Formulations of radiopharmaceuticals complexed with copper

Abstract

The present invention relates to formulations of Sar-bisPSMA that is complexed with a Cu ion. The present invention also relates to processes for preparing said formulations and kits comprising same. The formulations disclosed herein are of use in radioimaging, diagnosis and radiotherapy.

Description

Formulations of radiopharmaceuticals complexed with copperField

[0001] The present invention relates to formulations of Sar-bisPSMA that is complexed with a Cu ion. The present invention also relates to processes for preparing said formulations and kits comprising same. The formulations disclosed herein are of use in radioimaging, diagnosis and radiotherapy.Background

[0002] Sar-bisPSMA contains two PSMA -binding motifs, known to bind to PSMA receptors. These receptors are often expressed in certain cancers, e.g. prostate cancer, primary and secondary forms of cancer.

[0003] Radiolabelled complexes of compounds known to bind to PSMA have been used to locate and image cancers in subjects, however physical characteristics of the compounds, the radioisotopes complexed by the compounds and overall formulations of the complexes are inherently limited in their use. For example, where the radioisotope has a short half life, the formulation must be administered immediately after preparation to ensure images of sufficient quality are obtained for diagnosis. Stability of the compounds under physiological conditions may result in leaching of the radioisotope, which limits the amount of the radioisotope that localises at the tumour site and is then available for imaging. Radiolysis of the compound that is attributed to the natural decay of the radioisotope also leads to the loss of the radioisotope from the compound and again limits the amount of the radioisotope that is used meaningfully and also the time over which imaging and / or treatment can occur.

[0004] Where the formulation is unstable and results in the decomposition of the ligand that complexes the radioisotope, the radioisotope circulates freely in the subject and the decay products of the radioisotope can damage other tissues. This off-target effect is unwanted and may lead to the damage of healthy tissue in the subject.

[0005] Furthermore, it is known that the shelf life of many radiopharmaceuticals are limited, such that prepared formulations must be used within several hours. This in turn can lead to increased burden and limited flexibility for both the medical practitioner and patient. Where aformulation is prepared and cannot be used within this small window, this results in a significant waste in resources.

[0006] For at least the reasons above, there remains a need for stable formulations of a radiolabelled compound that are suitable for the imaging and treatment of cancers.Summary of the invention

[0007] The present inventors have found that the formulations disclosed herein comprising a compound of Formula (I) complexed with a Cu ion are useful for the imaging, diagnosis and / or treatment of a cancer. The formulations disclosed herein comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the compound of Formula (I) is complexed with a Cu ion, and where the formulation also comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof. The properties of a specific Cuion allow for the use of the formulation in methods of imaging, diagnosis and / or treatment of a cancer in a subject.

[0008] The present inventors have found that the formulations disclosed herein have excellent stability, where the complex of the compound of Formula (I) and the Cu ion remains intact and the formulation contains little to no free Cu ion in solution. This then provides a formulation that has the requisite radiochemical purity for administration to a subject. Furthermore, the present inventors have found that the formulations disclosed herein maintain a sufficient level of radiochemical purity fora time, such that the formulation doesnot require administration to the subject immediately after preparation. Without wishing the be bound by theory, the present inventors believe that the combination of the compound of Formula (I) complexed with a Cu ion in the presence of gentisic acid or a pharmaceutically acceptable salt thereof, with the radiostabilisers N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof allows for a formulation that shows exceptional stability and therefore radiochemical purity.

[0009] Since the formulations disclosed herein show exceptional stability, the formulations therefore maintain radiochemical purity for a longer time. This means that the shelf life of the formulation (once prepared) is also longer, as is the time for which the formulation remains fit for clinical use. This allows for greater efficiency when preparing multiple doses of the formulation, since the longer shelf life means that a larger batch of the formulation can be prepared and used. As shown herein, the processes for preparing the formulations as nowdisclosed can be scaled up to produce multiple doses at the same time, which allows fora single preparation step and the dosing of multiple patients. Even if there are delays in the dosing of a patient, the longer time in which the formulation remains viable can often mean that the patient can still receive the planned dose since the formulation has sufficient purity for the intended purpose.

[0010] The present inventors have also found that the stability of the formulations as disclosed herein is a measured at room temperature. This in turn means that efficiencies in relation to storage and transport can be achieved, i.e. the need for cold chain transport and storage at lowered temperatures is not absolutely necessary to ensure stability and usability of the formulation. While storage at lower temperatures is possible, this would likely result in even more prolonged stability of the formulations disclosed herein.

[0011] According to a first aspect, the present invention provides a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation further comprises N-acetyl cysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof. The present inventors have found that a formulation of the compound of Formula (I) complexed with a Cu ion that comprises each of N-acetylcysteine, gentisic acid and ascorbic acid, or their pharmaceutically acceptable salts, provides a formulation that results in the complexed compound of Formula (I) showing stability at room temperature for at least 72 hours. While the formulation comprises each of N-acetylcysteine, gentisic acid and ascorbic acid or their pharmaceutically acceptable salts, the inventors have found that the role of gentisic acid is to facilitate complexation or coordination of the metal isotope, i.e. a Cu ion, with the compound of Formula (I). This is distinct from the previous use of gentisic acid or its salts as a stabilising agent for other radiopharmaceuticals informulations. Additionally, the present inventors have found that the use of both N-acetylcysteine and ascorbic acid, or their pharmaceutically acceptable salts, each contribute to stability of the compound of Formula (I) complexed with a Cu ion when in solution, as a result of the radiostabilising properties of these components.

[0012] In some embodiments, the formulation comprises N -acetylcysteine in the form of a sodium salt.

[0013] In certain embodiments, the formulation comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof in an amount of between about 5 mg / mL to about 200 mg / mL. In certain embodiments, the formulation comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof in an amount of about 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL or 200 mg / mL.

[0014] The present inventors have also found that where the formulation comprises further excipients, the stability and radiochemical purity of the formulation may be further extended or enhanced. In certain embodiments, the formulations disclosed herein comprise one or more further excipients.

[0015] In certain embodiments, the formulation further comprises gentisic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the gentisic acid is in the form of a sodium salt.

[0016] In some embodiments, the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof present in an amount of between about 0.1 mg / mL to about 1.0 mg / mL. In some embodiments, the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof in an amount of about 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL or 1.0 mg / mL.

[0017] In other embodiments, the formulation further comprises ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the ascorbic acid is in the formof a sodium salt. In certain embodiments, the formulation comprises ascorbic acid or a pharmaceutically acceptable salt thereof in an amount of between about 5 mg / mL to about 200 mg / mL. In certain embodiments, the formulation comprises ascorbic acid or a pharmaceutically acceptable salt thereof in an amount of about 5 mg / rnL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL or 200 mg / mL.

[0018] In some embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable salt thereof to the concentration of ascorbic acid or a pharmaceutically acceptable salt thereof is between about 1:10 to about 10:1. In other embodiments, the ratio of N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof is about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1 or about 10:1. In certain embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable thereof to the concentration of ascorbic acid or a pharmaceutically acceptable thereof is about 1:1. In other embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable salt thereof to the concentration of ascorbic acid or a pharmaceutically acceptable salt thereof is about 1:2. In other embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable salt thereof to the concentration of ascorbic acid or a pharmaceutically acceptable salt thereof is about 1:3. In other embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable salt thereof to the concentration of ascorbic acid or a pharmaceutically acceptable salt thereof is about 1:4. In other embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable thereof to the concentration of ascorbic acid or a pharmaceutically acceptable thereof is about 4:1. In other embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable thereof to the concentration of ascorbic acid or a pharmaceutically acceptable thereof is about 3:1. In other embodiments, the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable thereof to the concentration of ascorbic acid or a pharmaceutically acceptable thereof is about 2:1.

[0019] The present inventors have also found that a formulation of the compound of Formula (I) complexed with a Cu ion comprising N-acetylcysteine, gentisic acid and ascorbic acid, ortheir respective pharmaceutically acceptable salts, provides a formulation that is stable and suitable for administration for up to about 3 days, i.e. 72 hours. In certain embodiments, the formulations disclosed herein are stable and suitable for administration over a period of up to about 3 days, wherein the formulation comprises free Cu ion at a concentration of not more than about 5%. In other embodiments, the formulation comprises free Cu ion ata concentration of not more than about 5%, about 4%, about 3%, about 2% or about 1% for a period of up to about 3 days. In other embodiments, the formulation comprises free Cu ion at a concentration of not more than about 5%, about 4%, about 3%, about 2% or about 1% for a period of up to about 2 days. In other embodiments, the formulation comprises free Cu ion at a concentration of not more than about 5%, about 4%, about 3%, about 2% or about 1% for a period of up to about 1 day.

[0020] In some embodiments, the pH of the formulation is between about 2 and about 10. In other embodiments, the pH of the formulation is about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10.

[0021] According to a second aspect, the present invention provides a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises N-acetylcysteine, sodium gentisate and sodium ascorbate.

[0022] In some embodiments, the pH of the formulation is between about 2 and about 10. In other embodiments, the pH of the formulation is about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10.

[0023] In certain embodiments of the above aspects, the formulation further comprises a buffer solution. In certain embodiments, the buffer solution is selected from the group consisting of aphosphate buffer, an acetate buffer and a citrate buffer. In certain embodiments, the formulation comprises a phosphate buffer solution.

[0024] In other embodiments, the formulation further comprises ethanol.

[0025] The compound of Formula (I) in the formulations disclosed herein may be complexed with a Cu ion.

[0026] In certain embodiments, the Cu ion is a Cu radioisotope. In some embodiments, the Cu radioisotope is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In certain embodiments, the Cu ion is60Cu. In certain embodiments, the Cu ion is61Cu. In certain embodiments, the Cu ion is62Cu. In certain embodiments, the Cu ion is64Cu. In certain embodiments, the Cu ion is67Cu.

[0027] The present inventors have found that the formulations disclosed herein can comprise a compound of Formula (I) complexed with a Cu ion, where the specific activity is in the range of from about 50 GBq to about 1000 GBq. Without wishing to be bound by theory the present inventors believe that the components of the formulations as disclosed herein allow for high specific activities to be achieved.

[0028] In certain embodiments, the formulation comprising a compound of Formula (I) complexed with a Cu ion as disclosed or prepared herein is in the range of about 5 GBq to about 1000 GBq. In certain embodiments, the activity of the formulation is about 5 GBq, about 10 GBq, about 20 GBq, about 30 GBq, about 40 GBq, about 50 GBq, about 60 GBq, about 70 GBq, about 80 GBq, about 90 GBq, about 100 GBq, about 110 GBq, about 120 GBq, about 130 GBq, about 140 GBq, about 150 GBq, about 160 GBq, about 170 GBq, about 180 GBq, about 190 GBq, about 200 GBq, about 250 GBq, about 300 GBq, about 350 GBq, about 400 GBq, about 450 GBq, about 500 GBq, about 550 GBq, about 600 GBq, about 650 GBq, about 700 GBq, about 750 GBq, about 800 GBq, about 850 GBq, about 900 GBq, about 950 GBq or about 1000 GBq.

[0029] According to a third aspect, the present invention provides a kit for the preparation of a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the kit comprising:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N -acetylcysteine or a pharmaceutically acceptable salt thereof.

[0030] In certain embodiments, the kit further comprises a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof.

[0031] In other embodiments, the kit further comprises a container comprising gentisic acid or a pharmaceutically acceptable salt thereof. In other embodiments, the kit further comprises ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises a container comprising gentisic acid or a pharmaceutically acceptable salt thereof and another container comprising ascorbic acid or a pharmaceutically acceptable salt thereof.

[0032] In certain embodiments, the kit comprises:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion;iii) one or more containers comprising gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof.

[0033] In certain embodiments, the kit comprises:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion;iii) a container comprising gentisic acid or a pharmaceutically acceptable salt thereof;iv) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof;v) a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N-acetylcysteine or a pharmaceutically acceptable salt thereof.

[0034] The present inventors have also found that specific processes allow for the preparation of formulations disclosed herein, wherein the formulation has sufficient stability for use as a radiopharmaceutical. Therefore, according to a fourth aspect, the present invention provides a process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising the steps of:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a Cu ion in hydrochloric acid to the solution of step i); and iii) adding ascorbic acid or a pharmaceutically acceptable salt thereof and N- acetylcysteine or a pharmaceutically acceptable salt thereof to the solution of step ii).

[0035] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt is reacted with a Cu ion in the presence of a buffer solution and gentisic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is provided as a chloride salt.

[0036] In other embodiments, the solution comprising N -acetylcysteine or a pharmaceutically acceptable salt thereof further comprises ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the solution comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof is prepared with a phosphate buffer solution.

[0037] In certain embodiments, the compound of Formula (I) is reconstituted in a phosphate buffer solution prior to reaction with a Cu ion.

[0038] In certain embodiments, the step of reacting the compound of Formula (I) with a Cu ion is performed at ambient temperature.

[0039] In further embodiments, the solution comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof, ascorbic acid or a pharmaceutically acceptable salt thereof, the compound of Formula (I) and a Cu ion is filtered. In certain embodiments, the solution is filtered and the filter is eluted with a further aliquot of a solution comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof.

[0040] In certain embodiments, the Cu ion is provided as a solution of a chloride salt of the Cu ion. In certain embodiments, the Cu ion is a Cu11ion. In certain embodiments, the Cu ion is a60Cu,61Cu,62Cu,64Cu or67Cu ion. In certain embodiments, the Cu ion is provided as CunC12 solution. In certain embodiments, the Cu ion is provided as a solution of [60Cu]CuC12, [61CU]CUC12, [62CU]CUC12, [64CU]CUC12or [67CU]CUC12.

[0041] In certain embodiments, the present invention provides a process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a64Cu ion in hydrochloric acid to the solution of step i); iii) adding a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or a pharmaceutically acceptable salt thereof; and iv) filtering the solution of step iii).

[0042] In certain embodiments, the present invention provides a process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a67Cu ion in hydrochloric acid to the solution of step i);iii) adding a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or a pharmaceutically acceptable salt thereof; and iv) filtering the solution of step iii).

[0043] In certain embodiments, the process further includes the step of adjusting the pH of the formulation to a physiologically acceptable pH. In some embodiments, the pH of the formulation is adjusted by the addition of abase. In certain embodiments, the base is an organic base. In other embodiments, the base is an inorganic base. In other embodiments, the base is a hydroxide. In certain embodiments, the base is sodium hydroxide. In other embodiments, the pH of the formulation is adjusted by first adjusting the buffer solution in which the formulation is prepared.

[0044] Some processes disclosed herein for preparing a formulation of the compound of Formula (I) complexed with a Cu ion include the stepwise addition of the excipients N-acetylcysteine and ascorbic acid (or their pharmaceutically acceptable salts) to a solution of the complexed compound of Formula (I). While a stepwise addition of excipients and a Cu ion to the compound of Formula (I) is disclosed herein, the present inventors believe that a single step process can be used to prepare the formulations disclosed herein. According to a fifth aspect, the present invention provides a process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof, wherein the process comprises the step of:reacting the compound of Formula (I) or a pharmaceutically acceptable salt thereof with a Cu ion in a buffer solution comprising gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof.

[0045] According to a sixth aspect, the present invention provides a process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof, wherein the process comprises combining:i) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, ii) gentisic acid or a pharmaceutically acceptable salt thereof,iii) ascorbic acid or a pharmaceutically acceptable salt thereof,iv) N-acetylcysteine or a pharmaceutically acceptable salt thereof; andv) a Cu ion in a solution of hydrochloric acid,in a buffer solution.

[0046] In certain embodiments, the process further includes the step of filtering of the solution. In certain embodiments, the solution is filtered through a resin. In particular embodiments, the solution is filtered through a cation binding resin.

[0047] In certain embodiments, the processes described herein are performed at ambient room temperature.

[0048] In certain embodiments, the buffer solution is a phosphate buffer solution.

[0049] In other embodiments, gentisic acid is present as sodium gentisate.

[0050] In other embodiments, ascorbic acid is present as sodium ascorbate.

[0051] In certain embodiments, the Cu ion is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

[0052] According to a sixth aspect, the present invention provides a formulation prepared in accordance with a process as defined in the fourth, fifth or sixth aspects.

[0053] According to a seventh aspect, the present invention provides a method for radioimaging and / or, diagnosing a cancer, the method comprising administering to a subject in need thereof a formulation according to the first, second or sixth aspects. In certain embodiments, the method further comprises the step of imaging of the subject at a time after administration of the formulation.

[0054] According to an eighth aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for radioimaging or diagnosing a cancer.

[0055] According to a ninth aspect, the present invention provides a method for treating a cancer, the method comprising administering to a subject in need thereof a formulation according to the first, second or sixth aspects.

[0056] According to a tenth aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a Cu ion, N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer.

[0057] In certain embodiments of the above aspects, the Cu ion complexed to the compound of Formula (I) is a Cu radioisotope. In certain embodiments of the methods disclosed herein, the Cu radioisotope is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In other embodiments, the Cu radioisotope is a6 xCu radioisotope. In other embodiments, the Cu radioisotope is a64Cu radioisotope. In other embodiments, the Cu radioisotope is a67Cu radioisotope.

[0058] In certain embodiments, the cancer is associated with a prostate specific membrane antigen (PSMA) receptor. In certain embodiments, the cancer is a prostate cancer. In certain embodiments, the cancer is a primary prostate cancer. In other embodiments, the cancer is asecondary prostate cancer. A person skilled in the art would understand that other cancers that are not associated with the prostate may express PSMA receptors and therefore may be radioimaged, diagnosed and / or treated by administration of one or more formulations as disclosed herein. In certain embodiments, the cancer is a breast cancer. In other embodiments, the cancer a neuroendocrine cancer. In other embodiments, the cancer is a colon cancer. In other embodiments, the cancer is a liver cancer. In other embodiments, the cancer is a brain cancer.Brief description of the figures

[0059] One or more embodiments of the present invention are hereinafter described, by way of example only, with reference to the accompanying figures.

[0060] Figure 1. High performance liquid chromatography (HPLC) chromatograms of a formulation comprising Sar-bisPSMA coordinated with64Cu2+, sodium gentisate and ascorbic acid taken at (A) end of synthesis, (B) 26 hours and (C) 48 hours. These chromatograms show that the formulation contained at least 16% and 23% free64Cu2+radioisotope after 26 hours and 48 hours, respectively, suggesting that the use of ascorbic acid alone as radiostabiliser provides only limited stability to a formulation of Sar-bisPSMA coordinated with64Cu2+. The formulation associated with these chromatograms is described in Example 4a.

[0061] Figure 2. Thin layer chromatography (TLC) chromatograms of a formulation comprising Sar-bisPSMA coordinated with64Cu2+, sodium gentisate and ascorbic acid taken at (A) end of synthesis, (B) 26 hours and (C) 48 hours. These chromatograms show that the formulation contained at least 30% and 12% free64Cu2+radioisotope after 26 hours and 48 hours, respectively, suggesting that the use of sodium ascorbate alone as radiostabiliser provides only limited stability to a formulation of Sar-bisPSMA coordinated with64Cu2+. The formulation associated with these chromatograms is described in Example 4a.

[0062] Figure 3. High performance liquid chromatography (HPLC) chromatograms of a formulation comprising Sar-bisPSMA coordinated with64Cu2+, sodium gentisate and N-acetylcysteine taken at (A) end of synthesis, (B) 26 hours and (C) 48 hours. These chromatograms show that the formulation contained at least 11% and 14% free64Cu2+radioisotope after 26 hours and 48 hours, respectively, suggesting that the use of N-acetylcysteine alone provides only limited stability to a formulation of Sar-bisPSMA coordinated with64Cu2+. The formulation associated with these chromatograms is described in Example 4b.

[0063] Figure 4. Thin layer chromatography (TLC) chromatograms of a formulation comprising Sar-bisPSMA coordinated with64Cu2+, sodium gentisate and N-acetylcysteine taken at (A) end of synthesis, (B) 26 hours and (C) 48 hours. These chromatograms show that the formulation contained at least 9% and 20% free64Cu2+radioisotope after 26 hours and 48 hours, respectively, suggesting that the use of N-acetylcysteine alone provides only limited stability to a formulation of Sar-bisPSMA coordinated with64Cu2+. The formulation associated with these chromatograms is described in Example 4a.

[0064] Figure 5. Representative high performance liquid chromatography (HPLC) chromatograms of a formulation comprising Sar-bisPSMA coordinated with64Cu2+, sodium gentisate, N-acetylcysteine and sodium ascorbate taken at (A) end of synthesis, (B) 24 hours, (C) 48 hours and (D) 72 hours. These chromatograms show the stability of the formulation, with less than 2% free64Cu2+detected in the formulation at least 72 hours after preparation. This shows that the use of both N-acetylcysteine and sodium ascorbate provides better stabilisation than either of these components alone. The formulation associated with these chromatograms is described in Example 4c.

[0065] Figure 6. Representative thin layer chromatography (TLC) chromatograms of a formulation comprising Sar-bisPSMA, sodium gentisate, N-acetylcysteine and sodium ascorbate taken at (A) end of synthesis, (B) 24 hours, (C) 48 hours and (D) 72 hours. These chromatograms show the stability of the formulation, with less than 1% free64Cu2+present in the formulation at least 72 hours after preparation. This shows that the use of both N-acetylcysteine and sodium ascorbate provides better radiostabilisation than either of these excipients alone. The formulation associated with these chromatograms is described in Example 4c.Detailed description

[0066] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will beunderstood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0067] Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of", and variations such as "consists essentially of" will be understood to indicate that the recited element(s) is / are essential i.e. necessary elements of the invention. The phrase allows for the presence of other non-recited elements which do not materially affect the characteristics of the invention but excludes additional unspecified elements which would affect the basic and novel characteristics of the invention defined.

[0068] The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. For the purposes of the present invention, the following terms are defined below, on how the value is measured or determined, i.e., the limitations of the measurement system.Formulations of the compound of Formula (I) complexed with a Cu ion

[0070] The present invention relates to formulations of a macrocyclic ligand of Formula (I) complexed with a Cu ion. The present inventors have found that the formulations of a complex disclosed herein minimise dissociation of the radioisotope from the ligand and / or minimise radiolysis of the ligand arising from the radioisotope. This in turn increases the shelflife of the formulation and reduces the amount of the ligand and isotope that is wasted. In relation to the patient experience, the formulations disclosed herein reduce the probability of any unwanted side effects related to the circulation of the free radioisotope around the patient and causing radiation damage to other healthy tissues.

[0071] It has previously been found that ligands containing a urea-based motif are known to bind to the catalytic site of prostate-specific membrane antigen (PSMA), which is typically expressed in prostate tissue and upregulated in some prostate cancers. An example of a ligand containing such a motif is Sar-bisPSMA, which is the macrocyclic ligand 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6.]icosane (also known as sarcophagine or "Sar"), where each terminal amine group is attached to a linker group and a urea -based motif.

[0072] Sar-bisPSMA is shown in Formula (I):Formula (I)

[0073] The compound of Formula (I) may be produced through a series of coupling reactions between the sarcophagine ligand, the linker and the urea motif. Procedures for the preparation of the compound of Formula (I) can be found in WO 2018 / 223180.

[0074] The compound of Formula (I) may have the structure of Formula (la) as depicted below, where the stereochemistry of compound is defined:Formula (la).

[0075] Where unspecified, any reference to the compound of Formula (I) below should be taken to include a reference to the compound of Formula (la) as well.

[0076] The present invention is related to the use of the compounds of Formula (I) and (la) in formulations. The compounds of Formula (I) and (la) may be used as a pharmaceutically acceptable salt. The compounds of Formula (I) and (la) contain two urea motifs that are independently capable of binding to the catalytic site of PSMA. The present inventors believe that the increased binding affinity of compounds of Formula (I) at the desired site is due to the presence of a second urea motif. Without wishing to be bound by theory, the present inventorsbelieve that the additional binding affinity of compounds of Formula (I), which appears to be more effective than the use of twice the amount of the analogous compound having only one urea motif, is related to the presence of the second urea motif. Subsequently, the formulations described herein containing a compound of Formula (I) or (la) show better efficacy than formulations of an analogous compound containing the urea motif.

[0077] The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) and (la) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic and arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[0078] In a preferred embodiment, the compound of Formula (I) is provided as a chloride salt.

[0079] The formulations of the present invention comprise a compound of Formula (I), or a salt thereof, and a radioisotope. The radioisotope, which may also be referred to as a radionuclide, may be a metal or a metal ion. The compound of Formula (I) of the present specification has been found tobe particularly successful in complexing copper ions, especially Cu2+ions. A person skilled in the art would appreciate that a complex of the compound of Formula (I) may be produced by contacting the compound of Formula (I) with the desired radioisotope, where the radioisotope is a Cu2+ion.

[0080] In an embodiment, the ligand is complexed with a Cu ion. The copper ion may be radioactive, and thus a radionuclide or radioisotope of copper. In an embodiment, the ligand is complexed with60Cu. In another embodiment, the ligand is complexed with61Cu. In another embodiment, the ligand is complexed with64Cu. In another embodiment, the ligand iscomplexed with67Cu. In a preferred embodiment, the ligand is complexed with64Cu. In another preferred embodiment, the ligand is complexed with67Cu.

[0081] The complex of Formula (I) with a Cu radioisotope may show some instability (or does not have the requisite stability) and may be prone to radiolysis when in solution. The present inventors have found that complex of Formula (I) and a Cu radioisotope may be stabilised in a formulation, where the formulation also comprises N -acetylcysteine or a pharmaceutically acceptable salt thereof.

[0082] N-acetylcysteine has the structure below and may also be known as acetylcysteine, N-acetyl-L-cysteine, NALC and NAC.HOrSO SH

[0083] In certain embodiments, the formulation comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof in an amount of between about 10 mg / mL to about 200 mg / mL. In some embodiments, the formulation comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL or 200 mg / mL.

[0084] The formulations disclosed herein may further comprise one or more excipients. Although the present inventors have shown that the addition of N-acetylcysteine to a formulation of the compound of Formula (I) complexed with a Cu ion increases the stability and radiochemical purity of the formulation, it is believed that the use of other stabilising excipients could further increase the stability and radiochemical purity of the formulation.

[0085] In certain embodiments, the formulation comprising a compound of Formula (I) complexed with a Cu ion and N-acetylcysteine further comprises one or more excipients. In certain embodiments, the excipient is a radiopharmaceutical stabiliser. In other embodiments, the one or more excipients is selected from gentisic acid, ascorbic acid, L-methionine and their pharmaceutically acceptable salts.

[0086] In some embodiments, the formulation comprising a compound of Formula (I) complexed with a Cu ion and N-acetylcysteine further comprises gentisic acid or a pharmaceutically acceptable salt thereof.

[0087] Gentisic acid is also known as 2,5-dihydroxybenzoic acid, 5 -hydroxy salicylic acid or hydroquinonecarboxylic acid and has the structure below. Salts of gentisic acid may include the sodium salt and the sodium salt hydrate. Any reference to gentisic acid may include a reference to salts thereof, where relevant. Other isomers of dihydroxybenzoic acid are also contemplated. Examples of other isomers include 2,4 -dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid, and salts thereof.

[0088] The present invention provides formulations of the compound of Formula (I) where the formulation comprises gentisic acid or a salt thereof. The present inventors have found that the use of gentisic acid or salts thereof in formulations of radiopharmaceuticals, for example, compounds of Formula (I) complexed with a Cu ion, facilitate the coordination or complexation of the radioisotope with the ligand. In other words, the primary function of gentisic acid. Without wishing to be bound by theory, while the present inventors believe that the role of gentisic acid or a pharmaceutically acceptable salt thereof is to facilitate complexation of the Cu ion, the use of gentisic acid in a formulation as disclosed herein may also contribute to the overall stability of the complexed compound of Formula (I) by preventing dissociation of the Cu ion.

[0089] In some embodiments, the formulation further comprises gentisic acid or a pharmaceutically acceptable salt thereof in an amount between about 0.1 mg / mL to about 0.1 mg / mL. In some embodiments, the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof in an amount of about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL or 1.0 mg / mL.

[0090] In other embodiments, the formulation comprising a compound of Formula (I) complexed with a Cu ion and N-acetylcysteine further comprises ascorbic acid or a pharmaceutically acceptable salt thereof.

[0091] Ascorbic acid is also known as 2,3-didehydro-L-threo-hexano-l,4-lactone or Vitamin C. Salts of ascorbic acid include sodium ascorbate, potassium ascorbate, calcium ascorbate and magnesium ascorbate. Any reference to ascorbic acid may include a reference to salts thereof, where relevant. One or more enantiomeric forms of ascorbic acid are also contemplated, for example, L-ascorbic acid.HOHO OH

[0092] In certain embodiments, the formulation further comprises ascorbic acid or a pharmaceutically acceptable salt thereof in an amount of between about 10 mg / mL to about 200 mg / mL. In certain embodiments, the formulation comprises ascorbic acid or a pharmaceutically acceptable salt thereof in an amount of about 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL or 200 mg / mL.

[0093] In other embodiments of the present invention, the formulation comprising a compound of Formula (I) complexed with a Cu ion and N-acetylcysteine comprises gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof.

[0094] The formulations of the present invention may comprise ethanol as a component. The ethanol used in the formulation may be anhydrous ethanol. Alternatively, the ethanol used in the formulation may not have been subject to drying processes and may be hydrated. The ethanol is preferably pharmaceutical grade ethanol. The ethanol present in the formulation may further assist in preventing radiolysis of the radiolabelled complex of Formula (I).

[0095] In an embodiment, ethanol is present in the formulation in an amount of about 7% to about 13% (v / v). In an embodiment, ethanol is present in the formulation in an amount of about 7% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about8% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 9% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 10% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 11% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 12% (v / v). In another embodiment, ethanol is present in the formulation in an amount of about 13% (v / v). In a preferred embodiment, ethanol is present in the formulation in an amount of about 10% (v / v). In other embodiments, the present invention also contemplates ethanol in ranges between the aforementioned amounts.

[0096] The formulations of the present invention may also comprise sodium chloride as a component. The sodium chloride in the formulations 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, normal saline is defined as an aqueous solution of sodium chloride at a concentration of 0.9% (w / v). In an embodiment of the present invention, the sodium chloride of a formulation is provided by a saline solution.

[0097] In an embodiment, sodium chloride is present in the formulation in an amount of about 0.6% to 1.2% (w / v). In an embodiment, sodium chloride is present in an amount of about 0.6% (w / v). In another embodiment, sodium chloride is present in an amount of about 0.7% (w / v). In another embodiment, sodium chloride is present in an amount of about 0.8% (w / v). In another embodiment, sodium chloride is present in an amount of about 0.9% (w / v). In another embodiment, sodium chloride is present in an amount of about 1.0% (w / v). In another embodiment, sodium chloride is present in an amount of about 1.1% (w / v). In another embodiment, sodium chloride is present in an amount of about 1.2% (w / v). In a preferred embodiment, sodium chloride is present in the formulation in an amount of about 0.9% (w / v). In other embodiments, the present invention also contemplates sodium chloride in ranges between the aforementioned amounts.

[0098] The formulations of the present invention have a pH of between about 2 to about 10. A person skilled in the art would understand that the pH of the formulation is an inherent characteristic of the formulation, attributed to the combination of the compound of Formula (I) or a complex with a Cu ion thereof, and the remaining excipients of the formulation. Alternatively, the pH of the formulation may be modified to a desired value by the addition of one or more buffering agents. An example of a suitable buffer solution includes an acetatebuffer, which may comprise a mixture of sodium acetate and acetic acid. In certain embodiments, formulations of the present invention comprise an acetate buffer. Another suitable buffer solution includes a phosphate buffer, which may comprise a mixture of various phosphate salts or hydrates thereof. Examples of phosphate salts that are suitable include sodium dihydrogen phosphate (NaBEPCh), disodium hydrogen phosphate (ISfeHPCh), potassium dihydrogen phosphate (KH2PO4) and dipotassium hydrogen phosphate (K2HPO4). In an embodiment, the phosphate buffer contains sodium phosphate salts. In another embodiment, the phosphate buffer contains potassium phosphate salts. In another embodiment, the phosphate buffer contains a mixture of sodium and potassium phosphate salts.

[0099] As used herein, the term "buffer" refers to a component that maintains the pH of the medium to which it is added at a constant level. In the context of the present disclosure, N-acetylcysteine, gentisic acid, ascorbic acid, and their salts or aqueous solutions thereof are not considered to be buffers, however the nature of these components may inherently modify the pH of a given formulation.

[0100] In an embodiment, the pH of the formulation is from about 2 to about 10. In an embodiment, the pH of the formulation is about 2. In an embodiment, the pH of the formulation is about 3. In an 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 an 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 another embodiment, the pH of the formulation is about 8.5. In another embodiment, the pH of the formulation is about 9.0. In another embodiment, the pH of the formulation is about 9.5. In another embodiment, the pH of the formulation is about 10.

[0101] In certain embodiments, the pH of the formulation is inherently due to the nature of the components in the formulation. In other embodiments, the pH of the formulation is a result of the use of a buffer solution in the formulation and therefore results in a modification of the pH.Processes for preparing formulations of the compound of Formula (I)

[0102] The present invention also relates to processes for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:O H / \ H O H H N ph A 7^ / — A N o H I n H N— THN NH / “ N H g I H OHHZNHH0^><O^NHHNV° O OH VHH X / \^NHN OH O'HoX? •o Formula (I)the process comprising:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a Cu ion in hydrochloric acid to the solution of step i); iii) adding a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or a pharmaceutically acceptable salt thereof; and iv) filtering the solution of step iii).

[0103] The present invention also relates to processes for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:o h 9 H / \ H 9 X / J2n / — A A N— T HN NH / — N AY J SH HH\ ,NHHOH oxy'^OH °yNHHNV° o X / ^ / NH HN 'OH O'■o Formula (I)the process comprising:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a Cu ion in hydrochloric acid to the solution of step i); iii) filtering the solution of step ii); andiv) adding a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof andN-acetylcysteine or a pharmaceutically acceptable salt thereof to the solution of step iii).

[0104] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt is reacted with a Cu ion in the presence of a buffer solution and gentisic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is provided as a chloride salt.

[0105] In certain embodiments, the buffer solution of step i) comprises a phosphate buffer. In certain embodiments, the buffer solution is a phosphate buffer solution, wherein the buffer solution comprises a mixture of phosphate salts. In other embodiments, the buffer solution comprises a mixture of potassium phosphate salts. In certain embodiments, the buffer solution comprises a mixture of a sodium phosphate salts. In certain embodiments, the buffer solution comprises a mixture of NaFhPCU (i.e. monosodium phosphate, monobasic sodium phosphate or sodium dihydrogen phosphate) and Na2HPO4 (i.e. disodium phosphate, dibasic sodium phosphate or sodium hydrogen phosphate). In certain embodiments, the concentration of the phosphatebufferis about 0.01 M, about 0.05 M, about 0.1 M, about 0.15 M, about 0.2 M, about 0.3 M, about 0.4 M or about 0.5 M.

[0106] In certain embodiments, the gentisic acid is present as a salt of gentisic acid. In certain embodiments, the gentisic acid is present as sodium gentisate. In other embodiments, sodium gentisate is added to the buffer solution and stirred. In certain embodiments, sodium gentisate is added to a phosphate buffer solution and stirred.

[0107] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is added to a buffer solution. In other embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is added to a phosphate buffer solution. In other embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof isadded to a solution comprising a phosphate buffer and gentisic acid or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is added to a solution comprising a phosphate buffer and sodium gentisate. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is added to a solution comprising a phosphate buffer and sodium gentisate and the solution is stirred.

[0108] In certain embodiments, the buffer solution is prepared at room temperature. In certain embodiments, the buffer solution is a phosphate buffer and is prepared at room temperature. In other embodiments, the gentisic acid or a pharmaceutically acceptable salt thereof is added to the phosphate buffer at room temperature. In other embodiments, the gentisic acid is added as sodium gentisate to the phosphate buffer at room temperature.

[0109] The buffer solution comprising a compound of Formula (I) or a pharmaceutically acceptable salt and gentisic acid or a pharmaceutically acceptable salt thereof is prepared and a solution of the Cu ion is then added to the buffer solution comprising the compound of Formula (I). The Cu ion for radiolabelling is added to a solution comprising gentisic acid or a pharmaceutically acceptable salt because gentisate is known to assist in the radiolabelling or complexation of Cu ions with the compound of Formula (I). The present inventors believe that the manner in which the formulations of the present invention are prepared is important in allowing for efficient radiolabelling of the compound and therefore yield of the formulation itself.

[0110] In accordance with the above aspect, a solution comprising a Cu ion is added to the solution obtained in step i). In certain embodiments, the Cu ion is a Cu radioisotope. In certain embodiments, the Cu ion is selected from the group consisting of60Cu,61Cu,62Cu,64Cuor67Cu ion. In certain embodiments, the Cu ion is provided as CunC12 solution. In certain embodiments, the Cu ion is provided as a solution of [60Cu]CuC12, [61Cu]CuCb, [62Cu]CuCb, [64Cu]CuCb or [67Cu]CuCb. In certain embodiments, the solution of the Cu ion is provided as a hydrochloric acid (HC1) solution. In certain embodiments, the solution comprising a Cu ion comprises a67Cu ion provided as a HC1 solution. In certain embodiments, the solution comprising a Cu ion comprises a67Cu ion provided as a HC1 solution, wherein the concentration of HC1 is between about 0.05 M to about 1 M. In certain embodiments, theconcentration of HC1 is between about 0.05 to about 0.5 M. In certain embodiments, the concentration of HC1 is about 0.1 M.

[0111] The formulations disclosed herein comprise ascorbic acid or a pharmaceutically acceptable salt thereof and N -acetylcysteine or a pharmaceutically acceptable salt thereof. In some embodiments, these components are added to a solution comprising the compound of Formula (I) and the Cu ion. In certain embodiments, a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or an acceptable salt thereof is prepared. In certain embodiments, a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or an acceptable salt thereof is added to a solution comprising a compound of Formula (I), gentisic acid or a pharmaceutically acceptable salt thereof and a Cu ion. Without wishing to be bound by theory, the present inventors believe that the addition of a compound of Formula (I) to a Cu ion in the presence of gentisic acid or a pharmaceutically acceptable salt thereof facilitates (at least in part) the complexation of the compound of Formula (I) with the Cu ion.

[0112] In certain embodiments, the solution obtained in step ii) is incubated at ambient temperature. In certain embodiments, the solution obtained in step ii) is incubated at room temperature. In other embodiments, the solution obtained in step ii) is incubated at a temperature in the range of about 15 °C to about 40 °C. In some embodiments, the solution obtained in step ii) is incubated at a temperature of about 15 °C, 16 °C, 17 °C, 18 °C, 19 °C, 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C or about 40 °C. In other embodiments, the present invention also contemplates a process for preparing a formulation where the solution obtained in step ii) of the process is incubated at a temperature in a range between the aforementioned amounts.

[0113] In certain embodiments, the solution obtained in step ii) is incubated for a time between about 5 minutes to about 30 minutes. In certain embodiments, the solution obtained in step ii) is incubated for a time between about 5 minutes to about 25 minutes. In other embodiments, the solution obtained in step ii) is incubated for a time between about 5 minutes to about 20 minutes. In other embodiments, the solution obtained in step ii) is incubated for a time between about 5 minutes to about 15 minutes. In other embodiments, the solution obtained in step ii) is incubated for a time between about 5 minutes to about 10 minutes. In some embodiments, thesolution obtained in step ii) is incubated for a time of about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes or about 30 minutes.

[0114] In certain embodiments, the solution obtained in step ii) is stirred. In other embodiments, the solution obtained in step ii) is not stirred.

[0115] In some embodiments, the solution comprising a compound of Formula (I) and a Cu ion is stirred for a time. In certain embodiments, the solution is stirred for about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes or about 60 minutes. In certain embodiments, the solution is stirred at ambient room temperature.

[0116] In certain embodiments, the solution obtained in step ii) is incubated for a time of about 5 minutes at room temperature. In other embodiments, the solution obtained in step ii) is incubated for a time of about 5 minutes at a temperature of between about 30 °C to about 40 °C. In other embodiments, the solution obtained in step ii) is incubated for a time of about 15 minutes at room temperature.

[0117] In certain embodiments, the solution obtained in step ii) is incubated without stirring for a time of about 5 minutes at room temperature. In other embodiments, the solution obtained in step ii) is incubated without stirring for a time of about 5 minutes at a temperature of between about 30 °C to about 40 °C. In other embodiments, the solution obtained in step ii) is incubated without stirring for a time of about 15 minutes at room temperature.

[0118] As used herein, the term "room temperature" refers to the ambient temperature of the room or the laboratory in which the process is performed. For example, room temperature may be a temperature in the range of about 15 °C to about 25 °C.

[0119] In certain embodiments, the ascorbic acid or pharmaceutically acceptable salt thereof as defined in step ii) is sodium ascorbate.

[0120] In certain embodiments, the final volume of the formulation prepared in accordance with a process as defined herein is between about 10 mL to about 200 mL. In certain embodiments, the final volume of the formulation is about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about90 mL, about 95 mL, about 100 mL, about 105 mL, about 110 mL, about 115 mL, about 120 mL, about 125 mL, about 130 mL, about 135 mL, about 140 mL, about 145 mL, about 150 mL, about 155 mL, about 160 mL, about 165 mL, about 170 mL, about 175 mL, about 180 mL, about 185 mL, about 190 mL or about 200 mL. In other embodiments, the present invention also contemplates a formulation having a volume in a range between the aforementioned amounts.

[0121] After stirring for a time, the solution comprising a compound of Formula (I) and a Cu ion is filtered. In certain embodiments, the solution is filtered through a resin. In some embodiments, the resin is a cation binding resin. Without wishing to be bound by theory, the present inventors believe that the filtration of the solution through a cation binding resin allows for the removal of any free Cu ion (i.e. cationic Cu ion) that remains in solution. In other words, the filtration step can remove any Cu ion in solution that has not complexed with the compound of Formula (I).

[0122] In certain embodiments, the Cu ion is provided a solution in hydrochloric acid. In certain embodiments, the Cu ion is provided as a chloride salt in a hydrochloric acid solution.

[0123] In certain embodiments, a solution comprising N -acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof is added to the filtered solution comprising the compound of Formula (I) and a Cu ion. In certain embodiments, a solution comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof is filtered and directly eluted into the filtered solution comprising the compound of Formula (I) and a Cu ion.

[0124] In other embodiments, the process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:i) reacting the compound of Formula (I) or a pharmaceutically acceptable salt thereof with a Cu ion in a solution comprising a phosphate buffer and gentisic acid or a pharmaceutically acceptable salt thereof; andii) adding a solution of N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof to the solution comprising the compound of Formula (I) and a Cu ion.

[0125] In certain embodiments, the compound of Formula (I) is reconstituted in a phosphate buffer solution prior to reaction with a Cu ion.

[0126] In certain embodiments, the step of reacting the compound of Formula (I) with a Cu ion is performed at ambient temperature.

[0127] In certain embodiments, the Cu ion is provided as a solution of a chloride salt of the Cu ion. In certain embodiments, the Cu ion is a Cu11ion. In certain embodiments, the Cu ion is a60Cu,61Cu,62Cu,64Cu or67Cu ion. In certain embodiments, the Cu ion is provided as CunC12 solution. In certain embodiments, the Cu ion is provided as a solution of [60Cu]CuC12, [61CU]CUC12, [62CU]CUC12, [64CU]CUC12or [67CU]CUC12.

[0128] The present invention also relates to processes for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a64Cu ion in hydrochloric acid to the solution of step i); iii) adding a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or a pharmaceutically acceptable salt thereof; and iv) filtering the solution of step iii).

[0129] The present invention also relates to processes for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a67Cu ion in hydrochloric acid to the solution of step i); iii) adding a solution comprising ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or a pharmaceutically acceptable salt thereof; and iv) filtering the solution of step iii).

[0130] In a further aspect, the present invention provides a process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising combining:i) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, ii) gentisic acid or a pharmaceutically acceptable salt thereof,iii) ascorbic acid or a pharmaceutically acceptable salt thereof,iv) N-acetylcysteine or a pharmaceutically acceptable salt thereof; andv) a Cu ion in hydrochloric acid,in a buffer solution, stirring the resultant solution and then filtering the solution.

[0131] In certain embodiments of the above aspects, the solution comprising the compound of Formula (I) complexed with a Cu ion and gentisic acid or a pharmaceutically acceptable salt thereof is stirred for a time at room temperature. In certain embodiments, the formulation comprising these components is stirred at room temperature for a time prior to the addition of other components of the formulation.

[0132] In certain embodiments of the above aspects, the solution comprising the compound of Formula (I) complexed with a Cu ion and gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof and N -acetylcysteine or a pharmaceutically acceptable salt thereof is stirred for a time at room temperature. In certain embodiments, the formulation comprising these components is stirred at room temperature for a time prior to filtering of the solution

[0133] In certain embodiments of the above aspects, the process further includes the step of filtering the solution. In certain embodiments, the solution is filtered through a resin. In some embodiments, the resin is a cation binding resin.

[0134] In some embodiments of the above aspects, the filtration step includes elution of the filtration medium with an aliquot of ethanol, such that formulations that incorporate a filtration step with ethanol elution therefore include ethanol in the final formulation. In certain embodiments, the filtration step includes elution with more than one aliquot of ethanol.

[0135] In certain embodiments, the process further includes the step of adjusting the pH of the formulation to a physiologically acceptable pH. In some embodiments, the pH of the formulation is adjusted by the addition of abase. In certain embodiments, the base is an organic base. In other embodiments, the base is an inorganic base. In other embodiments, the base is a hydroxide. In certain embodiments, the base is sodium hydroxide. In yet other embodiments,the pH of the formulation is adjusted by modifying the pH of the buffer solution from which the formulation is prepared.

[0136] As discussed above, the compound of Formula (I) complexes Cu ions. In an embodiment, the Cu ion is a radioisotope of Cu. In an embodiment, the Cu radioisotope is60Cu. In another embodiment, the Cu radioisotope is61Cu. In another embodiment, the Cu radioisotope is64Cu. In another embodiment, the Cu radioisotope is67Cu. The Cu radioisotope is provided as a Cu salt. In an embodiment, the Cu salt is provided as a Cu2+chloride salt. In an embodiment, theCu salt is provided as a [64Cu]CuCb salt. The Cu radioisotope is provided as a solution of hydrochloric acid. In an embodiment, the Cu radioisotope is64Cu and is provided as a solution of hydrochloric acid, where the hydrochloric acid has a concentration of about 0.02 M. In an embodiment, the Cu radioisotope is provided as a solution of [64Cu]CuCb in a solution of hydrochloric acid, where the hydrochloric acid has a concentration of about 0.02 M. One skilled in the art would understand that the Cu salt may be provided in other concentrations of hydrochloric acid. In another embodiment, the Cu radioisotope is provided as a Cu2+acetate salt. In an embodiment, the Cu salt is provided as a [64Cu]Cu(OAc)2 salt.

[0137] The solution of the Cu salt provided as a hydrochloric acid solution will have a particular starting radioactivity. The starting activity of the solution may vary, depending on the particular batch of the radioisotope. One skilled in the art would understand that the final activity of the compound of Formula (I) complexed with a Cu ion will depend on the activity of the Cu salt used to complex the compound of Formula (I) and that this will in turn depend on the activity of the solution of the Cu salt in hydrochloric acid. The overall radiochemical yield of the complex of Formula (I) and the copper salt may be determined with respect to the amount of the radioactivity initially present in the solution of the Cu salt. An aliquot of the Cu radioisotope in a solution of hydrochloric acid is added to the compound of Formula (I) in the acetate buffer. One skilled in the art would understand that radiochemical purity may be determined by radioHPLC or a similar method.

[0138] In an embodiment, the solution of the64Cu radioisotope has a radioactivity of between about 100 and about 5000 MBq. In an embodiment, the solution of the64Cu radioisotope has a radioactivity of about 100 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 250 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 500 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 750 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 1000 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 1500 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 2000 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 2500 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 3000 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 4000 MBq. In another embodiment, the solution of the64Cu radioisotope has a radioactivity of about 5000 MBq.

[0139] In an embodiment, the solution of the61Cu radioisotope has a radioactivity of between about 100 and about 5000 MBq. In an embodiment, the solution of the61Cu radioisotope has a radioactivity of about 100 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 250 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 500 MBq. In another embodiment, the solution of the6'Cu radioisotope has a radioactivity of about 750 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 1000 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 1500 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 2000 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 2500 MBq. In another embodiment, the solution of the61Curadioisotope has a radioactivity of about 3000 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 4000 MBq. In another embodiment, the solution of the61Cu radioisotope has a radioactivity of about 5000 MBq.

[0140] In an embodiment, the solution of the67Cu radioisotope has a radioactivity of between about 100 and about 5000 MBq. In an embodiment, the solution of the67Cu radioisotope has a radioactivity of about 100 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 250 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 500 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 750 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 1000 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 1500 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 2000 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 2500MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 3000 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 4000 MBq. In another embodiment, the solution of the67Cu radioisotope has a radioactivity of about 5000 MBq.

[0141] One skilled in the art would understand that radioactivity may also be measured in millicurie (mCi), which may be readily converted into becquerels and vice versa, where one curie is 37 billion Bq.

[0142] In certain embodiments, the Cu radioisotope is provided as a solution having an activity of from about 80 mCi / pg to about 800 mCi / pg. In certain embodiments, the Cu radioisotope is provided as a hydrochloric acid solution with an activity from about 80 mCi / pg to about 800 mCi / pg. In certain embodiments, the Cu radioisotope has an activity of about 80 mCi / pg, about 100 mCi / pg, about 125 mCi / pg, about 150 mCi / pg, about 175 mCi / pg, about 200 mCi / pg, about 225 mCi / pg, about 250 mCi / pg, about 275 mCi / pg, about 300 mCi / pg, about 325 mCi / pg, about 350 mCi / pg, about 375 mCi / pg, about 400 mCi / pg, about 425 mCi / pg, about 450 mCi / pg, about 475 mCi / pg, about 500 mCi / pg, about 525 mCi / pg, about 550 mCi / pg, about 575 mCi / pg, about 600 mCi / pg, about 625 mCi / pg, about 650 mCi / pg, about 675 mCi / pg, about 700 mCi / pg, about 725 mCi / pg, about 750 mCi / pg, about 775 mCi / pg or about 800 mCi / pg.

[0143] The Cu radioisotope may be provided as a solution in hydrochloric acid. In an embodiment, the Cu radioisotope is provided in a hydrochloric acid solution having a concentration of between about 0.01 M and about 0.05 M. In an embodiment, the concentration of the hydrochloric acid solution is about 0.01 M. In another embodiment, the concentration of the hydrochloric acid solution is about 0.02 M. In another embodiment, the concentration of the hydrochloric acid solution is about 0.03 M. In another embodiment, the concentration of the hydrochloric acid solution is about 0.04 M. In another embodiment, the concentration of the hydrochloric acid solution is about 0.05 M. In a further embodiment, the concentration of the hydrochloric acid solution is between about 0.02 M and about 0.05 M.

[0144] The formulations of the present invention comprise a compound of Formula (I) that is complexed with a Cu ion. The Cu ion is coordinated by the sarcophagine component of the compound of Formula (I), such that when the formulation is administered, the complex ofFormula (I) and a Cu ion localises at sites where PSMA receptors are expressed. The binding of compound via the PSMA urea (i.e. peptide) component of the compound then retains the Cu ion in the vicinity of the binding site. When the Cu ion undergoes spontaneous radioactive decay, the decay products make contact with the site expressing PSMA receptors (i.e. typically a tumour site) and therefore treat the tumour. Where the sarcophagine component of the compound of Formula (I) does not retain the Cu ion, e.g. where the Cu ion "leaks" out or dissociates from the sarcophagine, the Cu ion may be present in the formulation as free Cu ion. One parameter that may be used in quantifying the stability of the formulation is to consider the amount of free Cu ion over time. A formulation may be considered to be "more stable" when the amount of free Cu is minimised and does not increase (or increases only minimally) over the shelf life of the formulation. One skilled in the art would understand that "radiochemical purity", i.e. the proportion of the radioactivity present as the desired, radiolabelled species, can be used to quantify stability of the formulation.

[0145] In certain embodiments, the radiochemical purity of a formulation as disclosed herein is such that not more than (NMT) about 5% of the Cu ion is present as free Cu ion. In other embodiments, the formulation contains NMT about 4% free Cu ion. In other embodiments, the formulation contains NMT about 3% free Cu ion. In other embodiments, the formulation contains NMT about 2% free Cu ion.

[0146] The formulations of the present invention comprising a compound of Formula (I) complexed with a Cu ion show exceptional stability and radiochemical purity. Stability and purity of the formulation may be determined in accordance with one or more parameters, for example, the amount of free radioisotope present in solution at a given time. For instance, the formulations of the present invention show exceptional stability for a time of about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after preparation of the formulation. Stability of the formulation may be determined by considering the amount of free Cu ion present in the formulation at a given time. In certain embodiments, a formulation of the present invention has not more than (NMT) about 5% free Cu ion, about 4% free Cu ion, about 3% free Cu ion, about 2% free Cu ion or about 1% free Cu ion, with respect to the total amount of Cu ion in the formulation.

[0147] In certain embodiments, a formulation of the present invention has NMT about 5% free Cu ion at a time of about 24 hours, about 48 hours or about 72 hours after preparation of the31formulation. In other embodiments, a formulation of the present invention has NMT about 4% free Cu ion at a time of about 24 hours, about 48 hours or about 72 hours after preparation of the formulation. In other embodiments, a formulation of the present invention has NMT about 3% free Cu ion at a time of about 24 hours, about 48 hours or about 72 hours after preparation of the formulation. In other embodiments, a formulation of the present invention has NMT about 2% free Cu ion at a time of about 24 hours, about 48 hours or about 72 hours after preparation of the formulation. In other embodiments, a formulation of the present invention has NMT about 1% free Cu ion at a time of about 24 hours, about 48 hours or about 72 hours after preparation of the formulation.

[0148] In other embodiments, radiochemical purity may be determined with respect to the amount of copper that is complexed with the compound of Formula (I). In certain embodiments, the formulation comprises not less than (NLT) about 90% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 91% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 92% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 93% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 94% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 95% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 96% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 97% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 98% of the compound of Formula (I) complexed with a Cu ion. In certain embodiments, the formulation comprises NLT about 99% of the compound of Formula (I) complexed with a Cu ion.

[0149] The formulations disclosed herein may be characterised in terms of the radioactivity concentration (RAC) of the formulation. The RAC of a given formulation may be determined at any time, but is often determined at least at the end of the synthesis (EOS) or preparation of the formulation. In certain embodiments, the RAC of a formulation comprising the compound of Formula (I) complexed with a Cu ion is between about 0.5 GBq / mL to about 5.0 GBq / mL. In some embodiments, the RAC of a formulation comprising the compound of Formula (I) complexed with a Cu ion at EOS is about 0.5 GBq / mL, about 0.6 GBq / mL, about 0.7 GBq / mL,about 0.8 GBq / mL, about 0.9 GBq / mL, about 1.0 GBq / ml, about 1.5 GBq / mL, about 2.0 GBq / mL, about 2.5 GBq / mL, about3.0 GBq / mL, about 3.5 GBq / mL, about4.0 GBq / mL, about 4.5 GBq / mL or about 5.0 GBq / mL.

[0150] The formulations of the present invention comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion. The present invention also relates to processes for the preparation of such formulations, which include the step of adding a Cu ion to the compound of Formula (I) or a pharmaceutically acceptable salt thereof, such that the compound of Formula (I) is complexed with the Cu ion. These formulations comprising a complex of the compound of Formula (I) and a Cu ion can be characterised by its radiochemical yield.

[0151] As used herein, the term "radiochemical yield" or "yield" as used herein relates to the percentage of radioactivity in the formulation compared to the initial or starting amount of radioactivity used. For example, the radiochemical yield for a formulation refers to the percentage of the radioactivity associated with the radioisotope that is to be incorporated as part of the formulation. Accordingly, the radiochemical yield of a formulation as disclosed herein relates to the proportion of the Cu ion (i.e. radioisotope) present as part of a complex with the compound of Formula (I) compared to the total amount of the Cu ion added.

[0152] In certain embodiments, the radiochemical yield of a formulation as described herein is at least 99%. In other embodiments, the radiochemical yield is at least 95%. In other embodiments, the radiochemical yield is at least 90%. In other embodiments, the radiochemical yield is at least 85%. In other embodiments, the radiochemical yield is at least 80%. In other embodiments, the radiochemical yield is at least 75%. In other embodiments, the radiochemical yield is at least 70%. In some embodiments, the radiochemical yield of a formulation as described herein is about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71% or about 70%. In other embodiments, the present invention also contemplates a formulation having a radiochemical yield in a range between the aforementioned amounts.

[0153] In certain embodiments, the specific activity of a formulation comprising a compound of Formula (I) complexed with a Cu ion as disclosed or prepared herein is in the range of about5 GBqto about 1000 GBq. In certain embodiments, the activity of the formulation is about 5 GBq, about 10 GBq, about 20 GBq, about 30 GBq, about 40 GBq, about 50 GBq, about 60 GBq, about 70 GBq, about 80 GBq, about 90 GBq, about 100 GBq, about 110 GBq, about 120 GBq, about 130 GBq, about 140 GBq, about 150 GBq, about 160 GBq, about 170 GBq, about 180 GBq, about 190 GBq, about 200 GBq, about 250 GBq, about 300 GBq, about 350 GBq, about 400 GBq, about 450 GBq, about 500 GBq, about 550 GBq, about 600 GBq, about 650 GBq, about 700 GBq, about 750 GBq, about 800 GBq, about 850 GBq, about 900 GBq, about 950 GBq or about 1000 GBq. In other embodiments, the present invention also contemplates a formulation having a specific activity in a range between the aforementioned amounts.Kits for preparing formulations of the compound of Formula (I) complexed with a Cu ion

[0154] The present invention also provides a kit for preparing a formulation of the present invention. The kits of the present invention provide one or more containers with ingredients for the preparation of the formulations of the present invention. The kits may be used to prepare a formulation that is administered directly to the patient, i.e. the kits may be used to prepare a formulation comprising a compound of Formula (I) complexed with a Cu ion, where administration to a patient is used to image, diagnose and / or treat a cancer.

[0155] The kits of the present invention comprise a container with the compound of Formula (I), a container with a Cu ion and one or more containers comprising one or more excipients. In certain embodiments, the kits of the present invention comprise a container comprising gentisic acid or a pharmaceutically salt thereof. In other embodiments, the kits of the present invention comprise a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof. In other embodiments, the kits of the present invention comprise a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof.

[0156] In certain embodiments, the kits of the present invention also comprise instructions for preparing a formulation as defined herein. In certain embodiments, the instructions of the kit recite the reconstitution of the compound of Formula (I) ora pharmaceutically acceptable salt thereof and / or one or more excipients in a buffer solution. In other embodiments, the instructions of the kit recite the addition of a solution of a Cu ion.

[0157] In certain embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a Cu ion; andinstructions for preparing a formulation comprising a compound of Formula (I) complexed with a Cu ion.

[0158] In certain embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a64Cu2+ion; andinstructions for preparing a formulation comprising a compound of Formula (I) complexed with a Cu ion.

[0159] In certain embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a67Cu2+ion; andinstructions for preparing a formulation comprising a compound of Formula (I) complexed with a Cu ion.

[0160] In some embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a Cu ion;iii) a container comprising gentisic acid or a pharmaceutically acceptable salt thereof; iv) a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof; v) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation comprising each of the components of in parts i) to v) above.

[0161] In other embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a64Cu2+ion;iii) a container comprising gentisic acid or a pharmaceutically acceptable salt thereof; iv) a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof; v) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation comprising each of the components of in parts i) to v) above.

[0162] In other embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a67Cu2+ion;iii) a container comprising gentisic acid or a pharmaceutically acceptable salt thereof; iv) a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof; v) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation comprising each of the components of in parts i) to v) above.

[0163] In some embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a Cu ion;iii) a container comprising sodium gentisate;iv) a container comprising sodium ascorbate;v) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation comprising each of the components of in parts i) to v) above.

[0164] In other embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a64Cu2+ion;iii) a container comprising sodium gentisate;iv) a container comprising sodium ascorbate;v) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation comprising each of the components of in parts i) to v) above.

[0165] In other embodiments, the kits of the present invention comprise:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof;ii) a container comprising a67Cu2+ion;iii) a container comprising sodium gentisate;iv) a container comprising sodium ascorbate;v) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation comprising each of the components of in parts i) to v) above.

[0166] In some embodiments, a kit of the present invention may provide a single dose of a formulation of a compound of Formula (I) complexed with a Cu ion. In other embodiments, a kit of the present invention may provide multiple single doses of a formulation of a compound of Formula (I) complexed with a Cu ion. In some embodiments, a kit of the present invention may provide multiple doses of a formulation in a single aliquot obtained from the kit.Methods for the radio imaging, diagnosis and / or treatment of cancers

[0167] The present inventors have now shown that formulations comprising the compound of Formula (I) complexed witha Cu ion may be administered in a therapeutically effective amount for the radioimaging, diagnosis and / or treatment of a cancer associated with expression of a PSMA receptor.

[0168] One skilled in the art would understand that the use of a formulation as disclosed in herein in combination with a suitable imaging modality can provide radioimaging of a subject in need thereof for the identification of one or more cancers associated with the expression of PSMA. In certain embodiments, a method for radioimaging a subject in need thereof includesthe administration of an amount of a formulation as disclosed herein, followed by the imaging of the subject at a time thereafter. In certain embodiments, imaging of the subject may be at a time of 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours or 48 hours after administration of the formulation. After images of the subject are obtained, analysis by a clinician, oncologist, radiologist or the like can allow for the diagnosis of a cancer in the subject, wherein the cancer is associated with expression of PSMA. The present invention therefore also relates to a method for the radioimaging and / or diagnosis of a cancer in a subject in need thereof by administration of a formulation comprising a compound of Formula (I) complexed with a Cu ion. A person skilled in the art would understand that various Cu ions are suitable for complexation with a compound of Formula (I), where the combination of both the compound and Cu ion when administered as a formulation may be used for radioimaging and / or diagnosis of a cancer.

[0169] In certain embodiments, a method for radioimaging and / or diagnosis of a cancer includes imaging of the subject by one or more of positron emission tomography (PET), single photon emission computed tomography (SPECT) and computed tomography (CT). In certain embodiments, the method includes the step of imaging of the subject by PET. In other embodiments, the method includes the step of imaging of the subject by SPECT. In other embodiments, the method includes the step of imaging of the subject by CT. The present invention also contemplates a method for radioimaging and / or diagnosis of a cancer, wherein the method includes a step of further imaging of the subject after the initial imaging step. The formulations as disclosed herein allow for imaging of the subject more than once over a period of time, since the formulation comprising the compound of Formula (I) complexed with a Cu ion remains shows exceptional stability and radiochemical purity over a long period of time. The formulations disclosed herein containing a Cu ion have a long shelf life and are fit for clinical use for a longer time, when compared to other similar formulations, due to the stability of the compound of Formula (I) when complexed with a Cu ion as enhanced by formulation as described herein. Where a Cu ion having a longer halfdife and a formulation having stability over 24 hours, 48 hours and 72 hours, imaging of the subject more than once after administration of a single dose of the formulation can be achieved. Subsequent imaging can result in better identification of lesions associated with the cancer, since more of the compound of Formula (I) complexed with a Cu ion is allowed to accumulate at sites expressing PSMA receptors. This means that later images can have increased contrast, when compared to initial images obtained shortly after administration of a formulation as disclosed herein. As usedherein, the “term “fit for clinical use” in relation to a formulation of thepresent invention means that the formulation is therapeutical effective and efficacious when administered to a subject and where the formulation is within acceptable safety parameters.

[0170] The present invention also relates to methods for the treatment of one or more cancers associated with the expression of PSMA. In certain embodiments, a method for the treatment of a cancer includes the administration of a formulation comprising a compound of Formula (I) complexed with a Cu ion to a subject in need thereof. In certain embodiments, the subject that is administered a formulation as disclosed herein is previously determined to have, i.e. diagnosed with, a cancer associated with the expression of PSMA.

[0171] As used herein, the term "cancer" relates to one or more diseases characterised by the uncontrolled growth and spread of abnormal cells. Cancers may be classified by one or more of its site or location, its growth characteristics, its physical form and other parameters.

[0172] In certain embodiments, the cancer is a solid cancer, such as a tumour. In other embodiments, the cancer is a non-solid or "liquid" cancer, such as a leukemia or lymphoma. In certain embodiments, the cancer may be a "fixed" or "stationary" cancer, such as a tumour that remains in the same location. In other embodiments, the cancer is a "mobile" and may be a leukemia and may circulate throughout the subject.

[0173] In certain embodiments, the cancer is associated with the expression of PSMA receptors. In certain embodiments, the cancer is associated with the expression of PSMA receptors and is located in one or more of the brain, lung, bone, adrenal glands, breast, central nervous system, eye, female reproductive system, male reproductive system, head, neck, kidney, liver, lymphatic system, pancreas, peripheral nervous system, salivary glands, skin, spleen, soft tissue, stomach, thymus, thyroid, urinary tract and bladder and vasculature.

[0174] In certain embodiments, the cancer is associated with the adrenal glands. In certain embodiments, the cancer is an adrenocortical carcinoma. In other embodiments, the cancer is an adrenocortical adenoma.

[0175] In other embodiments, the cancer is associated with bone. In some embodiments, the cancer is osteosarcoma, Ewing sarcoma, Paget's disease, or is associated with fibrous dysplasia, osteofibrous dysplasia, fracture or osteoarthritis.

[0176] In some embodiments, the cancer is associated with the central nervous system. In some embodiments, the cancer is a meningioma, glioma or central nervous system lymphoma. In other embodiments, the cancer is a glioblastoma.

[0177] In other embodiments, the cancer is associated with the female reproductive system. In certain embodiments, the cancer is ovarian cancer, endometrial carcinoma, vulvar carcinoma, cervical carcinoma, squamous cell carcinoma.

[0178] In certain embodiments, the cancer is associated with the male reproductive system. In certain embodiments, the cancer is associated with the prostate. In certain embodiments, the cancer is a prostate cancer. In certain embodiments, the cancer is a penis squamous cell carcinoma, testicular embryonal carcinoma or amyloidosis of seminal vesicles.

[0179] In certain embodiments, the cancer is associated with the intestines. In some embodiments, the cancer is colorectal adenocarcinoma.

[0180] In certain embodiments, the cancer is associated with the kidneys. In some embodiments, the cancer is clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, onocytoma, angiomolipoma, transitional cell carcinoma or renal cell carcinoma not otherwise specified.

[0181] In some embodiments, the cancer is associated with the liver. In certain embodiments, the cancer is a hepatocellular carcinoma or a cholangiocarcinoma.

[0182] In some embodiments, the cancer is associated with the lungs. In some embodiments, the cancer is a non-small cell lung carcinoma, small-cell lung carcinoma or mesothelioma.

[0183] In some embodiments, the cancer is associated with the lymphatic system. In some embodiments, the cancer is a lymphoma or multiple myeloma.

[0184] In some embodiments, the cancer is associated with the pancreas. In certain embodiments, the cancer is a pancreatic adenocarcinoma, serous cystadenoma or neuroendocrine tumour.

[0185] In some embodiments, the cancer is associated with the peripheral nervous system. In some embodiments, the cancer is a schwannoma, other nerve sheath tumours, traumatic neuroma or a physiologic cancer in ganglia.

[0186] In certain embodiments, the cancer is associated with the salivary glands. In certain embodiments, the cancer is an adenoid cystic carcinoma or a physiologic cancer in acinar epithelium.

[0187] In certain embodiments, the cancer is associated with the skin. In other embodiments, the cancer is a melanoma, dermatofibroma or acrochordon.

[0188] In certain embodiments, the cancer is associated with the stomach. In other embodiments, the cancer is a gastric adenocarcinoma.

[0189] In certain embodiments, the cancer is associated with the thyroid. In some embodiments, the cancer is a papillary carcinoma, follicular carcinoma, anaplastic carcinoma, medullary carcinoma or adenoma.

[0190] In certain embodiments, the cancer is associated with the vasculature. In certain embodiments, the cancer is a hemangioma, hemangioendothelioma, angiosarcoma of soft tissue or artherosclerosis.

[0191] In certain embodiments, the cancer is a primary cancer. In other embodiments, the cancer is a secondary or metastatic cancer. In other embodiments, the cancer is a secondary primary cancer. In other embodiments, the cancer is a cancer of unknown primary origin.

[0192] The formulations of the present invention may be used or administered in combination with one or more additional active agents that are anti-cancer drugs and / or procedures (e.g. surgery, radiotherapy) for the treatment of the cancer. The components can be administered in the same formulation or in separate formulations. If administered separately, the formulationsof the present invention may be administered sequentially or simultaneously with the other formulations.

[0193] In addition to being able to be administered in combination with one or more additional active agents, including anti-cancer drugs, the formulations of the present invention may be used as part of a combination therapy. When this is done the formulations of the present invention are typically administered in combination with the other additional active agents. Thus one or more formulations of the invention may be administered either simultaneously or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of the formulations of the present invention and the additional active agent is different such that the combined effect of active agents administered provides an improved therapeutic result.

[0194] The methods disclosed herein may include the administration of one or more doses of a formulation comprising the compound of Formula (I) complexed with a Cu ion as disclosed herein. In certain embodiments, the time between doses of a formulation in a subject may be measured in days, weeks, months or years.

[0195] In some embodiments, the time between doses of a formulation as disclosed herein is about 1 week, about 2 weeks, about 4 weeks, about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, about 2 years, about 3 years or about 4 years. One skilled in the art would understand that the time between doses of a formulation as disclosed herein will depend on the requirements of the subject and the response and tolerance of the patient to a first dose of the formulation that is administered.

[0196] In some embodiments, where more than one dose of a formulation as disclosed herein is administered to a subject, the subsequent formulation administered may be the same or different. In certain embodiments, the subsequent dose of the formulation or the amount of radioactivity provided by the administered formulation is higher than the first dose. In other embodiments, the subsequent dose of the formulation or the amount of radioactivity provided by the administered formulation is lower than the first dose.

[0197] In relation to the methods disclosed herein, the patient to which the formulation is administered may undergo radioimaging shortly after administration of the formulation. Insome embodiments, the methods disclosed herein comprise the step of administering a compound of Formula (I) complexed with a Cu ion as defined herein and subsequently the step of radioimaging of the subject. In certain embodiments, radioimaging of the subject is by PET, SPECT or CT. Subsequent radioimaging of the subject after administration of a formulation comprising a compound of Formula (I) complexed with a Cu ion can occur a time of about 5 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 9 hours, about 12 hours, about 18 hours or about 24 hours after administration. In some embodiments, radioimaging may occur more than once after administration of a formulation as disclosed herein.

[0198] As used herein, the term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. An effective amount for radioimaging is typically sufficient to identify the radionuclide in the subject by one or more imaging modalities.

[0199] A therapeutically effective amount can be readily determined by an attending clinician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular radiolabelled compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.

[0200] The present invention also provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer.

[0201] Furthermore, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for radioimaging and / or diagnosing a cancer.

[0202] In certain embodiments, the N-acetylcysteine or a pharmaceutically acceptable salt thereof used is in an amount of between about 10 mg / mL to about 200 mg / mL. In some embodiments, the formulation comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL or 200 mg / mL.

[0203] In certain embodiments, the ascorbic acid or a pharmaceutically acceptable salt thereof used is in an amount between about 0.1 mg / mL to about 0.1 mg / mL. In some embodiments, the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof in an amount of about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL or 1.0 mg / mL.

[0204] In certain embodiments, the gentisic acid or a pharmaceutically acceptable salt thereof used is in an amount of bet ween about 10 mg / mL to about 200 mg / mL. In certain embodiments, the formulation comprises ascorbic acid or a pharmaceutically acceptable salt thereof in an amount of about 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL or 200 mg / mL.

[0205] In certain embodiments, the medicament includes the use of a buffer solution. In certain embodiments, the buffer solution is a phosphate buffer, which may comprise a mixture of various phosphate salts or hydrates thereof. Examples of phosphate salts that are suitable include sodium dihydrogen phosphate (NaELPCU), disodium hydrogen phosphate (Na2HPOr), potassium dihydrogen phosphate (KH2PO4) and dipotassium hydrogen phosphate (K2HPO4). In an embodiment, the phosphate buffer contains sodium phosphate salts. In another embodiment, the phosphate buffer contains potassium phosphate salts. In another embodiment, the phosphate buffer contains a mixture of sodium and potassium phosphate salts.

[0206] The compound of Formula (I) used in the manufacture of a medicament as disclosed herein is complexed with a Cu ion. In certain embodiments, the Cu ion is a Cu radioisotope. In some embodiments, the Cu radioisotope is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In certain embodiments, the Cu ion is60Cu. In certain embodiments, the Cu ion is61Cu. In certain embodiments, the Cu ion is62Cu. In certain embodiments, the Cu ion is64Cu. In certain embodiments, the Cu ion is67Cu.

[0207] The uses discussed herein are for the treatment, radioimaging and / or diagnosis of a cancer. In certain embodiments, the cancer is associated with expression of a prostate specific membrane antigen (PSMA) receptor.

[0208] In other embodiments, the cancer is a cancer of the brain, lung, bone, adrenal glands, breast, central nervous system, eye, female reproductive system, male reproductive system, head, neck, kidney, liver, lymphatic system, pancreas, peripheral nervous system, salivary glands, skin, spleen, softtissue, stomach, thymus, thyroid, urinary tract, bladder or vasculature. In some embodiments, the cancer is a prostate cancer. In other embodiments, the cancer is a primary prostate cancer. In other embodiments, the cancer is a secondary prostate cancer. In further embodiments, the cancer is a breast cancer.

[0209] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived fromit) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0210] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0211] The present invention may also be described in one or more of the following embodiments:1. A formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises N-acetyl cysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof.2. A formulation according to a preceding embodiment, wherein the gentisic acid is provided as sodium gentisate.3. A formulation according to one or more preceding embodiments, wherein the ascorbic acid is provided as sodium ascorbate.4. A formulation according to one or more preceding embodiments, wherein N-acetylcysteine is present in an amount of between about 5 mg / mL to about 200 mg / mL.5. A formulation according to one or more preceding embodiments, wherein gentisic acid or a pharmaceutically acceptable salt is present in an amount of between about 0.1 mg / mL to about 1.0 mg / mL.6. A formulation according to one or more preceding embodiments, wherein ascorbic acid or a pharmaceutically acceptable salt thereof is present in an amount of between about 5 mg / mL to about 200 mg / mL.7. A formulation according to one or more preceding embodiments, wherein the free Cu ion in the formulation is present at a concentration of not more than 5% with respect to the total amount of Cu in the formulation for least 24 hours.8. A formulation according to one or more preceding embodiments, wherein the free Cu ion in the formulation is present at a concentration of not more than 5% with respect to the total amount of Cu in the formulation for at least 36 hours.9. A formulation according to one or more preceding embodiments, wherein the free Cu ion in the formulation is present at a concentration of not more than 5% with respect to the total amount of Cu in the formulation for at least 48 hours.10. A formulation according to one or more preceding embodiments, wherein the free Cu ion in the formulation is present at a concentration of not more than 5% with respect to the total amount of Cu in the formulation for at least 72 hours.11. A formulation according to one or more preceding embodiments, wherein the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable salt thereof to the concentration of ascorbic acid or a pharmaceutically acceptable salt thereof is between about 1:10 to about 10:1.12. A formulation according to one or more preceding embodiments, wherein the ratio of the concentration of N-acetylcysteine or a pharmaceutically acceptable salt thereof to the concentration of ascorbic acid or a pharmaceutically acceptable salt thereof is about 1:1.13. A formulation according to one or more preceding embodiments, wherein the pH of the formulation is between about 2 to about 10.14. A formulation according to one or more preceding embodiments, wherein the Cu ion is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.15. A formulation according to one or more preceding embodiments, wherein the Cu ion is64Cu.16. A formulation according to one or more preceding embodiments, wherein the Cu ion is67Cu.17. A formulation according to one or more preceding embodiments, wherein the formulation comprises a buffer solution.18. A formulation according to one or more preceding embodiments, wherein the formulation comprises a phosphate buffer solution.19. A formulation according to one or more preceding embodiments, wherein the formulation has a radioactivity concentration of between about 0.5 GBq / mL to about 5.0 GBq / mL.20. A formulation according to one or more preceding embodiments, wherein the compound of Formula (I) has the structure of Formula (la):Formula (la).21. A formulation according to one or more preceding embodiments, wherein the compound of Formula (I) has the structure of Formula (la):Formula (la)wherein the formulation comprises N-acetylcysteine, sodium gentisate and sodium ascorbate, andwherein the compound of Formula (I) is complexed with a Cu ion selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.22. A formulation according to one or more preceding embodiments, wherein the formulation has a specific activity in the range of about 5 GBq to about 1000 GBq.23. A process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising the steps of:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a Cu ion in hydrochloric acid to the solution of step i); and iii) adding ascorbic acid or a pharmaceutically acceptable salt thereof and N- acetylcysteine or a pharmaceutically acceptable salt thereof to the solution of step ii).24. A process according to a preceding embodiment, wherein the gentisic acid is provided as sodium gentisate.25. A process according to one or more preceding embodiments, wherein the ascorbic acid is provided as sodium ascorbate.26. A process according to one or more preceding embodiments, wherein N -acetylcysteine is present in an amount of between about 5 mg / mL to about 200 mg / mL.27. A process according to one or more preceding embodiments, wherein gentisic acid or a pharmaceutically acceptable salt is present in an amount of between about 0.1 mg / mL to about 1.0 mg / rnL.28. A process according to one or more preceding embodiments, wherein ascorbic acid or a pharmaceutically acceptable salt thereof is present in an amount of between about 5 mg / mL to about 200 mg / mL.29. A process according to one or more preceding embodiments, wherein the buffer solution is a phosphate buffer solution.30. A process according to one or more preceding embodiments, wherein the solution obtained from step ii) is stirred for a time at room temperature.31. A process according to one or more preceding embodiments, wherein the solution obtained from step ii) is stirred for about 30 minutes at room temperature.32. A process according to one or more preceding embodiments, wherein the solution of a Cu ion in hydrochloric acid comprises a64Cu ion.33. A process according to one or more preceding embodiments, wherein the solution of a Cu ion in hydrochloric acid comprises a67Cu ion.34. A process according to one or more preceding embodiments, wherein the ascorbic acid is provided as a solution.35. A process according to one or more preceding embodiments, wherein the N-acetylcysteine is provided as a solution.36. A process according to one or more preceding embodiments, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof and N-acetylcysteine or a pharmaceutically acceptable salt thereof is provided in a single solution.37. A process according to one or more preceding embodiments, wherein the wherein the ascorbic acid or a pharmaceutically acceptable salt thereof and N -acetylcysteine or a pharmaceutically acceptable salt thereof is provided as a solution of sodium ascorbate and N-acetylcysteine.38. A process according to one or more preceding embodiments, wherein the process further comprises the step of:iv) filtering the solution obtained in step iii).39. A process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof, wherein the process comprises the step of:reacting the compound of Formula (I) or a pharmaceutically acceptable salt thereof with a Cu ion in a buffer solution comprising gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof.40. A process according to a preceding embodiment, wherein the process further comprises the step of filtering the solution.41. A process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)wherein the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof, wherein the process comprises combining:i) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, ii) gentisic acid or a pharmaceutically acceptable salt thereof,iii) ascorbic acid or a pharmaceutically acceptable salt thereof,iv) N-acetylcysteine or a pharmaceutically acceptable salt thereof; andv) a Cu ion in a solution of hydrochloric acid,in a buffer solution.42. A process according to a preceding embodiment, wherein the process further comprises the step of filtering the solution.43. A formulation prepared in accordance with a process of any one of the preceding embodiments.44. A kit for the preparation of a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the kit comprising:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N -acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof, and ascorbic acid or a pharmaceutically acceptable salt thereof.45. A kit according to a previous embodiment, wherein the kit comprises kit comprises: i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion;iii) one or more containers comprising gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof, and ascorbic acid or a pharmaceutically acceptable salt thereof.46. A kit according to one or more preceding embodiments, wherein the kit further comprises a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof.47. A kit according to one or more preceding embodiments, wherein the kit further comprises a container comprising gentisic acid or a pharmaceutically acceptable salt thereof.48. A kit according to one or more preceding embodiments, wherein the kit further comprises a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof.49. A kit according to one or more preceding embodiments, wherein the kit further comprises a container comprising gentisic acid or a pharmaceutically acceptable salt thereof, another container comprising ascorbic acid or a pharmaceutically acceptable salt thereof, and another container comprising N -acetylcysteine or a pharmaceutically acceptable salt thereof.50. A kit according to one or more preceding embodiments, wherein the kit comprises: i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion;iii) a container comprising gentisic acid or a pharmaceutically acceptable salt thereof; iv) a container comprising N-acetylcysteine or a pharmaceutically acceptable salt thereof;v) a container comprising ascorbic acid or a pharmaceutically acceptable salt thereof; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N-acetylcysteine or a pharmaceutically acceptable salt thereof.51. A method for radioimaging and / or diagnosing a cancer, the method comprising administering to a subject in need thereof a formulation as defined in one or more preceding embodiments.52. A method according to a preceding embodiment, wherein the method further comprises the step of radioimaging of the subject.53. A method for treating a cancer, the method comprising administering to a subject in need thereof a formulation as defined in one or more preceding embodiments.54. A method according to one or more preceding embodiments, wherein the cancer is associated with expression of a prostate specific membrane antigen (PSMA) receptor.55. A method according to one or more preceding embodiments, wherein the cancer is a cancer of the brain, lung, bone, adrenal glands, breast, central nervous system, eye, female reproductive system, male reproductive system, head, neck, kidney, liver, lymphatic system, pancreas, peripheral nervous system, salivary glands, skin, spleen, soft tissue, stomach, thymus, thyroid, urinary tract, bladder or vasculature.56. A method according to one or more preceding embodiments, wherein the cancer is a prostate cancer.57. A method according to one or more preceding embodiments, wherein the prostate cancer is a primary prostate cancer.58. A method according to one or more preceding embodiments, wherein the prostate cancer is a secondary prostate cancer.59. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:U H | U O JIH / H 2 H HN— TXN^NYXN N J SHHN Ntd / - N H n T HHH\ ,NHHo' yHNV° o O^NH OH °YNHHN / \ .NH 'OH O'HO^ ■oO Formula (I)N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for radioimaging and / or diagnosing a cancer.60. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer.61. Use according to one or more preceding embodiments, wherein the cancer is associated with expression of a prostate specific membrane antigen (PSMA) receptor.62. Use according to one or more preceding embodiments, wherein the cancer is a cancer of the brain, lung, bone, adrenal glands, breast, central nervous system, eye, female reproductive system, male reproductive system, head, neck, kidney, liver, lymphatic system, pancreas, peripheral nervous system, salivary glands, skin, spleen, soft tissue, stomach, thymus, thyroid, urinary tract, bladder or vasculature.63. Use according to one or more preceding embodiments, wherein the cancer is a prostate cancer.64. Use according to one or more preceding embodiments, wherein the prostate cancer is a primary prostate cancer.Examples

[0212] The following examples are illustrative of the disclosure and should not be construed as limiting in any way the general nature of the disclosure of the description throughout this specification.General experimental

[0213] Materials and reagents obtained from Sigma -Aldrich, Fluka, Millipore as required. Sar-bisPSMA was obtained from AusPep. Radioisotopes were obtained from Northstar Medical Radioisotopes, LLC.

[0214] Equipment used to perform quality control analysis on the formulations disclosed herein were obtained from LabLogic (TLC, HPLC pump, HPLC autosampler, MWD, PMT / plastic detector) and AtomLab (dose calibrator).Example 1 - Preparation of formulations

[0215] A solution comprising Sar-bisPSMA (200 pg) was prepared in a sodium phosphate buffer (5 mL, 0.1 M) containing sodium gentisate (10 mg). A solution of67CuCb in 0.1 M HC1 solution was added to the Sar-bisPSMA / sodium gentisate / phosphate buffer solution and the resulting mixture incubated at ambient room temperature (approx. 25 °C) for about 25 minutes. The requisite amounts of sodium ascorbate and / or N -acetylcysteine were added to the radiolabelled mixture of67Cu-Sar-bisPSMA in order to achieve the initial target radioactive concentration (RAC) of 0.9 GBq / mL (i.e. 24 mCi / mL).

[0216] The RAC target was used to determine final product volume, which ranges from 20 -28 mL at scale. For these experiments, changes to the formulation composition were analyzed for product appearance, free67Cu (TLC), radiochemical purity (HPLC), pH, and RAC at end of synthesis (EOS). Stability of the experiments were analyzed at EOS, 24-, 48-, and 72-hours, as applicable based on EOS results.Example 2 - Radiochemical purity experiments

[0217] Radiochemical purity of formulations was determined by both iTLC and HPLC at EOS (end of synthesis), 24, 48 and 72 hours after synthesis.iTLC

[0218] The amount of free and colloidal67Cu in the radiolabeled67Cu-SAR-bisPSMA preparations was evaluated using instant thin layer chromatography. iTLC was performed with a Silica gel 60 F254 aluminium-backed TLC plate as stationary phase with a mobile phase of 10 mM ED TA in 50 mM phosphate buffer. Approximately 2 pL of the formulation to be assayed was spotted on a 10 cm iTLC plate and developed in the mobile phase. The developed plate was then analyzed using a radioTLC scanner (LabLogic,) and the percentage of free / unbound copper determined.HPLC

[0219] The radiochemical purity of a67Cu-SAR-bisPSMA formulation was evaluated by analyzing 100 uL of the formulation by gradient HPLC (LabLogic, DL-241-45), with a Phenomenex Gemini 3 pm C18 100 A, 150 * 4.6 mm (00F-4439-E0) (or equivalent) stationary phase and a mobile phase consisting of 0.1% trifluoroacetic acid (TFA) in water (A) and 0.1% TFA in acetonitrile (B). The elution times were compared to a suitable standard and radiochemical purity of the formulation determined.Example 3 - Other experimentspH

[0220] The pH of a formulation was determined by spotting a ~0.5 - 1 pL aliquot on pH paper and then comparing the sample color to the color reference chart. For experiments analyzing pH, different pH paper with a broad pH 0 - 14 range and a narrower pH 2 - 9 range. Alternatively, the pH of a formulation may be determined by using a pH probe.Radioactive concentration

[0221] Radioactive concentration was determined by dividing the EOS product activity by the EOS product volume.Product appearance

[0222] The appearance of a formulation was tested by visual inspection of the final product vial while gently swirling the contents against contrasting background under appropriate lighting conditions. The final product should be clear and colorless to slightly yellow, and free of particulates.Bacterial Endotoxin Testing (BET)

[0223] The final product is tested for endotoxin content using the PTS Endosafe System (Charles River Laboratories, MA) according to the manufacturer instructions. BET testing is compliant with USP<85> guidelines. The finalBET is determined by dividingtheUSP defined equation of 175 EU7V, where V is the maximum allowable dose injection volume of the final drug product.Filter Integrity (Bubble Point Test)

[0224] The sterilizing filter used for terminal sterilization of the final drug product was tested to ensure that integrity was maintained during final sterilization. The filter was connected to a gas line, which also includes a pressure gauge. The effluent end of the filter was submergedinto a container of water of suitable size. The pressure inside the gas line was slowly increased until gas flows through the filter into the water producing a visible bubble stream. The pressure at which the bubble stream becomes visible is recorded. To meet the acceptance criteria for this test, the bubble stream must become visible above the filter integrity pressure specified by the filter manufacturer.Sterility

[0225] Sterility testing was performed using the direct inoculation of media method described in theUSP <71>. Sterility testing is initiated within 30 hours after preparation of the final drug product. One 10 mL tube containing tryptic soy broth (TSB) media and one 10 mL tube containing fluid thioglycolate (FTM) media are each inoculated with 0.1 mL of the final drug product sterility sample. FTM samples were incubated for 14 days at 30-35 °C, while TSB samples were incubated for 14 days at 20 - 25 °C. The samples were visually inspected daily for signs of bacterial growth. Acceptance criteria for post -release sterility testing is no visible growth after incubation for 14 days.Specific activity

[0226] Specific activity was measured in accordance with established procedures, for example, as provided in Luurtsema el al, EJNMMI Radiopharm. Chem. 2021, 6:34, http s : / / d oi. org / 10.1186 / s41181-021-00149-6.Example 4 - Stability of formulations

[0227] Formulations comprising excipients in the amounts listed below were prepared and stored at room temperature. The “reaction solution” comprises the compound of Formula (I) and gentisic acid (provided as sodium gentisate) in the given concentrations. The “formulation solution” comprises the excipients ascorbic acid (provided as sodium ascorbate) and / or N-acetylcysteine, at the requisite concentration in order to provide a formulation having the concentration of the component as listed below. In each case, the reaction solution and formulation solution were combined to give the overall formulation. Parameters such as pH of the formulation, the amount of free Cu2+ion, radiochemical purity, specific activity and appearance were assessed at various times. Determination of the amount of free Cu2+ion and radiochemical purity were assessed by either radioTLC (iTLC) and / or HPLC . Changes in the radiochemical purity over time were calculated based on the recorded values.Example 4a

[0228] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 50 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 2.5 - 3.5 - Free64Cu2+(iTLC) 0.5 31.7 12.1 - Radiochemical Purity (HPLC) 97.8 83.2 76.7 -% A RCP - (-14.6) (-6-5) -Example 4b

[0229] Reaction Solution: 5 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 100 mg / mL N-acetylcysteine (NAC), aq.CharacteristicEOS 26 Hours 48 Hours (Testing Method)pH 2.5 - - RAC @ EOS 0.78 - - Free64Cu2+(iTLC) 0.35 9.00 20.38 Radiochemical Purity (HPLC) 92.66 88.90 86.00% A RCP - (-3-76) (-2.9)Specific Activity (SA) 281 mCi / pg - -Example 4c

[0230] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 50 mg / mL N-acetylcysteine (NAC), 50 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 3 - 4 3.5 Free64Cu2+(iTLC) 2.4 0 0 0.2 Radiochemical Purity (HPLC) 98.2 98.2 98.4 98.3% A RCP - 0 (+0.2) (-o.i)Example 4d

[0231] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 25 mg / mL N-acetylcysteine (NAC), 50 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 4 - 4 3.5 Free64Cu2+(iTLC) 0 1.28 2.1 4.45 Radiochemical Purity (HPLC) 98.3 97.7 97.2 97.04% A RCP - -0.63 -1.11 -1.29Example 4e

[0232] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 68 mg / mL N-acetylcysteine (NAC), 22 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 4 - 4 3.5 Free64Cu2+(iTLC) 0 0 1.25 1.21 Radiochemical Purity (HPLC) 98.2 97.88 97.97 97.21% A RCP - -0.30 -0.21 -0.97Example 4f

[0233] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 50 mg / mL N-acetylcysteine (NAC), 50 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 5 5 5 5 Free64Cu2+(iTLC) 0 7.1 6.5 6.7 Radiochemical Purity (HPLC) 98.3 96.2 96.3 96.3% A RCP - (-2-1) (+o.i) 0Conforms Conforms Conforms ConformsAppearance (slight (slight (Clear) (Clear)yellow) yellow)Example 4g

[0234] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 25 mg / mL N-acetylcysteine (NAC), 50 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 5 5 5 5 Free64Cu2+(iTLC) 0 0 1.23 2.02 Radiochemical Purity (HPLC) 98.0 98.1 98.23 97.6% A RCP - (+o.i) (+0.2) (-0-5)Conforms Conforms Conforms ConformsAppearance (slight (slight (Clear) (Clear)yellow) yellow)Example 4h

[0235] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate, Formulation Solution: 25 mg / mL N-acetylcysteine (NAC), 25 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 5 5 5 5 Free64Cu2+(iTLC) 0 3.3 1.4 3.4 Radiochemical Purity (HPLC) 98.1 97.7 98.3 97.9% A RCP - (-0.4) (+0.9) (-0-4)Conforms Conforms Conforms ConformsAppearance (slight (slight (Clear) (Clear)yellow) yellow)Example 4i

[0236] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.36 mg / mL sodium gentisate Formulation Solution: 30 mg / mL N-acetylcysteine (NAC), 30 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 4.5 4.5 4.5 4.5 Free64Cu2+(iTLC) 1.5 8.8 5.2 4.7 Radiochemical Purity (HPLC) 97.5 92.6 94.5 95.1% A RCP (-4.9) (+1 9) (+0.6) Appearance Conforms Conforms Conforms ConformsSpecific Activity 318.9 - - -Example 4j

[0237] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 100 mg / mL N-acetylcysteine (NAC), 26 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 2 - 3 (2.5) - - - RAC @ EOS 0.824 - - - Free64Cu2+(iTLC) 1.38 0.00 0.00 0.00 Radiochemical Purity (HPLC) 97.69 98.66 98.70 98.93% A RCP - (+0.97) (+0.04) (+0.23)Specific Activity (SA) 299 mCi / pg - - -Example 4k

[0238] Reaction Solution: 10 pg / mL SAR-bisPSMA, 0.5 mg / mL sodium gentisate Formulation Solution: 25 mg / mL N-acetylcysteine (NAC), 50 mg / mL sodium ascorbate, aq.CharacteristicEOS 24 Hours 48 Hours 72 Hours (Testing Method)pH 5 5 5 5 Free64Cu2+(iTLC) 0 0 1.2 2.0 Radiochemical Purity (HPLC) 98.0 98.1 98.2 97.6% A RCP - (+o.i) (+o.i) (-0-6)Conforms Conforms Conforms ConformsAppearance (slight (slight (Clear) (Clear)yellow) yellow)Example 5

[0239] A formulation comprising a compound of Formula (I) (i.e. Sar-bisPSMA) complexed with a64Cu ion was prepared in accordance with Example 1 with amounts of each component listed below to a final formulation volume of 100 mL.Specific activity Yield (NDC) RCP • 0.9 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 19 mg sodium gentisate 102.49 GBq 89.9% 95.30% • 500 mg sodium ascorbate• 5 mL reaction buffer

[0240] The formulation has a specific activity of over 100 GBq and was radiolabelled in a yield of almost 90% and a radiochemical purity of over 95%. This formulation shows that large amounts of64Cu can be incorporated into a formulation.Example 6

[0241] Formulations comprising a compound of Formula (I) (i.e. Sar-bisPSMA) complexed with a64Cu ion was prepared in accordance with Example 1 with amounts of each component listed below to a final formulation volume of 20 mL.Specific activity Yield (NDC) RCP • 0.22 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 3.8 mg sodium gentisate 19.16 GBq 93.5% 95.30% • 100 mg sodium ascorbate• 1 mL reaction buffer• 0.22 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 5.7 mg sodium gentisate 19.3 GBq 93.40% 95.08% • 100 mg sodium ascorbate• 1 mL reaction buffer• 0.22 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 9.6 mg sodium gentisate 19.16 GBq 94.50% 92.37% • 100 mg sodium ascorbate• 1 mL reaction buffer• 0.22 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 9.6 mg sodium gentisate 23.8 GBq 94.80% 96.78% • 200 mg sodium ascorbate• 1 mL reaction buffer

[0242] Each formulation above contains varying amounts of sodium gentisate and sodium ascorbate and provided the compound of Formula (I) complexed with64Cuwith excellent radiochemical yield and purity.Example 7

[0243] Formulations comprising a compound of Formula (I) (i.e. Sar-bisPSMA) complexed with a64Cu ion was prepared in accordance with Example 1 with amounts of each component listed below to a final formulation volume of 20 mL. The formulations below were prepared at room temperature without stirring and a reaction time of 5 minutes.Specific activity Yield (NDC) RCP • 0.22 mg Sar-bisPSMA 18.5 GBq 95.2% 97.43% • 0.1 M sodium phosphate buffer• 9.6 mg sodium gentisate 23.8 GBq 94.8% 96.78%• 200 mg sodium ascorbate• 1 mL reaction buffer 19.2 GBq 94.9% 97.68%

[0244] These formulations show excellent radiochemical yield and purity, even with a shorter reaction time (i.e. 5 minutes) and without stirring during complexation of the compound of Formula (I) and the64Cu ion.Example 8

[0245] A formulation comprising a compound of Formula (I) (i.e. Sar-bisPSMA) complexed with a64Cu ion was prepared in accordance with Example 1 with amounts of each component listed below to a final formulation volume of 20 mL. The formulation was prepared at a temperature of 37 °C without stirring and a reaction time of 5 minutes.Specific activity Yield (NDC) RCP • 0.22 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 9.6 mg sodium gentisate 18.1 GBq 94.8% 96.73% • 200 mg sodium ascorbate• 1 mL reaction buffer

[0246] This shows that the preparation of formulations of the present invention can be performed at elevated temperatures without affecting the radiochemical yield or purity of the formulation.Example 9

[0247] A formulation comprising a compound of Formula (I) (i.e. Sar-bisPSMA) complexed with a64Cu ion was prepared in accordance with Example 1 with amounts of each component listed below to a final formulation volume of 20 mL. The formulation was prepared at room temperature without stirring and a reaction time of 15 minutes.Specific activity Yield (NDC) RCP • 0.22 mg Sar-bisPSMA• 0.1 M sodium phosphate buffer• 9.6 mg sodium gentisate 18.1 GBq 94.8% 92.88% • 200 mg sodium ascorbate• 1 mL reaction buffer

[0248] This shows that longer reaction times for the preparation of formulations of the present invention do not affect the radiochemical yield or purity of the formulation.

Claims

The claims defining the invention are as follows:

1. A formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:H fl H 1 fl0H / \ H0? I H 5? H N X A NN— \ HN NH / — N ^N H^ Y nN~'' ITNHH J o OHHHZNHHo'HNV° O OH HN .NH OH O'■Q Formula (I)wherein the formulation further comprises N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof.

2. A formulation according to claim 1, wherein the N-acetylcysteine or pharmaceutically acceptable salt thereof is present in an amount of between about 5 mg / mL to about 200 mg / mL.

3. A formulation according to claim 1, wherein the gentisic acid or pharmaceutically acceptable salt thereof is present in an amount of between about 0.1 mg / mL to about 1.0 mg / mL.

4. A formulation according to claim 1, wherein the ascorbic acid or pharmaceutically acceptable salt thereof is present in an amount of between about 5 mg / mL to about 200 mg / mL.

5. A formulation according to any one of claims 1 to 4, wherein the formulation comprises free Cu ion at a concentration of not more than 5% with respect to the total amount of Cu in the formulation for least 24 hours.

6. A formulation according to any one of claims 1 to 5, wherein the pH of the formulation is between about 2 to about 10.

7. A formulation according to any one of claims 1 to 6, wherein the Cu ion is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

8. A formulation according to any one of claims 1 to 7, wherein the formulation comprises a phosphate buffer solution.

9. A formulation according to any one of claims 1 to 8, wherein the compound of Formula (I) has the structure of Formula (la):Formula (la).

10. A process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the process comprising the steps of:i) preparing a buffer solution comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and gentisic acid or a pharmaceutically acceptable salt thereof;ii) adding a solution of a Cu ion in hydrochloric acid to the solution of step i); and iii) adding ascorbic acid or a pharmaceutically acceptable salt thereof and N- acetylcysteine or a pharmaceutically acceptable salt thereof to the solution of step ii).

11. A process according to claim 10, wherein the gentisic acid is provided as sodium gentisate.

12. A process according to claim 10, wherein the ascorbic acid is provided as sodium ascorbate.

13. A process according to claim 10, wherein the buffer solution is a phosphate buffer solution.

14. A process according to any one of claims 10 to 13, wherein the solution obtained from step ii) is stirred for a time at room temperature.

15. A process according to any one of claims 10 to 14, wherein the solution of a Cu ion in hydrochloric acid comprises a64Cu ion or a67Cu ion.

16. A process for preparing a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion: / A0H / \ H0H X / fy — I N J SHN— \ HN NH / - NHH\ZNHHHo IHo'HNV° O OH °YNHHN A ^NH ’OH O'■o Formula (I)wherein the formulation comprises gentisic acid or a pharmaceutically acceptable salt thereof, N-acetylcysteine or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof, wherein the process comprises combining:i) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, ii) gentisic acid or a pharmaceutically acceptable salt thereof,iii) ascorbic acid or a pharmaceutically acceptable salt thereof,iv) N-acetylcysteine or a pharmaceutically acceptable salt thereof; andv) a Cu ion in a solution of hydrochloric acid,in a buffer solution.

17. A process according to any one of claims 10 to 16, wherein the process further comprises the step of filtering the solution.

18. A formulation prepared in accordance with a process of any one of claims 10 to 17.

19. A kit for the preparation of a formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:Formula (I)the kit comprising:i) a container comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof,ii) a container comprising a solution of a Cu ion; andinstructions for preparing a formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion, including the addition of N -acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof, and ascorbic acid or a pharmaceutically acceptable salt thereof.

20. A kit according to claim 19, wherein the kit further comprises a container comprising theN-acetylcysteine or pharmaceutically acceptable salt thereof, and / or a container comprising the gentisic acid or pharmaceutically acceptable salt thereof, and / or a container comprising the ascorbic acid or pharmaceutically acceptable salt thereof.

21. A method for radioimaging and / or diagnosing a cancer, the method comprising administering to a subject in need thereof a formulation according to any one of claims 1 to 9 or 18.

22. A method for treating a cancer, the method comprising administering to a subject in need thereof a formulation according to any one of claims 1 to 9 or 18.

23. A method according to claim 21 or 22, wherein the cancer is associated with expression of a prostate specific membrane antigen (PSMA) receptor.

24. A method according to claim 23, wherein the cancer is a cancer of the brain, lung, bone, adrenal glands, breast, central nervous system, eye, female reproductive system, male reproductive system, head, neck, kidney, liver, lymphatic system, pancreas, peripheral nervous system, salivary glands, skin, spleen, soft tissue, stomach, thymus, thyroid, urinary tract, bladder or vasculature.

25. A method according to any one of claims 21 to 24, wherein the cancer is a prostate cancer.

26. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion: / A0H / \ H0H X / fy — X N J SHN— \ HN NH / - NHH\ZNHHHo IHo' YHNV° O OH °YNHHN A ^NH ’OH O'■o Formula (I).N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for radioimaging and / or diagnosing a cancer.

27. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a Cu ion:H O H / \ H O H N p h A 7^ / — X N N— THN NH / — N H I n H H g I H OH oHH\ ,NHHS OH o'^rHNV° o OH °YNHHN A / \ / NH OH O'•o Formula (I).N-acetylcysteine or a pharmaceutically acceptable salt thereof, gentisic acid or a pharmaceutically acceptable salt thereof and ascorbic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer.

28. Use according to claim 26 or 27, wherein the cancer is associated with expression of a prostate specific membrane antigen (PSMA) receptor.

29. Use according to claim 28, wherein the cancer is a cancer of the brain, lung, bone, adrenal glands, breast, central nervous system, eye, female reproductive system, male reproductive system, head, neck, kidney, liver, lymphatic system, pancreas, peripheral nervous system, salivary glands, skin, spleen, soft tissue, stomach, thymus, thyroid, urinary tract, bladder or vasculature.

30. Use according to any one of claims 26 to 29, wherein the cancer is a prostate cancer.

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