Formulations for radiotherapy and diagnostic imaging and their use in treatment, diagnosis and imaging of diseases

Abstract

The present invention relates to formulations of radiolabeled compounds for radiotherapy and diagnostic imaging. Specifically, the invention relates to an aqueous formulation of a 67Cu radiolabeled compound of formula (I), said aqueous formulation further comprising a buffer, gentisic acid, ethanol and ascorbic acid for radiotherapy and diagnostic imaging. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the preparation of radiolabeled compounds for use in radiotherapy and diagnostic imaging. Background Art

[0002] Radiolabeled compounds or ligands can be used as radiopharmaceuticals in applications such as radiotherapy or diagnostic imaging. Particularly useful are radiolabeled compounds that show some tendency to selectively target a specific site (e.g., a specific receptor) in vivo and subsequently deliver a radioisotope to the desired site of action. This requires that the ligand contain a component that complexes the radioisotope and an additional component that targets the desired site.

[0003] One of the known problems associated with such ligands is the premature dissociation of the radioisotope before the ligand-radioisotope complex reaches the site of action. This not only reduces the potency of the complex, but the loss of the radioisotope to areas not intended to produce a therapeutic effect can have adverse consequences.

[0004] Dissociation of the radioisotope from the ligand can occur due to transchelation, in which the radioisotope is transferred in vivo to another bioligand. Again, this results in a reduced therapeutic effect and also in the delivery of the radioisotope to areas not requiring treatment.

[0005] The ligand to be radiolabeled and the radioisotope are typically stored in separate containers and transported to the patient to minimize the above problems associated with dissociation prior to administration. The ligand can be transported as a lyophilized powder at a reduced temperature to extend the stability of the compound. Then, just prior to administration, the radioisotope can be combined with the ligand to form a radiopharmaceutical, which can be used to minimize the 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 cause radiolysis, or the destruction or partial destruction, of the ligand. When the radioisotope undergoes spontaneous decay and subsequently releases radiation, the energy can be sufficient to induce bond cleavage and result in the subsequent destruction of the ligand. In addition to a reduction in the potency of the radiopharmaceutical, the release of the radioisotope or fragments of the original drug product can also occur, resulting in the delivery of radiation to undesired sites.

[0007] Since many radiopharmaceuticals are designed for parenteral administration, i.e., non-oral administration, and are typically administered as solutions, 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. Although the solubility of a particular compound in a particular solvent may be known, the solubility of analogs of that compound in different solvent systems can be quite different. This then poses a difficulty for those seeking to develop formulations of compounds and especially pharmaceutically acceptable injectable formulations.

[0008] Pharmaceutical formulations generally include one or more excipients that affect the compound in some way, such as enhancing the solubility of the compound or improving the stability of the compound when it is in solution. Alternatively, additional excipients can be used to provide other characteristics to the formulation, such as preservatives, buffers, etc.

[0009] Although formulations of thousands of ligand-radioisotope complexes have been documented, it is not expected that the excipients used in such formulations will provide the solubility, stability, and bioavailability required for any newly developed complex. In addition, it cannot be expected that a particular combination of excipients will further prevent the dissociation of the radioisotope or minimize the dissociation of the radioisotope or minimize radiolysis. For example, a formulation containing a particular combination of excipients may provide the solubility, stability, and bioavailability required for a particular complex and be completely unsuitable for another complex. Additionally, stability may be present at low radioactivity levels and absent at high radioactivity levels. This can be the difference between the activity levels for diagnostic doses (e.g., on the order of several hundred megabecquerels) and higher therapeutic radioactivity doses (on the order of several gigabecquerels). Or, this difference may be in the radioactivity level when preparing large multi-dose batches and subsequently aliquoting them into smaller lower radioactivity doses. The difference in stability may also be due to the type of radioactivity, such as γ, β, or α emissions from one isotope to another, where the isotopes are used in the same drug substance for diagnostic imaging in one case and to deliver a therapeutic cell-killing dose in another case.

[0010] The extent of radiolysis of a ligand-radioisotope complex depends on the radioactivity level, the specific activity level, and the ligand structure. A formulation may provide the required stability for a complex with one radionuclide but may not be found to have such stability in the case of another radionuclide. A case in point is copper-64 ( 64 Cu, t 1 / 2 = 12.7 hours) which emits positrons and copper-67 ( 67 Cu, t 1 / 2= 2.58 days). β-emission usually results in the complex being less stable than its stably labeled counterpart, thus making the 67 Cu-labeled complex more prone to radiolysis. In view of this, the formulation can vary widely depending on the radionuclide used, for example, by adding stabilizers or increasing the amount of stabilizer. In addition to cost, an increase in the level of additional reagents in the formulation may pose new problems, such as precipitation in the formulation or pH imbalance of the formulation.

[0011] Therefore, the desired formulation of the ligand-radioisotope complex needs to be customized to exhibit the necessary stability related to the radiolysis and dissociation of the radioisotope while also being pharmaceutically acceptable. The present invention seeks to address these problems associated with specific ligand complexes. SUMMARY OF THE INVENTION

[0012] In one aspect of the present invention, there is provided an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions:

[0013]

[0014] Wherein:

[0015] X is where n is an integer from 1 to 10; and

[0016] R is a group selected from: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and a group of formula (A):

[0017]

[0018] The formulation further comprises a buffer and:

[0019] about 0.01% to about 0.1% (w / v) of gentisic acid or a salt thereof;

[0020] about 1% to about 7% (v / v) of ethanol; and

[0021] about 4% to about 10% (w / v) of ascorbic acid or a salt thereof.

[0022] In one embodiment of the first aspect, R is a group of formula (A):

[0023]

[0024] where X is as defined above, for example having the following stereochemistry:

[0025]

[0026] In one embodiment of the first aspect, R is optionally substituted C1-C 12 alkyl.

[0027] In another embodiment, R is methyl.

[0028] In one embodiment of the first aspect, X is wherein n is an integer from 1 to 10.

[0029] In another embodiment, X is and n is 4.

[0030] In certain embodiments, the radiochemical purity of the formulation exceeds about 90% over a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation exceeds about 92% over a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation exceeds about 94% over a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation exceeds about 96% over a period of at least 96 hours. In certain embodiments, the radiochemical purity of the formulation exceeds about 98% over a period of at least 96 hours.

[0031] In some embodiments, the amount of free 67 Cu present in the formulation does not exceed about 5%. In some embodiments, the amount of free 67 Cu present in the formulation does not exceed about 4%. In other embodiments, the amount of free 67 Cu present in the formulation is less than about 1%. In other embodiments, the amount of free 67 Cu present in the formulation is less than about 2%.

[0032] In certain embodiments, the pH of the formulation is from 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.

[0033] According to another aspect of the present invention, there is provided a method for preparing an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions, the method comprising the steps of:

[0034] i) dissolving the compound of formula (I) or a salt thereof in a buffer solution comprising gentisic acid or a salt thereof;

[0035] ii) adding to the solution of step i) 67 a solution of

[0036] iii) filtering the solution obtained from step ii); and

[0037] iv) Diluting the reactants by adding aqueous ethanol and ascorbic acid;

[0038] To recover an aqueous preparation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions.

[0039] According to another aspect of the present invention, there is provided an aqueous preparation prepared by the method defined above.

[0040] The aqueous preparation of the present invention can also be prepared by providing certain components of the preparation as a kit of parts, wherein the kit comprises at least a compound of formula (I) or a salt thereof, and 67 Cu ions intended to complex with the compound of formula (I) or a salt thereof, wherein the compound of formula (I) or a salt thereof and 67 Cu ions are provided separately in the kit and can be combined before administration to form the above complex.

[0041] Thus, in another aspect, the present invention provides a kit for preparing an aqueous preparation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions, the kit comprising:

[0042] A container containing a lyophilized compound of formula (I) or a salt thereof:

[0043]

[0044] Wherein:

[0045] X is where n is an integer from 1 to 10; and

[0046] R is a group selected from: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and a group of formula (A):

[0047]

[0048] A container containing 67 a solution of Cu ions; and

[0049] Instructions for preparing the aqueous preparation as defined in the previous aspect, including adding sodium phosphate buffer, gentisic acid or a salt thereof, ethanol and ascorbic acid or a salt thereof.

[0050] Another aspect of the present invention provides a kit for preparing an aqueous preparation for parenteral administration as defined in the previous aspect, the kit comprising:

[0051] A container containing a freeze-dried compound of formula (I) or a salt thereof:

[0052]

[0053] wherein:

[0054] X is where n is an integer from 1 to 10; and

[0055] R is a group selected from: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and the group of formula (A):

[0056]

[0057] containing 67 a container of a Cu ion solution;

[0058] a container consisting of a sodium phosphate buffer and gentisic acid or a salt thereof;

[0059] a container consisting of aqueous ethanol and ascorbic acid or a salt thereof; and

[0060] Instructions for preparing an aqueous formulation as defined in the previous aspect.

[0061] The radioactivity of the formulations disclosed herein is due to 67 the presence of a Cu radioisotope. In certain embodiments of the formulations disclosed herein, due to 67The radioactive concentration of the preparation is about 1.0 GBq / mL with a Cu radioactive isotope. In some other embodiments, the radioactive concentration of the preparation is about 0.95 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.90 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.85 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.80 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.75 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.70 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.65 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.60 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.55 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.50 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.45 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.40 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.35 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.30 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.25 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.20 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.15 GBq / mL. In some other embodiments, the radioactive concentration of the preparation is about 0.10 GBq / mL. Concentrations within the above value ranges are also considered part of the present invention.

[0062] Another aspect of the present invention provides a method for radioimaging, diagnosing, or treating cancer, the method comprising administering to a subject in need thereof an aqueous preparation according to the first aspect.

[0063] According to another aspect, the present invention provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof an aqueous preparation according to the first aspect.

[0064] According to another aspect, the present invention provides a method for radioimaging a subject, the method comprising administering to a subject in need thereof an aqueous preparation according to the first aspect.

[0065] The methods disclosed herein include the step of administering a preparation of the present invention, wherein the preparation comprises a compound of formula (I) complexed with a 67 Cu radioactive isotope. 67Administration of the complex of Cu and the compound of formula (I) results in localization of the compound at sites expressing the GRP receptor such that the radioisotope undergoes decay and provides a therapeutic effect on the area of the subject to which the complex binds. In some embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the invention having a radioactivity of from about 1 GBq to about 20 GBq.

[0066] In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 20 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 19 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 18 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 17 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 16 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 15 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 14 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 13 GBq. In some other embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 12 GBq. In some other embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 11 GBq. In some other embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 10 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 9 GBq. In some other embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 8 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 7 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 6 GBq. In some other embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 5 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 4 GBq. In some other embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 3 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 2 GBq. In certain embodiments, the methods disclosed herein include the step of administering a dose of the formulation of the present invention having a radioactivity of about 1 GBq. Doses within the above value ranges are also considered to be part of the present invention.

[0067] The inventors have found that the formulations disclosed herein containing 67Formulations of Cu-complexed compounds of formula (I) allow for the delivery of high doses of radioactivity to a subject, where the formulation and the complexed compound are stable and radiopure for at least 96 hours. Additionally, due to the 67 high concentration of the Cu-complexed compound of formula (I), the formulations disclosed herein allow for the delivery of high doses of radioactivity in the form of 67 Cu. The inventors have found that even when high concentrations of the radiolabeled compound are incorporated into the formulation, even when the concentration is increased in the formulation and in the presence of the radioisotope, the compound of formula (I) does not degrade by radiolysis. Without wishing to be bound by theory, the inventors believe that the formulations disclosed herein allow for the administration of the high dose of radiation to be delivered as part of a complex of the compound of formula (I), where even at such high concentrations and radioactivity, the formulation also prevents the compound of formula (I) from degrading by radiolysis. This is shown in Figures 1 to 4 which shows the stability of the formulation over a period of up to 96 hours.

[0068] In certain embodiments, the methods disclosed herein relate to cancers associated with the expression of the gastrin-releasing peptide (GRP) receptor. In certain embodiments, the cancer is a tumor. In other embodiments, the tumor is associated with prostate cancer, breast cancer, ovarian cancer, urinary system cancer, small cell lung cancer, glioblastoma, or gastrointestinal stromal tumor.

[0069] In certain methods for treating cancer disclosed herein, the method further includes performing a radioimaging of the subject after administering the formulation of the present invention. In certain embodiments, the subject is radioimaged by PET-CT or SPECT-CT. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] The present invention will be described by way of example only with reference to the following non-limiting drawings, in which:

[0071] Figure 1 is a chromatogram from the analysis by radioHPLC of a formulation containing 67 [[Cu]]Sar-BBN, 12 hours after the preparation of the formulation. The chromatogram shows a radiochemical purity of the formulation of 97.68%, indicating that the 67 Cu radioisotope present in the formulation is complexed with the compound of formula (I).

[0072] Figure 2 is a chromatogram from the analysis by radioHPLC of a formulation containing 67 [[Cu]]Sar-BBN, 96 hours after the preparation of the formulation. The chromatogram shows a radiochemical purity of the formulation of 93.96%, indicating that the67 The Cu radioisotope complexes with the compound of formula (I).

[0073] Figure 3 is a chromatogram from the analysis by radioTLC of a formulation containing 67 [[Cu]]Sar-BBN, 12 hours after preparation of the formulation. The chromatogram shows that most of the 67 Cu radioisotope present in the formulation is complexed with the compound of formula (I), and very little free 67 Cu is detected.

[0074] Figure 4 is a chromatogram from the analysis by radioTLC of a formulation containing 67 [[Cu]]Sar-BBN, 96 hours after preparation of the formulation. The chromatogram shows that most of the 67 Cu radioisotope present in the formulation is complexed with the compound of formula (I), and very little free 67 Cu is detected. DETAILED DESCRIPTION

[0075] The present invention relates to stable formulations of specific radioisotope-ligand complexes. The inventors have found that formulations of the complexes disclosed herein minimize the dissociation of the radioisotope from the ligand and / or minimize the radiolysis of the ligand caused by the radioisotope.

[0076] The preparation of the radioisotope-ligand complex mentioned in this text is stable in solution and under physiological conditions for a period of time. The stability of the preparation is related to the stability of the complex, where the radioisotope can undergo dissociation or the complex can undergo radiolysis. The stability of the complex can be measured by considering the radiochemical purity of the preparation. The radiochemical purity is defined as the amount of radioisotope complexed with the sarcophagine ligand, expressed as a percentage of the total amount of radioisotope present in the preparation. The radioisotope can be present in the preparation as a complex with the sarcophagine ligand, as a free radioisotope, or as part of a radiolysis product. In certain embodiments, the radiochemical purity of the preparation exceeds about 90% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 91% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 92% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 93% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 94% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 95% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 96% over a period of at least 96 hours. In other embodiments, the radiochemical purity of the preparation exceeds about 97% over a period of at least 96 hours. In some embodiments described herein, the radiochemical purity can be determined by techniques such as radio-HPLC, where the amount of radioisotope in its complexed or free form is determined and compared to the amount of radioisotope introduced into the preparation. Those skilled in the art will understand the requirements for separating, analyzing, and quantifying the preparation by radio-HPLC. Nevertheless, in certain embodiments, the mobile phase used for analyzing the preparation as disclosed herein by radio-HPLC contains about 0.1% trifluoroacetic acid (TFA) in water. In certain embodiments, the mobile phase used for analyzing the preparation as disclosed herein by radio-HPLC contains about 0.1% trifluoroacetic acid (TFA) in acetonitrile.

[0077] The stability of the complex can also be measured by considering the amount of free copper present in the formulation (i.e., the free copper radioisotope intended to complex with the sarcophagine ligand). In certain embodiments, the amount of free copper radioisotope present in the formulation does not exceed about 5%. In other embodiments, the amount of free copper radioisotope present in the formulation does not exceed about 4%. In other embodiments, the amount of free copper present in the formulation does not exceed about 3%. In other embodiments, the amount of free copper present in the formulation does not exceed about 2%. In other embodiments, the amount of free copper present in the formulation does not exceed about 1%. In other embodiments, the amount of free 67 Cu present is less than about 1%. In other embodiments, the amount of free 67 Cu present is less than about 2%.

[0078] The stable formulation of the present invention comprises a compound of formula (I) or a salt thereof:

[0079]

[0080] wherein X is wherein n is an integer from 1 to 10;

[0081] R is a group selected from: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide, optionally substituted aryl, and a group of formula (A):

[0082]

[0083] wherein X is as defined above.

[0084] The compound of formula (I) or a salt thereof contains a peptide, wherein the peptide has the sequence D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 and has the following structure:

[0085]

[0086] The above peptide fragments are related to the bombesin receptor peptide family, and the bombesin receptor peptides exhibit antagonist (or agonist) activity on gastrin-releasing peptide (GRP) receptors. It is known that GRP receptors are expressed or overexpressed on the membranes of various cancers and can be targets for diagnostic or therapeutic purposes. Compounds containing bombesin-like peptides as described herein can bind to sites expressing GRP receptors and, when a suitable radionuclide is also delivered as part of the compound, can provide a diagnostic or therapeutic effect locally. The amino acids of the bombesin-like peptides used herein can have specific stereochemistry, as described below:

[0087]

[0088] The compound of formula (I) or its salt also contains a nitrogen-containing macrocycle capable of chelating metal ions. The macrocycle of formula (I) is 3,6,10,13,16,19-hexaazabicyclo[6.6.0]icosane and can be referred to as "sarcophagine". The sarcophagine of formula (I) contains six nitrogen atoms, one or more of which can be protected with a suitable protecting group.

[0089] The compound of formula (I) or its salt contains sarcophagine and a bombesin-like peptide, wherein the peptide is bound to the terminal position of sarcophagine through a linker group. As described herein, the linker group contains a propionamide group directly bound to the terminal position of sarcophagine. The propionamide group is then linked to a linker containing a polyethylene glycol (PEG) group, which has 1 to 10 repeating units. The PEG group has the following structure:

[0090]

[0091] wherein n is an integer from 1 to 10.

[0092] The present inventors have found that the compound of formula (I) or its salt is capable of chelating metal ions and binding to target receptors, and the compound of formula (I) or its salt contains a combination of sarcophagine and a bombesin-like peptide or a peptide that acts as an agonist or antagonist of the gastrin-releasing peptide receptor. For example, in which sarcophagine and the bombesin-like peptide are bound together through a propionamide group (adjacent to sarcophagine) and a linker containing a PEG group. Without wishing to be bound by theory, the present inventors believe that the combination of sarcophagine, the bombesin-like peptide, the propionamide group, and the linker containing a PEG group provides the specific advantages observed and discussed below. Although the properties of the compounds of the present invention are the result of each component of the compound, the present inventors believe that the presence of the linker containing a PEG group alters the biodistribution, metabolism, and secretion properties, improves the overall biocompatibility of the compound, and may be the reason for the observed advantages.

[0093] In certain embodiments, the group R in the compound of formula (I) or its salt is selected from H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted C1-C 12 amide, optionally substituted C6-C 10 aryl, and the group of formula (A):

[0094]

[0095] wherein X is as defined above.

[0096] In certain embodiments, R is a group of formula (A) having the stereochemistry as defined below:

[0097]

[0098] In certain embodiments, R is optionally substituted C1-C 12 alkyl. In one embodiment, R is optionally substituted C1 alkyl. In another embodiment, R is optionally substituted methyl. In another embodiment, R is unsubstituted C1-C 12 alkyl. In another embodiment, R is unsubstituted C1 alkyl. In another embodiment, R is unsubstituted methyl.

[0099] In certain embodiments, the compound of formula (I) or its salt has the following structure:

[0100]

[0101] wherein n is an integer from 1 to 10.

[0102] In a specific embodiment, the compound of formula (I) or a salt thereof has the following structure:

[0103]

[0104] In certain embodiments, R is optionally substituted C1-C 12 amide group. In one embodiment, R is an optionally substituted C1 amide group. In one embodiment, R is a C1 amide group further substituted by one or more groups.

[0105] In certain embodiments, R is a group of formula (A):

[0106]

[0107] wherein X is as defined above.

[0108] In one embodiment, R is a group of formula (A), and X is a group of formula and n is an integer from 1 to 10.

[0109] In one embodiment, R is a group of formula (A), and X is a group of formula and n is 4.

[0110] In one embodiment, R is unsubstituted methyl, and X is a group of formula and n is an integer from 1 to 10.

[0111] In one embodiment, R is unsubstituted methyl, and X is a group of formula and n is 4.

[0112] In certain embodiments, the compound of formula (I) has the following structure of formula (Ia):

[0113]

[0114] 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:

[0115]

[0116] In another embodiment, the compound of formula (I) or a salt thereof has the structure of formula (Ib):

[0117]

[0118] 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:

[0119]

[0120] Unless otherwise indicated, the term "alkyl" as used herein refers to a group or part of a group that is a straight-chain or branched-chain aliphatic hydrocarbon group, preferably a C1-C 12 alkyl, more preferably a C1-C 10 alkyl, most preferably a C1-C6. Some examples of suitable straight-chain and branched-chain C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, hexyl, and the like.

[0121] The term "amide" as used herein 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 bearing additional substituents.

[0122] The term "aryl" as used herein refers to a group or part of a group that represents (i) an optionally substituted monocyclic or fused polycyclic aromatic carbocyclic ring (a ring structure having ring atoms that are all carbon), preferably each ring having 5 to 12 atoms. Some examples of aryl include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl group and a C 5-7 cycloalkyl or a C 5-7 cycloalkenyl are fused together to form a ring structure, such as tetrahydronaphthyl, indenyl, or indanyl. Generally, aryl is a C6-C 18 aryl.

[0123] Unless otherwise indicated, the term "cycloalkyl" as used herein refers to a saturated monocyclic or fused or spiro polycyclic carbocyclic ring, each ring preferably containing 3 to 9 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. Cycloalkyl is generally a C3-C9 cycloalkyl.

[0124] The term "halogen" as used herein represents chlorine, fluorine, bromine, or iodine.

[0125] The term "heteroalkyl" as used herein refers to a straight-chain or branched-chain alkyl group preferably having 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, wherein one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P, and NR', where R' is selected from H, optionally substituted C1-C 12 alkyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C6-C 18 aryl, and optionally substituted C1-C 18Heteroaryl. Exemplary heteroalkyls include alkyl ethers, secondary alkylamines and tertiary alkylamines, amides, alkyl sulfides, etc. Some examples of heteroalkyls also include hydroxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkylamino C1-C6 alkyl, and bis(C1-C6 alkyl)amino C1-C6 alkyl.

[0126] The term "heteroaryl" as used herein, 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 and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen, and sulfur. Some examples of heteroaryls include thiophene, benzothiophene, benzofuran, benzimidazole, benzo oxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, iso oxazole, furazane, phen azine, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolyl, 1-, 2-, or 3-indolyl, and 2- or 3-thienyl. Heteroaryl is generally C1-C 18 heteroaryl.

[0127] The term "C1-C 12 alkylene" as used herein refers to a divalent straight-chain or branched aliphatic hydrocarbon group having 1 to 12 carbon atoms in the chain.

[0128] As used herein, the term "optionally substituted" when used in connection with a particular group means that the group may or may not be further substituted or fused (to form a fused polycyclic system) with one or more non-hydrogen substituents. In certain embodiments, the substituents are one or more groups independently selected from the following: halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, 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, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenoxy, alkynoxy, cycloalkoxy, cycloalkenoxy, heterocycloalkoxy, heterocycloalkenoxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkoxy, 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 、NR a R b 、NR a C(=O)R b 、NR a C(=O)OR b 、NR a C(=O)NR b R c 、NR a C(=NR b )NR c R d 、NR a SO2R b 、-SR a 、SO2NR a R b 、-OR a 、OC(=O)NR a R b 、OC(=O)R a and acyl, where Ra , R b , R c and R d are each independently selected from 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 any two or more of R a , R b , R c and R d form a heterocyclic system having 3 to 12 ring atoms when taken together with the atoms to which they are attached.

[0129] In some embodiments, each optional substituent is independently selected from: halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenoxy, alkynoxy, cycloalkoxy, cycloalkenoxy, heterocycloalkoxy, heterocycloalkenoxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkoxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH and acyl.

[0130] Some examples of particularly suitable optional substituents include F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, COOH, COOCH3 and CN.

[0131] As used herein, the term "salt" refers to acid addition salts and base addition salts of a compound, where the salts are prepared from inorganic acids or organic acids or inorganic bases or organic bases. In some embodiments, the salts of the compounds of the invention can be pharmaceutically acceptable salts.

[0132] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the desired biological activity of the above compounds and may also be acid addition salts or base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from inorganic acids or from organic acids. Some examples of such inorganic acids are hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic and sulfonic acids, some examples of which are 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 acids, arylsulfonic acids. Additional information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case where the pharmaceutical agent is a solid, those skilled in the art will understand that the compounds, pharmaceutical agents and salts of the present invention can exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formula.

[0133] As used herein, the term "complex" refers to a compound that is subsequently coordinated by a metal ion, for example, a compound of formula (I) or a salt thereof coordinated with 67 Cu.

[0134] The administrable formulations of the present invention comprise a complex of a compound of formula (I) or a salt thereof with a radioisotope 67 Cu. A radioisotope may also be referred to as a radionuclide. It has been found that the ligands of the present specification are particularly successful in complexing copper ions, especially Cu 2+ ions. Those skilled in the art will also understand that a complex of a compound of formula (I) or a salt thereof with a radioisotope can be obtained by contacting the 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 is complexed with the radioisotope. This may involve mixing the compound of formula (I) or a salt thereof with the radioisotope in a suitable solvent system, such as the solvent systems specifically described herein.

[0135] In certain embodiments, the formulations disclosed herein comprise 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 understand that copper phosphate salts are prone to form and subsequently precipitate, which is undesirable for any pharmaceutically acceptable formulation and product. The formulations disclosed herein contain a copper radioisotope that provides a radiotherapeutic effect. In certain embodiments, the formulations disclosed herein comprise a buffer solution, and in some specific embodiments, the buffer solution is a phosphate buffer solution, which is a known physiologically acceptable component. Although formulations containing both copper ions and phosphate ions are known to have the potential to form insoluble precipitates, the inventors unexpectedly found that the formulations disclosed herein containing these two components do not produce the unwanted (and harmful) copper salt precipitates. The inventors also understand that the formation of metal salts (e.g., copper phosphate salts) also depends on the pH of the formulation, and careful consideration of factors such as pH, temperature, ionic concentration in solution, etc. is required to avoid or prevent the formation of unwanted metal salts. Since it is known that copper phosphates can form in the physiologically relevant pH range, the inventors unexpectedly found that the formulations disclosed herein containing both copper ions and phosphate ions in solution at physiological pH do not form copper phosphate salts and are thus pharmaceutically acceptable for administration to a subject.

[0136] In some embodiments, the formulation is an aqueous formulation, and the pharmaceutically acceptable carrier is a saline solution containing a phosphate buffer. In a preferred embodiment, the pharmaceutically acceptable carrier is a sodium phosphate buffer.

[0137] The formulations of the present invention are for administration to a subject in need thereof and thus have a pharmaceutically acceptable and physiologically tolerable pH to ensure the stability of the formulation components and the safety of the subject. In certain embodiments, the pH of the formulations of the present invention is from about 4 to about 8. In some embodiments, the pH of the formulation is about 4. In some other embodiments, the pH of the formulation is about 5. In some other embodiments, the pH of the formulation is about 6. In some other embodiments, the pH of the formulation is about 7. In some other embodiments, the pH of the formulation is about 8. In some embodiments, the pH of the formulation can be in the range between the pH values disclosed herein. In some embodiments, the pH of the formulation is generated by the chemical nature of the components present in the formulation. In some other embodiments, the pH of the formulation is generated by 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 thereof. In some embodiments, the buffer solution present in the formulation not only helps to determine and maintain the pH of the formulation, but also helps to ensure the stability of one or more components of the formulation. In some embodiments, one or more components responsible for ensuring the pH of the formulation can also stabilize the formulation and prevent radiolysis of the complex containing the radioisotope.

[0138] In one embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of from about 4% to about 12% (w / v). In one embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 4% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 4.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 5.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 6% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 6.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 7% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 7.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 8% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 8.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 9% (w / v). In another embodiment, the formulation of the present invention comprises one or more stabilizers in a total amount of about 9.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 10% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 10.5% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 11% (w / v). In another embodiment, the aqueous formulation of the present invention comprises one or more stabilizers in a total amount of about 11.5% (w / v). In another embodiment, the 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 present in ranges between the above amounts.

[0139] In one embodiment, comprising 67An aqueous formulation of a Cu-complexed compound of formula (I) or a salt thereof comprises gentisic acid or a salt thereof as a stabilizer. Gentisic acid is also known as 2,5-dihydroxybenzoic acid, 5-hydroxy salicylic acid or hydroquinone carboxylic acid. The salts of gentisic acid may include sodium salts and sodium hydrates. In relevant cases, any reference to gentisic acid may include a reference to its salts. As described above, the pH of the formulations disclosed herein is from about 4 to about 8. Since the pKa (i.e., acid dissociation constant) of gentisic acid is about 2.5, the gentisic acid present in the formulations disclosed herein will be in its dissociated form, i.e., as a gentisate. Without wishing to be bound by theory, the inventors believe that using the free acid (i.e., gentisic acid) or the corresponding substance will not result in any substantial difference in the formulation.

[0140] In one embodiment, gentisic acid or its salt is present in the formulation in an amount of from about 0.01% to about 0.1% (w / v). In one embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.01% (w / v). In one embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.015% (w / v). In one embodiment, 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 its salt is present in the formulation in an amount of about 0.085% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.09% (w / v). In another embodiment, gentisic acid or its salt is present in the formulation in an amount of about 0.095% (w / v). In another embodiment, gentisic acid or its salt 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 its salt within the ranges between the above amounts. In a preferred embodiment, gentisic acid or its salt is present in the formulation in an amount of from about 0.03 to about 0.04% (w / v).

[0141] Ascorbic acid or its salts are also present in the aqueous formulation as stabilizers. 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 ester of ascorbic acid, i.e., ascorbyl palmitate.

[0142] In one embodiment, ascorbic acid or a salt thereof is present in an amount of from about 4.0% to about 10.0% (w / v). In one embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 4.0% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 4.5% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 5.0% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 5.5% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 6.0% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 6.5% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 7.0% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 7.5% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 8.0% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 8.5% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 9.0% (w / v). In another embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of about 9.5% (w / v). In another embodiment, ascorbic acid or a salt thereof 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 a salt thereof within the ranges between the above amounts. In a preferred embodiment, ascorbic acid or a salt thereof is present in the formulation in an amount of from about 6.5% to about 8% (w / v).

[0143] L-methionine or a salt thereof can also be used as a stabilizer. The term L-methionine as used herein refers to the amino acid with an S-methylthioether side chain. Adding L-methionine to the formulation of the present invention can further enhance the stability of the formulation by preventing or minimizing the radiolysis of the radiolabeled complex of formula (I), thereby improving the radiochemical purity of the formulation.

[0144] The aqueous formulation of the present invention further comprises ethanol as a component. The ethanol used in the formulation can be anhydrous ethanol. Alternatively, the ethanol used in the aqueous formulation may not undergo a drying process and can be hydrated. In certain embodiments, the ethanol is aqueous ethanol. The ethanol is preferably pharmaceutical grade ethanol. The ethanol present in the formulation can also help prevent the radiolysis of the radiolabeled complex of formula (I).

[0145] In one embodiment, ethanol is present in the aqueous formulation in an amount of from 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 within the ranges between the above amounts.

[0146] 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 a saline solution. A saline solution is defined as an aqueous solution of sodium chloride. For example, physiological saline is defined as an aqueous solution of sodium chloride having a concentration of 0.9% (w / v). In one embodiment of the present invention, the sodium chloride of the formulation is provided by a saline solution.

[0147] The pH of the formulation of the present invention is from about 4 to about 8. Those skilled in the art will understand that the pH of the formulation is an inherent characteristic of the formulation, attributable to the combination of the compound of formula (I) or its complex with the remaining excipients of the formulation. The inventors have found that this pH range provides optimal radiolabeling efficiency.

[0148] In one embodiment, the pH of the formulation is from 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.

[0149] Without wishing to be bound by theory, the inventors believe that the stability of the formulations disclosed herein, which contain a radiolabeled complex of a compound of formula (I), gentisic acid or a salt thereof, ethanol, and ascorbic acid or a salt thereof, is the result of the combination of these components, and omission of one or more of these components results in formulations having a much lower stability. In addition, the inventors also believe that use of each of the listed components also results in preventing any radiolysis of the radiolabeled complex and minimizing any radiolysis of the radiolabeled complex, and the components of the formulation prevent the decomposition of the ligand containing 67 the Cu radioisotope. This in turn provides a radiotherapeutic compound, namely a compound of formula (I) complexed with 67 Cu, which remains intact and is thus therapeutically effective for a longer time, thereby increasing the efficiency of a given dose administered to a subject. This also means that the costs associated with the preparation of the formulations disclosed herein and treating a subject therewith are reduced, since more of the therapeutically active compound is effective and available for treatment over a longer period of time.

[0150] In one embodiment, the aqueous formulation of the present invention comprises a compound of formula (I) or a salt thereof complexed with 67 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, wherein the pH of the formulation is about 6.0. In one embodiment, the aqueous formulation of the present invention comprises a compound of formula (I) or a salt thereof complexed with 67A compound of formula (I) complexed with Cu ions or a salt thereof, about 4% (v / v) ethanol, about 6.5 to about 8% (w / v) ascorbic acid, and not more than 0.06% (w / v) gentisic acid or a salt thereof, wherein the pH of the formulation is about 6.0. In another embodiment, the aqueous formulation of the present invention comprises, in combination with 67 A compound of formula (I) complexed with Cu ions or a salt thereof, about 4% ethanol, about 6.5 to about 8% ascorbic acid, and about 0.035% (w / v) gentisic acid or a salt thereof, wherein the pH of the formulation is about 6.0.

[0151] Accordingly, the present invention also provides an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu ions or a salt thereof:

[0152]

[0153] wherein:

[0154] X is where n is an integer from 1 to 10; and

[0155] R is a group selected from: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide, and optionally substituted aryl, and a group of formula (A):

[0156]

[0157] The formulation further comprises a buffer and:

[0158] about 1% to about 7% (v / v) ethanol;

[0159] about 4% to about 10% (w / v) ascorbic acid or a salt thereof; and

[0160] about 0.01% to about 0.1% (w / v) gentisic acid or a salt thereof;

[0161] wherein the pH of the formulation is about 4 to about 8.

[0162] According to the present invention, 67 A formulation of a complex of Cu and a compound of formula (I) or a salt thereof may have a radiochemical purity of at least 90% for at least 96 hours. This means that at least about 90% of the 67 Cu radioisotope present in the formulation is complexed with the compound of formula (I) or a salt thereof at least 96 hours after the formulation is prepared. When the 67 Cu radioisotope present in the formulation is not complexed with the compound of formula (I) or a salt thereof, 67 the Cu radionuclide may be present as free 67Cu ions are present as part of the radiolysis products.

[0163] In one embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 90%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 91%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 92%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 93%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 94%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 95%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 96%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 97%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 98%. In another embodiment, at about 96 hours after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 99%.

[0164] In one embodiment, immediately after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67 a complex of Cu and a compound of formula (I) or a salt thereof is about 94%. In another embodiment, at about 1 hour after the preparation of the formulation, the radiochemical purity of the inventive formulation comprising 67The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 3 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 6 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 9 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 12 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 15 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 18 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 21 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 24 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 48 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%. In another embodiment, about 72 hours after the preparation of the pharmaceutical preparation, it contains 67 The radiochemical purity of the pharmaceutical preparation of the present invention, which is a complex of Cu and a compound of formula (I) or a salt thereof, is about 94%.

[0165] Preparation of the aqueous pharmaceutical preparation of the present invention

[0166] With 67 A compound of formula (I) or a salt thereof complexed with Cu ions can be provided by mixing a compound of formula (I) or a salt thereof with 67 A solution of Cu ions in the presence of a buffer and one or more stabilizers. Then the solution can be filtered, and subsequently the reactants can be diluted to provide a solution containing complexed with 67Formulations of 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, the reaction product between the compound of formula (I) and 67 the Cu ions is diluted with an aqueous ethanol solution containing ascorbic acid or a salt thereof.

[0167] Accordingly, the present invention provides a method for preparing an aqueous formulation comprising a compound of formula (I) complexed with 67 Cu ions, the method comprising the steps of:

[0168] i) dissolving the compound of formula (I) or a salt thereof in a buffer solution containing gentisic acid or a salt thereof;

[0169] ii) adding to the solution of step i) 67 a solution of Cu ions;

[0170] iii) filtering the solution obtained from step ii); and

[0171] iv) diluting the reaction product by adding aqueous ethanol and ascorbic acid;

[0172] to recover an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions.

[0173] The buffer can be an ammonium acetate solution. Alternatively, the buffer solution can be a sodium acetate solution. In a preferred embodiment, the buffer solution is a sodium phosphate buffer.

[0174] In certain embodiments, the buffer solution contains phosphate ions. In some embodiments, the buffer solution contains sodium phosphate salts. In other embodiments, the buffer solution contains one or more sodium phosphate salts. In some embodiments, the buffer solution contains two or more sodium phosphate salts. In some embodiments, the buffer solution contains disodium hydrogen phosphate. In other embodiments, the buffer solution contains sodium dihydrogen phosphate. In some embodiments, the buffer solution contains disodium hydrogen phosphate and another phosphate. In some embodiments, the buffer solution contains sodium dihydrogen phosphate and another phosphate. In other embodiments, the buffer solution contains disodium hydrogen phosphate and sodium dihydrogen 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.

[0175] The inventors understand that the combination of copper cations and phosphate anions generally results in the formation of insoluble copper phosphates. The inventors unexpectedly showed that in the method for preparing the formulations as defined herein, 67 a Cu radioisotope, which is used as Cu 2+The cations were introduced into a solution containing a phosphate buffer, but no insolubility and salt formation were observed. Without wishing to be bound by theory, the inventors believe that a combination of at least several characteristics (such as temperature, concentration, etc.) has been found that allows 67 the successful incorporation of the Cu radioisotope into the compound of formula (I).

[0176] The buffer solution further comprises gentisic acid or a salt thereof as a component. As previously described, the salt of gentisic acid may include the sodium salt or a sodium hydrate. Other salts of gentisic acid are also contemplated. The buffer solution may comprise sodium gentisate at a concentration of about 0.01 to about 0.1% (w / v). In one embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.01% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.015% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.02% (w / v). In another embodiment, the buffer solution comprises sodium gentisate at a concentration of about 0.025% (w / v). In another embodiment, the buffer solution comprises 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 comprises sodium gentisate at a concentration of about 0.035% to 0.04% (w / v).

[0177] The compound of formula (I) is then combined with 67The reactants between Cu ions are diluted with an ethanol aqueous solution. As previously described, the ethanol can be anhydrous or can have previously undergone a drying operation known in the art. The solution can 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).

[0178] As described above, the aqueous ethanol solution further contains ascorbic acid or its salts. Ascorbic acid is also known as L-ascorbic acid or vitamin C. The 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. In one embodiment, ascorbic acid or its salts are present in an amount of from about 4.0% to about 10.0% (w / v). In one embodiment, ascorbic acid or its salts are present in the solution in an amount of about 4.0% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 4.5% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 5.0% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 5.5% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 6.0% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 6.5% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 7.0% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 7.5% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 8.0% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 8.5% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 9.0% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 9.5% (w / v). In another embodiment, ascorbic acid or its salts are present in the solution in an amount of about 10.0% (w / v). In a preferred embodiment, ascorbic acid or its salts are present in the solution in an amount of from about 6.5% to about 8% (w / v).

[0179] 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 can 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.

[0180] Mix 67A solution of Cu ions is added to 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, and allowed to stand for a period of time.

[0181] In one embodiment, 67 the solution of Cu ions is 67 a solution of a Cu salt. In another embodiment, 67 the solution of Cu ions is a solution of a copper chloride salt. In another embodiment, 67 the solution of Cu ions is 67 a solution of Cu]CuCl2.

[0182] 67 The solution of Cu ions is provided as an aqueous solution. 67 Cu ions can be provided in an aqueous hydrochloric acid solution. In one embodiment, 67 Cu ions are provided in a solution of about 0.01 to about 0.1 mol / L hydrochloric acid. In one embodiment, 67 Cu ions are provided in a solution of about 0.01 mol / L hydrochloric acid. In another embodiment, 67 Cu ions are provided in a solution of about 0.02 mol / L hydrochloric acid. In another embodiment, 67 Cu ions are provided in a solution of about 0.05 mol / L hydrochloric acid. In another embodiment, 67 Cu ions are provided in a solution of about 0.075 mol / L hydrochloric acid. In another embodiment, 67 Cu ions are provided in a solution of about 0.1 mol / L hydrochloric acid. In a preferred embodiment, 67 Cu ions are provided in a solution of about 0.05 mol / L hydrochloric acid as 67 Cu]CuCl2.

[0183] 67 A solution of a Cu-radioisotope is provided in an aqueous solution having a radioactivity of about 1,000 to about 100,000 MBq. In one embodiment, 67 the radioactivity of the Cu-radioisotope is about 1,000 MBq. In another embodiment, 67 the radioactivity of the Cu-radioisotope is about 5,000 MBq. In another embodiment, 67 the radioactivity of the Cu-radioisotope is about 10,000 MBq. In another embodiment, 67 the radioactivity of the Cu-radioisotope is about 15,000 MBq. In another embodiment, 67 the radioactivity of the Cu-radioisotope is about 20,000 MBq. In another embodiment,67 The radioactivity of the Cu-radioisotope is about 25,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 30,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 35,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 40,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 45,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 50,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 55,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 60,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 65,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 70,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 75,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 80,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 85,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 90,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 95,000 MBq. In another embodiment, 67 The radioactivity of the Cu-radioisotope is about 100,000 MBq.

[0184] The mixture of 67 Cu ions, the compound of formula (I) or its salt and a sodium phosphate buffer solution containing gentisic acid or its salt can be allowed to stand at room temperature. The mixture can be allowed to stand with stirring, or alternatively, the mixture can be allowed to stand without stirring. The mixture can be allowed to stand for a time of about 5 to about 25 minutes. In one embodiment, 67 the mixture of Cu ions, the compound of formula (I) or its salt and a sodium phosphate buffer solution containing gentisic acid or its salt can be allowed to stand without stirring for about 5 minutes. In another embodiment, 67A 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. In another 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 15 minutes without stirring. In another 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 20 minutes without stirring. In another 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 25 minutes without stirring. In another 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 less than 25 minutes without stirring. In another preferred embodiment, 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. In certain embodiments, 67 A mixture of Cu ions and a compound of formula (I) or a salt thereof is allowed to stand at room temperature, where room temperature is defined as ambient temperature according to the USP. In certain embodiments, the ambient temperature is from about 15 °C to about 25 °C.

[0185] According to another embodiment of the present invention, 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 filtered. The mixture can be filtered by a solid-phase extraction process. The mixture can be filtered by a solid-phase extraction process, where the stationary phase of the solid-phase extraction column retains the compound of formula (I) or a salt thereof complexed with Cu ions, any uncomplexed compound of formula (I) or a salt thereof, and some gentisic acid present in salt form (such as sodium gentisate). The term "stationary phase" as used herein refers to a resin-like material that is retained within the solid-phase extraction column and allows for the separation of compounds based on their polarity.

[0186] The solid-phase extraction process as described herein can use a reverse-phase stationary phase. As used herein, the term "reverse-phase" in relation to the 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. Some examples of reverse-phase stationary phases can include Phenomenex Strata-X 33u polymeric reverse-phase, Waters tC18 or Waters C18. Other similar stationary phases can be used. Since the solid-phase extraction process uses a reverse-phase stationary phase, any free 67Neither the Cu ions nor the remaining gentisic acid or its salts are retained by the stationary phase, and these components are discarded.

[0187] In one embodiment, 67 A mixture of Cu ions, a compound of formula (I), and a sodium phosphate buffer solution containing gentisic acid or its salts is filtered through a solid-phase extraction column. In one embodiment, a mixture of Cu ions, a compound of formula (I), and a sodium phosphate buffer solution containing gentisic acid or its salts is filtered through a solid-phase extraction column with 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 column with a reversed-phase stationary phase. In a preferred embodiment, 67 A mixture of a Cu-radioisotope, a compound of formula (I), and a sodium phosphate buffer solution containing gentisic acid or its salts is filtered through a solid-phase extraction column with a reversed-phase stationary phase. In another preferred embodiment, 67 The compound of formula (I) complexed with Cu ions is retained by a solid-phase extraction column with a reversed-phase stationary phase.

[0188] The compound of formula (I) complexed with 67 Cu ions is eluted from the solid-phase extraction column containing the stationary phase by washing with a solvent. Since the solid-phase extraction column contains a reversed-phase stationary phase, eluting the compound of formula (I) complexed with 67 Cu ions requires washing the stationary phase with ethanol, brine, and / or another solvent. In one embodiment, the solid-phase extraction column is washed with ethanol to elute the compound of formula (I) complexed with 67 Cu ions. In another embodiment, the solid-phase extraction column is washed with brine to elute the compound of formula (I) complexed with 67 Cu ions. In another embodiment, the solid-phase extraction column is washed with ethanol and brine to elute the compound of formula (I) complexed with 67 Cu ions. In a preferred embodiment, the solid-phase extraction column is washed with ethanol and containing ascorbic acid to elute the compound of formula (I) complexed with 67 Cu ions. In a preferred embodiment, the solid-phase extraction column is washed with ethanol containing ascorbic acid to provide the formulation of the present invention.

[0189] Those skilled in the art will understand that the excipients of the formulation include the solvents used to elute the compound of formula (I) complexed with 67 Cu ions from the stationary phase, and the amount of each solvent used is related to the amount of each excipient in the formulation of the present invention.

[0190] Those skilled in the art will understand that the present disclosure provides an artificial method for producing the formulations according to the present invention. Those skilled in the art will understand that the steps described herein can be automated by using a suitable automated radiochemical synthesis module in order to obtain the formulations according to the present invention.

[0191] The inventors have found that, given the relatively high starting radioactivity, the formulations disclosed herein have a relatively high stability and exhibit reduced radiolysis. This enhanced stability can be attributed to an increase in the radiochemical purity of the formulations at a given radioactivity. The stability of the formulations of the present invention can be observed for up to 96 hours after preparation. When the formulations of the present invention are used for therapeutic or treatment purposes, the higher stability may mean that doses for multiple patients at multiple remote locations can be prepared at the same time in a single facility. This may mean that the resources for preparation need to be located in a single facility rather than multiple facilities, and higher efficiency in the production of the formulations can be achieved. When the formulations of the present invention are used for imaging purposes, additional advantages can be provided, since the clinical imaging sites can receive the dosage form ready for injection. This can be particularly advantageous for clinical sites where there is no dedicated radiopharmaceutical production facility.

[0192] The formulations of the present invention comprise 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 can be supplied in separate containers. Alternatively, the compound of formula (I) or a salt thereof and the radioisotope can be supplied together as a ligand-radioisotope complex.

[0193] The container comprising the compound of formula (I) or a salt thereof can provide the compound of formula (I) or a salt thereof as a lyophilized powder. The container can be provided at a temperature from -20 °C to 20 °C.

[0194] The formulation can be provided as a kit, which kit comprises 67 a container of a Cu radioisotope and a separate container having a ligand and instructions for preparing an aqueous formulation of the present invention. In one embodiment, the kit of the present invention comprises a container providing 67 a solution of a Cu radioisotope and a separate container providing the compound of formula (I) or a salt thereof. The container providing the radioisotope can contain 67 a solution of a Cu salt.

[0195] In one embodiment, the kit of the present invention comprises a container having 67 a solution of a Cu radioisotope. In another embodiment, the kit of the present invention comprises a container having a solution of a copper salt containing 67 a Cu radioisotope. In another embodiment, the kit of the present invention comprises a container having a solution of a copper salt containing 67A container of a chloride salt solution of a Cu radioisotope. In another embodiment, the kit of the present invention comprises a container having a radioactive copper (II) chloride salt solution. In another embodiment, the kit of the present invention comprises a container having a copper (II) chloride salt solution, wherein the copper ions are 67 Cu isotopes. In another embodiment, the kit of the present invention comprises a container having 67 Cu]CuCl2 solution.

[0196] Solutions of radioisotopes are typically provided as aqueous solutions. In one embodiment, the kit of the present invention provides a radioisotope in the form of an aqueous solution. In another embodiment, the kit of the present invention provides a radioisotope in the form of an acidic aqueous solution. In another embodiment, the kit of the present invention provides a radioisotope as a solution in hydrochloric acid. The radioisotope can be provided as a solution in hydrochloric acid at a concentration of about 0.01 to about 0.1 mol / L.

[0197] In one embodiment, the kit of the present invention comprises a container having a solution of 67 Cu]CuCl2 in hydrochloric acid. In another embodiment, the kit of the present invention comprises a container having a solution of 67 Cu]CuCl2 in hydrochloric acid, wherein the concentration of hydrochloric acid is about 0.02 mol / L. In another embodiment, the kit of the present invention comprises a container having a solution of 67 Cu]CuCl2 in hydrochloric acid, wherein the concentration of hydrochloric acid is about 0.05 mol / L. In another embodiment, the kit of the present invention comprises a container having a solution of 67 Cu]CuCl2 in hydrochloric acid, wherein the concentration of hydrochloric acid is about 0.1 mol / L.

[0198] The kit may also comprise a container consisting of sodium phosphate buffer, ethanol, gentisic acid or its salt, and ascorbic acid or its salt. The kit may comprise a container consisting of gentisic acid and sodium phosphate buffer in an aqueous solution, and a second container consisting of an aqueous ethanol and ascorbic acid or its salt solution, or alternatively, the container may consist only of ethanol, ascorbic acid or its salt, and gentisic acid or its salt. In one embodiment, the kit comprises a container containing sodium phosphate buffer and gentisic acid or its salt, and a second container containing aqueous ethanol and ascorbic acid or its salt.

[0199] Use of the preparation of the present invention

[0200] The formulations of the present invention can be particularly used for diagnostic and therapeutic purposes in medicine. Complexes with ligands having appropriate targeting fragments can be used to localize specific tissue types. For such complexes that are considered suitable for in vivo diagnosis and treatment, in addition to the necessary solubility and stability characteristics of the complex in solution, the complex must also exhibit appropriate kinetic, stability, and clearance characteristics under physiological conditions. The term "complex" as used herein can refer to a ligand-metal ion complex, where the metal ion is a radioisotope, or alternatively, the metal ion is a non-radioisotope.

[0201] The inventors have found that the formulations of the present invention comprising a compound of formula (I) or a salt thereof containing sarcophagine, a bombesin-like peptide, a propionamide linker, and a linker comprising a PEG group exhibit an affinity for the GRP receptor. The combination of each of these components in the compound of formula (I) allows for the administration of the corresponding complex containing a radionuclide, maintaining the stability of the complex in vivo and the accumulation of the complex at the intended target.

[0202] Comprising a complex with 67 The formulations of the present invention comprising a compound of formula (I) complexed with a Cu radionuclide can be used in methods of radioimaging, diagnosis, or treatment. Accordingly, 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, which comprises administering to the subject an effective amount of a formulation as defined herein. The inventors have found that the formulations of the present invention can be used in methods for radioimaging, methods for diagnosis, or methods for the treatment of cancer.

[0203] Radioimaging of a subject administered a 67 Cu-radiolabeled compound of formula (I) can be performed by positron emission tomography (PET) or single-photon emission computed tomography (SPECT). In one embodiment, the present invention provides a method for radioimaging a subject in need thereof, the method comprising administering a formulation of the present invention comprising a compound of formula (I) or a salt thereof complexed with a 67 Cu radionuclide. In certain embodiments, the present invention relates to a method for treating cancer in a subject in need thereof, the method comprising the step of administering an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions:

[0204]

[0205] Wherein:

[0206] X is where n is an integer from 1 to 10; and

[0207] R is a group selected from: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and a group of formula (A):

[0208]

[0209] The preparation further comprises a buffer and:

[0210] about 0.01% to about 0.1% (w / v) of gentisic acid or a salt thereof;

[0211] about 1% to about 7% (v / v) of ethanol; and

[0212] about 4% to about 10% (w / v) of ascorbic acid or a salt thereof.

[0213] In certain embodiments of the methods disclosed herein, R is a group of formula (A):

[0214]

[0215] where X is as defined above, for example having the following stereochemistry:

[0216]

[0217] In certain embodiments of the methods disclosed herein, R is optionally substituted C1-C 12 alkyl.

[0218] In another embodiment, R is methyl.

[0219] In another embodiment of the methods disclosed herein, X is where n is an integer from 1 to 10.

[0220] In another embodiment, X is and n is 4.

[0221] In certain embodiments, the method for treating cancer further comprises the step of performing a radioimaging on the subject. In certain embodiments, the radioimaging of the subject is performed about 12 hours after administration of the aqueous preparation. In other embodiments, the radioimaging of the subject is performed about 24 hours after administration of the aqueous preparation. In other embodiments, the radioimaging of the subject is performed about 36 hours after administration of the aqueous preparation. In other embodiments, the radioimaging of the subject is performed about 48 hours after administration of the aqueous preparation.

[0222] In one embodiment, after administration of a compound of formula (I) or a salt thereof complexed with a radionuclide, radioimaging of the subject is performed by PET. In another embodiment, after administration of a compound of formula (I) or a salt thereof complexed with a radionuclide, radioimaging of the subject is performed by SPECT.

[0223] The formulations of the present invention can be administered to a subject in need thereof by parenteral routes as a composition. Administration by intravenous injection may be preferred. Alternatively, the formulations of the present invention can be administered by intra-arterial or other routes for delivery into the systemic circulation. The subject to whom the compound has been administered is then placed in a PET (or SPECT) scanner, and an image showing the location of the complex and any subsequent cancer or tumor is obtained. This then allows for the diagnosis and detection of cancer or tumor.

[0224] The formulations of the present invention can be used in methods for treating diseases (such as cancer). The methods disclosed herein include administering to a subject in need thereof an effective amount of a formulation comprising a compound of formula (I) or a salt thereof complexed with a 67 64Cu radionuclide. The compound contains a bombesin-like peptide that binds to the GRP receptor expressed at the sites of various cancers. Given that the abundance of such receptors is associated with specific types of cancer, the accumulation of the compounds of the present invention detected by the radioactive decay of the radionuclide indicates the location of the cancer. The inventors have found that the compounds of the present invention show a specific affinity for the GRP receptor. In addition, the presence of both a propionamide linker and a linker containing a PEG group helps to provide a complex (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 formulations of the present invention comprising a compound of formula (I) or a salt thereof also have the stability necessary for 67 64Cu radionuclide. For example, sarcophagine present in the compound can chelate 67 64Cu such that 67 64Cu remains coordinated after administration to a subject and subsequent binding at the target site. Since 67 64Cu remains coordinated and localized at the target site due to its overall binding to the compound, radiation damage at other sites (such as healthy tissue) is minimized.

[0225] The term "cancer" as used herein 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 the GRP receptor. These are contrasted with benign tumors, which do not spread to other parts of the body, and thus the definition used herein includes all malignant (cancerous) disease states. Thus, the term encompasses the treatment of tumors.

[0226] Thus, the term "tumor" is generally used to define any malignant cancerous or precancerous cell growth and can 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 kidney cancer (and other cancers). In some embodiments, the tumor is associated with a cancer selected from: prostate cancer, breast cancer, ovarian cancer, urinary system cancer, small cell lung cancer, glioblastoma, and gastrointestinal stromal tumor.

[0227] In order for the complex to be suitable for radioimaging purposes, the radioisotope-ligand complex must exhibit sufficient metabolic stability, i.e., the complex retains the integrity of the radioisotope bound to the ligand for a necessary period of time. The present invention provides a complex of a compound of formula (I) or a salt thereof with 67 Cu that remains intact for up to 96 hours, as evidenced by the absence of radioisotope loss and metabolic degradation.

[0228] In one embodiment, the present invention provides the use of a formulation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu in a method for radioimaging a tumor or cancer. Those skilled in the art will understand that the information obtained from the radioimaging of a subject can be used to diagnose a tumor or cancer in the subject. In one embodiment, the present invention provides a method for diagnosing a tumor or cancer. In another embodiment, the tumor or cancer can be a tumor or cancer that expresses the 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 kidney tumor.

[0229] Administration of the formulation can treat the tumor or cancer. As described above, the compound of formula (I) or a salt thereof can bind to the GRP receptor on the surface of the tumor or cancer site, and the binding of such a compound to a location having the GRP receptor also brings 67 the Cu radioisotope into close proximity to that location. Since 67 the Cu radioisotope undergoes radioactive decay, the decay mode depending on the exact radioisotope selected, the decay products can be used to treat the tumor or cancer because the tumor or cancer is close to the compound of formula (I) or a salt thereof and67 Cu radionuclide.

[0230] In one embodiment, the present invention provides the use of a preparation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu in a method for treating a tumor or cancer. In one embodiment, the tumor or cancer can be a tumor or cancer that expresses the 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.

[0231] The citation in this specification of any prior publication (or information derived therefrom) or any known matter is not and should not be taken as an admission or acknowledgment 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.

[0232] In this specification and the appended claims, unless the context otherwise requires, the words "comprising / including" and variations thereof will be understood to imply the inclusion of the 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.

[0233] Embodiment

[0234] The phosphate buffer for radiolabeling is prepared using disodium hydrogen phosphate (anhydrous), sodium dihydrogen phosphate, and TraceSELECT water. All buffers are stored at room temperature when not in use.

[0235] Copper-67 ( 67 Cu) is obtained from NorthStar Medical Radioisotopes as 67 Cu]CuCl2 as a dry powder and reconstituted in TraceSELECT water, with an initial activity of 13.68 GBq and a total volume of 0.24 mL.

[0236] The analysis of the preparation is carried out by radio-HPLC and TLC. Using Ascentis Express C18, 2.7 μm, A 150 mm × 4.6 mm HPLC column was used for HPLC with a mobile phase of 0.1% trifluoroacetic acid (A) in water and 0.1% trifluoroacetic acid (B) in acetonitrile using a gradient of 15% B in A to 39% B in A over 12 minutes.

[0237] Silica gel 60F with dimensions of 1 cm × 10 cm was used 254 for TLC using a mobile phase of 10 mM NaEDTA in 50 mM phosphate buffer on an aluminum-backed TLC plate.

[0238] MeCN for HPLC (Honeywell, lot number S1RA1H), trifluoroacetic acid (TFA, ReagentPlus, 99%, Sigma Aldrich), (+)-L-sodium ascorbate (Sigma Aldrich, >99%, lot number: BCBV4424), and sodium gentisate hydrate (Sigma Aldrich, >99%, lot number: MKCC2280) used for HPLC were used as received. All HPLC mobile phases were prepared prior to use, filtered (using a 0.45 μm aqueous or organic filter), and degassed by a combination of vacuum and ultrasonic irradiation for 10 minutes. All ethanol used was 200 Proof USP ethanol. All syringes used were 'B Braun Injekt-F'.

[0239] The compound of formula (I), i.e., Sar-BBN, was obtained from Auspep Clinical Peptides, Tullarmine VIC, Australia with a purity of ≥95%.

[0240] Example 1 - Preparation of a single-dose formulation containing a compound of formula (Ib) complexed with 67 Cu

[0241] Sodium gentisate (10 mg) was dissolved in 0.1 M sodium phosphate buffer solution (14 mL) to provide a first solution (Solution A). Then 120 μg of the compound of formula (Ia) was dissolved in Solution A (14 mL) to provide a reaction vial.

[0242] For 67 the radioactivity of the Cu chloride solution was measured and the time was recorded. Then 67 the Cu chloride solution was added to the reaction vial containing the compound of formula (Ia) in solution and kept at ambient temperature for 25 minutes.

[0243] A second solution (Solution B) was prepared by dissolving sodium ascorbate (2 g) in TraceSELECT water (12 mL) and ethanol (1.1 mL).

[0244] Then transfer the contents of the reaction vial to the final product vial through a sterile filter. Aspirate solution B (4 mL) into a 10 mL syringe and use it to rinse the reaction vial. Transfer the contents of the reaction vial to the final product vial through a sterile filter and then gently homogenize the contents. Determine the activity in the final product vial and record the EOS time and the final product volume. After QC sampling, the final total volume is approximately 27 mL.

[0245] Table 1 below reproduces the summary of quality control tests for the aqueous formulation containing 67 Cu] of formula (Ib) prepared according to the above method.

[0246] Table 1. Summary of quality control tests for the aqueous formulation containing 67 Cu] of formula (Ib)

[0247]

[0248]

[0249] Stability of the formulations of the present invention

[0250] For 3 validation batches of the aqueous formulation containing 67 Cu] of formula (Ib) prepared as described above, monitor the product stability up to 96 hours after the end of synthesis (EOS). During the test, the radiochemical purity (RPC) did not drop below 94.0%. Figure 1 The radio-HPLC chromatogram at 96 hours after EOS is shown.

Claims

1. An aqueous preparation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions: Wherein: X is where n is an integer from 1 to 10; and R is a group selected from the following: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and the group of formula (A): The preparation further comprises a buffer solution and: About 0.01% to about 0.1% (w / v) of gentisic acid or its salt; About 1% to about 7% (v / v) of ethanol; and About 4% to about 10% (w / v) of ascorbic acid or its salt.

2. The aqueous preparation according to claim 1, wherein for the compound of formula (I) or its salt, R is a group of formula (A): Wherein X is defined as in claim 1.

3. The aqueous preparation according to claim 2, wherein the group of formula (A) has the following stereochemistry:

4. The aqueous preparation according to claim 1, wherein for the compound of formula (I) or a salt thereof, R is an optionally substituted C1-C 12 alkyl group.

5. The aqueous preparation according to claim 4, wherein R is methyl.

6. The aqueous preparation according to any one of claims 1 to 5, wherein for the compound of formula (I) or a salt thereof, X is wherein n is an integer from 1 to 10.

7. The aqueous preparation according to claim 6, wherein X is and n is 4.

8. The aqueous preparation according to claim 1, wherein the compound of formula (I) or its salt is selected from formula (Ia) or formula (Ib):

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

10. The aqueous preparation according to any one of claims 1 to 9, wherein the preparation comprises: About 0.03% to about 0.04% (w / v) of gentisic acid or its salt; About 4% (v / v) of ethanol; and About 6.5% to about 8% (w / v) of ascorbic acid or its salt.

11. The aqueous preparation according to any one of claims 1 to 10, wherein the gentisate is sodium gentisate.

12. The aqueous preparation according to any one of claims 1 to 11, wherein the concentration of gentisic acid or its salt does not exceed 0.04% (w / v).

13. The aqueous preparation according to any one of claims 1 to 12, wherein the pH of the preparation is about 4 to about 8.

14. The aqueous preparation according to any one of claims 1 to 13, wherein the radiochemical purity of the preparation exceeds about 90%, 92%, 94%, 96% or 98% over a period of at least 96 hours.

15. The aqueous formulation according to any one of claims 1 to 14, wherein the amount of free 67 Cu in the formulation does not exceed about 5%, 4%, 3%, 2% or 1% of the total amount of 67 Cu present.

16. The aqueous preparation according to any one of claims 1 to 15, wherein the radioactive concentration of the preparation is about 0.1 GBq / mL to about 1.0 GBq / mL.

17. A method for preparing an aqueous preparation of a compound of formula (I) or a salt thereof complexed with 67 Cu ions, said method comprising the steps of: i) Dissolving the compound of formula (I) or its salt in a buffer solution containing gentisic acid or its salt; ii) Add to the solution in step i) 67 a solution of Cu ions; iii) Filtering the solution obtained from step ii); and iv) Diluting the reaction mixture by adding aqueous ethanol and ascorbic acid; To recover an aqueous formulation comprising a compound of formula (I) or a salt thereof complexed with 67 Cu ions.

18. The method according to claim 17, wherein the buffer solution is sodium phosphate buffer.

19. The method according to claim 17 or 18, wherein the gentisic acid or its salt 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 its salt is present in an amount of about 4% to about 10% (w / v).

20. The method according to any one of claims 17 to 19, wherein the gentisic acid or its salt 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 its salt is present in an amount of about 6.5% to about 8% (w / v).

21. An aqueous preparation prepared by the method according to any one of claims 17 to 20.

22. A kit for preparing an aqueous preparation of a compound of formula (I) or a salt thereof complexed with 67 Cu ions, the kit comprising: A container containing a freeze-dried compound of formula (I) or a salt thereof: Wherein: X is where n is an integer from 1 to 10; and R is a group selected from the following: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and the group of formula (A): Containing 67 A container of Cu ion solution; And Instructions for preparing an aqueous formulation, including adding sodium phosphate buffer, ethanol, gentisic acid or a salt thereof, and ascorbic acid or a salt thereof.

23. Kit for preparing an aqueous preparation of a compound of formula (I) or a salt thereof complexed with 67 Cu ions, said kit comprising: A container containing a freeze-dried compound of formula (I) or a salt thereof: Wherein: X is where n is an integer from 1 to 10; and R is a group selected from the following: H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C 12 alkyl, optionally substituted amino, optionally substituted amide and optionally substituted aryl, and a group of formula (A): A container containing 67 a Cu ion solution; A container composed of sodium phosphate buffer and gentisic acid or a salt thereof; A container composed of aqueous ethanol and ascorbic acid or a salt thereof; and Instructions for preparing an aqueous formulation.

24. A method for radioimaging, diagnosing or treating cancer, the method comprising administering to a subject in need thereof an aqueous formulation according to any one of claims 1 to 16.

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

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

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

28. The method according to any one of claims 24 to 27, wherein the method is for treating cancer, and the method further comprises a step of radioimaging the subject.

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