Compounds for the treatment of a complex cancer

Abstract

The present invention relates to compounds that are useful in the treatment of a cancer, particularly in the case of complex cancers. The present invention also relates to a composition comprising said compounds and methods of treatment and uses thereof.

Description

Compounds for the treatment of a complex cancerField

[0001] The present invention relates to compounds that are useful in the treatment of a cancer, particularly in the case of complex cancers. The present invention also relates to a composition comprising said compounds and methods of treatment and uses thereof.Background

[0002] Current approaches for the treatment of a particular cancer may include administering a compound that is known to target a specific receptor associated with the cancer. This then involves understanding the pathophysiology of the cancer and the associated receptor profile. Where the receptor is known and there are existing therapies that are known to target the identified, this may be useful in the treatment of a particular subject. Such an approach is less effective if a cancer or a tumour is more complex and is less heterogeneous.

[0003] Where a cancer is more heterogenous, i.e. expressing different morphology and / or phenotypes in a given subject, the selection of a particular therapy or drug may not be as clear and furthermore, administration of such therapy may have limited efficacy. This may often be due to a change in the number and types of receptors expressed by the tumour as a result of tumour progression. Generally, where a cancer is more heterogeneous and complex, patient outcomes and success of treatment is less favourable.

[0004] Heterogenous cancers are considered to be more difficult to treat due to the diversity in receptor types that are expressed in the cancer and resistance of the cancer to existing therapies. Furthermore, heterogeneity is known to increase with progression of the cancer and is considered a mechanism of resistance of cancers to initial therapies. Even where a cancer in a particular subject is successfully treated with existing therapies, recurrence of the cancer (e.g. as a metastasis) often results in a more complex and heterogenous cancer such that the secondary cancer is harder to treat.

[0005] There remains a need for compounds and therapies that are capable of treating complex cancers having diverse cell types and therefore allow for better patient outcomes as a result of treatment.Summary of the invention

[0006] The present inventors have found that the compounds disclosed herein comprising different peptides are capable of simultaneously binding to different receptors. These compounds comprise different peptides, where one peptide binds a prostate-specific membrane antigen (PSMA) while the other peptide binds a gastrin-releasing peptide receptor (GRPR). Since the compounds of the present invention are capable of binding more than one receptor, the compounds provide a more efficient method for the treatment of a cancer, especially where the cancer has greater complexity and heterogeneity.

[0007] According to a first aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:Formula (I) wherein: the linker groups are the same or different and are selected from:and the binding groups are different and are selected from:

[0008] In certain embodiments of the above aspects, when the linker is the following group:the binding group attached directly to the linker is:

[0009] In certain embodiments of the above aspects, when the linker is the following group:the binding group attached directly to the linker is:

[0010] In certain embodiments, the compound of Formula (I) has the structure of Formula (la) or a pharmaceutically acceptable salt thereof:Formula (la)

[0011] In other embodiments, the compound of Formula (I) has the structure of Formula (lb) or a pharmaceutically acceptable salt thereof:Formula (lb)

[0012] In certain embodiments, the compound of Formula (I) is coordinated with a metal ion. In certain embodiments, the metal ion is a radionuclide. In other embodiments, the metal ion is an alpha-emitting radionuclide. In certain embodiments, the metal ion is a copper ion. In certain embodiments, the copper ion is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

[0013] In a further aspect, the present invention provides a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more excipients.

[0014] In a further aspect, the present invention provides a method for the treatment of a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In yet another aspect, the present invention provides a method for the radioimaging of a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and imaging of the subject.

[0016] In another aspect, the present invention provides a method for the diagnosis of a cancer in a subject in need thereof, i) administering to a subject in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt thereof; ii) imaging of the subject; and iii) considering the images of the subjection obtained in step ii).

[0017] In certain embodiments, imaging of the subject is by positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

[0018] In other embodiments, imaging of the subject is by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) combined with computed tomography (CT) or magnetic resonance imaging (MRI).

[0019] In an aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a cancer.

[0020] In another aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the imaging of a cancer.

[0021] In a further aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the diagnosis of a cancer.

[0022] In certain embodiments, the cancer is associated with the expression of a PSMA receptor. In other embodiments, the cancer is associated with the expression of a GRPR receptor.

[0023] In further aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the diagnosis of a cancer.

[0024] In yet another aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the imaging of a cancer.

[0025] In another aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a cancer.

[0026] The present invention also provides a process for the preparation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.Brief description of the figures

[0027] Figure 1. Mass spectrum (ESI-MS, +ve ion) of Sar-PSMA-BBN, showing both [M+4H]4+; [M+3H]3+signals.

[0028] Figure 2. iTLC chromatograms of (A) free64Cu ion, and (B) [64Cu]Cu-Sar-PSMA- BBN. Free64Cu ion eluted with the solvent front, while the64Cu-complexed compound Sar- PSMA-BBN is retained. This difference between the chromatograms shows the radiolabelling of the Sar-PSMA-BBN ligand with64Cu.

[0029] Figure 3. HPLC traces of [64Cu]Cu-Sar-PSMA-BBN (blue, radio-HPLC, Rt= 12.48 min), Cu-Sar-PSMA-BBN (red, RP-HPLC, Rt= 11.68 min) and Sar-PSMA-BBN (black, RP- HPLC, Rt= 11.44 min) with UV detection at 280 nm. The data is normalised and traces for Cu- coordinated Sar-PSMA-BBN complexes are offset by 1.5 and 3 minutes, respectively.

[0030] Figure 4. Plot of fluorescence intensity and log 1 ©(concentration) of Sar-PSMA-BBN, Sar-bisPSMA and PSMA-617 obtained by enzyme-based (NAALADase) assay. PSMA-617 was used as an internal standard in order to determine the binding affinity of Sar-PSMA-BBN and Sar-bisPSMA.

[0031] Figure 5. Radio-HPLC analysis of [67Cu]Cu-Sar-PSMA-BBN at t = 0 and t = 52 h in DPBS (Figures 5a and 5b), Solution A (8% ethanol + DPBS, Figures 5c and 5d), Solution B (0.5% sodium gentisate + DPBS, Figures 5e and 5f) and Solution C (5% ethanol + 0.5% sodium gentisate + DPBS, Figures 5g and 5h). These chromatograms show that [67Cu]Cu-Sar- PSMA-BBN has excellent stability up to at least 52 hours in the various solutions comprising different combinations of DPBS, ethanol and sodium gentisate.

[0032] Figure 6. Radio-HPLC analysis of [67Cu]Cu-Sar-PSMA-BBN after incubation for 20 h in Solution A (0.5% sodium gentisate + DPBS, Figure 6a), Solution B (5% ethanol + DPBS, Figure 6b) and Solution C (5% ethanol + 0.5% sodium gentisate + DPBS, Figure 6c). These chromatograms show that [67Cu]Cu-Sar-PSMA-BBN has excellent stability up to at least 20 hours in the various solutions comprising different combinations of DPBS, ethanol and sodium gentisate.

[0033] Figure 7. Chromatograms obtained by radio-HPLC analysis of [67Cu]Cu-SAR-PSMA- BBN (Figure 7a), [67Cu]Cu-SAR-BBN (Figure 7b) and [67Cu]Cu-SAR-BisPSMA (Figure 7c) at t = 0 min of incubation with serum from a healthy volunteer (drawn in 2023) at 37 °C.

[0034] Figure 8. Chromatograms obtained by radio-HPLC analysis of [67Cu]Cu-SAR-PSMA- BBN (Figure 8a), [67Cu]Cu-SAR-BBN (Figure 8b) and [67Cu]Cu-SAR-bisPSMA (Figure 8c) at t = 0 min of incubation serum obtained from Sigma Aldrich (2022) at 37 °C.

[0035] Figure 9. Chromatograms obtained by iTLC analysis of [67Cu]Cu-SAR-PSMA-BBN after 24 h incubation with either 1000-fold of cysteine (Figure 9a), histidine (Figure 9b) or EDTA (Figure 9c). The intact compound is retained at the baseline (i.e. origin), with free67Cu traveling with the solvent front. In each case, there is minimal dissociation of Cu-67 from the sarcophagine cage.

[0036] Figure 10. Figure 10a shows an iTLC chromatogram of [64Cu]Cu-SAR-PSMA-BBN. Figure 10b shows a stacked radio-HPLC chromatogram of [64Cu]Cu-SAR-PSMA-BBN (Red, Rt = 10.00 min), RP-HPLC of [liatCu]Cu-SAR-PSMA-BBN (Blue, Rt= 9.91 min) and RP- HPLC of the free ligand SAR-PSMA-BBN (Black, Rt = 9.64 min) with UV detection at 280 nm. The signals were normalised and the RP-HPLC of the ligand and radio-HPLC were offset by 1 and 2 minutes respectively. The iTLC chromatogram shows the stability of the compound Sar-PSMA-BBN when radiolabeled with64Cu, i.e. no free64Cu is observed, while the HPLC chromatograms show that the free compound Sar-PSMA-BBN and the same compound complexed with either64Cu ornatCu results in elution at the same time. These chromatograms together confirm the stability of the compound.

[0037] Figure 11 PET / CT images (maximum intensity projection) of male NSG mice bearing LNCaP-C42 and PC3 tumours, with images taken 1 hour (Figure Ila), 4 hours (Figure 11b)and 24 hours (Figure 11c) post-injection of [64Cu]Cu-SAR-PSMA-BBN (5-7 MBq), prepared according to Example 14 (Week 1). The mice bear LNCaP-C42 tumours on the left side and PC3 tumours on the right side. These images show uptake of the compound in the LNCaP-C42 tumour (right), but essentially no uptake of the compound in the GPCr expressing tumour (left).

[0038] Figure 12 PET / CT images (maximum intensity projection) of male NSG mice bearing LNCaP-C42 and PC3 tumours, with images taken 1 hour (Figure 12a), 4 hours (Figure 12b) and 24 hours (Figure 12c) post-injection of [64Cu]Cu-SAR-PSMA-BBN (5-7 MBq) with coinjection of 1000-fold 2-PMPA. The mice bear LNCaP-C42 tumours on the left side and PC3 tumours on the right side.

[0039] Figure 13. Graph showing ex vivo biodistribution and tumour uptake, expressed as percent injected activity per gram tissue (% lA / g) (mean ± SEM; n = 5 / group) in male NSG mice bearing LNCaP C42 and PC3 tumours following injection of [64Cu]Cu-SAR-PSMA- BBN, prepared in accordance with Example 14 (Week 1). Measurements were taken at 1 hour (blue), 4 hours (red) and 24 hours (green) after injection, and 24 hours after injection and coinjection of 1000-fold 2-PMPA (purple).

[0040] Figure 14. Chromatograms of [64Cu]Cu-SAR-BBN obtained by iTLC (Figure 14a) and radio-HPLC (Figure 14b). These chromatograms show the near-quantitative radiolabelling of the compound.

[0041] Figure 15. Graph showing ex vivo biodistribution and tumour uptake, expressed as % lA / g (mean ± SEM; n = 5 / group) in male NSG mice bearing LNCaP C42 and either ‘big’ (mice implanted on the same day as those used in Week 1 study) or ‘normal’ (mice implanted the week after those used in Week 1 study) PC3 tumours following injection of [64Cu]Cu-SAR- BBN, prepared in accordance with Example 14 (Week 1). Measurements were taken at 1 hour (blue, “big” PC3 and “normal” LNCaP C42 tumours), and 4 hours (red, “big” PC3 and “normal” LNCaP C42; green, similar size for PC3 and LNCaP 42) post-injection.

[0042] Figure 16. Figures 16a and 16b show chromatograms of [64Cu]Cu-SAR-PSMA-BBN analysed by iTLC and radio-HPLC, respectively. Figures 16c and 16d show chromatograms of [64CU]CU-SAR-BBN analysed by iTLC and radio-HPLC, respectively. Figures 16e and 16f show chromatograms of [64Cu]Cu-SAR-BisPSMA analysed by iTLC and radio-HPLC,respectively. Each of these chromatograms show the near quantitative radiolabeling of [64Cu]Cu-SAR-PSMA-BBN, [64CU]CU-SAR-BBN and [64Cu]Cu-SAR-BisPSMA.

[0043] Figure 17. Graph showing ex vivo biodistribution and tumour uptake, expressed as % lA / g (mean ± SEM; n = 5 / group) in male NSG mice bearing LNCaP C42 and PC3 tumours following injection of [64Cu]Cu-SAR-bisPSMA, prepared in accordance with Example 17 (Week 3). Measurements were taken at 1 hour (blue), 4 hours (red) and 24 hours (green) after injection.

[0044] Figure 18. Graph showing ex vivo biodistribution and tumour uptake, expressed as percent injected activity per gram tissue (% lA / g) (mean ± SEM; n = 5 / group) in male NSG mice bearing ‘only’ PC3 tumours (LNCaP C42 cells were implanted but remained too small for detection) following injection of [64Cu]Cu-SAR-PSMA-BBN, prepared in accordance with Example 17 (Week 3). Measurement was taken 1 hour after injection (blue). Additional data (red) represents biodistribution values taken from “PC3 only” mice (i.e. bearing PC3 tumours only) as recorded in Week 1 experiments in relation to the dual -turn our model.

[0045] Figure 19. Graph showing ex vivo biodistribution and tumour uptake, expressed as percent injected activity per gram tissue (% lA / g) (mean ± SEM; n = 5 / group) in male NSG mice bearing ‘only’ PC3 tumours (LNCaP C42 cells were implanted but remained too small for detection) following injection of [64Cu]Cu-SAR-BBN, prepared in accordance with Example 17 (Week 3). Measurement was taken 1 hour after injection (blue). Additional data (red) represents biodistribution values taken from “PC3 only” mice (i.e. bearing PC3 tumours only) as recorded in Week 2 experiments in relation to the dual -turn our model.Detailed description

[0046] 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.

[0047] 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 willdepend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0048] 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.

[0049] As used herein the terms "treating", "treatment", “preventing”, “prevention" and grammatical equivalents refer to any and all uses which remedy the stated neuroendocrine tumour, prevent, retard or delay the establishment of the disease, or otherwise prevent, hinder, retard, or reverse the progression of the disease. Thus the terms "treating" and “preventing” and the like are to be considered in their broadest context. For example, treatment does not necessarily imply that a patient is treated until total recovery. Where the disease displays or a characterized by multiple symptoms, the treatment or prevention need not necessarily remedy, prevent, hinder, retard, or reverse all of said symptoms, but may prevent, hinder, retard, or reverse one or more of said symptoms.

[0050] As used herein, the term “cancer” broadly encompasses neoplastic diseases characterised by abnormal cell growth with the potential to invade or spread to other parts of the body. The cancer may be benign, which does not spread to other parts of the body. The cancer may be malignant, meaning that the cancer cells can spread through the circulatory system or lymphatic system. The term as used herein includes all malignant, i.e. cancerous, disease states. The cancer may be present as a tumour. Accordingly, the term "tumour" is used generally to define any malignant cancerous or pre-cancerous cell growth, and may include leukemias, but is particularly directed to solid tumours or carcinomas such as melanomas, colon, lung, ovarian, skin, breast, pancreas, pharynx, brain, prostate, CNS, and renal cancers (as well as other cancers).

[0051] As used herein, the term "subject" as used herein refers to mammals and includes humans, primates, livestock animals (e.g. sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g. mice, rabbits, rats, guinea pigs), performance and show animals (e.g. horses, livestock, dogs, cats), companion animals (e.g. dogs, cats) and captive wild animals. Preferably, the mammal is human or a laboratory test animal. Even more preferably, the mammal is a human.

[0052] As used herein, the term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. A therapeutically effective amount can be readily determined by an attending clinician by 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 radio labelled 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. An effective amount can be administered in one or more administrations. For the purposes of radioimaging, an effective amount is sufficient for an image showing the localisation of the compound of Formula (I) administered to the subject, owing to the detection of the products of decay from the radioisotope that is complexed with the compound. For the purposes of treatment, an effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow and / or delay the progression of the cancer.

[0053] As used herein, 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) 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.

[0054] As used herein, the term "sarcophagine" or “sar” refers to the nitrogen-containing macrocyclic ligand with the formula 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane. The sarcophagine has six nitrogen atoms that contribute to the chelation of a metal ion. Each of thenitrogen atoms in the macrocycle may be protected with a suitable protecting group where necessary.

[0055] As used herein, the term “amino acid” refers to a molecule which contains both an amino and a carboxyl functional group. The amino acid may be a natural or unnatural amino and may also be in equilibrium with its zwitterionic form. The amino acid may contain modifications at either the amino and / or carboxyl terminus, or may contain a free amino group or carboxyl group. Further modification of the amino acid side chain or additional substitutions at other parts of the amino acid are also contemplated.

[0056] As used herein, the term “residue” refers to a part of a compound resulting from the removal of one or more atoms. The one or more atoms to be removed may be hydrogen atoms. A person skilled in the art would understand, for example, where a compound comprises a carboxylic acid (-COOH) functional group, the residue that is found in the compound of Formula (I) comprises the carboxylate of the amino acid (i.e. -COO), which is attached to the remainder of the compound.

[0057] As used herein, naturally occurring amino acids are the L- or D-form of the twenty amino acids commonly found in nature. These are glycine (Gly, G), alanine (Ala, A), valine (Vai, V), leucine (Leu, L), isoleucine (He, I), methionine (Met, M), proline (Pro, P), phenylalanine (Phe, F), tryptophan (Trp, W), serine (Ser, S), threonine (Thr, T), asparagine (Asn, N), glutamine (Gin, Q), tyrosine (Tyr, Y), cysteine (Cys, C), lysine (Lys, K), arginine (Arg, R), histidine (His, H), aspartic acid (Asp, D), and glutamic acid (Glu, E).

[0058] The compounds disclosed herein comprise a peptide with the amino acid sequence D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 as depicted below:

[0059] The peptide is a bombesin-like (BBN) peptide and targets the gastrin-releasing peptide receptor (GRPR). The peptide may also be referred to as a “BBN peptide” or Bombesin(7-14). Without wishing to be bound by theory, the present inventors believe that the use of compounds comprising this bombesin-like peptide as depicted herein allows for the compound itself to target and localise at GRPR, which are known to be expressed in various metastatic tissues.

[0060] In certain embodiments, the amino acid residues in the BBN peptide have the stereochemistry as depicted below:

[0061] The compounds disclosed herein also comprise an amino acid- substituted urea as depicted below, where the urea is attached to the remainder of the compound by a linker group:

[0062] The urea comprises glutamine and lysine amino acids both attached to a central urea functional group (also called a “PSMA urea”), where the sidechain of the lysine group is attached to the remainder of the compound through the linker group. Without wishing to be bound by theory, the present inventors believe that this amino acid-urea fragment is known to bind to prostate-specific membrane antigen (PSMA) receptors, which are expressed in some healthy tissues and also expressed higher concentrations on the surface of various cancers and tumours. This in turn allows for the localisation of the compounds of the present invention on the surface of various cancers expressing the PSMA receptor, where the compounds contain this Glu-urea-Lys peptide.

[0063] In certain embodiments, the amino acid residues in the PSMA urea have the stereochemistry as depicted below:

[0064] In all of the compounds disclosed herein, the binding peptides are attached to the sarcophagine via a linker. Without wishing to be bound by theory, the present inventors believe that the use of the specific linkers depicted contribute to the overall bioavailability, biodistribution and stability of the overall compounds. Additionally, the linkers also act to provide a suitable distance between each peptide that binds to its target receptor and the sarcophagine macrocycle.

[0065] The linker depicted below is a polyethylene glycol (PEG) group having four repeat units:

[0066] As disclosed herein, a PEG linker is used to attach the BBN peptide to the remainder of the compound. The present inventors believe that the use of a PEG linker in combination with a BBN peptide may modulate the overall biodistribution, metabolism and excretion of the compound when administered.

[0067] The linker depicted below comprises two phenylalanine (Phe) residues, where the two amino acid residues are attached to an aminooctanoic acid (AOC) group.

[0068] Where the compounds disclosed herein comprise a PSMA urea, the urea group is attached to the remainder of the molecule by the linker containing two Phe residues and the aminooctanoic acid group. Without wishing to be bound by theory, the present inventors believe that the use of this linker to join the PSMA urea to the sarcophagine may allow for improved metabolic stability of the overall compound, and also facilitate interaction of the PSMA urea with the binding pocket of the PSMA receptor.

[0069] In certain embodiments, the two phenylalanine residues in the linker above are both D- phenylalanine residues as depicted below:

[0070] In certain embodiments, the compound of Formula (I) has the structure of Formula (Ic) and is known as Sar-PSMA-BBN:Formula (Ic)

[0071] In other embodiments, the compound of Formula (I) has the following structure and stereochemistry as defined below:

[0072] The compounds of the present invention are intended to coordinate or chelate a metal ion through the sarcophagine component. In certain embodiments, the metal ion coordinated by the compound of Formula (I) is a copper ion. In certain embodiments, the metal ion coordinated by the compound of Formula (I) is a radioisotope or radionuclide. In certain embodiments, the metal ion coordinated by the compound of Formula (I) is a copper radioisotope. In certain embodiments, the metal ion coordinated by the compound of Formula (I) is a copper radioisotope selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In certain embodiments, the metal ion coordinated by the compound of Formula (I) is a64Cu radioisotope. In other embodiments, the metal ion coordinated by the compound of Formula (I) is a67Cu radioisotope.

[0073] The complexes as described herein are radiolabelled with a radioisotope that undergoes spontaneous decay, where these byproducts of decay are detected by various means, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The quality of the images obtained, and subsequently the confidence in any diagnosis based on these images, depend on the ability of the radiolabelled complex to bind to the desired receptor(s) and remain bound.

[0074] The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. The compositions are prepared in manners well known in the art.

[0075] Pharmaceutical compositions of this invention comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0076] These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.

[0077] If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0078] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.Methods of treatment and imaging

[0079] The present inventors have found that the compounds of the present invention may be used as ligands for therapy and / or treatment, radioimaging or diagnosis. For instance, the compounds of Formula (I) can be coordinated with an appropriate radioisotope, such that a complex chelating the radioisotope can be administered to a subject for the purposes of radioimaging and / or radiotherapy. An appropriate radioisotope is selected by considering the requirements of treatment and / or imaging and the half-life and decay properties of the radioisotope. For instance, for the purposes of radioimaging, a radioisotope having a shorter half-life may be more suitable than a radioisotope having a longer half-life. In other situations, for the purposes of treatment, the administration of a complex having a radioisotope with a longer half-life may be more suitable. The complexes of Formula (I) comprising a radioisotope are able to deliver the radioisotope to the desired location in the body, such that the products of radioactive decay derived from the radioisotope are delivered to the desired location.

[0080] The present inventors have found that the compound of Formula (I) complexed with a radioisotope may bind to PSMA receptors where the following peptide group is present in the compound:

[0081] The same compound of Formula (I) complexed with a radioisotope may bind to gastrinreleasing peptide receptors where the following peptide group is present in the compound:

[0082] Where both peptide groups depicted above are present in the compound of Formula (I), a complexed form of the compound may be administered in methods for the treatment of a cancer, where the cancer is associated with either a PSMA receptor and / or a gastrin-releasing peptide receptor.

[0083] The present invention therefore provides a method for the treatment of a cancer in a subject in need thereof, the method comprising administering a compound of Formula (I) complexed with a radioisotope.

[0084] The same complex comprising both peptide groups and a radionuclide may also be used in methods for radioimaging of a cancer, where the complex is administered to a subject and the subject then undergoes imaging by an appropriate modality.

[0085] In certain embodiments, radioimaging of the subject is by positron emission tomography (PET). In other embodiments, radioimaging of the subject is by single-photon emission computed tomography (SPECT). In other embodiments, radioimaging of the subject is by PET or SPECT in conjunction with computed tomography (CT) and / or magnetic resonance imaging (MRI).

[0086] The present invention therefore also provides a method for radioimaging of a subject in need thereof, the method comprising administering a compound of Formula (I) complexed with a radioisotope and imaging of the subject.

[0087] The complexes as described herein may be radiolabelled with a radionuclide or radioisotope that undergoes spontaneous decay, where these byproducts of decay are detected by various means, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The quality of the images obtained, and subsequently the confidence in any diagnosis based on these images, depend on the ability of the radiolabelled complex to specifically bind to the receptor site targeted by one of the peptides attached to the compounds disclosed herein. The compounds of Formula (I) as disclosed herein are able to coordinate and retain a radioisotope such that the administration of the coordinated complex to a subject results in the binding of the complex at the targeted receptor site. Since the complexed compounds remain bound for a time, the radioactive decay products derived from the radioisotope are detected when the subject is imaged by one or more modalities. The present inventors believe that since the compounds of the present invention both retain the coordinated radioisotope and remain bound to the target receptor for a time that is sufficient for the radioactive decay products to be detected, the obtained images are of a better quality and higher resolution than the same images obtained with other radiolabelled complexes.

[0088] As is known in the art, clinicians may use images of a subject obtained by radioimaging after administration of a radiolabelled complex to diagnose a cancer in the subject. The images may also be used to determine the presence or absence of a cancer. Where images of the same subject are obtained at different times, e.g. a subsequent image is taken days, weeks or months after the initial image, the images may be compared in order to determine progression of the cancer within the subject.

[0089] Therefore the present invention also provides a method for the diagnosis of a cancer in a subject in need thereof, the method comprising administering a compound of Formula (I) complexed with a radioisotope and radioimaging of the subject.

[0090] In certain embodiments of the methods described above, the compound of Formula (I) is complexed with a Cu radioisotope. In certain embodiments, the compound of Formula (I) is complexed with a Cu radioisotope selected from the group of60Cu,61Cu,62Cu,64Cu and67Cu. In some embodiments, the radioisotope is60Cu. In some embodiments, the radioisotope is61Cu. In some embodiments, the radioisotope is62Cu. In some embodiments, the radioisotope is64Cu. In some embodiments, the radioisotope is67Cu.

[0091] In certain embodiments, the method for the treatment of a cancer in a subject includes the administration of a compound of Formula (I) complexed with a67Cu radioisotope. In other embodiments, the method for the imaging of a cancer in a subject includes the administration of a compound of Formula (I) complexed with a64Cu radioisotope. In other embodiments, the method for the diagnosis of a cancer in a subject includes the administration of a compound of Formula (I) complexed with a64Cu radioisotope.

[0092] In certain embodiments, the cancer is lung cancer, testicular cancer, renal cancer, bladder cancer, kidney or renal cancer, ovarian cancer, breast cancer, fallopian tube cancer, uterine leiomyoma, prostate cancer, non-Hodgkin's lymphoma, colon cancer, lipoma, basal cell skin carcinoma, squamous cell skin carcinoma, osteosarcoma, acute myelogenous leukemia (AML), pancreatic cancer, prostate cancer, CNS cancer, retinoblastoma, neuroblastoma, glioblastoma, Kaposi’s sarcoma, Ewing’s sarcoma, rhabdomyosarcoma, hermangioma, a solid tumour, a blood-borne tumour, leukemia or melanoma.

[0093] Examples of other specific types of cancers include lung cancers (e.g. bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), kidney cancer (e.g. nephroblastoma or Wilms' tumour, renal cell carcinoma) acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g. lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g. cholangiocarcinoma), bladder cancer, breast cancer (e.g. adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g. meningioma, glioblastomas, glioma (e.g. astrocytoma, oligodendroglioma), medulloblastoma), bronchus cancer, carcinoid tumour, cervical cancer (e.g. cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g. colon cancer, rectal cancer, colorectal adenocarcinoma), connective tissue cancer, epithelial carcinoma, ependymoma, endotheliosarcoma (e.g. Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g. uterine cancer, uterine sarcoma), esophageal cancer (e.g. adenocarcinoma of the esophagus, Barrett's adenocarcinoma), Ewing's sarcoma, ocular cancer (e.g. intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g. stomach adenocarcinoma), gastroesophageal cancer, gastrointestinal stromal tumour (GIST), germ cell cancer, head and neck cancer (e.g. head and neck squamous cell carcinoma, oral cancer (e.g. oral squamous cell carcinoma), throat cancer (e.g. laryngealcancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), heavy chain disease (e.g. alpha chain disease, gamma chain disease, mu chain disease, hemangioblastoma, hypopharynx cancer, inflammatory myofibroblastic tumours, immunocytic amyloidosis), liver cancer (e.g. hepatocellular cancer (HCC), malignant hepatoma, hepatobiliary cancer), leiomyosarcoma (LMS), mastocytosis (e.g. systemic mastocytosis), muscle cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g. polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) or myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g. neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g. gastroenteropancreatic neuroendoctrine tumour (GEP-NET), carcinoid tumour), osteosarcoma (e.g. bone cancer), ovarian cancer (e.g. cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g. pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumours), penile cancer (e.g. Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumour (PNT), plasma cell neoplasia, paraneoplastic syndromes, intraepithelial neoplasm, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g. appendix cancer), soft tissue sarcoma (e.g. malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumour (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, small intestine cancer, sweat gland carcinoma, synovioma; testicular cancer (e.g. seminoma, testicular embryonal carcinoma), thyroid cancer (e.g. papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g. Paget's disease of the vulva).

[0094] Examples of specific types of breast cancer include lobular carcinoma in situ (LCIS), a ductal carcinoma in situ (DCIS), an invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, phyllodes tumour, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer, including triple negative (TNBC), HER positive, neoadjuvant HER2 negative, estrogen receptor positive, progesterone receptor positive, HERand estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive.

[0095] Examples of specific types of ovarian cancer include epithelial ovarian carcinoma (EOC), maturing teratoma, dysgerminoma, endodermal sinus tumour, granulosa-theca tumours Sertoli-Leydig cell tumour, primary peritoneal carcinoma, small cell carcinoma of the ovary (SCCO), teratoma of the ovary, sex cord-stromal ovarian cancer, dysgerminoma ovarian germ cell cancer, choriocarcinoma, carcinosarcoma, adenosarcoma, leiomyosarcoma, fibrosarcoma, and Krukenberg tumour.

[0096] Examples of specific types of pancreatic cancer include tumours affecting the exocrine gland, exocrine tumours, endocrine tumour, islet cell tumours, neurendocrine tumours, cystic tumours, cancer of the acinar cells, insulinoma, somatostatinoma, gastrinoma, glucagonoma, adenocarcinoma of the pancreas, pancreatoblastoma, sarcoma of the pancreas, adenosquamous carcinomas, colloid carcinoma, hepatoid carcinoma, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, pancreatic intraepithelial neoplasia, pancreatoblastoma, serous cystadenoma, signet ring cell carcinoma, solid-pseudopapillary neoplasm, and undifferentiated carcinoma with osteoclast-like giant cells.

[0097] Examples of specific types of prostate cancer include prostate adenocarcinoma, acinar adenocarcinoma, ductal adenocarcinoma, transitional cell (or urothelial) cancer, squamous cell cancer, small cell prostate cancer, carcinoid, sarcoma, small cell carcinoma, neuroendocrine tumour, and transitional cell carcinoma.

[0098] In certain embodiments, the cancer is selected from the group consisting of epithelial ovarian cancer, ovarian carcinoma, osteosarcoma, pancreatic adenocarcinoma, colorectal cancer, lung cancer, non-small cell lung cancer, gastric cancer, endometrial carcinoma, pancreatic adenocarcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, breast cancer, invasive ductal carcinoma of the breast, oral squamous cell carcinoma, esophageal cancer, renal cell cancer, insulinoma, prostate cancer, neuroendocrine differentiated prostate cancer, pheochromocytoma, adenoid cystic cancer, hepatocellular carcinoma, cervical cancer, small intestine cancer, neuroendocrine tumour, anal cancer, chordoma, desmoid tumour, head and neck cancer, thymus cancer, pancreatic cancer, cholangiocellular carcinoma, esophageal cancer, salivary gland cancer, sarcoma, carcinoma of unknown primary cancer.

[0099] Without wishing to be bound by theory, the present inventors believe that since the methods for the treatment and imaging of a subject both include the administration of a compound of Formula (I) coordinated with a radioisotope, a single administration of a suitable complex can be used in a method that both treats and images the subject. Therefore the present invention also relates to a method for the treatment and imaging of a subject in need thereof, wherein the method comprises the steps of: i) administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof coordinated with a radioisotope; and ii) imaging of the subject.Processes for preparing compounds of the present invention

[0100] The present inventors have found that compounds of Formula (I), for example, a compound having the structure of Formula (I) may be prepared in accordance with the route disclosed herein.

[0101] Accordingly, the present invention provides a process for producing a compound of Formula (Ic) or a salt thereof or a protected form thereof:Formula (Ic) the method comprising the step of: i) reacting a compound of Formula (A) or a salt thereof:Formula (A)wherein PG is a protecting group, and RG is a reactive group; with a compound of Formula (B) or a salt thereof and a compound of Formula (C) or a salt thereofFormula (C)

[0102] As used herein, the term “oxygen protecting group” refers to a group that can prevent the oxygen moiety reacting during further derivatization of the protected compound and which can be readily removed when desired. In one embodiment, the protecting group is removable in the physiological state by natural metabolic processes. Examples of oxygen protecting groups include acyl groups (such as acetyl), ethers (such as methoxy methyl ether (MOM), a-methoxy ethoxy methyl ether (MEM), p-methoxy benzyl ether (PMB), methylthio methyl ether, pivaloyl (Piv), tetrahydropyran (THP)), silyl ethers (such as trimethyl silyl (TMS) tert-butyl dimethyl silyl (TBDMS) and triisopropyl silyl (TIPS) groups, succinimides and phthalimides.

[0103] As used herein, the term “nitrogen protecting group” refers to a group that can prevent the nitrogen moiety reacting during further derivatization of the protected compound and which can be readily removed when desired. In one embodiment, the protecting group isremovable in the physiological state by natural metabolic processes and in essence the protected compound is acting as a prodrug for the active unprotected species. Examples of suitable nitrogen protecting groups that may be used include formyl, trityl, phthalimido, acetyl, tri chloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl; urethane-type blocking groups such as benzyloxycarbonyl (CBz), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3- chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 3 -bromobenzyloxy carbonyl, 4-nitrobenzyloxycarbonyl, 4- cyanobenzyloxy carbonyl, t-butoxy carbonyl (tBoc), 2-(4-xenyl)-isopropoxy carbonyl, 1,1- diphenyleth- 1 -yloxy carbonyl, 1 , 1 -diphenylprop- 1 -yloxy carbonyl, 2-phenylprop-2- yloxy carbonyl, 2-(p-toluyl)-prop-2-yloxy-carbonyl, cyclo-pentanyloxy-carbonyl, 1- methylcy cl opentanyloxy carbonyl, cy cl ohexanyloxy carbonyl, 1- methylcy cl ohexanyloxy carbonyl, 2-methylcy cl ohexanyloxy carbonyl, 2-(4-toluylsulfono)- ethoxycarbonyl, 2-(methylsulfono)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy carbonyl (Fmoc), 2-(trimethylsilyl)ethoxy carbonyl, allyloxy carbonyl, 1- (trimethylsilylmethyl)prop-l-enyloxy carbonyl, 5-benzisoxalylmethoxy carbonyl, 4- acetoxybenzyloxy carbonyl, 2, 2, 2-trichloroethoxy carbonyl, 2-ethynyl-2-propoxy carbonyl, cyclopropylmethoxy carbonyl, 4-(decyloxy)benzyloxy carbonyl, isobomyloxy carbonyl, 1- piperidyloxycarbonlyl and the like; benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphine oxide, and the like. The actual nitrogen protecting group employed is not critical so long as the derivatized nitrogen group is stable to the condition of subsequent reaction(s) and can be selectively removed as required without substantially disrupting the remainder of the molecule including any other nitrogen protecting group(s). Further examples of these groups are found in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Second edition; Wiley-Interscience: 1991; Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups, Second Edition, Thieme Medical Pub., 2000.

[0104] As used herein, the term “reactive group” refers to a functional group that facilitates a subsequent reaction. For example, a reactive group may be a group that is selected and installed to provide a group that has the reactivity required for a chemical reaction. In some instances, a reactive group may also be known as a reactive functional group, where the functional group has an established reactivity profile.

[0105] In some embodiments, the nitrogen protecting group in Formula A is a t- butoxycarbonyl (tBoc) group.

[0106] In some embodiments, the reactive group in Formula A is a succinimide group.

[0107] In some embodiments, the structure of Formula (A) is:

[0108] In certain embodiments, the process as described herein provides a compound of Formula (Ic) in its protected form. In some embodiments, the process further comprises a deprotection step.

[0109] The compounds of Formula (I) may be prepared using the reaction routes and synthesis schemes as described herein, employing the techniques available in the art using starting materials that are readily available. The preparation of particular compounds of Formula (I) can be seen in the following examples, however the chemical reactions described may be readily adapted to prepare a number of other embodiments. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments. Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.

[0110] 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 from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0111] Those skilled in the art will appreciate that the invention described herein in susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions andcompounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.Examples

[0112] 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 details

[0113] All reagents and solvents were obtained from commercial sources and used as received. The compound (LBoc)4-sMeCOSar was synthesized using a previously reported procedure. Peptide conjugation and synthesis of non-radioactive reference compounds were carried out using previously reported procedures.

[0114] NMR spectra were recorded on a Bruker Avance 500 spectrometer. The chemical shifts were internally referenced to the residual solvent signals relative to tetramethylsilane (1H,13C) or externally to CF3CO2H (19F).

[0115] Purification of the peptides was performed by semi-preparative HPLC on a Pursuit VRs 5 C18 column (21.2 x 250 mm) with a Pursuit XRs 5 C18 (50 x 21.2 mm) guard column attached, applying a gradient of either 20-29% (B) in 30 min or 10-40% (B) in 40 min (or similar) at a flow rate of 12.5 mL / min (0.1% formic acid in (A) water; (B) acetonitrile). Ultraviolet detection was performed at X = 214, 220, 254 and / or 280 nm. Quality control of the peptides was performed by analytical HPLC on a Luna C18 (150 x 4.6 mm) column using a gradient of 5-95% at a flow rate of 1 mL / min (0.1% TFA in (A) water; (B) acetonitrile) and the same UV detection wavelengths as previously mentioned.

[0116] Mass spectra were acquired using a Thermo Scientific Ultimate 3000 ESLMS (UHPLC+focused). Acquisition was performed using the Agilent Mass Hunter Acquisition software.

[0117] Cold’ standards of each compound (i.e. natural isotopic abundance copper complexes) were prepared by the addition of an equimolar amount of [liatCu]copper acetate monohydrate to a solution of each ligand and incubating for 30 minutes at ambient temperature.

[0118] For analysis of both radioactive and non-radioactive samples, radio-HPLC was performed on an Agilent 1100 Infinity system with an in-line Berthold Technologies Flowstar LB513 Radiodetector followed by an Agilent 1100 Series G1315B Diode Array Detector. Samples were analysed using a Luna C18 5 pm 4.6 * 150 mm column (5-95% of buffer B to A at 1 mL / min over 20 min, wash of 95% B over 5 minutes and re-equilibration with 5% B over 5 minutes; A = 0.05% TFA in Milli-Q and B = in 0.05% TFA in acetonitrile).

[0119] Radio-iTLCs were performed using an Elysia Raytest MiniGita TLC scanner system with MiniGita OFA Probe using silica gel impregnated glass fibre iTLC plates eluted with 10 mM EDTA in Dulbecco’s PBS.

[0120] Sar-bisPSMA and PSMA-617 were obtained for the purposes of comparative experiments as discussed below.Example 1 - Synthesis of Sar-PSMA-BBN (Formula (Ic))Formula (C)

[0121] Formula (A) ((tboc)s(succ)2bisCOsar, 4.15 mg, 3.36 mmol) and Formula (B) (PSMA, 2.53 mg, 3.36 pmol) were dissolved in dry DMF (320 uL) and dry DIPEA (5 uL) was added. The mixture was stirred at room temperature under N2 for 12 h. More PSMA (1 mg) and DIPEA (5 uL) were added and the mixture stirred for a further 12 h. Formula (C) (bombesin(7-14)-(PEG)4-NH2,4.56 mg, 3.36 mmol) was then added and the mixture stirred at room temperature under N2 for 48 h. A global deprotection was performed by addition of 1.5 mL of TFA / TIPS / H2O (95:2.5:2.5%). This mixture was shaken at room temperature for 2 h before the TFA was blown off with N2 gas. Precipitation was induced by the addition of ice- cold diethyl ether followed by centrifugation and decanting the ether. The white precipitate was washed with 3x ether and then dissolved in 2 mL of MeCN / FFO (20 / 80%) in 0.1% formic acid., frozen and lyophilised to yield 5.88 mg of crude product. The product was redissolved in 2 mL of MeCN / FFO (20 / 80%) in 0.1% formic acid and purified by preparative HPLC - gradient elution of buffer A = 0.1% formic acid in water and buffer B = 0.1% formic acid in acetonitrile (20 to 35% B in A over 30 min) at 12.5 mL / min and UV detection at 214 and 220 nm. Fractions containing pure material were combined, frozen and lyophilised. Sar-PSMA-BBN (2.5 mg) eluted at -18.4 min. ESI-MS: (+ve ion) m / z 100% [M+4H]4+656.3815 (experimental), 656.3777 (calculated); [M+3H]3+874.8368 (experimental), 874.8344 (calculated).Example 2 - Radiolabeling of Sar-PSMA-BBN

[0122] Copper-64 was supplied as copper chloride solution (1.5 MBq / pL in 0.05 M HC1). An aliquot (30 MBq, 20 pL) was removed and buffered to pH 5.6 by the addition of ammonium acetate buffer (10 pL, 1 M, pH 5.6) and water (MilliQ, 70 uL). Sar-PSMA-BBN, Sar-BisPSMA and Sar-BBN (1 pL, 1 mg / mL) were each added to an aliquot of the buffered copper-64 solution (33 pL, 10 MBq) and allowed to stand at room temperature. After 15 minutes, radio-iTLCs indicated quantitative radiochemical yield / purity without any purification steps. This was confirmed by radio-HPLC after 1 hour with injection of lOOpL with 2 MBq of activity per compound ([64Cu]Cu-Sar-PSMA-BBN Rt = 12.23 min, ([64Cu]Cu- Sar-BisPSMARt = 12.48 min, ([64Cu]Cu-Sar-BBN Rt= 11.56 min).Example 3 - Binding affinity studies (NAALADase assay)

[0123] Recombinant human PSMA (rhPSMA) was diluted to 0.4 pg / mL in assay buffer(50 mM HEPES, 0.1 M NaCl, pH 7.5). The substrate N-acetylaspartylglutamate was diluted to 40 pM in assay buffer. Sar-PSMA-BBN, Sar-BisPSMA and PSMA-617 were prepared with concentrations of lOOOpM and diluted by serial dilution to yield concentrations that allow forfinal concentrations of 0.0095, 0.038, 0.15, 0.61, 2.44, 9.77, 39.06, 156.25, 625, 2500 and 10000 pM. First, rhPSMA (30 pL, 0.4 pg / mL) was added to each prepared solution of the test compounds (15 pL), followed by addition of NAAG (40 pM, 15 pL). The mixtures were incubated at 37 °C for 1 hour. After incubation, a solution of ortho-phthalaldehyde (OPA) (15 mM, 60 pL) in OPA buffer (0.2 M NaOH, 0.1% beta-mercaptoethanol (%v / v) was added to each compound mixture and incubated for 10 minutes at room temperature. The final fluorescence of the final solutions was determined using the FLUOstar Omega plate reader (BMG Labtech) in fluorescence mode, with excitation at 330-10 nm and emission at 460 nm, with gain of 20%. Sar-PSMA-BBN and Sar-BisPSMA were done in triplicate and PSMA-617 in doublet. Data analysis was performed using the non-linear regression (curve fit) / one site fit logIC50 on GraphPad Prism.Example 4 - log(P) determination

[0124] PBS-saturated octanol (Oct(sat)) and octanol -saturated PBS (PBS(sat)) were freshly prepared. PBS(sat) (497 pL) and Oct(sat) (500 pL) were combined in Eppendorf tubes (5x each per compound) and each sample compound (3 pL, 0.5 MBq) added. The tubes were shaken vigorously for 5 minutes then centrifuged for 5 minutes before 300 pL of both the octanol and PBS layer were removed and dispensed into counting tubes containing methanol (1 mL each). The activity in the region of interest (490-520 keV) of each counting tube was measured using a well counter and the Log(P) determined using: Log(P) = Ln(octanol layer activity / water layer activity).Example 5 -67Cu-specific activity optimisation

[0125] Titration was performed by addition of various concentrations of Sar-PSMA- BBN to Cu-67, confirming efficient labelling in ammonium acetate buffer (pH 5.5) down to a specific activity of at least 0.2 MBq / ng.Example 6 - Formulation tests for stability / radiolysis of / ,7Cu]Cu-SAR-BBN:

[0126] Cu-67 was supplied as a CuCh solution in 0.01 M HC1 (4 GBq, IdahoAccelerator Centre). An aliquot (44.3 MBq, 2 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (4 pL, 1 M, pH 5.5) and diluted with MilliQ H2O (36 pL). Aliquots of this buffered solution (4 MBq, 4 pL) were added to Sar-PSMA-BBN (1 pg) pre-dissolved in either 21 pL of either DPBS only, or stabilising solution A (8% ethanol in DPBS), B (0.5% sodium gentisate in DPBS) or C (0.5% sodium gentisate + 8% ethanol inDPBS). iTLC was performed after 15 min and radio-HPLC was performed immediately after (t = 0) and 52 hours after incubation at ambient temperature.Example 7 - Serum stability

[0127] Cu-67 was supplied as a CuCh solution in 0.01 M HC1 (4 GBq, IdahoAccelerator Centre). An aliquot (37 MBq @ 11 : 15 am, 2 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (2 pL, 1 M, pH 5.5). Stabilising solution (5 pL, 0.5% sodium gentisate in MilliQ H2O) was also added before a solution of Sar-PSMA- BBN (4 pL, 1 mg / mL in MilliQ H2O) was added to the buffered copper-64 solution and allowed to stand at ambient temperature. iTLC was performed after 15 min and radio-HPLC was performed after 30 min.

[0128] An aliquot of supplied Cu-67 (20 MBq @ 1 pm, 1 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (1 pL, 1 M, pH 5.5). Stabilising solution (8 pL, 0.5% sodium gentisate in MilliQ H2O) was also added before the buffered solution (5 pL) was added to either SAR-BBN or SAR-BisPSMA (1 pL each, 1 mg / mL in MilliQ H2O, see structures in Example 17) and allowed to stand at ambient temperature. iTLC was performed after 15 min and radio-HPLC was performed after 30 min.

[0129] Samples of each Cu-67 compound (5 MBq each) were added to human serum (obtained from a healthy volunteer) or supplied by Sigma Aldrich (2022), 250 pL), incubated at 37 °C with gentle rocking, and aliquots removed at various timepoints. At each timepoint, an aliquot (25 pL) was removed and added to ice-cold acetonitrile (75 pL) to precipitate the protein, pelleted by centrifugation and then some of the supernatant removed and analysed by radio-HPLC.Stability of [67Cu]Cu-SAR-PSMA-BBN was determined in both Janelle’s serum and serum obtained from Sigma-Aldrich (see Figures 7 and 8, respectively). The compound showed similar degradation in both experiments.Example 8 - Cu-67 - EDTA, cysteine and histidine challenge experiments

[0130] Cu-67 was supplied as a CuCh solution in 0.01 M HC1 (4 GBq, IdahoAccelerator Centre). An aliquot (24.7 MBq @ 11 :40 am, 4pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (2 pL, 1 M, pH 5.5). Stabilising solution(9 pL, 8% ethanol + 0.5% sodium gentisate in MilliQ H2O) was also added before a solution of Sar-PSMA-BBN (1.3 pL, 1 mg / mL in MilliQ H2O) was added to the buffered copper-64 solution and allowed to stand at ambient temperature. iTLC was performed after 15 min and radio-HPLC was performed after 30 min. 1000-fold excess of cysteine hydrocholoride, histidine hydrochloride or EDTA were then added to [64Cu]Cu-Sar-PSMA-BBN and the solutions left at ambient temperature for 24 hours before being re-analysed by iTLC.

[0131] Analysis by iTLC showed that the Cu radioisotope does not readily dissociate from Sar-PSMA-BBN, even in the presence of a 1000-fold excess of EDTA, cysteine or histidine over 24 hours (see Figure 9).Example 9 - Formulation tests for adhesion of [7Cu]Cu-Sar-BBN and ^CuJCu-Sar-BBN:

[0132] Since Cu- SAR-PSMA-BBN showed extensive adhesion to syringes and vials, testing was performed to determine methods to reduce this adhesion.

[0133] Aliquots of [67Cu]Cu-Sar-BBN or [64Cu]Cu-Sar-BBN (10 MBq) were added to 100 pL of various test solutions and mixed thoroughly. Solutions were then removed by pipette into a fresh To-bind’ tube, analysed on a dose calibrator and left to sit at ambient temperature for 30 min. The solution was then removed, and the To-bind’ tube reanalysed on a dose calibrator. The solutions were similarly tested for adhesion to insulin syringes.

[0134] Formulation tests revealed that for both [64Cu]Cu-SAR-PSMA-BBN and [67Cu]Cu-SAR- PSMA-BBN, the addition of a solution containing 0.01% (v / v) Tween 20, 0.5% (w / v) sodium gentisate and 5% (v / v) ethanol in DPBS was sufficient to decrease adhesion to plastic surfaces to <5% (see Tables 1 and 2 below) This formulation also reduced radiolysis of [64Cu]Cu- SAR-PSMA-BBN and [67Cu]Cu-SAR-PSMA-BBN, with analysis by radio- HPLC demonstrating stability of the compounds for up to at least 20 and 52 hours, respectively (see Figures 1 and 2).Table 1. Formulation tests to reduce adhesion of [67Cu]Cu-SAR-PSMA-BBN to lo-bind Eppendorf tubes and insulin syringes for in vivo studies.Table 2. Formulation test to reduce adhesion of [64Cu]Cu-SAR-PSMA-BBN to lo-bind Eppendorf tubes and insulin syringes for in vivo studies.Example 10 Cell binding confirmation studies

[0135] The PC3 (GRPr over-expressing) and LNCaP C42 (PSMA over-expressing) cell lines were grown in the usual manner. In all experiments, the radiolabelled compound / ligand added was in large excess to cell receptors due to limitations of the sensitivity of the gamma counter (see Table 3). This means that expressing the amount of the bound compound as a percentage of the unbound compound is not an accurate representation of binding. Nonetheless, these calculations can also be seen in Table 3.Table 3. Binding of [64Cu]Cu-SAR-PSMA-BBN to LNCaP C42 and PC3 cells with and without 1000-fold blocks, showing bound / unbound and % specific binding.

[0136] These results in Table 3 confirm that SAR-PSMA-BBN binds to GRPr and PSMA receptors. Even though the calculated percentage of the compound that binds to a particular receptor is not an accurate representation of binding, it can be seen that there is a large difference between the “test” and the “block” cells for both cell lines, which suggests that the compound binds to both GRPr and PSMA receptors.LNCaP C42 cells

[0137] LNCaP C42 cells (passage 4) were lysed, viability confirmed and washed with ice-cold DPBS to remove media. The cells were resuspended in buffer (0.01% Tween 20 and 0.5% sodium gentisate in DPBS) and split into 2 vials for test solutions and 2 vials including blocking agent (1 million cells per vial). The block vials were pre-incubated with blocking agent (1000-fold 2-PMPA, 2-(phosphonomethyl)pentanedioic acid) for 1 hour, before [64Cu]Cu-Sar-PSMA-BBN (10 pL, 1 MBq) was added to each vial and the vials incubated at ambient temperature with gentle rocking for 90 minutes. The cells were pelleted (supernatant removed to a counting tube) and washed (each wash also added to a counting tube) with buffer. Ethanol was added to the remaining cell pellets and the cells were washed into counting tubes. All counting tubes were counted using a gamma counter.PC3 cells

[0138] PC3 cells (passage 6) were lysed, viability confirmed and washed with ice-cold DPBS to remove media. The cells were resuspended in buffer (0.01% Tween 20 and 0.5% sodium gentisate in DPBS) and split into 4 vials for test solutions and 6 vials including blocking agent (1 million cells per vial). The block vials were pre-incubated with blocking agent (1000- fold NH2-PEG4-BBN) for 1 hour, before [64Cu]Cu-Sar-PSMA-BBN(5 pL, 0.5 MBq) was addedto each vial and the vials incubated at ambient temperature with gentle rocking for 90 minutes. The cells were pelleted (supernatant removed to a counting tube) and washed (each wash also added to a counting tube) with buffer. Ethanol was added to the remaining cell pellets and the cells were washed into counting tubes. All counting tubes were counted using a gamma counter.Example 11 Formulation tests for stability / radiolysis of I64Cu]Cu-Sar-PSMA-BBN

[0139] Cu-64 was supplied as copper chloride in water (Austin Health). An aliquot(21.6 MBq @ 3 pm, 15 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (7.5 pL, 1 M, pH 5.5). Aliquots of this buffered solution (3 MBq, 3 pL) were added to Sar-PSMA-BBN (0.5 pg) pre-dissolved in either Solution A (0.5% sodium gentisate in DPBS), Solution B (5% ethanol in DPBS), Solution C (0.5% sodium gentisate + 5% ethanol in DPBS), Solution D (50 mg / mL sodium ascorbate in DPBS), Solution E (50 mg / mL sodium ascorbate + 0.5% sodium gentisate in DPBS) or Solution F (50 mg / mL sodium ascorbate + 0.5% sodium gentisate +5% ethanol in DPBS). iTLC was performed after 15 min and radio- HPLC was performed immediately after (t = 0) and 20 hours after incubation at ambient temperature.Example 12 - Cu-64 - Specific activity optimisation

[0140] Titration was performed by addition of various concentrations of Sar-PSMA- BBN to Cu-64, which confirmed efficient labelling in ammonium acetate buffer (pH 5.5) down to a specific activity of at least 0.2 MBq / ng.Example 13 In vivo study mouse model

[0141] The mouse model used was a dual tumour model with male NSG mice bearing LNCaP C42 and PC3 tumours. All mouse studies were done in replicate (n=5).

[0142] To mimic a mouse model with a PC3-only tumour (i.e. “PC3 only” mice) and no LNCaP C42 tumour, mice with LNCaP C42 tumours that were immeasurable in size were used.Example 14 - Preparation of [ 64Cu]Cu-SAR-PSMA-BBN and PSMA block for in vivo biodistribution studies (Week 1 study)

[0143] All buffers and solutions were prepared fresh on the day of the experiment and sterile filtered using a Millex 0.22 pm syringe filter before addition to radioactive samples. Cu-64 was supplied as copper chloride in water (Austin Health). An aliquot (311 MBq @ 6:57 am, 106 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (36 pL, 1 M, pH 5.5). A solution of SAR-PSMA-BBN (15.2 pL, 1 mg / mL in 50 / 50 MilliQ / EtOH) was added to the buffered copper-64 solution and allowed to stand at ambient temperature. iTLC was performed after 15 min and radio-HPLC was performed after 30 min ([64Cu]Cu- SAR-PSMA-BBN Rt = 10.02 min). This solution was then diluted to 250 pL with Tween 20 (2.5 pL, 1% in MilliQ), sodium gentisate (25 pL, 5% in MilliQ), ethanol (4.9 pL) and DPBS (87.5 pL) to yield the test solution buffered in: Tween 20 (0.01%), sodium gentisate (0.5%) and ethanol (5%) in DPBS. Of this, a 50 pL aliquot was added to a solution containing 230 pg of 2-PMPA, forming the ‘PSMA block’ (lOOOx 2-PMPA). The PSMA block (53.9 MBq @ 8:50 am, 73 pL) and the test solution (157.5 MBq @ 8:43 am, 150 pL) were supplied to the PMCC for in vivo testing, along with 50 mL of formulation buffer A (0.01% Tween 20, 0.5% sodium gentisate and 5% ethanol in DPBS).

[0144] Biodistribution values were calculated and can be found in Figures 13 and 14. Since the rate of growth of the LNCaP and PC3 tumours differed among the mice in the cohort, the PC3 tumour was substantially larger in size than the corresponding LNCaP-42 tumour on the same mouse. The “big” PC3 tumours ranged in size from around 0.37-0.70 g while the “normal” PC3 tumours ranged from 0.13-0.25 g. Given the different growth rates of the tumours, the number of mice with “normal” tumours was sufficient for measurement at the 1- and 4- hour timepoints, meaning that mice with “big” PC3 tumours were used. Since tumours of different sizes can affect the percentage of injected dose per gram (%IA / g) measurement, results obtained from Week 1 of the study (i.e. with administration of Sar-PSMA-BBN to mice with “normal” PC3 tumours) were used as a comparator for the 4-hour timepoint.Table 4. PC3 and LNCaP C42 tumour uptake of [64Cu]Cu-SAR-PSMA-BBN in PC3 and LNCaP C42 tumour-bearing male NSG mice, including mean %IA / g and SEM at 1, 4, 24 h and 24 h + block, post-injection. These values correspond to those determined through the biodistribution studies described in Figure 13.Example 15 - Cell binding test with cells used in mice:

[0145] Frozen PC3 cells (10 million x 6) were provided by the Peter MacCallum Cancer Centre. The cells were thawed by gentle agitation at 37 °C for no longer than 2 min. The cells were washed 3 times with buffer (0.5% sodium gentisate in DPBS) before being resuspended in the same buffer and separated into 6 vials (10 million cells, 0.5 mL). To this, either [64Cu]Cu-SAR-PSMA-BBN (10 pL, 100 kBq) or [64Cu]Cu-SAR-BBN (10 pL, 100 kBq) was added to each vial in triplicate. The vials were gently rocked at ambient temperature for 1 hour before the cells were pelleted (supernatant removed to a counting tube) and washed (each wash also added to a counting tube) with buffer. Ethanol was added to the remaining cell pellets and the cells were washed into counting tubes. All counting tubes were counted using a gamma counter.Example 16 - Preparation of [4Cu]Cu-SAR-BBN for in vivo biodistribution studies (Week 2 study)

[0146] All buffers and solutions were prepared fresh on the day of the experiment and sterile filtered using a Millex 0.22 pm syringe filter before addition to radioactive samples. Cu- 64 was supplied as copper chloride in water (Austin Health). An aliquot (178 MBq @ 9:35 am, 75 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (30 pL, 1 M, pH 5.5). A solution of SAR-PSMA-BBN (7.2 pL, 1 mg / mL in 50 / 50 MilliQ / EtOH) was added to the buffered copper-64 solution and allowed to stand at ambient temperature. iTLC was performed after 15 min and radio-HPLC was performed after 20 min ([64Cu]Cu- SAR-BBN Rt = 9.14 min). This solution was diluted to 150 pL with Tween 20 (1.5 pL, 1% inMilliQ), sodium gentisate (15 pL, 0.3% in MilliQ), sodium ascorbate (15 pL, 500 mg / mL), ethanol (3.9 pL) and DPBS (3.9 pL) to yield the test solution buffered in: Tween 20 (0.01%), sodium gentisate (0.03%), sodium ascorbate (50 mg / mL) and ethanol (5%) in DPBS. 125 pL of this test solution was sent to the PMCC for in vivo testing, along with 50 mL of formulation buffer B (0.01% tween 20, 0.03% sodium gentisate, 50 mg / mL sodium ascorbate and 5% ethanol in DPBS).

[0147] Biodistribution values were calculated and can be found in Figure 15 and in Table 5 below. Since the rate of growth of the LNCaP and PC3 tumours differed among the mice in the cohort, the PC3 tumour was substantially larger in size than the corresponding LNCaP -42 tumour on the same mouse. The “big” PC3 tumours ranged in size from around 0.37-0.70 g while the “normal” PC3 tumours ranged from 0.13-0.25 g. Given the different growth rates of the tumours, the number of mice with “normal” tumours was sufficient for measurement at the 1- and 4- hour timepoints, meaning that mice with “big” PC3 tumours were used. Since tumours of different sizes can affect the percentage of injected dose per gram (%IA / g) measurement, results obtained from Week 1 of the study (i.e. with administration of Sar-PSMA-BBN to mice with “normal” PC3 tumours) were used as a comparator for the 4 hour timepoint.Table 5. Tumour uptake of [64Cu]Cu-SAR-BBN in ‘big’ and ‘similar’ PC3 tumours, in PC3 and LNCaP C42 tumour-bearing male NSG mice, including mean %IA / g and SEM at 1 and / or 4 h post-injection. These values correspond to those determined through the biodistribution studies described in Figure 15.Example 17 - Preparation of [64Cu]Cu-SAR-PSMA-BBN, [64Cu]Cu-SAR-BBN and [64Cu]Cu-SAR-BisPSMA for in vivo biodistribution studies (Week 3 study)

[0148] All buffers and solutions were prepared fresh on the day of the experiment and sterile filtered using a Millex 0.22 pm syringe filter before addition to radioactive samples. Cu-64 was supplied as copper chloride in water (Austin Health). An aliquot (290 MBq @ 5:50 am,65 pL) was removed and buffered to pH 5.5 by the addition of ammonium acetate buffer (35 pL, 1 M, pH 5.5). Aliquots of this solution were removed and adjusted as described below, for the radiolabelling of each compound.SAR-PSMA-BBN

[0149] SAR-PSMA-BBN (3 pL, 1 mg / mL in 50 / 50 MilliQ / EtOH) was added to an aliquot of the buffered copper-64 solution (20.5 pL, 60 MBq) and allowed to stand at room temperature. iTLC was performed after 15 min and radio-HPLC was performed after 20 min. This solution was diluted to 100 pL with Tween 20 (1 pL, 1% in MilliQ), sodium gentisate (1 pL, 5% in MilliQ), ethanol (3.5 pL) and DPBS (62 pL) to yield the test solution buffered in: Tween 20 (0.01%), sodium gentisate (0.03%) and ethanol (5%) in DPBS. This test solution (49.5 MBq @8:04 am, 100 pL) was used for in vivo testing. Biodistribution of the compound was determined (see Figure 17).SAR-BisPSMA

[0150] SAR-BisPSMA (6.8 pL, 1 mg / mL in 50 / 50 MilliQZEtOH) having the structure depicted below was added to an aliquot of the buffered copper-64 solution (58 pL, 170 MBq) and allowed to stand at room temperature. iTLC was performed after 15 min and radio-HPLC was performed after 30 min. This solution was diluted to 200 pL with Tween 20 (2 pL, 1% in MilliQ), sodium gentisate (2 pL, 5% in MilliQ), ethanol (6.6 pL) and DPBS (106.6 pL) to yield the test solution buffered in: Tween 20 (0.01%), sodium gentisate (0.03%) and ethanol (5%) in DPBS. This test solution (143 MBq @8:02 am, 200 pL) was used for in vivo testing. Biodistribution of the compound was determined (see Figure 18).SAR-BBN

[0151] SAR-BBN (2.3 pL, 1 mg / mL in 50 / 50 MilliQ / EtOH) ) having the structure depicted below was added to an aliquot of the buffered copper-64 solution (20.5 pL, 60 MBq) and allowed to stand at room temperature. iTLC was performed after 15 min and radio-HPLC was performed after 30 min. This solution was diluted to 100 pL with Tween 20 (1 pL, 1% in MilliQ), sodium gentisate (1 pL, 3% in MilliQ), sodium ascorbate (10 pL, 500 mg / mL), ethanol (3.8 pL) and DPBS (65 pL) to yield the test solution buffered in: Tween 20 (0.01%), sodium gentisate (0.03%), sodium ascorbate (50 mg / mL) and ethanol (5%) in DPBS. This test solution (49.7 MBq @8:03 am, 100 pL) was used for in vivo testing. Biodistribution of the compound was determined (see Figure 19).

[0152] Although LNCaP-C42 cells were implanted and the resultant tumours were too small for detection and measurement (i.e. the mice are considered to bear “only” PC3- associated tumours), this Figure indicates that there is in fact uptake associated with LNCaP- C42 (see Figure 19, blue bar, Tumour RIGHT (LNCaP 42)). Upon dissection, LNCaP-C42 tumours were located in these mice and excised, even though the tumours were very small (< 0.04 g). It is likely that the uptake of the compound now observed is inflated due to the low tumour mass. Given the size of the error bars for this value, uptake of the compound can be considered negligible.

Claims

The claims defining the invention are as follows:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:Formula (I) wherein the linker groups are the same or different and are selected from:and the binding groups are different and selected from:

2. A compound according to claim 1, wherein when the linker is:the binding group attached directly to the linker is:

3. A compound according to claim 1, wherein when the linker is:the binding group attached directly to the linker is:

4. A compound according to any one of claims 1 to 3, wherein the compound has the following structure:

5. A compound according to any one of claims 1 to 4, wherein the compound is coordinated with a metal ion.

6. A compound according to claim 5, wherein the metal ion is a copper ion.

7. A compound according to claim 6, wherein the copper ion is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

8. A composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and one or more excipients.

9. A method for the treatment of a cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8.

10. A method for the radioimaging of a cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8 and imaging of the subject.

11. A method for the diagnosis of a cancer in a subj ect, the method comprising: i) administering to a subject in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8; ii) imaging of the subject; and iii) considering the images of the subjection obtained in step ii).

12. A method according to claim 10 or 11, wherein the imaging of the subject is by positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

13. A method according to claim 10 or 11, wherein imaging of the subject is by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) combined with computed tomography (CT) or magnetic resonance imaging (MRI).

14. A method according to any one of claims 9 to 13, wherein the cancer is associated with expression of a PSMA receptor.

15. Amethod according to any one of claims 9 to 13, wherein the cancer is associated with the expression of a gastrin-releasing peptide receptor (GRPR).

16. A method according to any one of claims 9 to 15, wherein the cancer is a complex, heterogeneous cancer.

17. A method according to claim 16, wherein the complex, heterogeneous cancer is associated with the expression of both a PSMA receptor and a gastrin-releasing peptide receptor (GRPR).

18. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the treatment of a cancer.

19. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the imaging of a cancer.

20. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the diagnosis of a cancer.

21. A process for the preparation of a compound of Formula (I) or a salt thereof or a protected form thereof:Formula (Ic) the process comprising the step of: i) reacting a compound of Formula (A) or a salt thereof:Formula (A)wherein PG is a protecting group, and RG is a reactive group; with a compound of Formula (B) or a salt thereof and a compound of Formula (C) or a salt thereofFormula (C)22. Process according to claim 21, wherein the compound obtained is in a protected form and the process further comprises a global deprotection step.

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