patients in multiple remote locations can be prepared simultaneously at a single facility. This can mean that manufacturing resources are required at a single facility rather than multiple facilities, and greater efficiency in the production of the formulation can be achieved. When the formulations of the present invention are used for imaging purposes, an additional advantage can be achieved because clinical imaging sites can receive ready-to-inject dosage forms. This can be particularly advantageous for clinical settings that do not have dedicated radiopharmaceutical production facilities.

[0115] The formulation of the present invention comprises a ligand-radioisotope complex, wherein the ligand is a compound of formula (I) or a salt thereof. The compound of formula (I) or a salt thereof and the radioisotope may be provided in separate containers. Alternatively, the compound of formula (I) or a salt thereof and the radioisotope may be provided together as a ligand-radioisotope complex.

[0116] A container comprising the compound of formula (I) or a salt thereof may provide the compound of formula (I) or a salt thereof as a lyophilized powder. The container may be provided at a temperature of -20°C to 20°C.

[0117] The formulation is 67 The present invention may be provided as a kit comprising a container of Cu radioisotope and another container containing the ligand and instructions for making the aqueous formulation of the present invention. 67 The container for providing a solution of a Cu radioisotope and another container for providing a compound of formula (I) or a salt thereof. The container for providing the radioisotope contains: 67 It may contain a solution of Cu salts.

[0118] In one embodiment, the kit of the invention comprises: 67 In another embodiment, the kit of the present invention comprises: 67 In another embodiment, the kit of the present invention comprises: 67 In another embodiment, the kit of the present invention comprises a container containing a solution of a chloride salt containing a Cu radioisotope. In another embodiment, the kit of the present invention comprises a container containing a solution of a radioactive copper(II) chloride salt, wherein the copper ions are 67 In another embodiment, the kit of the present invention comprises: 67 Cu]CuCl2 solution.

[0119] The solution of the radioisotope is typically provided as an aqueous solution. In one embodiment, the kit of the present invention provides the radioisotope in the form of an aqueous solution. In a further embodiment, the kit of the present invention provides the radioisotope in the form of an acidic aqueous solution. In another embodiment, the kit of the present invention provides the radioisotope as a hydrochloric acid solution. The radioisotope may be provided as a hydrochloric acid solution having a concentration of about 0.01 to about 0.1 mol / L.

[0120] In one embodiment, the kit of the present invention comprises: 67 In another embodiment, the kit of the present invention comprises a container containing a solution of [Cu]CuCl in hydrochloric acid. 67 In another embodiment, the kit of the present invention comprises a container containing a solution of [Cu]CuCl in hydrochloric acid, wherein the hydrochloric acid has a concentration of about 0.02 mol / L. 67 In another embodiment, the kit of the present invention comprises a container containing a solution of [Cu]CuCl in hydrochloric acid, wherein the hydrochloric acid has a concentration of about 0.05 mol / L. 67 Cu]CuCl2 in a hydrochloric acid solution, the hydrochloric acid having a concentration of about 0.1 mol / L.

[0121] The kit may further comprise a container containing sodium phosphate buffer, ethanol, gentisic acid or a salt thereof, and ascorbic acid or a salt thereof. The kit may comprise a container containing sodium phosphate buffer and gentisic acid in aqueous solution, and a second container containing a solution of aqueous ethanol and ascorbic acid or a salt thereof, or the container may consist solely of ethanol, ascorbic acid or a salt thereof, and gentisic acid or a salt thereof. In some embodiments, the kit comprises a container containing sodium phosphate buffer and gentisic acid or a salt thereof, and a second container containing aqueous ethanol and ascorbic acid or a salt thereof.

[0122] Uses of the formulations of the present invention The preparation of the present invention can be particularly useful for medical diagnosis and treatment purposes.The complex of the ligand with the appropriate targeting fragment can be used to locate specific tissue types.In order for such a complex to be considered suitable for use in in vivo diagnosis and treatment, the complex must exhibit the necessary solubility and stability properties of the complex in solution, as well as appropriate kinetic, stability and clearance properties under physiological conditions.As used herein, the term "complex" can refer to a ligand-metal ion complex in which the metal ion is a radioisotope, or alternatively, the metal ion is a non-radioisotope.

[0123] The present inventors have found that formulations of the present invention, comprising a compound of formula (I) or a salt thereof containing sarcofagin, a bombesin-like peptide, a propylamide linker, and a linker containing a PEG group, exhibit affinity for the GRP receptor. The combination of each of these components in a compound of formula (I) allows for the administration of the corresponding conjugate containing a radionuclide while maintaining the stability of the conjugate in vivo and its accumulation at the intended target.

[0124] 67 The formulation of the present invention, comprising a compound of formula (I) complexed with a Cu radionuclide, can be used in radioimaging, diagnosis, or treatment methods. Thus, the present invention provides a method for radioimaging, a method for diagnosing a disease in a subject, or a method for treating a disease in a subject, comprising administering to the subject an effective amount of the formulation as defined herein. The inventors have found that the formulation of the present invention can be used in a method for radioimaging cancer, a method for diagnosing cancer, or a method for treating cancer.

[0125] of formula (I) 67 Radioimaging of a subject to which a Cu radiolabeled compound is administered can be by positron emission tomography (PET) or single photon emission computed tomography (SPECT). In an embodiment, the present invention provides a method for radioimaging a subject in need thereof, comprising: 67The present invention provides a method for treating cancer in a subject in need thereof, comprising administering a formulation of the present invention comprising a compound of formula (I) or a salt thereof complexed with a Cu radionuclide, the method comprising: 67 administering an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions: [ka] During the ceremony, X is [ka] where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO, NH, optionally substituted C-C 12 A group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): [ka] The formulation may be a buffer solution: about 0.01% to about 0.1% (w / v) gentisic acid or a salt thereof; about 1% to about 7% (v / v) ethanol; and About 4% to about 10% (w / v) ascorbic acid or its salt The present invention relates to a method, further comprising:

[0126] In certain embodiments of the methods disclosed herein, R is a group of formula (A): [ka] wherein X is as defined above, for example with the following stereochemistry: [ka]

[0127] In certain embodiments of the methods disclosed herein, R is an optionally substituted C1-C 12 It is alkyl.

[0128] In a further embodiment, R is methyl.

[0129] In a further embodiment of the methods disclosed herein, X is [ka] where n is an integer from 1 to 10.

[0130] In a further embodiment, X is [ka] and n is 4.

[0131] In certain embodiments, the method for treating cancer further comprises the step of radioimaging the subject.In certain embodiments, the radioimaging of the subject is performed about 12 hours after the aqueous formulation is administered.In other embodiments, the radioimaging of the subject is performed about 24 hours after the aqueous formulation is administered.In other embodiments, the radioimaging of the subject is performed about 36 hours after the aqueous formulation is administered.In other embodiments, the radioimaging of the subject is performed about 48 hours after the aqueous formulation is administered.

[0132] In one embodiment, radioimaging of a subject after administration of a radionuclide-complexed compound of Formula (I) or a salt thereof is by PET. In another embodiment, radioimaging of a subject after administration of a radionuclide-complexed compound of Formula (I) or a salt thereof is by SPECT. The formulation of the present invention can be administered to a subject in need thereof by parenteral route as a composition. Administration by intravenous injection may be preferred. Alternatively, the formulation of the present invention can be given by intra-arterial or other route for delivery to the systemic circulation. The subject to which the compound is administered is then placed in a PET (or SPECT) scanner to obtain an image showing the localization of the complex and the subsequent location of any cancer or tumor. This allows for the diagnosis and detection of cancer or tumor.

[0133] The formulations of the present invention can be used in methods for treating diseases such as cancer. The methods disclosed herein comprise administering to a subject in need thereof: 67 The present invention includes administering an effective amount of a formulation as defined herein, comprising a compound of formula (I) or a salt thereof complexed with a Cu radionuclide. The compound contains a bombesin-like peptide that binds to the GRP receptor, which is expressed at various cancer sites. Given that the abundance of such receptors is associated with certain types of cancer, the accumulation of the compounds of the present invention, detected by radioactive decay of the radionuclide, indicates the location of the cancer. The inventors have found that the compounds of the present invention exhibit specific affinity for the GRP receptor. Furthermore, the presence of both a propylamide linker and a linker containing a PEG group contributes to providing a conjugate (when the compound is radiolabeled with a radionuclide) that can be administered to a subject and subsequently localized at sites overexpressing the GRP receptor. The formulation of the present invention, comprising a compound of formula (I) or a salt thereof, can also be 67 It has the necessary stability for Cu radionuclides. For example, the sarcofazine present in the compound has the required stability upon administration to a subject and subsequent binding at the target site. 67 So that Cu remains coordinated 67 It is possible to chelate Cu. 67 Because Cu remains coordinated and localized at the target site through binding of the whole compound, radiation damage at other sites (e.g., healthy tissue) is minimized.

[0134] As used herein, the term "cancer" broadly encompasses a class of neoplastic diseases characterized by abnormal cell growth that has the potential to invade or spread to other parts of the body. In one embodiment, the cancer is a cancer that expresses or overexpresses GRP receptors. These should be contrasted with benign tumors that do not spread to other parts of the body, and therefore, the definition as used herein includes all malignant (cancerous) disease states. Thus, this term encompasses the treatment of tumors.

[0135] Thus, the term "tumor" is used generally to define a malignant cancerous or precancerous cell growth and may include blood-based cancers, but is particularly directed to solid tumors or carcinomas, such as prostate cancer, breast cancer, glioma, gastrointestinal stromal tumor, melanoma, colon cancer, lung cancer, ovarian cancer, skin cancer, pancreatic cancer, pharyngeal cancer, brain cancer, CNS cancer, and renal cancer (as well as other cancers). In some embodiments, the tumor is associated with a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, urinary cancer, small cell lung cancer, glioblastoma, and gastrointestinal stromal tumor.

[0136] For a conjugate to be suitable for radioimaging purposes, the radioisotope-ligand conjugate must demonstrate sufficient metabolic stability, i.e., the conjugate remains intact for the required time period with respect to the radioisotope bound to the ligand. The present invention provides a compound of formula (I) or a salt thereof that remains intact for up to 96 hours, as evidenced by the absence of radioisotope loss and metabolic degradation. 67 Provides a complex with Cu.

[0137] In one embodiment, the present invention provides a method for radiological imaging of a tumor or cancer, comprising: 67Use of a formulation comprising a compound of Formula (I) or a salt thereof complexed with Cu is provided. One skilled in the art will appreciate that information obtained from radiological imaging of a subject can be used to diagnose a tumor or cancer in a subject. In certain embodiments, the present invention provides a method for diagnosing a tumor or cancer. In further embodiments, the tumor or cancer can be a tumor or cancer that expresses a GRP receptor. In certain embodiments, the tumor or cancer is prostate cancer. In another embodiment, the tumor or cancer is breast cancer. In another embodiment, the tumor or cancer is a glioma. In another embodiment, the tumor or cancer is a gastrointestinal stromal tumor. In another embodiment, the tumor or cancer is brain cancer. In another embodiment, the tumor or cancer is melanoma. In another embodiment, the tumor or cancer is lung cancer. In another embodiment, the tumor or cancer is colon cancer. In another embodiment, the tumor is a pancreatic tumor. In another embodiment, the tumor is a kidney tumor.

[0138] Administration of the formulation can treat tumors or cancer. As described above, the compound of formula (I) or its salt can bind to GRP receptors on the surface of tumor or cancer sites, and the binding of the compound to a site having a GRP receptor can also 67 A Cu radioisotope is placed in close proximity to this location. 67 Since the Cu radioisotope undergoes radioactive decay in a decay mode that depends on the exact radioisotope selected, the decay products are: a compound of formula (I) or a salt thereof; 67 The proximity of the tumor or cancer to the Cu radioisotope may be useful in treating the tumor or cancer.

[0139] In one embodiment, the present invention provides a method for treating a tumor or cancer, comprising: 67

[0013] Provided is the use of a formulation comprising a compound of Formula (I) or a salt thereof complexed with Cu. In one embodiment, the tumor or cancer can be a tumor or cancer that expresses a GRP receptor. In one embodiment, the tumor or cancer is prostate cancer. In another embodiment, the tumor or cancer is breast cancer. In another embodiment, the tumor or cancer is glioma. In another embodiment, the tumor or cancer is gastrointestinal stromal tumor. In another embodiment, the tumor or cancer is brain cancer. In another embodiment, the tumor or cancer is melanoma. In another embodiment, the tumor or cancer is lung cancer. In another embodiment, the tumor or cancer is colon cancer. In another embodiment, the tumor is a pancreatic tumor. In another embodiment, the tumor is a renal tumor.

[0140] Reference herein to any prior publication (or information derived therefrom) or any known matter is not, and should not be construed as, an acknowledgement or admission or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification pertains.

[0141] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to mean the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0142] Example Phosphate buffer for radiolabeling was prepared using dibasic sodium phosphate (anhydrous), monobasic sodium phosphate, and TraceSELECT water. All buffers were stored at room temperature between uses.

[0143] Copper-67( 67 Cu) was purchased from NorthStar Medical Radioisotopes. 67Cu]CuCl2 as a dry powder and reconstituted in TraceSELECT water with a starting activity of 13.68 GBq in a total volume of 0.24 mL.

[0144] Analysis of the formulations was performed by radio-HPLC and TLC using an Ascentis Express C18, 2.7 μm, 90 Å, 150 mm × 4.6 mm HPLC column with 0.1% trifluoroacetic acid in water (A) and 0.1% trifluoroacetic acid in acetonitrile (B) as the mobile phase, running a gradient from 15% B in A to 39% B in A over 12 minutes.

[0145] TLC was performed using silica gel 60 F with dimensions of 1 cm x 10 cm. 254 Aluminum-backed TLC plates were used with a mobile phase of 10 mM NaEDTA in 50 mM phosphate buffer.

[0146] HPLC-grade MeCN (Honeywell, lot number S1RA1H) and HPLC-grade trifluoroacetic acid (TFA, ReagentPlus, 99%, Sigma Aldrich), (+)-L-ascorbate sodium (Sigma Aldrich, >99%, lot number: BCBV4424), and gentisic acid sodium salt hydrate (Sigma Aldrich, >99%, lot number: MKCC2280) were used as received. All HPLC mobile phases were prepared before use, filtered (using a 0.45 μm aqueous or organic filter), and degassed by a combination of vacuum and 10 minutes of sonication. All ethanol used was 200 Proof USP ethanol. All syringes used were "B Braun Injekt-F."

[0147] The compound of formula (I), i.e., Sar-BBN, was obtained with a purity of greater than 95% from Auspep Clinical Peptides, Tullarmine VIC, Australia.

[0148] Example 1 67Preparation of a single dose formulation containing a compound of formula (Ib) complexed with Cu Sodium gentisate (10 mg) is dissolved in 0.1 M sodium phosphate buffer solution (14 mL) to obtain a first solution (Solution A). Then, 120 μg of the compound of formula (Ia) is dissolved in Solution A (14 mL) to obtain a reaction vial.

[0149] 67 The radioactivity of the Cu chloride solution is measured and the time is recorded. 67 The Cu chloride solution is added to the reaction vial containing the compound of formula (Ia) in solution and held at ambient temperature for 25 minutes.

[0150] A second solution (Solution B) is prepared by dissolving sodium ascorbate (2 g) in TraceSELECT water (12 mL) and ethanol (1.1 mL).

[0151] The contents of the reaction vial are then transferred to the final product vial through a sterile filter. Solution B is drawn up (4 mL) into a 10 mL syringe and used to rinse the reaction vial. The contents of the reaction vial are then transferred to the final product vial through a sterile filter before gently homogenizing the contents. The activity in the final product vial is assayed, and the EOS time and final product volume are recorded. The total final volume after QC sampling is approximately 27 mL.

[0152] The following Table 1 is prepared according to the above method: 67 Cu]. The quality control testing outline for aqueous formulations containing formula (Ib) is reproduced. [Table 1]

[0153] Stability of the formulation of the present invention In the aqueous formulation prepared as outlined above 67Cu] Product stability was monitored for up to 96 hours after end of synthesis (EOS) for three validation batches of formula (Ib). Radiochemical purity (RPC) did not fall below 94.0% during the study period. Figure 1 shows the radio-HPLC chromatogram 96 hours after EOS.

Claims

1. ６７ 1. An aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions, comprising: 【Chemical 1】 During the ceremony, X is 【Chemistry 2】 where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO ２ , N.H. ２ , optionally substituted C １ ~C １２ A group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): 【Chemistry 3】 Buffer: about 0.01% to about 0.1% (w / v) gentisic acid or a salt thereof; about 1% to about 7% (v / v) ethanol; and About 4% to about 10% (w / v) ascorbic acid or a salt thereof 10. The aqueous formulation, further comprising:

2. For the compound of formula (I) or the salt thereof, R is a group of formula (A): 【Chemistry 4】 wherein X is as defined in claim 1.

2. The aqueous formulation of claim 1.

3. The group of formula (A) has the following stereochemistry: 【Chemistry 5】 3. The aqueous formulation according to claim 2.

4. For the compound of formula (I) or the salt thereof, R is optionally substituted C １ ~C １２ 2. The aqueous formulation of claim 1, wherein the alkyl group is alkyl.

5. 5. The aqueous formulation of claim 4, wherein R is methyl.

6. For the compound of formula (I) or the salt thereof, X is 【Chemistry 6】 6. The aqueous preparation according to claim 1, wherein n is an integer from 1 to 10.

7. X is 【Chemistry 7】 7. The aqueous formulation according to claim 6, wherein n is 4.

8. The compound of formula (I) or the salt thereof is of formula (Ia): 【Chemistry 8】 or formula (Ib): 【Chemistry 9】 2. The aqueous formulation of claim 1, wherein the aqueous formulation is selected from the group consisting of:

9. 9. The aqueous formulation according to any one of claims 1 to 8, wherein the buffer is a sodium phosphate buffer.

10. about 0.03% to about 0.04% (w / v) gentisic acid or a salt thereof About 4% (v / v) ethanol; and About 6.5% to about 8% (w / v) ascorbic acid or a salt thereof 10. The aqueous formulation of claim 1, comprising:

11. 11. The aqueous formulation of claim 1, wherein the gentisate is sodium gentisate.

12. 12. The aqueous preparation according to claim 1, wherein the concentration of gentisic acid or a salt thereof is 0.04% (w / v) or less.

13. 13. The aqueous formulation of any one of claims 1 to 12, having a pH of from about 4 to about 8.

14. 14. The aqueous formulation of any one of claims 1 to 13, having a radiochemical purity of greater than about 90%, 92%, 94%, 96% or 98% for a period of at least 96 hours.

15. Free radicals in the formulation ６７ The amount of Cu present ６７ 15. The aqueous formulation of any one of claims 1 to 14, wherein the total amount of Cu is no more than about 5%, 4%, 3%, 2%, or 1%.

16. 16. The aqueous formulation of any one of claims 1 to 15, wherein the radioactivity concentration of the formulation is from about 0.1 GBq / mL to about 1.0 GBq / mL.

17. ６７ 1. A process for preparing an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions, comprising: i) dissolving a compound of formula (I) or a salt thereof in a buffer solution containing gentisic acid or a salt thereof; ii) ６７ adding a solution of Cu ions to the solution of step i); iii) filtering the solution obtained from step ii); iv) diluting the reaction by addition of aqueous ethanol and ascorbic acid; ６７ and recovering the aqueous formulation comprising the compound of formula (I) or a salt thereof complexed with Cu ions.

18. 18. The process of claim 17, wherein the buffer solution is a sodium phosphate buffer.

19. 19. The process of claim 17 or 18, wherein the gentisic acid or salt thereof is present in an amount of about 0.01% to about 0.1% (w / v), the aqueous ethanol is present in an amount of about 1% to about 7% (v / v), and the ascorbic acid or salt thereof is present in an amount of about 4% to about 10% (w / v).

20. 20. The process of any one of claims 17 to 19, wherein the gentisic acid or salt thereof is present in an amount of about 0.03% to about 0.04% (w / v), the aqueous ethanol is present in an amount of about 4% (v / v), and the ascorbic acid or salt thereof is present in an amount of about 6.5% to about 8% (w / v).

21. 21. An aqueous formulation prepared by the process of any one of claims 17 to 20.

22. ６７ 1. A kit for preparing an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions, comprising: a container containing a lyophilized compound of formula (I) or a salt thereof; 【Chemistry 10】 During the ceremony, X is 【Chemistry 11】 where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO ２ , N.H. ２ , optionally substituted C １ ~C １２ is a group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): 【Chemistry 12】 ６７ a vessel containing a solution of Cu ions; and instructions for preparing an aqueous formulation comprising adding sodium phosphate buffer, ethanol, gentisic acid or a salt thereof, and ascorbic acid or a salt thereof.

23. ６７ 1. A kit for preparing an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with Cu ions, comprising: a container containing a lyophilized compound of formula (I) or a salt thereof; 【Chemistry 13】 During the ceremony, X is 【Chemistry 14】 where n is an integer from 1 to 10; and R is H, OH, halogen, cyano, NO ２ , N.H. ２ , optionally substituted C １ ~C １２ is a group selected from the group consisting of alkyl, optionally substituted amino, optionally substituted amido, and optionally substituted aryl and a group of formula (A): 【Chemistry 15】 ６７ a vessel containing a solution of Cu ions; a container comprising a sodium phosphate buffer and gentisic acid or a salt thereof; a container comprising aqueous ethanol and ascorbic acid or a salt thereof; and instructions for preparing the aqueous formulation.

24. 17. A method for radioimaging, diagnosis or treatment of cancer, comprising administering to a subject in need thereof the aqueous formulation of any one of claims 1 to 16.

25. 25. The method of claim 24, wherein the cancer is associated with expression of a GRP receptor.

26. 26. The method of claim 24 or 25, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, urinary cancer, small cell lung cancer, glioblastoma, and gastrointestinal stromal tumor.

27. 27. The method of any one of claims 24 to 26, wherein the administered formulation contains a dose of radioactivity of about 1 GBq to about 20 GBq.

28. 28. The method of any one of claims 24 to 27, for the treatment of cancer, said method further comprising the step of radioimaging said subject.

Images