Dual receptor targeting radioligands and uses thereof

Abstract

# imgabs0. The present invention discloses compounds of formula (I) and complexes thereof with radionuclides, which can recognize both the somatostatin type 2 receptor (SSTR2) and the cholecystoxin 2 receptor (CCK2R) and can be used in the diagnosis and treatment of diseases in which either or both receptors are overexpressed.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority of co-pending U.S. Provisional Patent Application No. 63 / 417,915, filed on October 20, 2022, the content of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application generally relates to the field of radioligands that target cell surface receptors such as somatostatin receptors, cholecystokinin receptors, or both. In particular, it relates to compounds and complexes of such compounds containing radionuclides. This application also relates to methods of using such compounds and complexes to target and / or kill target cells. Background Art

[0004] Somatostatin and its receptor family, which consists of five G protein-coupled receptors (GPCRs), play important roles in regulating the secretion of several essential hormones. Abnormalities in this signaling pathway have been found to be associated with various diseases, including cancer. It has been well studied that the overexpression of somatostatin receptor type 2 (SSTR2) is an important characteristic of neuroendocrine tumors. Consequently, SSTR2 has been widely explored as a therapeutic agent for delivering radionuclides complexed with SSTR2-binding peptides to tumor tissues, which enables PET or SPECT / CT-based diagnosis and α or β internal radiotherapy. These efforts have led to FDA-approved ( 68 Ga-DOTATATE) and ( 177 Lu-DOTATATE), which are a diagnostic and therapeutic pair clinically used for detecting and treating gastroenteropancreatic neuroendocrine tumors (GEP-NET). It has also been found that SSTR2 is overexpressed in other tumors, such as small cell lung cancer (SCLC); consequently, 177 Lu-DOTATATE and other SSTR2-targeting radioligands have been studied in various approaches for treating SCLC, but the desired results have not been achieved [1]. Similarly, 177 Lu-DOTATATE has also been clinically explored for treating medullary thyroid cancer (MTC) [2].

[0005] Cholecystokinin 2 receptor (CCK2R, also known as cholecystokinin B receptor or CCKBR) has also been found to be overexpressed in various tumors, including medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), astrocytoma, stromal ovarian tumors, and gastrointestinal stromal tumors (GIST) [3]. CCK2R is one of two GPCR receptors in the cholecystokinin receptor (CCKR) family, and the endogenous ligand of this receptor is cholecystokinin (CCK) and its N-terminal truncated forms. To interfere with the CCK2R-mediated pathway, both peptide agonists derived from natural CCK or gastrin sequences and small molecule-based antagonists have been developed. More recently, targeted radioligand approaches have also been explored, with most using peptide agonists as carriers, and the F 11 N-radionuclide complex [4 - 6] being a notable example. Small molecule CCK2R antagonists have also been evaluated using radionuclide carriers more recently [7 - 8].

[0006] Targeting receptors overexpressed on the surface of tumors has been a fruitful approach, which has led to many effective cancer treatments. However, it is also widely recognized that tumor heterogeneity has limited its potential, and additional challenges arise if the receptor has a relatively low copy number per cell.

[0007] Methods that will address these challenges have not been developed and are highly desirable. Summary of the Invention

[0008] The applicant has developed a dual-targeting compound that can recognize both somatostatin receptor type 2 (SSTR2) and cholecystokinin 2 receptor (CCK2R). When complexed with a radionuclide, this compound can be used, for example, in tumor diagnostics and / or therapy for tumors overexpressing either SSTR2 or CCK2R.

[0009] Accordingly, the present application includes a compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0010]

[0011] wherein

[0012] E is a chelating group;

[0013] T is a trivalent branching group;

[0014] Z 1 is a cholecystokinin-2 receptor (CCK2R) binding group;

[0015] Z 2 is a somatostatin receptor 2 (SSTR2) binding group;

[0016] L 1 、L2 and L 3 are each independently a direct bond or a divalent linker.

[0017] This application also includes a radionuclide complex or a pharmaceutically acceptable salt and / or solvate thereof, which comprises a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radionuclides.

[0018] This application also includes a composition, which comprises one or more compounds of Formula I or one or more complexes thereof and a carrier.

[0019] This application includes a kit, which comprises: (1) one or more compounds of Formula I or a pharmaceutically acceptable salt and / or solvate thereof, and (2) instructions for administering the one or more compounds of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0020] This application includes a kit, which comprises: (1) one or more compounds of Formula I or a pharmaceutically acceptable salt and / or solvate thereof; (2) one or more radioactive isotopes as defined above; and (3) optionally, instructions for administering the one or more compounds of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof and for administering the radioactive isotope to a subject in need thereof.

[0021] This application includes a kit, which comprises: (1) one or more complexes of this application or a pharmaceutically acceptable salt and / or solvate thereof as defined above, and (2) instructions for administering the one or more compound complexes to a subject in need thereof.

[0022] This application includes a method for treating a disease or disorder, which comprises administering a therapeutically effective amount of one or more compounds of Formula I or one or more complexes thereof to a subject in need thereof.

[0023] This application includes a method for inhibiting proliferative activity in cells, which comprises administering a therapeutically effective amount of one or more compounds of any Formula I or one or more complexes thereof to the cells.

[0024] This application includes a method for imaging tissue in a subject, which comprises administering an imaging effective amount of one or more compounds of Formula I or one or more complexes thereof for imaging to a subject in need thereof, and applying an imaging technique to detect the emitted γ-rays.

[0025] This application includes a method for diagnosing cancer in a subject, which comprises administering a diagnostically effective amount of one or more compounds of Formula I or one or more complexes thereof to a subject in need thereof, and applying an imaging technique to detect the emitted γ-rays.

[0026] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that although the detailed description and specific embodiments indicate embodiments of the present application, they are given by way of example only, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the whole of the description. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Embodiments of the present application will now be described in more detail with reference to the accompanying drawings, in which:

[0028] Figure 1 is a drawing showing the chelating groups derived from DOTA (left structure) and DOTAGA (right structure) on a compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof when complexed with Lu-177. The complex formed between the chelating group derived from the DOTA group (left structure) on the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof and Lu-177 has a net charge of 0. The complex formed between the chelating group derived from the DOTAGA group (right structure) on the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof and Lu-177 has a net charge of -1.

[0029] Figure 2 is a drawing showing in AR42J tumor-bearing mice (n = 3) 177 the biodistribution (%ID / g) of Lu-C-1. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (%ID / g) at 4 hours, the middle bar at each organ / tissue point shows the biodistribution (%ID / g) at 24 hours, and the rightmost bar at each organ / tissue shows the biodistribution (%ID / g) at 72 hours.

[0030] Figure 3 is a drawing showing in AR42J tumor-bearing mice (n = 3) 177 the biodistribution of Lu-C-4. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (%ID / g) at 4 hours, and the rightmost bar at each organ / tissue point shows the biodistribution (%ID / g) at 24 hours.

[0031] Figure 4 is a drawing showing in AR42J tumor-bearing mice (n = 3) 177Chart of biodistribution of Lu-I-13. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (% ID / g) at 4 hours, the middle bar at each organ / tissue point shows the biodistribution (% ID / g) at 24 hours, and the rightmost bar at each organ / tissue shows the biodistribution (% ID / g) at 72 hours.

[0032] Figure 5 is a chart showing in AR42J tumor-bearing mice (n = 3) 177 Chart of biodistribution of Lu-I-35. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (% ID / g) at 4 hours, the middle bar at each organ / tissue point shows the biodistribution (% ID / g) at 24 hours, and the rightmost bar at each organ / tissue shows the biodistribution (% ID / g) at 72 hours.

[0033] Figure 6 is a chart showing in AR42J tumor-bearing mice (n = 3) 177 Chart of biodistribution of Lu-I-36. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (% ID / g) at 4 hours, the middle bar at each organ / tissue point shows the biodistribution (% ID / g) at 24 hours, and the rightmost bar at each organ / tissue shows the biodistribution (% ID / g) at 72 hours.

[0034] Figure 7 is a chart showing in AR42J tumor-bearing mice (n = 3) 177 Chart of biodistribution of Lu-I-37. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (% ID / g) at 4 hours, the middle bar at each organ / tissue point shows the biodistribution (% ID / g) at 24 hours, and the rightmost bar at each organ / tissue shows the biodistribution.

[0035] Figure 8 is a chart showing in AR42J tumor-bearing mice (n = 3) 177 Chart of biodistribution of Lu-I-54. The leftmost bar (the darkest bar) at each organ / tissue point shows the biodistribution (% ID / g) at 4 hours, the middle bar at each organ / tissue point shows the biodistribution (% ID / g) at 24 hours, and the rightmost bar at each organ / tissue shows the biodistribution. Detailed Description

[0036] I. Definitions

[0037] Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to apply to all embodiments and aspects of the present application as would be understood by one of ordinary skill in the art and suitable for the present application described herein.

[0038] As used herein, the term "comprising" and its derivatives are intended to be open-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not preclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The foregoing also applies to words having similar meanings, such as the terms "including", "having", and their derivatives.

[0039] As used herein, the term "consisting of" and its derivatives are intended to be closed-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers, and / or steps.

[0040] As used herein, the term "consisting essentially of" is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps, as well as features, elements, components, groups, integers, and / or steps that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps.

[0041] Degree terms such as "substantially", "about", and "approximately" as used herein mean a reasonable amount of deviation of the term being modified such that the end result is not significantly changed. If the deviation does not negate the meaning of the term being modified, these degree terms should be understood to include a deviation of at least ±5% of the term being modified.

[0042] As used in this application, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents.

[0043] In embodiments that include an "additional" or "second" component, the second component as used herein is chemically different from the other components or the first component. The "third" component is different from the other components, the first component, and the second component, and further recited or "additional" components are similarly different.

[0044] As used herein, the term "and / or" means that the listed items are present or used individually or in combination. In fact, this term means that "at least one" or "one or more" of the listed items are used or present.

[0045] As used herein, the term "compounds of the present application" and the like refer to compounds of formula I or pharmaceutically acceptable salts and / or solvates thereof.

[0046] As used herein, terms such as "the complex of the present application" refer to a complex comprising one or more compounds of formula I or pharmaceutically acceptable salts and / or solvates thereof and one or more radionuclides.

[0047] As used herein, terms such as "the composition of the present application" refer to a composition comprising one or more compounds or complexes of the present application.

[0048] As used herein, the term "radioligand" refers to a compound comprising a targeting moiety and a radionuclide. The complexes of the present application are examples of radioligands.

[0049] As used herein, the term "radionuclide" refers to any atom capable of undergoing radioactive decay. The term radionuclide is used synonymously herein with radioisotope, radioactive isotope, and radioisotope.

[0050] As used herein, the term "suitable" means that the choice of a particular compound or condition will depend on the specific synthetic manipulations to be performed, the identity of the molecule to be transformed, and / or the specific use of the compound, but the choice will be entirely within the skill of a person trained in the art.

[0051] This description involves many chemical terms and abbreviations used by those skilled in the art. However, definitions of the selected terms are provided for clarity and consistency.

[0052] As used herein, terms such as "protecting group" or "PG" etc. refer to a chemical moiety that protects or masks the reactive moieties of a molecule to prevent side reactions in those reactive moieties of the molecule while manipulating or reacting different parts of the molecule. After the manipulation or reaction is completed, the protecting group is removed under conditions that do not degrade or decompose the remainder of the molecule. Those skilled in the art can make a choice of suitable protecting groups. Many conventional protecting groups are known in the art, such as those described in "Protective Groups in Organic Chemistry", edited by McOmie, J.F.W., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999, and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0053] As used herein, the term "alkyl", whether used alone or as part of another group, means a straight-chain or branched-chain saturated alkyl group. The possible number of carbon atoms in the alkyl group referred to is indicated by the prefix "C n1-n2 ". For example, the term C 1-10 alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Unless otherwise indicated, all alkyl groups are optionally substituted with fluorine.

[0054] As used herein, the term "alkylene", whether used alone or as part of another group, means a straight-chain or branched-chain saturated alkylene group, i.e., a saturated carbon chain having substituents at both ends. The possible number of carbon atoms in the alkylene group referred to is indicated by the prefix "C n1-n2 ". For example, the term C 2-6 alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise indicated, all alkylene groups are optionally substituted with fluorine.

[0055] As used herein, the term "alkenyl", whether used alone or as part of another group, means a straight-chain or branched-chain unsaturated alkyl group containing at least one double bond. The possible number of carbon atoms in the alkenyl group referred to is indicated by the prefix "C n1-n2 ". For example, the term C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond. Unless otherwise indicated, all alkenyl groups are optionally substituted with fluorine.

[0056] As used herein, the term "alkenylene", whether used alone or as part of another group, means a straight-chain or branched-chain unsaturated alkyl group containing at least one double bond and having substituents at both ends. The possible number of carbon atoms in the alkenylene group referred to is indicated by the prefix "C n1-n2 ". For example, the term C 2-6 alkenylene means an alkenylene group having 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise indicated, all alkenylene groups are optionally substituted with fluorine.

[0057] As used herein, the term "aryl", whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and having 6 to 20 carbon atoms.

[0058] As used herein, the term "cycloalkyl", whether used alone or as part of another group, means a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings. The possible number of carbon atoms in the cycloalkyl group referred to is indicated by the numerical prefix "C n1-n2 ". For example, the term C 3-10Cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0059] As used herein, the term "heterocycloalkyl", whether used alone or as part of another group, means a cyclic group containing at least one non-aromatic ring having 3 to 20 atoms, one or more of which are heteroatoms selected from O, S and N, and the remaining atoms are C. Heterocycloalkyl groups are saturated or unsaturated (i.e., contain one or more double bonds). When a heterocycloalkyl group contains the prefix C n1-n2 then this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more (suitably 1 to 5) of the ring atoms are replaced by heteroatoms selected from O, S and N, and the remaining atoms are C. Heterocycloalkyl groups are optionally benzo-fused.

[0060] As used herein, the term "heteroaryl", whether used alone or as part of another group, means a cyclic group containing at least one heteroaromatic ring having 5 - 20 atoms, one or more of which are heteroatoms selected from O, S and N, and the remaining atoms are C. When a heteroaryl group contains the prefix C n1-n2 then this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more (suitably 1 to 5) of the ring atoms are replaced by heteroatoms as defined above. Heteroaryl groups are optionally benzo-fused.

[0061] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups, contain one or more than one ring (i.e., are polycyclic). When a cyclic group contains more than one ring, these rings can be fused, bridged, spiro-fused or linked by a bond.

[0062] As used herein, the term "benzo-fused" means a polycyclic group in which a benzene ring is fused to another ring.

[0063] The first ring is "fused" to the second ring means that the first ring and the second ring share two adjacent atoms therebetween.

[0064] The first ring is "bridged" to the second ring means that the first ring and the second ring share two non-adjacent atoms therebetween.

[0065] The first ring is "spiro-fused" to the second ring means that the first ring and the second ring share one atom therebetween.

[0066] As used herein, the term "target binding group" means the moiety recognized by the target site to which it binds.

[0067] As used herein, the term "target" or "target site" means a receptor, such as a cell surface receptor, an antigen, such as somatostatin type 2 receptor (SSTR2) and / or cholecystokinin 2 receptor (CCK2R) on the cell surface to which a first target binding group, a second targeting group, or both can bind.

[0068] As used herein, the term "chelating group" is a chelating agent capable of complexing a radionuclide.

[0069] As used herein, the term "trivalent branching group" refers to any molecular structure comprising at least three terminal functional groups, and each terminal functional group is linked to another molecular structure. The at least three terminal functional groups may be the same or different.

[0070] As used herein, the term "linker" refers to any molecular structure that links two or more other molecular structures together.

[0071] As used herein, the term "atomic length" refers to the number of atoms in a chain. For example, the atomic length of the atomic chain of "N-C-C" is 3 atoms.

[0072] As used herein, the term "length" with respect to a linker refers to the linker L 1 、L 2 and / or L 3 of the backbone of the atomic length.

[0073] As used herein, the term "L 1 、L 2 and L 3 collective length" refers to the total atomic length of the backbone of each bivalent linker L 1 、L 2 and L 3 , that is, the total number of atoms in the backbone of the linker that separates the chelating group (E), the first target binding group (Z 1 ) and / or the second target binding group (Z 2 ) from the trivalent branching group (T). For example, the length of a bivalent linker comprising a glycine residue that separately links the chelating group (E), the first target binding group (Z 1 ) or the second target binding group (Z 2 ) to the trivalent branching group (T) through its amino and carboxyl functional groups is 3 atoms (i.e., the backbone atomic chain is "N-C-C").

[0074] As used herein, the term "amino acid residue" refers to an amino acid without the "-OH" of its carboxyl group and the "H" portion of its amino group.

[0075] As used herein, the term "amino acid" comprises a carboxyl (-CO 2 H) functional group and an amine (-NH2 ) any compound of a functional group.

[0076] As used herein, the term "unnatural amino acid" refers to an amino acid that is not naturally occurring and is obtained by synthesis or by modifying a natural amino acid.

[0077] As used herein, the term "naturally occurring amino acid" refers to an amino acid that is naturally occurring and encoded by the genetic code, as well as those encoded amino acids that are subsequently modified in vivo.

[0078] When referring to a compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof when complexed with a radionuclide, the term "net charge" as used herein is the balance of the number of positive and negative charges of the complex. The net charge is measured at physiological pH.

[0079] The term "at least one", when preceding an item, refers to a single member of that item, or when preceding a list of items, refers to a single member of that item and any combination of those items. For example, "at least one of a, b, or c" is intended to cover a, b, c, a-b, a-c, b-c, and a-b-c, as well as any combination having multiple identical elements (e.g., a-a, a-a-a, a-a-b, a-a-c, a-b-b, a-c-c, b-b, b-b-b, b-b-c, c-c, and c-c-c, or any other permutation of a, b, and c).

[0080] As used herein and as is well understood in the art, the term "treatment" means a method for obtaining a beneficial or desired result (including a clinical result). Beneficial or desired clinical results include, but are not limited to, alleviating or improving one or more symptoms or conditions, reducing the severity of a disease, stabilizing a disease state (i.e., preventing it from worsening), preventing the spread of a disease, delaying or slowing the progression of a disease, improving or alleviating a disease state, reducing the recurrence of a disease, and remission (whether partial or complete), whether detectable or not. "Treatment" can also mean prolonging survival compared to the expected survival in the absence of treatment. For example, a subject with early-stage cancer can be treated to prevent its progression, or alternatively, a subject in remission can be treated with a compound or composition of the present application to prevent recurrence. Treatment methods include administering to a subject a therapeutically effective amount of one or more compounds of the present application, and optionally consisting of a single administration, or alternatively including a series of administrations.

[0081] "Mitigating" a disease, disorder, or condition means reducing the severity and / or adverse clinical manifestations of the disease, disorder, or condition, and / or slowing or prolonging the course of progression, compared to not treating the condition.

[0082] As used herein, the term "prevent" or "prevention" or synonyms thereof refers to reducing the risk or probability that a patient will develop a disease, disorder or condition or exhibit symptoms associated with a disease, disorder or condition.

[0083] As used herein, the term "therapeutically effective amount" means an amount of a compound or one or more compounds of the present application or a complex or one or more complexes of the present application that is effective at the dosage and for the time period necessary to achieve the desired result.

[0084] When used in connection with one or more complexes of the present application, the term "imaging effective amount" is the amount of the complex sufficient to produce a visible image when the complex is administered to a subject and the radiation emitted by the complex is detected using positron emission tomography ("PET") or single photon emission computed tomography ("SPECT") or autoradiography or ex vivo or in vitro binding assays.

[0085] As used herein, the term "diagnostically effective amount" means an amount of a compound or one or more compounds of the present application or a complex or one or more complexes of the present application that is effective at the dosage and for the time period necessary to achieve the desired diagnostic effect (e.g., including diagnosing a particular condition being evaluated).

[0086] As used herein, the term "administer" means to apply a therapeutically effective amount of one or more compounds, complexes or compositions of the present application to a cell, tissue, organ or subject.

[0087] As used herein, the term "cancer" refers to a state of a cell proliferative disease.

[0088] As used herein, the term "subject" includes all members of the animal kingdom (including mammals) and is suitable to refer to a human. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0089] As used herein, the term "cell" refers to a single cell or multiple cells and includes cells in either a cell culture or a subject.

[0090] The term "pharmaceutically acceptable" means compatible with the treatment of a subject (e.g., a human).

[0091] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with the active ingredient to permit the formation of a pharmaceutical composition (i.e., a dosage form capable of being administered to a subject).

[0092] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a subject.

[0093] An acid addition salt suitable for use in the treatment of a subject or compatible therewith is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0094] A base addition salt suitable for use in the treatment of a subject or compatible therewith is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0095] As used herein, the term "solvate" means a compound, or a salt and / or prodrug of a compound, in which the lattice contains suitable solvent molecules. The suitable solvent is physiologically tolerable at the dosage administered.

[0096] The symbol When drawn vertically across a bond indicates the covalent attachment point of a chemical group.

[0097] When used, for example, in connection with the treatment methods, uses, compositions, packages, and / or kits of the present application, a subject (e.g., a "subject in need") is a subject who would benefit from the administration of one or more compounds or complexes or pharmaceutically acceptable salts and / or solvates thereof of the present application.

[0098] As used herein, the term "DCM" refers to dichloromethane.

[0099] As used herein, the term "DMF" refers to dimethylformamide.

[0100] As used herein, the term "DIC" refers to N,N′-diisopropylcarbodiimide.

[0101] As used herein, the term "DMAP" refers to 4-dimethylaminopyridine.

[0102] As used herein, the term "PyBOP" refers to benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate.

[0103] As used herein, the term "HOBt" refers to hydroxybenzotriazole.

[0104] As used herein, the term "DIEA" refers to diisopropylethylamine.

[0105] As used herein, the term "HFIP" refers to hexafluoroisopropanol.

[0106] As used herein, the term "TFA" refers to trifluoroacetic acid.

[0107] As used herein, the term "TIS" refers to triisopropylsilane.

[0108] As used herein, the term "MTBE" refers to methyl tert-butyl ether.

[0109] As used herein, the term "ACN" refers to acetonitrile.

[0110] As used herein, the term "BSA" refers to N,O-bis(trimethylsilyl)acetamide.

[0111] As used herein, the term "PBS" refers to phosphate buffered saline.

[0112] As used herein, the term r.t. refers to room temperature.

[0113] II. Compounds and Complexes of the Present Application

[0114] The Applicant has developed a dual-targeting radioligand capable of recognizing both somatostatin receptor type 2 (SSTR2) and cholecystokinin receptor type 2 (CCK2R). When complexed with a radionuclide, the radioligand forms a radiopharmaceutical that can be used, for example, in the diagnosis and / or treatment of tumors (such as tumors overexpressing either SSTR2 or CCK2R).

[0115] Those skilled in the art will understand that a dual-receptor targeting radioligand will need to maintain sufficient and balanced binding affinities for both receptors. Further, since the dual-targeting radioligand is based on two single-target receptor-binding compounds, it will be understood that the dual-targeting radioligand will have physicochemical properties significantly different from either of the single-target receptor-binding parent compounds. Thus, the non-target-driven biodistribution pattern of the single-target receptor-binding compound can be greatly altered. In addition, the undesired distribution of the radioligand in vivo can also be target-driven, so the dual-targeting vector may exacerbate this target-directed normal organ accumulation.

[0116] The Applicant has investigated chemical and biophysical properties such as molecular size, hydrophobicity, net charge, charge distribution, and distribution of hydrophobic regions to determine the factors contributing to the biodistribution profile of the radioligand when complexed with a radionuclide. By modulating the net charge and / or hydrophobicity of the radioligand when complexed with a radionuclide, the Applicant has developed the dual-targeting radioligand compounds of the present application that exhibit good binding affinities for both somatostatin receptor type 2 (SSTR2) and cholecystokinin receptor type 2 (CCK2R).

[0117] Further, the exemplary dual-targeting radioligand compounds of the present application have been shown to have increased target cell radionuclide uptake while keeping off-target normal organ accumulation to a minimum. Normal organs include, but are not limited to, the kidneys and the liver.

[0118] Accordingly, the present application includes a compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0119]

[0120] wherein

[0121] E is a chelating group;

[0122] T is a trivalent branching group;

[0123] Z 1 is a cholecystokinin-2 receptor (CCK2R) binding group;

[0124] Z 2 is a somatostatin receptor 2 (SSTR2) binding group;

[0125] L 1 、L 2 and L 3 are each independently a direct bond or a divalent linker.

[0126] In some embodiments, the CCK2R binding group is a benzodiazepine moiety of formula II moiety,

[0127]

[0128] wherein

[0129] R 1 is selected from H, halogen, and C 1-6 alkyl;

[0130] R 2 is selected from C 1-6 alkyl, NH 2 、NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ;

[0131] R 3 is selected from H, halogen, and C 1-6 alkyl;

[0132] R 4 is selected from C 5-6 cycloalkyl and phenyl; and

[0133] m is 0, 1, 2, or 3; and

[0134] n is 0, 1, 2, or 3.

[0135] In some embodiments, the somatostatin receptor 2 (SSTR2) binding group is a somatostatin analog. In some embodiments, Z 2Selected from D-Phe-c[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Thr(ol) (Tyr 3-octreotide), the H-D-Phe-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr(ol) (octreotide) moiety, and the D-Phe-c[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Thr(Tyr3-octreotate) moiety.

[0136] Thus, in some embodiments, Z 2 is a somatostatin receptor 2 (SSTR2) binding group, and the somatostatin receptor 2 (SSTR2) binding group is a moiety of Formula III,

[0137]

[0138] wherein:

[0139] R 3a is selected from CH 2 OH, CO 2 H, and CONH 2 .

[0140] Thus, in some embodiments, the compound of Formula I is a compound of Formula I-A or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0141]

[0142] where

[0143] E is a chelating group;

[0144] T is a trivalent branching group;

[0145] L 1 , L 2 , and L 3 are each independently a direct bond or a divalent linker;

[0146] R 1 is selected from H, halogen, and C 1-6 alkyl;

[0147] R 2 is selected from C 1-6 alkyl, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 alkyl) 2 ;

[0148] R 3 is selected from H, halogen, and C 1-6 alkyl;

[0149] R 3a is selected from CH 2 OH, CO 2 H, and CONH 2 ;

[0150] R 4 is selected from C 5-6 cycloalkyl and phenyl; and

[0151] m is 0, 1, 2, or 3; and

[0152] n is 0, 1, 2, or 3.

[0153] In some embodiments, R 1 and R 3 are independently selected from H, F, Cl, CH 3 , CH 2 CH 3 CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 3 CH(CH 3 ) 2 and C(CH 3 ) 3 . In some embodiments, R 1 and R 3 are independently selected from H, CH 3 , CH 2 CH 3 CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 3 CH(CH 3 ) 2 and C(CH 3 ) 3 . In some embodiments, R 1 and R 3 are both H.

[0154] In some embodiments, R 2 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH2 CH 3 、CH(CH 3 ) 2 , C(CH 3 ) 3 NH 2 NH(CH 3 ) and N(CH 3 ) 2 In some embodiments, R 2 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 、CH(CH 3 ) 2 and C(CH 3 ) 3 In some embodiments, R 2 It is C(CH 3 ) 3 .

[0155] In some embodiments, R 3a Selected from CH 2 OH and CONH 2 In some embodiments, R 3a Yes CH 2 OH. In some embodiments, R 3a It is CONH 2 In some embodiments, R 3a It is CO 2 H.

[0156] In some embodiments, R 4 is selected from the group consisting of cyclopentyl, cyclohexyl and phenyl. 4 is selected from cyclohexyl and phenyl. 4 It is cyclohexyl.

[0157] In some embodiments, m is 0 or 1. In some embodiments, m is 1.

[0158] In some embodiments, n is 0 or 1. In some embodiments, n is 0.

[0159] In some embodiments, Z 1 is a CCK2R binding group, and the CCK2R binding group is a Z360 portion, and Z360 has the following structure

[0160]

[0161] Thus, in some embodiments, the compound of formula I has the following structure,

[0162]

[0163] or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof

[0164] wherein

[0165] E, T, L 1 , L 2 and L 3 are as defined in formula I, and

[0166] R 3a is selected from CH 2 OH, CO 2 H, and CONH 2 .

[0167] In some embodiments, Z 2 is an SSTR2 binding group, and the SSTR2 binding group is a moiety of formula III, wherein R a is CO 2 H, and the compound of formula III is the Tyr 3-octreotate moiety, and Tyr 3-octreotate has the following structure:

[0168]

[0169] Thus, in some embodiments, the compound of formula I is a compound of formula I-A(i) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,

[0170]

[0171] wherein

[0172] E, T, L 1 , L 2 and L 3 are as defined in formula I.

[0173] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from positive two (+2) to negative five (-5) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from positive one (+1) to negative five (-5) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from positive one (+1) to negative two (-2) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from positive one (+1) to negative one (-1) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from zero (0) to negative five (-5) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from zero (0) to negative four (-4) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from zero (0) to negative three (-3) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from zero (0) to negative two (-2) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of zero (0) or negative one (-1) when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of 0 when complexed with a radionuclide. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of -1 when complexed with a radionuclide.

[0174] Those skilled in the art will understand that the net charge of the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof upon complexation represents the radionuclide chelation state of an exemplary compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof at physiological pH. For example, in an exemplary embodiment, when the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof comprises a chelating group E that comprises three free carboxylic acid groups (e.g., when E is derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)), then the chelating group of the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, upon complexation with a radionuclide having a positive three charge (e.g., 177When complexed, it will have a net charge of 0. In a further exemplary embodiment, when the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof comprises a chelating group E which comprises four free carboxylic acid groups (e.g., when E is derived from a 1,4,7,10-tetraazacyclodecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA) moiety), then the chelating group of the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof will have a net charge of -1 when complexed with a radionuclide having a positive three charge (e.g., Lu-177). A schematic diagram of the chelating group of the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof (e.g., derived from DOTA or DOTAGA) when complexed with Lu-177 is shown in Figure 1 is shown.

[0175] Those skilled in the art will further understand that additional charged groups may be present in the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. For example, additional charged groups may be present in each of the cholecystokinin-2 receptor (CCK2R) binding group, the somatostatin receptor 2 (SSTR2) binding group or the bivalent linker. Any additional free carboxyl groups (e.g., may be from glutamic acid or γ-glutamic acid residues) will be considered to contribute a net -1 charge per free carboxyl group, and any additional free amino groups (e.g., may be from the ε amine of a lysine residue or the guanidine group of an arginine residue) will be considered to contribute a +1 charge per free amine.

[0176] In some embodiments, L 1 、L 2 and L 3 have a combined length of from 0 atoms to 80 atoms. In some embodiments, L 1 、L 2 and L 3 have a combined length of from 0 atoms to 80 atoms, from 0 atoms to 51 atoms, from 0 atoms to 49 atoms, from 0 atoms to 47 atoms, from 0 atoms to 37 atoms, from 0 atoms to 27 atoms, from 0 atoms to 26 atoms, from 0 atoms to 22 atoms, from 0 atoms to 21 atoms, from 0 atoms to 18 atoms, from 0 atoms to 15 atoms, from 0 atoms to 13 atoms, from 0 atoms to 12 atoms, from 0 atoms to 9 atoms, from 0 atoms to 7 atoms, from 0 atoms to 6 atoms, from 0 atoms to 3 atoms. In some embodiments, L 1 、L 2 and L 3 have a combined length of from 0 atoms to 70 atoms. In some embodiments, L 1 、L 2 and L 3The total length is from 0 atoms to 70 atoms, from 0 atoms to 69 atoms, from 0 atoms to 67 atoms, from 0 atoms to 63 atoms, from 0 atoms to 60 atoms, from 0 atoms to 56 atoms, from 0 atoms to 54 atoms, from 0 atoms to 50 atoms, from 0 atoms to 46 atoms, from 0 atoms to 43 atoms, from 0 atoms to 40 atoms, from 0 atoms to 36 atoms, from 0 atoms to 33 atoms, from 0 atoms to 30 atoms, from 0 atoms to 27 atoms, from 0 atoms to 26 atoms, from 0 atoms to 21 atoms, from 0 atoms to 18 atoms, from 0 atoms to 15 atoms, from 0 atoms to 13 atoms, from 0 atoms to 12 atoms, from 0 atoms to 9 atoms, from 0 atoms to 7 atoms, from 0 atoms to 6 atoms, from 0 atoms to 3 atoms, from 3 atoms to 70 atoms, from 3 atoms to 69 atoms, from 3 atoms to 67 atoms, from 3 atoms to 63 atoms, from 3 atoms to 60 atoms, from 3 atoms to 56 atoms, from 3 atoms to 54 atoms, from 3 atoms to 50 atoms, from 3 atoms to 46 atoms, from 3 atoms to 43 atoms, from 3 atoms to 40 atoms, from 3 atoms to 36 atoms, from 3 atoms to 33 atoms, from 3 atoms to 30 atoms, from 3 atoms to 27 atoms, from 3 atoms to 21 atoms, from 3 atoms to 18 atoms, from 3 atoms to 15 atoms, from 3 atoms to 13 atoms, from 3 atoms to 12 atoms, from 3 atoms to 9 atoms, from 3 atoms to 7 atoms, from 3 atoms to 6 atoms, from 6 atoms to 70 atoms, from 6 atoms to 69 atoms, from 6 atoms to 67 atoms, from 6 atoms to 63 atoms, from 6 atoms to 60 atoms, from 6 atoms to 56 atoms, from 6 atoms to 54 atoms, from 6 atoms to 50 atoms, from 6 atoms to 46 atoms, from 6 atoms to 43 atoms, from 6 atoms to 40 atoms, from 6 atoms to 36 atoms, from 6 atoms to 33 atoms, from 6 atoms to 30 atoms, from 6 atoms to 27 atoms, from 6 atoms to 21 atoms, from 6 atoms to 18 atoms, from 6 atoms to 15 atoms, from 6 atoms to 13 atoms, from 6 atoms to 12 atoms, from 6 atoms to 9 atoms, from 9 atoms to 70 atoms, from 9 atoms to 69 atoms, from 9 atoms to 67 atoms, from 9 atoms to 63 atoms, from 9 atoms to 60 atoms, from 9 atoms to 56 atoms, from 9 atoms to 54 atoms, from 9 atoms to 50 atoms, from 9 atoms to 46 atoms, from 9 atoms to 43 atoms, from 9 atoms to 40 atoms, from 9 atoms to 36 atoms, from 9 atoms to 33 atoms, from 9 atoms to 30 atoms, from 9 atoms to 27 atoms, from 9 atoms to 21 atoms, from 9 atoms to 18 atoms, from 9 atoms to 15 atoms, from 9 atoms to 12 atoms, from 12 atoms to 70 atoms, from 12 atoms to 69 atoms,from 12 to 67 atoms, from 12 to 63 atoms, from 12 to 60 atoms, from 12 to 56 atoms, from 12 to 54 atoms, from 12 to 50 atoms, from 12 to 46 atoms, from 12 to 43 atoms, from 12 to 40 atoms, from 12 to 36 atoms, from 12 to 33 atoms, from 12 to 30 atoms, from 12 to 27 atoms, from 12 to 21 atoms, from 12 to 18 atoms, from 12 to 15 atoms, from 15 to 70 atoms, from 15 to 69 atoms, from 15 to 67 atoms, from 15 to 63 atoms, from 15 to 60 atoms, from 15 to 56 atoms, from 15 to 54 atoms, from 15 to 50 atoms, from 15 to 46 atoms, from 15 to 43 atoms, from 15 to 40 atoms, from 15 to 36 atoms, from 15 to 33 atoms, from 15 to 30 atoms, from 15 to 27 atoms, from 15 to 21 atoms, from 15 to 18 atoms, from 18 to 70 atoms, from 18 to 69 atoms, from 18 to 67 atoms, from 18 to 63 atoms, from 18 to 60 atoms, from 18 to 56 atoms, from 18 to 54 atoms, from 18 to 50 atoms, from 18 to 46 atoms, from 18 to 43 atoms, from 18 to 40 atoms, from 18 to 36 atoms, from 18 to 33 atoms, from 18 to 30 atoms, from 18 to 27 atoms, from 18 to 21 atoms, from 21 to 27 atoms, from 21 to 70 atoms, from 21 to 67 atoms, from 21 to 60 atoms, from 21 to 54 atoms, from 21 to 46 atoms, from 21 to 27 atoms, from 27 to 70 atoms, from 27 to 67 atoms, from 27 to 60 atoms, from 27 to 54 atoms, from 27 to 46 atoms, from 21 to 35 atoms, from 33 to 70 atoms, from 33 to 67 atoms, from 33 to 60 atoms, from 33 to 54 atoms, from 33 to 46 atoms, from 33 to 36 atoms, from 40 to 70 atoms, from 40 to 67 atoms, from 40 to 60 atoms, from 40 to 54 atoms, from 40 to 46 atoms or from 45 to 60 atoms.

[0177] In some embodiments, L 1 、L 2 and L 3has a total length of from 0 atoms to 47 atoms, from 0 atoms to 46 atoms, from 0 atoms to 43 atoms, from 0 atoms to 41 atoms, from 0 atoms to 40 atoms, from 0 atoms to 36 atoms, from 0 atoms to 37 atoms, from 0 atoms to 33 atoms, from 0 atoms to 30 atoms, from 0 atoms to 27 atoms, from 0 atoms to 26 atoms, from 0 atoms to 22 atoms, from 0 atoms to 21 atoms, from 0 atoms to 18 atoms, from 0 atoms to 15 atoms, from 0 atoms to 13 atoms, from 0 atoms to 12 atoms, from 0 atoms to 9 atoms, from 0 atoms to 7 atoms, from 0 atoms to 6 atoms, or from 0 atoms to 3 atoms. In some embodiments, L 1 、L 2 and L 3 has a total length of from 0 atoms to 47 atoms, from 0 atoms to 46 atoms, from 0 atoms to 43 atoms, from 0 atoms to 41 atoms, from 0 atoms to 40 atoms, from 0 atoms to 36 atoms, from 0 atoms to 37 atoms, from 0 atoms to 33 atoms, from 0 atoms to 30 atoms, or from 0 atoms to 27 atoms. In some embodiments, L 1 、L 2 and L 3 has a total length of from 0 atoms to 27 atoms.

[0178] In some embodiments, L 1 、L 2 and L 3 has a total length of from 0 atoms to 26 atoms, from 0 atoms to 21 atoms, from 0 atoms to 18 atoms, from 0 atoms to 15 atoms, from 0 atoms to 12 atoms, from 0 atoms to 9 atoms, from 0 atoms to 7 atoms, from 0 atoms to 6 atoms, from 0 atoms to 3 atoms, from 3 atoms to 27 atoms, from 3 atoms to 21 atoms, from 3 atoms to 18 atoms, from 3 atoms to 15 atoms, from 3 atoms to 12 atoms, from 3 atoms to 9 atoms, from 3 atoms to 6 atoms, from 6 atoms to 27 atoms, from 6 atoms to 21 atoms, from 6 atoms to 18 atoms, from 6 atoms to 15 atoms, from 6 atoms to 12 atoms, from 6 atoms to 9 atoms, from 9 atoms to 27 atoms, from 9 atoms to 21 atoms, from 9 atoms to 18 atoms, from 9 atoms to 15 atoms, from 9 atoms to 12 atoms, from 12 atoms to 27 atoms, from 12 atoms to 21 atoms, from 12 atoms to 18 atoms, from 12 atoms to 15 atoms, from 15 atoms to 27 atoms, from 15 atoms to 21 atoms, from 15 atoms to 18 atoms, from 18 atoms to 27 atoms, from 18 atoms to 21 atoms, or from 21 atoms to 27 atoms.

[0179] In some embodiments, L 1 、L 2 and L 3 have a combined length of from 0 atoms to 27 atoms, from 0 atoms to 21 atoms, from 0 atoms to 18 atoms, from 0 atoms to 15 atoms, from 0 atoms to 12 atoms, from 0 atoms to 9 atoms, from 0 atoms to 7 atoms, from 0 atoms to 6 atoms, from 0 atoms to 3 atoms, from 3 atoms to 27 atoms, from 3 atoms to 21 atoms, from 3 atoms to 18 atoms, from 3 atoms to 15 atoms, from 3 atoms to 12 atoms, from 3 atoms to 9 atoms, from 3 atoms to 6 atoms, from 6 atoms to 27 atoms, from 6 atoms to 21 atoms, from 6 atoms to 18 atoms, from 6 atoms to 15 atoms, from 6 atoms to 12 atoms, from 6 atoms to 9 atoms, from 9 atoms to 27 atoms, from 9 atoms to 21 atoms, from 9 atoms to 18 atoms, from 9 atoms to 15 atoms, from 9 atoms to 12 atoms, from 18 atoms to 27 atoms, or from 18 atoms to 21 atoms.

[0180] In some embodiments, L 1 、L 2 and L 3 have a combined length of 0 atoms, 3 atoms, 6 atoms, 7 atoms, 9 atoms, 12 atoms, 13 atoms, 15 atoms, 18 atoms, 21 atoms, 24 atoms, or 27 atoms. In some embodiments, L 1 、L 2 and L 3 have a combined length of 0 atoms, 3 atoms, 6 atoms, 7 atoms, 9 atoms, 12 atoms, 13 atoms, 15 atoms, or 18 atoms. In some embodiments, L 1 、L 2 and L 3 have a combined length of 9 atoms.

[0181] In some embodiments, each of L 1 、L 2 and L 3 independently has a length of from 0 atoms to 80 atoms. In some embodiments, each of L 1 、L 2 and L 3 independently has a length of from 0 atoms to 70 atoms.

[0182] In some embodiments, each of L 1 、L 2 and L 3 independently has a length of from 0 atoms to 80 atoms. In some embodiments, L 1, L 2 and L 3 each independently has a length of from 0 atoms to 70 atoms. In some embodiments, L 1 , L 2 and L 3Each independently has from 0 to 70 atoms, from 0 to 69 atoms, from 0 to 67 atoms, from 0 to 63 atoms, from 0 to 60 atoms, from 0 to 56 atoms, from 0 to 54 atoms, from 0 to 50 atoms, from 0 to 46 atoms, from 0 to 43 atoms, from 0 to 40 atoms, from 0 to 36 atoms, from 0 to 33 atoms, from 0 to 30 atoms, from 0 to 27 atoms, from 0 to 26 atoms, from 0 to 21 atoms, from 0 to 18 atoms, from 0 to 15 atoms, from 0 to 13 atoms, from 0 to 12 atoms, from 0 to 9 atoms, from 0 to 7 atoms, from 0 to 6 atoms, from 0 to 3 atoms, from 3 to 70 atoms, from 3 to 69 atoms, from 3 to 67 atoms, from 3 to 63 atoms, from 3 to 60 atoms, from 3 to 56 atoms, from 3 to 54 atoms, from 3 to 50 atoms, from 3 to 46 atoms, from 3 to 43 atoms, from 3 to 40 atoms, from 3 to 36 atoms, from 3 to 33 atoms, from 3 to 30 atoms, from 3 to 27 atoms, from 3 to 21 atoms, from 3 to 18 atoms, from 3 to 15 atoms, from 3 to 13 atoms, from 3 to 12 atoms, from 3 to 9 atoms, from 3 to 7 atoms, from 3 to 6 atoms, from 6 to 70 atoms, from 6 to 69 atoms, from 6 to 67 atoms, from 6 to 63 atoms, from 6 to 60 atoms, from 6 to 56 atoms, from 6 to 54 atoms, from 6 to 50 atoms, from 6 to 46 atoms, from 6 to 43 atoms, from 6 to 40 atoms, from 6 to 36 atoms, from 6 to 33 atoms, from 6 to 30 atoms, from 6 to 27 atoms, from 6 to 21 atoms, from 6 to 18 atoms, from 6 to 15 atoms, from 6 to 13 atoms, from 6 to 12 atoms, from 6 to 9 atoms, from 9 to 70 atoms, from 9 to 69 atoms, from 9 to 67 atoms, from 9 to 63 atoms, from 9 to 60 atoms, from 9 to 56 atoms, from 9 to 54 atoms, from 9 to 50 atoms, from 9 to 46 atoms, from 9 to 43 atoms, from 9 to 40 atoms, from 9 to 36 atoms, from 9 to 33 atoms, from 9 to 30 atoms, from 9 to 27 atoms, from 9 to 21 atoms, from 9 to 18 atoms, from 9 to 15 atoms, from 9 to 12 atoms, from 12 to 70 atoms, from 12 to 69 atoms,Lengths of from 12 to 67 atoms, from 12 to 63 atoms, from 12 to 60 atoms, from 12 to 56 atoms, from 12 to 54 atoms, from 12 to 50 atoms, from 12 to 46 atoms, from 12 to 43 atoms, from 12 to 40 atoms, from 12 to 36 atoms, from 12 to 33 atoms, from 12 to 30 atoms, from 12 to 27 atoms, from 12 to 21 atoms, from 12 to 18 atoms, from 12 to 15 atoms, from 15 to 70 atoms, from 15 to 69 atoms, from 15 to 67 atoms, from 15 to 63 atoms, from 15 to 60 atoms, from 15 to 56 atoms, from 15 to 54 atoms, from 15 to 50 atoms, from 15 to 46 atoms, from 15 to 43 atoms, from 15 to 40 atoms, from 15 to 36 atoms, from 15 to 33 atoms, from 15 to 30 atoms, from 15 to 27 atoms, from 15 to 21 atoms, from 15 to 18 atoms, from 18 to 70 atoms, from 18 to 69 atoms, from 18 to 67 atoms, from 18 to 63 atoms, from 18 to 60 atoms, from 18 to 56 atoms, from 18 to 54 atoms, from 18 to 50 atoms, from 18 to 46 atoms, from 18 to 43 atoms, from 18 to 40 atoms, from 18 to 36 atoms, from 18 to 33 atoms, from 18 to 30 atoms, from 18 to 27 atoms, from 18 to 21 atoms, from 21 to 27 atoms, from 21 to 70 atoms, from 21 to 67 atoms, from 21 to 60 atoms, from 21 to 54 atoms, from 21 to 46 atoms, from 21 to 27 atoms, from 27 to 70 atoms, from 27 to 67 atoms, from 27 to 60 atoms, from 27 to 54 atoms, from 27 to 46 atoms, from 21 to 35 atoms, from 33 to 70 atoms, from 33 to 67 atoms, from 33 to 60 atoms, from 33 to 54 atoms, from 33 to 46 atoms, from 33 to 36 atoms, from 40 to 70 atoms, from 40 to 67 atoms, from 40 to 60 atoms, from 40 to 54 atoms, from 40 to 46 atoms or from 45 to 60 atoms.,

[0183] In some embodiments, L 1 、L 2 and L 3Each independently has a length of from 0 atoms to 80 atoms. In some embodiments, L 1 、L 2 and L 3 Each independently has a length of from 0 atoms to 70 atoms. In some embodiments, L 1 、L 2 and L 3Each independently has from 0 to 70 atoms, from 0 to 69 atoms, from 0 to 67 atoms, from 0 to 63 atoms, from 0 to 60 atoms, from 0 to 56 atoms, from 0 to 54 atoms, from 0 to 50 atoms, from 0 to 46 atoms, from 0 to 43 atoms, from 0 to 40 atoms, from 0 to 36 atoms, from 0 to 33 atoms, from 3 to 70 atoms, from 3 to 69 atoms, from 3 to 67 atoms, from 3 to 63 atoms, from 3 to 60 atoms, from 3 to 56 atoms, from 3 to 54 atoms, from 3 to 50 atoms, from 3 to 46 atoms, from 3 to 43 atoms, from 3 to 40 atoms, from 3 to 36 atoms, from 3 to 33 atoms, from 3 to 30 atoms, from 6 to 70 atoms, from 6 to 69 atoms, from 6 to 67 atoms, from 6 to 63 atoms, from 6 to 60 atoms, from 6 to 56 atoms, from 6 to 54 atoms, from 6 to 50 atoms, from 6 to 46 atoms, from 6 to 43 atoms, from 6 to 40 atoms, from 6 to 36 atoms, from 6 to 33 atoms, from 9 to 70 atoms, from 9 to 69 atoms, from 9 to 67 atoms, from 9 to 63 atoms, from 9 to 60 atoms, from 9 to 56 atoms, from 9 to 54 atoms, from 9 to 50 atoms, from 9 to 46 atoms, from 9 to 43 atoms, from 9 to 40 atoms, from 9 to 36 atoms, from 9 to 33 atoms, from 9 to 30 atoms, from 12 to 70 atoms, from 12 to 69 atoms, from 12 to 67 atoms, from 12 to 63 atoms, from 12 to 60 atoms, from 12 to 56 atoms, from 12 to 54 atoms, from 12 to 50 atoms, from 12 to 46 atoms, from 12 to 43 atoms, from 12 to 40 atoms, from 12 to 36 atoms, from 12 to 33 atoms, from 15 to 70 atoms, from 15 to 69 atoms, from 15 to 67 atoms, from 15 to 63 atoms, from 15 to 60 atoms, from 15 to 56 atoms, from 15 to 54 atoms, from 15 to 50 atoms, from 15 to 46 atoms, from 15 to 43 atoms, from 15 to 40 atoms, from 15 to 36 atoms, from 15 to 33 atoms, from 18 to 70 atoms, from 18 to 69 atoms, from 18 to 67 atoms, from 18 to 63 atoms, from 18 to 60 atoms, from 18 to 56 atoms, from 18 to 54 atoms,a length of from 18 to 50 atoms, from 18 to 46 atoms, from 18 to 43 atoms, from 18 to 40 atoms, from 18 to 36 atoms, from 21 to 70 atoms, from 21 to 67 atoms, from 21 to 60 atoms, from 21 to 54 atoms, from 21 to 46 atoms, from 21 to 27 atoms, from 27 to 70 atoms, from 27 to 67 atoms, from 27 to 60 atoms, from 27 to 54 atoms, from 27 to 46 atoms, from 21 to 35 atoms, from 33 to 70 atoms, from 33 to 67 atoms, from 33 to 60 atoms, from 33 to 54 atoms, from 33 to 46 atoms, from 33 to 36 atoms, from 40 to 70 atoms, from 40 to 67 atoms, from 40 to 60 atoms, from 40 to 54 atoms, from 40 to 46 atoms, or from 45 to 60 atoms.

[0184] In some embodiments, L 1 , L 2 and L 3 each independently has a length of from 0 to 47 atoms, from 0 to 46 atoms, from 0 to 43 atoms, from 0 to 41 atoms, from 0 to 40 atoms, from 0 to 36 atoms, from 0 to 37 atoms, from 0 to 33 atoms, from 0 to 30 atoms, from 0 to 27 atoms, from 0 to 26 atoms, from 0 to 22 atoms, from 0 to 21 atoms, from 0 to 18 atoms, from 0 to 15 atoms, from 0 to 13 atoms, from 0 to 12 atoms, from 0 to 9 atoms, from 0 to 7 atoms, from 0 to 6 atoms, or from 0 to 3 atoms. In some embodiments, L 1 , L 2 and L 3 each independently has a length of from 0 to 47 atoms, from 0 to 46 atoms, from 0 to 43 atoms, from 0 to 41 atoms, from 0 to 40 atoms, from 0 to 36 atoms, from 0 to 37 atoms, from 0 to 33 atoms, from 0 to 30 atoms, or from 0 to 27 atoms. In some embodiments, L 1 , L 2 and L 3 each independently has a length of from 0 to 27 atoms.

[0185] In some embodiments, L 1 , L 2 and L 3Each of them independently has a length of from 0 atoms to 27 atoms, from 0 atoms to 21 atoms, from 0 atoms to 18 atoms, from 0 atoms to 15 atoms, from 0 atoms to 13 atoms, from 0 atoms to 12 atoms, from 0 atoms to 9 atoms, from 0 atoms to 6 atoms, from 3 atoms to 27 atoms, from 3 atoms to 18 atoms, from 6 atoms to 27 atoms, from 6 atoms to 18 atoms, from 9 atoms to 27 atoms, from 9 atoms to 21 atoms, or from 9 atoms to 18 atoms.

[0186] In some embodiments, L 1 , L 2 and L 3 each independently has a length of 0 atoms, 3 atoms, 6 atoms, 7 atoms, 9 atoms, 12 atoms, 13 atoms, 15 atoms, 18 atoms, 21 atoms, 24 atoms, or 27 atoms. In some embodiments, L 1 , L 2 and L 3 each has a length of 0 atoms, 3 atoms, 6 atoms, 7 atoms, 9 atoms, 12 atoms, 13 atoms, 15 atoms, or 18 atoms.

[0187] In some embodiments, one of L 1 , L 2 and L 3 is a direct bond. In some embodiments, L 1 is a direct bond. In some embodiments, two of L 1 , L 2 and L 3 are direct bonds. In some embodiments, L 2 and L 3 are both direct bonds. In some embodiments, L 1 , L 2 and L 3 are both direct bonds.

[0188] Those skilled in the art will understand that L 1 , L 2 and / or L 3 having a length of 0 atoms or the total length of L 1 , L 2 and L 3 being 0 respectively means that L 1 , L 2 and / or L 3 is a direct bond or each of L 1 , L 2 and L 3 is a direct bond.

[0189] In some embodiments, E is any chelating group capable of binding and / or complexing with a metal ion. In some embodiments, E is any chelating group capable of binding and / or complexing with a metal ion to form a heterocycle including the metal ion. In some embodiments, E is any chelating group derived from any chelating agent known in the art (e.g., as disclosed in Banerjee et al., Nucl. Med. Biol., 2005, 32, 1-20, Wadas et al., Chem. Rev., 2010, 110, 2858-2902, U.S. Patent Nos. 5,367,080, 5,364,613, 5,021,556, 5,075,099, and 5,886,142).

[0190] Thus, in some embodiments, E is a chelating group derived from a chelating agent. In some embodiments, the chelating agent is selected from cyclic or acyclic bifunctional chelating agents capable of binding and / or complexing with one or more radionuclides. In some embodiments, the chelating agent is selected from 1,4,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic acid-N',N"-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic acid-N',N"-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N"-tris(methylenephosphonic acid) (NOTP); 1,4,7,10-tetraazacyclododecane (

[12] aneN4) (cyclen); 1,4,7,10-tetraazacyclotridecane (

[13] aneN4); 1,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecane-1-yl)acetate (DO1A); 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A); 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid) (DOTP); 1,4,7,10-tetraazacyclododecane-1,7-di(methylenephosphonic acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methylenephosphonic acid) (DO3P); 1,4,7,10-tetraazacyclo-decane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane (

[14] aneN4) (cyclam); 1,4,8,12-tetraazacyclopentadecane (

[15] aneN4); 1,5,9,13-tetraazacyclohexadecane (

[16] aneN4); 1,4-ethyl-bridged-1,4,8,11-tetraazacyclo-tetradecane (et-cyclam); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexaazabicyclo[6.6.6]Eicosane (Sar); 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N′-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine; porphyrin; PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadec-1(15),11,13-triene-3,6,9-triacetic acid); DEPA (7-[2-(bis-carboxymethylamino)ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl-acetic acid); DTPA (1,1,4,7,7-diethylenetriaminepentaacetic acid); CHX-DTPA (cyclohexane-1,2-diamine N,N,N′,N′-tetraacetate); BATPA (1,2-bis[2-aminophenoxy]ethane-N,N,N′,N′-tetraacetic acid); TTHA (triethylenetetramine N,N,N″,N″′,N″′,N″′-hexaacetic acid); HBED (N,N′-bis[2-hydroxybenzyl]ethylenediamine-N,N′-diacetic acid); EGTA (ethylene glycol bis[2-aminoethyl ether]-N,N,N′,N′-tetraacetic acid); EDTMP (ethylenediamine tetra-[methylenephosphonic acid]); TRAP (triazacyclononane phosphinic acid); SHBED (N,N′-bis[2-hydroxy-5-sulfobenzyl]ethylenediamine diacetic acid); H6Sbbpen (N,N′-bis-[2-hydroxy-5-sulfonylbenzyl]-N,N′-bis[2-methylpyridyl]ethylenediamine); THP (tris(3,4-hydroxypyridone); DFO (deferoxamine); FSC (fusarinine C); 6SS (N,N′-bis[2,2-dimethyl-2-mercaptoethyl]ethylenediamine-N,N′-diacetic acid); ECC (ethylenecysteamine cysteine); ECD (cysteine ethyl ester dimer); NETA ([2-{4,7-bis-carboxymethyl(1,4,7)triazacyclononan-1-yl-ethyl}carbonylmethylamino]acetic acid; THPN (tetrakis(3-hydroxy-4-pyridone)); H2dedpa (1,2-[{6-(carboxy-)pyridin-2-yl}methylamino]-ethane); H4octapa (N,N′-bis[6-carboxy-2-pyridylmethyl]-ethylenediamine-N,N′-diacetic acid); H2bispa2 (6,6′-[{9-hydroxy-1,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.{[3,7-Nonanediyl]bis(methylene)}dipicolinic acid); DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetra(methylphosphonic acid)); PEPA (1,4,7,10,13-pentaazacyclopentadecane pentaacetic acid); HEHA (1,4,7,10,13,16-hexaazacyclooctadecane hexaacetic acid); H2hox; H2CHXhox; H2octox; H2pyhox; H4neunopa; TETPA; H4pypa; H4py4pa; DTPAm; EGTAm; ampam; Me-3,2-HOPO; 3,4,3-(LI-1,2-HOPO); macrocyclic tetra-phthalimide; or any derivative thereof. In some embodiments, E is selected from DOTA and DOTAGA. In some embodiments, E is DOTA. In some embodiments, E is DOTAGA.

[0191] Those skilled in the art will understand that as used herein, a "chelating group derived from a chelating agent" refers to a chelating agent derivative formed after the chelating agent is attached to a compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof (e.g., attached to L 1 (or when L 1 is a direct bond, attached to T)). For example, a "chelating group derived from a chelating agent" can be a chelating agent with an available carboxyl group (or its ester) without "-OH" (or its ester), an available amino group on the chelating agent without the "H" moiety, an available isothiocyanate on the chelating agent without the "NCS" moiety, a chelating agent with an available maleimide group without the "H" moiety, a chelating agent whose available acetylene group has reacted to attach to a compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, or a chelating agent whose available tetrazole group has reacted to attach to a compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof. For example, those skilled in the art will understand that when E is a chelating group derived from DOTA, one "-OH" from one of the four available carboxyl groups on DOTA is removed to form a connection, such as an amide bond, with L 1 (or when L 1 is a direct bond, T therein), leaving three available carboxyl groups.

[0192] In some embodiments, E is attached to L through any available functional group 1 . In some embodiments, E is a chelating group containing two or more carboxyl groups, and E is attached to L through a carboxyl functional group 1. In some embodiments, E is a chelating group derived from DOTA or DOTAGA and is attached to L through any available carboxyl functional group 1 .

[0193] . In some embodiments, one or more radionuclides are radioisotopes of C, N, O, F, P, S, Cl, Br, I, As, Se, At, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Fr, Pm, lanthanide elements (such as La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), actinide elements (such as Ac, Th, U), Mg, Al, Ca, Cd or Ba.

[0194] . In some embodiments, the lanthanide element is Lu, Sm, Ho or Tb.

[0195] . In some embodiments, the actinide element is Ac, Th or U.

[0196] . In some embodiments, one or more radionuclides are selected from 14 C, 15 N, 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 123 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195mPt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 188 Re, 186 Re, 153 Sm, 66 Ho, 86 Y, 87 Y, 90 Y, 89 Sr, 153 Gd, 159 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 101m Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 55 Co, 57 Co, 47 Sc, 149 Pm, 142 Pr, 161 Ho, 166 Ho, 175 Yb or 51 Cr.

[0197] In some embodiments, one or more radionuclides are used for imaging or for therapy.

[0198] In some embodiments, one or more radionuclides for imaging are selected from 99m Tc, 188 Re, 186 Re,153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 203 Pb, 44 Sc, 51 Cr, 101m Rh, 166 Ho or 123 I.

[0199] In some embodiments, one or more radionuclides for treatment are selected from 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra,224 Ra, 227 Th, 229 Th, 149 Tb, 32 P, 161 Tb, 33 P, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 47 Sc, 149 Pm, 161 Ho, 159 Gd, 142 Pr, 166 Ho or 175 Yb.

[0200] In some embodiments, one or more radionuclides for therapy are selected from 177 Lu, 212 Pb and 225 Ac. In some embodiments, the radionuclide for therapy is 177 Lu or 225 Ac. In some embodiments, one or more radionuclides for therapy are 177 Lu. In some embodiments, one or more radionuclides for therapy are 225 Ac.

[0201] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of from positive 2 (+2) to negative five (-5). In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of from positive (+1) to negative five (-5). In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of from zero (0) to negative five (-5). In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of from zero (0) to negative four (-4). In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of from zero (0) to negative three (-3). In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177When complexed with Lu, it has a net charge of zero (0) to minus two (-2). In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of zero (0) or minus one (-1). In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of 0. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, when complexed with 177 Lu, has a net charge of -1.

[0202] In some embodiments, T is a trivalent branched group containing at least three terminal functional groups. Thus, in some embodiments, T is a trivalent branched group containing at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which are the same or different and are respectively bonded to L 1 (or alternatively, E), L 2 (or alternatively, Z 1 ) and L 3 (or alternatively, Z 2 ) through complementary functional groups. In some embodiments, T contains at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which are the same or different and are bonded to L 1 (or alternatively, E), L 2 (or alternatively, Z 1 ) and L 3 (or alternatively, Z 2 ) through complementary functional groups, respectively forming an amide group, a urea group, a thiourea group, or a thioamide group.

[0203] In some embodiments, T contains at least a first terminal functional group, a second terminal functional group, and a third terminal functional group, which are the same or different, and when bonded to L 1 (or alternatively, E), L 2 (or alternatively, Z 1 ) and L 3 (or alternatively, Z 2 ) through complementary functional groups, independently form amide groups respectively.

[0204] In some embodiments, T is selected from an amino acid residue derived from lysine, ornithine, homolysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamate, or glutamine. In some embodiments, T is an amino acid residue derived from lysine.

[0205] Thus, in some embodiments, the compound of Formula I is a compound of Formula IB or a compound of Formula IC, or a pharmaceutically acceptable salt and / or solvate thereof:

[0206]

[0207] Thus, in some embodiments, the compound of Formula I is a compound of Formula IB(i) or a compound of Formula IC(i) or a pharmaceutically acceptable salt and / or solvate thereof:

[0208]

[0209]

[0210] It will be understood by those skilled in the art that when L 1 , L 2 and L 3 When any one of is a divalent linker, the divalent linker and E, Z 1 or Z 2 Thus, in some embodiments, the divalent linker is capable of forming covalent bonds with E, Z 1 or Z 2 In some embodiments, the divalent linker comprises a linker moiety selected from the group consisting of amine, ether, thioether, carbonyl, thiocarbonyl, sulfone, sulfoxide, urea, thiourea, and amide. In some embodiments, the divalent linker comprises at the end a linker moiety capable of bonding to E, Z, 1 or Z 2 The complementary functional groups on E and T respectively form covalent bonds. For example, in some embodiments, the divalent linker comprises an amine at the terminal end that reacts with the carboxylic acid group on E. In some embodiments, the divalent linker comprises an amine at the terminal end that reacts with the carboxylic acid group on E to form an amide.

[0211] In some embodiments, L 1 , L 2 and L 3 Each is independently a direct bond or a divalent linker. 1 , L 2 and L 3 are each independently a direct bond or a divalent linker, and these divalent linkers comprise independently selected from amino acid residues, C 1-27Alkylene, C 2-27 Alkenylene and C 2-27 The total number of alkynylene groups is 1 to 15. 1-27 Alkylene, C 2-27 Alkenylene and C 2-27 The alkynylene groups are independently and optionally interrupted by one or more linker moieties selected from the group consisting of amine, ether, thioether, carbonyl, thiocarbonyl, sulfone, sulfoxide, urea, thiourea, and amide.

[0212] Therefore, in some embodiments, L 1 , L 2 and L 3 Each is independently a direct bond or a divalent linker, and these divalent linkers comprise amino acid residues, W a , R a , R a –W a , W a –R b , R a –W a –R b and W a –R b –W b A total of 1 to 15 groups,

[0213] Each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O)、C(S)、NR 5 C(O),NR 5 C(S), C(O)NR 5 、C(S)NR 5 , (C 1-6 Alkylene (Y) p and Y-(C 1-6 Alkylene Y') p ; Each R a and R b Independently selected from C 1-20 Alkylene, C 2-20 Alkenylene and C 2-20 Alkynylidene;

[0214] Each Y and Y' is independently selected from O, S, C(O) and NR 6 ;

[0215] Each R 5 Independently selected from H and C 1-6 alkyl;

[0216] Each R 6Independently selected from H and C 1-3 Alkyl; and

[0217] p is an integer selected from 1-8.

[0218] As used herein, "a divalent linker comprises 1 to 15 groups in total" means that the groups from the 1, 2 or 3 divalent linkers total 0 to 15. For example, in which L 1 It is a direct key, L 2 is an amino acid residue, and L 3 In compounds of formula I where the residues are identical or different amino acid residues, the total number of the residues is 2.

[0219] One skilled in the art will appreciate that two adjacent groups in a divalent linker should be selected to avoid a direct bond between the two groups that would result in a partial structure that is unstable in aqueous media, for example at room temperature (such as about 18°C ​​to about 25°C).

[0220] In some embodiments, each R a and R b Independently selected from C 1-10 Alkylene, C 2-10 Alkenylene and C 2-10 In some embodiments, each R a and R b Independently selected from C 1-20 In some embodiments, each R a and R b Independently selected from C 1-10 Alkylene.

[0221] In some embodiments, each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O)、C(S)、C(S)NR 5 NR 5 C(S), C(O)NR 5 NR 5 C(O),(C 1-6 Alkylene (Y) p and Y-(C 1-6 Alkylene Y') p In some embodiments, W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O)、C(S)、(C 1-6 Alkylene (Y) p and Y-(C1-6 Alkylene Y') p .

[0222] In some embodiments, each Y and Y' is independently selected from O, S, C(O) and NR 6 In some embodiments, each Y and Y' is independently selected from O, C(O) and NR 6 In some embodiments, each Y and Y' is O. In some embodiments, each Y and Y' is independently selected from O, C(O) and NR 6 , and each W a and W b (C 1-6 Alkylene (Y) p Independently selected from (C 1-6 Alkylene (O) p , (C 1-6 Alkylene (C(O)) p and O-(C 1-6 Alkylene NR 6 ) p .

[0223] In some embodiments, each Y and Y' is independently selected from O, C(O) and NR 6 , and each W a and W b Y-(C 1-6 Alkylene Y') p Independently selected from O-(C 1-6 Alkylene (O) p 、O-(C 1-6 Alkylene (C(O)) p 、O-(C 1-6 Alkylene NR 6 ) p 、C(O)-(C 1-6 Alkylene (O) p 、C(O)-(C 1-6 Alkylene (C(O)) p 、C(O)-(C 1-6 Alkylene NR 6 ) p NR 6 -(C 1-6 Alkylene (O) p NR 6 -(C 1-6 Alkylene (C(O)) p and NR 6 -(C 1-6 Alkylene NR 6 ) p .

[0224] In some embodiments, each Y and Y' is independently selected from O, C(O) and NR 6 , and each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O), C(S), C(S)NR 5 NR 5 C(S), C(O)NR 5 NR 5 C(O),(C 1-6 Alkylene (O) p , (C 1-6 Alkylene NR 6 ) p , (C 1-6 Alkylene (C(O)) p 、O-(C 1-6 Alkylene (O) p 、O-(C 1-6 Alkylene NR 6 ) p 、O-(C 1-6 Alkylene (C(O)) p NR 6 -(C 1-6 Alkylene (O) p NR 6 -(C 1-6 Alkylene NR 6 ) p NR 6 (C 1-6 Alkylene (C(O)) p 、C(O)-(C 1-6 Alkylene (O) p 、C(O)-(C 1-6 Alkylene NR 6 ) p and C(O)-(C 1-6 Alkylene C(O) p In some embodiments, each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O),(C 1-6 Alkylene (O) p , (C 1-6 Alkylene NR 6 ) p , (C 1-6 Alkylene (C(O))p 、O-(C 1-6 Alkylene (O) p 、O-(C 1-6 Alkylene NR 6 ) p 、O-(C 1-6 Alkylene (C(O)) p NR 6 -(C 1-6 Alkylene (O) p NR 6 -(C 1-6 Alkylene NR 6 ) p NR 6 -(C 1-6 Alkylene (C(O)) p 、C(O)-(C 1-6 Alkylene (O) p 、C(O)-(C 1-6 Alkylene NR 6 ) p and C(O)-(C 1-6 In some embodiments, each of Y and Y' is selected from O, C(O) and NR 6 , and therefore each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O), C(S), C(S)NR 5 NR 5 C(S), C(O)NR 5 NR 5 C(O),(C 1-6 Alkylene (O) p , (C 1-6 Alkylene NR 6 ) p , (C 1-6 Alkylene (C(O)) p 、O-(C 1-6 Alkylene (O) p 、O-(C 1-6 Alkylene NR 6 ) p 、O-(C 1-6 Alkylene (C(O)) p NR 6 -(C 1-6 Alkylene (O) p NR 6 -(C 1-6 Alkylene NH) p NR 6 -(C1-6 Alkylene N(CH 3 )) p NR 6 (C 1-6 Alkylene (C(O)) p 、C(O)-(C 1-6 Alkylene (O) p 、C(O)-(C 1-6 Alkylene NR 6 ) p and C(O)-(C 1-6 Alkylene C(O) p In some embodiments, each Y and Y' is independently selected from O, C(O) and NR 6 , and therefore each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O),(C 1-6 Alkylene (O) p , (C 1-6 Alkylene NR 6 ) p , (C 1-6 Alkylene (C(O)) p 、O-(C 1-6 Alkylene (O) p 、O-(C 1-6 Alkylene NR 6 ) p 、O-(C 1-6 Alkylene (C(O)) p NR 6 -(C 1-6 Alkylene (O) p NR 6 -(C 1-6 Alkylene NH) p NR 6 -(C 1-6 Alkylene N(CH 3 )) p NR 6 -(C 1-6 Alkylene (C(O)) p 、C(O)-(C 1-6 Alkylene (O) p 、C(O)-(C 1-6 Alkylene NR 6 ) p and C(O)-(C 1-6 Alkylene C(O).

[0225] In some embodiments, the bivalent linker comprises an amino acid residue selected from the group consisting of: a , R a , R a –W a , W a –R b and W a –R b –W b In some embodiments, the divalent linker comprises an amino acid residue, a a , R a and W a –R b –W b The total number of groups is 1 to 15.

[0226] In some embodiments, each W a and W b independently selected from O, S, S(O), SO 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O),(C 1-6 Alkylene (O) p , (C 1-6 Alkylene NR 6 ) p , (C 1-6 Alkylene (C(O)) p 、O-(C 1-6 Alkylene (O) p 、O-(C 1-6 Alkylene NR 6 ) p 、O-(C 1-6 Alkylene (C(O)) p NR 6 -(C 1-6 Alkylene (O) p NR 6 -(C 1-6 Alkylene NH) p NR 6 -(C 1-6 Alkylene N(CH 3 )) p NR 6 -(C 1-6 Alkylene (C(O)) p 、C(O)-(C 1-6 Alkylene (O) p 、C(O)-(C 1-6 Alkylene NR 6 ) pand C(O)-(C 1-6 Alkylene C(O), and each R a and R b Independently selected from C 1-20 alkylene, and the divalent linker comprises in total an amino acid residue, O, S, S(O), SO 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O), C 1-20 Alkylene, OC 1-20 Alkylene O, OC 1-20 Alkylene NR 5 , OC 1-20 Alkylene C(O), NR 5 C 1-20 Alkylene O, NR 5 C 1-20 Alkylene NR 5 NR 5 C 1-20 Alkylene C(O), C(O)C 1-20 Alkylene O, C(O)-C 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene C(O), O-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, O-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C1-20 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene C(O), NR 6 -(C 1-6 Alkylene (O) p C 1-20 Alkylene O, NR 6 -(C 1-6 Alkylene (O) p C 1-20 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-20 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), NR 6 (C 1-6 Alkylene (C(O)) p C 1-20 Alkylene O, NR 6 (C 1-6 Alkylene (C(O)) p C 1-20 Alkylene NR 5 NR 6 (C 1-6 Alkylene (C(O)) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene (O) p C 1-20 Alkylene NR 5 、C(O)-(C 1-6 Alkylene (O) p C 1-20 Alkylene C(O), C(O)-(C1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene C(O)C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene C(O)C 1-20 Alkylene NR 5 and C(O)-(C 1-6 Alkylene C(O)C 1-20 The total number of alkylene groups C(O) is 1 to 15. In some embodiments, Y and Y' are selected from O, C(O), NH and N(CH 3 ), W a and W b As defined above, and R a and R b Independently selected from C 1-20 The alkylene group, and thus the divalent linker collectively comprises an amino acid residue, O, S, S(O), SO 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O), C 1-10 Alkylene, OC 1-20 Alkylene O, OC 1-20 Alkylene NR 5 , OC 1-20 Alkylene C(O), NR 5 C 1-20 Alkylene O, NR 5 C 1-20 Alkylene NR 5 NR 5 C 1-20 Alkylene C(O), C(O)(C 1-20 Alkylene O, C(O)-C 1-20 Alkylene C(O), C(O)C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene O, O-(C 1-6Alkylene (C(O)) p C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene C(O), O-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, O-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-20 Alkylene C(O), NR 6 -(C 1-6 Alkylene (O) p C 1-20 Alkylene O, NR 6 -(C 1-6 Alkylene (O) p C 1-20 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-20 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20Alkylene C(O), NR 6 (C 1-6 Alkylene (C(O)) p C 1-20 Alkylene O, NR 6 (C 1-6 Alkylene (C(O)) p C 1-20 Alkylene NR 5 NR 6 (C 1-6 Alkylene (C(O)) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene (O) p C 1-20 Alkylene NR 5 、C(O)-(C 1-6 Alkylene (O) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene C(O)C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene C(O)C 1-20 Alkylene NR 5 and C(O)-(C 1-6 Alkylene C(O)C 1-20 The total number of alkylene groups C(O) is 1 to 15 groups.

[0227] In some embodiments, the bivalent linker comprises in total amino acid residues independently selected from the group consisting of: 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O), C 1-12 Alkylene, OC 1-12 Alkylene O, OC1-12 Alkylene NR 5 , OC 1-12 Alkylene C(O), NR 5 C 1-12 Alkylene O, NR 5 C 1-12 Alkylene NR 5 NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene O, C(O)C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), O-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene O, O-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 、O-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene C(O), O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene O, NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene NR5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene O, NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene C(O), NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene O, NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene O, C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene O, C(O)-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C1-6 Alkylene (C(O)) p C 1-6 Alkylene O, C(O)-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 and C(O)-(C 1-6 Alkylene (C(O)) p C 1-6 In some embodiments, the divalent linker comprises in total 1 to 15 groups independently selected from amino acid residues, O, S, S(O), SO 2 NR 5 、C(O)、C(O)NR 5 NR 5 C(O), C 1-12 Alkylene, OC 1-12 Alkylene O, OC 1-12 Alkylene NR 5 , OC 1-12 Alkylene C(O), NR 5 C 1-12 Alkylene O, NR 5 C 1-12 Alkylene NR 5 NR 5 C 1-12 Alkylene C(O), C(O)(C 1-12 Alkylene O, C(O)-C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), O-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene O, O-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 、O-(C 1-6 Alkylene NR 6 ) p C1-6 Alkylene C(O), O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene O, O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 、O-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene O, NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene O, NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene C(O), NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene O, NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene O, C(O)-(C 1-6 Alkylene (O)p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene O, C(O)-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene C(O)C 1-6 Alkylene O, C(O)-(C 1-6 Alkylene C(O)C 1-6 Alkylene NR 5 and C(O)-(C 1-6 Alkylene C(O)C 1-6 1 to 15 radicals of alkylene C(O).

[0228] In some embodiments, the bivalent linker comprises in total amino acid residues independently selected from the group consisting of: 5 C 1-12 Alkylene C(O), C(O)-C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 NR 5 C 1-12 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 NR 6 -(C 1-6 Alkylene NR 6 )p C 1-6 Alkylene C(O), NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 and C(O)-(C 1-6 Alkylene (C(O)) p C 1-6 In some embodiments, the divalent linker comprises in total 1 to 15 groups independently selected from amino acid residues, NR 5 C 1-12 Alkylene C(O), C(O)-C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene C(O), NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 NR 6 (C 1-6 Alkylene (C(O)) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene NR 6 ) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene C(O)C 1-6 Alkylene NR 5 and C(O)-(C 1-6 Alkylene C(O)C 1-6 1 to 15 radicals of alkylene C(O).

[0229] In some embodiments, the bivalent linker comprises in total amino acid residues independently selected from the group consisting of: 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 NR 5 C 1-12 Alkylene NR 5 NR 6 -(C 1-6 Alkylene (O) p C 1-6 Alkylene C(O), C(O)-(C 1-6 Alkylene (O) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR6 ) p C 1-6 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene (C(O)) p C 1-6 Alkylene NR 5 and C(O)-(C 1-6 Alkylene (C(O)) p C 1-6 In some embodiments, the divalent linker comprises in total 1 to 15 groups independently selected from amino acid residues, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6 1 to 15 radicals of alkylene C(O).

[0230] In some embodiments, the amino acid residues of the divalent linker are amino acid residues derived from naturally occurring amino acids, naturally occurring amino acids that have been modified to provide modified amino acids, the D enantiomer of naturally occurring amino acid residues or modified amino acid residues, and amino acid residues derived from β-amino acids or γ-amino acids.

[0231] In some embodiments, the amino acid residues of the divalent linker are amino acid residues derived from naturally occurring amino acids. In some embodiments, the naturally occurring amino acids are selected from, but not limited to, alanine (A, Ala), arginine (R, Arg), asparagine (N, Asn), aspartic acid (D, Asp), cysteine ​​(C, Cys), glutamine (Q, Gln), glutamic acid (E, Glu), glycine (G, Gly), histidine (H, His), isoleucine (I, Ile), leucine (L, Leu), lysine (K, Lys), methionine (M, Met), phenylalanine (F, Phe), proline (P, Pro), serine (S, Ser), threonine (T, Thr), tryptophan (W, Trp), tyrosine (Y, Tyr), valine (V, Val), pyrrolysine (Pyl), selenocysteine ​​(Sec) and pyrroline-carboxy-lysine (PCL) One or more naturally occurring amino acids.

[0232] In some embodiments, the amino acid residue derived from naturally occurring amino acids is a naturally occurring amino acid residue derived from Glu. In some embodiments, the amino acid residue of the divalent linker is further selected from naturally occurring amino acid residues derived from Glu. In some embodiments, the amino acid residue derived from Glu is connected via the amino and α-carboxyl or amino and γ-carboxyl termini. Thus, in some embodiments, the amino acid residue derived from Glu is selected from (γGlu, γ-Glu) one or two. In some embodiments, the amino acid residue derived from naturally occurring amino acids is a naturally occurring amino acid residue derived from Asp. In some embodiments, the amino acid residue is further selected from the amino acid residue derived from Asp. In some embodiments, the amino acid residue derived from Asp is connected by an amino group and an α-carboxyl group, or by an amino group and a β-carboxyl terminal. In some embodiments, the amino acid residue derived from naturally occurring amino acids is a naturally occurring amino acid residue derived from Lys. In some embodiments, the amino acid residue is further selected from the amino acid residue derived from Lys. In some embodiments, the amino acid residue derived from Lys is connected by an amino group and an α-carboxyl group or an amino group and an ε-amino terminal. Therefore, in some embodiments, the amino acid residue derived from Lys is selected from One or both of.

[0233] In some embodiments, the amino acid residues of the divalent linker are further selected from naturally occurring amino acids that have been modified to provide modified amino acids. Thus, in some embodiments, the amino acid residues are further selected from one or more modified amino acids selected from, but not limited to, 4-carboxy-L-phenylalanine (Cbp), hydroxyproline, γ-carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2, 4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelate, 2,3-diaminopropionic acid (Dap), N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthylalanine, norvaline, norleucine, ornithine, pentylglycine, hexahydropicolinic acid and thioproline. In some embodiments, the amino acid residues of the divalent linker are further selected from naturally occurring amino acids that have been modified to provide a modified amino acid. Thus, in some embodiments, the amino acid residues are further selected from one or more modified amino acids selected from, but not limited to, hydroxyproline, γ-carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, Butyric acid, desmosine, 2,2′-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allohydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthylalanine, norvaline, norleucine, ornithine, pentylglycine, hexahydropicolinic acid, and thioproline.

[0234] In some embodiments, the amino acid residue of the divalent linker is further selected from the D enantiomer of a naturally occurring amino acid residue or a modified amino acid residue.

[0235] In some embodiments, the amino acid residue of the divalent linker is further selected from an amino acid residue derived from a β-amino acid or a γ-amino acid. In some embodiments, the β-amino acid is β-alanine.

[0236] By adjusting the hydrophobicity and / or net charge of the radioligand when complexed with the radionuclide, applicants have provided radioligands that exhibit good binding affinity for both the somatostatin type 2 receptor (SSTR2) and the cholecystokinin 2 receptor (CCK2R), and that can also exhibit increased target cellular radionuclide uptake while keeping off-target normal organ accumulation to a minimum.

[0237] Therefore, in some embodiments, the amino acid residues of the divalent linker include zero negatively charged amino acid residues or at least one negatively charged amino acid residue. In some embodiments, the amino acid residues include zero negatively charged amino acid residues. In some embodiments, the amino acid residues include at least one negatively charged amino acid residue. In some embodiments, the amino acid residues are amino acids derived from naturally occurring amino acids, and include at least one negatively charged amino acid residue. In some embodiments, the negatively charged amino acid residues are selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the negatively charged amino acid residues are selected from D-Glu, L-Glu, D-γGlu and L-γGlu.

[0238] Therefore, in some embodiments, the bivalent linker comprises a total of at least one amino acid residue selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of at least one to five amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of at least one to four amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of at least one to three amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of at least one to two amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of one amino acid residue selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of one to five amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of one to four amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of one to three amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of one to two amino acid residues selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu and L-γGlu.

[0239] In some embodiments, the amino acid residue is an amino acid derived from naturally occurring amino acids, and includes at least one positively charged amino acid residue. In some embodiments, the amino acid residue further includes a positively charged amino acid residue. Therefore, in some embodiments, one or more amino acid residues are further selected from D-His, L-His, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys and L-εLys.

[0240] It will be understood by those skilled in the art that a net negative charge of a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof when complexed with a radionuclide can be achieved when the divalent linker comprises a total of at least one negatively charged amino acid residue, or alternatively, the divalent linker comprises both positively charged amino acid residues and negatively charged amino acid residues, and the total number of negatively charged amino acid residues is greater than the total number of positively charged amino acid residues, and the net charge between the chelating group E of the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof and the radionuclide complexed by E is zero. Similarly, it will be understood by those skilled in the art that when the divalent linker comprises amino acid residues that collectively have a zero charge, or alternatively, the divalent linker comprises the same number of positively charged amino acid residues and negatively charged amino acid residues, when the net charge between the chelating group E of the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug and the radionuclide complexed by E is negative, a net negative charge of the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug when complexed with the radionuclide can also be achieved.

[0241] In some embodiments, the amino acid residues include one or more hydrophilic amino acid residues. In some embodiments, the amino acid residues are selected from D-Ser and L-Ser.

[0242] In some embodiments, the amino acid residues include one or more neutral amino acid residues, such as Gly, D-Pro, and L-Pro.

[0243] Thus, in some embodiments, the bivalent linker comprises a member independently selected from the group consisting of 4-carboxy-L-phenylalanine (Cbp), 2,3-diaminopropionic acid (Dap), Gly, D-His, L-His, D-Ala, L-Ala, D-Val, L-Val, D-Leu, L-Leu, D-Phe, L-Phe, D-Pro, L-Pro, D-Met, L-Met, D-Trp, L-Trp, D-Thr, L-Thr, D-Tyr, L-Tyr, D-Nle, L-Nle, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6The total number of alkylene C(O) groups is 1 to 15. In some embodiments, the divalent linker comprises independently selected from Gly, D-Ala, L-Ala, D-Val, L-Val, D-Leu, L-Leu, D-Phe, L-Phe, D-Pro, L-Pro, D-Met, L-Met, D-Trp, L-Trp, D-Thr, L-Thr, D-Tyr, L-Tyr, D-Nle, L-Nle, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6 The total number of alkylene groups C(O) is 1 to 15 groups.

[0244] In some embodiments, the bivalent linker comprises a Cbp, Dap, Gly, D-His, L-His, D-Ala, L-Ala, D-Val, L-Val, D-Leu, L-Leu, D-Phe, L-Phe, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6 The total number of alkylene C(O) groups is 1 to 15. In some embodiments, the divalent linker comprises a group selected from Gly, D-Ala, L-Ala, D-Val, L-Val, D-Leu, L-Leu, D-Phe, L-Phe, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6 The total number of alkylene groups C(O) is 1 to 15 groups.

[0245] In some embodiments, the bivalent linker comprises a Cbp, Dap, Gly, D-His, L-His, D-Ala, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6 The total number of alkylene C(O) groups is 1 to 15. In some embodiments, the divalent linker comprises independently selected from Gly, D-Ala, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 Alkylene C(O), C(O)C 1-12 Alkylene NR 5 and NR 6 -(C 1-6 Alkylene (O) p C 1-6 The total number of alkylene groups C(O) is 1 to 15 groups.

[0246] In some embodiments, the bivalent linker comprises a Cbp, Dap, Gly, D-His, L-His, D-Ala, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 2-8 Alkylene C(O), C(O)C 2-8 Alkylene NR 5and NR 6 -(C 1-3 Alkylene (O) p C 1-3 The total number of alkylene groups C(O) is 1 to 15 groups.

[0247] In some embodiments, the bivalent linker comprises a Cbp, Dap, Gly, D-Ala, D-His, L-His, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 5 Alkylene C(O)(Ahx), NR 5 C 7 Alkylene C(O)(Aoc), NR 5 C 10 Alkylene C(O)(Aun), NR 6 -(C 2 Alkylene (O) p C 1 Alkylene C(O) and NR 6 -(C 2 Alkylene (O) p C 2 The total number of alkylene C(O) groups is 1 to 15. In some embodiments, the divalent linker comprises independently selected from Gly, D-Ala, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 5 Alkylene C(O)(Ahx), NR 5 C 7 Alkylene C(O)(Aoc), NR 5 C 10 Alkylene C(O)(Aun), NR 6 -(C 2 Alkylene (O) p C 1 Alkylene C(O) and NR 6 -(C 2 Alkylene (O) p C 2 The total number of alkylene groups C(O) is 1 to 15 groups.

[0248] In some embodiments, p is an integer selected from 1-7, 1-6, or 2-6.

[0249] In some embodiments, p is an integer selected from 1 to 6, and the bivalent linker comprises an independently selected from Cbp, Dap, Gly, D-His, L-His, D-Ala, L-Ala, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 6 -(C 2 Alkylene (O) 2 C 1 Alkylene C(O)( (OEG))、NR 6 -(C 2 Alkylene O)C 2 Alkylene C(O)( (PEG1))、NR 6 -(C 2 Alkylene (O) 3 C 2 Alkylene C(O)( (PEG3))、NR 6 -(C 2 Alkylene (O) 6 C 2 Alkylene C(O)( (PEG6))、NR 5 C 7 Alkylene C(O)( (Aoc))、NR 5 C 10 Alkylene C(O)( (Aun)) and NR 5 C 5 Alkylene C(O)( (Ahx)) totals 1 to 15 groups. In some embodiments, p is an integer selected from 1 to 6, and the divalent linker comprises independently selected from Gly, D-Ala, L-Ala, D-Ser, L-Ser, D-Pro, L-Pro, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 6 -(C 2 Alkylene (O) 2 C 1 Alkylene C(O)( (OEG))、NR 6-(C 2 Alkylene O)C 2 Alkylene C(O)( (PEG1))、NR 6 -(C 2 Alkylene (O) 3 C 2 Alkylene C(O)( (PEG3))、NR 6 -(C 2 Alkylene (O) 6 C 2 Alkylene C(O)( (PEG6))、NR 5 C 7 Alkylene C(O)( (Aoc))、NR 5 C 10 Alkylene C(O)( (Aun)) and NR 5 C 5 Alkylene C(O)( (Ahx)) contains 1 to 15 groups in total.

[0250] In some embodiments, the bivalent linker comprises 1 to 15 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx. In some embodiments, the bivalent linker comprises 1 to 15 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx.

[0251] In some embodiments, the divalent linker comprises a total of 1 to 14 groups, 1 to 12 groups, 1 to 10 groups, 1 to 9 groups, 1 to 8 groups, 1 to 7 groups, 1 to 6 groups, 1 to 5 groups, 1 to 4 groups, 1 to 3 groups, 1 to 2 groups, or 1 group. In some embodiments, the divalent linker comprises a total of 1 to 7 groups, 1 to 6 groups, 1 to 5 groups, 1 to 4 groups, 1 to 3 groups, 1 to 2 groups, or 1 group. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug comprises a net charge of negative five (-5) when complexed with a radionuclide. In some embodiments, the divalent linker group comprises at least 4 or 5 negatively charged amino acid residues selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of 4 to 11 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 4 or 5 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 4 to 11 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 4 or 5 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 4 to 11 groups independently selected from Cbp, Dap, Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 4 or 5 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of 4 to 11 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 4 or 5 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu.In some embodiments, the divalent linker comprises 5 to 11 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 4 or 5 groups are selected from L-Glu and L-γGlu. In some embodiments, the divalent linker comprises 4 to 11 groups independently selected from Gly, L-Glu, L-γGlu and OEG, wherein at least 4 or 5 groups are selected from L-Glu and L-γGlu.

[0252] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug comprises a net charge of negative four (-4) when complexed with a radionuclide. In some embodiments, the divalent linker comprises at least 3 or 4 amino acid residues selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 3 to 11 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 3 or 4 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 3 to 11 groups independently selected from Cbp, Dap, Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu and L-γGlu, wherein at least 3 or 4 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 3 to 11 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 3 or 4 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 3 to 11 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu and L-γGlu, wherein at least 3 or 4 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 3 to 11 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 4 or 5 groups are selected from L-Glu and L-γGlu. In some embodiments, the divalent linker comprises 3 or 4 groups independently selected from L-Glu and L-γGlu.In some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), the divalent linker comprises a total of 3 to 11 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 4 groups are selected from L-Glu and L-γGlu, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in combination with. 177 Lu has a net charge of negative four (-4) when complexed. In some embodiments, E is a chelating group comprising four free carboxylic acid groups (such as a chelating group derived from DOTAGA), the divalent linker comprises 3 to 11 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 3 groups are selected from L-Glu and L-γGlu, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in contact with 177 The net charge of Lu when complexed is negative four (-4).

[0253] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug comprises a net charge of negative three (-3) when complexed with a radionuclide. In some embodiments, the divalent linker comprises at least 2 or 3 amino acid residues selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 2 or 3 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 2 to 9 groups independently selected from Cbp, Dap, Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 2 or 3 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 2 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 2 or 3 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 2 or 3 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 2 or 3 groups are selected from L-Glu and L-γGlu. In some embodiments, the divalent linker group comprises 2 to 9 groups independently selected from Gly, L-Glu, L-γGlu and OEG, wherein 2 or 3 groups are selected from L-Glu and L-γGlu.In some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), the divalent linker comprises a total of 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 3 groups are selected from L-Glu and L-γGlu, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in combination with. 177 Lu has a net charge of negative three (-3) when complexed. In some embodiments, E is a chelating group comprising four free carboxylic acid groups (such as a chelating group derived from DOTAGA), the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 2 groups are selected from L-Glu and L-γGlu, and the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in contact with 177 Lu contains a net charge of negative three (-3) when complexed.

[0254] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug comprises a net charge of negative two (-2) when complexed with a radionuclide. In some embodiments, the divalent linker group comprises at least 1 or 2 amino acid residues selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 1 or 2 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of 2 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Arg, L-Arg, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 1 or 2 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 1 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 1 or 2 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 1 or 2 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises a total of 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 2 or 3 groups are selected from L-Glu and L-γGlu.In some embodiments, the divalent linker comprises 1 or 2 groups independently selected from Gly, L-Glu, L-γGlu and OEG, wherein at least 1 or 2 groups are selected from L-Glu and L-γGlu. In some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), and the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 2 groups are selected from L-Glu and L-γGlu, and the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is with. 177 Lu comprises a net charge of negative two (-2) when complexed. In some embodiments, E is a chelating group comprising four free carboxylic acid groups (such as a chelating group derived from DOTAGA), the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least one group is selected from L-Glu and L-γGlu, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in contact with 177 Lu contains a net charge of negative two (-2) when complexed.

[0255] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug comprises a net charge of negative one (-1) when complexed with a radionuclide. In some embodiments, the divalent linker comprises a total of 0 or 1 amino acid residues selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 0 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of 2 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-Arg, L-Arg, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the bivalent linker comprises a total of 2 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-Arg, L-Arg, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu.In some embodiments, the divalent linker comprises 0 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 or 1 group is selected from L-Glu and L-γGlu. In some embodiments, the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Glu, L-γGlu, OEG and Aoc, wherein 0 or 1 group is selected from L-Glu and L-γGlu. In some embodiments, E is a chelating group (such as DOTA) comprising three free carboxylic acid groups, and the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein at least 1 group is selected from L-Glu and L-γGlu, and the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is with. 177 Lu comprises a net charge of negative one (-1) when complexed. In some embodiments, E is a chelating group comprising four free carboxylic acid groups (such as DOTAGA), the divalent linker comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 groups are selected from L-Glu and L-γGlu, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in combination with 177Lu comprises a net charge of negative one (-1) when complexed. In some embodiments, E is a chelating group comprising four free carboxylic acid groups (such as DOTAGA), the divalent linker comprises a total of 2 to 9 groups independently selected from Gly, L-Pro, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 groups are selected from L-Glu and L-γGlu, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug is in contact with 177 Lu contains a net charge of negative one (-1) when complexed.

[0256] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof comprises a net charge of zero (0) when complexed with a radionuclide. In some embodiments, the divalent linker comprises a total of 0 or 1 amino acid residues selected from D-Lys, L-Lys, D-εLys, L-εLys. In some embodiments, the bivalent linker comprises 0 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Arg, L-Arg, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Lys, L-Lys, D-εLys, L-εLys. In some embodiments, the bivalent linker comprises 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Arg, L-Arg, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Lys, L-Lys, D-εLys and L-εLys. In some embodiments, the divalent linker comprises 1 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Lys, L-Lys, D-εLys, L-εLys. In some embodiments, the bivalent linker comprises 0 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Lys, L-Lys, D-εLys, L-εLys.In some embodiments, the divalent linker comprises 1 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, OEG, PEG1, PEG3, PEG6, and Aoc, wherein 0 or 1 group is selected from L-Lys and L-εLys. In some embodiments, the divalent linker comprises 0 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, OEG, PEG1, PEG3, PEG6, and Aoc, wherein 0 or 1 group is selected from L-Lys and L-εLys. In some embodiments, the divalent linker comprises 1 to 9 groups in total.

[0257] In some embodiments, E is a chelating group comprising four free carboxylic acid groups (such as a chelating group derived from DOTAGA), the divalent linker comprises 1 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 1 group is selected from L-Lys and L-εLys, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is in combination with 177 Lu, when complexed, contains a net charge of zero (0).

[0258] In some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), the divalent linker comprises 0 to 9 or 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 groups are selected from L-Lys and L-εLys, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is in combination with 177 Lu comprises a net charge of zero (0) when complexed. Thus, in some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), the divalent linker comprises a total of 0 to 9 groups or 1 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, OEG, PEG1, PEG3, PEG6 and Aoc, and the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is in combination with 177Lu comprises a net charge of zero (0) when complexed. In some embodiments, the divalent linker comprises 0 to 9 groups independently selected from Cbp, Dap, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx. In some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), and the divalent linker comprises 0 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, OEG, PEG1, PEG3, PEG6 and Aoc, wherein 0 groups are selected from L-Lys and L-εLys, and the compound of Formula I or its pharmaceutically acceptable salt, solvate and / or prodrug is in combination with 177 Lu comprises a net charge of zero (0) when complexed. Thus, in some embodiments, E is a chelating group comprising three free carboxylic acid groups (such as a chelating group derived from DOTA), the divalent linker comprises a total of 0 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, OEG, PEG1, PEG3, PEG6, and Aoc, and the compound of Formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof is in contact with 177 Lu comprises a net charge of zero (0) when complexed. In some embodiments, the divalent linker comprises a total of 0 to 9 groups independently selected from Gly, D-Pro, L-Pro, D-Ser, L-Ser, OEG, PEG1, PEG3, PEG6, Aoc, Aun, and Ahx.

[0259] In some embodiments, the divalent linker comprises a total of 1 to 7 groups independently selected from Gly, D-γGlu, L-γGlu, OEG, and Gly.

[0260] In some embodiments, the divalent linker comprises 1 to 7 groups in total independently selected from Gly, D-γGlu, L-γGlu, D-Lys, L-Lys, D-εLys, and L-εLys, and OEG.

[0261] In some embodiments, the bivalent linker comprises a total of 1 to 7 groups independently selected from Cbp, Dap, Gly, D-γGlu, L-γGlu, D-Ser, L-Ser, D-His, L-His and OEG.

[0262] In some embodiments, the divalent linker comprises a total of 2 to 6 groups independently selected from Gly and L-Pro. In some embodiments, the divalent linker comprises a total of 2 to 5 groups independently selected from Gly and L-Pro.

[0263] In some embodiments, the divalent linker comprises a total of 1 to 6 groups independently selected from Gly and L-Ser. In some embodiments, the divalent linker comprises a total of 1 to 4 groups independently selected from Gly and L-Ser.

[0264] In some embodiments, the divalent linker comprises 1 to 6 groups in total, and the 1 to 6 groups are Gly. In some embodiments, the divalent linker comprises 1 to 4 groups in total, and the 1 to 4 groups are Gly.

[0265] In some embodiments, the divalent linker comprises a total of 1 to 4 groups independently selected from Gly and L-Ser.

[0266] In some embodiments, the divalent linker comprises 1 to 2 groups in total, wherein the 1 to 2 groups are selected from PEG1, PEG3, or PEG6.

[0267] In some embodiments, the divalent linker comprises 1 to 2 groups in total, and the 1 to 2 groups are Aoc.

[0268] In some embodiments, the divalent linker comprises 1 to 2 groups in total, and the 1 to 2 groups are Ahx.

[0269] In some embodiments, the divalent linker comprises 1 to 4 groups in total, and the 1 to 4 groups are OEG. In some embodiments, the divalent linker comprises 1 to 3 groups in total, and the 1 to 3 groups are OEG. In some embodiments, the divalent linker comprises 1 to 2 groups in total, and the 1 to 2 groups are OEG. In some embodiments, the divalent linker comprises 1 group in total, and the 1 group is OEG.

[0270] In some embodiments, L 1 , L 2 and L 3 In some embodiments, L 1 is a direct bond. In some embodiments, L 1 , L 2 and L 3 In some embodiments, two of L are direct bonds. 1 and L 2 In some embodiments, L 1 , L 2and L 3 All are direct keys.

[0271] In some embodiments, L 1 , L 2 and L 3 One or two of the following are divalent linkers, and the divalent linker comprises 1 to 15 groups selected from the group consisting of Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Arg, L-Arg, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun, and Ahx, and L 1 , L 2 and L 3 The other two or one of L are direct bonds. 1 , L 2 and L 3 One or two of the following are divalent linkers, and the divalent linker comprises 1 to 11 groups selected from the group consisting of Cbp, Dap, D-His, L-His, Gly, D-Pro, L-Pro, D-Arg, L-Arg, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun, and Ahx, and L 1 , L 2 and L 3 The other two or one of L are direct bonds. 1 , L 2 and L 3 One or two of the following are divalent linkers, and the divalent linker comprises 1 to 6 groups selected from the group consisting of Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun, and Ahx, and L 1 , L 2 and L 3 The other two or one of L are direct bonds. 1 , L 2 and L 3One or two of are divalent linkers, and the divalent linker comprises 1 to 15 groups selected from the group consisting of Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, and L 1 , L 2 and L 3 The other two or one of L are direct bonds. 1 , L 2 and L 3 One or two of are divalent linkers, and the divalent linker comprises 1 to 11 groups selected from the group consisting of Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, and L 1 , L 2 and L 3 The other two or one of L are direct bonds. 1 , L 2 and L 3 One or two of are divalent linkers, and the divalent linker comprises 1 to 6 groups selected from the group consisting of Gly, D-Pro, L-Pro, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, and L 1 , L 2 and L 3 The other two or one of them are direct keys.

[0272] In some embodiments, L 1 , L 2 and L 3 One of the two is a divalent linker, and the divalent linker comprises 1 to 3 OEG groups, and L 1 , L 2 and L 3 The other two of L are direct bonds. 1 , L 2 and L 3 One of the two is a divalent linker, and the divalent linker comprises 1 to 2 OEG groups, and L 1 , L2 and L 3 The other two of L are direct bonds. 1 , L 2 and L 3 One of the following is a divalent linker, and the divalent linker comprises 1 OEG group, and L 1 , L 2 and L 3 The other two of L are direct bonds. 3 is a divalent linker, and the divalent linker comprises 1 to 3 OEG groups, and L 1 and L 2 is a direct bond. In some embodiments, L 3 is a divalent linker, and the divalent linker comprises 1 to 2 OEG groups, and L 1 and L 2 is a direct bond. In some embodiments, L 3 is a divalent linker, and the divalent linker comprises 1 OEG group, and L 1 and L 2 All are direct keys.

[0273] In some embodiments, E is a chelating group derived from DOTA, L 1 , L 2 and L 3 One of the following is a divalent linker, and the divalent linker comprises 1 OEG group, and L 1 , L 2 and L 3 The other two of them are direct bonds, and the compound of formula I or its pharmaceutically acceptable salt, solvate and / or prodrug is 177 Lu, when complexed, contains a net charge of zero (0).

[0274] In some embodiments, each R 5 Independently selected from H and C 1-4 In some embodiments, each R 5 Independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 2 ) 2 and C(CH 2 ) 3 In some embodiments, each R 5 Independently selected from H and CH 3 .

[0275] In some embodiments, each R 6 Independently selected from H and C 1-2 In some embodiments, each R 6 Independently selected from H, CH 3 and CH 2 CH 3 In some embodiments, each R 6 Independently selected from H and CH 3 .

[0276] In some embodiments, the compound of Formula I is selected from the following list of compounds or pharmaceutically acceptable salts and / or solvates thereof:

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] abbreviation:

[0314] T: threonine; C: cysteine; K: lysine; w: D-tryptophan; Y: tyrosine; f: D-phenylalanine; A: alanine; G: glycine; W: tryptophan; Nle: norleucine; D: aspartic acid; S: serine; p: D-proline; R: arginine; H: histidine:

[0315] gE: γ-glutamic acid; eK: ε-lysine

[0316] -OH: C-terminal acid; -NH2: C-terminal amide; Thr(ol): C-terminal alcohol

[0317] [CXXXXC]: disulfide bond

[0318] DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;

[0319] DOTAGA: 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid

[0320] OEG:H2N-[CH2CH2O]2-CH2CO2H

[0321] PEG1: H2N-CH2CH2O-CH2CH2CO2H

[0322] PEG3: H2N-[CH2CH2O]3-CH2CH2CO2H

[0323] PEG6: H2N-[CH2CH2O]6-CH2CH2CO2H

[0324] Aoc: 8-amino-octanoic acid

[0325] Cbp: 4-carboxy-L-phenylalanine

[0326] Dap: 2,3-diaminopropionic acid

[0327] Z360: Nastorazepide; CAS number 343326-69-2

[0328] The chelate binding group is capable of binding and / or complexing with a radionuclide. Thus, in some embodiments, the compound of formula I further comprises a radionuclide complexed with a chelate binding group.

[0329] Therefore, the present application also includes a radionuclide complex (radioligand) or a pharmaceutically acceptable salt and / or solvate thereof, which comprises a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radionuclides.

[0330] In some embodiments, the radionuclide is selected from transition metals, rare earth metals, lanthanides, actinides, and metalloids.

[0331] In some embodiments, the one or more radionuclides are radioisotopes of C, N, O, F, P, S, Cl, Br, I, As, Se, At, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Fr, Pm, lanthanides (such as La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), actinides (such as Ac, Th, U), Mg, Al, Ca, Cd, or Ba.

[0332] In some embodiments, the lanthanide is Lu, Sm, Ho, or Tb.

[0333] In some embodiments, the actinide is Ac, Th, or U.

[0334] In some embodiments, the radionuclide is selected from 225 Ac, 226 Ac, 228 Ac, 105 Ag, 106 mAg, 110 mAg, 111 Ag, 112 Ag, 113 Ag, 239 Am, 240 Am, 242 Am, 244 Am, 37 Ar, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 209 At 210 At 191 Au, 192 Au, 193 Au, 194 Au, 195 Au, 196 Au, 196 mAu, 198 Au, 198 mAu, 199 Au, 200 mAu, 128 8. 131 8. 133 mBa, 135 mBa, 140Well, 7 Be、 203 Yes, 204 Yes, 205 Yes, 206 Yes, 210 Yes, 212 Yes, 243 Bk、 244 Bk、 245 Bk、 246 Bk、 248 mBk、 250 Bk、 76 Br、 77 Br、 80 mBr、 82 Br、 11 C、 14 C、 45 That, 47 That, 107 CD, 115 CD, 115 mCd、 117 mCd、 132 What, 133 What? 134 What, 135 What, 137 What, 137 What? 139 What, 141 What, 143 What, 144 What, 246 See, 247 See, 253 See, 254 See, 240 Cm、 241 Cm、 242 Cm、 252 Cm、 55 Who, 56 Who, 57 Who, 58 Who, 58 mCo, 60 Who, 48 Cr、 51 Cr、 127 Cs, 129 Cs, 131 Cs, 132 Cs, 136 Cs, 137 Cs, 61 With, 62 With, 64 With, 67 With, 153 Dy,155 Dy, 157 Dy, 159 Dy, 165 Dy, 166 Dy, 160 Err, 161 Err, 165 Err, 169 Err, 171 Err, 172 Err, 250 Yes, 251 Yes, 253 Yes, 254 Yes, 254 mEs, 255 Yes, 256 mEs, 145 I, 146 I, 147 I, 148 I, 149 I, 150 my, 152 my, 156 I, 157 I, 52 Fe、 59 Fe、 251 Fm, 252 Fm, 253 Fm, 254 Fm, 255 Fm, 257 Fm, 66 Ga、 67 Ga、 68 Ga、 72 Ga、 73 Ga、 146 Gd、 147 Gd、 149 Gd、 151 Gd、 153 Gd、 159 Gd、 68 Ge、 69 Ge、 71 Ge、 77 Ge、 170 Hf、 171 Hf、 173 Hf、 175 Hf、 179 m 2 Hf、 180 mHf、 181 Hf、 184 Hf、 192 Hg、 193 Hg、 193 mHg,195 Hg、 195 mHg、 197 Hg、 197 mHg、 203 Hg、 160 mHo、 166 You、 167 You、 123 OF, 124 OF, 126 OF, 130 OF, 132 OF, 133 OF, 135 OF, 109 Through, 110 Through, 111 Through, 114 name, 115 name, 184 They、 185 They、 186 They、 187 They、 188 They、 189 They、 190 They、 190 m 2 They、 192 They、 193 mIr、 194 They、 194 m 2 They、 195 mIr、 42 K、 43 K、 76 Kr、 79 Kr、 81 mKr、 85 mKr、 132 Get, 133 Get, 135 Get, 140 Get, 141 Get, 262 Lr、 169 Head, 170 Head, 171 Head, 172 Head, 174 mLu、 176 mLu、 177 Head, 177 mLu、 179 Head, 257 Md、 258 Md、 260 Md、 28 Mg、 52 Mn、 90 Bride, 93mMo、Mo、 13 N、 24 And、 90 Nb、 91 mNb、 92 mNb、 95 Nb、 95 mNb、 96 Nb、 138 Nd、 139 mNd、 140 Nd、 147 Nd、 56 Nor, 57 Nor, 66 Nor, 234 Np、 236 mNp、 238 Np、 239 Np、 15 O、 182 Os、 183 Os、 183 mOs、 185 Os、 189 mOs、 191 Os、 191 mOs、 193 Os、 32 P、 33 P、 228 Pa、 229 Pa、 230 Pa、 232 Pa、 233 Pa、 234 Pa、 200 Pb、 201 Pb、 202 mPb、 203 Pb、 209 Pb、 212 Pb、 100 Pd、 101 Pd、 103 Pd、 109 Pd、 111 mPd、 112 Pd、 143 Pm、 148 Pm、 148 mPm、 149 Pm、 151 Pm、 204 Month, 206 Month, 207 Month, 210 Month, 139 Pr、 142 Pr、 143 Pr、 145 Pr、 188Pt、 189 Pt、 191 Pt、 193 mPt、 195 mPt、 197 Pt、 200 Pt、 202 Pt、 234 Pu、 237 Pu、 243 Pu、 245 Pu、 246 Pu、 247 Pu、 223 Ra、 224 Ra、 225 Ra、 81 Rb、 82 Rb、 82 mRb、 83 Rb、 84 Rb、 86 Rb、 181 Re、 182 Re、 182 mRe、 183 Re、 184 Re、 184 mRe、 186 Re、 188 Re、 189 Re、 190 mRe、 99 Rh、 99 mRh、 100 Rh、 101 mRh、 102 Rh、 103 mRh、 105 Rh、 211 Rn、 222 Rn、 97 Ru、 103 Ru、 105 Ru、 35 S、 118 mSb、 119 Sb、 120 Sb、 120 mSb、 122 Sb、 124 Sb、 126 Sb、 127 Sb、 128 Sb、 129 Sb、 43 Sc、 44 Sc、 44 mSc、 46 Sc、 47 Sc、 48 Sc、 72Se、 Se、 73 Se、 Se、 75 Se、 Se、 153 Sm、 156 Sm、 110 Sn、 113 Sn、 117 mSn、 119 mSn、 121 Sn、 123 Sn、 125 Sn、 82 Sr、 83 Sr、 85 Sr、 89 Sr、 91 Sr、 173 Belong, 175 Belong, 176 Belong, 177 Belong, 180 Belong, 182 Belong, 183 Belong, 184 Belong, 149 Tb、 150 Tb、 151 Tb、 152 Tb、 153 Tb、 154 Tb、 154 mTb、 154 m 2 Tb、 155 Tb、 156 Tb、 156 mTb、 156 m 2 Tb、 160 Tb、 161 Tb、 94 Tc、 95 Tc、 95 mTc、 96 Tc、 97 mTc、 99 mTc、 118 Little, 119 Little, 119 mTe、 121 Little, 121 mTe、 123 mTe、 125 mTe、 127 Little, 127 mTe、 129 mTe、 131 mTe、 132 Little, 227Th 、 、 231 Th、 234Th 、 、 45 Do,198 Tl, 199 Tl, 200 Tl, 201 Tl, 202 Tl, 204 Tl, 165 Tm, 166 Tm, 167 Tm, 168 Tm, 170 Tm, 172 Tm, 173 Tm, 230 U. 231 U. 237 U. 240 U. 48 V. 178 W. 181 W. 185 W. 187 W. 188 W. 122 Xe, 125 Xe, 127 Xe, 129 mXe, 131 mXe, 133 Xe, 133 mXe, 135 Xe, 85 mY, 86 Y. 87 Y. 87 mY, 88 Y. 90 Y. 90 mY, 91 Y. 92 Y. 93 Y. 166 Yb, 169 Yb, 175 Yb, 62 Zn, 65 Zn, 69 mZn, 71 mZn, 72 Zn, 86 Zr, 88 Zr, 89 Zr, 95 Zr and 97 Zr.

[0335] In some embodiments, the one or more radionuclides are selected from 14 C. 15 N. 18 F. 75 Br, 76 Br, 77 Br, 123OF, 124 OF, 125 OF, 131 OF, 35 S、 99 Tc、 99m Tc、 188 Re、 186 Re、 153 Sm、 66 Ga、 67 Ga、 68 Ga、 111 Through, 123 Through, 59 Fe、 63 Zn、 52 Fe、 52 Mn、 45 Water, 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 82 Rb、 195m Pt、 191m Pt、 193m Pt、 117m Sn、 89 Zr、 177 Head, 18 F、 188 Re、 186 Re、 153 Sm、 66 You、 86 Y、 87 Y、 90 Y、 89 Sr、 153 Gd、 159 Gd、 225 Ac、 212 Bi、 213 Bi、 211 And、 198 Shout, 199 Shout, 193m Pt、 197 Pt、 103 Pd、 109 Pd、 105 Rh、 101m Rh、 103m Rh、 223 Ra、 224 Ra、 97 Ru、 227 Th、 229 Th、 32 P、 161 Tb、 33 P、149 Tb, 125 I. 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co. 55 Co. 57 Co. 47 Sc, 149 Pm, 142 Pr, 161 Ho, 166 Ho, 175 Yb or 51 Cr.

[0336] In some embodiments, one or more radionuclides are used for imaging or diagnosis, or for therapy.

[0337] In some embodiments, the one or more radionuclides used for imaging or diagnosis are selected from 99m Tc, 188 Re, 186 Re, 153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 203 Pb, 44 Sc, 51 Cr, 101m Rh, 166 Ho or 123 I.

[0338] In some embodiments, the one or more radionuclides used for treatment are selected from 188 Re, 186 Re,153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 32 P. 161 Tb, 33 P. 125 I. 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co. 47 Sc, 149 Pm, 161 Ho, 159 Gd, 142 Pr, 166 Ho or 175 Yb.

[0339] In some embodiments, the radionuclide used for treatment is selected from 177 Lu, 153 Sm, 212 Pb, 90 Y and 225 Ac. In some embodiments, the radionuclide used for treatment is 177 Lu or 225 Ac. In some embodiments, the radionuclide used for treatment is 177 Lu. In some embodiments, the radionuclide used for treatment is 225 Ac.

[0340] Therefore, in exemplary embodiments, the present application includes a radionuclide complex or a pharmaceutically acceptable salt and / or solvate thereof, which comprises a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof, and a lanthanide radionuclide. In some embodiments, the lanthanide radionuclide is 177 Lu.

[0341] In one embodiment, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. Suitable salts can be selected by one skilled in the art (see, for example, SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0342] Acid addition salts suitable for the treatment of an object or compatible therewith are any nontoxic organic or inorganic acid addition salts of any basic compound. Basic compounds forming acid addition salts include, for example, compounds comprising an amine group. Illustrative inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and acidic metal salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids forming suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids. Illustrative organic acids of this type are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In one embodiment, an acid or di-acid salt is formed, and this salt exists in a hydrated form, a solvated form, or a substantially anhydrous form. Generally speaking, acid addition salts are more soluble in water and various hydrophilic organic solvents than their free base forms, and generally exhibit higher melting points. The selection criteria for suitable salts will be known to those skilled in the art. Other non-pharmaceutically acceptable salts (such as, but not limited to, oxalates) can, for example, be used to separate the compounds of the present application for laboratory use, or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0343] The base addition salts suitable for the treatment of the object or compatible therewith are any nontoxic organic or inorganic base addition salts of any acidic compound. The acidic compound forming the base addition salts, for example, includes compounds comprising carboxylic acid groups. The illustrative inorganic bases forming suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide and ammonia. The illustrative organic bases forming suitable salts include aliphatic, alicyclic or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, halamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Exemplary inorganic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The selection of appropriate salts can be used, for example, to prevent ester functionality (if any) elsewhere in the compound from being hydrolyzed. The selection criteria for appropriate salts will be known to those skilled in the art.

[0344] Solvates of the compounds of the present application include, for example, solvates made with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are referred to as hydrates) and ethanol, etc. Suitable solvents are physiologically tolerable at the administered dose.

[0345] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. In the case where a compound has more than one asymmetric center, it may exist as a diastereoisomer. It should be understood that all such isomers and mixtures of any ratio thereof are included within the scope of the present application. It should be further understood that, although the stereochemistry of the compound may be as shown in any given compound listed herein, such a compound may also contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of the compound of the present application with alternative stereochemistry. Any optical isomer as a separated pure optical isomer or a partially purified optical isomer or a racemic mixture thereof is intended to be included within the scope of the present application.

[0346] The compounds of the present application may also exist in different tautomeric forms, and any tautomeric forms formed by the compounds and mixtures thereof are intended to be included within the scope of the present application.

[0347] The compounds of the present application may further exist in different polymorphic forms, and any polymorphic form or mixture thereof is considered to be included within the scope of the present application.

[0348] III. Compositions and kits of the present application

[0349] The compounds and complexes of the present application are suitable for being formulated into compositions in a conventional manner using one or more carriers. Therefore, the present application also includes a composition comprising one or more compounds or complexes and carriers of the present application. The compounds or complexes of the present application are suitable for being formulated into pharmaceutical compositions for being applied to objects in a biocompatible form suitable for in vivo administration. Therefore, the present application further includes a pharmaceutical composition comprising one or more compounds or complexes of the present application and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is used for the treatment of any disease, disorder or condition described herein.

[0350] The present application also includes a kit comprising

[0351] one or more compounds of formula I as defined above, or pharmaceutically acceptable salts and / or solvates thereof, and

[0352] Instructions for administering the one or more compounds of Formula I or pharmaceutically acceptable salts and / or solvates thereof to a subject in need thereof.

[0353] The present application also includes a kit comprising

[0354] one or more compounds of formula I as defined above, or pharmaceutically acceptable salts and / or solvates thereof, and

[0355] one or more radioactive isotopes as defined above, and

[0356] Optionally, instructions for administering the one or more compounds of Formula I, or pharmaceutically acceptable salts and / or solvates thereof, to a subject in need thereof and administering the radioisotope to a subject in need thereof.

[0357] The present application also includes a kit comprising

[0358] One or more complexes of the present application as defined above or pharmaceutically acceptable salts and / or solvates thereof, and

[0359] Instructions for administering the one or more compound complexes to a subject in need thereof.

[0360] In some embodiments, one or more compounds of Formula I as defined above, or pharmaceutically acceptable salts and / or solvates thereof, one or more complexes as defined above, or pharmaceutically acceptable salts and / or solvates thereof, or one or more radioactive isotopes as defined above, are each present in the kit in one or more pharmaceutical compositions.

[0361] In some embodiments, a pharmaceutical composition comprising one or more compounds of formula I as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, one or more complexes as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, or one or more radioactive isotopes as defined above is formulated for parenteral administration as described below. In some embodiments, parenteral administration is by injection.

[0362] In some embodiments, the kit further comprises a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. In some embodiments, the pharmaceutically acceptable buffer is present in the kit in one or more containers, such as vials or ampoules.

[0363] In some embodiments, the kit is used for imaging. In some embodiments, the kit is used for treatment. In some embodiments, the kit is used for treating cancer. In some embodiments, the kit is transformed and / or arranged to implement any method of the application. Therefore, the application also includes a drug package or kit that is transformed and / or arranged to implement any method of the application.

[0364] As will be appreciated by those skilled in the art, the compound or complex of the present application is applied to the object in various forms depending on the selected route of administration. For example, the compound of the present application is applied by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, micropump, topical or transdermal administration, and the pharmaceutical composition is formulated accordingly. In some embodiments, it is applied in the form of a pump for periodic or persistent delivery. The conventional procedures and ingredients for selecting and preparing suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000–20th edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19) published in 1999.

[0365] Parenteral administration includes systemic delivery routes outside the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0366] In some embodiments, the compound or complex of the present application is administered orally, for example, with an inert diluent or with an assimilable edible carrier, or it is encapsulated in a hard or soft shell gelatin capsule, or it is compressed into a tablet, or it is directly blended with food in the diet. In some embodiments, the compound is blended with an excipient and used in the form of an ingestible tablet, buccal tablet, lozenge, capsule, caplet, pill, granule, lozenge, chewing gum, powder, syrup, elixir, flake, aqueous solution, and suspension. In the case of tablets, the carrier used includes lactose, corn starch, sodium citrate, and phosphate. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). In some embodiments, tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pills or granules for oral administration, a pH-sensitive enteric coating such as Eudragits designed to control the release of the active ingredient is optionally used. TM Oral dosage forms also include modified release formulations, such as immediate release and gradual release formulations. Examples of modified release formulations include, for example, sustained release (SR), prolonged release (ER, XR or XL), gradual release, controlled release (CR) or sustained release (CR or Contin) in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., as molecular sieve-type particles) or thin hollow permeable fiber bundles or short-cut hollow permeable fibers agglomerated or contained in fiber packages. Gradually released compositions are, for example, formulated as liposomes or compositions in which the active compound is protected by a differentially degradable coating (such as by microcapsule encapsulation, multiple coatings, etc.). Liposomal delivery systems, for example, include small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed by various phospholipids (such as cholesterol, stearylamine or phosphatidylcholine). For oral administration in capsule form, useful carriers or diluents include lactose and dry corn starch.

[0367] In some embodiments, the liquid preparation for oral administration is, for example, in the form of a solution, syrup or suspension, or it is suitable for being presented as a dry product for redissolution with water or other suitable vehicles before use. When an aqueous suspension and / or emulsion is administered orally, the compound of the present application is suitable for suspension or dissolution in an oil phase combined with an emulsifier and / or suspending agent. If desired, certain sweeteners and / or flavoring agents and / or coloring agents are added. This liquid preparation for oral administration is prepared by conventional means with a pharmaceutically acceptable additive, such as a suspending agent (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fat); an emulsifier (e.g., lecithin or gum arabic); a non-aqueous vehicle (e.g., almond oil, oil esters or ethanol); and a preservative (e.g., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0368] The compounds of the present application can also be freeze-dried and the lyophilized products obtained can be used, for example, for the preparation of products for injection.

[0369] In some embodiments, the compound or complex of the present application is administered parenterally. For example, the solution of the compound of the present application is prepared in water suitable for mixing with a surfactant such as hydroxypropyl cellulose. In some embodiments, the dispersant is prepared in glycerol, liquid polyethylene glycol, DMSO and its alcohol or alcohol-free mixture and in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. Those skilled in the art will know how to prepare suitable preparations. For parenteral administration, a sterile solution of the compound of the present application is usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. For ocular administration, ointment or drop-in liquid is delivered, for example, by an ocular delivery system known in the art (such as an applicator or an eye dropper). In some embodiments, this composition includes a mucus mimetic (such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol), a preservative (such as sorbic acid, EDTA or benzyl chromium chloride) and a diluent or carrier of a usual amount. For pulmonary administration, an appropriate diluent or carrier will be selected to allow for the formation of an aerosol.

[0370] In some embodiments, the compound or complex of the present application is formulated for parenteral administration by injection (including using conventional catheter insertion techniques or infusion). Injectable preparations are presented, for example, in unit dosage forms (e.g., in ampoules or multidose containers) with the addition of preservatives. In some embodiments, the composition takes the form of a sterile suspension, solution or emulsion in an oil or water vehicle, and contains a formulation such as a suspending agent, a stabilizer and / or a dispersant. In all cases, the form must be sterile and must be fluid to achieve an extent that is easy to inject. Alternatively, the compound or complex of the present application is suitable for a sterile powder form for redissolving with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0371] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, solutions, gels, and powders.

[0372] Suitable compositions for buccal or sublingual administration include tablets, lozenges and pastilles wherein the compound or complex of the present application is formulated with a substance such as sugar, acacia, tragacanth or gelatin and glycerin.

[0373] The compounds or complexes of the present application can be used in the form of suppositories for vaginal, urethral and rectal administration.

[0374] In some embodiments, the compound or complex of the present application is coupled with a soluble polymer as a targetable drug carrier. Such polymers include, for example, polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, in some embodiments, the compound of the present application is coupled with a class of biodegradable polymers that can be used to achieve controlled release of drugs, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymers, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block hydrogel copolymers.

[0375] The compounds or complexes of the present application (including pharmaceutically acceptable salts and / or solvates thereof) are suitable for use alone, but will generally be administered in the form of a pharmaceutical composition, wherein one or more compounds (active ingredients) of the present application are associated with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain about 0.05 wt % to about 99 wt % or about 0.10 wt % to about 70 wt % of the active ingredient and about 1 wt % to about 99.95 wt % or about 30 wt % to about 99.90 wt % of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[0376] IV. Methods and Uses of the Present Application

[0377] Accordingly, the present application also includes a method for treating a disease or condition, comprising administering a therapeutically effective amount of one or more compounds or complexes of the present application to a subject in need. The present application also includes the use of one or more compounds or complexes of the present application for treating a disease or condition and the use of one or more compounds or complexes of the present application for preparing a medicament for treating a disease or condition. The present application further includes one or more compounds or complexes of the present application for treating a disease or condition.

[0378] In one embodiment, the target of the target binding group of the compound or complex is present on disease cells. In fact, the presence and / or overexpression of receptors on the cell surface is a sign of many cells (including cancer cells) associated with diseases. Therefore, in another embodiment, the target of the target binding group (e.g., cell surface receptor) is present on cancer cells, and the disease or condition is cancer. In some embodiments, the first targeting group, the second targeting group, or both are present on disease cells. For example, in one embodiment, the target of the first target binding group is a cholecystokinin receptor, and the disease or condition is medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), astrocytoma, stromal ovarian tumor, or gastrointestinal stromal tumor (GIST). In another embodiment, the target of the second target binding group is somatostatin receptor 2 (SSTR2), and the disease or condition is a neuroendocrine tumor, small cell lung cancer (SCLC), or medullary thyroid carcinoma (MTC). In some embodiments, the targets of the first targeted binding group and the second targeted binding group are both cholecystokinin receptor (CCK2R) and somatostatin receptor 2 (SSTR2), and the disease or disorder is MTC or SCLC, wherein both SSTR2 and CCK2R are overexpressed.

[0379] In one embodiment, the disease or disorder is cancer.

[0380] In one embodiment, the cancer is selected from, but is not limited to, adult acute lymphoblastic leukemia; childhood acute lymphoblastic leukemia; adult acute myeloid leukemia; adrenocortical carcinoma; childhood adrenocortical carcinoma; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; childhood cerebellar astrocytoma; childhood cerebral astrocytoma; extrahepatic bile duct cancer; bladder cancer; childhood bladder cancer; osteosarcoma / malignant fibrous histiocytoma bone cancer; childhood brain stem glioma; adult brain tumor; childhood brain stem glioma brain tumor; childhood cerebellar astrocytoma brain tumor; childhood cerebral astrocytoma / malignant glioma brain tumor; childhood ependymoma brain tumor; childhood medulloblastoma brain tumor; childhood supratentorial primitive neuroectodermal tumor brain tumor; Childhood Visual Pathway and Hypothalamic Glioma Brain Tumors; Childhood Brain Tumors (Other); Breast Cancer; Breast Cancer and Pregnancy; Childhood Breast Cancer; Male Breast Cancer; Childhood Bronchial Adenocarcinoma / Carcinoid; Childhood Carcinoid Tumors; Gastrointestinal Carcinoid Tumors; Adrenal Cortical Carcinoma; Islet Cell Carcinoma; Cancer of Unknown Primary; Primary Central Nervous System Lymphoma; Childhood Cerebellar Astrocytoma; Childhood Cerebral Astrocytoma / Malignant Glioma; Cervical Cancer; Childhood Cancer; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Myeloproliferative Disorders; Tenosynovial Clear Cell Sarcoma; Colon Cancer; Childhood Colorectal Cancer; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Childhood Ependymoma; Ovarian Epithelial Cancer; Esophageal Cancer; Childhood Esophageal Cancer; Ewing's Family of Tumors Family of Tumor; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Biliary Carcinoma; Intraocular Melanoma Eye Cancer; Retinoblastoma Eye Cancer; Gallbladder Cancer; Gastric Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Ovarian Germ Cell Tumor; Gestational Trophoblastic Tumor; Brain Stem Glioma, Childhood; Visual Pathway and Hypothalamic Glioma, Childhood; Hairy Cell Leukemia; Head and Neck Cancer; Adult (Primary) Hepatocellular (Liver) Cancer; Childhood (Primary) Hepatocellular (Liver) Cancer; Adult Hodgkin's Lymphoma (Hodgkin's Lymphoma, Adult); Childhood Hodgkin's Lymphoma; Pregnancy Hodgkin's Lymphoma; Hypopharyngeal Cancer; Childhood Hypothalamic and Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma (Kaposi's Sarcoma); Kidney cancer; Laryngeal cancer; Laryngeal cancer, childhood; Acute lymphoblastic leukemia, adult; Acute lymphoblastic leukemia, childhood; Acute myeloid leukemia, adult; Acute myeloid leukemia, childhood; Chronic lymphocytic leukemia; Chronic myeloid leukemia; Hairy cell leukemia; Lip and oral cancer; Liver cancer, adult (primary); Liver cancer, childhood (primary); Non-small cell lung cancer; Small cell lung cancer; Acute lymphoblastic leukemia, adult; Acute lymphoblastic leukemia, childhood; Chronic lymphocytic leukemia; AIDS-related lymphoma;Central nervous system (primary) lymphoma; cutaneous T-cell lymphoma; adult Hodgkin's lymphoma; childhood Hodgkin's lymphoma; pregnancy Hodgkin's lymphoma; adult non-Hodgkin's lymphoma; childhood non-Hodgkin's lymphoma; pregnancy non-Hodgkin's lymphoma; primary central nervous system lymphoma; Waldenstrom's macroglobulinemia; male breast cancer; adult malignant mesothelioma; childhood malignant mesothelioma; malignant thymoma; childhood medulloblastoma; melanoma; intraocular melanoma; Merkel cell carcinoma Carcinoma); malignant mesothelioma; squamous neck cancer with occult metastatic primary site; multiple endocrine neoplasia syndrome, childhood; multiple myeloma / plasma cell neoplasms; mycosis fungoides; myelodysplastic syndrome; chronic myeloid leukemia; acute myeloid leukemia, childhood; multiple myeloma; chronic myeloproliferative disorder; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; nasopharyngeal cancer, childhood; neuroblastoma; adult non-Hodgkin's lymphoma; childhood non-Hodgkin's lymphoma; pregnancy non-Hodgkin's lymphoma; non-small cell lung cancer; childhood oral cancer; oral cavity and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; childhood ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; ovarian low-grade malignant potential tumor; pancreatic cancer; childhood pancreatic cancer; islet cell pancreatic cancer; paranasal sinuses and Nasal cancer; Parathyroid cancer; Penile cancer; Pheochromocytoma; Pineal and supratentorial primitive neuroectodermal tumors in children; Pituitary tumors; Plasma cell neoplasms / multiple myeloma; Pleuropulmonary blastoma; Pregnancy and breast cancer; Pregnancy and Hodgkin lymphoma; Pregnancy and non-Hodgkin lymphoma; Primary central nervous system lymphoma; Primary liver cancer in adults; Primary liver cancer in children; Prostate cancer; Rectal cancer; Renal cell (kidney) cancer; Renal cell carcinoma in children; Transitional cell carcinoma of the renal pelvis and ureter; Retinoblastoma; Rhabdomyosarcoma in children; Salivary gland cancer; Salivary gland cancer in children; Ewing family tumor sarcoma; Kaposi's sarcoma; Sarcoma of bone (osteosarcoma) / malignant fibrous histiocytoma; Rhabdomyosarcoma sarcoma in children; Soft tissue sarcoma in adults; Soft tissue sarcoma in children; Sezary syndrome Syndrome); Skin cancer; Skin cancer in children; Skin cancer (melanoma); Merkel cell skin cancer; Small cell lung cancer; Small intestinal cancer; Soft tissue sarcoma in adults; Soft tissue sarcoma in children; Squamous neck cancer with occult metastatic primary; Gastric cancer; Gastric cancer in children; Supratentorial primitive neuroectodermal tumor in children; Cutaneous T-cell lymphoma; Testicular cancer; Thymoma in children; Malignant thymoma; Thyroid cancer; Thyroid cancer in children; Medullary thyroid cancer; Transitional cell carcinoma of the renal pelvis and ureter; Gestational trophoblastic tumor; Cancer of unknown primary site in children; Unusual cancers in children; Transitional cell carcinoma of the ureter and renal pelvis; Urethra cancer; Uterine sarcoma; Vaginal cancer; Visual pathway and hypothalamic glioma in children; Vulvar cancer;Waldenstrom's macroglobulinemia; Wilms' Tumor and neuroendocrine tumors. Metastases of the above cancers can also be treated according to the methods described herein. ;

[0381] In another embodiment, the cancer is a cancer that overexpresses SSTR2, CCK2R, or both. As used herein, a cancer that "overexpresses" a cell surface receptor is a cancer that has a higher cell surface level expression level of the receptor compared to non-cancerous cells of the same tissue type. "Overexpressing" cancers include cancers that express the cell surface receptor when non-cancerous cells of the same tissue type do not express the cell surface receptor.

[0382] In one embodiment, the cancer is medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), or a neuroendocrine tumor. In one embodiment, the cancer is medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), or a neuroendocrine tumor, wherein SSTR2, CCK2R, or both SSTR2 and CCK2R are expressed.

[0383] The effectiveness of the treatment is determined in conjunction with any known method for diagnosing or treating a particular cancer. Alleviation of one or more symptoms of cancer indicates that the compound or complex confers a clinical benefit.

[0384] The compound or complex can be administered in combination with at least one additional cancer therapy, including chemotherapy, radiation, and / or immuno-oncology therapy. Another cancer therapy can be administered in any order with the at least one additional cancer therapy, such as simultaneously, sequentially, or separately.

[0385] As used herein, "treating cancer" includes but is not limited to reversing, alleviating or inhibiting the progression of cancer or symptoms or conditions associated with cancer. "Treating cancer" also includes extending the survival of a subject. The survival period is optionally extended by at least 1, 2, 3, 6 or 12 months, or at least 2, 3, 4, 5 or 10 years compared to the survival period expected in the absence of treatment with a cytotoxic agent or composition as described herein. "Treating cancer" also includes reducing tumor mass and / or reducing tumors. Optionally, after treatment with a cytotoxic agent or composition as described herein, tumor mass and / or tumor burden are reduced by at least 5, 10, 25, 50, 75 or 100%. "Treating cancer" also includes reducing the aggressiveness, grade and / or invasiveness of a tumor.

[0386] The present application also includes a method for inhibiting proliferation activity in a cell, comprising administering an effective amount of one or more compounds or complexes of the present application to the cell. The present application also includes the use of one or more compounds or complexes of the present application for inhibiting proliferation activity in a cell and the use of one or more compounds or complexes of the present application for preparing a drug for inhibiting proliferation activity in a cell. The present application further includes one or more compounds or complexes of the present application for inhibiting proliferation activity in a cell. In one embodiment, one or more compounds or complexes contain a radionuclide for treatment, which is optionally 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 32 P. 161 Tb, 33 P. 125 I. 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co. 47 Sc, 149 Pm, 161 Ho, 159 Gd, 142 Pr, 166 Ho or 175 Yb.

[0387] The present application also includes a method for imaging tissue in a subject by administering an imaging effective amount of one or more compounds or complexes of the present application for imaging to a subject in need thereof, and applying imaging technology to detect the emitted gamma rays. The present application also includes the use of one or more compounds or complexes of the present application for imaging for imaging tissues and the use of one or more compounds or complexes of the present application containing radionuclides for imaging for the preparation of drugs for imaging tissues. The present application further includes one or more compounds or complexes of the present application for imaging tissues, which contain radionuclides for imaging. In some embodiments, the use further includes applying imaging technology to detect the emitted gamma rays. In one embodiment, one or more compounds or complexes contain radionuclides for imaging, which are optionally 99m Tc, 188 Re, 186 Re, 153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 203 Pb, 44 Sc, 51 Cr, 101m Rh, 166 Ho or 123 I.

[0388] The present application also includes a method for diagnosing cancer in a subject by administering a diagnostically effective amount of one or more compounds or complexes of the present application to a subject in need thereof, and applying imaging technology to detect the emitted gamma rays. The present application also includes the use of one or more compounds or complexes of the present application for diagnosing cancer and the use of one or more compounds or complexes of the present application for diagnosing cancer. The present application further includes one or more compounds or complexes of the present application for diagnosing cancer, which contain a radionuclide for imaging. In some embodiments, the use further includes applying imaging technology to detect the emitted gamma rays. In one embodiment, one or more compounds or complexes contain a radionuclide for imaging, which is optionally 99m Tc, 188 Re, 186 Re, 153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 203 Pb, 44 Sc, 51 Cr, 101m Rh, 166 Ho or 123 I.

[0389] In one embodiment, the effective amount varies according to factors such as the disease state, age, sex and / or weight of the subject. In further embodiments, the amount of a given compound or complex that will correspond to an effective amount will vary depending on factors such as the given compound or complex, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, etc., but can be routinely determined by one skilled in the art. In one embodiment, an effective amount is an amount that manifests as an improvement or reduction in any disease symptom following treatment therewith.

[0390] In one embodiment, the compound or complex is administered at least once a week. However, in another embodiment, the compound or complex is administered to the subject approximately once every two weeks, three weeks, or once a month. In another embodiment, the compound or complex is administered approximately once a week to approximately once a day. In another embodiment, the compound or complex is administered 2, 3, 4, 5, or 6 times a day. The length of the treatment period depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or a combination thereof. It will also be understood that within the course of treatment of a particular treatment regimen, the effective dose of the compound or complex used for treatment may increase or decrease. Changes in dosage may occur and become apparent through standard diagnostic assays known in the art. In some cases, long-term administration is required. For example, the compound or complex is applied to the subject in an amount and duration sufficient to treat the subject.

[0391] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In one embodiment, the subject is a non-human animal. In one embodiment, the subject is a canine. In one embodiment, the subject is a cat. Thus, the compounds, methods, and uses of the present application relate to both human and veterinary diseases, disorders, and conditions.

[0392] The dosage of the compound or complex of the present application varies depending on many factors, such as the pharmacokinetic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment and the type of concurrent treatment (if any), and the clearance rate of the compound in the object to be treated. Those skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, the compound or complex of the present application is initially administered at a suitable dosage, which is adjusted as needed depending on the clinical response. The dosage will generally be selected to maintain the serum level of the compound of the present application at from about 0.01 μg / cc to about 1000 μg / cc or about 0.1 μg / cc to about 100 μg / cc. As a representative example, for adults, the oral dosage of one or more compounds of the present application will be in the range of about 1 mg per day to about 1000 mg per day, suitable for about 1 mg per day to about 500 mg per day, and more suitable for about 1 mg per day to about 200 mg per day. For parenteral administration, the representative amount to be administered is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For oral administration, the representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For administration in the form of a suppository, the representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg.

[0393] V. Methods for preparing the compounds of the present application

[0394] The compounds and / or complexes or control compounds of the present application can be prepared by various synthesis processes. The selection of specific structural features and / or substituents can affect the selection of one process rather than another process. The selection of a specific process for preparing a given compound of the present application and / or complex or control compound is within the capabilities of those skilled in the art. Some starting materials for preparing the compounds of the present application can be obtained from commercial chemical sources. Other starting materials (such as described below) are easily prepared from available precursors using simple conversions well known in the art.

[0395] In some embodiments, compounds of Formula I or reference compounds are prepared in whole or in part using solid phase peptide synthesis (SPPS) or solution phase coupling techniques known in the art (e.g., using the synthetic procedures found in Stewart and Young, 1984, Solid Phase Synthesis, 2nd ed., Pierce Chemical Co., Rockford, III.; Fields and Noble, 1990, “Solid phase peptide synthesis utilizing 9-fluorenylmethyloxycarbonyl amino acids,” Int. J. Pept. Protein Res. 35:161-214; Geysen et al., 1987, J. Immunol. Methods 102:259-274).

[0396] Thus, in some embodiments, in SPPS, an Nα protected linker group (such as tert-butyloxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) amino acid linker group) is activated at the α-carbonyl and coupled to the deprotected Nα functionality of the solid support. The newly added Nα protected linker group is then deprotected and coupled to the next Nα protected linker group (if necessary) until the final cleavage step. It will be appreciated by those skilled in the art that the chemistry of the steps of coupling, deprotection, and final cleavage from the solid support of the linker depends on the choice of the αN protecting group. In some embodiments, cleavage is accomplished by treatment with an acid, such as trifluoroacetic acid (TFA), optionally in the presence of a scavenger reagent such as triisopropylsilane. In some embodiments, when the αN protecting group is Fmoc, cleavage in acid will also result in deprotection of the side chain.

[0397] Thus, in exemplary embodiments, the compounds of Formula I or control compounds are prepared using fluorenylmethoxycarbonyl (Fmoc) solid phase peptide synthesis chemistry known in the art. Thus, in some embodiments, the compounds of Formula I or fragments are prepared manually or by using an automated multi-solid phase peptide synthesizer using Wang resin, Rink Amide-MBHA or equivalent resin and a Fmoc protected linker group derivative with suitable side chain protection, such as Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc- Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Nle-OH, Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH), Fmoc-Glu-OtBu. The resin is swollen using a suitable solvent such as a combination of dichloromethane (DCM) and dimethylformamide (DMF). Before each coupling step, the base-labile Na protecting group Fmoc is cleaved from the Fmoc protected linker group using a suitable base (such as piperidine) in a suitable solvent (such as DMF) with a cleavage time (e.g., about 10-15 min) to cleave the Fmoc protecting group. The resin is then washed with a suitable solvent (such as DMF) to, for example, remove the piperidine. A coupling agent known in the art (e.g., N, N'-diisopropylcarbodiimide (DIC) and ethyl cyanoxime (Oxyma, for example)) is then used in a suitable solvent (such as DMF). ) or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 1-hydroxybenzotriazole (HOBt)) are coupled with an excess of Fmoc linker groups (e.g., 4 to 8 molar equivalents) for about 1 to about 2 hours, followed by further washing with a suitable solvent (such as DMF). The coupling step is repeated once for each linker group.

[0398] If necessary, the methyltrityl (Mtt) group in the Fmoc-Lys(Mtt)-OH (i.e., N-α-Fmoc-N-ε-4-methyltrityl-L-lysine) linker group or the deprotected Lys(Mtt) residue in the linker fragment is removed by treating the group or residue with hexafluoroisopropanol (HFIP) (e.g., about 30% v / v) in a suitable solvent (such as dichloromethane (DCM)) for a suitable amount of time (e.g., about 1 hour), followed by washing the resin with a suitable solvent and repeating the treatment with HFIP in DCM, followed by a final wash with DCM.

[0399] After coupling, the compound of formula I, the reference compound or its fragment is cut from the solid phase by treating with a suitable acid (e.g., trifluoroacetic acid (TFA)) and optionally in the presence of a trialkylsilane such as triisopropylsilane (TIP) and water, and then precipitated with a suitable solvent such as diethyl ether. The product is dissolved in a suitable solvent such as water and acetonitrile and purified using high performance liquid chromatography (HPLC), such as reversed phase HPLC using a suitable solvent or solvent mixture such as water with acetonitrile and TFA, with a gradient increase of acetonitrile. The relevant fractions are checked by analytical UPLC. The fractions containing the pure target compound are merged and freeze-dried.

[0400] Chelating groups such as DOTA are conjugated to linker fragments, e.g., the epsilon amine of a lysine residue of a linker fragment or a linker fragment attached to a tumor binding group and / or a cycle-enhancing group using active ester chemistry known in the art. For example, DOTA is combined with a linker fragment in the presence of a base such as an amine.

[0401] Chelating groups can be synthesized by methods known in the art or can be obtained commercially. For example, DOTA can be obtained from Sigma-Aldrich (St. Louis, Missouri, United States).

[0402] Formation of the desired compound is achieved using standard techniques, for example, by treating the neutral compound with an acid or base in a suitable solvent and isolating the salt formed by filtration, extraction or any other suitable method.

[0403] The formation of solvates will vary depending on the compound and the solvate. Generally speaking, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are usually dried or azeotropic at ambient conditions. Those skilled in the art can make a selection of the conditions suitable for forming a specific solvate. Examples of suitable solvents are ethanol, water, etc. When water is a solvent, the molecule is referred to as a "hydrate". The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. Generally speaking, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are usually dried or azeotropic at ambient conditions. Those skilled in the art can make a selection of the conditions suitable for forming a specific solvate.

[0404] In all processes described herein, it should be understood that, when appropriate, suitable blocking groups will be added to various reactants and intermediates and subsequently removed from various reactants and intermediates in a manner that will be readily understood by those skilled in the art. The conventional procedures for using this blocking group and the example of suitable blocking groups are described in, for example, " Protective Groups in Organic Synthesis ", TW Green, PGM Wuts, Wiley-Interscience, New York, (1999). It should also be understood that the conversion of a group or substituent to another group or substituent by chemical manipulation can be carried out on any intermediate or final product on the synthetic path toward the final product, wherein possible conversion types are only limited to other functionalities carried by the molecule of this stage and the inherent incompatibility of the conditions or reagents used in the conversion. This inherent incompatibility and the mode of circumventing this incompatibility by implementing appropriate conversion and synthesis steps in a suitable order will be readily understood by those skilled in the art. The example of conversion is given herein, and it should be understood that the described conversion is not limited to the universal group or substituent that illustrates the conversion. References and descriptions of other suitable transformations are given in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations" RC Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in organic chemistry textbooks such as "Advanced Organic Chemistry", March, 4th Edition McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purifying intermediates and final products include, for example, normal and reverse phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which will be readily understood by those skilled in the art.

[0405] The following non-limiting examples illustrate the present application.

[0406] Example

[0407] The following non-limiting examples illustrate the present application.

[0408] 332. Synthesis of Exemplary Formula I Compounds

[0409] General Methods

[0410] Reagents

[0411] Unless otherwise specifically stated, the Fmoc-protected amino acid derivatives used were standard recommendations: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-D-Phe-OH, Fmoc- c-Pro-OH, Fmoc-D-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)- OH, Fmoc-Lys(ivDde)-OH, Fmoc-Glu-OtBu, Fmoc-Thr(tBu)-ol(CAS#189337-28-8), Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH), Fmoc-8-amino-octanoic acid (Fmoc-Aoc-OH), Fmoc-PEG 1 -OH(Fmoc-HN-CH 2 CH 2 O-CH 2 CH 2 CO 2 H), Fmoc-PEG 3 -OH(Fmoc-HN-[CH 2 CH 2 O] 3 -CH 2 CH 2 CO 2 H), Fmoc-PEG 6 -OH(Fmoc-HN-[CH 2 CH 2 O] 6 -CH 2 CH 2 CO 2 H), etc. Other reagents used include DOTA-tri(tert-butyl ester), DOTAGA-tetra(t-Bu ester), nastorazepide (Z360, CAS No. 343326-69-2), etc.

[0412] Loading of C-Terminal Residues

[0413] C-terminal acid peptide

[0414] The C-terminal peptides were prepared using Wang resin. The coupling of the first C-terminal residue was initiated by 2 Wang resin (loading 1.1 mmol / g, 5.0 mmol) was swollen in DCM (50 mL) in a SPPS reactor bubbling for 30 min. The resin was then filtered and washed 3 times with DMF (50 mL). In another flask, a mixture of Fmoc-Thr(tBu)-OH (15 mmol), DIC (15 mmol) and 4-dimethylaminopyridine (DMAP) (0.5 mmol) in DMF (60 mL) was stirred at rt for 15 min and then transferred to the above reactor. The resulting mixture was washed with N 2 The mixture was bubbled for 4 h, then filtered and washed 6 times with DMF (50 mL), followed by the addition of DMF (60 mL), acetic anhydride (50 mmol) and DMAP (0.50 mmol). 2 Bubble for 2 h, then filter dry and wash the resin 6 times with DMF (50 mL).

[0415] C-terminal amide peptide

[0416] C-terminal amide peptides were prepared using Rink Amide-MBHA resin. Standard amide bond coupling conditions were followed to attach the first C-terminal residue (Fmoc-Lys(Mtt)-OH or Fmoc-Thr(tBu)-OH) using PyBOP / HOBt / DIEA as coupling reagents. The resin was washed 6 times with DMF before coupling the second residue.

[0417] C-terminal alcohol peptide

[0418] The C-terminal alcohol peptide was prepared using chlorotrityl chloride (CTC) resin, and the first C-terminal residue Fmoc-Thr(tBu)-ol was attached to the CTC resin by mixing 2 equivalents of Fmoc-Thr(tBu)-ol with the resin in the presence of 3 equivalents of DIEA in DMF at rt for 4 h, followed by washing and blocking with 50% MeOH / DMF at RT for 1 h. The resin was then washed 6 times with DMF.

[0419] Standard Solid-Phase Assembly Protocol

[0420] The synthesis was performed manually using Fmoc-based chemistry. The step-by-step assembly was performed as follows:

[0421] 1) Pre-swelling the resin with DCM and DMF;

[0422] 2) Remove the Fmoc group by 20% piperidine; treat twice, each time for 10 min;

[0423] 3) washing the resin with DMF to remove piperidine;

[0424] 4) Fmoc-amino acid (1 mmol), PyBOP (1 mmol), HOBt (0.2 mmol) and DMF (5 mL) were added to a reactor containing 0.20 mmol of resin, followed by DIEA (2 mmol), and the resulting mixture was mixed by bubbling nitrogen for 1-2 h;

[0425] 5) Filter the resin and wash it with DMF 6 times;

[0426] 6) If necessary, the N-ε-lysine Mtt protecting group can be removed by treating the resin with 30% (v / v) HFIP in DCM for 1 h and twice; drain the resin and wash with DCM and DMF;

[0427] 8) Final washes before resin cleavage were completed with DMF (3 times), DCM (3 times) and MeOH (3 times), respectively.

[0428] Resin cleavage conditions and purification

[0429] After solid-phase peptide assembly was complete, the resin was subjected to TFA / triisopropylsilane (TIS) / H 2 The resin was filtered off and washed once with TFA, and the combined filtrates were treated with methyl tert-butyl ether (MTBE) to precipitate the crude peptide from the solution. The precipitate was collected by centrifugation and washed three times with diethyl ether, dried briefly, and then in acetonitrile (ACN) and H 2 Redissolve in HO to a concentration of 1 mM or less. ACN and HO 2 The volume ratio of O can be adjusted to a relatively low ACN percentage while ensuring that a completely clear solution can still be achieved. The pH of the resulting solution is adjusted to 4-5 by adding acetic acid, and then an iodine solution in methanol (1.0 grams of iodine in 100 mL of methanol) is added dropwise until the iodine purple color is maintained. The slightly purple mixture is then gently stirred for another 30 min, and then ascorbic acid solid (several mg per portion) is added until the purple color disappears completely. The resulting crude product is subjected to purification using a reverse phase preparative HPLC system (Waters Delta Prep 4000) with a C18 reverse phase column. Mobile phase: A: 0.1% TFA / H 2O; B: 0.1% TFA / ACN. Relevant fractions were analyzed by analytical ultra-performance liquid chromatography (UPLC). Pure fractions were combined and freeze-dried to give the product as a white lyophilized powder.

[0430] LC-MS conditions

[0431] Instrument: Agilent prime-6125B_2LCMS

[0432] Column: Boltimate EXT C18 core-shell 4.6 x 50 mm, 2.7 μm

[0433] Detection: UV (254nm 214nm 280nm) and MS (ESI, 100 to 2000amu)

[0434] Mobile phase: A:H 2 O (0.05% formic acid); B: ACN (0.05% formic acid)

[0435] Flow rate: 2.0mL / min

[0436] Column temperature: 45°C

[0437] Gradient: 10% to 95% B in 1.5 min, then 95% B for 1.0 min

[0438] Analytical HPLC conditions

[0439] Instrument: WATERS ARC UPLC

[0440] Column: XBridge BEH Peptide BEH C18, 3.5 μm, 2.1 mm x 150 mm

[0441] Detection: UV 254nm, 214nm, 280nm

[0442] Mobile phase: A:H 2 O(0.1% TFA); B: ACN(0.1% TFA)

[0443] Column temperature: 40°C

[0444] Flow rate: 0.6mL / min

[0445] gradient:

[0446] Time (min) 0 1 11 13 13.5 15 A％ 90 90 5 5 90 90 B％ 10 10 95 95 10 10

[0447] Radiochemical methods

[0448] 125 I-Complex Synthesis

[0449] To 38 μL of exemplary or control compound solution (20 μM in 100 mM sodium sulfate pH 7.5) was added Na 125 I solution (2.0 mCi, Perkin Elmer), followed by 14 μL of chloramine-T solution (fresh, 500 μM in 100 mM sodium sulfate, pH 7.5). The resulting solution was mixed thoroughly and then allowed to stand at room temperature for 5 min before the addition of 2 μL of sodium ascorbate solution (fresh, in H 2 The crude product was mixed at room temperature for 2 min and then loaded onto an Oasis HLB column (10 mg) for purification. The column was first washed with 0.80 mL x 3 H 2 O wash, then elute the product by 0.40mL x 3-80% ethanol in water. Fractions were analyzed by radioactive thin layer chromatography (TLC) on a polyamide membrane using methanol and 1M ammonium acetate as mobile phase (v / v: 4:1) and detected by Mini Scan (Eckert & Ziegler Radiopharma Inc.). Selected fractions were combined and diluted to a final activity of about 50-100 μCi / mL with 1% bovine serum albumin (BSA) and pH 7.5 100mM sodium sulfate buffer containing 5mg / mL sodium ascorbate. Aliquots of the product were stored at -80°C until used for radioligand binding assays and expired 4 weeks after synthesis.

[0450] 125 I-C1 and 125 I-C3 was prepared using the procedure described above.

[0451] 177 Synthesis of Lu complex

[0452] To 0.5 M NaOAc buffer (20-50 μL, pH = 4.5) was added 4 μL of DMSO stock solution (2000 μM) of exemplary or control compounds and 2 mCi 177 Lu (ITM Isotope Technologies Munich), the resulting mixture was heated to 95°C for 15 min. The chromatograms were analyzed by radio-TLC and radio-HPLC (column: Shim-pack GIST 5 μm 4.6*150 mm; buffer A: 0.2% formic acid H 2 O; Buffer B: 0.1% formic acid acetonitrile; Flow rate: 1 mL / min; Gradient: 0-5 min: 10% B to 95% B; then 5-8 min: 95% B) The resulting products were analyzed. The labeled products were used directly or diluted with PBS buffer containing freshly added 3 mg / mL ascorbate.

[0453] This application 177 The Lu complex was prepared using the procedure described above.

[0454] Synthesis of Exemplary Formula I Compounds

[0455] The above method was used to prepare the following exemplary compounds of Formula I:

[0456] Example A1: DOTA-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-1)

[0457]

[0458] Calculated molecular weight (average): 2397.8 g / mol.

[0459] Determined by LC-MS: (M+2H)2+: 1199.7; (M+3H)3+: 799.9; (M+4H)4+: 600.4.

[0460] Purity by UPLC (214 nm): >99.0%.

[0461] Example A2: DOTA-K(-gE-G-Z360)-OEG-OEG-f[CYwKTC]T-OH (I-2)

[0462]

[0463] Calculated molecular weight (average): 2542.9 g / mol.

[0464] Determined by LC-MS: (M+2H)2+: 1271.8; (M+3H)3+: 848.3; (M+4H)4+: 636.7.

[0465] Purity by UPLC (214 nm): 98.8%.

[0466] Example A3: DOTA-K(-E-Z360)-OEG-f[CYwKTC]T-NH 2 (I-3)

[0467]

[0468] Calculated molecular weight (average): 2339.7 g / mol

[0469] Determined by LC-MS: (M+2H)2+: 1170.4; (M+3H)3+: 780.8; (M+4H)4+: 585.8

[0470] Purity by UPLC (214nm): >99.0%

[0471] Example A4: DOTA-K(-E-Z360)-f[CYwKTC]T-NH 2 (I-4)

[0472]

[0473] Calculated molecular weight (average): 2194.6 g / mol

[0474] Determined by LC-MS: (M+2H)2+: 1097.9; (M+3H)3+: 732.2; (M+4H)4+: 549.5

[0475] Purity by UPLC (214 nm): 90.3%

[0476] Example A5: DOTA-K(-E-Z360)-OEG-f[CYwKTC]-Thr(ol) (I-5)

[0477]

[0478] Calculated molecular weight (average): 2326.7 g / mol

[0479] Determined by LC-MS: (M+2H)2+: 1163.9; (M+3H)3+: 776.3; (M+4H)4+: 582.7

[0480] Purity by UPLC (214nm): >99.0%

[0481] Example A6: DOTA-K(-E-Z360)-f[CYwKTC]-Thr(ol)(I-6)

[0482]

[0483] Calculated molecular weight (average): 2181.6 g / mol

[0484] Determined by LC-MS: (M+2H)2+: 1091.4; (M+3H)3+: 728.0; (M+4H)4+: 546.3

[0485] Purity by UPLC (214 nm): 93.6%

[0486] Example A7: DOTA-gE-gE-gE-gE-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-7)

[0487]

[0488] Calculated molecular weight (average): 3059.4 g / mol

[0489] Determined by LC-MS: (M+2H)2+: 1530.0; (M+3H)3+: 1020.4; (M+4H)4+: 765.7

[0490] Purity by UPLC (214 nm): 94.7%

[0491] Example A8: DOTA-gE-gE-gE-OEG-Lys(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-8)

[0492]

[0493] Calculated molecular weight (average): 2930.3 g / mol

[0494] Determined by LC-MS: (M+2H)2+: 1465.4; (M+3H)3+: 977.3; (M+4H)4+: 733.4

[0495] Purity by UPLC (214nm): >99.0%

[0496] Example A9: DOTA-gE-K(-gE-G-Z360)-gE-f[CYwKTC]T-OH(I-9)

[0497]

[0498] Calculated molecular weight (average): 2510.8 g / mol

[0499] Determined by LC-MS: (M+2H)2+: 1255.8; (M+3H)3+: 837.7; (M+4H)4+: 628.6

[0500] Purity by UPLC (214nm): >99.0%

[0501] Example A10: DOTA-gE-gE-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-10)

[0502]

[0503] Calculated molecular weight (average): 2656.0 g / mol

[0504] Determined by LC-MS: (M+2H)2+: 1328.2; (M+3H)3+: 886.0; (M+4H)4+: 664.8

[0505] Purity by UPLC (214 nm): 91.4%

[0506] Example A11: DOTA-gE-gE-OEG-K(-E-Z360)-OEG-f[CYwKTC]T-OH (I-11)

[0507]

[0508] Calculated molecular weight (average): 2744.1 g / mol

[0509] Determined by LC-MS: (M+2H)2+: 1372.4; (M+3H)3+: 915.5; (M+4H)4+: 686.8

[0510] Purity by UPLC (214 nm): 95.5%

[0511] Example A12: (Z360)-E-gE-OEG-gE-K(DOTA)-OEG-f[CYwKTC]T-OH (I-12)

[0512]

[0513] Calculated molecular weight (average): 2744.1 g / mol

[0514] Determined by LC-MS: (M+2H)2+: 1372.4; (M+3H)3+: 915.4; (M+4H)4+: 687.0

[0515] Purity by UPLC (214nm): 97.4%

[0516] Example A13: (Z360)-gE-gE-OEG-K(DOTAGA)-OEG-f[CYwKTC]T-OH (I-13)

[0517]

[0518] Calculated molecular weight (average): 2687.0 g / mol

[0519] Determined by LC-MS: (M+3H)3+: 896.3; (M+4H)4+: 672.6

[0520] Purity by UPLC (214 nm): 87.1%

[0521] Example A14: DOTA-gE-gE-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-14)

[0522]

[0523] Calculated molecular weight (average): 2801.1 g / mol

[0524] Determined by LC-MS: (M+2H)2+: 1401.0; (M+3H)3+: 934.2; (M+4H)4+: 701.2

[0525] Purity by UPLC (214nm): >99.0%

[0526] Example A15: DOTA-gE-gE-OEG-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-15)

[0527]

[0528] Calculated molecular weight (average): 2946.3 g / mol

[0529] Determined by LC-MS: (M+3H)3+: 982.8; (M+4H)4+: 737.4

[0530] Purity by UPLC (214nm): >99.0%

[0531] Example A16: DOTA-gE-gE-OEG-OEG-K(-gE-G-Z360)-OEG-OEG-f[CYwKTC]T-OH (I-16)

[0532]

[0533] Calculated molecular weight (average): 3091.5 g / mol

[0534] Determined by LC-MS: (M+3H)3+: 1031.2; (M+4H)4+: 773.7

[0535] Purity by UPLC (214nm): 91.8%

[0536] Example A17: (Z360)-gE-gE-OEG-OEG-K(DOTAGA)-OEG-OEG-f[CYwKTC]T-OH(I-17)

[0537]

[0538] Calculated molecular weight (average): 2977.4 g / mol

[0539] Determined by LC-MS: (M+3H)3+: 993.0; (M+4H)4+: 745.2

[0540] Purity by UPLC (214 nm): 87.5%

[0541] Example A18: DOTA-gE-OEG-OEG-OEG-OEG-K(-gE-G-Z360)-OEG-gE-OEG-OEG-f[CYwKTC]T-OH(I-18)

[0542]

[0543] Calculated molecular weight (average): 3526.9 g / mol

[0544] Determined by LC-MS: (M+2H)2+: 1176.3; (M+3H)3+: 882.5; (M+4H)4+: 706.3

[0545] Purity by UPLC (214nm): >99.0%

[0546] Example A19: DOTAGA-OEG-K(-gE-G-Z360)-f[CYwKTC]T-OH (I-19)

[0547]

[0548] Calculated molecular weight (average): 2469.8 g / mol

[0549] Determined by LC-MS: (M+2H)2+: 1235.6; (M+3H)3+: 823.9; (M+4H)4+: 618.4

[0550] Purity by UPLC (214 nm): 93.7%

[0551] Example A20: DOTAGA-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-20)

[0552]

[0553] Calculated molecular weight (average): 2615.0 g / mol

[0554] Determined by LC-MS: (M+2H)2+: 1307.9; (M+3H)3+: 872.3; (M+4H)4+: 654.7

[0555] Purity by UPLC (214 nm): 93.9%

[0556] Example A21: DOTA-gE-OEG-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-21)

[0557]

[0558] Calculated molecular weight (average): 2817.2 g / mol

[0559] Determined by LC-MS: (M+2H)2+: 1409.1; (M+3H)3+: 939.8; (M+4H)4+: 705.3

[0560] Purity by UPLC (214nm): >99.0%

[0561] Example A22: DOTA-gE-OEG-OEG-OEG-OEG-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH(I-22)

[0562]

[0563] Calculated molecular weight (average): 3252.7 g / mol

[0564] Determined by LC-MS: (M+3H) 3+: 1084.9; (M+4H) 4+: 814.0; (M+5H) 5+: 651.4

[0565] Purity by UPLC (214nm): >99.0%

[0566] Example A23: DOTA-OEG-OEG-OEG-K(-gE-G-Z360)-OEG-gE-OEG-OEG-f[CYwKTC]T-OH(I-23)

[0567]

[0568] Calculated molecular weight (average): 3252.7 g / mol

[0569] Determined by LC-MS: (M+2H)2+: 1626.6; (M+3H)3+: 1084.9; (M+4H)4+: 814.0

[0570] Purity by UPLC (214nm): >99.0%

[0571] Example A24: DOTA-gE-OEG-OEG-OEG-OEG-K(-gE-G-Z360)-OEG-OEG-OEG-OEG-f[CYwKTC]T-OH(I-24)

[0572]

[0573] Calculated molecular weight (average): 3543.0 g / mol

[0574] Determined by LC-MS: (M+3H) 3+: 1181.6; (M+4H) 4+: 886.5; (M+5H) 5+: 709.4

[0575] Purity by UPLC (214nm): >99.0%

[0576] Example A25: DOTA-K(-E-Z360)-f[CYwKTC]T-OH(I-25)

[0577]

[0578] Calculated molecular weight (average): 2195.5 g / mol

[0579] Determined by LC-MS: (M+2H)2+: 1098.4; (M+3H)3+: 732.6; (M+4H)4+: 549.8

[0580] Purity by UPLC (214 nm): 96.7%

[0581] Example A26: DOTA-K(-gE-G-Z360)-f[CYwKTC]T-OH (I-26)

[0582]

[0583] Calculated molecular weight (average): 2252.6 g / mol

[0584] Determined by LC-MS: (M+2H)2+: 1126.9; (M+3H)3+: 751.6; (M+4H)4+: 564.2

[0585] Purity by UPLC (214nm): 96.6%

[0586] Example A27: DOTA-K(-E-Z360)-f[CYwKTC]T-OH (I-27)

[0587]

[0588] Calculated molecular weight (average): 2340.7 g / mol

[0589] Determined by LC-MS: (M+2H)2+: 1170.2; (M+3H)3+: 780.8; (M+4H)4+: 586.1

[0590] Purity by UPLC (214nm): 99.0%

[0591] Example A28: DOTA-K(-OEG-E-Z360)-f[CYwKTC]T-OH (I-28)

[0592]

[0593] Calculated molecular weight (average): 2340.7 g / mol

[0594] Determined by LC-MS: (M+2H)2+: 1170.9; (M+3H)3+: 781.1; (M+4H)4+: 586.0

[0595] Purity by UPLC (214nm): 90.2%

[0596] Example A29: DOTA-K(-OEG-OEG-E-Z360)-f[CYwKTC]T-OH (I-29)

[0597]

[0598] Calculated molecular weight (average): 2485.9 g / mol

[0599] Determined by LC-MS: (M+2H)2+: 1244.0; (M+3H)3+: 829.4; (M+4H)4+: 622.4

[0600] Purity by UPLC (214 nm): 95.7%

[0601] Example A30: DOTA-K(-OEG-E-Z360)-OEG-f[CYwKTC]T-OH (I-30)

[0602]

[0603] Calculated molecular weight (average): 2485.9 g / mol

[0604] Determined by LC-MS: (M+2H)2+: 1243.5; (M+3H)3+: 829.4; (M+4H)4+: 622.3

[0605] Purity by UPLC (214nm): 98.4%

[0606] Example A31: Z360-OEG-K(DOTAGA)-OEG-f[CYwKTC]T-OH (I-31)

[0607]

[0608] Calculated molecular weight (average): 2428.8 g / mol

[0609] Determined by LC-MS: (M+2H)2+: 1215.1; (M+3H)3+: 810.4; (M+4H)4+: 608.1

[0610] Purity by UPLC (214nm): >99.0%

[0611] Example A32: Z360-G-gE-OEG-OEG-OEG-K(DOTA)-OEG-f[CYwKTC]T-OH (I-32)

[0612]

[0613] Calculated molecular weight (average): 2833.2 g / mol

[0614] Determined by LC-MS: (M+2H)2+: 1417.4; (M+3H)3+: 945.2; (M+4H)4+: 709.2

[0615] Purity by UPLC (214nm): >99.0%

[0616] Example A33: DOTA-OEG-OEG-OEG-OEG-OEG-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH(I-33)

[0617]

[0618] Calculated molecular weight (average): 3268.7 g / mol

[0619] Determined by LC-MS: (M+3H) 3+: 1090.3; (M+4H) 4+: 816.0; (M+5H) 5+: 654.7

[0620] Purity by UPLC (214nm): >99.0%

[0621] Example A34: DOTA-K(Z360)-f[CYwKTC]T-OH (I-34)

[0622]

[0623] Calculated molecular weight (average): 2066.4 g / mol

[0624] Determined by LC-MS: (M+2H)2+: 1033.7; (M+3H)3+: 689.6

[0625] Purity by UPLC (214nm): 99.3%

[0626] Example A35: DOTA-OEG-K(Z360)-f[CYwKTC]T-OH(I-35)

[0627]

[0628] Calculated molecular weight (average): 2211.6 g / mol

[0629] Determined by LC-MS: (M+2H)2+: 1106.4; (M+3H)3+: 738.0; (M+4H)4+: 553.8

[0630] Purity by UPLC (214nm): >99.0%

[0631] Example A36: DOTA-K(-OEG-Z360)-f[CYwKTC]T-OH (I-36)

[0632]

[0633] Calculated molecular weight (average): 2211.6 g / mol

[0634] Determined by LC-MS: (M+2H)2+: 1106.2; (M+3H)3+: 738.0; (M+4H)4+: 553.9

[0635] Purity by UPLC (214nm): >99.0%

[0636] Example A37: DOTA-K(Z360)-OEG-f[CYwKTC]T-OH (I-37)

[0637]

[0638] Calculated molecular weight (average): 2211.6 g / mol

[0639] Determined by LC-MS: (M+2H)2+: 1106.0; (M+3H)3+: 738.0; (M+4H)4+: 553.8

[0640] Purity by UPLC (214nm): >99.0%

[0641] Example A38: DOTA-K(Z360)-PEG3-f[CYwKTC]T-OH (I-38)

[0642]

[0643] Calculated molecular weight (average): 2269.7 g / mol

[0644] Determined by LC-MS: (M+2H)2+: 1135.4; (M+3H)3+: 757.3; (M+4H)4+: 568.3

[0645] Purity by UPLC (214nm): 99.3%

[0646] Example A39: DOTA-K(Z360)-OEG-OEG-f[CYwKTC]T-OH (I-39)

[0647]

[0648] Calculated molecular weight (average): 2356.7 g / mol

[0649] Determined by LC-MS: (M+2H)2+: .1178.8; (M+3H)3+: 786.5; (M+4H)4+: 590.2

[0650] Purity by UPLC (214nm): >99.0%

[0651] Example A40: DOTA-K(Z360)-PEG6-f[CYwKTC]T-OH(I-40)

[0652]

[0653] Calculated molecular weight (average): 2401.8 g / mol

[0654] Determined by LC-MS: (M+2H)2+: 1201.4; (M+3H)3+: 801.4; (M+4H)4+: 601.4

[0655] Purity by UPLC (214nm): 97.6%

[0656] Example A41: DOTA-OEG-OEG-K(Z360)-f[CYwKTC]T-OH(I-41)

[0657]

[0658] Calculated molecular weight (average): 2356.7 g / mol

[0659] Determined by LC-MS: (M+2H)2+: 1179.1; (M+3H)3+: 786.3; (M+4H)4+: 590.0

[0660] Purity by UPLC (214nm): >99.0%

[0661] Example A42: DOTA-K(-OEG-OEG-Z360)-f[CYwKTC]T-OH (I-42)

[0662]

[0663] Calculated molecular weight (average): 2356.7 g / mol

[0664] Determined by LC-MS: (M+2H)2+: 1178.9; (M+3H)3+: 786.3; (M+4H)4+: 590.1

[0665] Purity by UPLC (214 nm): 91.0%

[0666] Example A43: DOTA-K(-OEG-Z360)-OEG-f[CYwKTC]T-OH (I-43)

[0667]

[0668] Calculated molecular weight (average): 2356.7 g / mol

[0669] Determined by LC-MS: (M+2H)2+: 1178.8; (M+3H)3+: 786.2; (M+4H)4+: 590.0

[0670] Purity by UPLC (214nm): >99.0%

[0671] Example A44: DOTA-OEG-K(-OEG-Z360)-f[CYwKTC]T-OH (I-44)

[0672]

[0673] Calculated molecular weight (average): 2356.7 g / mol

[0674] Determined by LC-MS: (M+2H)2+: 1179.4; (M+3H)3+: 786.4; (M+4H)4+: 590.1

[0675] Purity by UPLC (214nm): 98.4%

[0676] Example A45: DOTA-K(Z360)-OEG-OEG-OEG-f[CYwKTC]T-OH (I-45)

[0677]

[0678] Calculated molecular weight (average): 2501.9 g / mol

[0679] Determined by LC-MS: (M+2H)2+: 1251.9; (M+3H)3+: 834.8; (M+4H)4+: 626.4

[0680] Purity by UPLC (214nm): >99.0%

[0681] Example A46: DOTA-K(-OEG-OEG-OEG-Z360)-f[CYwKTC]T-OH (I-46)

[0682]

[0683] Calculated molecular weight (average): 2501.9 g / mol

[0684] Determined by LC-MS: (M+2H)2+: 1251.4; (M+3H)3+: 834.7; (M+4H)4+: 626.3

[0685] Purity by UPLC (214nm): 90.2%

[0686] Example A47: DOTA-eK-OEG-OEG-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-47)

[0687]

[0688] Calculated molecular weight (average): 2961.4 g / mol

[0689] Determined by LC-MS: (M + 3H)3+: 987.8; (M + 4H)4+: 741.2; (M + 5H)5+: 593.2

[0690] Purity by UPLC (214 nm): 92.0%

[0691] Example A48: DOTA-PEG3-K(Z360)-f[CYwKTC]T-OH (I-48)

[0692]

[0693] Calculated molecular weight (average): 2269.7 g / mol

[0694] Determined by LC-MS: (M + 2H)2+: 1135.3; (M + 3H)3+: 757.3; (M + 4H)4+: 568.3

[0695] Purity by UPLC (214 nm): 96.1%

[0696] Example A49: DOTA-G-G-K(Z360)-f[CYwKTC]T-OH (I-49)

[0697]

[0698] Calculated molecular weight (average): 2180.5 g / mol

[0699] Determined by LC-MS: (M + 2H)2+: 1090.7; (M + 3H)3+: 727.6; (M + 4H)4+: 546.1

[0700] Purity by UPLC (214 nm): 98.8%

[0701] Example A50: DOTA-S-S-K(Z360)-f[CYwKTC]T-OH (I-50)

[0702]

[0703] Calculated molecular weight (average): 2240.6 g / mol

[0704] Determined by LC-MS: (M + 2H)2+: 1120.7; (M + 3H)3+: 747.7; (M + 4H)4+: 561.0

[0705] Purity by UPLC (214 nm): 97.9%

[0706] Example A51: DOTA-PEG1-K(Z360)-f[CYwKTC]T-OH (I-51)

[0707]

[0708] Calculated molecular weight (average): 2181.6 g / mol

[0709] Determined by LC-MS: (M+2H)2+: 1091.5; (M+3H)3+: 728.0; (M+4H)4+: 546.4

[0710] Purity by UPLC (214 nm): 97.2%

[0711] Example A52: DOTA-OEG-K(Z360)-OEG-f[CYwKTC]T-OH (I-52)

[0712]

[0713] Calculated molecular weight (average): 2356.7 g / mol

[0714] Determined by LC-MS: (M+2H)2+: 1178.9; (M+3H)3+: 786.4; (M+4H)4+: 590.0

[0715] Purity by UPLC (214 nm): >99.0%

[0716] Example A53: DOTA-K(Z360)-OEG-G-f[CYwKTC]T-OH (I-53)

[0717]

[0718] Calculated molecular weight (average): 2268.6 g / mol

[0719] Determined by LC-MS: (M+2H)2+: 1134.7; (M+3H)3+: 757.0; (M+4H)4+: 568.1

[0720] Purity by UPLC (214 nm): 95.5%

[0721] Example A54: DOTA-K(Z360)-G-S-G-f[CYwKTC]T-OH (I-54)

[0722]

[0723] Calculated molecular weight (average): 2267.6 g / mol

[0724] Determined by LC-MS: (M+2H)2+: 1134.2; (M+3H)3+: 756.6; (M+4H)4+: 567.8

[0725] Purity by UPLC (214 nm): 98.9%

[0726] Example A55: DOTA-K(Z360)-G-p-G-p-G-f[CYwKTC]T-OH (I-55)

[0727]

[0728] Calculated molecular weight (average): 2431.8 g / mol

[0729] Determined by LC-MS: (M+2H)2+: 1216.6; (M+3H)3+: 811.3; (M+4H)4+: 608.8

[0730] Purity by UPLC (214 nm): >99.0%

[0731] Example A56: DOTA-G-p-G-K(Z360)-f[CYwKTC]T-OH (I-56)

[0732]

[0733] Calculated molecular weight (average): 2277.7 g / mol

[0734] Determined by LC-MS: (M+2H)2+: 1139.4; (M+3H)3+: 759.8; (M+4H)4+: 570.2

[0735] Purity by UPLC (214 nm): >99.0%

[0736] Example A57: DOTA-p-G-p-G-K(Z360)-f[CYwKTC]T-OH (I-57)

[0737]

[0738] Calculated molecular weight (average): 2374.8 g / mol

[0739] Determined by LC-MS: (M+2H)2+: 1187.8; (M+3H)3+: 792.3; (M+4H)4+: 594.7

[0740] Purity by UPLC (214 nm): >99.0%

[0741] Example A58: DOTA-G-S-K(Z360)-G-S-f[CYwKTC]T-OH (I-58)

[0742]

[0743] Calculated molecular weight (average): 2354.7 g / mol

[0744] Determined by LC-MS: (M+2H)2+: 1177.5; (M+3H)3+: 785.6; (M+4H)4+: 589.6

[0745] Purity by UPLC (214 nm): 95.6%

[0746] Example A59: DOTA-Aoc-K(Z360)-f[CYwKTC]T-OH (I-59)

[0747]

[0748] Calculated molecular weight (average): 2207.6 g / mol

[0749] Determined by LC-MS: (M+2H)2+: 1104.2; (M+3H)3+: 736.7; (M+4H)4+: 552.8

[0750] Purity by UPLC (214 nm): 96.5%

[0751] Example A60: DOTA-K(-G-G-G-Z360)-f[CYwKTC]T-OH (I-60)

[0752]

[0753] Calculated molecular weight (average): 2237.6 g / mol

[0754] Determined by LC-MS: (M+2H)2+: 1119.2; (M+3H)3+: 746.7; (M+4H)4+: 560.4

[0755] Purity by UPLC (214 nm): 92.4%

[0756] Example A61: DOTA-K(Z360)-Aoc-f[CYwKTC]T-OH (I-61)

[0757]

[0758] Calculated molecular weight (average): 2207.6 g / mol

[0759] Determined by LC-MS: (M+2H)2+: 1104.3; (M+3H)3+: 736.5; (M+4H)4+: 552.7

[0760] Purity by UPLC (214 nm): 92.6%

[0761] Example A62: DOTA-R-K(Z360)-f[CYwKTC]T-OH (I-62)

[0762]

[0763] Calculated molecular weight (average): 2222.6 g / mol

[0764] Determined by LC-MS: (M+2H)2+: 1111.9; (M+3H)3+: 741.6; (M+4H)4+: 556.6

[0765] Purity by UPLC (214 nm): 97.5%

[0766] Example A63: DOTA-K(Z360)-R-f[CYwKTC]T-OH (I-63)

[0767]

[0768] Calculated molecular weight (average): 2222.6 g / mol

[0769] Determined by LC-MS: (M+2H)2+: 1111.9; (M+3H)3+: 741.7; (M+4H)4+: 556.6

[0770] Purity by UPLC (214 nm): >99.0%

[0771] Example A64: DOTA-K(-OEG-Z360)-f[CYwKTC]T-NH 2 (I-64)

[0772]

[0773] Calculated molecular weight (average): 2210.6 g / mol

[0774] Determined by LC-MS: (M+2H)2+: 1105.9; (M+3H)3+: 737.6; (M+4H)4+: 553.6

[0775] Purity by UPLC (214 nm): >99.0%

[0776] Example A65: DOTA-eK-eK-OEG-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-65)

[0777]

[0778] Calculated molecular weight (average): 2944.4 g / mol

[0779] Determined by LC-MS: (M+2H)2+: 1472.9; (M+3H)3+: 982.1; (M+4H)4+: 737.0; (M+5H)5+: 589.9

[0780] Purity by UPLC (214 nm): 96.3%

[0781] Example A66: DOTA-eK-eK-eK-OEG-K(-gE-G-Z360)-OEG-f[CYwKTC]T-OH (I-66)

[0782]

[0783] Calculated molecular weight (average): 2927.4 g / mol

[0784] Determined by LC-MS: (M+3H)3+: 976.3; (M+4H)4+: 732.6; (M+5H)5+: 586.5

[0785] Purity by UPLC (214 nm): >99.0%

[0786] Example A67: DOTAGA-K(Z360)-OEG-f[CYwKTC]T-OH (I-67)

[0787]

[0788] Calculated molecular weight (average): 2283.64 g / mol

[0789] Determined by LC-MS: 1142.1 (M+2H + ) ; 761.8 (M+3H + ) ; 571.8 (M+4H + )

[0790] Purity by UPLC (214 nm): 100%

[0791] Example A68: DOTAGA-K(-Glu-Z360)-OEG-f[CYwKTC]T-OH (I-68)

[0792]

[0793] Calculated molecular weight (average): 2412.76 g / mol

[0794] Determined by LC-MS: 1206.8 (M+2H + );805.0 (M+3H + );604.0 (M+4H + )

[0795] Purity by UPLC (214 nm): 96%

[0796] Example A69: DOTAGA-K(-Glu-Z360)-f[CYwKTC]T-OH (I-69)

[0797]

[0798] Calculated molecular weight (average): 2267.60 g / mol

[0799] Determined by LC-MS: 1134.1 (M+2H + );756.7 (M+3H + );567.8 (M+4H + ) Purity by UPLC (214 nm): 97%

[0800] Example A70: DOTA-K(-Glu-Z360)-Ahx-f[CYwKTC]T-OH (I-70)

[0801]

[0802] Calculated molecular weight (average): 2308.70 g / mol

[0803] Determined by LC-MS: 1154.8 (M+2H + );770.2 (M+3H + );578.0 (M+4H + )

[0804] Purity by UPLC (214 nm): 96%

[0805] Example A71: DOTAGA-K(-Glu-Z360)-Ahx-f[CYwKTC]T-OH (I-71)

[0806]

[0807] Calculated molecular weight (average): 2380.76 g / mol

[0808] Determined by LC-MS: 1190.8 (M+2H + );794.3 (M+3H + );596.0 (M+4H + )

[0809] Purity by UPLC (214 nm): 94%

[0810] Example A72: DOTAGA-K(-Glu-Z360)-Ahx-Ahx-f[CYwKTC]T-OH (I-72)

[0811]

[0812] Calculated molecular weight (average): 2493.92 g / mol

[0813] Determined by LC-MS: 1247.5 (M+2H + );831.9 (M+3H + );624.4 (M+4H + )

[0814] Purity by UPLC (214 nm): 100%

[0815] Example A73: DOTAGA-K(-Glu-Z360)-Aoc-Aoc-f[CYwKTC]T-OH (I-73)

[0816]

[0817] Calculated molecular weight (average): 2550.03 g / mol

[0818] Determined by LC-MS: 1275.4 (M+2H + );850.8 (M+3H + );638.4 (M+4H + )

[0819] Purity by UPLC (214 nm): 100%

[0820] Example A74: DOTA-K(Z360)-gGlu-OEG-OEG-f[CYwKTC]T-OH (I-74)

[0821]

[0822] Calculated molecular weight (average): 2485.85 g / mol

[0823] Determined by LC-MS: 1243.8 (M+2H + );829.3 (M+3H + );622.3 (M+4H + )

[0824] Purity by UPLC (214 nm): 100%

[0825] Example A75: DOTA-K(Z360)-Glu-gGlu-OEG-OEG-f[CYwKTC]T-OH (I-75)

[0826]

[0827] Calculated molecular weight (average): 2614.97 g / mol

[0828] Determined by LC-MS: 872.3 (M+3H + );654.5 (M+4H + )

[0829] Purity by UPLC (214 nm): 100%

[0830] Example A76: DOTA-K(-OEG-OEG-Glu-Z360)-OEG-f[CYwKTC]T-OH (I-76)

[0831]

[0832] Calculated molecular weight (average): 2631.01 g / mol

[0833] Determined by LC-MS: 1315.9 (M+2H + );877.6 (M+3H + );658.5 (M+4H + )

[0834] Purity by UPLC (214 nm): 99%

[0835] Example A77: DOTA-K(-OEG-gGlu-Ser-Z360)-OEG-f[CYwKTC]T-OH (I-77)

[0836]

[0837] Calculated molecular weight (average): 2572.93 g / mol

[0838] Determined by LC-MS: 1286.9 (M+2H + );858.2 (M+3H + );644.0 (M+4H + )

[0839] Purity by UPLC (214 nm): 100%

[0840] Example A78: DOTA-K(-OEG-gGlu-Dap-Z360)-OEG-f[CYwKTC]T-OH (I-78)

[0841]

[0842] Calculated molecular weight (average): 2571.95 g / mol

[0843] Determined by LC-MS: 857.9 (M+3H + );643.8 (M+4H + );515.3 (M+5H+)

[0844] Purity by UPLC (214 nm): 100%

[0845] Example A79: DOTA-K(-OEG-His-Glu-Z360)-OEG-f[CYwKTC]T-OH (I-79)

[0846]

[0847] Calculated molecular weight (average): 2608.97 g / mol

[0848] Determined by LC-MS: 874.9 (M+3H + );656.5 (M+4H + );525.5 (M+5H+)

[0849] Purity by UPLC (214 nm): 100%

[0850] Example A80: DOTA-K(-OEG-OEG-Cbp-Z360)-OEG-f[CYwKTC]T-OH (I-80)

[0851]

[0852] Calculated molecular weight (average): 2693.08 g / mol

[0853] Determined by LC-MS: 898.2 (M+3H + ); 674.0 (M+4H + )

[0854] Purity by UPLC (214 nm): 98%

[0855] The following reference compounds were synthesized using the above method for the reference compounds:

[0856] Reference 1: DOTA-f[CYwKTC]T-OH (C-1)

[0857]

[0858] Calculated molecular weight (average): 1435.6 g / mol

[0859] Determined by LC-MS: (M+2H)2+: 718.4; (M+3H)3+: 479.4 Purity by UPLC (214 nm): 93.7%

[0860] Reference 2: DOTA-e-e-e-e-e-e-AYGW-Nle-DF-NH 2 (C-2)

[0861]

[0862] Calculated molecular weight (average): 2031.1 g / mol

[0863] Determined by LC-MS: (M+2H)2+: 1016.4; (M+3H)3+: 677.8

[0864] Purity by UPLC (214 nm): 95.5%

[0865] Reference 3: Ac-Tyr-Gly-e-e-e-e-e-e-AYGW-Nle-DF-NH 2 (C-3)

[0866]

[0867] Calculated molecular weight (average): 1906.9 g / mol

[0868] Determined by LC-MS: (M+2H)2+: 953.9

[0869] Purity by UPLC (214 nm): 94.6%

[0870] Reference 4: Z360-gE-gE-gE-K(-OEG-OEG-DOTAGA)-NH 2 (C-4)

[0871]

[0872] Calculated molecular weight (average): 1783.9 g / mol

[0873] Determined by LC-MS: (M+2H)2+: 892.4; (M+3H)3+: 595.5

[0874] Purity by UPLC (214 nm): 96.2%

[0875] Reference 5: DOTA-e-e-e-e-e-e-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2 (C-5)

[0876] Calculated molecular weight (average): 2031.1 g / mol

[0877] Determined by LC-MS: (M+2H)2+: 1016.4

[0878] Purity by UPLC (214 nm): 95%

[0879] B: Biological data

[0880] Example B1: Cell-based binding affinity of the exemplary compounds of the present application

[0881] AR42J cells (ATCC) were maintained in RPMI-1640 medium (Gibco) supplemented with 15% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (BI) in a humidified incubator with 5% CO 2 at 37 °C. The medium was changed every 2 - 3 days with fresh medium. Experiments were performed with cells at 70 - 80% confluence.

[0882] Binding affinity was tested using 125 I-labeled competitive ligands.

[0883] By using 125 I-C1 and 125 I-C3 as competitive ligands in a competitive cell binding assay to determine the binding affinity of the test compounds. At a concentration of 1 - 3 x 10 6AR42J cells suspended in binding buffer (RPMI-1640 medium supplemented with 0.25% bovine serum albumin) at a density of 125 I-C1 and 125 I-C3 (0.02 μCi / well) were incubated at 37 °C for 1 h (n = 3). The final volume in each well was kept at 200 μL, and the insufficient volume was adjusted with binding buffer. After 1 h incubation, unbound 125 I competitive ligands were removed by filtration using a Multiscreen vacuum manifold (Millipore), followed by rinsing with binding buffer (3 times). The filters were collected and their radioactivity was measured individually by a gamma counter (2480 WIZARD2, PerkinElmer). The best-fit IC 50 values of the test compounds were calculated by fitting the data with non-linear regression using GraphPad Prism 8.0.1 (the inhibitory concentration when 50% of the bound 125 I-C1 and 125 I-C3 on the cells was replaced).

[0884] The results are shown in Table 1. The relative binding affinities of the exemplary compounds of the present application based on the average value of the IC 50 numbers are shown in Table 2.

[0885] In the radioligand competitive binding assay described above, all the exemplary compounds of the present application showed binding affinities with IC 50 values in the range of about 100 pM to about 1.0 μM for SSTR2 and CCK2R. Compared with their respective monofunctional controls C-1 and C-2, most of the bifunctional compounds showed comparable or stronger activities against SSTR2 and CCK2R receptors.

[0886] Table 1. IC 125 I-C1 and 125 I-C3 as competitive ligands for the compounds selected in the radioligand competitive binding assay. 50 .

[0887]

[0888] Table 2 shows the relative binding affinities of the exemplary compounds of the present application based on the average value of their respective IC 50 numbers.

[0889] Table 2. Relative activities of exemplary compounds of the present application based on the average of their respective IC50 values.

[0890]

[0891]

[0892]

[0893]

[0894] Abbreviations:

[0895] T: Threonine; C: Cysteine; K: Lysine; w: D-Tryptophan; Y: Tyrosine; f: D-Phenylalanine; A: Alanine; G: Glycine; W: Tryptophan; Nle: Norleucine; D: Aspartic acid; S: Serine; p: D-Proline; R: Arginine;

[0896] gE: γ-Glutamic acid; eK: ε-Lysine

[0897] -OH: C-terminal acid; -NH 2 : C-terminal amide; Thr(ol): C-terminal alcohol

[0898] [CXXXXC]: Disulfide bond

[0899] DOTA: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid;

[0900] DOTAGA: 2-[1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid

[0901] OEG: H 2 N-[CH 2 CH 2 O] 2 -CH 2 CO 2 H

[0902] PEG1: H 2 N-CH 2 CH 2 O-CH 2 CH 2 CO 2 H

[0903] PEG3: H 2 N-[CH 2 CH 2 O] 3 -CH 2 CH 2 CO2 H

[0904] PEG6:H 2 N-[CH 2 CH 2 O] 6 -CH 2 CH 2 CO 2 H

[0905] Aoc: 8-Amino-octanoic acid

[0906] Z360: Nastorazepide; CAS No. 343326-69-2

[0907] ND: Not determined

[0908] Binding affinity was tested using Cy5-labeled competitive ligands.

[0909] HEK 293T cells were transfected with SSTR2 or CCK2R expression plasmids using Lipofectamine 2000 reagent. Twenty-four hours after transfection, the cells were harvested and suspended in assay buffer (1% OVA in DMEM). The cells were then seeded in 96-well plates, and Cy5-labeled DOTA-TATE (for SSTR2, sequence: Cy5-OEG-Lys(DOTA)-f[CYwKTC]T-OH) and Cy5-labeled Z360 (for CCK2R, sequence: Z360-Glu-Glu-Glu-Lys(-OEG-Cy5)-NH2) were used as competitive ligands for Compounds I-26, I-1, I-21, I-37, I-28, I-29, I-30, I-25, or the cells were seeded in 96-well plates, and Cy5-labeled DOTA-TATE (for SSTR2, sequence: Cy5-OEG-Lys(DOTA)-f[CYwKTC]T-OH) and Cy5-labeled F11N derivative (for CCK2R, sequence: Cy5-OEG-Lys(DOTA)-OEG-e-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) were used as competitive ligands for Compounds I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80. The test compounds were further supplemented into the wells at different concentrations. After incubation for 1 hour in the dark, the cells were washed and suspended in FACS buffer (1% OVA in DPBS). The fluorescence signals were detected by a FACS machine, and the binding affinity of the test compounds was evaluated by calculating the IC 50 of the competitive binding of the reference compound.

[0910] As shown in Tables 3 and 4, in the described assays, the exemplary compounds of the present application all showed binding affinities with IC 50 values in the range of about 100 pM to about 1.0 μM for SSTR2 and CCK2R.

[0911] Table 3. IC of exemplary compounds using Cy5-labeled DOTA-TATE and Cy5-labeled Z360 as competitive ligands 50

[0912]

[0913] Abbreviations:

[0914] T: Threonine; C: Cysteine; K: Lysine; w: D-Tryptophan; Y: Tyrosine; f: D-Phenylalanine; A: Alanine; G: Glycine; W: Tryptophan; Nle: Norleucine; D: Aspartic acid; S: Serine: p: D-Proline; R: Arginine:

[0915] gE: γ-Glutamic acid; eK: ε-Lysine

[0916] -OH: C-terminal acid; -NH 2 : C-terminal amide; Thr(ol): C-terminal alcohol

[0917] [CXXXXC]: Disulfide bond

[0918] DOTA: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid;

[0919] DOTAGA: 2-[1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid

[0920] OEG: H 2 N-[CH 2 CH 2 O] 2 -CH 2 CO 2 H

[0921] PEG1: H 2 N-CH 2 CH 2 O-CH 2 CH 2 CO 2 H

[0922] PEG3: H 2 N-[CH 2 CH 2 O] 3 -CH 2CH 2 CO 2 H

[0923] PEG6:H 2 N-[CH 2 CH 2 O] 6 -CH 2 CH 2 CO 2 H

[0924] Aoc: 8 - amino - octanoic acid

[0925] Z360: Nastorazepide; CAS No. 343326 - 69 - 2

[0926] ND: Not determined

[0927] Table 4. IC of exemplary compounds using Cy5 - labeled DOTA - TATE and Cy5 - labeled F11N derivatives as competitive ligands 50

[0928]

[0929]

[0930] Abbreviations:

[0931] T: Threonine; C: Cysteine; K: Lysine; w: D - Tryptophan; Y: Tyrosine; f: D - Phenylalanine; A: Alanine; G: Glycine; W: Tryptophan; Nle: Norleucine; D: Aspartic acid; S: Serine: p: D - Proline; R: Arginine; H: Histidine, E: Glutamic acid:

[0932] gE: γ - Glutamic acid; eK: ε - Lysine

[0933] -OH: C - terminal acid; -NH2: C - terminal amide; Thr(ol): C - terminal alcohol

[0934] [CXXXXC]: Disulfide bond

[0935] DOTA: 1,4,7,10 - Tetraazacyclododecane - 1,4,7,10 - tetraacetic acid;

[0936] DOTAGA: 2 - [1,4,7,10 - Tetraazacyclododecane - 4,7,10 - triacetic acid] - glutaric acid

[0937] OEG: H2N - [CH2CH2O]2 - CH2CO2H

[0938] PEG1: H2N-CH2CH2O-CH2CH2CO2H

[0939] PEG3: H2N-[CH2CH2O]3-CH2CH2CO2H

[0940] PEG6: H2N-[CH2CH2O]6-CH2CH2CO2H

[0941] Aoc: 8-Amino-octanoic acid

[0942] Cbp: 4-Carboxy-L-phenylalanine

[0943] Dap: 2,3-Diaminopropionic acid

[0944] Z360: Nastorazepide; CAS No. 343326-69-2

[0945] ND: Not determined

[0946] Example B2: Biodistribution study

[0947] All animal care and experimental procedures were conducted in accordance with the animal protocol approved by the Ethics Committee of China Institute of Radiation Protection. These studies utilized BALB / c nude mice (Charles River, Beijing). The mice were housed in sterile micro-isolator cages at a density of less than 5 per cage under temperature- and humidity-controlled conditions, with a 12 h light / 12 h dark schedule, and were fed irradiated rodent chow and reverse osmosis (RO) sterile water ad libitum. When preparing for tumor cell inoculation, the mice were anesthetized with isoflurane (RWD Life Science Inc.) at an induction rate of 4%, and maintained at a rate of 2.5% with 0.4 L of oxygen delivered via a precision vaporizer and a non-rebreathing device. These mice received approximately 4×10 suspended in 200 μL of phosphate buffered saline (PBS) and Matrigel (Corning) (1 / 1) 6Subcutaneous posterior flank injection of AR42J cells (human pancreatic cancer cell line). After inoculation, the xenograft tumors were allowed to grow for about 2 - 4 weeks, and their mass ranged from 0.05 to 0.50 g (average tumor size was 0.20 g). Biodistribution studies were conducted in nude mice by tail vein injection of each test compound, which was about 10–50 μCi (about 0.37–1.85 MBq), with a specific activity of 50 - 250 μCi / nmol, delivered in 100 μL of 0.9% NaCl. The mice were euthanized, and tissues and organs were excised from the animals at 4, 24, and 72 h post - injection. The tissues and organs were weighed, counted in a PerkinElmer 2480 WIZARD2 γ - counter, and the percentage of injected dose (%ID) and %ID / g in each organ or tissue were calculated.

[0948] All of the exemplary compounds tested exhibited measurable radionuclide tumor uptake. The uptake of radionuclide in normal organs, including the kidneys and liver, was found to depend on the net charge of the compound - radionuclide complex and the length and chemical nature of the linker.

[0949] Table 5 - 15 shows the biodistribution of various compounds in AR42J tumor - bearing mice.

[0950] Table 5 shows the effect of net charge number and total combined linker length on biodistribution: 24 hours after administration 177 Tumor and organ uptake of Lu - labeled compounds of formula I and the respective tumor - to - organ ratios.

[0951] Charge is presented as the 177 Lu - chelation state of exemplary compounds of formula I at physiological pH. For example, when E is a DOTA moiety containing three free carboxylic acid groups (chelating moiety from DOTA), this DOTA moiety will have a 0 net charge when complexed with 177 Lu. Similarly, when E is a DOTAGA moiety containing four free carboxylic acid groups, this DOTAGA moiety will have a - 1 net charge when complexed with Lu - 17. Further, C - terminal and side - chain groups with free carboxyl groups (such as including glutamic acid or γ - glutamic acid) will be counted as contributing - 1 charge for each free carboxyl group; and N - terminal and side - chain groups with free amines (e.g., the ε - amine of lysine or the guanidine group of arginine) will be counted as contributing + 1 charge for each free amine.

[0952] Table 5. 24 hours after administration 177 Uptake (%ID / g) of Lu - labeled compounds in tumors and normal organs and the respective tumor - to - organ ratios.

[0953]

[0954] T / K: Tumor / Kidney; T / L: Tumor / Liver; T / Sp: Tumor / Spleen; T / St: Tumor / Stomach; T / P: Tumor / Pancreas.

[0955] Table 6 and Figure 2 shows 177 the biodistribution of Lu-C-1 in AR42J tumor-bearing mice (n = 3).

[0956] Table 6

[0957]

[0958]

[0959] Table 7 shows 177 the biodistribution of Lu-C-2 in AR42J tumor-bearing mice (n = 3).

[0960] Table 7

[0961]

[0962] Table 8 and Figure 3 shows 177 the biodistribution of Lu-C-4 in AR42J tumor-bearing mice (n = 3).

[0963] Table 8

[0964]

[0965]

[0966] Table 9 and Figure 4 shows 177 the biodistribution of Lu-I-13 in AR42J tumor-bearing mice (n = 3).

[0967] Table 9

[0968]

[0969] Table 10 shows 177 the biodistribution of Lu-I-14 in AR42J tumor-bearing mice (n = 3).

[0970] Table 10

[0971]

[0972]

[0973] Table 11 and Figure 5 shows 177 the biodistribution of Lu-I-35 in AR42J tumor-bearing mice (n = 3).

[0974] Table 11

[0975]

[0976] Table 12 and Figure 6 shows 177 the biodistribution of Lu-I-36 in AR42J tumor-bearing mice (n = 3).

[0977] Table 12

[0978]

[0979] Table 13 and Figure 7 shows 177 the biodistribution of Lu-I-37 in AR42J tumor-bearing mice (n = 3).

[0980] Table 13

[0981]

[0982] Table 14 shows 177 the biodistribution of Lu-I-39 in AR42J tumor-bearing mice (n = 3).

[0983] Table 14

[0984]

[0985] Table 15 and Figure 8 shows 177 the biodistribution of Lu-I-54 in AR42J tumor-bearing mice (n = 3).

[0986] Table 15

[0987]

[0988] Discussion

[0989] Based on structure-activity relationship studies, a trifunctional radiopharmaceutical ligand consisting of an SSTR2-binding group, a CCK2R-binding group, and a radionuclide chelating group has been constructed in such a way that the radiopharmaceutical ligand has a dual-targeting carrier, each carrier having a good binding affinity for the original binding site of its respective receptor.

[0990] Subsequently, the in vivo biodistribution and imaging profile of exemplary dual-receptor targeting radioligands were optimized. Chemical and biophysical properties such as molecular size, hydrophobicity, net charge, charge distribution, and distribution of hydrophobic regions were investigated to identify factors contributing to the biodistribution profile. Such studies unexpectedly revealed that minor changes in these physicochemical properties can have an impact on the biodistribution profile of radioligands. For example, it was found that some radioligands with a high negative net charge resulted in high renal uptake when complexed with a radionuclide, while radioligands with a net charge of, for example, +2 to -3 provided a good overall biodistribution profile when complexed with a radionuclide. In addition, it was observed that radioligands with a hydrophobic bivalent linker or sometimes without a bivalent linker led to higher radionuclide uptake in the liver, while radioligands with a longer hydrophilic linker could be detrimental to the tumor / kidney ratio. Some exemplary radioligands providing high tumor uptake and minimal normal organ accumulation were found to consist of a short hydrophilic linker and a net charge of 0 or -1 when complexed with a radionuclide (e.g., 177 Lu).

[0991] Accordingly, novel SSTR2 and CCK2R dual-targeting radioligands have been identified. The radioligands of the present application have been shown to possess a strong and balanced binding affinity for both the SSTR2 and CCK2R receptors. Further, when chelated with 177 Lu, the radioligands of the present application have been shown to exhibit a favorable in vivo biodistribution profile in an AR42J tumor-bearing mouse model. The radioligands of the present application showed both high tumor uptake and a good tumor / kidney biodistribution ratio as well as a good tumor / liver biodistribution ratio. Accordingly, such radioligands with this unexpectedly favorable distribution profile will have an acceptable safety window and desirable therapeutic efficacy in cancer patients with overexpression of either SSTR2 or CCK2R.

[0992] Complete citation of references in this specification

[0993] Numerous publications are cited herein. The complete citation of these references is provided below. Each of these references is hereby incorporated by reference in its entirety into the present disclosure to the same extent as if each individual reference was specifically and separately indicated to be incorporated by reference.

[0994] 1. Lehman J.M. and aMassion P.P., Somatostatin receptor 2 targeting in small cell lung carcinoma: perspectives, Oncotarget. Jul 30, 2019; 10(46):4727 - 4730. PMID: 31413814.

[0995] 2. Parghane R.V., et al., Clinical utility of 177 Lu-DOTATATE PRRT in somatostatin receptor-positive metastatic medullary carcinoma of thyroid patients with assessment of efficacy, survival analysis, prognostic variables, and toxicity, Head Neck, March 2020; 42(3):401-416

[0996] 3. Klingler M et al., Cholecystokinin-2 Receptor Targeting with Radiolabeled Peptides: Current Status and Future Directions. Curr Med Chem. 2020;27(41):7112-7132.

[0997] 4. Rottenburger C, et al., Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study. J Nucl Med. April 2020; 61(4):520-526. 5. Aloj L et al., Comparison of the binding and internalization properties of 12DOTA-coupled and 111 In-labelled CCK2 / gastrin receptor binding peptides: a collaborative project under COST Action BM0607. Eur J Nucl Med Mol Imaging. August 2011; 38(8):1417-25.

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Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein E is a chelating group; T is a trivalent branched group; Z 1 is a cholecystokinin-2 receptor (CCK2R) binding group; Z 2 is a somatostatin receptor 2 (SSTR2) binding group; L 1 、L 2 and L 3 each independently is a direct bond or a divalent linker.

2. The compound according to claim 1, wherein the CCK2R binding group is a benzodiazepine moiety of formula II moiety wherein R 1 selected from H, halogen, and C 1-6 alkyl; R 2 selected from C 1-6 alkyl, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ; R 3 selected from H, halogen, and C 1-6 alkyl; R 4 selected from C 5-6 cycloalkyl and phenyl; and m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

3. The compound according to claim 2, wherein R 1 and R 3 are independently selected from H, F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and C(CH 3 ) 3 .

4. The compound according to claim 3, wherein R 1 and R 3 are both H.

5. The compound according to any one of claims 2 to 4, wherein R 2 is selected from CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、NH 2 、NH(CH 3 ) and N(CH 3 ) 2 .

6. The compound according to claim 5, wherein R 2 is C(CH 3 ) 3 .

7. The compound according to any one of claims 2 to 6, wherein R 4 is selected from cyclopentyl, cyclohexyl and phenyl.

8. The compound according to claim 7, wherein R 4 is cyclohexyl.

9. The compound according to any one of claims 2 to 8, wherein m is 1 and n is 0.

10. The compound according to any one of claims 1 to 9, wherein the somatostatin receptor 2 (SSTR2) binding group is a moiety of formula III, wherein: R 3a Selected from CH 2 OH, CO 2 H and CONH 2 .

11. The compound according to claim 10, wherein R 3a is selected from CH 2 OH and CONH 2 .

12. The compound according to claim 11, wherein R 3a is CO 2 H.

13. The compound according to any one of claims 2 to 8, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of from +2 to -5 when complexed with a radionuclide.

14. The compound according to any one of claims 2 to 8, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of 0 or -1 when complexed with a radionuclide.

15. The compound according to any one of claims 1 to 14, wherein the total length of L 1 , L 2 and L 3 is from 0 atoms to 80 atoms.

16. The compound according to any one of claims 1 to 14, wherein L 1 , L 2 and L 3 have a combined length of from 0 atoms to 47 atoms, from 0 atoms to 46 atoms, from 0 atoms to 43 atoms, from 0 atoms to 41 atoms, from 0 atoms to 40 atoms, from 0 atoms to 36 atoms, from 0 atoms to 37 atoms, from 0 atoms to 33 atoms, from 0 atoms to 30 atoms or from 0 atoms to 27 atoms.

17. The compound according to any one of claims 1 to 16, wherein E is a chelating group derived from a chelating agent selected from cyclic or acyclic bifunctional chelating agents capable of binding and / or complexing with one or more radionuclides.

18. The compound according to claim 17, wherein E is a chelating group derived from a chelating agent selected from 1,4,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic acid-N',N"-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic acid-N',N"-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N"-tris(methylenephosphonic acid) (NOTP); 1,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen); 1,4,7,10-tetraazacyclotridecane ([13]aneN4); 1,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A); 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A); 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid) (DOTP); 1,4,7,10-tetraazacyclododecane-1,7-bis(methylenephosphonic acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenephosphonic acid) (DO3P); 1,4,7,10-tetraazacyclodecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam); 1,4,8,12-tetraazacyclopentadecane ([15]aneN4); 1,5,9,13-tetraazacyclohexadecane ([16]aneN4); 1,4-ethyl-bridged-1,4,8,11-tetraazacyclotetradecane (et-cyclam); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecan-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexaazabicyclo[6.6.6]Eicosane (Sar); 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine; porphyrin; PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadec-1(15),11,13-triene-3,6,9-triacetic acid); DEPA (7-[2-(bis(carboxymethyl)amino)ethyl]-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl-acetic acid); DTPA (1,1,4,7,7-diethylenetriaminepentaacetic acid); CHX-DTPA (cyclohexane-1,2-diamine N,N,N',N'-tetraacetate); BATPA (1,2-bis[2-aminophenoxy]ethane-N,N,N',N'-tetraacetic acid); TTHA (triethylenetetramine N,N,N',N”,N”',N”'-hexaacetic acid); HBED (N,N'-bis[2-hydroxybenzyl]ethylenediamine-N,N'-diacetic acid); EGTA (ethylene glycol bis[2-aminoethyl ether]-N,N,N',N'-tetraacetic acid); EDTMP (ethylenediamine tetra-[methylenephosphonic acid]); TRAP (triazacyclononane phosphonic acid); SHBED (N,N'-bis[2-hydroxy-5-sulfobenzyl]ethylenediamine diacetic acid); H6Sbbpen (N,N'-bis-[2-hydroxy-5-sulfonylbenzyl]-N,N'-bis[2-methylpyridyl]ethylenediamine); THP (tris(3,4-hydroxypyridone); DFO (deferoxamine); FSC (fusarinine C); 6SS (N,N'-bis[2,2-dimethyl-2-mercaptoethyl]ethylenediamine-N,N'-diacetic acid); ECC (ethylenecysteamine cysteine); ECD (cysteine ethyl ester dimer); NETA ([2-{4,7-bis(carboxymethyl)(1,4,7)triazacyclononan-1-yl-ethyl}carbonylmethylamino]acetic acid; THPN (tetrakis(3-hydroxy-4-pyridone)); H2dedpa (1,2-[{6-(carboxy-)pyridin-2-yl}methylamino]-ethane); H4octapa (N,N'-bis[6-carboxy-2-pyridylmethyl]-ethylenediamine-N,N'-diacetic acid); H2bispa2 (6,6’-[{9-hydroxy-1,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.{3,7-Nonanediyl}bis(methylene)]dipicolinic acid); DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetra(methylphosphonic acid)); PEPA (1,4,7,10,13-pentaazacyclopentadecane pentaacetic acid); HEHA (1,4,7,10,13,16-hexaazacyclooctadecane hexaacetic acid); H2hox; H2CHXhox; H2octox; H2pyhox; H4neunopa; TETPA; H4pypa; H4py4pa; DTPAm; EGTAm; ampam; Me-3,2-HOPO; 3,4,3-(LI-1,2-HOPO); macrocyclic tetraphthalimide; or any derivative thereof.

19. The compound according to claim 18, wherein the chelating agent is selected from DOTA and DOTAGA.

20. The compound according to any one of claims 17 to 19, wherein the one or more radionuclides are radioisotopes of C, N, O, F, P, S, Cl, Br, I, As, Se, At, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Fr, Pm, lanthanide elements (such as La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), actinide elements (such as Ac, Th, U), Mg, Al, Ca, Cd, or Ba.

21. The compound according to claim 20, wherein the lanthanide element is Lu, Sm, Ho, or Tb.

22. The compound according to claim 20 or claim 21, wherein the one or more radionuclides are selected from 14 C, 15 N, 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 123 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 188 Re, 186 Re, 153 Sm, 66 Ho, 86 Y, 87 Y, 90 Y, 89 Sr, 153 Gd, 159 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 101m Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 55 Co, 57 Co, 47 Sc, 149 Pm, 142 Pr, 161 Ho, 166 Ho, 175 Yb or 51 Cr.

23. The compound according to any one of claims 17 to 22, wherein the one or more radionuclides are used for imaging or for therapy.

24. A compound according to any one of claims 17 to 23, wherein the one or more radionuclides are 177 Lu.

25. A compound according to any one of claims 1 to 24, wherein T is a trivalent branched group comprising at least a first terminal functional group, a second terminal functional group and a third terminal functional group, the first terminal functional group, the second terminal functional group and the third terminal functional group being the same or different and being attached to L 1 (or alternatively, E), L 2 (or alternatively, Z 1 ) and L 3 (or alternatively, Z 2 ) via complementary functional groups thereon.

26. The compound according to claim 25, wherein T is selected from amino acid residues derived from lysine, ornithine, homoarginine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamate, or glutamine.

27. The compound according to claim 26, wherein T is an amino acid residue derived from lysine 28. A compound according to any one of claims 1 to 27, wherein L 1 , L 2 and L 3 are each independently a direct bond or a divalent linker, and the divalent linkers together comprise from 1 to 15 groups selected from amino acid residues, W a , R a , R a -W a , W a -R b , R a -W a -R b and W a -R b -W b . wherein Each W a and W b are independently selected from O, S, S(O), S(O) 2 , NR 5 , C(O), C(S), NR 5 C(O), NR 5 C(S), C(O)NR 5 , C(S)NR 5 , (C 1-6 alkylene Y) p and Y-(C 1-6 alkylene Y’) p , Each R a and R b is independently selected from C 1-20 alkylene, C 2-20 alkenylene, and C 2-20 alkynylene; Each Y and Y' is independently selected from O, S, C(O), and NR 6 ; Each R 5 is independently selected from H and C 1-6 alkyl; Each R 6 is independently selected from H and C 1-3 alkyl; and p is an integer selected from 1 to 8.

29. The compound according to claim 28, wherein each R a and R b is independently selected from C 1-10 alkylene, C 2-10 alkenylene and C 2-10 alkynylene.

30. The compound according to claim 28, wherein each R a and R b is independently selected from C 1-20 alkylene.

31. A compound according to any one of claims 28 to 30, wherein Y and Y' are independently selected from O, S, C(O) and NR 6 .

32. The compound according to claim 31, wherein each Y and Y' is independently selected from O, C(O) and NR 6 .

33. A compound according to any one of claims 28 to 32, each W a and W b independently selected from O, S, S(O), SO 2 , NR 5 , C(O), C(S), C(S)NR 5 , NR 5 C(S), C(O)NR 5 , NR 5 C(O), (C 1-6 alkylene O) p , (C 1-6 alkylene NR 6 ) p , (C 1-6 alkylene C(O)) p , O-(C 1-6 alkylene O) p , O-(C 1-6 alkylene NR 6 ) p , O-(C 1-6 alkylene C(O)) p , NR 6 -(C 1-6 alkylene O) p , NR 6 -(C 1-6 alkylene NR 6 ) p , NR 6 (C 1-6 alkylene C(O)) p , C(O)-(C 1-6 alkylene O) p , C(O)-(C 1-6 alkylene NR 6 ) p and C(O)-(C 1-6 alkylene C(O) p .

34. A compound according to any one of claims 30 to 33, wherein the divalent linker collectively comprises selected from amino acid residues, O, S, S(O), SO 2 , NR 5 , C(O), C(O)NR 5 , NR 5 C(O), C 1-20 alkylene, OC 1-20 alkyleneO, OC 1-20 alkyleneNR 5 , OC 1-20 alkyleneC(O), NR 5 C 1-20 alkyleneO, NR 5 C 1-20 alkyleneNR 5 , NR 5 C 1-20 alkyleneC(O), C(O)C 1-20 alkyleneO, C(O)-C 1-20 alkyleneC(O), C(O)C 1-20 alkyleneNR 5 , O-(C 1-6 alkyleneC(O)) p C 1-20 alkyleneO, O-(C 1-6 alkyleneC(O)) p C 1-20 alkyleneNR 5 , O-(C 1-6 alkyleneC(O)) p C 1-20 alkyleneC(O), O-(C 1-6 alkyleneNR 6 ) p C 1-20 alkyleneO, O-(C 1-6 alkyleneNR 6 ) p C 1-20 alkyleneNR 5 , O-(C 1-6 alkyleneNR 6 ) p C 1-20 alkyleneC(O), O-(C 1-6 alkyleneC(O)) p C 1-20 alkyleneO, O-(C 1-6 alkyleneC(O)) p C 1-20 alkyleneNR 5 , O-(C 1-6 alkyleneC(O)) p C 1-20 Alkylene C(O), NR 6 -(C 1-6 Alkylene O) p C 1-20 Alkylene O, NR 6 -(C 1-6 Alkylene O) p C 1-20 Alkylene NR 5 、NR 6 -(C 1-6 Alkylene O) p C 1-20 Alkylene C(O), NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 、NR 6 -(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), NR 6 (C 1-6 Alkylene C(O)) p C 1-20 Alkylene O, NR 6 (C 1-6 Alkylene C(O)) p C 1-20 Alkylene NR 5 、NR 6 (C 1-6 Alkylene C(O)) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene O) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene O) p C 1-20 Alkylene NR 5 、C(O)-(C 1-6 Alkylene O) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene NR 5 、C(O)-(C 1-6 Alkylene NR 6 ) p C 1-20 Alkylene C(O), C(O)-(C 1-6 Alkylene C(O)) p C 1-20 Alkylene O, C(O)-(C 1-6 Alkylene C(O)) p C 1-20 Alkylene NR 5 and C(O)-(C 1-6 Alkylene C(O)) p C 1-20 A total of 1 to 15 groups of alkylene C(O).

35. The compound according to claim 34, wherein the divalent linker collectively comprises independently selected from amino acid residues, NR 5 C 1-12 alkylene C(O), C(O)-C 1-12 alkylene C(O), C(O)C 1-12 alkylene NR 5 、NR 5 C 1-12 alkylene NR 5 、NR 6 -(C 1-6 alkylene O) p C 1-6 alkylene NR 5 、NR 6 -(C 1-6 alkylene O) p C 1-6 alkylene C(O), NR 6 -(C 1-6 alkylene NR 6 ) p C 1-6 alkylene NR 5 、NR 6 -(C 1-6 alkylene NR 6 ) p C 1-6 alkylene C(O), NR 6 (C 1-6 alkylene C(O)) p C 1-6 alkylene NR 5 、NR 6 (C 1-6 alkylene C(O)) p C 1-6 alkylene C(O), C(O)-(C 1-6 alkylene O) p C 1-6 alkylene NR 5 、C(O)-(C 1-6 alkylene O) p C 1-6 alkylene C(O), C(O)-(C 1-6 alkylene NR 6 ) p C 1-6 alkylene NR 5 、C(O)-(C 1-6 alkylene NR 6 ) p C 1-20 alkylene C(O), C(O)-(C 1-6 alkylene C(O)) p C 1-6 alkylene NR 5 and C(O)-(C 1-6 alkylene C(O)) p C 1-6 from 1 to 15 groups of alkylene C(O).

36. The compound according to claim 35, wherein the divalent linker collectively comprises from 1 to 15 groups independently selected from amino acid residues, NR 5 C 1-12 alkylene C(O), C(O)C 1-12 alkylene NR 5 and NR 6 -(C 1-6 alkylene O) p C 1-6 alkylene C(O).

37. A compound according to any one of claims 27 to 35, wherein the amino acid residue is an amino acid residue derived from a naturally occurring amino acid, a naturally occurring amino acid that has been modified to provide a modified amino acid, the D-enantiomer of the naturally occurring amino acid residue or the modified amino acid residue, and an amino acid residue derived from a β-amino acid or a γ-amino acid.

38. A compound according to any one of claims 28 to 37, wherein the amino acid residue comprises an amino acid residue with a zero charge.

39. A compound according to any one of claims 28 to 38, wherein the amino acid residue comprises at least one negatively charged amino acid residue selected from D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, and L-γGlu.

40. A compound according to any one of claims 28 to 39, wherein the amino acid residue comprises a positively charged amino acid residue selected from D-His, L-His, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, and L-εLys.

41. A compound according to any one of claims 28 to 40, wherein the amino acid residue comprises one or more hydrophilic amino acid residues selected from D-Ser and L-Ser.

42. A compound according to any one of claims 28 to 41, wherein the amino acid residue comprises one or more neutral amino acid residues selected from Gly, D-Pro, and L-Pro.

43. A compound according to claim 36 or claim 37, wherein the divalent linker comprises independently selected from 4-carboxy-L-phenylalanine (Cbp), 2,3-diaminopropionic acid (Dap), Gly, D-His, L-His, D-Ala, L-Ala, D-Val, L-Val, D-Leu, L-Leu, D-Phe, L-Phe, D-Pro, L-Pro, D-Met, L-Met, D-Trp, L-Trp, D-Thr, L-Thr, D-Tyr, L-Tyr, D-Nle, L-Nle, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 1-12 alkylene C(O), C(O)C 1-12 alkylene NR 5 and NR 6 -(C 1-6 alkylene O) p C 1-6 a total of 1 to 15 groups of alkylene C(O).

44. The compound according to claim 43, wherein the divalent linker comprises a group selected from Cbp, Dap, Gly, D-His, L-His, D-Ala, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 2-8 alkylene C(O), C(O)C 2-8 alkylene NR 5 and NR 6 -(C 1-3 alkylene O) p C 1-3 a total of 1 to 15 groups of alkylene C(O).

45. The compound according to claim 44, wherein the divalent linker independently comprises Cbp, Dap, Gly, D-Ala, D-His, L-His, L-Ala, D-Val, L-Val, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 5 C 5 alkylene C(O)(Ahx), NR 5 C 7 alkylene C(O)(Aoc), NR 5 C 10 alkylene C(O)(Aun), NR 6 -(C 2 alkylene O) p C 1 alkylene C(O) and NR 6 -(C 2 alkylene O) p C 2 a total of 1 to 15 groups of alkylene C(O).

46. The compound according to claim 45, wherein p is an integer selected from 1 to 6, and the divalent linker comprises groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Ala, L-Ala, D-Ser, L-Ser, D-Pro, L-Pro, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Asp, L-Asp, D-Glu, L-Glu, D-γGlu, L-γGlu, NR 6 -(C 2 alkylene O) 2 C 1 alkylene C(O)(OEG), NR 6 -(C 2 alkylene O)C 2 alkylene C(O)(PEG1), NR 6 -(C 2 alkylene O) 3 C 2 alkylene C(O)(PEG3), NR 6 -(C 2 alkylene O) 6 C 2 alkylene C(O)(PEG6), NR 5 C 7 alkylene C(O)(Aoc), NR 5 C 10 alkylene C(O)(Aun) and NR 5 C 5 alkylene C(O)(Ahx) in a total of 1 to 15 groups.

47. A compound according to claim 46, wherein the divalent linker comprises a total of 1 to 15 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun, and Ahx.

48. A compound according to any one of claims 13 to 47, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of negative five (-5) when complexed with a radionuclide, and the divalent linker comprises a total of 4 to 11 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun, and Ahx, wherein at least 4 or 5 groups are selected from D-Glu, L-Glu, D-γGlu, and L-γGlu.

49. A compound according to any one of claims 13 to 47, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof comprises a net charge of minus four (-4) when complexed with a radionuclide, and the divalent linker comprises in total 3 to 11 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 3 or 4 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu.

50. A compound according to any one of claims 13 to 47, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof comprises a net charge of minus three (-3) when complexed with a radionuclide, and the divalent linker comprises in total 2 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 2 or 3 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu.

51. A compound according to any one of claims 13 to 47, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof comprises a net charge of minus two (-2) when complexed with a radionuclide, and the divalent linker comprises in total 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein at least 1 or 2 groups are selected from D-Glu, L-Glu, D-γGlu and L-γGlu.

52. A compound according to any one of claims 13 to 47, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof has a net charge of minus one (-1) when complexed with a radionuclide, and the bivalent linker comprises a total of 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Ser, L-Ser, D-Arg, L-Arg, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Glu, L-Glu, D-γGlu and L-γGlu.

53. A compound according to any one of claims 13 to 47, wherein E is a chelating group derived from DOTA, the divalent linker collectively comprises 2 to 9 groups independently selected from Gly, L-Pro, L-Glu, L-γGlu, OEG, PEG1, PEG3, PEG6, and Aoc, wherein at least 1 group is selected from L-Glu and L-γGlu, and the compound of formula I or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof has a net charge of minus one (-1) when complexed with 177 Lu.

54. A compound according to any one of claims 13 to 47, wherein the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof has a net charge of zero (0) when complexed with a radionuclide, and the bivalent linker comprises a total of 1 to 9 groups independently selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Arg, L-Arg, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, wherein 0 or 1 group is selected from D-Lys, L-Lys, D-εLys and L-εLys.

55. A compound according to claim 47, wherein the bivalent linker comprises a total of 2 to 5 groups independently selected from Gly and L-Pro.

56. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 to 4 groups independently selected from Gly and L-Ser.

57. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 to 4 groups, and the 1 to 4 groups are Gly.

58. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 to 2 groups selected from PEG1, PEG3 or PEG6.

59. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 to 2 groups, and the 1 to 2 groups are Aoc.

60. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 to 4 groups, and the 1 to 4 groups are OEG.

61. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 group, and the 1 group is OEG.

62. A compound according to claim 47, wherein the bivalent linker comprises a total of 1 to 7 groups independently selected from Gly, D-γGlu, L-γGlu, OEG and Gly.

63. The compound according to claim 47, wherein the divalent linker comprises a total of 1 to 7 groups independently selected from Gly, D-γGlu, L-γGlu, D-Lys, L-Lys, D-εLys, L-εLys, and OEG.

64. The compound according to claim 47, wherein the divalent linker comprises a total of 1 to 7 groups independently selected from Cbp, Dap, Gly, D-γGlu, L-γGlu, D-Ser, L-Ser, D-His, L-His, and OEG.

65. The compound according to any one of claims 1 to 64, wherein one of L 1 , L 2 and L 3 is a direct bond.

66. A compound according to any one of claims 1 to 64, wherein L 1 is a direct bond.

67. A compound according to any one of claims 1 to 64, wherein two of L 1 , L 2 and L 3 are direct bonds.

68. A compound according to any one of claims 1 to 28, wherein L 1 , L 2 and L 3 are each a direct bond.

69. A compound according to any one of claims 1 to 47, wherein one or two of L 1 , L 2 and L 3 are divalent linkers, and the divalent linker comprises a total of 1 to 15 groups selected from Cbp, Dap, Gly, D-His, L-His, D-Pro, L-Pro, D-Arg, L-Arg, D-Ser, L-Ser, D-Lys, L-Lys, D-εLys, L-εLys, D-Glu, L-Glu, D-γGlu, L-γGlu, OEG, PEG1, PEG3, PEG6, Aoc, Aun and Ahx, and the other two or one of L 1 , L 2 and L 3 are direct bonds, respectively.

70. A compound according to any one of claims 1 to 47, wherein L 1 , L 2 and L 3 one of which is a divalent linker, and the divalent linker comprises 1 to 3 OEG groups, and L 1 , L 2 and L 3 the other two of which are direct bonds.

71. A compound according to any one of claims 1 to 47, wherein one of L 1 , L 2 and L 3 is a divalent linker, and the divalent linker comprises 1 OEG group, and the other two of L 1 , L 2 and L 3 are direct bonds.

72. A compound according to any one of claims 1 to 47, wherein E is a chelating group derived from DOTA, and one of L 1 , L 2 and L 3 is a divalent linker, and the divalent linker contains 1 OEG group, and the other two of L 1 , L 2 and L 3 are direct bonds, and the compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof has a net charge of zero (0) when complexed with 177 Lu.

73. A compound according to any one of claims 13 to 72, wherein each R 5 is independently selected from H and CH 3 .

74. A compound according to any one of claims 13 to 73, wherein each R 6 is independently selected from H and CH 3 .

75. The compound according to claim 1, wherein the compound of formula I is selected from the following list of compounds: or a pharmaceutically acceptable salt and / or solvate thereof.

76. A radionuclide complex or a pharmaceutically acceptable salt and / or solvate thereof, comprising the compound according to any one of claims 1 to 75 or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radionuclides.

77. The radionuclide complex according to claim 76, wherein the one or more radionuclides are selected from 14 C, 15 N, 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 66 Ga, 67 Ga, 68 Ga, 111 In, 123 In, 59 Fe, 63 Zn, 52 Fe, 52 Mn, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F, 188 Re, 186 Re, 153 Sm, 66 Ho, 86 Y, 87 Y, 90 Y, 89 Sr, 153 Gd, 159 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 101m Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 55 Co, 57 Co, 47 Sc, 149 Pm, 142 Pr, 161 Ho, 166 Ho, 175 Yb or 51 Cr.

78. The radionuclide complex according to claim 76 or claim 77, wherein the one or more radionuclides are for imaging or diagnosis, or for treatment.

79. The radionuclide complex according to claim 78, wherein the radionuclide is 177 Lu or 225 Ac.

80. A composition comprising one or more compounds according to any one of claims 1 to 75 or one or more complexes according to any one of claims 76 to 79 and a carrier.

81. A kit comprising one or more compounds of formula I according to any one of claims 1 to 75 or a pharmaceutically acceptable salt and / or solvate thereof, and instructions for administering the one or more compounds of formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

82. A kit comprising one or more compounds of formula I according to any one of claims 1 to 75 or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radioactive isotopes as defined above, and optionally, instructions for administering the one or more compounds of formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof and for administering the radioactive isotope to a subject in need thereof.

83. A kit comprising one or more complexes according to any one of claims 76 to 79 or a pharmaceutically acceptable salt and / or solvate thereof as defined above, and instructions for administering the one or more compound complexes to a subject in need thereof.

84. A method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds according to any one of claims 1 to 71 or one or more complexes according to any one of claims 76 to 79.

85. The method according to claim 84, wherein the disease or disorder is cancer.

86. The method according to claim 84, wherein the cancer is a cancer that overexpresses SSTR2, CCK2R, or both.

87. The method according to claim 85, wherein the cancer is medullary thyroid carcinoma (MTC) or small cell lung cancer (SCLC) or neuroendocrine tumor.

88. A method for inhibiting proliferative activity in a cell, comprising administering to the cell a therapeutically effective amount of one or more compounds according to any one of claims 1 to 75 or one or more complexes according to any one of claims 76 to 79.

89. A method for imaging tissue in a subject by administering to the subject in need thereof an imaging effective amount of one or more compounds according to any one of claims 1 to 75 or one or more complexes according to any one of claims 76 to 79 for imaging, and applying an imaging technique to detect the emitted gamma rays.

90. A method for diagnosing cancer in a subject by administering to the subject in need thereof a diagnostically effective amount of one or more compounds according to any one of claims 1 to 75 or one or more complexes according to any one of claims 76 to 79, and applying an imaging technique to detect the emitted gamma rays.

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