Dimeric radiopharmaceuticals, compositions thereof and uses thereof

Abstract

The present invention relates to compounds comprising a metal chelating agent and two fragments capable of binding to the somatostatin type 2 receptor, compositions thereof and their use in methods of treatment.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compounds for use as radiopharmaceuticals, which comprise a metal chelator and a fragment capable of binding to a somatostatin receptor. The invention also relates to compositions of the compounds and their use in radiography and cancer treatment methods. BACKGROUND OF THE INVENTION

[0002] Somatostatin receptor type 2 (SSTR2) is a G protein-coupled receptor expressed on the surface of certain cancerous tumors. Binding of these receptors can inhibit tumor growth, and it is believed that delivering internal radiation by exposing the tumor to a radiation source can further inhibit tumor growth. Although SSTR2 may be a target for cancer treatment, selective targeting is often difficult because the receptor is also expressed in other tissues and organ systems. In addition, even when selective targeting of SSTR2 on tumor cells is achieved, the ligand that binds to the receptor must have sufficient retention time and appropriate physical properties at the tumor site.

[0003] Other difficulties encountered in the design and production of radiopharmaceuticals include: low yields of compounds during synthesis and radiolabeling processes, limited or reduced radiochemical stability of compounds when coordinated with radioisotopes, and overall solubility and stability of compounds under in vitro and in vivo conditions. Since the compounds are designed to coordinate with radioisotopes, they must also exhibit sufficient radiostability over a period of time (e.g., for at least one half-life of the desired radioisotope). When the compounds do not have the necessary radiostability, unnecessary toxicity and off-target damage to healthy tissues may occur. While one option for the treatment and / or radiography of cancers known to express SSTR2 is to administer known compounds at higher doses to increase therapeutic efficacy or image resolution, this may lead to an exacerbation of adverse side effects associated with the administered compounds.

[0004] Therefore, for the purposes of cancer radiography and treatment, there is still a need for radiopharmaceuticals that exhibit higher retention at the tumor site while limiting toxicity and off-target radiation damage to acceptable limits (or below acceptable limits). SUMMARY OF THE INVENTION

[0005] The present invention relates to compounds for use as radiopharmaceuticals, wherein the compounds comprise a moiety capable of binding to somatostatin receptor type 2 (SSTR2), compositions thereof, and their use in treatment and radiography methods. The inventors believe that the compounds disclosed herein, which comprise a moiety capable of binding to SSTR2 and a radioisotope coordinated with a suitable chelator, can more effectively treat cancer in a subject and are capable of obtaining higher resolution images for diagnosis.

[0006] Although the compounds disclosed herein contain a moiety capable of binding to SSTR2 and other linkers, the inventors believe that these compounds exhibit greater affinity for tumor sites expressing SSTR2 compared to compounds containing a single linker and a binding group. Without wishing to be bound by theory, the inventors believe that this may result in an increased amount of the drug retained in the tumor, thereby further inhibiting tumor growth or reducing the amount of radiolabeled compound administered to the patient. Since the treatment of cancer typically requires multiple rounds of treatment, the administration of compounds that can provide more effective treatment can reduce the number of treatment rounds and thereby alleviate the burden on the patient.

[0007] Compared to compounds containing a single octreotate moiety, the inventors have found that the compounds disclosed herein exhibit higher binding and retention at sites expressing SSTR2, that is, a greater proportion of the administered compound binds and is retained at the desired site. This in turn more effectively treats and images cancers associated with SSTR2 expression. Since the compounds disclosed herein exhibit better binding to the target, a smaller dose of the compound can be administered to the subject. Since the compounds disclosed herein are capable of chelating a suitable radionuclide, this means that a smaller dose of radiation can be administered to the subject while still providing the desired standard of imaging or treatment. When a smaller dose of radiation is administered, the likelihood and / or severity of any adverse side effects (i.e., off-target radiation damage) resulting from the administration of the radionuclide is reduced.

[0008] Since the compounds of the present invention contain a radionuclide for radioimaging and radiotherapy, the compound must be retained for a sufficient length of time for imaging or treatment; however, the compound must also be metabolized and excreted from the subject's body after a period of time. The inventors have found that even though the compounds of the present invention contain two SSTR2 binding moieties and thus have a greater molecular weight, the compounds still exhibit improved binding and retention and, due to retention at cancer sites expressing SSTR2, are able to provide better images during radioimaging and better treatment during radiotherapy, and the compounds also exhibit the stability and physical properties required for metabolism within an acceptable time frame. Nevertheless, those skilled in the art will understand that even when using the same targeting group, larger compounds (and thus compounds with a greater molecular weight) do not necessarily provide comparable therapeutic effects. This may be because increasing the size and molecular weight can have an adverse effect on the physical properties of the compound, such as solubility at a given pH. When the solubility of the compound is reduced, this will result in a reduced therapeutic effect (compared to similar compounds with a single linker / SSTR2 binding moiety) because less of the administered compound reaches the target. As Figure 1 and 2As shown, the compounds of the present invention having two peptide moieties and thus a relatively large molecular weight show binding to tumors expressing SSTR2. Without wishing to be bound by theory, the inventors believe that even though the compounds disclosed herein are large and have a relatively large molecular weight, the compounds are still able to show the necessary binding to tumor sites expressing SSTR2 and can thus be used for the treatment and / or radioimaging of cancers associated with SSTR2 expression. In addition, the compounds of the present invention not only bind to SSTR2 but also remain bound for a period of time, thereby delivering the desired therapeutic effect to the target tumor site.

[0009] The compounds of the present invention comprise a single sarcophagine and two linker moieties that bind a moiety having an affinity for SSTR2 binding, wherein the octreotate moiety has an affinity for SSTR2 binding. The sarcophagine component is capable of chelating copper radioisotopes, which are known to be useful for radioimaging and radiotherapy. A known disadvantage of radioisotope-based imaging and therapy is that the loss of radioisotope from the chelator can cause radiation damage to healthy tissue because unchelated radioisotopes can circulate freely. In addition, since not all of the administered radioisotope reaches the target, more chelating compound may be required to provide the desired therapeutic effect.

[0010] Existing compounds capable of chelating copper compounds for radioimaging and radiotherapy include, for example, compounds having DOTA or NOTA macrocycles. The inventors believe that the sarcophagine-containing compounds disclosed herein are capable of improving the treatment method because the sarcophagine chelator used herein retains copper radioisotopes better under both in vitro and in vivo conditions compared to compounds having different chelators. The inventors believe that this advantage is related to the better ability of sarcophagine to resist the radioactive decay products of copper radioisotopes, and thus radiolysis of the compound is generally reduced.

[0011] In a first aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, complex / complex, isomer, solvate or prodrug thereof: Wherein: Each R is a moiety that binds to SSTR2; and Each –L– is a linker moiety that couples a moiety that binds to SSTR2 and sarcophagine.

[0012] In a second aspect, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, complex / complex, isomer, solvate or prodrug thereof: Wherein: Each –L– is a linker moiety that is coupled to the moiety that binds to SSTR2 and sarcophagine.

[0013] In some embodiments, each linker group “–L–” is independently an optionally substituted –C1-C 10 alkylene–, -C2-C 10 alkenylene– or -C2-C 10 alkynylene– group, one or more amino acid residues, one or more PEG groups, or a combination thereof; wherein one or more carbon atoms in the alkylene, alkenylene, or alkynylene may be substituted with NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group.

[0014] The compounds of formulas (I) and (II) contain sarcophagine, i.e., 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane, which is capable of chelating metal ions. The sarcophagine of formula (I) contains six nitrogen atoms, one or more of which may be protected with a suitable protecting group. The compounds also contain a linker group that connects two octreotate moieties to sarcophagine, thereby providing the compounds of formula (I). Without wishing to be bound by theory, the inventors believe that each component of the compounds disclosed herein (i.e., sarcophagine, linker group, and octreotate) contributes to providing the necessary metabolic and / or radiolytic stability, solubility, and flexibility such that the compounds of formula (I) can be used as radiopharmaceuticals.

[0015] In certain embodiments, the compound of formula (II) or a pharmaceutically acceptable salt, complex / coordination complex, isomer, solvate, or prodrug thereof has the structure of formula (IIa):

[0016] In certain embodiments, the compound of formula (II) has the structure of formula (IIb):

[0017] In certain embodiments, the metal chelator in the compound of formula (I) complexes with the ions of a metal selected from the group consisting of: Cu, Tc, Gd, Ga, In, Co, Re, Fe, Mg, Ag, Rh, Pt, Cr, Ni, V, Ir, Zn, Cd, Mn, Ru, Pd, Hg, Ti, Lu, Sc, Zr, Y, Ac, As, Ra, and Pb.

[0018] In some embodiments, the metal ion complexed in the metal chelator is a radionuclide.

[0019] In some embodiments, the compound of formula (I) is complexed with a radionuclide selected from the group consisting of: 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 177 Lu, 188 Re, 211 As, 212 Pb and 225 Ac.

[0020] In a third aspect, the present invention provides a composition comprising a compound of formula (I) as defined in the first aspect and one or more pharmaceutically acceptable excipients.

[0021] The inventors believe that a compound that coordinates with a radionuclide can be used as a radiopharmaceutical or a radioimaging agent if it can bind sufficiently to the desired site and deliver the radionuclide to the same site for imaging or therapeutic purposes.

[0022] In a fourth aspect, the present invention provides a method for radioimaging cancer in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) according to the first aspect or a composition according to the second aspect, wherein the compound is coordinated with a radionuclide.

[0023] In certain embodiments, the method of radioimaging comprises imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0024] In a fifth aspect, the present invention provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) according to the first aspect or a composition according to the second aspect, wherein the compound is coordinated with a radionuclide.

[0025] In certain embodiments, the cancer is characterized by the expression of somatostatin receptor type 2 (SSTR2).

[0026] In a sixth aspect, the present invention provides the use of a compound of formula (I) according to the first aspect in the preparation of a medicament for radioimaging cancer, wherein the compound is coordinated with a radionuclide.

[0027] In certain embodiments, the radioimaging comprises imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0028] In a seventh aspect, the present invention provides the use of a compound of formula (I) according to the first aspect in the preparation of a medicament for treating cancer, wherein the compound is coordinated with a radionuclide.

[0029] In certain embodiments, the cancer is characterized by the expression of somatostatin receptor subtype 2 (SSTR2). BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 : showing the mean ± SEM of the injected dose per gram of tissue (%ID / g) of each tissue at 1 hour, 4 hours, 24 hours, and 48 hours after injection of SARbisTATE (A); and mean ± SEM with a split y-axis (B).

[0031] Figure 2 : Four subjects were administered 5 MBq 64 of 64Cu-SarbisTATE, and the biodistribution of the radiolabeled compound was determined at 1 hour, 4 hours, 24 hours, and 48 hours. DETAILED DESCRIPTION

[0032] Throughout the specification and the following claims, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" shall be understood to imply the inclusion of the stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0033] As used herein, the term "about" or "approximately" means within an acceptable error range of a 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.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For the purposes of this invention, the following terms are defined below.

[0035] In a first aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, complex / coordination compound, isomer, solvate, or prodrug thereof: wherein: each R is a moiety that binds to SSTR2; and each –L– is a linker moiety that couples the moiety that binds to SSTR2 and sarcophagine.

[0036] Many suitable moieties that bind to SSTR2 are known in the art, including but not limited to:

[0037] In one embodiment, R is selected from octreotide, lanreotide, pasireotide, octreotate, and combinations thereof.

[0038] In another embodiment, each R is octreotate. Accordingly, in another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, complex / coordination compound, isomer, solvate, or prodrug thereof: Wherein: Each –L– is a linker moiety that is coupled to a moiety that binds to SSTR2 and sarcophagine.

[0039] In certain embodiments, the linkers in the compounds of formula (I) or (II) can be the same or different. In certain embodiments, the linkers in the compounds of formula (I) or (II) are different. In certain embodiments, the linkers in the compounds of formula (I) or (II) are the same. For example, suitable linkers include N-succinimidyl 4-(2-pyridylthio)propionate (SPDP), N-succinimidyl 4-(2-pyridylthio)valerate (SPP).

[0040] In certain embodiments, the linker has the following formula (III): Wherein, L2 is cycloalkylene-carbonyl, (C2-C6)alkyl, or (C2-C6)alkyl-carbonyl; W is an amino acid unit; w is an integer from 0 to 5; Y is PAB-carbonyl, wherein PAB is x can be H or y is 0 or 1; and The wavy line represents the point of attachment to the moiety that binds to SSTR2 and sarcophagine.

[0041] In an embodiment, L2 has the following formula: Wherein, The asterisk represents the point of attachment to (W)w; and The wavy line represents the point of attachment to the nitrogen atom of a maleimide moiety having the following formula:

[0042] In one embodiment of the present invention, when w = 0 or w = 2, (W)w is selected from: Among them, The asterisk indicates the connection point with (Y)y; and The wavy line indicates the connection point with L2.

[0043] In one embodiment of the present invention, the linker is selected from: Among them, the wavy line indicates the connection point of the part binding to SSTR2 and sarcophagine.

[0044] In other embodiments, the linker has the following formula (IV): Among them, L’2 is cycloalkylene-carbonyl, (C2-C6) alkylene or (C2-C6) alkylene-carbonyl; W' is an amino acid unit; w' is an integer from 0 to 5; Y' is PAB-carbonyl, where PAB is x can be H or y' is 0 or 1; R' is C1-C3 alkenyl or H.

[0045] In one embodiment, the compound of formula (IV) is a compound of formula (IV'):

[0046] In an embodiment, the compound of formula (IV') is characterized in that L2' is C2 alkylene-carbonyl and w' is 2.

[0047] In an embodiment, the linker of formula (IV') is:

[0048] In another embodiment, the linker of formula (IV') is:

[0049] In another embodiment, the linker of formula (IV') is:

[0050] In a preferred embodiment, the linker “-L-” is unsubstituted propylene. Therefore, on the other hand, the present invention provides a compound of formula (IIa) or a pharmaceutically acceptable salt, complex / complex, isomer, solvate or prodrug thereof:

[0051] In one embodiment, the compound of formula (IIa) has the stereochemistry shown by the compound of formula (IIb):

[0052] The linker of the present invention can be synthesized using amide bond coupling. There are many methods for amide synthesis. Some methods (but not limited to) are described in Montalbetti, Christian A.G.N (Tetrahedron 61(46), 2005, 10827-10852). Alternatively, the linker can be synthesized using, for example, a peptide or protein synthesizer by standard stepwise addition of one or more residues. Alternatively, other methods that can be used for amide formation include but are not limited to Beckmann rearrangement, Schmidt reaction, nitrile hydrolysis, Willgerodt-Kindler reaction, Passerini reaction, Ugi reaction, Bodroux reaction, Chapman rearrangement, Leuckart amide synthesis, Ritter reaction, ester aminolysis, Schotten-Baumann reaction, ruthenium-based alcohol and amine catalysis, or photolytic addition of formamide to an alkene.

[0053] "Alkyl" refers to a saturated monovalent hydrocarbon group, which can be straight-chain or branched-chain, and preferably has 1 to 10 carbon atoms, or more preferably has 1 to 6 carbon atoms or 1 to 9 carbon atoms (i.e., C1-C4 alkyl). Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl, and the like.

[0054] "Alkylene" refers to a divalent alkyl group, preferably having 1 to 10 carbon atoms, more preferably having 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and propylene isomers (e.g., -CH2CH2CH2- and –CH(CH3)CH2-), and the like.

[0055] "Alkenylene" refers to a divalent hydrocarbon group having at least one unsaturated site (i.e., a carbon-carbon, sp2 double bond), which can be straight-chain or branched-chain, and preferably has 2 to 10 carbon atoms, more preferably has 2 to 6 carbon atoms, and has at least 1 carbon-carbon double bond. Alkenylene groups include groups having "cis" and "trans" orientations, or "E" and "Z" orientations. Examples include vinyl (-CH=CH-), n-propenyl (-CH2CH=CH-), isopropenyl (-C(CH3)=CH-), but-2-enyl (-CH2CH=CHCH2-), and the like.

[0056] "Alkynylene" refers to a straight-chain or branched-chain divalent hydrocarbon group having at least one unsaturated site (i.e., a carbon-carbon sp triple bond), preferably having 2 to 10 carbon atoms, more preferably having 2 to 6 carbon atoms, and having at least 1 carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡C-), propargyl (-CH2C≡C-), pent-2-ynyl (-CH2C≡CCH2-CH2-), etc.

[0057] In this specification, "optionally substituted (with)" means that a group may or may not be further substituted with one or more groups selected from the group consisting of: hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, aralkyl, aralkyloxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphonyl, sulfo, phosphonoamino, phosphino, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, trifluorovinyl, mono- and dialkylamino, mono- and di(substituted alkyl)amino, mono- and diarylamino, mono- and diheteroarylamino, mono- and diheterocyclicamino, and asymmetric disubstituted amines having different substituents selected from alkyl, aryl, heteroaryl, and heterocyclic, etc., and may also include bonding to a solid support material (e.g., substitution onto a polymer resin). For example, an "optionally substituted amino" group may include amino acids and peptide residues.

[0058] In an embodiment, the "optionally substituted" group is selected from halogen (e.g., chlorine, fluorine or bromine), CN, -NO2, -CO2H, -CO2C 1-6 alkyl, -CONH2, -CONH(C 1-6 alkyl), -CONH(C 1-6 alkyl)2, -OH, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 acyl, carboxyC 1-6 alkyl, acetyl, trifluoromethyl, benzyloxy, phenyl, phenoxy, -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2.

[0059] As used herein, the term "residue" refers to the moiety produced after removing one or more atoms from a compound. The one or more atoms removed may be hydrogen atoms. For example, those skilled in the art will understand that when a compound contains a carboxylic acid (-COOH) functional group, the residue in the compound of formula (I) includes the carboxylate of an amino acid (i.e., -COO-), which is connected to the remaining part of the compound.

[0060] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological activity of the above compounds, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic acids, examples including formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid and arylsulfonic acid. Pharmaceutically acceptable salts also include salts where the main compound acts as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with a suitable inorganic or organic acid by any of a variety of known methods. Alternatively, alkali metal salts and alkaline earth metal salts can be prepared by reacting the compound with a suitable base by a variety of known methods. The following are additional examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, mesylate, mesylate and undecanoate. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, Pennsylvania 1995. In cases where the example is a solid, those skilled in the art will understand that the compounds, reagents, and salts of the present invention can exist in different crystalline or polymorphic forms, all of which are intended to fall within the scope of the present invention and the specified chemical formula.

[0061] As used herein, the term "complex(es)" refers to a moiety that includes a ligand and a metal coordinated to an appropriate moiety of the ligand. For example, the compounds of formula (I) disclosed herein act as ligands for one or more metal ions, where the metal ions are coordinated to the ligand through a metal chelator.

[0062] As used herein, the term "isomer" refers to and includes all regioisomers and stereoisomers of the compounds of the present invention. Examples of stereoisomers include diastereoisomers and enantiomers (as appropriate).

[0063] Examples of ions that can form complexes / chelates with the compounds of the present invention include ions of metals selected from the group consisting of: Cu, Tc, Gd, Ga, In, Co, Re, Fe, Mg, Ag, Rh, Pt, Cr, Ni, V, Ir, Zn, Cd, Mn, Ru, Pd, Hg, Ti, Lu, Sc, Zr, Lu, Sc, Zr, Y, Ac, As, Ra, and Pb.

[0064] In some embodiments, the metal ion complexed in the metal chelator is a radionuclide.

[0065] In some embodiments, the compound of formula (I) or (II) is complexed with a radionuclide selected from the group consisting of: 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 177 Lu, 188 Re, 211 As, 212 Pb, and 225 Ac.

[0066] As used herein, the term "solvate" refers to a complex / chelate of a compound, wherein the complex / chelate may have a variable stoichiometry formed by the solute and the solvent. Such solvents in the solvate should not interfere with the biological activity of the solute. Examples of suitable solvents can include water, ethanol, or acetic acid. Methods for solvating compounds are well known in the art.

[0067] As used herein, the term "prodrug" refers to and includes derivatives that are converted in vivo into the compounds of the present invention. Such derivatives are readily envisioned by those skilled in the art and include, for example, compounds containing free hydroxyl groups that are converted into ester derivatives, or compounds containing ring nitrogen atoms that are converted into N-oxides. Examples of ester derivatives include alkyl esters, phosphate esters, and esters formed from amino acids.

[0068] As used herein, the terms "treatment", "treatment of", "prevention", "prophylaxis" and their grammatical synonyms refer to any and all uses for treating said neuroendocrine tumors, preventing, delaying or deferring the onset of disease, or otherwise preventing, impeding, delaying or reversing disease progression. Thus, terms such as "treatment" and "prevention" should be considered in their broadest context. For example, treatment does not necessarily mean treating a patient until complete recovery. When a disease presents with multiple symptoms or is characterized by multiple symptoms, treatment or prevention does not necessarily require treating, preventing, impeding, delaying or reversing all of said symptoms, but may prevent, impede, delay or reverse one or more of said symptoms.

[0069] As used herein, the term "cancer" broadly encompasses neoplastic diseases characterized by abnormal cell growth and the potential to invade or spread to other parts of the body. Cancers may be benign, i.e., not spread to other parts of the body. Cancers may be malignant, meaning that cancer cells can spread through the circulatory system or lymphatic system. The term as used herein includes all malignant (i.e., cancerous) disease states. Cancers may exist as tumors. Thus, the term "tumor" is generally used to define any malignant cancerous or pre-cancerous cell growth and may include leukemia, but particularly refers to solid tumors or carcinomas.

[0070] In certain embodiments, the cancer is associated with the expression of somatostatin receptor type 2 (SSTR2). In specific embodiments, the cancer is selected from the group consisting of: pituitary tumors, neuroendocrine tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid cancer, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer and hematological malignancies such as lymphoma or leukemia. In particular embodiments, the cancer is a neuroendocrine tumor, such as a carcinoid tumor or pancreatic neuroendocrine tumor in the lung, appendix, digestive tract, prostate, thymus or rectum. In other embodiments, the cancer is a neuroendocrine tumor, such as a gastrinoma, insulinoma or non-functional islet cell tumor.

[0071] In some embodiments, the cancer is selected from the group consisting of: epithelial ovarian cancer, ovarian cancer, osteosarcoma, pancreatic adenocarcinoma, colorectal cancer, lung cancer, non-small cell lung cancer, gastric cancer, endometrial cancer, pancreatic adenocarcinoma, medullary thyroid cancer, differentiated thyroid cancer, breast cancer, breast invasive ductal carcinoma, oral squamous cell carcinoma, esophageal cancer, renal cell carcinoma, insulinoma, prostate cancer, neuroendocrine differentiated prostate cancer, pheochromocytoma, adenoid cystic carcinoma, hepatocellular carcinoma, cervical cancer, small intestine cancer, neuroendocrine tumor, anal cancer, chordoma, fibroma, head and neck cancer, thymic cancer, pancreatic cancer, cholangiocarcinoma, esophageal cancer, salivary gland cancer, sarcoma and cancer of unknown primary site.

[0072] As used herein, the term "expression" in relation to SSTR2 refers to the presentation of the receptor on the surface of a tumor or cancer cell. Healthy tissue may also express SSTR2, while cancerous or tumor cells and / or tissues may show upregulation or "overexpression" of SSTR2, which means that the abundance of the receptor on cancer cells is greater than that on healthy tissue.

[0073] The present invention contemplates the use of a compound of formula (I) or (II) complexed / chelated with a suitable radionuclide for treating cancer in a subject. In some embodiments, a compound of formula (I) or (II) complexed / chelated with a radionuclide can be used to treat cancers associated with SSTR2 expression. In other embodiments, the compounds of the present invention complexed / chelated with a radionuclide are used to treat cancers selected from the group consisting of pituitary tumors, neuroendocrine tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid carcinoma, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, and hematological malignancies such as lymphoma or leukemia. In a particular embodiment, the cancer is a neuroendocrine tumor, such as a carcinoid tumor or pancreatic neuroendocrine tumor in the lung, appendix, digestive tract, prostate, thymus, or rectum. In other embodiments, the cancer is a neuroendocrine tumor, such as a gastrinoma, insulinoma, or non-functional islet cell tumor.

[0074] The present invention also discloses the use of a compound of formula (I) or (II) complexed / chelated with a suitable radionuclide for radioimaging a subject. In certain embodiments, a compound of formula (I) or (II) complexed / chelated with a suitable radionuclide is used for radioimaging cancers associated with SSTR2 expression. In other embodiments, the compounds of the present invention are used for radioimaging cancers selected from the group consisting of pituitary tumors, neuroendocrine tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid carcinoma, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, and hematological malignancies such as lymphoma or leukemia. In a particular embodiment, the cancer is a neuroendocrine tumor, such as a carcinoid tumor or pancreatic neuroendocrine tumor in the lung, appendix, digestive tract, prostate, thymus, or rectum. In other embodiments, the cancer is a neuroendocrine tumor, such as a gastrinoma, insulinoma, or non-functional islet cell tumor.

[0075] As used herein, the term "subject" refers to a mammal, including a human, a primate, a domestic animal (e.g., sheep, pig, cow, horse, donkey), a laboratory test animal (e.g., mouse, rabbit, rat, guinea pig), a performing and exhibition animal (e.g., horse, domestic animal, dog, cat), a companion animal (e.g., dog, cat), and a captive wild animal. Preferably, the mammal is a human or a laboratory test animal. More preferably, the mammal is a human.

[0076] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to produce a beneficial or desired clinical outcome. The effective amount can be administered in one or more doses. For radiological imaging purposes, an effective amount is sufficient to display an image of the localization of a compound of formula (I) or (II) administered to a subject by detecting decay products of a radioisotope complexed / chelated with the compound. For therapeutic purposes, an effective amount is generally sufficient to alleviate, ameliorate, stabilize, reverse, slow down, and / or delay the progression of cancer.

[0077] The compounds of the invention complexed / chelated with a radionuclide can be administered to a subject in need thereof as a composition by a parenteral route. Administration by intravenous injection may be preferred. Alternatively, the formulations of the invention can be administered by an intra-arterial or other route, such as by an intrathecal, intratumoral, or intraperitoneal route. It should be understood that the route of administration may vary depending on the type of cancer being diagnosed or treated. In one embodiment, the cancer being diagnosed or treated is a brain cancer, and a compound of formula (I) complexed / chelated with a radionuclide is administered by intratumoral or intrathecal administration. In certain embodiments, the compounds of the invention complexed / chelated with a radionuclide can be administered intravenously and allowed to circulate and localize at the cancer site. In other embodiments, the compounds of the invention complexed / chelated with a radionuclide can be administered directly to the cancer site of the subject or to a blood vessel leading directly to the cancer site. The inventors believe that administering a compound complexed / chelated with a radionuclide directly to the cancer can produce a better therapeutic effect and that the dose administered does not have to undergo an elimination process in the subject. This, in turn, can allow for a reduction in the dose of the compound required to produce a therapeutic effect, which is a more cost-effective method of treating cancer.

[0078] The cancer treatment methods disclosed herein can further include the further administration of one or more therapeutically effective agents. Other therapeutically effective agents include chemotherapeutic agents, other radiotherapeutic agents and / or radiological imaging agents, immune checkpoint inhibitors, nucleic acid therapeutics, cancer vaccines, RNAi therapeutics, siRNA therapeutics, and mRNA therapeutics.

[0079] In certain embodiments, the method further includes the administration of one or more therapeutically effective agents. In some embodiments, the therapeutically effective agent is a chemotherapeutic agent. In some embodiments, the therapeutically effective agent is a radiotherapeutic agent. In other embodiments, the therapeutically effective agent is a radiological imaging agent. In another embodiment, the therapeutically effective agent is an immune checkpoint inhibitor.

[0080] In some embodiments, the immune checkpoint inhibitor is an antibody or a fragment thereof. In some embodiments, the immune checkpoint inhibitor is related to PD-1, PD-L1 or CTLA-4. In other embodiments, the immune checkpoint inhibitor is related to PD-L2, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, A2AR, TIM-3 or VISTA. In certain embodiments, one or more immune checkpoint inhibitors are antibodies against immune checkpoint proteins. In some embodiments, one or more immune checkpoint inhibitors are anti-PD-L1 antibodies, anti-PD-1 antibodies or anti-CTLA-4 antibodies. In some embodiments, one or more immune checkpoint inhibitors are selected from the group consisting of durvalumab, avelumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, cemiplimab, envafolimab, BMS-936559, CK-301, CS-1001 and SHR-1316.

[0081] As used herein, the term "immune checkpoint inhibitor" refers to a compound that modulates the function of the immune system of a subject. Cancer cells are able to proliferate because they can bypass the subject's immune system at various "checkpoints" by binding to and inactivating immune cells that would otherwise target and destroy the cancer cells. In the context of cancer treatment, immune checkpoint inhibitors and their administration to inhibit the immunosuppressive effects that cancer cells may have on the subject's immune system are well known. Immune checkpoint inhibitors are generally proteins that bind to tumor cells or immune system cells to prevent inactivation of the subject's immune system. Conversely, immune checkpoint inhibitors can be considered to enhance the immune response that occurs in the presence of an antigen, i.e., a cancer cell. Immune checkpoint proteins include PD-1 (also known as CD279), PD-L1 (also known as CD274), CTLA-4, A2AR, B7-H3 (also known as CD276), B7-H4 (also known as VTCN1), BTLA (also known as CD272), IDO, KIR, LAG3, TIM-3, and VISTA. Immune checkpoint inhibitors may be specific for a particular immune checkpoint protein, i.e., an anti-immune checkpoint antibody. Such antibodies include anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab, pidilizumab, tislelizumab, and RG7446), and anti-PD-L1 antibodies (e.g., BMS-93655, MPDL3280A, MSBOO10718C, and MED14736). Preferred immune checkpoint inhibitors are antibodies that bind to a particular immune checkpoint protein, whether that protein is the immune checkpoint protein itself, its receptor, or its ligand.

[0082] In some embodiments, one or more immune checkpoint inhibitors are antibodies or fragments thereof. Suitable antibodies include anti-PD1 antibodies or fragments thereof, anti-PDL1 antibodies or fragments thereof, and anti-CTLA4 antibodies or fragments thereof. Thus, in some embodiments, the checkpoint inhibitor is related to PD-1, PD-L1, or CTLA-4.

[0083] In other embodiments, the checkpoint inhibitor is related to PD-L2, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, A2AR, TIM-3, or VISTA.

[0084] In certain embodiments, one or more immune checkpoint inhibitors are antibodies against immune checkpoint proteins.

[0085] In some embodiments, one or more immune checkpoint inhibitors are selected from the group consisting of durvalumab, avelumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, cemiplimab, envafolimab, BMS-936559, CK-301, CS-1001, and SHR-1316.

[0086] Compounds are generally used in the form of pharmaceutical compositions formulated according to the desired mode of administration. The compositions are prepared in a manner well known in the art.

[0087] In the above embodiments, the composition of the present invention contains ethanol as a component. The ethanol used in the composition can be anhydrous ethanol. Alternatively, the ethanol used in the composition may not have undergone a drying process and may be hydrated. Preferably, the ethanol is pharmaceutical-grade ethanol. The ethanol present in the composition can help prevent the radiolytic decomposition of the radiolabeled complex / complex of formula (I).

[0088] In the above embodiments, the composition of the present invention further contains sodium chloride as a component. The sodium chloride in the preparation of the present invention can be provided in the form of a salt solution. A salt solution is defined as an aqueous solution of sodium chloride. For example, physiological saline is defined as an aqueous solution of sodium chloride with a concentration of 0.9% (w / v). In one embodiment of the present invention, the sodium chloride in the preparation is provided by a salt solution.

[0089] In the above embodiments, the composition of the present invention contains gentisic acid or a pharmaceutically acceptable salt and / or hydrate thereof as a component. Gentisic acid is also known as 2,5-dihydroxybenzoic acid, 5-hydroxybenzoic acid, or hydroquinone carboxylic acid. Gentisate salts can include sodium salts and sodium salt hydrates. In relevant cases, any reference to gentisic acid may include a reference to its salts. The inventors have determined that gentisic acid or its salts in the composition of the present invention can help prevent or minimize the radiolytic decomposition of the radiolabeled complex / complex of formula (I).

[0090] In other embodiments, the present invention provides a pharmaceutical package or kit that includes one or more containers containing one or more ingredients of the pharmaceutical composition of the present invention. At least one container can be found in such a package or kit that contains a unit dose of one or more reagents. Conveniently, in the kit, a single dose can be provided in a sterile vial so that a clinician can use the vial directly, where the vial will have the desired amounts and concentrations of the compound and the radionuclide, which can be mixed prior to use. Associated with such a container can be various written materials, such as instructions for use, or a notice in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, imaging agents, or biologics, which reflects the agency's approval for the manufacture, use, or sale for human administration.

[0091] The compounds of the present invention can be used in combination with one or more other drugs, which are anti-cancer drugs and / or methods (such as surgery, radiotherapy) for treating the disorder / disease. These components can be administered in the form of the same formulation or separate formulations. If administered in the form of separate formulations, the compounds of the present invention can be administered sequentially or simultaneously with the other drugs.

[0092] In addition to being able to be used in combination with one or more other drugs including anti-cancer drugs, the compounds of the present invention can also be used in combination therapies. When doing so, the compounds are generally administered in combination with each other. Thus, one or more compounds of the present invention can be administered simultaneously (as a combination formulation) or sequentially to achieve the desired effect. This is particularly desirable when the therapeutic properties of the individual compounds are different, such that the combined action of the two drugs provides a better therapeutic outcome.

[0093] The pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). For example, appropriate fluidity can be maintained by using coating materials such as lecithin, maintaining the desired particle size in the case of dispersions, and using surfactants.

[0094] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. By incorporating various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc., the action of microorganisms can be ensured to be prevented. It may also be necessary to incorporate isotonic agents such as sugars, sodium chloride, etc. By incorporating agents that delay absorption, such as aluminum monostearate and gelatin, the absorption of the injectable pharmaceutical form can be prolonged.

[0095] If desired and for more effective distribution, the compounds can be incorporated into sustained release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0096] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0097] In another aspect, the present invention also provides a method for preparing a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0098] Compounds of formula (I) can be prepared by a series of peptide coupling steps using appropriate amines and carboxylic acid derivatives. The coupling partners may require one or more protecting groups which are to be removed after the coupling reaction. A list of suitable protecting groups in organic synthesis and their procedures for installation and removal can be found in Protective Groups in Organic Synthesis by TW Greene, 3rd Edition (John Wiley & Sons, 1991). When peptide coupling steps are used to prepare the compounds of the present invention or their precursors, the reactions can be carried out as required in liquid or solid phase conditions in the presence of one or more bases or other reagents. The coupling partners used in a given reaction step can be modified with one or more suitable groups (such as leaving groups) which facilitate the coupling reaction. The preparation of compounds of formula (I) can include the selection and installation of one or more protecting groups, etc., to facilitate the coupling of components with the desired site selectivity. For example, the steps required to prepare a compound of formula (I) can include the installation of one or more nitrogen or oxygen protecting groups at one or more amine or carboxylic acid functional groups.

[0099] As used herein, the term "oxygen protecting group" refers to a group which can prevent the oxygen moiety from reacting during further derivatization of the protected compound and which can be readily removed when desired. In one embodiment, the protecting group can be removed by natural metabolic processes under physiological conditions. Examples of oxygen protecting groups include acyl groups (such as acetyl), ethers (such as methoxymethyl ether (MOM), α-methoxyethoxymethyl ether (MEM), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyran (THP)), and silyl ethers (such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) groups).

[0100]

[0101] ​As used herein, the term "nitrogen protecting group" refers to a group that can prevent the nitrogen moiety from reacting during further derivatization of the protected compound and can be readily removed when desired. In one embodiment, the protecting group can be removed by natural metabolic processes under physiological conditions, and the protected compound in essence serves as a prodrug of the active unprotected substance. Examples of suitable nitrogen protecting groups that can be used include formyl, trityl, phthalimido, acetyl, trichloroacetyl, 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-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, tert-butoxycarbonyl (tBoc), 2-(4-biphenylyl)-isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-tolyl)-prop-2-yloxycarbonyl, cyclopentyloxycarbonyl, 1-methylcyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl, 2-methylcyclohexyloxycarbonyl, 2-(4-toluenesulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphine)-ethoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxaloylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, etc.; benzoylmethylsulfonyl groups, 2-nitrophenylsulfinyl, diphenylphosphine oxide, etc. The nitrogen protecting group actually used is not important as long as the derivatized nitrogen group is stable to subsequent reaction conditions and can be selectively removed as needed without significantly damaging the rest of the molecule, including any other nitrogen protecting groups.Additional examples of such groups can be found in: Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd 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, 2nd Edition, Thieme Medical Pub., 2000.

[0102] The compounds of formula (I), (II), (IIa) or (IIb) disclosed herein or their pharmaceutically acceptable salts can be synthesized by coupling the moiety that binds to SSTR2 with the desired linker (if present) and then coupling with a chelating agent. Various protection and deprotection steps can also be employed, with the conditions of each step being compatible with the rest of the compound. An exemplary synthetic scheme is provided in Scheme 1:

[0103] Scheme 1 describes the synthesis of a compound of formula (II) in which sarcophagine is coupled simultaneously to the two moieties of the linker-octreotate group. The reaction can be carried out under standard peptide coupling conditions with a suitable peptide coupling reagent and base, where the linker-octreotate group contains an amine functionality and the metal chelator contains a carboxylic acid functionality that will participate in the coupling reaction.

[0104] Alternatively, the compounds of formula (I), (II) and (IIa) disclosed herein or their pharmaceutically acceptable salts can be synthesized according to Scheme 2:

[0105] Scheme 2 also describes a particular embodiment of the method described herein. The two moieties of the linker-octreotate group are coupled to sarcophagine, however in this synthetic route the amine group participating in the coupling reaction is located on sarcophagine and the carboxylic acid group is located on the linker-octreotate group. The reaction can also be carried out under standard peptide coupling reaction conditions with a peptide coupling reagent and base.

[0106] In certain embodiments, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, wherein the method comprises one or more peptide coupling steps. Optionally, the method may further comprise one or more protection and deprotection steps. In other embodiments, the method for preparing a compound of formula (I) comprises a peptide coupling step carried out under solution phase conditions using one or more peptide coupling reagents and one or more bases.

[0107] The changes in the sarcophagine structure and subsequently the nature and position of one or more functional groups will naturally determine the synthetic route required to obtain the compound of formula (I). For example, when the terminal group on sarcophagine is an oxygen-based group (e.g., carboxylic acid), the protecting group (if required) and subsequent reactions should be compatible and allow coupling to provide the compound of formula (I). Conversely, when the terminal group of sarcophagine is a nitrogen-based group (e.g., amine), the protecting group (if required) present on either coupling partner should be compatible with the subsequent synthetic steps to provide the compound of formula (I).

[0108] The synthetic schemes described herein show the coupling of the linker-octreotate group to the two terminal amine groups of sarcophagine. The synthetic schemes disclosed herein include modifications to the protection / deprotection strategy that allow the linker-SSTR2 binding moiety fragment to couple at the desired center to provide the compound of formula (I).

[0109] The reference in this specification to any prior publication (or information derived therefrom) or to any matter known, and is not or should not be taken as an admission or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field to which this specification pertains.

[0110] Those skilled in the art will appreciate that changes and adaptations to the invention described herein are readily made outside the specifically described circumstances. It is to be understood that the invention includes all such variations and modifications that fall within the spirit and scope of the invention. The invention also includes all the steps, features, compositions and compounds mentioned or indicated in the specification, either singly or in combination, and any combination and all combinations of any two or more of said steps or features. Examples

[0111] The following examples are illustrative of the present disclosure and should not be construed in any way as limiting the general nature of the disclosure described in this specification. Synthesis of Compounds of the Invention

[0112] A variety of starting materials and other reagents are available from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and can be used without further purification, unless otherwise stated. Solvents can be purified using standard methods in the art if required. [Co((NO2)2sar)]Cl3, [Co((NH2)2sar)]Cl3, (NH2)2sar, and [Cu(NH3)2sar](CF3SO3)4 can be prepared according to established procedures. (1) Geue, R. J.; Hambley, T. W.; Harrowfield, J. M.; Sargeson, A. M.; Snow, M. R. J. Am. Chem. Soc. 1984, 106, 5478 - 5488. (2) Bottomley, G. A.; Clark, I. J.; Creaser, I. I.; Engelhardt, L. M.; Geue, R. J.; Hagen, K. S.; Harrowfield, J. M.; Lawrance, G. A.; Lay, P. A.; Sargeson, A. M.; See, A. J.; Skelton, B. W.; White, A. H.; Wilner, F. R. Aust. J. Chem. 1994, 47, 143 - 179, and (3) Bernhardt, P. V.; Bramley, R.; Engelhardt, L. M.; Harrowfield, J. M.; Hockless, D. C. R.; Korybut-Daszkiewicz, B. R.; Krausz, E. R.; Morgan, T.; Sargeson, A. M.; Skelton, B. W.; White, A. H. Inorg. Chem. 1995, 34, 3589 - 3599.

[0113] The following reactions are carried out under a positive pressure of nitrogen, argon, or a drying tube, at ambient temperature (unless otherwise stated), in an anhydrous solvent, and the reaction flask is equipped with a rubber septum for the introduction of substrates and reagents by syringe.

[0114] Workup was generally carried out by doubling the reaction volume with reaction or extraction solvent followed by washing with the indicated aqueous solution, where the extraction volume was 25% (unless otherwise stated). The product solution was dried over anhydrous sodium sulfate before filtration, the solvent was evaporated under reduced pressure on a rotary evaporator, and recorded as removal of the solvent in vacuo. Flash column chromatography [Still et al., J. Org. Chem., 43, 2923 (1978)] was carried out using E Merck grade flash silica gel (47–61 mm), with a silica:crude material ratio of approximately 20:1 to 50:1, unless otherwise stated. Hydrogenolysis was carried out at the indicated pressure or ambient pressure.

[0115] Mass spectra were recorded in positive ion mode on an Agilent 6510 Q-TOF LC / MS mass spectrometer coupled to an Agilent 1100 LC system (Agilent Technologies, Palo Alto, CA). Using the factory defined calibration procedure, data were acquired and reference masses corrected by dual spray electrospray ionization source. Each scan or data point of the total ion chromatogram was an average of 9652 transients, yielding 1.02 scans / s. Spectra were created by averaging the scans of each peak. Mass spectrometer conditions: Fragmentor: 200–300 V; Drying gas flow: 7 L / min; Nebulizer: 30 psi; Drying gas temperature: 325 °C; Vcap: 4000 V; Skimmer / Cone: 65 V; OCT RfV: 750 V; Acquisition scan range: 150–3000 m / z.

[0116] HPLC-MS traces were recorded using an Agilent Eclipse Plus C18 column (5 μm, 2.1 x 150 mm) coupled to the above Agilent 6510 Q-TOF LC / MS mass spectrometer. A 1 μL aliquot of each sample was injected onto the column using an Agilent 1100 LC system at a flow rate of 0.5 mL / min. Data acquisition parameters were the same as those for the mass spectra above, except for the Fragmentor (Fragmentor voltage: 100 V).

[0117] NMR spectra were recorded on a Varian FT-NMR 500 spectrometer, with 1H NMR at 500 MHz and 13C-NMR at 125.7 MHz. NMR spectra were obtained as D2O solutions (reported in ppm), using acetone as the reference standard (2.22 ppm and 30.89 ppm, respectively). Other NMR solvents were used as required. When reporting peak multiplicities, the following abbreviations were used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants (if given) were reported in Hertz.

[0118] Semi-preparative HPLC purification was carried out using an Agilent 1200 series HPLC system with a flow rate of 5 mL / min. Solvent gradients and column specifications are described in the examples. An automated Agilent 1200 fraction collector was used to collect 1 - 3 mL fractions, and fraction collection was based on UV-Vis detection at 214 or 220 nm, with a lower threshold between 100 - 400 mAU. The fractions were analyzed using MS and analytical HPLC. Example 1: Preparation of SARbisTATE Tyr3 - Octreotate

[0119] The linear [Tyr3]-octreotate peptide (dPhe-Cys-Tyr-dTrp-Lys-Thr-Cys-Thr-OH) was synthesized on 2-chlorotrityl chloride resin using standard Fmoc solid-phase peptide synthesis procedures. An excess of resin (0.06 g, approximately 0.8 mmol / g) was swollen in N,N-dimethylformamide (DMF), and then amino acid residues were coupled sequentially. Fmoc deprotection was carried out by treating the peptide resin with 20% piperidine / DMF (v / v; 5 ml). The reaction supernatant was then drained, and the resin was washed with DMF (3 x 5 mL) and dichloromethane (DCM) (3 x 5 mL). The resin was transferred to a falcon tube, and trifluoroacetic acid (5 mL), deionized water (0.15 mL), and triisopropylsilane (0.15 mL) were added. The falcon tube was placed on an oscillator for 40 minutes. The peptide material was precipitated from the solution using diethyl ether (15 mL), and the mixture was centrifuged (3 minutes, 3000 rpm). The supernatant was discarded, and the precipitate was dissolved in A:B (70:30). The solution was filtered (MilliQ 0.45 μm syringe filter) and lyophilized.

[0120] The crude peptide material was purified by semi-preparative reverse-phase HPLC (Eclipse XDB-C18 5 μm 9.5 x 250 mm column) using a linear 1% A → B / min gradient. The linear peptide was determined by ESI-MS, and the fractions containing the linear peptide were lyophilized. The dried fractions were then redissolved in ammonium acetate (25 mM, pH 6.5, 8 mL), and an excess of 2,2-dithiopyridine (12 mg) was added. The solution was then applied to a semi-preparative reverse-phase HPLC column and purified using a linear 1% A → B / min gradient. The cyclic peptide was identified, and the fractions containing the cyclic peptide were lyophilized.

[0121] The cyclic peptide was then reacted with (tBoc)4(NHS)2Sar in the presence of diisopropylethylamine to produce the Boc-protected SAR-bisTATE compound. The compound was globally deprotected in the presence of TFA to remove the Boc group. Example 2: 64 Biodistribution of Cu-SARbisTATE in SSTR2-positive tumor-bearing mice

[0122] Fifty-eight female mice (BALB / c-Foxn1ν mice, 8 to 12 weeks old) were subcutaneously inoculated on the right side with 3 million AR42J (rat SSTR2-expressing pancreatic cancer cell line) cells in PBS:Matrigel (1:1). Mice were weighed twice a week and tumors were measured using an electronic caliper. Tumor volume (mm 3 ) was calculated as length x width x height x π / 6. Mice were randomly divided into tumor volume-matched groups for biodistribution studies (tumor volume range: 54 - 411 mm 3 , group mean 265 mm 3 ).

[0123] SARbisTATE was labeled with 64 Cu and injected into mice via the tail vein with saline. Parallel groups (n = 4 - 6) were harvested for tissue biodistribution, and blood was collected by cardiac puncture at 1 hour, 4 hours, 24 hours, and 48 hours after injection. Biodistribution tissues were excised, weighed, and counted using a Capintec (Captus 4000e) gamma counter. Data were analyzed using Prism 9 for Windows (GraphPad).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof: Wherein, each R is a moiety that binds to SSTR2; and each –L– is a linker moiety that couples a moiety that binds to SSTR2 and sarcophagine.

2. The compound or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof according to claim 1, wherein, Each R is independently selected from octreotide, lanreotide, pasireotide, octreotide acid and combinations thereof.

3. A compound of formula (II) or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof: Wherein –L– is a linker moiety.

4. The compound or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof according to any one of claims 1 to 3, wherein, Each -L- is independently an optionally substituted -C1-C 10 alkylene-, -C2-C 10 alkenylene- or -C2-C 10 alkynylene- group, one or more amino acid residues, one or more PEG groups or a combination thereof; One or more carbon atoms in the alkylene, alkenylene or alkynylene can be substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group or a C5-C8 aromatic or aliphatic heterocyclic group.

5. The compound or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof according to claim 3, wherein, The compound of formula (II) has the structure of formula (IIa):

6. The compound or a pharmaceutically acceptable salt, complex, isomer, solvate or prodrug thereof according to claim 3, wherein, The compound of formula (II) has the structure of formula (IIb):

7. A compound according to any one of claims 1 to 6, wherein, The metal chelator complexes with ions of metals selected from the group consisting of: Cu, Ga, Lu, F, Tc, In, Zr, Y, Rb, Ac, Rd, Re, Sm, Lu, Sc, Zr, Y, Ac, As, Ra and I.

8. The compound according to claim 7, wherein, The ion is a radionuclide.

9. The compound according to any one of claims 1 to 8, wherein, The compound complexes with a Cu radionuclide.

10. The compound according to claim 9, wherein, The Cu radionuclide is selected from 60 Cu, 61 Cu, 62 Cu, 64 Cu, and 67 Cu.

11. A composition comprising the compound according to any one of claims 1 to 10 and one or more pharmaceutically acceptable excipients.

12. A method for radiographically imaging cancer in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 7 to 10.

13. The method according to claim 12, wherein, The cancer is characterized by the expression of SSTR2.

14. The method according to claim 12 or 13, wherein The cancer is selected from the group consisting of: neuroendocrine tumors, including carcinoids in the lung, appendix, digestive tract, prostate, thymus or rectum, pancreatic neuroendocrine tumors, pituitary tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid cancer, gastrinoma, insulinoma or non-functional islet cell tumor, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, thyroid cancer and hematological malignancies such as lymphoma or leukemia.

15. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject the compound according to any one of claims 7 to 10.

16. The method according to claim 15, wherein, The cancer is characterized by the expression of SSTR2.

17. The method according to claim 15 or 16, wherein, The cancer is selected from the group consisting of: neuroendocrine tumors, including carcinoids in the lung, appendix, digestive tract, prostate, thymus or rectum, pancreatic neuroendocrine tumors, pituitary tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid cancer, gastrinoma, insulinoma or non-functional islet cell tumor, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, thyroid cancer and hematological malignancies such as lymphoma or leukemia.

18. Use of the compound according to any one of claims 1 to 8 in the preparation of a medicament for radiographically imaging cancer.

19. The use according to claim 14, wherein, The cancer is characterized by the expression of SSTR2.

20. The use according to claim 14 or 15, wherein, The cancer is selected from the group consisting of: neuroendocrine tumors, including carcinoids in the lung, appendix, digestive tract, prostate, thymus or rectum, pancreatic neuroendocrine tumors, pituitary tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid cancer, gastrinoma, insulinoma or non-functional islet cell tumor, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, thyroid cancer and hematological malignancies such as lymphoma or leukemia. Use of the compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of cancer.

22. The use according to claim 19, wherein, The cancer is characterized by the expression of SSTR2.

23. The use according to claim 19 or 20, wherein The cancer is selected from the group consisting of: neuroendocrine tumors, including carcinoids in the lung, appendix, digestive tract, prostate, thymus or rectum, pancreatic neuroendocrine tumors, pituitary tumors, renal cell carcinoma, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid cancer, gastrinoma, insulinoma or non-functional islet cell tumor, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, thyroid cancer and hematological malignancies such as lymphoma or leukemia.

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