Alpha emitter labeled somatostatin receptor antagonists

Abstract

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

Description

[0001] The present invention relates to a somatostatin receptor antagonist. The present invention further provides a pharmaceutical composition comprising the somatostatin receptor antagonist. The present invention further relates to the somatostatin receptor antagonist or the pharmaceutical composition, which is used in medicine, particularly for the diagnosis and / or treatment of cancer. The present invention also relates to a kit comprising the somatostatin receptor antagonist or the pharmaceutical composition. The present invention also relates to a method for labeling the somatostatin receptor antagonist.

[0002] Radiopharmaceutical therapy (RPT) can be defined as the delivery of radioactive atoms to tumor-associated targets. Radionuclides with different emission characteristics (mainly β-particles or high-efficiency α-particles) are used to deliver radiation. In almost all cases, the radionuclides can be visualized by nuclear medicine imaging techniques to evaluate the targeting of the agent, which provides a substantial advantage over existing treatment methods and enables a precision medicine approach for the delivery of radiopharmaceutical therapy (RPT). Despite efforts to use new chemotherapeutic agents, small molecule inhibitors, biologics, immune checkpoint inhibitors, and various combinations of these, cancer patients with distant metastases still have a poor prognosis; therefore, new treatment methods are crucial (Sgourous G. et al. "Radiopharmaceutical therapy in Cancer: clinical advances and challenges, Nature Reviews, Vol. 19, July 29, 2020). The treatment of neuroendocrine tumors (NETs) largely relies on radioligands that target somatostatin receptor type 2 (SSTR2). 177 Lu]Lu-DOTA-TATE is a leading radiopharmaceutical that has received approval from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Various studies have shown that SSTR2 antagonists are more effective than SSTR2 agonists as they are able to bind to more receptor binding sites. As a result, several SSTR2 antagonist peptides have been labeled for diagnostic or therapeutic purposes. However, the rapid blood clearance and significant accumulation in non-target tissues of such SSTR2 radiopharmaceuticals pose limitations for higher tumor dose delivery and more effective 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). Therefore, there is a need in the art for new radiopharmaceutical therapies such as SSTR2 antagonists that effectively deliver radioactivity to the tumor site and subsequently induce radiation-induced killing of tumor cells.

[0003] The present invention provides somatostatin receptor antagonists. The SSTR antagonist is labeled with an α-emitting radionuclide and the antagonist binds to somatostatin receptor 2 and is thus a somatostatin receptor 2 antagonist. In particular, the α-emitting radionuclide contained in the SSTR2 antagonist is 212 Pb or 225 Ac.

[0004] The SSTR2 antagonists of the present invention in particular offer the following advantages over the prior art: (i) increased favorable efficacy and delayed and inhibited tumor growth compared to SSTR2 antagonists labeled with a β-emitting radioactive moiety rather than an α-emitting radioactive moiety; and / or (ii) favorable stability characteristics; and / or (iii) effective delivery to the source organ, meaning one or more tumors or tumor cells; and / or reduced exposure of the body to radioactivity due to a lower dose compared to SSTR2 antagonists labeled with a β-emitting radioactive moiety rather than an α-emitting radioactive moiety, or compared to SSTR2 agonists labeled with an α-emitting radioactive moiety, while maintaining or increasing efficacy.

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

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

[0007] The third aspect of the present invention relates to the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention, and the SSTR antagonist or the pharmaceutical composition is used in medicine.

[0008] The fourth aspect of the present invention relates to the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention, and the SSTR antagonist or the pharmaceutical composition is used for diagnosing and / or treating cancer.

[0009] The fifth aspect of the present invention relates to a kit comprising the SSTR antagonist of the first aspect of the present invention, and the kit is used for diagnosing cancer.

[0010] The sixth aspect of the present invention relates to a method for labeling the SSTR antagonist of the first aspect of the present invention. Description of the Drawings

[0011] Hereinafter, the content of the drawings included in this specification is described. In this context, reference is made to the detailed description of the present invention above and / or below.

[0012] Figure 1 : Structure of Compound 1. Figure 1 The chemical structure of Compound 1 of the present invention is depicted, which comprises a cyclic peptide structure and a complexing moiety, the complexing moiety being attached to the chlorophenylalanine residue of the peptide and being 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid. As Figure 1 shown, Compound 1 is not labeled with a radioisotope.

[0013] Figure 2 : 212 Bio-distribution of Pb-Compound 1 in the NCI-H69 mouse model of small cell lung cancer (SCLC) expressing SSTR2. Figure 2 The combined tissue distribution within 1, 4, and 24 hours is shown, wherein 212 Pb-Compound 1 has significant uptake in tumor tissues. After 24 hours, 212 the uptake distribution of Pb-Compound 1 is between two major tissue compartments (kidney and tumor).

[0014] Figure 3 : 212 Single-dose efficacy study of Pb-Compound 1 in the NCI-H69 mouse SCLC model expressing SSTR2. Figure 3 A shows that compared to the control of Compound 1, after a single injection of one dose of 177 Lu-Compound 1 (20 MBq) and three different doses of 212After Pb-compound 1 (1.6 MBq, 0.75 MBq, 0.35 MBq), tumor growth relative to the initial starting point at 250 mm over several weeks. Tumors in the control group grew further rapidly until the end point of 1000 mm, while in all groups, radiolabeled compound 1 delayed tumor growth and also reduced tumor size (see 1.6 MBq figure and 0.75 MBq figure). 3 At the initial starting point of tumor growth relative to the initial starting point at 250 mm over several weeks after a single injection of 3 Lu-compound 1 (21.5 MBq) or three different doses of Figure 3 B shows tumor growth relative to the initial starting point at 200 - 250 mm over several weeks after a single injection of 177 Lu-compound 1 (21.5 MBq) or three different doses of 212 Pb-compound 1 (503 kBq, 236 kBq, 113 kBq) compared to the control of compound 1. Tumors in the control group grew rapidly until the end point of 1000 mm, while in all groups, radiolabeled compound 1 delayed tumor growth. Unexpectedly, the highest tested dose of 3 Pb-compound 1 (503 kBq) led to an initial decrease in mean tumor volume relative to d0. 3 At the initial starting point of tumor growth relative to the initial starting point at 200 - 250 mm over several weeks after a single injection of 212 Pb-compound 1 (503 kBq) led to an initial decrease in mean tumor volume relative to d0. Figure 3 C shows the percentage of survival after a single injection of 177 Lu-compound 1 (21.5 MBq) or three different doses of 212 Pb-compound 1 (503 kBq, 236 kBq, 113 kBq) compared to the control compound 1. Treatment with all single doses of radiolabeled compound 1 prolonged the median survival of NCI-H69 tumor-bearing mice compared to the control group, and treatment with the highest dose of 212 Pb-compound 1 (503 kBq) resulted in the longest median survival.

[0015] Figure 4 : Results of the stability of 225 Ac-compound 1 radiolabeling.

[0016] Figure 4 Shows TLC (thin layer chromatography) analysis after the synthesis of 225 Ac-compound 1 and analysis at several time points (up to 72 h) after synthesis. The radiochemical purity of compound 1 was stable over the monitored time period, resulting in acceptable stability of the formulation.

[0017] Figure 5 : 225 Biodistribution of Figure 5 A shows 225Tissue distribution of Ac-compound 1 at 4, 24, and 96 hours. 225 Ac-compound 1 was significantly taken up by tumor tissues, and %ID / g reached >10% at the 4 h time point. Figure 5 B shows the tumor / kidney ratio at each time point, indicating an increase in the tumor-to-background ratio over the course of 96 h, thus indicating tumor persistence.

[0018] Figure 6 : Analyzed in the SSTR2-positive NCI-H69 mouse SCLC model 225 Ac-compound 1 compared to 177 Efficacy study of Lu-compound 1. Figure 6 A and Figure 6 B show the individual tumor growth curves of mice treated with unlabeled compound 1 alone, 177 Lu-compound 1 (20 MBq Q2W x3) or different doses and regimens of 225 Ac-compound 1 (90 kBq QW, 30 kBq QW, 30 kBq Q2W x 3, 30 kBq QW x3). Figure 6 C shows the median survival in each group. Tumors in the control group grew rapidly until the end point of 1000 mm 3 while all groups treated with radiolabeled compound 1 and even those treated with a single dose of 30 kBq 225 Ac-compound 1 significantly inhibited tumor growth, resulting in a high complete remission rate.

[0019] Figure 7 : Analyzed in the SSTR2-positive NCI-H69 mouse SCLC model 212 Pb-compound 1 compared to 177 Efficacy study of Lu-compound 1. Figure 7 A and Figure 7 B show the individual tumor growth curves of mice treated with unlabeled compound 1 (Q2W x 3), 177 Lu-compound 1 (20 MBq Q2W x 3) or different doses and regimens of 212 Pb-compound 1 (750 kBq QW, 500 kBq Q2W x 3, 250 kBqQW x 3, 250 kBq Q2W x 3). Figure 7 C shows the median survival in each group. Tumors in the control group grew rapidly until the end point of 1000 mm 3 while all groups treated with radiolabeled compound 1 significantly induced a reduction in tumor growth, and 177 Lu-compound 1 showed the strongest effect of complete remission in 100% of the mice.

[0020] Figure 8 : Analysis of different doses of 225 Single-dose efficacy study of Ac-compound 1 in SSTR2-positive NCI-H69 mouse SCLC model. Figure 8 Shows the mean tumor volume ± SEM of mice treated with vehicle or different doses of 225 Ac-compound 1 (30 kBq QW, 10 kBq QW, 3.33 kBq QW). Up to day 9 after treatment initiation, single doses of 10 kBq and 30 kBq 225Ac-compound 1 induced reduced tumor growth compared to vehicle control and 3.33 kBq 225Ac-compound 1.

[0021] Sequence Listing

[0022]

[0023] Before the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as these may vary. It should also 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 defined solely by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0024] Throughout the text of this specification, several documents are cited. Each document cited herein, whether above or below (including all patents, patent applications, scientific publications, manufacturer's instructions, guides, etc.), is hereby incorporated by reference in its entirety. Nothing in this application should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of a prior invention. Some of the documents cited herein are characterized as "incorporated by reference". In the event of a conflict between the definitions or teachings of such incorporated references and the definitions or teachings set forth in this specification, the text of this specification shall prevail.

[0025] Hereinafter, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that these specific embodiments can be combined in any way and in any number to produce additional embodiments. The differentially described examples and preferred embodiments should not be considered as limiting the present invention to only the explicitly described embodiments. This specification should be understood to support and cover embodiments that combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, unless the context otherwise indicates, the specification of this application should be considered to disclose any permutation and combination of all the described elements in this application.

[0026] To practice the present invention, unless otherwise indicated, conventional methods of chemical, biochemical, and recombinant DNA techniques as explained in the literature in the art are employed (see, for example, Molecular Cloning: A Laboratory Manual, 2nd Edition, edited by J. Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0027] In the following, some definitions of terms frequently used in this specification are provided. These terms will have the meanings and preferred meanings respectively defined in the remainder of this specification in each case where they are used.

[0028] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0029] The term " Somatostatin receptor (SSTR) " in the context of the present invention refers to the receptor for the ligand " Somatostatin ", a small neuropeptide associated with neural signal transduction, particularly in the postsynaptic response to NMDA receptor co-stimulation / activation and also known as somatostatin (GHIH). Somatostatin regulates the endocrine system via its receptor (which is a G-protein coupled seven-transmembrane receptor) and affects neurotransmission and cell proliferation. Somatostatin has two active forms produced by selective cleavage of a single preproprotein: one consisting of 14 amino acids and the other consisting of 28 amino acids. In vertebrates, there are six different somatostatin genes, which are named SS1, SS2, SS3, SS4, SS5, and SS6. The six different genes and five different somatostatin receptors endow somatostatin with a wide 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 signal transduction cascades that inhibit tumor cell proliferation, survival, and angiogenesis. There are five known human somatostatin receptor subtypes:

[0030] SST1 (SSTR1);

[0031] SST2 (SSTR2);

[0032] SST3 (SSTR3);

[0033] SST4 (SSTR4);

[0034] SST5 (SSTR5).

[0035] Somatostatin receptors are expressed under pathological conditions, particularly in neuroendocrine tumors of the gastrointestinal tract. Most human tumors derived from somatostatin target tissues possess conserved somatostatin receptors. They were first seen in growth hormone-producing adenomas and TSH-producing adenomas; approximately half of endocrine-inactive adenomas show somatostatin receptors. Ninety percent of carcinoids and most islet cell carcinomas (including their metastases) usually possess a high density of somatostatin receptors. However, only 10% of colorectal carcinomas contain somatostatin receptors and no exocrine pancreatic carcinomas contain somatostatin receptors. Somatostatin receptors in tumors can be identified using in vitro binding methods or using in vivo imaging techniques, the latter allowing precise localization of tumors and their metastases in patients. Somatostatin receptors have a widespread but variable tissue expression in normal tissues. They are differentially expressed in a variety of tumor types, including subsets of breast cancer, prostate cancer, pancreatic cancer, neuroendocrine carcinoma, Merkel cell carcinoma, and hepatocellular carcinoma.

[0036] “ Somatostatin receptor 2 ” (SSTR2) is overexpressed in most neuroendocrine tumors, particularly including small cell lung cancer (SCLC). SSTR2 is the most characterized member of the SSTR family and has multiple direct and indirect effects on the cell cycle, angiogenesis, apoptosis, and growth factor signaling. SSTR2 is found concentrated on the surface of tumor cells, particularly those associated with the neuroendocrine system. The synthetic form of the somatostatin hormone, octreotide (which acts as an SSTR2 agonist), has been successfully used in combination with a radiolabeled peptide tracer to localize adrenal tumors by scintigraphy. Due to the somatostatin receptor gene expression of these cells, SSTR2 and SSTR5 are also being investigated as biomarkers to track the progression of neuroendocrine tumors, including circulating tumor cells, and for treatment. There are several somatostatin analogs that target SSTRs that can be used as positron emission tomography (PET) radioligands to visualize neuroendocrine tumors. Ligands for SSTRs can be classified as agonists and antagonists.

[0037] The term “ Somatostatin receptor agonists ” in the context of the present invention refers to analogs of the naturally occurring ligand somatostatin as described above. Examples of somatostatin receptor agonists are octreotide, octreotate, lanreotide, or pasireotide.

[0038] The term “ Somatostatin receptor antagonists"In the context of the present invention, it refers to a molecule that binds to a somatostatin receptor (SSTR) and antagonizes the action of the natural agonist somatostatin, for example, reducing or decreasing the biological response induced by the binding of the agonist when binding to the receptor, that is, the antagonist inactivates the biological function of the receptor when binding, rather than activating it as the agonist does when binding. Somatostatin receptor antagonists do not internalize into cells when binding to the receptor, and thus can bind to a large number of receptors because they are independent of the receptor activation state.

[0039] The term " Peptides "In the context of the present invention, it refers to a short polymer of amino acids linked by peptide bonds. It has the same chemical bond (peptide bond) as proteins, but is usually shorter in length. The shortest peptide is a dipeptide composed of two amino acids linked by a single peptide bond. There can also be tripeptides, tetrapeptides, pentapeptides, etc. Typically, peptides have a length of up to 8, 10, 12, 15, 18, or 20 amino acids. Peptides have an amino terminus and a carboxyl terminus, unless they are cyclic peptides. "Amino acid" in the context of the present invention refers to any monomer unit containing a substituted or unsubstituted amino group, a substituted or unsubstituted carboxyl group, and one or more side chains or groups, or analogs of any of these groups. Exemplary side chains include, for example, thiol, seleno group, sulfonyl group, alkyl group, aryl group, acyl group, keto group, azide group, hydroxyl group, hydrazine, cyano group, halogen group, acyl hydrazide, alkenyl group, alkynyl group, ether, borate ester, boronate ester, phosphate group, phosphonyl group, phosphine, heterocycle, enone, imine, aldehyde, ester, thioacid, hydroxylamine, or any combination of these groups. Other representative amino acids include, but are not limited to, amino acids containing a photoactivatable crosslinker, metal-binding amino acids, spin-labeled amino acids, fluorescent amino acids, metal-containing amino acids, amino acids with novel functional groups, amino acids that interact covalently or non-covalently with other molecules, photocaged and / or photoisomerizable amino acids, radioactive amino acids, amino acids containing biotin or a biotin analog, glycosylated amino acids, other carbohydrate-modified amino acids, amino acids containing polyethylene glycol or polyether, heavy atom-substituted amino acids, chemically cleavable and / or photocleavable amino acids, amino acids containing a carbon-linked sugar, redox-active amino acids, amino acids containing aminothioacid, and amino acids containing one or more toxic moieties.

[0040] As used herein, the term " Amino Acids” includes the following twenty natural or genetically encoded α-amino acids: alanine (Ala or A), arginine (Arg or R), asparagine (Asn or N), aspartic acid (Asp or D), cysteine (Cys or C), glutamine (Gln or Q), glutamic acid (Glu or E), glycine (Gly or G), histidine (His or H), isoleucine (Ile 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 (Val or V). The structures of these twenty natural amino acids are shown, for example, in Stryer et al., Biochemistry, 5th Edition, Freeman and Company (2002). Additional amino acids (such as selenocysteine and pyrrolysine) can also be genetically encoded (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 non-natural 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-hydroxytryptophan 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. Sel. 16(9):699-706, Chin et al. (2003) “. Abbreviations used in the context of the present invention refer to certain amino acids used in the context of this application and are explained as follows:

[0041] (i) “Aph” refers to aminophenylalanine, where the amino group is preferably attached to the 4-position of the benzene ring, but attachment at the 2- or 3-position is generally equivalent;

[0042] (ii) “Aph(Cbm)” refers to 4-ureido-phenylalanine;

[0043] (iii) Aph(OH-Cbm) refers to 4-(3-hydroxy)-ureido-phenylalanine;

[0044] (iv) “Aph(CH3-Cbm)” refers to 4-(3-methyl)-ureido-phenylalanine;

[0045] (v) “Aph(OCH3-Cbm)” refers to 4-(3-methoxy)-ureido-phenylalanine;

[0046] (vi) “Aph[(EtOhEt-Cbm]” refers to 4-{3-[2-(2-ethoxy-ethoxy)-ethyl]}-ureido-phenylalanine;

[0047] (vii) Cpa refers to chlorophenylalanine, also known as chloro-Phe or 4-ClPhe;

[0048] (viii) “ITyr” means iodo-L-tyrosine;

[0049] (ix) “Aph(Hor)” means 4-[(2,6-dioxo-hexahydropyrimidin-4-carbonyl)-amino]-phenylalanine.

[0050] Standard three-letter abbreviations identify α-amino acid residues, and where the amino acid residue has isomeric forms, the L-form of the amino acid is represented unless otherwise specifically indicated (e.g., Ser = L-serine). L or D refers to either the D- or L-isomer of a particular α-amino acid. In the context of the present invention, examples of peptides are SSTR agonists (such as the natural agonist neuropeptide somatostatin and its analogs that selectively bind to SSTR) or SSTR antagonists.

[0051] The term “ Complexing part ” in the context of the present invention refers to the organic moiety of a molecule capable of complexing an ion, preferably a metal ion and more preferably a divalent and trivalent metal ion. This process is also referred to as “caging” since the complexing moiety can build a cage around the ion, preferably a metal ion. Preferred complexing moieties are chelating agents, complexing agents or coupling agents. The complexing moiety can be used for therapeutic and / or diagnostic purposes since it allows the immobilization of a therapeutic agent, such as a radionuclide. An example of a chelating agent is 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (IUPAC definition).

[0052] The term “ Radioactive part ” in the context of the present invention refers to a molecule containing or consisting of a radioisotope.

[0053] The term “ radioactivity ” in the context of the present invention can be defined, for example, as the activity。Radioactivity is an attribute of individual atomic nuclei. Unstable atomic nuclei will spontaneously disassemble or decay into more stable configurations, but only in several specific ways by emitting certain particles or certain forms of electromagnetic energy. Radioactive decay is a characteristic of several naturally occurring elements and artificially produced isotopes of these elements. The rate of decay of a radioactive element is expressed by its half-life; that is, the time required for half of any given quantity of the isotope to decay. The products of the radioactive decay process are called daughter isotopes of the parent isotope, which may itself be unstable, in which case it will also decay. The process continues until a stable nuclide is formed. The emissions of the most common form of spontaneous radioactive decay are alpha (α) particles, beta (β) particles, gamma (γ) rays, and neutrinos. These emissions are considered ionizing radiation because their energy is sufficient to release electrons from another atom. In α decay, a high-energy helium ion (α particle) is ejected, leaving a daughter nucleus with an atomic number 2 less than that of the parent nucleus and an atomic mass 4 less than that of the parent nucleus. An example is the abundant isotope of uranium 238 U decaying to a thorium daughter nucleus plus an α particle. The activity of a given quantity of radioactive material is defined as the number of transitions or decays per unit time. The SI unit of said activity is the becquerel (Bq), which is equivalent to one transition per second. The traditional unit of activity is expressed as Ci. For example, 1 MBq is equal to 27 μCi, and 1 mCi is equal to 37 MBq.

[0054] The term " Specific activity " in the context of the present invention refers to the activity per unit mass of a radionuclide, which is described as Bq / kg or Bq / mol.

[0055] The term " Human equivalent dose " in the context of the present invention is a measure of the biological effect of a radioactive dose, which takes into account the absorbed dose of radiation and the biological effectiveness and thus the type of radiation. The SI unit is the sievert (Sv), and the traditional unit is the rem, with 1 Sv equal to 100 rem. The equivalent dose depends on the RBE. The RBE can be defined as the Bioavailability Ratio。Compared with beta particles, as well as gamma and X-rays, alpha particles have a higher RBE. For oncology drugs, an RBE of five can be assigned to alpha particles, which means that the toxicity associated with alpha radiation is five times that of 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 formula for the equivalent dose in humans is as follows: Equivalent dose (Sv) = RBE x Absorbed dose (D) (Gy).

[0056] The term “ Absorbed dose ” in the context of the present invention refers to the energy of ionizing radiation deposited per unit mass of an organ or tissue. The SI unit of absorbed dose is the gray (Gy), where 1 Gy is equal to 1 J / kg (International Commission on Radiation Units and Measurements (ICRU); 2011). The traditional unit of absorbed dose is expressed as the rad. 1 Gy is equal to 100 rad; and 1 cGy is equal to 1 rad.

[0057] The term “ alpha particles ” respectively refers to helium ions (alpha particles) ejected during the alpha decay of a radionuclide or radioisotope.

[0058] The term “ Covalent ” in the context of the present invention refers to a covalent bond between atoms, characterized by the sharing of a pair of electrons between two atoms.

[0059] The term “ One or more tumor cells"In the context of the present invention, it refers to one or more cells of a tumor, which are cell masses produced by abnormal cell growth of a neoplasm. A neoplasm is an abnormal and excessive tissue growth. The process of forming or producing a neoplasm is called neoplasia. The growth of a neoplasm is not coordinated with the growth of the normal surrounding tissue and continues to grow abnormally even if the original triggering factor of the uncontrolled growth is removed. The International Statistical Classification of Diseases and Related Health Problems (ICD; 10th Revision) - the medical classification list published by the World Health Organization (WHO) - classifies neoplasms into four major categories: benign neoplasms, in situ neoplasms, malignant neoplasms, and neoplasms of uncertain or unknown behavior. Malignant neoplasms are also simply referred to as cancers. Preferably, tumor cells express somatostatin receptors (SSTR), especially SSTR2. Molecules that are agonists of STTR or especially SSTR2 bind to their respective receptors and internalize into tumor cells, and thus, if they are radiolabeled, they allow radioactive accumulation.

[0060] The term " cancer " in the context of the present invention refers to a disease in which some cells of the body grow uncontrollably and spread to other parts of the body. Under normal circumstances, human cells grow and reproduce according to the needs of the body to form new cells. When cells age or are damaged, they die, and new cells replace their positions. Sometimes this orderly process is disrupted, and abnormal or damaged cells grow and reproduce in an uncontrolled manner. These cells can form tumors, which can be cancerous or non-cancerous (benign). Cancerous tumors spread to or invade nearby tissues and can move to distant parts of the body to form new tumors (this process is called metastasis). Cancerous tumors can also be referred to as malignant tumors. Many cancers form solid tumors, but blood cancers (such as leukemia) usually do not. Benign tumors do not spread to or invade nearby tissues. Documents providing cancer therapy guidelines include Cancer, Principles and Practice of Oncology, 4th Edition, edited by DeVita et al., J.B. Lippincott Co., Philadelphia, Pa. (1993). The appropriate treatment method is selected according to the specific type of cancer and other factors such as the general health status of the patient, as is recognized in the relevant art. The SSTR antagonists of the present invention can be used alone or can be added to a treatment regimen using other anti-cancer agents commonly used to treat cancer patients.

[0061] The term " Proliferative diseases " (such as cancer) involves dysregulated and / or inappropriate proliferation of cells.

[0062] The term " Neuroendocrine tumors (NET)"In the context of the present invention, it refers to a specific type of cancer. The term NET is a general term for a relatively uncommon type of cancer that originates from neuroendocrine cells in many organs. The term "neuroendocrine" refers to the dual characteristics of these cells, which are the intersection between nerve cells and hormone-producing endocrine cells, that is, such cells produce neuropeptides and hormones. The characteristics of these tumors may vary depending on their location. However, NETs are considered rare because they usually grow slowly and are usually accompanied by an extended survival period, and more people are living with this disease. NETs can be difficult to diagnose because the symptoms may vary from patient to patient, and NETs are often misdiagnosed as other conditions, such as irritable bowel syndrome (IBS), Crohn's disease, peptic ulcer disease, or gastritis. Except for the pituitary gland, thyroid gland, pancreas, and adrenal glands, NETs occur more frequently in the gastrointestinal tract, pancreatic islets of Langerhans, and the bronchopulmonary system. NETs often express multiple SSTRs, among which SSTR2 is expressed at the highest level. Small cell lung cancer (SCLC) is a high-grade, poorly differentiated, and metastatic neuroendocrine cancer of the lung. SCLC is associated with early metastasis and poor patient survival rates.

[0063] The term " Tagged " or " mark " in the context of the present invention refers to introducing, attaching, or complexing a radioactive moiety as defined above to a somatostatin receptor antagonist to deliver radioactivity to one or more tumor cells or cancer cells. Typically, the radioactive moiety is provided in a solution containing a stabilizer.

[0064] In the following, different aspects of the present invention are defined in more detail. Unless explicitly indicated to the contrary, each aspect so defined can be combined with any one or more of the other aspects. In particular, any feature indicated as being preferred or advantageous can be combined with any one or more of the other features indicated as being preferred or advantageous.

[0065] The term "about" in the context of the present invention and when used in reference to a specific recited numerical value refers to a value and means that the value can differ 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 between them (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).

[0066] Throughout this application, the term "and / or" is a grammatical conjunction that should be interpreted to cover one or more of the situations that may occur with its connection. For example, the phrase "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.

[0067] Furthermore, throughout this application, the term "comprising" should be interpreted to cover all specifically mentioned features as well as optional, additional, unspecified features. As used herein, the use of the term "comprising" also discloses embodiments in which there are no features other than the specifically mentioned features (i.e., "consisting of").

[0068] 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 advantageously.

[0069] It has been observed in the context of the present invention that, compared to an SSTR2 antagonist labeled with a beta-emitting radionuclide or radioisotope in a tumor xenograft mouse model or an SSTR agonist labeled with an alpha- or beta-emitting radionuclide or radioisotope in a tumor xenograft mouse model, an SSTR antagonist labeled with an alpha-particle-emitting radionuclide or radioisotope results in advantageous efficacy in treating tumors, particularly in delaying and inhibiting the tumor growth of non-small cell lung cancer (NSCLC). In addition, the inventors can separately show the good stability and excellent delivery to the target organ (i.e., the tumor or one or more tumor cells) of the alpha-radionuclide-labeled SSTR antagonist compared to an SSTR2 antagonist labeled with a beta-emitting radioactive moiety rather than an alpha-emitting radioactive moiety.

[0070] Somatostatin receptor antagonist

[0071] A first aspect of the present invention relates to a somatostatin receptor antagonist (SSTR antagonist). The SSTR antagonist binds to the SSTR receptor but does not internalize into the cell and thus is capable of binding to multiple receptor binding sites. Thus, compared to an SSTR agonist, this results in higher biological activity. Compound 1 as described throughout this application comprises a peptide 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”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid.

[0072] 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”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety containing a radioisotope that emits alpha particles. In one embodiment, the SSTR antagonist of the first aspect of the present invention 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”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety containing a radioisotope that emits alpha particles.

[0073] 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”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety containing a radioisotope that emits alpha particles.

[0074] 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”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety containing a radioisotope that emits alpha particles.

[0075] In another embodiment of the first aspect of the present 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. Preferably, if the SSTR selectively binds to SSTR2, it also binds with high affinity. In the context of the present invention, " Binding affinity " or " Affinity " can be expressed, for example, as the half maximal effective concentration (EC 50 ) or the equilibrium dissociation constant (K D ). " Selectively combine"In the context of the present invention, it is meant that the SSTR antagonist binds to the target receptor (e.g., SSTR2) and (if any) exhibits weak binding or no binding to other SSTRs (such as SSTR1, SSTR3, SSTR4, and / or SSTR5). In other words, the SSTR antagonist selectively binds with a K D or EC 50 . Preferably, the selectivity of the SSTR2 antagonist for SSTR2 is at least about 200-fold, more preferably at least about 500-fold, that for any other SSTR receptor.

[0076] In one embodiment of the first aspect of the present invention, the SSTR antagonist comprises a radioactive moiety, which comprises a radioisotope emitting alpha particles. Alpha particles are positively charged, and the particle energy ranges from 5 to 9 MeV, and the very short range ranges from 40 - 100 μm. Thus, it is considered that the range of the particles is equivalent to the thickness of 1 - 3 cell widths. Due to the short therapeutic range, it is preferred that the intracellular accumulation of alpha particles ensures a higher chance of target damage to the cell nucleus. Linear energy transfer (LET) is a term used in ionizing radiation to measure the ionization density and thus the molecular damage per unit length of the particle. The LET for alpha particles is very high (80 - 100 keV / μm; 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). Compared with low-LET radiation, high-LET radiation results in more severe and less repairable cell damage: alpha particles produce a high ionization density, which leads to a large number of double-strand breaks compared with beta particles having a lower ionization density. A greater degree of double-strand breaks makes DNA repair more difficult and thus less efficient. High-LET radiation also has an indirect effect on tumors, making cell damage less likely to be repaired. These include increased cell division time, relative independence from the cell cycle stage, and reduced enzyme repair mechanisms. Therefore, it is particularly preferred that the alpha particles used have a shorter half-life compared with beta particles, thereby producing reduced toxicity while maintaining the efficacy of inhibiting or delaying tumor size. In a preferred embodiment, the radioactive moiety comprises a radioisotope of lead (Pb) or actinium (Ac). In another preferred embodiment, the radioactive moiety comprises a radioisotope, which is 212 Pb or 225Ac. In another preferred embodiment, the radioactive moiety comprises a radioisotope which is 212 Pb. In another preferred embodiment, the radioactive moiety comprises a radioisotope 225 Ac.

[0077] In another embodiment of the first aspect of the present invention, the SSTR antagonist comprises a complexing moiety, said complexing moiety comprising or consisting of 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid, wherein said 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).

[0078] 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 mole of peptide comprised in the SSTR antagonist. Even more preferably, said amount of radioactivity is initially used per mole of SSTR antagonist. Most preferably, the amount of radioactivity is used per mole 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 specific specific activity, which refers to the activity per unit mass of the radionuclide and is described as Bq / kg or Bq / mol as defined above. In one embodiment, the specific activity range of the SSTR antagonist is 100 - 2000 GBq / mmol. In another embodiment, if the 212 Pb radioisotope is used to label the SSTR antagonist, the specific activity range is 100 - 2000 GBq / mmol. In another embodiment, the specific activity range is 1 - 30 GBq / mmol. In another embodiment, if the 225 Ac radioisotope is used to label the SSTR antagonist, the specific activity range is 1 - 30 GBq / mmol.

[0079] 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-NH2, a complexing moiety consisting of 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety consisting of the radioisotope 212 Pb. In a preferred embodiment, the SSTR antagonist is an SSTR2 antagonist according to formula I:

[0080]

[0081] Formula I.

[0082] 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”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and a radioactive moiety consisting of the radioisotope 225 Ac. In a preferred embodiment, the SSTR antagonist is an SSTR2 antagonist according to Formula II:

[0083]

[0084] Formula II.

[0085] Pharmaceutical composition

[0086] A second aspect of the present invention relates to a pharmaceutical composition comprising the SSTR of the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0087] The term " Pharmaceutical composition " or " Therapeutic Compositions"In the context of the present invention refers to a compound or composition that is formulated to be suitable for administration to a patient and that, when appropriately administered to a subject, is capable of inducing a desired therapeutic effect, such as treating neoplasia or a persistent tumor, such as a NET. Such a therapeutic or pharmaceutical composition may comprise a therapeutically effective amount of an SSTR antagonist of the present invention or an SSTR antagonist further comprising a therapeutic agent, the antigen-binding protein being admixed with a pharmaceutically or physiologically acceptable formulation selected for suitability with the mode of administration. The somatostatin receptor antagonists of the present invention will typically be provided as part of a sterile pharmaceutical composition, which will generally comprise a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may be formulated for parenteral application and include parenteral vehicles. Parenteral administration includes intravenous, intramuscular, subcutaneous, and intradermal routes of administration. Examples of parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, 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 admixing the somatostatin receptor antagonist of the desired purity with an optional physiologically acceptable carrier, other excipients, stabilizers, surfactants, buffers, and / or tonicity agents. Acceptable carriers, other excipients, and / or stabilizers are non-toxic to the recipient at the dosages and concentrations employed and include buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid, glutathione, cysteine, methionine, and citric acid; preservatives (such as ethanol, benzyl alcohol, phenol, m-cresol, p-chloro-m-cresol, methyl or propyl p-hydroxybenzoate, 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 nonionic surfactants, such as Tween, Brij, Pluronic, Triton-X, or polyethylene glycol (PEG). The pharmaceutical composition may be in liquid form, lyophilized form, or liquid form reconstituted from the lyophilized form, wherein the lyophilized preparation is reconstituted with a sterile solution prior to administration. Standard procedures for reconstituting lyophilized compositions are to add back a certain volume of pure water (usually equal to the volume removed during lyophilization).

[0088] The term " Pharmaceutical " or " Pharmaceutically acceptable"In the context of the present invention, it refers to molecular entities and compositions that do not cause adverse reactions, allergic reactions or other adverse responses when administered to mammals, especially humans (as the case may be). A pharmaceutically acceptable carrier or excipient refers to any type of non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid.

[0089] The term " Pharmaceutically acceptable carrier " may also be referred to as " Pharmaceutically acceptable dilute Release agent " or " Pharmaceutically acceptable vehicle " and may include solvents, bulking agents, stabilizers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and physiologically compatible analogues.

[0090] The term " Therapeutic agents " in the context of the present invention refers to an agent having a therapeutic effect.

[0091] The form, route of administration, dose and regimen of the pharmaceutical composition naturally depend on the condition to be treated, the severity of the disorder, the age, weight and sex of the patient, the desired duration of treatment, etc. The pharmaceutical composition in the context of the present invention may be in any suitable form (depending on the desired method of administering it to the patient). It may be provided in unit dosage form, usually in a sealed container, and may be provided as part of a kit. Such a kit will usually (but not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

[0092] Empirical considerations such as biological half-life will generally assist in the determination of the dose. The frequency of administration can be determined and adjusted during the course of treatment and is based on reducing the number of cancer cells, maintaining the reduction of cancer cells, reducing the proliferation of cancer cells or killing cancer cells.

[0093] In particular, the pharmaceutical composition contains a vehicle that is pharmaceutically acceptable for a formulation that can be injected. In particular, these may be isotonic, sterile saline solutions, or dry, especially lyophilized, compositions that, upon addition of sterile water or physiological saline as the case may be, permit the formation of an injectable solution.

[0094] To prepare the pharmaceutical composition, an effective amount of the SSTR antagonist of the present invention can be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[0095] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations comprising 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 should be fluid to the extent that is easy to inject. 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.

[0096] Solutions of the active compounds, as the 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 in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0097] The SSTR antagonists of the present invention can be formulated into compositions in neutral or salt form using pharmaceutically acceptable salts.

[0098] Sterile injectable solutions are prepared by incorporating the required amount of the active compound into a suitable solvent with the various 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 a 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 ingredients from a previously sterile-filtered solution.

[0099] After formulation, the solution will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are readily administered in a variety of dosage forms such as the type of injectable solutions described above, but drug-release capsules etc. can also be employed.

[0100] Therapeutic methods and uses

[0101] The third aspect of the present invention relates to the SSTR antagonists of the first aspect of the present invention and / or the pharmaceutical compositions of the second aspect of the present invention, which SSTR antagonists and / or pharmaceutical compositions are for medicine. The present invention also relates to the use of the SSTR antagonists of the first aspect of the present invention and / or the pharmaceutical compositions of the second aspect of the present invention in the manufacture of a medicament.

[0102] The fourth aspect of the present invention relates to the SSTR antagonists of the first aspect of the present invention or the pharmaceutical compositions of the second aspect of the present invention, which SSTR antagonists or pharmaceutical compositions are for the diagnosis and / or treatment of cancer. Accordingly, the SSTR antagonists of the first aspect of the present invention, in particular those containing a radioisotope 212 Pb or225 The SSTR2 antagonist of Ac or the pharmaceutical composition of the second aspect of the present invention can be used for treating cancer. The SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention can be used for therapeutic purposes in humans and / or non-human mammals, preferably humans.

[0103] In one embodiment, the SSTR antagonist of the first aspect of the present invention can bind to SSTR2 expressed on tumor cells and reduce the growth of tumor cells expressing SSTR2 and / or kill the tumor cells. It should be understood that the SSTR antagonist of the first aspect of the present invention is administered under certain conditions that promote its binding to the SSTR2 receptor under physiological (e.g., in vivo) conditions.

[0104] In one embodiment, the SSTR antagonist of the first aspect of the present invention can be used for tumor treatment of 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 present invention can bind to tumor cells and reduce the growth of tumor cells and / or kill the tumor cells.

[0105] In one embodiment, the SSTR antagonist of the first aspect of the present invention can be used for the treatment of tumors (such as Merkel cell carcinoma). In another embodiment, the SSTR antagonist of the first aspect of the present invention can bind to tumor cells and reduce the growth of tumor cells and / or kill the tumor cells.

[0106] In one embodiment, preferably the 225 Ac-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof at a dose between 4 MBq and 10 MBq. In one embodiment, preferably the 225 Ac-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof at a dose between 5 MBq and 10 MBq. In one embodiment, preferably the 225 Ac-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof at a dose between 6 MBq and 10 MBq. In one embodiment, preferably the 225 Ac-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof at a dose between 7 MBq and 10 MBq. In one embodiment, preferably the 225 Ac-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof at a dose between 8 MBq and 10 MBq. In one embodiment, preferably the225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 9 MBq and 10 MBq. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 5 MBq and 9 MBq. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 6 MBq and 8 MBq. In a preferred embodiment, the 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof at a dose of 6 MBq.

[0107] In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 200 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 190 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 180 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 170 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 160 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 150 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 140 MBq. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 130 MBq. In one embodiment, the preferred 212The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 120 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 110 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 100 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 90 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 80 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 70 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 60 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 50 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 30 MBq and 40 MBq.

[0108] In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 40 MBq and 180 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 170 MBq. In a preferred embodiment, the use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose of 180 MBq.

[0109] In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is preferably used 225The [Ac label] is administered to a subject in need thereof at a dose between 6 MBq and 8 MBq every 6 to 8 weeks. In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is preferably labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose between 6 MBq and 8 MBq every 6 to 8 weeks. In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is preferably labeled with 225 The [Ac label] 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 present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is preferably labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose of 8 MBq every 6 to 8 weeks.

[0110] In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is preferably labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose between 6 MBq and 8 MBq every 6 to 8 weeks, for a total of 3 doses. In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose of 7 MBq every 6 to 8 weeks, for a total of 3 doses. In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose of 8 MBq every 6 to 8 weeks, for a total of 3 doses. In a preferred embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention (the antagonist or the composition is labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose of 6 MBq every 6 to 8 weeks, for a total of 3 doses.

[0111] In one embodiment, the SSTR antagonist preferably labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose between 0.5 MBq and 6 MBq every 3 to 6 weeks. In one embodiment, the SSTR antagonist preferably labeled with 225 The [Ac label] is administered to a subject in need thereof at a dose between 0.5 MBq and 5 MBq every 3 to 6 weeks. In one embodiment, the SSTR antagonist preferably labeled with 225The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 4 MBq. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 3 MBq. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 2 MBq. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 1 MBq. In a preferred embodiment, the 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose of 6 MBq.

[0112] In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 6 MBq, for a total of 3 doses. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 5 MBq, for a total of 3 doses. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 4 MBq, for a total of 3 doses. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 3 MBq, for a total of 3 doses. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 2 MBq, for a total of 3 doses. In one embodiment, the preferred 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 1 MBq, for a total of 3 doses. In a preferred embodiment, the 225 The Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose of 6 MBq, for a total of 3 doses.

[0113] In one embodiment, the preferred 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 6 MBq, for a total of 4 doses. In one embodiment, the preferred 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 5 MBq, for a total of 4 doses. In one embodiment, the preferred 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 4 MBq, for a total of 4 doses. In one embodiment, the preferred 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 3 MBq, for a total of 4 doses. In one embodiment, the preferred 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 2 MBq, for a total of 4 doses. In one embodiment, the preferred 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose between 0.5 MBq and 1 MBq, for a total of 4 doses. In a preferred embodiment, the 225 Ac-labeled SSTR antagonist is administered to a subject in need thereof every 3 to 6 weeks at a dose of 6 MBq, for a total of 4 doses.

[0114] In one embodiment, the preferred 212 Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 180 MBq. In one embodiment, the preferred 212 Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 170 MBq. In one embodiment, the preferred 212 Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 160 MBq. In one embodiment, the preferred 212 Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 150 MBq. In one embodiment, the preferred 212The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 140 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 130 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 120 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 110 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 100 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 90 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 80 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 70 MBq. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 60 MBq. In a preferred embodiment, the use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose of 180 MBq.

[0115] In a preferred embodiment, the use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 180 MBq for a total of 3 doses. In another preferred embodiment, the use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof every 6 to 8 weeks at a dose between 50 MBq and 170 MBq for a total of 3 doses. In another preferred embodiment, the use of the first aspect of the present invention212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 160 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 150 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 140 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 130 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 120 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 110 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 100 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 90 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 80 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 70 MBq every 6 to 8 weeks for a total of 3 doses. In another preferred embodiment, the first aspect of the present invention using 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 50 MBq and 60 MBq every 6 to 8 weeks for a total of 3 doses. In a preferred embodiment, the first aspect of the present invention using 212The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose of 180 MBq every 6 to 8 weeks for a total of 3 doses.

[0116] In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 100 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 110 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 120 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 130 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 140 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 150 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 160 MBq and 180 MBq every 3 to 6 weeks. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 170 MBq and 180 MBq every 3 to 6 weeks. In a preferred embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose of 180 MBq every 3 to 6 weeks.

[0117] In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212 at a dose between 100 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred Pb-labeled SSTR antagonist of the first aspect of the present invention is administered to a subject in need thereof 212The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 110 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 120 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 130 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 140 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 150 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 160 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 170 MBq and 180 MBq every 3 to 6 weeks for a total of 3 doses. In a preferred embodiment, the 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose of 180 MBq every 3 to 6 weeks for a total of 3 doses.

[0118] In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 100 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 110 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 120 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred 212The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 130 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 140 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 150 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 160 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In one embodiment, the preferred use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose between 170 MBq and 180 MBq every 3 to 6 weeks for a total of 4 doses. In a preferred embodiment, the use of the first aspect of the present invention 212 The Pb-labeled SSTR antagonist is administered to a subject in need thereof at a dose of 180 MBq every 3 to 6 weeks for a total of 4 doses.

[0119] The fourth aspect of the present invention further relates to a method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of the SSTR antagonist of the first aspect of the present invention as defined above or the pharmaceutical composition of the second aspect of the present invention.

[0120] A preferred embodiment relates to a method for treating a subject suffering from cancer, the method comprising administering to the subject the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention.

[0121] The fourth aspect of the present invention further relates to the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention, the SSTR antagonist or the pharmaceutical composition being used for diagnosing and / or treating cancer. One embodiment relates to the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention, the SSTR antagonist or the pharmaceutical composition being used for preparing a medicament for diagnosing and / or treating cancer.

[0122] The term " Subjects " or " individual " can be used interchangeably in the context of the present invention and can be, for example, a human or non-human mammal, preferably a human.

[0123] In the context of the present invention, the term " Treatment” or “ Treatment ” refers to a therapeutic use (i.e., in a subject suffering from a given disease) and means reversing, alleviating, and inhibiting the progression of one or more symptoms of such a disorder or condition. Thus, treatment refers not only to treatment that results in a complete cure of the disease, but also to treatment that slows the progression of the disease and / or prolongs the survival of the subject.

[0124] The term “ Need for treatment ” refers to a subject who already has a disorder (such as cancer). In one embodiment, the subject is thus a patient.

[0125] In the context of the present invention, a cancer is considered to be “ SSTR2-positive ” if the cancer cells or tumor cells express the SSTR2 receptor on their cell surface, respectively. In one embodiment, the cancer can be readily determined (i.e., diagnosed), for example, by using the SSTR antagonist of the first aspect of the present invention. Methods for identifying SSTR2-expressing cancers using SSTR antagonists by in vivo imaging are known to those skilled in the art.

[0126] In one embodiment, “ SSTR2-positive ” i.e., cancers presenting the target receptor are selected from neuroendocrine tumors such as small cell lung cancer (SCLC), small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, typical carcinoid or atypical carcinoid. In another embodiment, the cancer is Merkel cell carcinoma. Appropriate treatment methods are selected according to the specific cancer type and other factors such as the general health status of the patient, as is recognized in the relevant art. The SSTR antagonists of the present invention can be used alone or can be added to a treatment regimen using other anti-cancer agents commonly used to treat cancer patients.

[0127] In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention can be administered simultaneously, before, or after various drugs and treatments widely used in cancer treatment (such as chemotherapeutic agents, non-chemotherapeutic agents, anti-tumor agents, and / or radiation, preferably chemotherapeutic agents).

[0128] The term “ diagnosis ” in the context of the present invention refers to a medical diagnosis and means determining which disease or condition explains an individual's symptoms and signs.

[0129] In one embodiment, the efficacy of treatment with the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention is determined in vivo, for example, in a mouse cancer model and by measuring, for example, the change in tumor volume between a treatment group and a control group.

[0130] The SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention can be administered by any feasible method.

[0131] Kit

[0132] The fifth aspect of the present invention relates to a kit comprising the SSTR antagonist of the first aspect of the present invention, said kit being for the diagnosis of cancer.

[0133] In one embodiment, the kit comprises an SSTR antagonist labeled with a radioactive moiety. Preferably, the radioactive moiety comprises a radioisotope 212 Pb or 225 Ac. Preferably, the labeled SSTR antagonist comprises a stabilizer, such as a stabilizer in the form of a stable buffer. Examples of components included in the stable buffer are ascorbic acid or its salts. In another embodiment, the kit comprises an unlabeled SSTR antagonist and a radioactive moiety in a suitable container for labeling. The kit preferably comprises a stable buffer to provide stability of the solution after the SSTR antagonist is labeled with the radioactive moiety. In one embodiment, the stable buffer comprises ascorbic acid or its salts. Preferably, the radioactive moiety comprises a radioisotope 212 Pb or 225 Ac. In another embodiment, the kit comprises an unlabeled SSTR antagonist that can subsequently be labeled with a radioactive moiety. The kit preferably comprises a stable buffer to provide stability of the solution after the SSTR antagonist is labeled with the radioactive moiety. In one embodiment, the stable buffer comprises ascorbic acid or its salts. Preferably, the radioactive moiety comprises a radioisotope 212 Pb or 225 Ac. In one embodiment, the kit further comprises a packaging material and optionally a label or package insert contained within the packaging material, said label or package insert indicating that the SSTR antagonist or its pharmaceutical composition is effective in treating cancer or is suitable for treating cancer.

[0134] In one embodiment, the SSTR antagonist of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention is contained in a single-chamber and / or multi-chamber pre-filled syringe (such as a liquid syringe and a lyophilized syringe) ready to be labeled with a radioactive moiety, said pre-filled syringe preferably comprising a radioisotope 212 Pb or 225 Ac.

[0135] In one embodiment, the present invention encompasses a kit for generating a single-dose administration unit. In one embodiment, the SSTR antagonist of the kit of the present invention is the dried SSTR antagonist of the first aspect of the present invention contained in a first container. The kit also contains a second container having an aqueous formulation, preferably a buffer formulation. The kit further comprises a third container, said third container containing a radioactive moiety, preferably comprising a radioisotope212 Pb or 225 Ac. The kit further comprises a fourth container containing a stabilizing buffer, preferably containing ascorbic acid or its salts.

[0136] Thus, in one embodiment, the kit comprises

[0137] a) a first container containing at least one dried SSTR antagonist as defined above

[0138] b) a second container containing a conjugation buffer;

[0139] c) a third container containing the radioactive moiety, preferably containing a radioisotope 212 Pb;

[0140] d) a fourth container containing a stabilizing buffer;

[0141] e) optionally packaging material, and

[0142] f) optionally a label or package insert contained within the packaging material, the label or package insert indicating that the SSTR antagonist is effective in treating cancer or for use in treating cancer.

[0143] In another embodiment, the kit comprises

[0144] a) a first container containing at least one dried SSTR antagonist as defined above

[0145] b) a second container containing a conjugation buffer;

[0146] c) a third container containing the radioactive moiety, preferably containing a radioisotope 225 Ac;

[0147] d) a fourth container containing a stabilizing buffer;

[0148] e) optionally packaging material, and

[0149] f) optionally a label or package insert contained within the packaging material, the label or package insert indicating that the SSTR antagonist is effective in treating cancer or for use in treating cancer.

[0150] The aqueous formulation is typically a solution comprising a pharmaceutically acceptable carrier as defined above.

[0151] The sixth aspect of the present invention relates to a method of labeling an SSTR antagonist of the first aspect of the present invention. In one embodiment, the method for labeling an SSTR antagonist of the first aspect of the present invention or a pharmaceutical composition of the second aspect of the present invention comprises the step of labeling the SSTR antagonist with a radioactive moiety, wherein the SSTR antagonist individually comprises a peptide, a complexing moiety; and a radioactive moiety. In another embodiment, the method for labeling an SSTR antagonist of the first aspect of the present invention or a pharmaceutical composition of the second aspect of the present invention comprises the step of labeling the SSTR antagonist with a radioactive moiety, wherein the SSTR antagonist individually comprises a peptide, a complexing moiety; and a radioactive moiety. Preferably, the labeling comprises a heating step, wherein the SSTR antagonist (preferably in solution) and the radioactive moiety are heated at a temperature between about 75 °C and about 95 °C. In a preferred embodiment, the radioactive moiety comprises a radioisotope 212 Pb. In another preferred embodiment, the radioactive moiety comprises a radioisotope 225 Ac.

[0152] The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention in any way as indicated by the appended claims. Examples

[0153] Example 1: Peptide and Chelator Synthesis

[0154] Compound 1 was synthesized by Bachem AG (Lot No.: 4083738) and the reagents for preparing the reaction buffer (acetate solution; Catalog No. N13120, for 212 Pb) were purchased from IPSEN Pharma Biotech, and the formulation (ascorbate, diethylenetriamine-N,N,N',N,N-pentaacetic acid (DTPA) solution, Catalog No. N16106) was purchased from Fresenius Kabi. Tris buffer was prepared using Tris hydrochloride (Sigma Aldrich PHG0002) and tromethamine (Merck 1.08386). The isotopes were provided by specific manufacturers: respectively, 212 Pb solution was provided by Advancell and 225 Ac solution was provided by ITM.

[0155] Example 2: Radioactive Labeling with 212 Pb

[0156] Compound 1 was dissolved in the reaction buffer (e.g., at a concentration of 1 mg / mL) and added to 212Solution of Pb (in HCl). The resulting mixture was heated at a temperature of 75 °C - 95 °C for 20 - 45 min and then cooled to room temperature. The specific activity during radiolabeling ranged between 100 - 2000 GBq / mmol. The reaction mixture was added to a formulated buffer consisting of sodium ascorbate to stabilize the final dose and ensure the quality and safety of the dose. Within 6 h, the radiochemical purity was >90% and no radiolytic degradation was observed by high performance liquid chromatography (HPLC).

[0157] Example 3: 212 Biodistribution of Pb - Compound 1

[0158] Performed using xenograft Balb / c nude mice with NCI - H69 model expressing SST2 212 1 h, 4 h, 24 h biodistribution studies of Pb - Compound 1. NCI - H69 cells (cells from the human small cell lung cancer cell line NCI - H69) were grown in DMEM medium containing 10% FBS. After 80% confluence, the cells were collected and dissolved in a 1:1 mixture of PBS and Matrigel for injection. 50 μl of the cell solution containing 5x10 6 cells was injected into the right flank (Balb / C nude female mice, 6 - 8 weeks). 15 mice were injected with 1.3 - 1.5 MBq of 212 Pb - Compound 1 (approx. 50 μL injection solution). At 1 hour, 4 hours, and 24 hours after injection, 5 mice were sacrificed by cervical dislocation and blood samples were immediately taken by cardiac puncture. The mice were dissected and the organs were washed in PBS to remove blood and added to pre - weighed gamma counter tubes for further analysis. High tumor uptake (>5% ID / g; percentage of injected dose per gram of tissue) was observed at t = 1 h and persisted for over 24 h (>2% ID / g). Moderate uptake was observed in the radiosensitive organ (kidney), and the tumor - to - kidney ratio remained constant at 0.4 throughout the experiment.

[0159] Example 4: 225 Biodistribution of Ac - Compound 1

[0160] Performed using xenograft Balb / c nude mice transplanted with NCI - H69 tumor cells expressing SST2 225 4 h, 24 h, 96 h biodistribution studies of Ac - Compound 1. NCI - H69 cells (cells from the human small cell lung cancer cell line NCI - H69) were grown in RPMI1640 medium containing 10% FBS. After 80% confluence, the cells were collected and dissolved in a 1:1 mixture of PBS and Matrigel for injection. 100 μl of the cell solution containing 5x10 6The cell solution of the cells was injected into the right abdomen of Balb / C nude female mice at about 7 weeks of age. Twelve mice were injected with 90 kBq of 225 Ac-compound 1 in 100 μL. At 4 hours, 24 hours, and 96 hours after injection, four mice were sacrificed by overdosing with a mixture of ketamine and xylazine, and then bled by intracardiac puncture. The mice were dissected and the organs were rinsed in 0.9% NaCl to remove contaminated blood and subjected to blotting, then weighed and subsequently transferred to scintillation vials. Solvable was used as a tissue solubilizer to dissolve the tissues. Before scintillation counting, each solution was decolorized by adding 30% H2O2. Pico-Fluor Plus was used as a liquid scintillation counting mixture. The radioactivity of 225 Ac radionuclide was measured using a calibrated Hidex 300SL. High tumor uptake (>10% ID / g; percentage of injected dose per gram of tissue) was observed at t = 4 h, with a lower decline (>4.5% ID / g) within 96 h. Moderate uptake was observed in the radiosensitive organ (kidney), which rapidly decreased within 96 h, resulting in 225 the tumor-to-kidney ratio of Ac-compound 1 increasing from 0.75 at 4 h to 1.38 at 96 h.

[0161] Example 5: 212 Dose efficacy study of Pb-compound 1

[0162] A single-dose study was conducted using tumor-bearing mice with the NCI-H69 model expressing SST2. Three weeks before treatment, 5 x 10 6 NCI-H69 cells were injected into the right abdomen of 25 Balb / C nude female mice at 6 - 8 weeks of age. The mice were observed daily for 14 days before treatment and continuously for 60 days after treatment. The mice were treated when the tumor reached approximately 250 mm 3 and euthanized when any tumor reached 1000 mm 3 or the mice reached the euthanasia state on the health score sheet.

[0163] The mice were divided into five groups for different treatments:

[0164] Group activity Peptide content Injection volume Comparison N / A 10 μg / mL 100uL <![CDATA 177 Lu-compound 1]]> 20MBq 10 μg / mL 100uL <![CDATA 212 Pb-compound 1, low dose]]> 0.35MBq 10 μg / mL 100uL <![CDATA 212 Pb-compound 1, medium dose]]> 0.75MBq 10 μg / mL 100uL <![CDATA 212 Pb-compound 1, high dose]]> 1.6MBq 10 μg / mL 100μL

[0165] Table 1: Different treatment groups.

[0166] There was a control group injected only with compound 1 (without any radiolabel), and tumor growth progressed in the animals without any effect. Comparator 177Lu-compound 1 showed a response and delay in tumor growth at an injected radioactivity of 20 MBq, but there was no decrease in tumor size. This corresponds to a human equivalent dose of 3.7 GBq typically used in clinical trials. Compared to the group receiving only compound 1 without any radioactivity, 212 The group of Pb-compound 1 showed a growth delay in tumor size even at the lowest level (0.35 MBq). Compared to 177 Lu-compound 1, the medium and high doses (0.75 MBq and 1.6 MBq) showed comparable tumor reduction at 1 / 12 or less of the radioactivity used for 177 Lu-compound 1 (see Figure 3 A).

[0167] A single-dose study was conducted using tumor-bearing mice with the NCI-H69 model expressing SST2. Three weeks before treatment, 5 x 10 6 NCI-H69 cells were injected into the right flank of 25 6-8-week-old female Balb / C nude mice. The mice were observed daily for 14 days before treatment and for 60 days after treatment. The mice were treated when the tumors reached approximately 250 mm 3 and were euthanized when any tumor reached 1000 mm 3 or when the mice reached the euthanasia state on the health score sheet.

[0168] The mice were divided into five groups for different treatments:

[0169] Group activity Peptide content Injection volume Comparison N / A 10 μg / mL 100uL <![CDATA 177 Lu-compound 1]]> 21.5MBq 10 μg / mL 100uL <![CDATA 212 Pb-compound 1, low dose]]> 113kBq 10 μg / mL 100uL <![CDATA 212 Pb-compound 1, medium dose]]> 236kBq 10 μg / mL 100uL <![CDATA 212 Pb-compound 1, high dose]]> 503kBq 10 μg / mL 100uL

[0170] Table 2: Different treatment groups.

[0171] There was a control group injected only with compound 1 (without any radioactive label), and tumor growth progressed in the animals without any effect. The comparator 177 Lu-compound 1 showed a response and delay in tumor growth at an injected radioactivity of 21.5 MBq, but there was no decrease in tumor size. This corresponds to a human equivalent dose of approximately 3.7 GBq typically used in clinical trials. Compared to the group receiving only compound 1 without any radioactivity, 212 The group of Pb-compound 1 showed a growth delay in tumor size even at the lowest level (113 kBq). Compared to 177 Lu-compound 1, the medium and high doses (236 kBq and 503 kBq) showed comparable tumor reduction at 1 / 42 or less of the radioactivity used for 177 Lu-compound 1 (see Figure 3B). The growth rate of NCI-H69 tumors was as expected. Control (Compound 1) animals reached the ethical limit within <28 days. Treatment with 177 Lu-Compound 1 (21.5 MBq) showed visible effects approximately 3 days after treatment and controlled tumor growth for up to 20 days. 212 The treatment effect of Pb-Compound 1 was visible approximately 3 days after treatment, and treatment with a low dose (113 kBq) resulted in controlled tumor growth for 10 days. Treatment with a medium dose (236 kBq) induced a slight reduction in tumor volume (approximately 5% on day 10) and resulted in controlled tumor growth for 14 days. The high dose (503 kBq) reduced the tumor size by 15% on day 14 after treatment and resulted in controlled tumor growth for up to 20 days. 212 Treatment with Pb-Compound 1 (503 kBq) resulted in a 177 longer median survival compared to

[0172] deal with Median survival Compound 1 (control) 22 days <![CDATA 177 Lu-compound 1 (21.5 MBq)]]> 42 days <![CDATA 212 Pb-compound 1 (503 kBq)]]> 49 days <![CDATA 212 Pb-compound 1 (236 kBq)]]> 38 days <![CDATA 212 Pb-compound 1 (113 kBq)]]> 41 days

[0173] Table 3: Different treatment groups and median survival (in days).

[0174] In single-dose treatment, 503 kBq 177 Pb-Compound 1 showed higher potency in tumor growth inhibition and survival prolongation compared to 21.5 MBq 212 Lu-Compound 1 (see Figure 3 B and Figure 3 C).

[0175] Example 6: Radioactive labeling with 225 Ac

[0176] Radioactive labeling was initially carried out as described in Example 3, but using a reaction buffer containing 0.25 M TRIS buffer at pH 8. Subsequently, radioactive labeling was carried out by dissolving Compound 1 at a concentration of 1 mg / mL in the reaction buffer and adding it to a solution of 225 Ac (in HCl). The resulting mixture was heated at a temperature of 75 °C - 95 °C for 20 - 45 min and then cooled to room temperature. The specific activity during radioactive labeling ranged between 1 - 10 GBq / mmol. The reaction mixture was added to a formulation buffer consisting of sodium ascorbate to stabilize the final dose.

[0177] Example 7: 225 Single-dose and multi-dose efficacy study of

[0178] Single-dose and multi-dose efficacy studies were conducted in SST2-positive NCI-H69 tumor-bearing mice. 60 Balb / C nude female mice, 6-8 weeks old, were injected subcutaneously in the right flank with 5x10 6 NCI-H69 cells and treatment was initiated when the tumors reached an average tumor volume of 140 mm 3 . Animals were euthanized when any tumor volume exceeded 1000 mm 3 or other ethical criteria were met.

[0179] Group activity Peptide content Injection volume plan Control compound 1 N / A 10 μg / mL 100μL QW <![CDATA 177 Lu-compound 1]]> 20MBq 10 μg / mL 100μL Q2W x 3 <![CDATA 225 Ac - Compound 1, high dose]]> 90kBq 10 μg / mL 100μL QW <![CDATA 225 Ac - Compound 1, low dose]]> 30kBq 10 μg / mL 100μL QW <![CDATA 225 Ac - Compound 1, low dose]]> 30kBq 10 μg / mL 100μL Q2W x 3 <![CDATA 225 Ac - Compound 1, low dose]]> 30kBq 10 μg / mL 100μL QW x 3

[0180] Table 4: Different treatment groups. QW once a week; Q2W once every 2 weeks

[0181] Tumor progression was rapid in the control group receiving unlabeled Compound 1, and animals reached the ethical limit within 21-55 days (median survival 34 days; see Figure 6 A, Figure 6 B, and Figure 6 C). In contrast, all treatment groups using radiolabeled Compound 1 showed significant tumor growth inhibition starting at d5 and did not reach the median survival during the 84-96 day follow-up period (see Table 5). Unexpectedly, single-dose treatment (QW) with 90 kBq and only 30 kBq of 225 Ac-Compound 1 was equally effective in the initial induction of tumor regression as 177 Lu-Compound 1 co-administered 3 times every 2 weeks and was even superior in terms of the complete remission rate to 177 Lu-Compound 1 (Table 5).

[0182]

[0183]

[0184] Table 5: Median survival and complete remission of different treatment groups.

[0185] Example 8: 212 Single-dose and multi-dose efficacy study of

[0186] Pb-Compound 1 Single-dose and multi-dose efficacy studies were conducted in SST2-positive NCI-H69 tumor-bearing mice. 55 Balb / C nude female mice, 6-8 weeks old, were injected subcutaneously in the right flank with 5x10 6 NCI-H69 cells and treatment was initiated when the tumors reached an average tumor volume of 260 mm 3 . Animals were euthanized when any tumor volume exceeded 1000 mm 3 or other ethical criteria were met.

[0187] Group activity Peptide content Injection volume plan Control compound 1 N / A 10 μg / mL 100uL Q2W x 3 <![CDATA 177 Lu-compound 1]]> 20MBq 10 μg / mL 100uL Q2W x 3 <![CDATA 212 Pb-compound 1, high dose]]> 750kBq 10 μg / mL 100uL QW <![CDATA 212 Pb-compound 1, medium dose]]> 500kBq 10 μg / mL 100uL Q2W x 3 <![CDATA 212 Pb-compound 1, low dose]]> 250kBq 10 μg / mL 100μL Q2W x 3 <![CDATA 212 Pb-compound 1, low dose]]> 250kBq 10 μg / mL 100uL QW x 3

[0188] Table 6: Different treatment groups. QW once a week; Q2W once every 2 weeks

[0189] Tumor progression in the control group receiving unlabeled Compound 1 was rapid, and the animals reached the ethical limit within 16 - 53 days (median survival 30 days, see Figure 7 A, Figure 7 B, Figure 7 C). In contrast, all treatment groups using radiolabeled Compound 1 showed a significant reduction in tumor growth. Multiple doses of 177 Lu-Compound 1 were more effective than 212 Pb-Compound 1 at different regimens and doses. We observed tumor recurrence in all 212 Pb-Compound 1 treatment groups, while this was not the case after 177 Lu-Compound 1 Q2W x 3 (100% complete remission, see Table 7).

[0190] Group activity plan Median survival Complete remission Control compound 1 N / A Q2W x 3 34 days 0 / 10(0％) <![CDATA 177 Lu-compound 1]]> 20MBq Q2W x 3 Not reached 10 / 10(100％) <![CDATA 212 Pb-compound 1, high dose]]> 750kBq QW Not reached 2 / 5(40％) <![CDATA 212 Pb-compound 1, medium dose]]> 500kBq Q2W x 3 Not reached 5 / 10(50％) <![CDATA 212 Pb-compound 1, low dose]]> 250kBq Q2W x 3 70 days 0 / 10(0％) <![CDATA 212 Pb-compound 1, low dose]]> 250kBq QW x 3 Not reached 4 / 9(44％)

[0191] Table 7: Median survival and complete remission of different treatment groups.

[0192] Example 9: 225 Single-dose efficacy study of Ac-Compound 1

[0193] A single-dose efficacy study was conducted in SST2-positive NCI-H69 tumor-bearing mice. 5x10 6 NCI-H69 cells were injected into the flanks of 6 - 8-week-old Balb / C nude female mice, and treatment was initiated when the tumors reached an average tumor volume of 160 mm 3 .

[0194] Group activity Peptide content Injection volume plan vehicle N / A N / A 100uL QW <![CDATA 225 Ac - Compound 1, high dose]]> 30kBq 10 μg / mL 100uL QW <![CDATA 225 Ac - Compound 1, medium dose]]> 10kBq 10 μg / mL 100 μL QW <![CDATA 225 Ac - Compound 1, low dose]]> 3.33 kBq 10 μg / mL 100 μL QW

[0195] Table 8: Different treatment groups. QW once a week (equivalent to single administration)

[0196] Tumors in the vehicle control group progressed during the study, and until day 9 after treatment, a dose of 3.33 kBq of 225Ac-Compound 1 showed no significant effect on tumor growth (see Figure 8 ). In contrast, mice treated with as low as 10 kBq and 30 kBq doses of 225Ac-SSO110 started to show tumor growth inhibition on day 4 after treatment.

Claims

1. A somatostatin receptor (SSTR) antagonist, the somatostatin receptor (SSTR) antagonist comprising (i) a peptide, the peptide comprising Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2 (SEQ ID NO:1) or consisting of the same, 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, the complexing moiety comprising 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid or consisting of the same; and (iii) a radioactive moiety, the 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 claims 1-2, wherein the radioisotope contained in the radioactive moiety is 212 Pb or 225 Ac.

4. The SSTR antagonist according to any one of claims 1-3, 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 1-5, 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, the SSTR antagonist comprising (i) a peptide, the 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, the complexing moiety consisting of 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and (iii) Radioactive part, said radioactive part containing a radioisotope 212 Pb.

8. The SSTR antagonist according to claim 7, wherein the SSTR antagonist has the formula I:

9. The SSTR antagonist according to any one of claims 1 to 6, the SSTR antagonist comprising (i) a peptide, the 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, said complexing moiety consisting of 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and (iii) Radioactive portion, said radioactive portion comprising a radioisotope 225 Ac.

10. The SSTR antagonist according to claim 9, said SSTR antagonist having formula II:

11. A pharmaceutical composition, said pharmaceutical composition comprising the SSTR antagonist according to any one of claims 1 to 10, a pharmaceutically acceptable carrier, diluent, stabilizer and / or excipient.

12. The SSTR antagonist according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11, said SSTR antagonist or said pharmaceutical composition being used as a medicine.

13. The SSTR antagonist according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11, said SSTR antagonist or said pharmaceutical composition being used for diagnosing and / or treating cancer, preferably wherein (i) said cancer expresses somatostatin receptor 2 (SSTR2); or (ii) said cancer is a neuroendocrine tumor (NET), more preferably wherein said neuroendocrine tumor is small cell lung cancer, preferably small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, typical carcinoid or atypical carcinoid.

14. A kit for diagnosing cancer, said kit comprising an SSTR antagonist or a pharmaceutical composition containing said SSTR antagonist, wherein said SSTR antagonist comprises (i) a peptide, said peptide comprising Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2 (SEQ ID NO:1) or consisting thereof, 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, said complexing moiety comprising 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid or consisting thereof; and wherein (1) Label the SSTR antagonist with a radioactive moiety, which preferably comprises a radioisotope that emits alpha particles, and more preferably wherein the isotope is 212 Pb or 225 Ac; or (2) said SSTR antagonist is unlabeled and provided together with said radioactive moiety in a suitable container for labeling; or (3) said SSTR antagonist is unlabeled and capable of being subsequently labeled with said radioactive moiety.

15. A method for labeling an SSTR antagonist or a pharmaceutical composition containing said SSTR antagonist, wherein said SSTR antagonist comprises (i) a peptide, said peptide comprising Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2 (SEQ ID NO:1) or consisting thereof, wherein (a) Cpa is chlorophenylalanine; (b) Aph(Hor) is [(2,6-dioxo-hexahydro-pyrimidin-4-ylcarbonyl)-amino]-phenylalanine; (c) Aph(Cbm) is 4-amino-phenylcarbamoyl (4-ureido-phenylalanine); (ii) a complexing moiety comprising or consisting of 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; and wherein the SSTR antagonist is labeled with a radioactive moiety, the radioactive moiety comprising a radioisotope that emits alpha particles, preferably wherein the isotope is 212 Pb or 225 Ac.

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