Alpha emitter labelled somatostatin receptor antagonists

Abstract

The present invention relates a somatostatin receptor antagonist. The present invention further provides a pharmaceutical composition comprising the somatostatin receptor antagonist. The invention further relates to the somatostatin receptor antagonist or the pharmaceutical composition for use in medicine, in particular for use in the diagnosis and / or treatment of cancer. The invention also relates to a kit comprising the somatostatin receptor antagonist or the pharmaceutical composition. The invention also relates to a method for labeling the somatostatin receptor antagonist.

Description

[0001] Alpha emitter labelled somatostatin receptor antagonists

[0002] The present invention relates a somatostatin receptor antagonist. The present invention further provides a pharmaceutical composition comprising the somatostatin receptor antagonist. The invention further relates to the somatostatin receptor antagonist or the pharmaceutical composition for use in medicine, in particular for use in the diagnosis and / or treatment of cancer. The invention also relates to a kit comprising the somatostatin receptor antagonist or the pharmaceutical composition. The invention also relates to a method for labeling the somatostatin receptor antagonist.

[0003] Radiopharmaceutical therapy (RPT) can be defined as the delivery of radioactive atoms to tumor associated targets. Radionuclides with different emission properties - primarily P-particles or highly potent a-particles - are used to deliver radiation. In almost all cases, the radionuclides may be visualized by nuclear medicine imaging techniques to assess targeting of the agent, which provides a substantial advantage over existing therapeutic approaches and enables a precision medicine approach to radiopharmaceutical therapy (RPT) delivery. Patients with cancer with distant metastases continue to have a grim prognosis despite ongoing efforts with new chemotherapeutics, small molecule inhibitors, biologies, immune checkpoint inhibitors and various combinations of these; novel therapeutic approaches are therefore vital (Sgourous G. et al. “Radiopharmaceutical therapy in Cancer: clinical advances and challenges, Nature Reviews, vol. 19, July 29, 2020). Treatment of neuroendocrine tumors (NETs) largely depends on radioligands targeting somatostatin receptor type 2 (SSTR2). [177Lu]Lu-DOTA-TATE (Lutathera®) is the leading radioligand with approval from both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Various studies have shown that SSTR2 antagonists are more potent than SSTR2 agonists due to their ability to bind to more receptor binding sites. Therefore, several SSTR2 antagonist peptides have been labelled for diagnostic or therapeutic purposes. However, the rapid blood clearance of such SSTR2 radioligands and the significant accumulation in non-target tissues pose a limit for higher tumor dose delivery and more efficient treatment (Kostoulidou S. et al , “Synthesis and Evaluation of two long-acting SSTR2 antagonists for radionuclide therapy of neuroendocrine tumors”, Pharmaceutical, vol. 15, 1155, September 16, 2022) Accordingly, there is a need in the art for novel radiopharmaceutical therapies, such as SSTR2 antagonists, effectively delivering radioactivity to the tumor site and subsequent radiation- induced killing of tumor cells. The present invention provides somatostatin receptor antagonists. The SSTR antagonists are labelled with an alpha-emitting radionuclide and bind to somatostatin receptor 2 and thus, are somatostatin receptor 2 antagonists. In particular, the alpha emitting radionuclide comprised in the SSTR2 antagonists is212Pb or225Ac.

[0004] The SSTR2 antagonists of the invention provide inter alia the following advantages over the art: (i) increased favorable efficacy and delay and inhibition of tumor growth compared to a SSTR2 antagonist labelled with a beta-emitting radioactive moiety instead of the alpha-emitting radioactive moiety; and / or (ii) favorable stability profile; and / or (iii) effective delivery to the source organ meaning the tumor or tumor cell(s), respectively; and / or decreased exposure of the body to radioactivity due to lower doses while efficacy is maintained or increases compared to SSTR2 antagonist labelled with a beta-emitting radioactive moiety instead of the alpha-emitting radioactive moiety or compared to SSTR2 agonist labelled with an alpha-emitting radioactive moiety.

[0005] A first aspect of the invention relates to a somatostatin receptor antagonist (SSTR antagonist).

[0006] A second aspect of the invention relates to a pharmaceutical composition comprising the somatostatin receptor antagonist of the first aspect of the invention and a pharmaceutically acceptable carrier.

[0007] A third aspect of the invention relates to the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention for use in medicine.

[0008] A fourth aspect of the invention relates to the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention for use in the diagnosis and / or treatment of cancer.

[0009] A fifth aspect of the invention relates to kit comprising the SSTR antagonist of the first aspect of the invention for the diagnosis of cancer.

[0010] A sixth aspect of the invention relates to a method of labeling the SSTR antagonist of the first aspect of the invention.

[0011] List of Figures

[0012] In the following, the content of the figures comprised in this specification is described. In this context reference is made to the detailed description of the invention above and / or below.

[0013] Figure 1 : Compound 1 structure. Figure 1 depicts the chemical structure of Compound 1 of the invention comprising a cyclic peptide structure and a complexing moiety which is attached to the chlorophenylalanine residue of the peptide and is 2,2',2'',2'"-(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid. Compound 1 as depicted in Figure 1 is not labelled with a radioactive isotope.

[0014] Figure 2: Biodistribution212Pb-Compound 1 in the NCI-H69 mouse model of small cell lung cacner (SCLC) expressing SSTR2. Figure 2 shows the combined tissue distribution over 1, 4 and 24 hours, with a clear uptake of212Pb-Compound 1 in the tumor tissue. After 24 hours the uptake of212Pb -Compound 1 is distributed between two major tissue compartments (kidneys and tumor).

[0015] Figure 3: Single dose efficacy study212Pb-Compound 1 in the NCI-H69 mouse model of SCLC expressing SSTR2. Figure 3A shows the relative tumor growth to the initial starting point at 250mm3after a single injection of a dose of177Lu-Compound 1 (20MBq) and three different doses of212Pb-Compound 1 (1.6 MBq, 0.75 MBq, 0.35 MBq) versus the control of Compound 1 over several weeks. While the tumors for the control group grow rapidly further until the end point of 1000 mm3, the radiolabelled Compound 1 delays the tumor growth in all groups and also reduces tumor size (see 1.6 MBq panel and 0.75 MBq panel). Figure 3B shows the relative tumor growth to the initial starting point at 200-250 mm3after a single injection of177Lu-Compound 1 (21.5 MBq) or three different doses of212Pb-Compound 1 (503 kBq, 236 kBq, 113 kBq) versus the control Compound 1 over several weeks. While the tumors for the control group grow rapidly until the end point of 1000 mm3, the radiolabelled Compound 1 delays the tumor growth in all groups. Surprisingly, the highest dose tested ofthe212Pb-Compound 1 (503 kBq) leads to an initial reduction of the mean tumor volume relative to dO. Figure 3C shows the percent survival after a single injection of177Lu-Compound 1 (21.5 MBq) or three different doses of212Pb-Compound 1 (503 kBq, 236 kBq, 113 kBq) versus the control Compound 1. All single dose treatments with radiolabelled Compound 1 prolonged median survival of NCI-H69 tumor-bearing mice compared to the control group and treatment with the highest dose of212Pb-Compound 1 (503 kBq) resulted in the longest median survival.

[0016] Figure 4: Stability results for225Ac-Compound 1 radiolabelling.

[0017] Figure 4 shows the TLC (thin layer chromatography) analysis after the synthesis of the225Ac -Compound 1 and the analysis at several time points after the synthesis (up to 72h). The radiochemical purity of Compound 1 over the monitored period is stable resulting in an acceptable stability of the formulation.

[0018] Figure 5: Biodistribution of225Ac-Compound 1 in the NCI-H69 mouse model of SCLC expressing SSTR2. Figure 5A shows the tissue distribution of225Ac-Compound 1 over 4, 24 and 96 hours. ^Ac- Compound 1 was clearly taken up in the tumor tissue and %ID / g reached >10% at the 4h time point. Figure 5B shows the tumor / kidney ratio at the respective time points showing an increase of tumor to background ratio over the course of 96 h indicating tumor persistence.

[0019] Figure 6: Efficacy study analyzing225Ac-Compound 1 in comparison to177Lu-Compound 1 in the SSTR2-positive NCI-H69 mouse model of SCLC. Figure 6A and 6B show individual tumor growth curves of mice either treated with unlabelled Compound 1 alone,177Lu-Compound 1 (20MBq Q2W x 3) or different doses and regimens of225Ac-Compound 1 (90 kBq QW, 30 kBq QW, 30 kBq Q2W x 3, 30 kBq QW x 3). Figure 6C shows the median survival in each group. While the tumors for the control group grew rapidly until the end point of 1000 mm3, treatment with all radiolabelled Compound 1 groups and even single doses of 30 kBq225Ac-Compound 1 only substantially inhibited tumor growth resulting in a high rate of complete remissions. Figure 7: Efficacy study analyzing212Pb-Compound 1 in comparison to177Lu-Compound 1 in the SSTR2-positive NCI-H69 mouse model of SCLC. Figure 7A and 7B show individual tumor growth curves of mice either treated with unlabelled Compound 1 alone (Q2W x 3),177Lu-Compound 1 (20MBq Q2W x 3) or different doses and regimens of212Pb-Compound 1 (750 kBq QW, 500 kBq Q2W x 3, 250 kBq QW x 3, 250 kBq Q2W x 3). Figure 7C shows the median survival in each group. While the tumors for the control group grew rapidly until the end point of 1000 mm3, treatment with all radiolabelled Compound 1 groups substantially induced tumor growth reduction with177Lu-Compound 1 showing the strongest effect with complete remissions in 100% of the mice.

[0020] Figure 8: Single-dose efficacy study analyzing different doses of225Ac-Compound 1 in the SSTR2- positive NCI-H69 mouse model of SCLC. Figure 8 shows the mean tumor volume ± SEM of mice either treated with vehicle or different doses of225Ac-Compound 1 (30 kBq QW, 10 kBq QW, 3.33 kBq QW). Until day 9 after start of treatment, single doses of 10 kBq and 30 kBq 225 Ac-Compound 1 induce a tumor growth reduction in comparison to the vehicle control and 3.33 kBq 225Ac-Compound 1.

[0021] List of sequences

[0022] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0023] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the documents cited herein are characterized as being “incorporated by reference In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence. In the following, the elements of the present invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0024] To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques are employed which are explained in the literature in the field (cf. , e.g., Molecular Cloning: A Laboratory Manual, 2ndEdition, J. Sambrook el al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0025] In the following, some definitions of terms frequently used in this specification are provided. These terms will, in each instance of its use, in the remainder of the specification have the respectively defined meaning and preferred meanings.

[0026] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents, unless the content clearly dictates otherwise.

[0027] The term “somatostatin receptor (SSTR)” refers in the context of this invention to receptors for the ligand “somatostatin”, a small neuropeptide associated with neural signalling, particularly in the post- synaptic response to NMDA receptor co-stimulation / activation and also known as growth hormone- inhibiting hormone (GHIH). Somatostatin regulates the endocrine system and affects neurotransmission and cell proliferation via its receptors which are G protein coupled seven transmembrane receptors. Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 amino acids, the other consisting of 28 amino acids. Among vertebrates, there exist six different somatostatin genes that are designated SSI, SS2, SS3, SS4, SS5 and SS6. The six different genes, along with the five different somatostatin receptors, allow somatostatin to possess a large range of functions. Humans have only one somatostatin gene. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) have a wide expression pattern in both normal tissues and solid tumors. They are involved in the regulation of signalling cascades that suppress tumor cell proliferation, survival and angiogenesis. There are five known human somatostatin receptor subtypes:

[0028] SST1 (SSTR1);

[0029] SST2 (SSTR2);

[0030] SST3 (SSTR3);

[0031] SST4 (SSTR4);

[0032] SST5 (SSTR5). Somatostatin receptors are expressed in pathological states, particularly in neuroendocrine tumors of the gastrointestinal tract. Most human tumors originating from the somatostatin target tissue have conserved their somatostatin receptors. It was first observed in growth hormone producing adenomas and TSH-producing adenomas; about one-half of endocrine inactive adenomas display somatostatin receptors. Ninety percent of the carcinoids and a majority of islet cell carcinomas, including their metastasis, usually have a high density of somatostatin receptors. However, only 10 percent of colorectal carcinomas and none of the exocrine pancreatic carcinomas contain somatostatin receptors. The somatostatin receptors in tumors can be identified using in vitro binding methods or using in vivo imaging techniques, the latter allowing the precise localization of the tumors and their metastasis in the patients. Somatostatin receptors have widespread but variable tissue expression in normal tissue. They are diversely expressed in multiple tumor types including a subset of breast, prostate, pancreatic, neuroendocrine, Merkel-cell carcinomas and hepatocellular carcinomas.

[0033] The “somatostatin receptor 2” (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including inter alia small-cell lung carcinomas (SCLCs). SSTR2 is the best characterized member of the SSTR family and has multiple direct and indirect effects on cell cycling, angiogenesis, apoptosis and growth factor signaling. SSTR2s have been found in concentration on the surface of tumor cells, particularly those associated with the neuroendocrine system A synthetic version of the somatostatin hormone, octreotide -acting as an SSTR2 agonist- has been successfully used in combination with radiopeptide tracers to locate adrenal gland tumors through scintigraphic imaging. The use of SSTR2 and SSTR5 as biomarkers to frack the progress of and treat neuroendocrine tumors comprising circulating tumor cells is also being investigated due to these cells’ somatostatin receptor gene expressivity. There are several somatostatin analogues to target SSTRs that can be used as positron emission tomography (PET) radioligands to visualize neuroendocrine tumors. Ligands for SSTRs can be divided into agonists and antagonists.

[0034] The term “somatostatin receptor agonist” refers in the context of this invention to analogues of the naturally occurring ligand somatostatin as described herein above. Examples of somatostatin receptor agonists are octreotide, octreotate, lanreotide or pasireotide.

[0035] The term “somatostatin receptor antagonist” refers in the context of this invention to a molecule that binds to a somatostatin receptor (SSTR) and antagonizes the effects of the natural agonist somatostatin, for example diminishes or decreases a biological response induced by binding of said agonist upon binding to the receptor, i.e. the antagonist deactivates the biological function of the receptor upon binding rather than activating it upon binding, such as an agonist would do. Somatostatin receptor antagonist are not internalized into the cell upon binding to the receptor and thus, can bind to a larger number of receptors because they are independent of the receptor activation state. The term “peptide” refers in the context of this invention to a short polymer of amino acids linked by peptide bonds. It has the same chemical (peptide) bonds as proteins but is commonly shorter in length. The shortest peptide is a dipeptide, consisting of two amino acids joined by a single peptide bond. There can also be a tripeptide, tetrapeptide, pentapeptide, etc. Typically, a peptide has a length of up to 8, 10, 12, 15, 18 or 20 amino acids. A peptide has an amino end and a carboxyl end, unless it is a cyclic peptide. Amino acids refer in the context of the present invention to any monomer unit that comprises a substituted or unsubstituted amino group, a substituted or unsubstituted carboxy group, and one or more side chains or groups, or analog of any of these groups. Exemplary side chains include, e.g., thiol, seleno, sulfonyl, alkyl, aryl, acyl, keto, azido, hydroxyl, hydrazine, cyano, halo, hydrazide, alkenyl, alkynl, ether, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, ester, thioacid, hydroxylamine, or any combination of these groups. Other representative amino acids include, but are not limited to, amino acids comprising photoactivatable cross-linkers, metal binding amino acids, spin-labelled amino acids, fluorescent amino acids, metal-containing amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and / or photoisomerizable amino acids, radioactive amino acids, amino acids comprising biotin or a biotin analog, glycosylated amino acids, other carbohydrate modified amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and / or photocleavable amino acids, carbon-linked sugar-containing amino acids, redox-active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moieties.

[0036] As used herein, the term “amino acid” includes the following twenty natural or genetically encoded alpha-amino acids: alanine (Ala or A), arginine (Arg or R), asparagine (Asn or N), aspartic acid (Asp or D), cysteine (Cys or C), glutamine (Gin or Q), glutamic acid (Glu or E), glycine (Gly or G), histidine (His or H), isoleucine (He or I), leucine (Leu or L), lysine (Lys or K), methionine (Met or M), phenylalanine (Phe or F), proline (Pro or P), serine (Ser or S), threonine (Thr or T), tryptophan (Trp or W), tyrosine (Tyr or Y), and valine (Vai or V). The structures of these twenty natural amino acids are shown in, e.g., Stryer et al., Biochemistry, 5th ed., Freeman and Company (2002). Additional amino acids, such as selenocysteine and pyrolysine, can also be genetically coded for (Stadtman (1996) “Selenocysteine,” Annu Rev Biochem. 65:83-100 and Ibba et al. (2002) “Genetic code: introducing pyrrolysine,” Curr Biol. 12(13):R464-R466). The term “amino acid” also includes unnatural amino acids, modified amino acids (e.g., having modified side chains and / or backbones), and amino acid analogs. See, e.g., Zhang et al. (2004) “Selective incorporation of 5 -hydroxy tryptophan into proteins in mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 101(24): 8882-8887, Anderson et al. (2004) “An expanded genetic code with a functional quadruplet codon” Proc. Natl. Acad. Sci. U.S.A. 101(20):7566-7571, Ikeda et al. (2003) “Synthesis of a novel histidine analogue and its efficient incorporation into a protein in vivo,” Protein Eng. Des. Sei. 16(9):699-706, Chin et al. (2003) “. As used in the context of the present invention Abbreviations refer to certain amino acids used in the context of the present application and are explained in the following:

[0037] (i) "Aph" refers to aminophenylalanine, where the amino group is preferably attached to the 4- position on the phenyl ring, but attachment at either the 2-or 3 -position is generally equivalent;

[0038] (ii) "Aph(Cbm)" refers to 4-ureido-phenylalanine;

[0039] (iii) Aph(OH-Cbm) is meant 4-(3 -hydroxy)-ureido-phenylalanine;

[0040] (iv) "Aph (CH3-Cbm)" refers to 4-(3-methyl)-ureido-phenylalanine;

[0041] (v) “Aph(0CH3-Cbm)" refers to 4-(3-methoxy)-ureido-phenylalanine;

[0042] (vi) "Aph[(EtOhEt-Cbm]" refers to 4-{3-[2-(2-ethoxy-ethoxy)-ethyl]}-ureido-phenylalanine;

[0043] (vii) Cpa refers to chlorophenylalanine, also designated as cloro-Phe or 4-ClPhe;

[0044] (viii) "ITyr" refers to iodinated L-tyrosine;

[0045] (ix) "Aph(Hor)" refers to 4-[(2,6-dioxo-hexahydropyrimidine-4-carbonyl)-amino]-phenylalanine.

[0046] The standard three-letter abbreviations identify the alpha-amino acid residues, and where the amino acid residue has isomeric forms, it is the L-form of the amino acid that is represented unless otherwise expressly indicated (e.g., Ser = L-serine). By L- or D is meant either of the D-and L-isomers of a particular a-amino acid. Examples for peptides in the context of the present invention are either SSTR agonists, such as the natural agonistic neuropeptide somatostatin and analogs thereof which selectively bind to SSTRs or SSTR antagonists.

[0047] The term “complexing moiety” refers in the context of the present invention, to an organic part of a molecule which is capable of complexing ions, preferably metal ions and more preferably grade two and grade three metal ions. This process is also called “caging” because the complexing moiety can build a cage around the ion, preferably a metal ion. Preferred complexing moieties are chelating agents, complexing agents or conjugating agent. The complexing moiety is useful for therapeutic and / or diagnostic purposes because it allows the fixation of a therapeutic agent, for example, a radionuclide. Examples for a chelating agent is 2,2',2'',2'"-(l,4,7,10-Tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid (IUPAC definition).

[0048] The term “radioactive moiety” refers in the context of the present invention, to a molecule comprising or consisting of a radioisotope.

[0049] The term “radioactivity” in the context of the present invention may be defined for example as the activity of a radioactive moiety as defined herein above. Radioactivity is an attribute of individual atomic nuclei. An unstable nucleus will decompose spontaneously, or decay, into a more stable configuration but will do so only in a few specific ways by emitting certain particles or certain forms of electromagnetic energy. Radioactive decay is a property of several naturally occurring elements as well as of artificially produced isotopes of the elements. The rate at which a radioactive element decays is expressed in terms of its half-life; i.e., the time required for one-half of any given quantity of the isotope to decay. The product of a radioactive decay process - called the daughter of the parent isotope - may itself be unstable, in which case it, too, will decay. The process continues until a stable nuclide has been formed. The emissions of the most common forms of spontaneous radioactive decay are the alpha (a) particle, the beta (P) particle, the gamma (y) ray, and the neutrino. These emissions are considered ionizing radiation because they are energetic enough to liberate an electron from another atom. In alpha decay, an energetic helium ion (alpha particle) is ejected, leaving a daughter nucleus of atomic number two less than the parent and of atomic mass number four less than the parent. An example is the decay of the abundant isotope of uranium,238U, to a thorium daughter plus an alpha particle. The activity of a given amount of radioactive material is defined as the number of transitions or decays per unit of time. The SI unit of said activity is Becquerel (Bq) which amounts to one transition per second. The legacy unit of activity is denoted Ci. 1 MBq equals 1 pCi and ImCi equals 37 MBq, for example.

[0050] The term “specific activity” refers in the context of the present invention to the activity per unit mass of a radionuclide which is either described as Bq / kg or Bq / mol.

[0051] The term “human equivalent dose” in the context of the present invention is a measure of biological effect of the radioactive dose that takes into account both the absorbed dose and the biological effectiveness of the radiation, and hence, the radiation type. The SI unit is Sievert (Sv) and the legacy unit is rem, 1 Sv equals 100 rem. The equivalent dose is dependent on the RBE. RBE can be defined as the Ratio of Biological Effectiveness of one type of ionizing radiation to another radiation of interest (e.g., alpha particles to gamma rays or beta particles). The RBE of alpha particles is higher compared to beta particles and gamma and X- rays. For oncology pharmaceuticals, an RBE of five can be assigned to alpha particles, signifying that there is a fivefold higher toxicity associated with alpha irradiation than there would be for beta particles, gamma, or X-rays delivering the same absorbed dose (D, SI unit Gray (Gy)) (see for example “Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry”; US department of Health and Human Service, Food and Drug Administration (FDA), published in August 2019). RBE has no unit. The equation for the human equivalent dose is as follows: Equivalent dose (Sv) = RBE x absorbed dose (D) (Gy).

[0052] The term “absorbed dose” in the context of the present invention refers to the ionizing-radiation energy deposited per unit mass of an organ or tissue. The SI unit of absorbed dose is Gray (Gy), where 1 Gy equals 1 J / kg (International Commission on Radiation Units and Measurements (ICRU); 2011). The legacy unit of absorbed dose is denoted rad. 1 Gy equals 100 rad; and 1 cGy equals 1 rad.

[0053] The term “alpha particles” refers to helium ions (alpha particles) that are ejected during alpha decay of a radionuclide or radioisotope, respectively.

[0054] The term “covalent” refers in the context of the present invention to a covalent bond between to atoms that is characterized by the sharing of an electron pair between the two atoms.

[0055] The term “tumor cell or tumor cells“ refers in the context of the present invention to one or more cells of a tumor, which is a cell mass resulting from abnormal cell growth of a neoplasm. A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger for uncontrolled growth is removed. The International Statistical Classification of Diseases and Related Health Problems (I CD; 10threvision)), a medical classification list by the World Health Organization (WHO) classifies the neoplasms into four main groups: benign neoplasms, in situ neoplasms, malignant neoplasms, and neoplasms of uncertain or unknown behavior. Malignant neoplasms are also simply known as cancers. Preferably tumor cells express somatostatin receptors (SSTRs), in particular SSTR2. Molecules that are agonists to STTRs or, in particular, to SSTR2, bind to their respective receptors, internalize into tumor cells and thus, permit accumulation of radioactivity if they are labelled with a radionuclide.

[0056] The term “cancer” refers in the context of the present invention to a disease in which some of the body’s cells grow uncontrollably and spread to other parts of the body. Normally, human cells grow and multiply to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place. Sometimes this orderly process breaks down, and abnormal or damaged cells grow and multiply in an uncontrolled manner. These cells may form tumors, which can be cancerous or not cancerous (benign). Cancerous tumors spread into, or invade, nearby tissues and can travel to distant places in the body to form new tumors (a process called metastasis). Cancerous tumors may also be called malignant tumors. Many cancers form solid tumors, but cancers of the blood, such as leukemias, generally do not. Benign tumors do not spread into, or invade, nearby tissues. Among the texts providing guidance for cancer therapy is Cancer, Principles and Practice of Oncology, 4th Edition, DeVita et al, Eds. J. B. Lippincott Co., Philadelphia, Pa. (1993). An appropriate therapeutic approach is chosen according to the particular type of cancer, and other factors such as the general condition of the patient, as is recognized in the pertinent field. The SSTR antagonists of the present invention can be used by itself or can be added to a therapy regimen using other anti-cancer agents typically used in treating a cancer patient.

[0057] The term “proliferative diseases”, such as cancer, involve the unregulated and / or inappropriate proliferation of cells.

[0058] The term “neuroendocrine tumor (NET)” refers in the context of the present invention to a specific type of cancer. The term NET is an umbrella term for a group of relatively uncommon cancers originating in the neuroendocrine cells of numerous organs. The term “neuroendocrine” refers to the dual features of these cells which are a cross between nerve cells and hormone-producing endocrine cells, i.e. such cell produce neuropeptides and hormones. Characteristics of these tumors can vary, depending on where they are located. NETs are considered rare, however, since NETs are often slow-growing and generally associated with prolonged survival, there are many more people living with the disease. NETs can be difficult to diagnose because symptoms can vary widely from patient to patient and NET s are often mistaken for other conditions such as irritable bowel syndrome (IBS), Crohn’s disease, peptic ulcer diseases or gastritis. NETs appear mostly in the gastrointestinal tract, pancreas Langerhans islets, and the bronchopulmonary system beyond the hypophysis, thyroid, pancreas and adrenal glands. NETs frequently express multiple SSTRs with SSTR2 being expressed at the highest level. Small cell lung cancer (SCLC) is a high-grade poorly differentiated and metastatic neuroendocrine carcinoma of the lung. SCLC is associated with early metastasis and poor patient survival.

[0059] The term “labelled” or “labelling” refers in the context of the present invention to introducing, attaching or complexing a radioactive moiety as defined herein above to the somatostatin receptor antagonist in order to deliver radioactivity to a tumor cell or tumor cells or cancer cells where cell. Typically, the radioactive moiety is provided in a solution including a stabilizing agent.

[0060] In the following different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0061] The term “about” refers in the context of this invention and when used in reference to a particular recited numerical value, to a value and means that the value may vary from the recited value by no more than 5%, no more than 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, or 0.5%. For example, as used herein, the expression "about 100" includes 95 and 105 and all values in between (e.g. 95.0, 95.5, 96.0, 96.5, 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 100.5, 101.0, 101.5, 102.0, 102.5, 103.0, 103.5, 104.0, 104.5 and 105.0).

[0062] Throughout the instant application, the term “and / or” is a grammatical conjunction that is to be interpreted as encompassing that one or more of the cases it connects may occur. For example, the wording "such native sequence proteins can be prepared using standard recombinant and / or synthetic methods" indicates that native sequence proteins can be prepared using standard recombinant and synthetic methods or native sequence proteins can be prepared using standard recombinant methods or native sequence proteins can be prepared using synthetic methods.

[0063] Furthermore, throughout the instant application, the term “comprising” is to be interpreted as encompassing all specifically mentioned features as well optional, additional, unspecified ones. As used herein, the use of the term “comprising” also discloses the embodiment wherein no features other than the specifically mentioned features are present (i.e. “consisting of’).

[0064] Furthermore the indefinite article "a“ or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. It was observed in the context of the present invention that labelling of an SSTR antagonist with a radionuclide or radioactive isotope emitting alpha particles leads to favorable efficacy in the treatment of tumors, in particular to delay and inhibition of tumor growth of non-small cell lung cancer (NSCLC) in a lower dose compared to an SSTR2 antagonist labelled with a beta emitting radionuclide or radioactive isotope in a tumor xenograft mice model or a SSTR agonist labelled with an alpha or beta emitting radionuclide or radioactive isotope in a tumor xenograft mice model. Furthermore, the inventors could show favorable stability of alpha radionuclide labelled SSTR antagonists and excellent delivery to the target organ, i.e. the tumor or tumor cell(s), respectively compared to a SSTR2 antagonist labelled with a beta emitting radioactive moiety instead of the alpha emitting radioactive moiety.

[0065] Somatostatin Receptor Antagonists

[0066] A first aspect of the invention relates to a somatostatin receptor antagonist (SSTR antagonist). The SSTR antagonist binds to an SSTR receptor, but is not internalized into the cell and thus, is able to bind to multiple receptor binding sites. Consequently, this leads to a higher biological activity compared to a SSTR agonist. Compound 1 as described throughout the application comprises the peptide of Cpa-cyclo[D-Cys- Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]-D-Tyr-NH2, and a complexing moiety comprising of 2, 2', 2", 2'"- (1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetrayl)tetraacetic acid.

[0067] In one embodiment, the SSTR antagonist comprises a peptide comprising of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]-D-Tyr-NH2, and a complexing moiety comprising of 2, 2', 2", 2'"- (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety comprising a radioactive isotope that emits alpha particles. In one embodiment the SSTR antagonist of the first aspect of the invention comprises a peptide consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]- D-Tyr-NFU; and a complexing moiety comprising of 2,2',2'',2'"-(l,4,7,10-tetraazacyclododecane-l,4,7,10- tetrayl)tetraacetic acid; and a radioactive moiety comprising a radioactive isotope that emits alpha particles.

[0068] In one embodiment the SSTR antagonist comprises a peptide comprising of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]-D-Tyr-NH2; and a complexing moiety consisting of 2, 2', 2", 2'"- (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety comprising a radioactive isotope that emits alpha particles.

[0069] In one embodiment the SSTR antagonist comprises a peptide consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]-D-Tyr-NH2; and a complexing moiety consisting of 2, 2', 2", 2'"- (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety comprising a radioactive isotope that emits alpha particles.

[0070] In another embodiment of the first aspect of the invention the SSTR antagonist binds to somatostatin receptors. In a preferred embodiment the SSTR antagonist binds to SSTR2. In another preferred embodiment the SSTR antagonist selectively binds to SSTR2. It is preferred that if the SSTR selectively binds to SSTR2 that it also binds with high affinity. The “binding affinity” or “affinity” in the context of the present invention may be expressed for example in half-maximal effective concentration (EC50) or the equilibrium dissociation constant (KD). “Selectively binding” in the context of the present invention means that the SSTR antagonist binds to the target receptor, e.g. SSTR2 and - if at all - exerts weak or no binding to other SSTRs, such as SSTR1, SSTR3, SSTR4 and / or SSTR5. In other words, the SSTR antagonist selectively binding exhibits a KD or an EC50 which is about one hundredth or less compared to the other SSTR receptors, such as SSTR1, SSTR3, SSTR4 and SSTR5. Preferably, the SSTR2 antagonist is at least about 200 times more selective for SSTR2 than for any other SSTR receptor, more preferably at least about 500 times more selective.

[0071] In one embodiment of the first aspect of the present invention, the SSTR antagonist comprises a radioactive moiety comprising a radioactive isotope that emits alpha particles. Alpha particles are positively charged and have particle energy ranging from 5 to 9 MeV and a very short range of 40-100 pm. The range of the particle is thus, considered to be equivalent to the thickness of 1-3 cell widths. Due to the short therapeutic range, intracellular accumulation of the alpha particle is preferred to ensure a higher chance of target damage to the cell’s nucleus. Linear energy transfer (LET) is a term used in ionizing radiation to measure the ionizing density and hence, molecular damage of a particle per unit length. LET is very high for alpha particles (80-100 keV / pm; Navalkissoor et al , Targeted Alpha Particle Therapy for Neuroendocrine Tumors: The Next Generation of Peptide Receptor Radionuclide Therapy; Neuroendocrinology; 108:256-264, October 23, 2018). High-LET radiation results in more severe and less reparable cell damage than low-LET radiation: alpha particles create a high ionization density, which causes a high number of double-strand breaks as compared with beta particles, which have a lower ionization density. The greater extent of double-strand breaks makes DNA repair more difficult and thus less effective. High-LET radiation also has indirect effects on tumors to make cell damage less likely to be repaired. These include an increased cell division time, being relatively independent of cell cycle phase, and reduced enzymatic repair mechanisms. Therefore, it is particularly preferred that the alpha particles used have a shorter half-life compared to beta particles and thus, exert reduced toxicity while maintaining efficacy in inhibiting or delay tumor size. In a preferred embodiment, the radioactive moiety comprises a radioactive isotope of lead (Pb) or Actinium (Ac). In another preferred embodiment, the radioactive moiety comprises a radioactive isotope, which is212Pb or225Ac. In another preferred embodiment, the radioactive moiety comprises the radioactive isotope which212Pb. In another preferred embodiment, the radioactive moiety comprises the radioactive isotope225Ac.

[0072] In another embodiment of the first aspect of the present invention the SSTR antagonist comprises a complexing moiety comprising or consisting of 2,2',2'',2'"-(l,4,7,10-tefraazacyclododecane-l,4,7,10- tetrayl)tefraacetic acid, wherein the complexing moiety is attached to the Cpa of the peptide of step (i). Preferably, the complexing moiety is covalently attached to the Cpa of the peptide of step (i). In another embodiment of the first aspect of the present invention, the SSTR antagonist comprises a certain amount of radioactivity. Preferably, said amount of radioactivity is initially used per mol of peptide comprised in the SSTR antagonist. Even more preferably, said amount of radioactivity is initially used per mol of SSTR antagonist. Most preferably, the amount of radioactivity is used per mol of SSTR2 antagonist. In a further preferred embodiment, the amount of radioactivity is up to 9500 GBq / mmol. More preferably, the amount of radioactivity is up to 500 GBq / mmol. In another preferred embodiment the SSTR antagonist comprises a certain specific activity which refers to the activity per unit mass of a radionuclide which is either described as Bq / kg or Bq / mol as defined herein above. In one embodiment, the specific activity of the SSTR antagonist ranges from 100-2000 GBq / mmol. In another embodiment the specific activity ranges from 100-2000 GBq / mmol if the SSTR antagonist is labelled with212Pb radioisotope. In another embodiment the specific activity ranges from 1-30 GBq / mmol. In another embodiment the specific activity ranges from 1-30 GBq / mmol if the SSTR antagonist is labelled with the225Ac radioisotope.

[0073] In another embodiment of the first aspect of the present invention the SSTR antagonist comprises a peptide consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]- D-Tyr-Ntk, a complexing moiety consisting of 2,2',2'',2'"-(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety consisting of the radioactive isotope212Pb. In a preferred embodiment, the SSTR antagonist is an SSTR2 antagonist according to the formula I:

[0074] In another embodiment, the SSTR antagonist comprises a peptide consisting of Cpa-cyclo[D-Cys- Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]-D-Tyr-NH2, a complexing moiety consisting of 2, 2', 2", 2'"- (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety consisting of the radioactive isotope225Ac. In a preferred embodiment, the SSTR antagonist is an SSTR2 antagonist according to the formula II:

[0075] Pharmaceutical compositions

[0076] A second aspect of the invention relates to a pharmaceutical composition comprising the SSTR of the first aspect of the invention and a pharmaceutically acceptable carrier.

[0077] The term "pharmaceutical composition" or "therapeutic composition" refers in the context of the present invention to a compound or composition formulated to be suitable for administration to a patient and capable of inducing a desired therapeutic effect, for example to treat neoplasia or persisting tumors, such as for example NETs, when properly administered to a subject. Such therapeutic or pharmaceutical compositions may comprise a therapeutically effective amount of a SSTR antagonist of the invention or a SSTR antagonist further comprising a therapeutic agent, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration. The somatostatin receptor antagonist of the present invention will usually be supplied as part of a sterile, pharmaceutical composition, which will normally include a pharmaceutically acceptable carrier. The pharmaceutical compositions of the invention are may be formulated for parenteral application and include parenteral vehicles. Parenteral administration comprises intravenous, intramuscular, subcutaneous and intradermal administration routes. Examples of Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Pharmaceutical compositions comprising a somatostatin receptor antagonist of the present invention are prepared by mixing a somatostatin receptor antagonist having the desired degree of purity with optional physiologically acceptable carriers, other excipients, stabilizers, surfactants, buffers and / or tonicity agents. Acceptable carriers, other excipients and / or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid, glutathione, cysteine, methionine and citric acid; preservatives (such as ethanol, benzyl alcohol, phenol, m-cresol, p-chlor- m-cresol, methyl or propyl parabens, benzalkonium chloride, or combinations thereof); amino acids such as arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline and combinations thereof; monosaccharides, disaccharides and other carbohydrates; low molecular weight polypeptides; proteins, such as gelatin or serum albumin; chelating agents such as EDTA; sugars such as trehalose, sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, glucosamine, N- methylglucosamine, galactosamine, and neuraminic acid; and / or non-ionic surfactants such as Tween, Brij Pluronics, Triton-X, or polyethylene glycol (PEG). The pharmaceutical composition can be in a liquid form, a lyophilized form or a liquid form reconstituted from a lyophilized form, wherein the lyophilized preparation is to be reconstituted with a sterile solution prior to administration. The standard procedure for reconstituting a lyophilized composition is to add back a volume of pure water (typically equivalent to the volume removed during lyophilization).

[0078] The term "pharmaceutically" or "pharmaceutically acceptable" refers in the context of the present invention to molecular entities and compositions that do not lead to an adverse, allergic or other unwanted reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0079] The term “pharmaceutically-acceptable carrier” in the context of the present invention may also be referred to as “pharmaceutically acceptable diluent” or “pharmaceutically acceptable vehicle“ and may include solvents, bulking agents, stabilizing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are physiologically compatible.

[0080] The term “therapeutic agent” refers in the context of the present invention to an agent that has a therapeutic effect.

[0081] The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and gender of the patient, the desired duration of the treatment etc. The pharmaceutical composition in the context of this invention may be in any suitable form (depending upon the desired method of administering it to a patient). It may be provided in a unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms. Empirical considerations, such as the biological half-life, generally will contribute to the determination of the dosage. Frequency of administration may be determined and adjusted over the course of therapy and is based on reducing the number of cancer cells, maintaining the reduction of cancer cells, reducing the proliferation of cancer cells, or killing the cancer cells.

[0082] In particular, the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions, or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

[0083] To prepare pharmaceutical compositions, an effective amount of the SSTR antagonist of the invention may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[0084] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0085] Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0086] A SSTR antagonist of the invention can be formulated into a composition in a neutral or salt form using pharmaceutically acceptable salts.

[0087] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0088] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. Therapeutic methods and uses

[0089] A third aspect of the invention relates to the SSTR antagonist of the first aspect of the invention and / or the pharmaceutical composition of the second aspect of the invention for use in medicine. The invention also relates to the use of the SSTR antagonist of the first aspect of the invention and / or the pharmaceutical composition of the second aspect of the invention in the manufacture of a medicament.

[0090] A fourth aspect of the invention relates to the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention for use in the diagnosis and / or treatment of a cancer. Accordingly, the SSTR antagonist of the first aspect of the present invention, in particular the SSTR2 antagonist comprising the radioactive isotope212Pb or225Ac or the pharmaceutical composition of the second aspect of the invention, may be used to treat cancer. The SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention may be used for therapeutic purposes in humans and / or non-human mammalian animals, preferably in humans.

[0091] In one embodiment, the SSTR antagonist of the first aspect of the invention can bind to SSTR2 expressed on tumor cells and reduce the growth of and / or kill the tumor cells expressing SSTR2. It is understood that the SSTR antagonist of the first aspect of the invention is administered at a concentration that promotes binding to its SSTR2 receptor at physiological (e.g. in vivo) conditions.

[0092] In one embodiment, the SSTR antagonist of the first aspect of the invention can be used therapy of tumors directed against tumor cells of neuroendocrine tumors (NETs), such as small cell lung cancer, preferably small cell neuroendocrine carcinoma, large neuroendocrine carcinoma, typical carcinoid or atypical carcinoid. In another embodiment the cancer is Merkel-cell carcinoma. In another embodiment, the SSTR antagonist of the first aspect of the invention can bind to and reduce the growth of and / or kill tumor cells.

[0093] In one embodiment, the SSTR antagonist of the first aspect of the invention can be used therapy of tumors such as Merkel-cell carcinoma. In another embodiment, the SSTR antagonist of the first aspect of the invention can bind to and reduce the growth of and / or kill tumor cells.

[0094] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 4 MBq and 10 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 5 MBq and 10 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 6 MBq and 10 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 7 MBq and 10 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 8 MBq and 10 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 9 MBq and 10 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 5 MBq and 9 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 6 MBq and 8 MBq. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 6 Mbq.

[0095] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 200 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 190 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 180 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 170 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 160 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 150 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 140 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 130 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 120 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 110 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 100 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 90 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 80 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 70 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 60 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 50 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 30 MBq and 40 MBq.

[0096] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 40 MBq and 180 MBq. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 MBq and 170 MBq. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with212Pb is administered to a subject in need thereof at a dose of 180 MBq.

[0097] In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 6 MBq and 8 MBq, every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 6 MBq and 8 MBq, every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of 7 MBq, every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of 8 MBq, every 6 to 8 weeks.

[0098] In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 6 MBq and 8 MBq, 3 doses every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 7 MBq, 3 doses every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 8 MBq, 3 doses every 6 to 8 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 6 MBq, 3 doses every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 6 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 5 MBq every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 4 MBq every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 3 MBq every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 2 MBq every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 1 MBq every 3 to 6 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 6 MBq every 3 to 6 weeks.

[0099] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 6 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 5 MBq 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 4 MBq 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 3 MBq 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 2 MBq 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 1 MBq 3 doses every 3 to 6 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 6 MBq 3 doses every 3 to 6 weeks.

[0100] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 6 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 5 MBq 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 4 MBq 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 3 MBq 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 2 MBq 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with225Ac is administered to a subject in need thereof at a dose of between 0.5 MBq and 1 MBq 4 doses every 3 to 6 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with225Ac is administered to a subject in need thereof at a dose of 6 MBq 4 doses every 3 to 6 weeks.

[0101] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 180 MBq, every 6 to 8 weeks.In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 170 MBq doses every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 160 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 150 MBq, every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 140 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 130 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 120 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 110 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 100 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 90 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 80 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 70 MBq every 6 to 8 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 60 MBq every 6 to 8 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with212Pb is administered to a subject in need thereof at a dose of 180 MBq every 6 to 8 weeks.

[0102] In a preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 180 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 170 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 160 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 150 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 140 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 130 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 120 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 110 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 100 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 90 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 80 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 70 MBq, 3 doses every 6 to 8 weeks. In another preferred embodiment the SSTR antagonist of the first aspect of the invention labelled with212Pb is administered to a subject in need thereof at a dose of between 50 and 60 MBq, 3 doses every 6 to 8 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with212Pb is administered to a subject in need thereof at a dose of 180 MBq 3 doses every 6 to 8 weeks.

[0103] In one embodiment SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 100 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 110 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 120 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 130 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 140 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 150 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 160 and 180 MBq, every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 170 and 180 MBq, every 3 to 6 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of 180 MBq, every 3 to 6 weeks.

[0104] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 100 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 110 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 120 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 130 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 140 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 150 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 160 and 180 MBq, 3 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 170 and 180 MBq, 3 doses every 3 to 6 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with212Pb is administered to a subject in need thereof at a dose of 180 MBq, 3 doses every 3 to 6 weeks.

[0105] In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 100 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 110 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 120 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 130 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 140 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 150 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 160 and 180 MBq, 4 doses every 3 to 6 weeks. In one embodiment the SSTR antagonist of the first aspect of the invention, preferably labelled with212Pb is administered to a subject in need thereof at a dose of between 170 and 180 MBq, 4 doses every 3 to 6 weeks. In a preferred embodiment the SSTR antagonist of the first aspect of the invention, labelled with212Pb is administered to a subject in need thereof at a dose of 180 MBq, 4 doses every 3 to 6 weeks.

[0106] The fourth aspect of the present invention also relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention as defined herein above.

[0107] A preferred embodiment relates to a method of treating a subject who has a cancer comprising administering to said subject the SSTR antagonist of the first aspect of the invention or the pharmaceutical compositions of the second aspect of the invention.

[0108] The fourth aspect of the invention further relates to the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention for use in the diagnosis and / or treatment of cancer. One embodiment relates to the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention for use in the manufacture of a medicament for the diagnosis and / or treatment of cancer.

[0109] The term “subject” or “individual” in the context of this invention is used interchangeably and may be, for example, a human or a non-human mammal, preferably, a human.

[0110] The term "treating" or "treatment" refers in the context of this invention to a therapeutic use (i.e. on a subject having a given disease) and means reversing, alleviating, and inhibiting the progress of one or more symptoms of such disorder or condition. Therefore, treatment does not only refer to a treatment that leads to a complete cure of the disease, but also to treatments that slow down the progression of the disease and / or prolong the survival of the subject. The term “in need of treatment” refers to a subject having already the disorder, e.g. cancer. In one embodiment, the subject is thus, a patient.

[0111] In the context of the present invention, a cancer is considered to be “SSTR2 positive”, if the cancer or tumor cells, respectively, express said SSTR2 receptors on their cell surface. In one embodiment, the cancer is readily assayed (i.e. diagnosed) for instance by using an SSTR antagonist of the first aspect of the invention. Methods to identify an SSTR2 expressing cancer using an SSTR antagonist by in vivo imaging, for example, are known to the skilled person in the art.

[0112] In one embodiment, the cancer that is “SSTR2 positive”, i.e. that presents the target receptor, is selected from the group consisting of neuroendocrine tumors, such as small cell lung cancer (SCLC), small cell neuroendocrine carcinoma, large neuroendocrine carcinoma, typical carcinoid or atypical carcinoid. In another embodiment the cancer is Merkel-cell carcinoma. An appropriate therapeutic approach is chosen according to the particular type of cancer, and other factors such as the general condition of the patient, as is recognized in the pertinent field. The SSTR antagonist of the present invention can be used by itself or can be added to a therapy regimen using other anti-cancer agents typically used in treating a cancer patient.

[0113] In one embodiment, the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention can be administered concurrently with, before, or after a variety of drugs and treatments widely employed in cancer treatment such as, for example, chemotherapeutic agents, non-chemotherapeutic, anti-neoplastic agents, and / or radiation, preferably chemotherapeutic agents.

[0114] The term “diagnosis” refers in the context of this invention to a medical diagnosis and refers to determining which disease or condition explains a person's symptoms and signs.

[0115] In one embodiment, efficacy of the treatment with SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention is assayed in vivo, for instance in a mouse model of cancer and by measuring, for example, changes in tumor volume between treated and control groups.

[0116] The SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention can be administered by any feasible method.

[0117] Kits

[0118] A fifth aspect of the invention relates to kit comprising the SSTR antagonist of the first aspect of the invention for the diagnosis of cancer.

[0119] In one embodiment, the kit comprises the SSTR antagonist labelled with the radioactive moiety. Preferably, the radioactive moiety comprises the radioactive isotope212Pb or225Ac. It is preferred that the labelled SSTR antagonist comprises a stabilizing agent, for example, in form of a stabilizing buffer. An example of an ingredient comprised in a stabilizing buffer is ascorbic acid or salts thereof. In another embodiment, the kit comprises the SSTR antagonist unlabeled and comprises the radioactive moiety in a suitable container for labeling. The kit preferably comprises the stabilizing buffer in order to provide stabilization of the solution once the SSTR antagonist is labelled with the radioactive moiety. In one embodiment the stabilizing buffer comprises ascorbic acid or salts thereof. Preferably, the radioactive moiety comprises the radioactive isotope212Pb or225Ac. In another embodiment, the kit comprises the SSTR antagonist unlabeled and capable of being subsequently labelled with the radioactive moiety. The kit preferably comprises the stabilizing buffer in order to provide stabilization of the solution once the SSTR antagonist is labelled with the radioactive moiety. In one embodiment the stabilizing buffer comprises ascorbic acid or salts thereof. Preferably, the radioactive moiety comprises the radioactive isotope212Pb or225Ac. In one embodiment, the kit further comprises packaging material, and optionally a label or packaging insert contained within said packaging material indicating that said SSTR antagonist or pharmaceutical composition thereof is effective in treating cancer or is suitable for use in the treatment of cancer.

[0120] In one embodiment, the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition of the second aspect of the invention is contained in a single and / or multi-chambered pre-filled syringe / s (e.g., liquid syringes and lyosyringes) ready to be labelled with the radioactive moiety, preferably comprising the radioactive isotope212Pb or225Ac.

[0121] In one embodiment, the invention encompasses kits for producing a single -dose administration unit. In one embodiment, the SSTR antagonist of the kit of the invention is a dried SSTR antagonist of the first aspect of the invention contained in a first container. The kit further contains a second container with an aqueous formulation, preferably a buffer formulation. The kit further comprises a third contained comprising the radioactive moiety, preferably comprising the radioactive isotope of212Pb or225Ac. The kit further comprises a fourth contained comprising a stabilization buffer, preferably comprising ascorbic acid or salts thereof.

[0122] Accordingly, in one embodiment, the kit comprises a) a first container comprising at least one dried SSTR antagonist as defined herein above b) a second container comprising a conjugation buffer; c) a third container comprising the radioactive moiety, preferably comprising the radioactive isotope 212Pb; d) a fourth container comprising a stabilizing buffer; e) optionally packaging material, and f) optionally a label or packaging insert contained within said packaging material indicating that said SSTR antagonist is effective in treating cancer or for use in the treatment of cancer.

[0123] In another embodiment, the kit comprises a) a first container comprising at least one dried SSTR antagonist as defined herein above b) a second container comprising a conjugation buffer; c) a third container comprising the radioactive moiety, preferably comprising the radioactive isotope 225Ac; d) a fourth container comprising a stabilizing buffer; e) optionally packaging material, and f) optionally a label or packaging insert contained within said packaging material indicating that said SSTR antagonist is effective in treating cancer or for use in the treatment of cancer.

[0124] The aqueous formulation is typically an aqueous solution comprising pharmaceutically acceptable carriers as defined herein above.

[0125] A sixth aspect of the invention relates to a method of labeling the SSTR antagonist of the first aspect of the invention. In one embodiment, the method for labeling the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition the second aspect of the invention comprises steps of labeling the SSTR antagonist with the radioactive moiety wherein the SSTR antagonist comprises the peptide and a complexing moiety; and the radioactive moiety separately. In another embodiment, the method for labeling the SSTR antagonist of the first aspect of the invention or the pharmaceutical composition the second aspect of the invention comprises steps of labeling the SSTR antagonist with the radioactive moiety wherein the SSTR antagonist comprises the peptide, the complexing moiety; and the radioactive moiety separately. Preferably, the labeling comprises a heating step wherein the SSTR antagonist, preferably in solution, and the radioactive moiety is heated at a temperature between about 75°C and about 95°C. In a preferred embodiment the radioactive moiety comprises the radioactive isotope212Pb. In another preferred embodiment, the radioactive moiety comprises the radioactive isotope225Ac.

[0126] The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.

[0127] Examples

[0128] Example 1 : Peptide and chelator synthesis

[0129] Compound 1 was synthesised by Bachem AG (batch no: 4083738) and the reagent used for the preparation of the reaction buffer (acetate solution; cat. no. N13120, for212Pb) was purchased from IPSEN Pharma Biotech and for the formulation (ascorbate, diethylenetriamine-N,N,N',N,N-pentaacetic acid (DTPA) solution, cat. no. N16106) was purchased from Fresenius Kabi. Tris buffer was prepared by using Tris hydrochloride (Sigma Aldrich PHG0002) and Trometamol (Merck 1.08386). Isotopes were supplied by specific manufacturers: the212Pb solution was supplied by Advancell and the225Ac solution was supplied by ITM, respectively. Example 2: Radiolabelling with212Pb

[0130] Compound 1 was dissolved in reaction buffer, e.g. at a concentration of 1 mg / mL and added to a solution of212Pb (in HC1). The resulting mixture was heated at temperatures between 75-95°C for 20-45 min, and then allowed to cool to room temperature. The specific activity during radiolabeling ranged between 100- 2000 Gbq / mmol. The reaction mixture was added to a formulation buffer consisting of sodium ascorbate to stabilize the final dose and to guarantee the quality and safety of the dose. The radiochemical purity was >90 % over 6 h and no radiolytic degradation was observed by high performance liquid chromatography (HPLC).

[0131] Example 3: Biodistribution212Pb-Compound 1

[0132] The 1 h, 4 h, 24 h biodistribution study of212Pb-Compound 1 was performed with xenograft Balb / c nude mice with a NCI-H69 model for expressing SST2. NCI-H69 cells (cells from the human small cell lung cancer cell line NCI-H69) were grown in DMEM media with 10% FBS. Upon 80% confluency, cells were collected and dissolved in 1: 1 of PBS and matrigel for injection. 50 pl of cell solution with 5 x 106cells were injected in right flank (Balb / C nude female mice 6-8 weeks). 15 mice were injected with 1.3 -1.5 MBq of212Pb-Compound 1 (approximately 50 pL injection). At 1 hour, 4 hours and 24 hours post injection, 5 mice were sacrificed by cervical dislocation and a blood sample immediately removed by cardiac puncture. Mice were dissected and organs were washed in PBS to remove blood and added to pre-weighed gamma counter tubes for further analysis. A high tumor uptake was observed at t = 1 h (>5% ID / g; percent injected dose per gram of tissue) which persisted over the 24 h (>2% ID / g). A moderate uptake within the radiosensitive organ (kidney) was observed, with a tumor to kidney ratio staying constant at 0.4 over the entire experimental period.

[0133] Example 4: Biodistribution of225Ac-Compound 1

[0134] The 4 h, 24 h, 96 h biodistribution study of225Ac-Compound 1 was performed with xenograft Balb / c nude mice engrafted withNCI-H69 tumor cells expressing SST2. NCI-H69 cells (cells from the human small cell lung cancer cell line NCI-H69) were grown in RPMI1640 media with 10% FBS. Upon 80% confluency, cells were collected and dissolved in 1 :1 of PBS and matrigel for injection. 100 pl of cell solution with 5xl06cells were injected in the right flank of Balb / C nude female mice at an age of ~7 weeks. 12 mice were injected with 90 kBq of225Ac-Compound 1 in 100 pL. At 4 hours, 24 hours and 96 hours post injection, 4 mice were sacrificed by overdose of a mixture of ketamine and xylazine followed by exsanguination via intracardiac puncture. Mice were dissected and organs were rinsed in 0.9% NaCl to eliminate contaminating blood and blotted before being weighed and subsequently transferred into scintillation vials. Tissues were dissolved using Solvable as tissue solubilizer. Each solution was decolorized by adding 30% H2O2 before scintillation counting. Pico-Fluor Plus was used as liquid scintillation counting cocktail. The radioactivity was measured using a Hidex 300 SL calibrated for225Ac radionuclide. A high tumor uptake was observed at t = 4 h (>10% ID / g; percent injected dose per gram of tissue) with a low decline over 96 h (>4.5% ID / g). A moderate uptake within the radiosensitive organ (kidney) was observed which rapidly decreased over 96h leading to an increase of the tumor-to-kidney ratio of225Ac-Compound 1 from 0.75 at 4h to 1.38 at 96h.

[0135] Example 5: Dose efficacy study212Pb- Compound 1

[0136] A single dose study with tumor bearing mice with an NCI-H69 model for expressing SST2 was performed. 25 Balb / C nude female mice aged 6-8 weeks were injected with 5 x 106NCI-H69 cells in the right flank three weeks prior to treatment. Mice were observed daily 14 days prior to and for 60 days following treatment. Mice were treated when tumors reach approximately 250 mm3and were euthanized when either tumors reach 1000 mm3or mice reach an euthanize status on the health score sheet.

[0137] The mice were distributed into five groups for different treatments:

[0138] Table 1 : Different treatment groups.

[0139] There was a control group with only Compound 1 (without being labelled with any radioactivity) injection, and the tumor growth progressed in the animals without any impact. The comparator177Lu-Compound 1 showed a response and delay of the tumor growth but no reduction of the tumor size at an amount of 20 MBq radioactivity injected. This corresponds to a human equivalent dose of 3.7 GBq typically used in clinical trials. The groups for212Pb-Compound 1 showed all delay of growth of the tumor size compared to the group only receiving Compound 1 without any radioactivity even at the lowest level (0.35 MBq). The mid and high dose (0.75 MBq and 1.6 MBq) showed a comparable tumor reduction at 1 / 12 or less of the radioactivity used compared to177Lu-Compound 1 (see Figure 3A).

[0140] A single dose study with tumor bearing mice with an NCI-H69 model for expressing SST2 was performed. 25 Balb / C nude female mice aged 6-8 weeks were injected with 5 x 106NCI-H69 cells in the right flank three weeks prior to treatment. Mice were observed daily 14 days prior to and for 60 days following treatment. Mice were treated when tumors reach approximately 250 mm3and were euthanized when either tumors reach 1000 mm3or mice reach an euthanize status on the health score sheet.

[0141] The mice were distributed into five groups for different treatments:

[0142] Table 2: Different treatment groups.

[0143] There was a control group with only Compound 1 (without being labelled with any radioactivity) injection, and the tumor growth progressed in the animals without any impact. The comparator177Lu-Compound 1 showed a response and delay of the tumor growth but no reduction of the tumor size at an amount of 21.5 MBq radioactivity injected. This corresponds to a human equivalent dose of ~3.7 GBq typically used in clinical trials. The groups for212Pb-Compound 1 showed all delay of growth of the tumor size compared to the group only receiving Compound 1 without any radioactivity even at the lowest level (113 kBq). The mid and high dose (236 kBq and 503 kBq) showed a comparable tumor reduction at 1 / 42 or less of the radioactivity used compared to177Lu-Compound 1 (see Figure 3B).The growth rate of NCI-H69 tumors was as expected. Control (Compound 1) animals reached the ethical limit in <28 days. Treatment with ’^Lu- Compound 1 (21.5 MBq) showed visible effects ~3 days after treatment and controlled tumor growth for up to 20 days.212Pb -Compound 1 treatment effects were visible ~3 days after treatment and low dose (113 kBq) treatment led to controlled tumor growth for 10 days. Medium-dose (236 kBq) treatment induced a slight decrease in tumor volume (~5% at day 10) and led to controlled tumor growth for 14 days. High-dose (503 kBq) reduced tumor size by 15% 14 days after treatment and led to controlled tumor growth for up to 20 days.212Pb-Compound 1 (503 kBq) treatment resulted in longer median survival compared to ’^Lu- Compound 1 (21.5 MBq). No significant change in animal weight during the experiment was observed. Median survival rates were observed as follows:

[0144] Table 3: Different treatment groups and median survival in days. In a single dose treatment, 503 kBq212Pb-Compound 1 showed higher potency compared to 21.5 MBq177Lu-Compound 1 regarding tumor growth inhibition and prolongation of survival (see Figure 3B and Figure 3C).

[0145] Example 6: Radio labelling with225Ac

[0146] Radiolabelling was initially performed as described in Example 3 but with reaction buffer comprising 0.25 M TRIS buffer at pH 8. Subsequently, the radiolabelling was performed by dissolving Compound 1 in the reaction buffer at a concentration of 1 mg / mL and added to a solution of225Ac (in HC1). The resulting mixture was heated at temperatures between 75-95°C for 20 - 45 min, and then allowed to cool to room temperature. The specific activity during radiolabeling ranged between 1-10 GBq / mmol. The reaction mixture was added to a formulation buffer consisting of sodium ascorbate to stabilize the final dose.

[0147] Example 7: Single- and multi-dose efficacy study of225Ac- Compound 1

[0148] A single- and multi-dose efficacy study in SST2-positive NCI-H69 tumor-bearing mice was conducted. 60 Balb / C nude female mice aged 6-8 weeks were injected with 5 x IO6NCI-H69 cells in the right flank and treatment started when tumors reached a mean tumor volume of 140 mm3. Animals were euthanized when either tumor volumes of more than 1000 mm3were observed or other ethical criteria were reached.

[0149] Table 4: Different treatment groups. QW once weekly; Q2W once every 2 weeks

[0150] Tumors in the control group receiving unlabelled Compound 1 progressed rapidly and animals reached the ethical limits within 21-55 days (median survival 34 days; see Figure 6A, 6B and 6C). In contrast, all treatment groups using radiolabelled Compound 1 showed substantial tumor growth suppression starting on d5 and median survival was not reached in a follow up period of 84-96 days (see table 5). Surprisingly, the single dose treatments (QW) of 90 kBq and only 30 kBq of225Ac-Compound 1 were as effective as ’^Lu- Compound 1 given 3x every 2 weeks with regards to initial induction of tumor regression and even outperformed177Lu-Compound 1 in the rate of the complete remissions that were observed (table 5).

[0151] Table 5: Median survival and complete remissions in different treatment groups.

[0152] Example 8: Single- and multi-dose efficacy study of212Pb- Compound 1

[0153] A single- and multi-dose efficacy study in SST2-positive NCI-H69 tumor-bearing mice was conducted. 55 Balb / C nude female mice aged 6-8 weeks were injected with 5 x 106NCI-H69 cells in the right flank and treatment started when tumors reached a mean tumor volume of 260 mm3. Animals were euthanized when either tumor volumes of more than 1000 mm3were observed or other ethical criteria were reached.

[0154] Table 6: Different treatment groups. QW once weekly; Q2W once every 2 weeks

[0155] Tumors in the control group receiving unlabelled Compound 1 progressed rapidly and animals reached the ethical limits within 16-53 days (median survival 30 days, see figure 7A, 7B, 7C). In contrast, all treatment groups using radiolabelled Compound 1 showed substantial tumor growth reduction. Multiple doses of177Lu-Compound 1 were more effective than different regimens and doses of212Pb-Compound 1. We observed recurrence of tumors in all212Pb-Compound 1-treated groups, but not after177Lu-Compound 1

[0156] Q2W x 3 (100% complete remissions, see table 7).

[0157] Example 9: Single-dose efficacy study of225Ac- Compound 1

[0158] A single-dose efficacy study in SST2-positive NCI-H69 tumor-bearing mice was conducted. Balb / c nude female mice aged 6-8 weeks were injected with 5 x 106NCI-H69 cells in the flank and treatment started when tumors reached a mean tumor volume of 160 mm3.

[0159] Table 8: Different treatment groups. QW once weekly (equals single dose) Tumors in the vehicle control group progressed during the study and up to day 9 after treatment, the dose of 3.33 kBq 225Ac-Compound 1 showed no significant effect on tumor growth (see Figure 8). In contrast, mice treated with a dose as low as 10 kBq and 30 kBq of 225 Ac-SSO 110 showed tumor growth suppression starting on day 4 after treatment.

Claims

Claims1 . A somatostatin receptor (SSTR) antagonist comprising(i) a peptide comprising or consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys- Thr-Cys]-D-Tyr-NH2 (SEQ ID NO: 1), wherein(a) Cpa is chlorophenylalanine;(b) Aph (Hor) is [(2,6-dioxo-hexahydro-pyrimidine-4-carbonyl)-amino]-phenylalanine;(c) Aph (Cbm) is 4-amino-phenylcarbamoyl (4-ureido-phenylalanine);(ii) a complexing moiety comprising or consisting of 2,2',2'',2'"-(l,4,7,10- tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and(iii) a radioactive moiety comprising a radioactive isotope that emits alpha particles.

2. The SSTR antagonist according to claim 1, wherein the SSTR antagonist binds to somatostatin receptor 2 (SSTR2).

3. The SSTR antagonist according to any one of claim 1 or 2, wherein the radioactive isotope comprised in the radioactive moiety is212Pb or225Ac.

4. The SSTR antagonist according to any one of claims 1 to 3, wherein the complexing moiety is attached to the Cpa of the peptide of step (i).

5. The SSTR antagonist according to claim 4, wherein the complexing moiety is covalently attached to the Cpa of the peptide of step (i).

6. The SSTR antagonist according to any one of claims 1 to 5, wherein the SSTR antagonist comprises a certain amount of radioactivity, preferably wherein the amount of radioactivity is up to about 9500 GBq / mmol.

7. The SSTR antagonist according to any one of claims 1 to 6, comprising(i) a peptide consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]- D-Tyr- NH2(SEQ ID NO: 1) , wherein(a) Cpa is chlorophenylalanine;(b) Aph (Hor) is [(2,6-dioxo-hexahydro-pyrimidine-4-carbonyl)-amino]-phenylalanine;(c) Aph (Cbm) is 4-amino-phenylcarbamoyl (4-ureido-phenylalanine);(ii) a complexing moiety consisting of 2,2',2'',2'"-(l,4,7,10-tetraazacyclododecane-l,4,7,10- tetrayl)tetraacetic acid; and(iii) a radioactive moiety comprising the radioactive isotope212Pb.The SSTR antagonist according to claim 7 having Formula I:The SSTR antagonist according to any one of claims 1 to 6, comprising(i) a peptide consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys-Thr-Cys]-D-Tyr- NH2(SEQ ID NO: 1), wherein(a) Cpa is chlorophenylalanine;(b) Aph (Hor) is [(2,6-dioxo-hexahydro-pyrimidine-4-carbonyl)-amino]-phenylalanine;(c) Aph (Cbm) is 4-amino-phenylcarbamoyl (4-ureido-phenylalanine);(ii) a complexing moiety consisting of 2,2',2'',2"'-(l,4,7,10-tetraazacyclododecane-l,4,7,10- tetrayl)tetraacetic acid; and(iii) a radioactive moiety comprising the radioactive isotope225Ac. The SSTR antagonist according to claim 9 having Formula II:A pharmaceutical composition comprising the SSTR antagonist according to any one of claims 1 to 10, a pharmaceutically acceptable carrier, diluent, stabilizer, and / or excipient. The SSTR antagonist according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 for use as a medicament. The SSTR antagonist according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 for use in diagnosing and / or treating cancer, preferably wherein(i) the cancer expresses somatostatin receptor 2 (SSTR2); or(ii) the cancer is a neuroendocrine tumor (NET), more preferably wherein the neuroendocrine tumor is small cell lung cancer, preferably small cell neuroendocrine carcinoma, large neuroendocrine carcinoma, typical carcinoid or atypical carcinoid. A kit comprising an SSTR antagonist or a pharmaceutical composition comprising said SSTR antagonist for the diagnosis of cancer, wherein the SSTR antagonist comprises(i) a peptide comprising or consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys- Thr-Cys]-D-Tyr-NH2 (SEQ ID NO: 1), wherein(a) Cpa is chlorophenylalanine;(b) Aph (Hor) is [(2,6-dioxo-hexahydro-pyrimidine-4-carbonyl)-amino]-phenylalanine;(c) Aph (Cbm) is 4-amino-phenylcarbamoyl (4-ureido-phenylalanine);(ii) a complexing moiety comprising or consisting of 2,2',2'',2'"-(l,4,7,10- tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and wherein(1) the SSTR antagonist is labelled with a radioactive moiety, preferably comprising a radioactive isotope that emits alpha particles, more preferably wherein the isotope is212Pb or225Ac; or(2) the SSTR antagonist is unlabeled and provided with the radioactive moiety in a suitable container for labeling; or(3) the SSTR antagonist is unlabeled and capable of being subsequently labelled with the radioactive moiety. A method for labeling an SSTR antagonist or a pharmaceutical composition comprising said SSTR antagonist, wherein the SSTR antagonist comprises(i) a peptide comprising or consisting of Cpa-cyclo[D-Cys-Aph (Hor)-D-Aph (Cbm)-Lys- Thr-Cys]-D-Tyr-NH2 (SEQ ID NO: 1), wherein(a) Cpa is chlorophenylalanine;(b) Aph (Hor) is [(2,6-dioxo-hexahydro-pyrimidine-4-carbonyl)-amino]-phenylalanine;(c) Aph (Cbm) is 4-amino-phenylcarbamoyl (4-ureido-phenylalanine);(ii) a complexing moiety comprising or consisting of 2,2',2'',2'"-(l,4,7,10- tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid; and wherein the SSTR antagonist is labelled with a radioactive moiety comprising a radioactive isotope that emits alpha particles, preferably wherein the isotope is212Pb or225Ac.

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