Chelating agents and metal complexes for use in radiotherapy

Abstract

The present invention relates to the field of metal complexes and their use in therapy. The present disclosure provides chelating agents and metal complexes thereof, particularly complexes of radioactive nuclides, such as radioisotopes of antimony, as well as methods and uses thereof.

Description

[0001] Chelating agents and metal complexes for use in radiotherapy

[0002] Technical field

[0003] The present invention relates to the field of metal complexes and their use in therapy. The present disclosure provides chelating agents and metal complexes thereof, particularly complexes of radioactive nuclides, such as radioisotopes of antimony, as well as methods and uses thereof.

[0004] Background

[0005] The radioisotopes of antimony (Sb), antimony-119 (119Sb) and antimony-117 (117Sb), have an unexploited potential as a theranostic pair for Auger electron therapy and single photon emission computed tomography (SPECT) imaging respectively [Filosofov et al., 2021 , Thisgaard & Jensen, 2008], As an Auger electron emitter (AEE)119Sb exhibits ideal characteristics for targeted therapy of small metastases and disseminated cancer cells. Theoretical dosimetry calculations at a subcellular scale have identified119Sb as an isotope which should attain some of the highest calculated tumour-to-normal-tissue dose ratios [Thisgaard & Jensen, 2008], It emits on average 23.7 Auger electrons (AEs) per decay [Ku et al., 2019] and has a half-life of 38.19 h, thereby offering a suitable time window for therapy. Additionally, it emits low energy gamma rays with low intensities, minimising the unwanted dose to healthy tissues. [Filosofov etal., 2021] Its sister isotope117Sb has suitable properties for single-photon emission computer tomography (SPECT) imaging and can be used for diagnostics. It decays predominantly by electron capture, primarily emitting a gamma ray of 158.56 keV (86%), like the widely used SPECT isotope123l which emits a gamma ray of 158.97 keV (83%). Lastly, both119Sb and117Sb can be produced using a low-energy cyclotron with a solid target system. Together, they constitute a true theranostic pair possessing identical chemical properties that will result in identical kinetics, both in vitro and in vivo.

[0006] However, no suitable biocompatible chelating ligand system is known for delivering radioantimony. The nearly universal chelator currently implemented for metallic radionuclides, DOTA, does not form stable complexes with antimony [Chen et al., 2022] rendering it unsuitable for radioantimony delivery. Known complexes with Sb(lll) include the tartrate complex which is a known emetic and has been used to treat the tropical parasitic disease Leishmaniasis before being phased out by the Sb(V) compounds sodium stibogluconate and meglumine antimoniate [Brahmachari et al., 1989; Haidar et al., 2011 ; Aronson etal., 2017], Tartrate has been labelled with117Sb [Thakuref al. 1970], however low stability of this complex in vivo was observed [Sun et al. 2000],

[0007] Recently a trithiolato ligand coordinated to Sb(lll) was labelled with119Sb, albeit with low radiochemical yields (65% ± 20%) [Olson et al. 2021], The labelling method described is time consuming (> 3.5 hours) making it unsuitable for labelling with117Sb, due to its short half-life of 2.8 h. Additionally, the non-radioactive version of this Sb(lll) complex compound was synthesized under concentrated and non-aqueous conditions. Typically dilute aqueous conditions at close to pH 7 are used for application in nuclear medicine. Under these conditions, hydrolysis reactions - the bane of antimony chemistry - may be competing.

[0008] Thus, there is a strong unmet need in the field for the provision of complexes of antimony with superior stability in physiological conditions and increased radiolabelling efficiency.

[0009] Summary

[0010] The present invention addresses the above-mentioned problems by providing chelating agents based on bis(thiosemicarbazone) moieties and metal complexes thereof.

[0011] The inventors demonstrate in the examples that the chelating agents of the present disclosure form stable complexes with radioisotopes of Sb(lll) in aqueous conditions at concentrations typical for radiopharmaceutical applications, achieving suitable radiolabelling yields conveniently and efficiently. The Sb(lll) complexes described herein remain stable in aqueous solutions under physiological conditions for extended periods of time and are resistant to transmetallation with relevant metal ions present in biological systems.

[0012] These properties are highly warranted in the application of metal complexes in medicine, and particularly in the field of radiotherapy, diagnostics and targeted delivery, where practical application of radioisotopes of antimony is hindered by their instability during aqueous handling and under physiological conditions. In one main aspect, the present disclosure provides a metal complex, or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, comprising: a. a metal atom, or a radioisotope thereof, and b. a chelating agent according to formula III: (formula III), wherein

[0013] X and X’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, (=0), or aryl;

[0014] R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT, or two R1groups are together forming a cycle, each of which may be optionally substituted;

[0015] R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle, each of which may be optionally substituted;

[0016] R3is Ci-Ce alkyl, C3-C6 cycloalkyl, , aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; n is an integer from 0 to 3; each dashed line individually represents a double or a single bond;

[0017] Ra, Rb, Rb’, Rc, Rc’ are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; or Rcand Rc’ are together forming a cycle;

[0018] L is a linker; and

[0019] RTis a targeting moiety. In another aspect, the present disclosure provides a compound of formula III, formula III, wherein

[0020] R1, R2, R2’, R3, X, X’, n, and each dashed line, are each respectively as defined herein in the embodiments of formula III.

[0021] In yet another aspect, the present disclosure provides a composition comprising a metal complex as described herein.

[0022] In another aspect, the present disclosure provides for a metal complex as described herein, or the composition as described herein for use as a medicament.

[0023] In another aspect, the present disclosure provides for a metal complex as described herein, or a composition as described herein, for use in a method of diagnosis of a disease.

[0024] In a final aspect, the present disclosure provides for a metal complex as described herein, or a composition as described herein for use in the treatment, prevention, or alleviation of cancer in a subject.

[0025] Description of Drawings

[0026] Figure 1 : Crystal structure of ligand 3. Black: nitrogen, Dark grey: oxygen, Grey: carbon, Light grey: Sulfur.

[0027] Figure 2: Crystal structure of complex 10. Black: nitrogen, Dark grey: carbon, Light grey: Sulfur. Chlorine and antimony atoms have been labelled in the drawing.

[0028] Figure 3: Crystal structure of complex 11 . Black: nitrogen, Dark grey: carbon, Light grey: Sulfur. Chlorine and antimony atoms have been labelled in the drawing. Figure 4: Crystal structure of complex 12. Black: nitrogen, Dark grey: carbon, Light grey: Sulfur. O and antimony have been labelled in the drawing.

[0029] Figure 5: Crystal structure of complex 13 (A), 20 (B) and 21 (C). Black: nitrogen, Dark grey: carbon, Light grey: Sulfur. O and antimony have been labelled in the drawing.

[0030] Figure 6: MALDI mass spectrum of ligand-peptide conjugate H2nabptsc-PEG2-Angiopep-2.

[0031] Figure 7: Absorbances of 11 at 330, 370, and 470 nm measured at pH values from ca. pH = 1 to pH = 14. The pH-range within which 11 is stable is marked by the grey region (Stability window). Further experimental details are given in Example 6.

[0032] Figure 8: UV-vis absorption spectra of 11 at pH = 7.4 after 0 hours (grey line) and 24 hours (light grey line) from preparation of the solution. Further experimental details are given in Example 6.

[0033] Figure 9: ESI mass spectrum of 10 doped with 2 equivalents of ZnCh. Further experimental details are given in Example 7.

[0034] Figure 10: UV-vis spectra of complexes 11 (A), 20 (B), and 21 (C) in 9:1 DMSO / PBS buffer solution (pH 7.4) recorded immediately after dissolution and very 24 hours for 3 days. Spectrum of the free ligand is added for comparison. Further experimental details are given in Example 6A.

[0035] Definitions

[0036] The term “complex” as used herein refers to the association involving two or more component molecular or ionic entities. For example, a complex may be used to refer to the coordination entity consisting of a central atom, usually metallic, to which there is attached, or bonded, a surrounding array of other groups of atoms referred to as ligands. The complex may involve the formation of a coordination entity formed by chelation, where there is presence of bonds between two or more separate binding sites within the same ligand and the central atom.

[0037] “Radioactive” refers to the property of a nuclide of undergoing spontaneous nuclear transformations with the emission of radiation. Radiation refers to electromagnetic waves and particles emitted during a nuclear process. Radioactive is used here to describe said property of compositions, compounds, or agents comprising radioactive nuclei.

[0038] “Radioisotope” is a radioactive isotope of a specified element. “Auger electron-emitting radioisotopes” are radioisotopes that emit Auger electrons during their radioactive decay. Auger electrons differ from other forms of radiation therapy because the electrons emitted in the radioactive decay, the Auger electrons, are released in large numbers with low kinetic energy, leading to high linear-energy-transfer (LET) effects. Because of their low energy, these electrons exert their damaging effect on cellular structures over a very short nanometer scale range being less than the size of a single cell. This very short-range delivery of energy provides a highly targeted therapy because the radiation-emitting nuclide is located inside the cell to cause damage to the genomic DNA.

[0039] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0040] The term “alkyl” as used herein refers to a straight or branched hydrocarbon chains. For example, the terms “C1-C3 alkyl”, “C1-C5 alkyl” and “Ci-Ce alkyl” refer to a straight or branched hydrocarbon chains containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. Representative examples of C1-C3 alkyl, C1-C5 alkyl and Ci-Ce alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, pentyl and hexyl.

[0041] As used herein the term “cycloalkyl” or “carbocycle” refers to a monocyclic or polycyclic system. For example, “C3-C6 cycloalkyl” as used herein refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms.

[0042] As used herein the term “heterocycloalkyl” or “heterocycle” refers to a cycloalkyl wherein one or more C carbon atoms of the cyclic framework have been substituted by a heteroatom, for example wherein one or more carbon atoms have been individually substituted by O, N, or S.

[0043] The term “halogen” as used herein refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0044] The term “halo” as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is independently selected at each occurrence. The term "aromatic" or “aryl” refers to a cyclic or polycyclic moiety having a conjugated unsaturated (4n+2)TT electron system (where n is a positive integer), sometimes referred to as a delocalized TT electron system.

[0045] The term "heteroaromatic" or “heteroaryl” as used herein, alone or in combination, refers to an aromatic ring or an aromatic polycyclic system containing from 5 to 10 ring atoms where at least one of the ring atoms are heteroatom(s), such as O, N or S.

[0046] As described herein, compounds of the present invention may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position, i.e. the substituent may be individually / independently selected from a group of substituents. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0047] When two groups are together forming a cycle, as described herein, e.g. when two R1groups, or R2and R2’ groups, are forming a cycle; it means said two groups are forming a carbocycle, heterocycle, aryl group.

[0048] When a formula described herein includes a dashed line “ > ”, said line represents a single or a double bond. The number of hydrogens connected directly to the atoms joined

[0049] HH by said dashed line is adjusted accordingly. For example, represents when the dashed line is a single bond, and the dashed line is a double

[0050] H2 H2bond. For example, represents when the dashed line is a single bond,

[0051] H and when the dashed line is a double bond. When two dashed lines join on a single carbon atom, only one of said lines may be a double bond.

[0052] The term “compound” or “complex” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, acid-base forms, and isotopes of the structures depicted, unless otherwise specified. “Acid-base” forms refer to any form which exists in acid / base equilibrium with said compound or complex.

[0053] Bis(thiosemicarbazone) compounds described herein present at least two protons which are susceptible to exchange to form different acid-base forms, as depicted below for formula Illa. In the present disclosure, when complexes wherein said compounds act as chelating agents are mentioned, it is referred to complexes with any of said acid-base forms, or tautomers thereof.

[0054] When complexes with Sb(lll) are illustrated in formulas II, lla-1 to lla-6, llb-1 to llb-5, He, llc-1 , lid, and lld-1 , generally the twice deprotonated form of the chelating agent is depicted in said formulas, but said formulas also refer to complexes with each of the other acid-base forms of the chelating agent, or tautomers thereof.

[0055] Complexes of Sb(lll) with the bis(thiosemicarbazone) chelating agent according to the present disclosure present themselves generally with the bis(thiosemicarbazone) chelating agent forming a pentadentate chelate with Sb(lll) and an additional ligand (Z), as shown in formulas II, lla-1 to lla-6, llb-1 to llb-6, He, Hc-1 , lid, and Hd-1. According to the nature of the ligand (Z) or the acid-base form of the chelating agent, the complex may bear a net charge, and thus said complexes may form salts with suitable counter ions. The present disclosure relates to any such salts. Examples of suitable counter ions include but are not limited to: hydroxide, halide, nitrate, phosphate, sulphate, acetate, benezenesulfonate, benzoate, citrate, fumarate, glutamate, glycolate, perchlorate, tetrafluoroborate, hexafluorophosphate, or trifluoromethanesulfonate. In one embodiment, the salt is a pharmaceutically acceptable salt.

[0056] Detailed description

[0057] A metal complex

[0058] In one main aspect, the present disclosure provides for a metal complex, or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, comprising: a. a metal atom (M), or a radioisotope thereof, and b. a chelating agent according to formula III: (formula III), wherein

[0059] X and X’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, (=0), or aryl;

[0060] R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT, or two R1groups are together forming a cycle, each of which may be optionally substituted;

[0061] R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle, each of which may be optionally substituted;

[0062] R3is Ci-Ce alkyl, C3-C6 cycloalkyl, , , aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; n is an integer from 0 to 3;

[0063] Ra, Rb, Rb’, Rc, and Rc’ are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; or Rband Rb’, or Rcand Rc’ are together forming a cycle; each dashed line individually represents a double or a single bond;

[0064] L is a linker; and

[0065] RTis a targeting moiety.

[0066] In one embodiment, the metal complex is according to formula III, wherein R3is are each individually -H, Ci-Ce alkyl, C3- Ce cycloalkyl, aryl, heteroaryl, or -L-RTeach of which may be optionally substituted. In one embodiment, Rcand Rc’ are together forming a cycle, that may be optionally substituted.

[0067] The inventors have found that chelating agents having a bis(thiosemicarbazone) scaffold can form pentadentate complexes with metal atoms due to their arrangement of donor groups having N and S atoms and provide advantageous properties for their application in radiotherapy. In addition to the bis(thiosemicarbazone) chelating agent, the complexes of the present disclosure may comprise additional ligands (Z).

[0068] Thus, in one embodiment, the metal complex comprises formula I, (formula I), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0069] M is a metal or a radioisotope thereof,

[0070] R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT; or R2and R2’ are together forming a cycle; each of which may be optionally substituted;

[0071] R4and R4’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT; or R4and R4’ are together forming a cycle; each of which may be optionally substituted; and

[0072] X, X’, R1, n, each dashed line, Ra, Rb, Rb’, L and RTare as defined elsewhere herein.

[0073] In addition to the bis(thiosemicarbazone) chelating agent, the complexes of the present disclosure may comprise additional ligands (Z) bound to the metal (M), thus in one embodiment M is M-Z.

[0074] The metal may suitably be an ion, particularly a cation, that is forming a coordination entity with the chelating agent. For application in therapy, metal ions having therapeutic activity are preferred. For example, the metal (M) is a radioisotope having radioactive properties that are useful in the treatment or diagnosis of diseases, such as cancer. In one embodiment, M is a radioisotope of antimony (Sb), cobalt (Co), or bismuth (Bi).

[0075] In one embodiment, M is an Auger-emitting radioisotope of a metal. Auger-emitting radioisotopes provide a promising mode of radiotherapy due to its unique cell-killing mechanism. Auger electrons have low energy, resulting in extremely short particle path lengths within cells, which is highly desirable, because it minimizes collateral damage.

[0076] In one embodiment, M is an Auger-emitting radioisotope of Sb, Co, or Bi.

[0077] In one embodiment, M is117Sb,119Sb,58mCo, or213Bi.

[0078] Currently, no stable complexes of antimony suitable for radiotherapy exist. The inventors have found that the chelating agents of the present disclosure form complexes with Sb(lll) that can be produced conveniently and efficiently and possess superior stability under physiological conditions. Thus, in one embodiment, M is any isotope of Sb, particularly any isotope of Sb(lll).

[0079] In one embodiment, M is Sb or a radioisotope of Sb, a radioisotope of cobalt (Co), or a radioisotope of bismuth (Bi).

[0080] In one embodiment, M is121Sb,123Sb,117Sb,119Sb, or any combination thereof.121Sb and123Sb are stable (non-radioactive) isotopes of Sb. In one embodiment, M is121Sb, or123Sb.

[0081] In one embodiment, M is117Sb, and / or119Sb.119Sb is a radioisotope of Sb with advantageous Auger-emitting properties.117Sb is a radioisotope of Sb with suitable properties for single-photon emission computer tomography (SPECT). In one embodiment, M is117Sb. In one embodiment, M is119Sb. In addition of the bis(thiosemicarbazone) chelating agent described herein, complexes of Sb(lll), or radioisotopes thereof, of the present disclosure comprise may comprise an additional ligand (Z). In one embodiment, M is Sb-Z.

[0082] The ligand (Z) may be any suitable monodentate ligand known in the art, such as for example but not limited to: hydroxide ion (OH-), chloride ion (Cl-), fluoride ion (F-) bromide ion (Br), iodide ion (I-), H2O, an alkoxide ion, such as methoxide, ethoxide, or isopropoxide; a carboxylate ion, such as formate, acetate, or propanoate; cyanate (OCN-), thiocyanate (SCN-), an amine, such as a primary, secondary or tertiary amine (N(Rd)3), or ammonia; carbon monoxide (CO), a nitrile group (RdCN), a cyanide (CN-), an isonitrile group (RdNC), an isocyanide (NC‘), a tertiary phosphine (P(Rd)3, a carbene, or an aryl carbanion (Ar); where Rdmay in each instance alkyl, cycloalkyl, aryl or heteroaryl group, each of which may be optionally substituted.

[0083] Thus, in one aspect, the present disclosure provides for a metal complex according to formula II, (formula II), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0084] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0085] Z is -OH, H2O, -F, -Cl, -Br, -I, -ORd, -OOCRd, SON-, OCN-, -CN, NH3, -N(Rd)3, CO, RdCN-, RdNC-, or -P(Rd)3; each instance of Rdis individually selected from an alkyl, cycloalkyl, aryl or heteroaryl group, each of which may be optionally substituted; and

[0086] X, X’, R1, R2, R2’, R4, R4’, n, and each instance of a dashed line are each respectively as defined elsewhere herein.

[0087] In one embodiment, Z is an halide, such as -F, -Cl, -Br, -I. In one embodiment, Z is -Cl.

[0088] In one embodiment, Z is -OH. In one embodiment, Z is H2O. In one embodiment, X and X’ are each individually H, Ci-Ce alkyl, or (=0).

[0089] In one embodiment, wherein X and / or X’ are Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci, C2, C3 , or C4 alkyl, each of which may be optionally substituted. In one embodiment, X and / or X’ are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl.

[0090] In one embodiment, X and / or X’ are C3-C6 cycloalkyl. In one embodiment, X and / or X’ are aryl.

[0091] In one embodiment, X and / or X’ are H.

[0092] In one embodiment, X and / or X’ are CH3. In one embodiment, X and / or X’ are (=0).

[0093] In one embodiment, X and X’ are the same. In one embodiment, X and X’ are different.

[0094] In one embodiment the metal complex is according to any one of formulas lla-1 , lla-2, or lla-3:

[0095] Formula lla-3 or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0096] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb; and

[0097] Z, R1, R2, R2’, R4, R4’, and n, are each respectively as described elsewhere herein.

[0098] In one embodiment, n is 0. In one embodiment, n is 1.

[0099] The one or more substituents R1as described herein may be in any available position on the pyridyl ring, such as positions 3, 4, or 5 of the pyridyl ring. Thus, in one embodiment, the metal complex according to the present disclosure is according to any one of formulas lla-4, lla-5, or lla-6:

[0100] Formula lla-6 or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof wherein Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb; Z, R1, R2, R2, R4, R4X, X’ and each dashed line are each respectively as defined elsewhere herein.

[0101] In one embodiment, R1is halogen, -COORa, -CON(Rb)(Rb), Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, two R1are together forming a forming a cycle, or -L-RT.

[0102] In one embodiment, R1is H.

[0103] In one embodiment, R1is -COORa, or -CON(Rb)(Rb), wherein Ra, Rband Rb’ are as defined elsewhere herein. In one embodiment, each of Ra, Rband Rb’ is individually a C1-C6alkyl, C3-C6 cycloalkyl, an aryl or an heteroaryl. In one embodiment, R1is -COOH or -CONH2.

[0104] In one embodiment, R2, R2’, R4and R4’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT.

[0105] In one embodiment, R2and / or R2’ are each individually Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl. In one embodiment, R4and / or R4’ are each individually methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl.

[0106] In one embodiment, R2and / or R2’ are -CH3.

[0107] In one embodiment, R2and / or R2’ are -H.

[0108] In one embodiment, R2and / or R2’ are aryl or heteroaryl.

[0109] In one embodiment, R2and / or R2’ are , wherein from 1 to 3. In one embodiment, k is 1 , 2, or 3. In one embodiment, k is 1.

[0110] In one embodiment, one embodiment,

[0111] In one embodiment, Reis on each instance halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C1-6 haloalkyl or C3-C6 cycloalkyl.

[0112] In one embodiment, Reis F, Cl, Br, or I, preferably F or Cl, more preferably Cl. In one embodiment, Reis Ci-Ce alkoxy, such as Ci , C2, C3, C4, C5, or Ce alkoxy, preferably -O-CH3.

[0113] In one embodiment, Reis Ci-Ce alkyl, such as Ci , C2, C3, C4, C5, or Ce alkyl.

[0114] In one embodiment, Reis Ci-Ce haloalkyl, such as Ci , C2, C3, C4, C5, or Ce haloalkyl.

[0115] In one embodiment, Reis C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

[0116] In one embodiment, R2and / or R2’ are phenyl.

[0117] In one embodiment, R2and R2’ are each individually C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl. In one embodiment, R2and R2’ are each individually cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted.

[0118] In one embodiment, R2and R2’ are together forming a cycle.

[0119] In one embodiment, R2and R2’ are different. In one embodiment, R2and R2’ are the same.

[0120] In one embodiment, R2is H and R2’ is a substituent as described herein different than H. Preferably, R2is H and R2’ is a substituted phenyl group as described herein, more preferably, R2is H and R2’ is phenyl.

[0121] In one embodiment, R4and / or R4’ are each individually Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl. In one embodiment, R4and / or R4’ are each individually methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl.

[0122] In one embodiment, R4and / or R4’ are -CH3.

[0123] In one embodiment, R4and / or R4’ are -H.

[0124] In one embodiment, R4and / or R4’ are aryl or heteroaryl.

[0125] In one embodiment, R4and / or R4’ are , wherein k’ is an integer selected from 1 to 3. In one embodiment, k’ is 1 , 2, or 3. In one embodiment, k’ is 1. , In one embodiment, Rfis on each instance halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C1-6 haloalkyl or C3-C6 cycloalkyl.

[0126] In one embodiment, Rfis F, Cl, Br, or I, preferably F or Cl, more preferably Cl.

[0127] In one embodiment, Rfis Ci-Ce alkoxy, such as Ci, C2, C3, C4, C5, or Ce alkoxy, preferably -O-CH3.

[0128] In one embodiment, Rfis Ci-Ce alkyl, such as Ci , C2, C3, C4, C5, or Ce alkyl.

[0129] In one embodiment, Rfis Ci-Ce haloalkyl, such as Ci , C2, C3, C4, C5, or Ce haloalkyl.

[0130] In one embodiment, Rfis C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

[0131] In one embodiment, R4and / or R4’ are phenyl.

[0132] In one embodiment, R4and R4’ are each individually C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl. In one embodiment, R4and R4’ are each individually cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted.

[0133] In one embodiment, R4is H and R4’ is a substituent as described herein different than H. Preferably, R4is H and R4’ is a substituted phenyl group as described herein, more preferably, R4is H and R4’ is phenyl.

[0134] In one embodiment, R4and R4’ are together forming a cycle.

[0135] In one embodiment, R4and R4’ are different. In one embodiment, R4and R4’ are the same.

[0136] In one embodiment: i. R2and R2’ are individually H, Ci-Ce alkyl, such as -CH3, or phenyl; and ii. R4and R4’ are individually H, Ci-Ce alkyl, such as -CH3, or phenyl.

[0137] In one embodiment: i. R2and R2’ are individually H, -CH3, or phenyl; and ii. R4and R4’ are individually H, -CH3, or phenyl.

[0138] In one embodiment: i. R2and R4are H and ii. R4and R4’ are aryl, such as a substituted phenyl group as described herein. In one embodiment, the present disclosure provides for a complex according to any one of the complexes shown in Table A, or an isomer, stereoisomer, tautomer, acidbase form thereof; or a pharmaceutically acceptable salt thereof.

[0139] Table A.

[0140]

[0141] Targeting moiety

[0142] The present inventors have demonstrated that the complexes of Sb(lll) according to the present disclosure are stable under physiological conditions in aqueous media. This property is necessary for practical use in biological systems, such as in therapeutic or diagnostic applications, and particularly for targeted applications.

[0143] Targeted therapy and diagnostic strategies employ targeting moieties with affinity for a specific biological target, such as a receptor, to direct a therapeutic or diagnostic agent to cells and tissues expressing said target. This strategy provides advantages in increasing efficacy and reducing off-target effects. For example, the therapeutic or diagnostic agent may be a radioisotope of a metal, or a complex thereof.

[0144] Thus, in one embodiment the metal complex as defined herein comprises a targeting moiety (RT). Preferably, the metal complex is covalently linked to the targeting moiety. The targeting moiety may be joined via a linker (L).

[0145] In one embodiment, one of R1, R2, R2’, R4, or R4’ is -L-RT; wherein L is a linker and RTis a targeting moiety. In one embodiment, two of R1, R2, R2’, R4, or R4’ are -L-RT.

[0146] In one embodiment, the present disclosure provides for a metal complex according to any one of formulas llb-1 , llb-2, llb-3, llb-4, or llb-5:

[0147] Formula llb-4

[0148] Formula llb-3

[0149] Formula llb-5 or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof wherein

[0150] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0151] RTis a targeting moiety as described herein,

[0152] L is a linker as described herein, and

[0153] Z, R1, R2, R2’, R4, R4’ X, X’ and each dashed line are each respectively as defined elsewhere herein.

[0154] In one embodiment, RTis a peptide, an antibody, or an antigen-binding fragment thereof.

[0155] In one embodiment, RTbinds to a cell surface protein, such as a receptor. In one embodiment, RTbinds to a cell surface protein, such as a receptor which is overexpressed in cancer. In one embodiment, RTbinds to a cell surface protein, such as a receptor which is overexpressed in glioblastoma.

[0156] In one embodiment, RTbinds to the epidermal growth factor receptor (EGFR).

[0157] In one embodiment, RTbinds to low-density lipoprotein receptor-related protein 1 (LRP1).

[0158] In one embodiment, RTis a peptide from the angiopep family, particularly angiopep-2.

[0159] In one embodiment, RTcomprises or consist of SEQ ID NO.: 1 TFFYGGSRGKRNNFKTEEY (SEQ ID NO.:1). In one embodiment, the metal complex as described herein comprises or consist of formula He:

[0160] L- TFFYGGSRGKRNNFKTEEY (SEQ ID NO. : 1 ) (formula He) or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0161] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0162] L is a linker as defined elsewhere herein, and R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined elsewhere herein.

[0163] In one embodiment, RTbinds to a receptor which is overexpressed in prostate cancer. In one embodiment, RTbinds to prostate-specific membrane antigen (PSMA) on prostate cancer cells. In one embodiment, RTcomprises the PSMA-binding motif Lys-urea-Glu:

[0164] In one embodiment, RTcomprises or consists of In one embodiment, RTcomprises or consists of

[0165] In one embodiment, RTcomprises or consists of In one embodiment, the metal complex as described herein comprises or consist of formula llc-1 : llc-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0166] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb

[0167] L is a linker, and

[0168] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined elsewhere herein.

[0169] As defined herein, L is a linker that connects the metal complex with a targeting moiety. In one embodiment, L comprises or consists of a linear bivalent, saturated or unsaturated, C1-C50 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, - N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, - NHC(=S)NH-, -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally

[0170] JL -Nsubstituted heterocycle; an optionally substituted aromatic heterocycle,N, ; wherein RL1is selected from the group consisting of C1-

[0171] C5 alkyl and the moiety ‘A’ comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle.

[0172] In one embodiment, L comprises comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle.

[0173] In one embodiment, L comprises , wherein m is an integer from 1 to 30.

[0174] In one embodiment, L comprises or consists of: , wherein m is an integer from 1 to 30. In one embodiment, m is an integer from 1 to 20, or 1 to 10. In one embodiment, m is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0175] In one embodiment, L comprises or consists of:

[0176] In one embodiment, the metal complex is according to formula lid:

[0177] (formula lid), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0178] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb

[0179] Z, R2, R2’, R4, R4’, X, X’ and each dashed line are respectively as defined elsewhere herein.

[0180] In one embodiment, the metal complex is:

[0181] (16), or

[0182]

[0183] (16a) or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof. In one embodiment, the metal complex is according to formula I Id-1 :

[0184] I Id-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0185] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb,

[0186] Z, R2, R2’, R4, R4’, X, X’ and each dashed line are respectively as defined elsewhere herein.

[0187] In one embodiment, the metal complex is or a pharmaceutically acceptable salt thereof.

[0188] The complexes of the present disclosure may be prepared according to known techniques of inorganic and organic chemical synthesis, in adequate solvents. For example, by combining a source of the metal, e.g. a suitable metal salt, such as a Sb(lll) salt e.g. SbCh; with the chelating agent and additional ligands. The chelating agent is in one embodiment, as described herein the section “A compound”.

[0189] The skilled person is aware of different adequate solvents, reagents and conditions, e.g. temperature, that may be used. The complexes may be isolated or purified as solids or in solution. For the isolation, well-known techniques and protocols may be used such as precipitation, crystallization, filtration and chromatographic techniques. The examples provide further guidance on methods for the preparation of complexes described herein.

[0190] The complexes can be characterized using equipment and procedures commonly known in the field, such as by their ultraviolet and visible (UV-Vis) absorption spectra, infra-red (IR) absorption spectra, NMR spectra, mass spectra, X-ray diffraction pattern / single crystal X-ray structure, or retention times in chromatographic separations. Said techniques will also allow the skilled person to test the stability of the complexes under different conditions. For example, the stability may be tested by studying the change in the UV-Vis spectrum, the NMR signals, or the mass spectrum, or the presence of different peaks in a chromatogram of a sample under different conditions. The stability may also be assessed qualitatively via a visual change in the colour of a solution of the complex. The examples provide further guidance on exemplary methods and protocols to test the stability of complexes described herein.

[0191] In one embodiment, the metal complex according to the present disclosure is stable in aqueous solutions in a range of pH from 3.5 - 12. In one embodiment, the complex described herein is stable in a range of physiological pH, such as 5.5 to 7.5, such as 7.3 to 7.5, such as 7.4.

[0192] In one embodiment, the metal complex is stable to transmetallation in aqueous solutions. Transmetallation refers to the exchange of the metal atom in the complex, e.g. Sb(lll) by other metal ions. Thus, as shown in the examples, the Sb(lll) complex according to the present disclosure present with low degree of transmetallation in aqueous conditions. Transmetallation may be assessed using techniques to assess stability of the complexes as described herein. For example, in one embodiment the complex is stable to transmetallation with Ca2+, Mg2+or Zn2+ions.

[0193] A compound

[0194] The present disclosure provides compounds that act as chelating agents forming stable complexes with metals, particularly with Sb as described herein.

[0195] Thus, in one aspect, the present disclosure provides for a compound of formula III, (formula III), or an isomer, stereoisomer, tautomer, acid- base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0196] X and X’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, (=0), or aryl; R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, or two R1groups are together forming a cycle, or -L-RT, each of which may be optionally substituted;

[0197] R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle, each of which may be optionally substituted;

[0198] R3is Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; n is an integer from 0 to 3;

[0199] Ra, Rb, Rb’, Rc, and Rc’ are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; or Rband Rb’, or Rcand Rc’ are together forming a cycle; each dashed line individually represents a double or a single bond;

[0200] L is a linker; and

[0201] RTis a targeting moiety.

[0202] In one embodiment, the compound is according to formula Illa, (formula Illa), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof wherein R1, R2, R2’, R4, R4’, X, X’, n, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex”.

[0203] In one embodiment, the compound is according to any one of formulas llla-1 , llla-2, or llla-3:

[0204]

[0205] Formula llla-3 wherein R1, R2, R2’, R4, R4’, X, X’, n, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex” or “Targeting moiety”.

[0206] In one embodiment, the compound is according to any one of formulas lllb-1 , lllb-2, lllb-3, lllb-4, or lllb-5:

[0207] Formula lllb-1 Formula lllb-2

[0208]

[0209] Formula lllb-5 wherein

[0210] RTis a targeting moiety as described herein,

[0211] L is a linker as defined herein,

[0212] R1, R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex” or “Targeting moiety”.

[0213] In one embodiment, RTis as described in any one of the embodiments in the section “Targeting moiety”.

[0214] In one embodiment, L is as described in any one of the embodiments in the section “Targeting moiety”. In one embodiment, the compound is according to formula I lie: l_— TFFYGGSRGKRNNFKTEEY (SEQ ID NO.: 1 ) (formula lllc) or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein L is linker as defined herein R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex” or “Targeting moiety”.

[0215] In one embodiment, the compound is according to formula lllc-1 : (formula Hlc-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0216] L is linker as defined herein

[0217] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex” or “Targeting moiety”.

[0218] The targeting moiety may be connected to formulas III, Illa, llla-1 to llla-6, lllb-1 to lllb-5, lllc, or lllc-1 , as described herein using different suitable functional groups and chemistries, via the linker. Thus, when the chelating agent comprises a targeting moiety it is possible to prepare it by combining a suitable precursor of the targeting moiety (pRT) with a precursor of the chelating agent (pC). Upon reaction of said precursors, the linker is formed.

[0219] Different reactions and chemistries to connect the targeting moieties with the chelating agent described herein are known in the art. For example, formation of amides by reaction of acid and amines, formation of carbamate, urea or thiourea groups among others.

[0220] It is also possible to use click-chemistry to form the linker. Thus, the linker (L) described herein may be formed by a click-reaction between an alkyne group and an azide, such as in a copper-assisted click reaction (CuAAC) or copper-free click reaction (SPAAC). Copper-free click reactions, such as those employing strained alkynes, are preferred for biological applications. For example, the precursor of the chelating agent may comprise an azide and the precursor of the peptide comprises and alkyne e.g. a terminal alkyne or a strained alkyne; or the precursor of the chelating agent may comprise an alkyne e.g. a terminal alkyne or a strained alkyne, and the precursor of the targeting moiety may comprise an azide.

[0221] In one embodiment, the compound is according to formula Hid:

[0222] (formula Hid), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0223] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex”. In one embodiment, the compound is according to formula llld-1 :

[0224] (formula llld-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0225] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined herein in any of the embodiments in the section “A metal complex”.

[0226] In one embodiment, the compound is according to any one of the compounds shown in Table B, or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof.

[0227] Table B

[0228]

[0229] Medical use

[0230] In one aspect, the present disclosure provides a composition comprising the metal complex as described herein. For example, the metal complex of the present disclosure may be formulated in a suitable aqueous solution acceptable for use in medicine. In one embodiment, the metal complex as described herein is formulated in an isotonic saline buffer, or PBS buffer. In one embodiment, the composition comprises DMSO. In some embodiments, the composition may comprise DMSO in an amount sufficient to ensure solubility of the complex.

[0231] In one aspect, the present disclosure provides for a metal complex as described herein, or a composition as described herein for use as a medicament.

[0232] The present disclosure provides stable complexes of radioisotopes of metals with therapeutic and diagnostic value, particularly complexes of radioisotopes of Sb,117Sb or119Sb.

[0233] 119Sb is an Auger-emitting radioisotopes with excellent properties for the treatment of cancer. In one aspect, the present disclosure provides for a metal complex as described herein, or a composition as described herein for use in the treatment, prevention or alleviation of cancer in a subject. Particularly, in one embodiment, the metal complex for use in the treatment of cancer as described herein is a119Sb complex as described herein. The cancer may be any type of cancer.

[0234] In one embodiment, the cancer is brain cancer. In one embodiment, the brain cancer is a brain tumor or an intracerebral neoplasm. In one embodiment, the brain tumor or intracerebral neoplasm involves glial cells. In one embodiment, the brain tumor or intracerebral neoplasm is a glioma.

[0235] In one embodiment, the intracerebral neoplasm is a high-grade glioma, i.e. grade III or grade IV glioma.

[0236] In one embodiment, the metal complex or the composition for use in the treatment of cancer as described herein, is administered intravenously.

[0237] In one embodiment the metal complex or the composition for use in the treatment of brain cancer as described herein, is administered by direct intracerebral administration or by intrathecal administration. In one embodiment the metal complex or the composition for use in the treatment of brain cancer as described herein, is administered by convection-enhanced delivery (CED). In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a PSMA-positive prostate cancer, preferably a cancer wherein cells present overexpression of PSMA.

[0238] In one embodiment, the prostate cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is a metastatic castration-resistant prostate cancer.

[0239] In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0240] 117Sb is a radioisotope that has suitable properties for SPECT imaging and can be used for diagnostic purposes. Thus, in one aspect the present disclosure provides for a metal complex as described herein, or a composition as described herein for use in a method of diagnosis of a disease. In one embodiment, the method of diagnosis comprises performing single-photon emission computer tomography. Particularly, in one embodiment, the metal complex for use in a method of diagnosis as described herein is a117Sb complex as described herein.

[0241] In one aspect, the present disclosure provides a method of treatment, prevention or alleviation of cancer, said method comprising administration of a metal complex as described, or a pharmaceutical composition as described herein, to a subject in need thereof.

[0242] In one aspect, the present disclosure provides a use of a metal complex as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment, prevention or alleviation of cancer.

[0243] Items

[0244] 1. A metal complex, or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, comprising: a. a metal atom (M), or a radioisotope thereof, and b. a chelating agent according to formula III:

[0245] X and X’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, (=0), or aryl;

[0246] R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT, or two R1groups are together forming a cycle, each of which may be optionally substituted;

[0247] R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle, each of which may be optionally substituted;

[0248] R3is Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; n is an integer from 0 to 3; each dashed line individually represents a double or a single bond;

[0249] Ra, Rb, Rb’, Rc, Rc’ are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted; or Rband Rb’, or Rcand Rc’ are together forming a cycle;

[0250] L is a linker; and

[0251] RTis a targeting moiety. e metal complex according to item 1 , wherein wherein Rcand Rcare as defined in item 1. 3. The metal complex according to item 1 , wherein the metal complex comprises formula I (formula I), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0252] M is a metal or a radioisotope thereof,

[0253] R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle, each of which may be optionally substituted;

[0254] R4and R4’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R4and R4’ are together forming a cycle, each of which may be optionally substituted;

[0255] X, X’, R1, n, each dashed line, Ra, Rb, Rb’, L and RTare as defined in item 1.

[0256] 4. The metal complex according to any one of items 1 to 3, wherein M is a radioisotope of a metal, such as a radioisotope of antimony (Sb), cobalt (Co), or bismuth (Bi).

[0257] 5. The metal complex according to any one of items 1 to 3, wherein M is an Augeremitting radioisotope of a metal.

[0258] 6. The metal complex according to any one of items 1 to 3, wherein M is117Sb,119Sb, 58mCo, or213Bi.

[0259] 7. The metal complex according to any one of items 1 to 3, wherein M is Sb, such as 121Sb,123Sb,117Sb,119Sb, or any combination thereof.

[0260] 8. The metal complex according to any one of items 1 to 3, wherein M is a radioisotope of Sb.

[0261] 9. The metal complex according to item 8, wherein M is117Sb, and / or119Sb. 10. The metal complex according to any one of items 1 to 3, wherein the complex is according to formula II formula II, or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0262] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0263] Z is -OH, H2O, -F, -Cl, -Br, -I, -ORd, -OOCRd, SCN-, OCN-, -CN, NH3, -N(Rd)3, CO, RdCN-, RdNC-, or -P(Rd)3; each instance of Rdis individually selected from an alkyl, cycloalkyl, aryl or heteroaryl group, each of which may be optionally substituted;

[0264] X, X’, R1, R2, R2’, R4, R4’, n, and each instance of a dashed line are each respectively as defined in item 3.

[0265] 11 . The metal complex according to item 10, wherein Z is Cl’.

[0266] 12. The metal complex according to item 10, wherein Z is OH’.

[0267] 13. The metal complex according to item 10, wherein Z is H2O.

[0268] 14. The metal complex according to any one of items 1 to 13, wherein X and X’ are each individually H, Ci-Ce alkyl, C3-Ce cycloalkyl, or (=0).

[0269] 15. The metal complex according to any one of items 1 to 14, wherein X and / or X’ are H.

[0270] 16. The metal complex according to any one of items 1 to 14, wherein X and / or X’ are Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3, or C4 alkyl, each of which may be optionally substituted.

[0271] 17. The metal complex according to any one of items 1 to 14, wherein X and / or X’ are C3-Ce cycloalkyl. 18. The meta complex according to any one of items 1 to 14, wherein X and / or X’ are aryl.

[0272] 19. The metal complex according to any one of items 1 to 14, wherein X and / or X’ are CH3.

[0273] 20. The metal complex according to any one of items 1 to 14, wherein X and / or X’ are (=0). 21. The metal complex according to any one of items 1 to 14, wherein X and X’ are the same.

[0274] 22. The metal complex according to any one of items 1 to 14, wherein X and X’ are different.

[0275] 23. The metal complex according to any one of items 1 to 14, wherein the metal complex is according to any one of formulas lla-1 , lla-2, or lla-3:

[0276] Formula lla-2

[0277] Formula lla-1

[0278]

[0279] Formula lla-3 or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0280] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb; and

[0281] Z, R1, R2, R2’, R4, R4’, n, are each as defined in item 3.

[0282] 24. The metal complex according to any one of items 1 to 23, wherein R1is halogen, -COORa, -CON(Rb)(Rb), Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, two R1are together forming a forming a cycle, or -L-RT.

[0283] 25. The metal complex according to any one of items 1 to 23, wherein R1is H.

[0284] 26. The metal complex according to any one of items 1 to 23, wherein R1is Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl, each of which may be optionally substituted.

[0285] 27. The metal complex according to any one of items 1 to 23, wherein R1is C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

[0286] 28. The metal complex according to any one of items 1 to 23, wherein R1is -COORa, or -CON(Rb)(Rb), wherein -COORa, or -CON(Rb)(Rb) are as described in item 1.

[0287] 29. The metal complex according to item 28, wherein R1is -COOH or -CONH2.

[0288] 30. The metal complex according to any one of items 1 to 29, wherein n is 1.

[0289] 31 . The metal complex according to any one of items 1 to 23, wherein n is 0. The metal complex according to any one of items 1 to 30, wherein the metal complex is according to any one of formulas lla-4, lla-5, lla-6:

[0290] Formula lla-6 or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof wherein

[0291] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0292] Z, R1, R2, R2’, R4, R4’ X, X’ and each dashed line are each respectively as defined in any one of items 1 to 30. The metal complex according to any one of items 1 to 32, wherein R2, R2’, R4and R4’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT. The metal complex according to any one of items 1 to 32, wherein R2and / or R2’ are each individually Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl. 35. The metal complex according to any one of items 1 to 32, wherein R2and / or R2’ are -CH3.

[0293] 36. The metal complex according to any one of items 1 to 32, wherein R2and / or R2’ are -H.

[0294] 37. The metal complex according to any one of items 1 to 32, wherein R2and / or R2’ are aryl or heteroaryl.

[0295] 38. The metal complex according to any one of items 1 to 32, wherein R2and / or R2’

[0296] ?^-(Re)k are , wherein k is an integer selected from 1 to 3, such as k is 1.

[0297] 39. The metal complex according to item 38, wherein

[0298] 40. The metal complex according to any one of items 38 to 39, wherein Reis on each instance halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C1-6 haloalkyl or C3-C6 cycloalkyl.

[0299] 41 . The metal complex according to any one of items 38 to 40, wherein Reis F, Cl, Br, or I, preferably F or Cl, more preferably Cl.

[0300] 42. The metal complex according to any one of items 38 to 40, wherein Reis Ci-Ce alkoxy, such as Ci , C2, C3, C4, C5, or Ce alkoxy, preferably -O-CH3.

[0301] 43. The metal complex according to any one of items 1 to 32, wherein R2and / or R2’ are phenyl.

[0302] 44. The metal complex according to any one of items 1 to 32, wherein R2and R2’ are each individually C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

[0303] 45. The metal complex according to any one of items 1 to 32, wherein R2and R2’ are together forming a cycle.

[0304] 46. The metal complex according to any one of items 1 to 32, wherein R2and R2’ are different.

[0305] 47. The metal complex according to any one of items 1 to 32, wherein R2and R2’ are the same.

[0306] 48. The metal complex according to any one of items 1 to 47, wherein R4and / or R4’ are each individually Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl. 49. The metal complex according to any one of items 1 to 47, wherein R4and / or R4are -CH3.

[0307] 50. The metal complex according to any one of items 1 to 47, wherein R4and / or R4’ are -H.

[0308] 51 . The metal complex according to any one of items 1 to 47, wherein R4and / or R4’ are aryl or heteroaryl.

[0309] 52. The metal complex according to any one of items 1 to 47, wherein R4and / or R4’

[0310] 53. The metal complex according to item 52, wherein

[0311] 54. The metal complex according to any one of items 52 to 53, wherein Rfis on each instance halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C1-6 haloalkyl, or C3-C6 cycloalkyl.

[0312] 55. The metal complex according to any one of items 52 to 54, wherein Rfis F, Cl, Br, or I, preferably F or Cl, more preferably Cl.

[0313] 56. The metal complex according to any one of items 52 to 54, wherein Rfis Ci-Ce alkoxy, such as Ci , C2, C3, C4, C5, or Ce alkoxy, preferably -O-CH3.

[0314] 57. The metal complex according to any one of items 1 to 47, wherein R4and / or R4’ are phenyl.

[0315] 58. The metal complex according to any one of items 1 to 47, wherein R4and R4’ are each individually C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

[0316] 59. The metal complex according to any one of items 1 to 47, wherein R4and R4’ are together forming a cycle.

[0317] 60. The metal complex according to any one of items 1 to 59, wherein R4and R4’ are different.

[0318] 61. The metal complex according to any one of items 1 to 59, wherein R4and R4’ are the same.

[0319] 62. The metal complex according to any one of items 1 to 61 , wherein one of R1, R2,

[0320] R2’, R4, or R4’ is -L-RT The metal complex according to any one of items 1 to 61 , wherein two of R1, R2, R2’, R4, or R4’ are -L-RTThe metal complex according to any one of items 1 to 61 , wherein the metal complex is according to any one of formulas llb-1 , llb-2, llb-3, llb-4, or llb-5:

[0321] Formula llb-4

[0322] Formula llb-3

[0323] Formula llb-5 or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0324] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb; L is a linker,

[0325] RTis a targeting moiety, and

[0326] Z, R1, R2, R2’, R4, R4’, X, X’, n and each dashed line are respectively as defined in any one of items 1 to 61 .

[0327] 65. The metal complex according to any one of items 1 to 64, wherein RTis a peptide, an antibody, or an antigen-binding fragment thereof.

[0328] 66. The metal complex according to item 65, wherein RTbinds to a cell surface protein, such as a receptor,

[0329] 67. The metal complex according to any one of items 65 to 66, wherein RTbinds to a cell surface protein, such as a receptor which is overexpressed in cancer, particularly in glioblastoma.

[0330] 68. The metal complex according to any one of items 65 to 67, wherein RTbinds to the epidermal growth factor receptor (EGFR).

[0331] 69. The metal complex according to any one of items 1 to 64, wherein RTbinds to low-density lipoprotein receptor-related protein 1 (LRP1).

[0332] 70. The metal complex according to item 69, wherein RTis a peptide from the angiopep family, particularly angiopep-2.

[0333] 71 . The metal complex according to any one of items 69 to 70, wherein RTcomprises or consist of:

[0334] TFFYGGSRGKRNNFKTEEY (SEQ ID NO.:1)

[0335] 72. The metal complex according to any one of items 69 to 71 , wherein the metal complex comprises formula He: l_— TFFYGGSRGKRNNFKTEEY (SEQ ID NO. : 1 ) (formula I Ic) or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0336] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb

[0337] L is a linker, and

[0338] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of items 1 to 61 . . The metal complex according to any one of claims 1 to 64, wherein RTbinds to prostate-specific membrane antigen (PSMA) on prostate cancer cells. The metal complex according to claim 73, wherein RTconsists of The metal complex according to any one of claims 72 to 73, wherein the metal complex comprises formula llc-1

[0339] (formula llc-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0340] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb

[0341] L is a linker, and

[0342] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of claims 1 to 61. The metal complex according to any one of items 1 to 72, wherein L comprises or consists of a linear bivalent, saturated or unsaturated, C1-C50 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)- , -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, -S-, -S(=O)-, -S(=O)2- , -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle, wherein

[0343] RL1is selected from the group consisting of C1-C5 alkyl and the moiety ‘A’ comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle.

[0344] The metal complex according to item 76, wherein L comprises wherein ‘A’ comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle.

[0345] The metal complex according to any one of items 76 to 77, wherein L comprises wherein Axis either -CH- or N. The metal complex according to any one of items 76 to 78, wherein L comprises , wherein m is an integer from 1 to 30. 80. The metal complex according to any one of items 76 to 79, wherein L comprises or consists , wherein m is an integer from 1 to 30.

[0346] 81 . The metal complex according to any one of items 76 to 80, wherein m is an integer from 1 to 20, or 1 to 10.

[0347] 82. The metal complex according to any one of items 76 to 81 , wherein L comprises or consists

[0348] 83. The metal complex according to any one of items 1 to 82, wherein the metal complex is according to formula lid:

[0349] (formula lid), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof wherein

[0350] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0351] Z, R2, R2’, R4, R4’, X, X’ and each dashed line are respectively as defined in any one of items 1 to 61.

[0352] 84. The metal complex according to any one of items 1 to 83, wherein the complex is:

[0353]

[0354] ; or a pharmaceutically acceptable salt thereof. The metal complex according to any one of claims 1 to 82, wherein the metal complex is according to formula lld-1 :

[0355] (formula lld-1), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof wherein

[0356] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0357] Z, R2, R2’, R4, R4’, X, X’ and each dashed line are respectively as defined in any one of claims 1 to 61. The metal complex according to item 85, wherein the complex is a pharmaceutically acceptable salt thereof. The metal complex according to any one of items 1 to 82, wherein the metal complex is according to any one of the complexes shown in Table A in the section “A metal complex”. A compound of formula III, (formula III), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof wherein R1, R2, R2’ R3, X, X’, n, and each dashed line, are respectively as defined in item 1. The compound according to item 88, wherein the compound is according to formula Illa, (formula Illa), wherein R1, R2, R2’, R4, R4’, X, X’, n, and each dashed line are respectively as defined in item 3.

[0358] 90. The compound according to any one of items 88 to 89, wherein X and X’, are as defined in any one of items 14 to 22.

[0359] 91 . The compound according to any one of items 88 to 90, wherein R1is as defined in any one of items 24 to 32.

[0360] 92. The compound according to any one of items 88 to 90, wherein R1is -COOH, -CO(NH2).

[0361] 93. The compound according to any one of items 88 to 90, wherein R2, R2’, R4, and R4’ are each as defined in any one of items 33 to 61 .

[0362] 94. The compound according to item 93, wherein R2, R2’, R4, and R4’, are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, or heteroaryl.

[0363] 95. The compound according to item 93, wherein R2and R2’, are each individually H, or phenyl.

[0364] 96. The compound according to item 93, wherein R4and R4’, are each individually H, or phenyl.

[0365] 97. The compound according to any one of items 88 to 90, wherein the compound is according to any one of formulas llla-1 , llla-2, or llla-3:

[0366]

[0367] Formula llla-3 wherein R1, R2, R2’, R4, R4’, X, X’, and n are respectively as defined in any one of items 24 to 61.

[0368] 98. The compound according to any one of items 88 to 97, wherein one of R1, R2, R2’, R4, or R4’ is -L-RT. 99. The compound according to any one of items 88 to 97, wherein two of R1, R2, R2’,

[0369] R4, or R4’ are -L-RT.

[0370] 100. The compound according to any one of items 88 to 97, wherein the compound is according to any one of formulas lllb-1 , lllb-2, lllb-3, lllb-4, or lllb-5:

[0371] Formula lllb-1 Formula lllb-2

[0372]

[0373] Formula lllb-5 wherein R1, R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of items 24 to 61.

[0374] 101. The compound according to any one of items 88 to 100, wherein RTis a peptide, an antibody, or an antigen-binding fragment thereof.

[0375] 102. The compound according to any one of items 88 to 101 , wherein RTbinds a receptor which is overexpressed in cancer, particularly in glioblastoma.

[0376] 103. The compound according to any one of items 88 to 102, wherein RTbinds the epidermal growth factor receptor (EGFR).

[0377] 104. The compound according to any one of items 88 to 100, wherein RTbinds to low- density lipoprotein receptor-related protein 1 (LRP1).

[0378] 105. The compound according to item 104, wherein RTis a peptide from the angiopep family, particularly angiopep-2. 106. The compound according to any one of items 104 to 105, wherein RTcomprises or consist of:

[0379] TFFYGGSRGKRNNFKTEEY (SEQ ID NO.:1)

[0380] 107. The compound according to any one of items 104 to 106, wherein the compound is according to formula I lie: l_— TFFYGGSRGKRNNFKTEEY (SEQ ID NO.: 1 ) (formula II Ic) or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof wherein R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of items 1 to 61 .

[0381] 108. The compound according to any one of items 88 to 102, wherein wherein RTbinds to prostate-specific membrane antigen (PSMA) on prostate cancer cells. 109. The compound according to item 108, wherein the compound is according to formula lllc-1 :

[0382] (formula lllc-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein L is linker as defined herein

[0383] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of items 1 to 61.

[0384] 110. The compound according to any one of items 88 to 107, wherein L is as defined in any one of items 76 to 82.

[0385] 111. The compound according to any one of items 88 to 108, wherein the compound is according to formula Hid:

[0386] (formula Hid), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof wherein

[0387] R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of items 1 to 61 .

[0388] 112. The compound according to any one of items 88 to 102, and 108 to 109 wherein the compound is according to formula llld-1 :

[0389] (formula 11 Id-1 ), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; wherein

[0390] R1, R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined herein in any of items 1 to 61. 13. The compound according to any one of items 88 to 111 , wherein the compound is according to any one of the compounds shown in Table B in the section “A compound”. 14. A composition comprising the metal complex according to any one of items 1 to 87. 15. The composition according to item 114, wherein the metal complex is formulated in an isotonic saline buffer or PBS buffer. 16. A metal complex according to any one of items 1 to 87, or the composition according to items 114-115, for use as a medicament. 17. A metal complex according to any one of items 1 to 87, or the composition according to items 114-115, for use in the treatment, prevention, or alleviation of cancer in a subject.

[0391] 118. The metal complex or the composition for use according to item 117, wherein the cancer is brain cancer.

[0392] 119. The metal complex or the composition for use according to any one of items 117 to 118, wherein the brain cancer is a brain tumor or an intracerebral neoplasm.

[0393] 120. The metal complex or the composition for use according to item 119, wherein the brain tumor or intracerebral neoplasm involves glial cells. 121. The metal complex or the composition for use according to any one of items 119 to 120, wherein the brain tumor or intracerebral neoplasm is a glioma.

[0394] 122. The metal complex or the composition for use according to item 121 , wherein the intracerebral neoplasm is a high-grade glioma, i.e. grade III or grade IV glioma.

[0395] 123. The metal complex or the composition for use according to item 122, wherein the glioma is astrocytoma, glioblastoma, diffuse midline glioma, diffuse hemispheric glioma, or diffuse paediatric-type high-grade glioma.

[0396] 124. The metal complex or the composition for use according to any one of items 117 to 123, wherein the metal complex or composition is administered intravenously.

[0397] 125. The metal complex or the composition for use according to any one of items 117 to 123, wherein the metal complex or composition is administered by direct intracerebral administration or by intrathecal administration.

[0398] 126. The metal complex or the composition for use according to item 125, wherein the metal complex or composition is administered by convection-enhanced delivery (CED).

[0399] 127. The metal complex or the composition for use according to item 117, wherein the cancer is prostate cancer.

[0400] 128. The metal complex or the composition for use according to item 127, wherein the prostate cancer is a PSMA-positive prostate cancer.

[0401] 129. The metal complex or the composition for use according to any one of items 127 to 128, wherein the prostate cancer is a metastatic prostate cancer, such as metastatic castration-resistant prostate cancer.

[0402] 130. The metal complex for use, or the composition for use according to any one of items 117 to 126, wherein the subject is a mammal.

[0403] 131. The metal complex for use, or the composition for use according to any one of items 117 to 131 , wherein the subject is a human.

[0404] 132. A metal complex according to any one of items 1 to 87, or the composition according to any one of items 114-115, for use in a method of diagnosis of a disease or condition. 133. A method of treatment, prevention or alleviation of cancer, said method comprising administration of a metal complex according to any one of items 1 to 87, or the composition according to any one of items 114-115, to a subject in need thereof.

[0405] 134. Use a metal complex according to any one of items 1 to 87, or the composition according to any one of items 114-115, in the manufacture of a medicament for the treatment, prevention or alleviation of cancer.

[0406] Items A

[0407] A1.A metal complex comprising formula I, (formula I), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0408] M is antimony (Sb) or a radioisotope of Sb, a radioisotope of cobalt (Co), or a radioisotope of bismuth (Bi); each of which may optionally be bound to one or more ligand(s) (Z),

[0409] X and X’ are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, (=0), or aryl;

[0410] R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT; or two R1groups are together forming a cycle; each of which may be optionally substituted;

[0411] R2and R2’ are each individually, -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle; each of which may be optionally substituted;

[0412] R4and R4’ are each individually, -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R4and R4’ are together forming a cycle; each of which may be optionally substituted; each dashed line individually represents a double or a single bond; n is an integer from 0 to 3; Ra, Rb, Rb’ are each individually -H, Ci-Ce alkyl, C3-Ce cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted;

[0413] L is a linker; and

[0414] RTis a targeting moiety.

[0415] A2. The metal complex according to item A1 , wherein the complex is according to formula II, (formula II), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0416] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;

[0417] Z is -OH, H2O, -F, -Cl, -Br, -I, -ORd, -OOCRd, SCN-, OCN-, -CN, NH3, -N(Rd)3, CO, RdCN-, RdNC-, or -P(Rd)3; each instance of Rdis individually selected from an alkyl, cycloalkyl, aryl or heteroaryl group, each of which may be optionally substituted;

[0418] X and X’ are each individually -H, Ci-Ce alkyl, C3-Ce cycloalkyl, (=0), or aryl; R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT; or two R1groups are together forming a cycle; each of which may be optionally substituted;

[0419] R2and R2’ are each individually, -H, Ci-Ce alkyl, C3-Ce cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle; each of which may be optionally substituted;

[0420] R4and R4’ are each individually, -H, Ci-Ce alkyl, C3-Ce cycloalkyl, aryl, heteroaryl, -L-RT, or R4and R4’ are together forming a cycle; each of which may be optionally substituted; each dashed line individually represents a double or a single bond; n is an integer from 0 to 3; Ra, Rb, Rb’ are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted;

[0421] L is a linker; and

[0422] RTis a targeting moiety.

[0423] A3. The metal complex according to any one of items A1 to A2, wherein the complex is according to any one of formula lla-1 to lla-3:

[0424] Formula lla-3 or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein

[0425] Sb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb; and

[0426] Z, R1, R2, R2’, R4, R4’, and n, are each as defined in item 2. A4. The metal complex according to any one of items A1 to A3, wherein Z is -Cl, or - OH.

[0427] A5. The metal complex according to any one of items A1 to A4, wherein X and X’ are -CH3.

[0428] A6. The metal complex according to any one of items A1 to A5, wherein i. R2and R2’ are individually H, Ci-Ce alkyl, such as -CH3, or phenyl; and ii. R4and R4’ are individually H, Ci-Ce alkyl, such as -CH3, or phenyl.

[0429] A7. The metal complex according to any one of items A1 to A6, R2and R4are H; and R2and R4’ are phenyl.

[0430] A8. The metal complex according to any one of items A1 to A7, wherein R1is -H.

[0431] A9. The metal complex according to any one of items A1 to A7, wherein R1is -L-RT, wherein L is a linker and RTis a targeting moiety.

[0432] A10. The metal complex according to item A9, wherein RTcomprises or consists of: TFFYGGSRGKRNNFKTEEY (SEQ ID NO.:1).

[0433] A11 . The metal complex according to any one of items A9 to A10, wherein L comprises or consists of a linear bivalent, saturated or unsaturated, C1-C50 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)- , -NHC(=O)NH-, -NHC(=S)NH-, -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2- , -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle, wherein RL1is selected from the group consisting of C1-C5 alkyl and the moiety ‘A’ comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle. A12. The metal complex according to item A11 , wherein L comprises wherein m is an integer from 1 to 30.

[0434] A13. The metal complex according to any one of items A1 to A12, wherein the metal complex is (9), (10), (11), (12), (13) or (16):

[0435]

[0436] A14. The metal complex according to any one of items A1 to A13, wherein Sb is117Sb, or119Sb.

[0437] A15. A metal complex according to any one of items A1 to A14, for use in the treatment, prevention or alleviation of cancer. Examples

[0438] Equipment

[0439] 1H NMR spectroscopy samples were prepared in deuterated solvents and spectra were recorded on a Bruker Advance III 400 MHz spectrometer or a Jeol JNM-ECZR 500 MHz spectrometer. Data were processed with MestReNova software.

[0440] HRMS spectra were recorded with Electrospray ionisation (ESI) on a Bruker micrOTOFQ II spectrometer (nanospray, capillary temperature = 180 °C, spray voltage = 3.7 kV).

[0441] UV-vis spectra were recorded on an Agilent 8453 spectrophotometer in 1 cm quartz cuvettes across 260-800 nm.

[0442] Crystals used for SCXRD were taken directly from the mother liquor and coated in Fomblin® Y or Paratone oil to allow the crystal to adhere to the mounting loop. The data sets were collected at either 100 K or 298 K on a Synergy, Dualflex, AtlasS2 diffractometer with the CrysAlis PRO suite, using CuKa radiation. The structures were solved by dual space methods (SHELXT85) using Olex2. All the non-hydrogen atoms were refined using anisotropic atomic displacement parameters; hydrogen atoms bonded to carbon were inserted at calculated positions using a riding model, and those bound to O or N were located from difference maps and their coordinates refined.

[0443] Peptide synthesis was carried out in a Liberty Blue™ automated microwave peptide synthesizer, using standard peptide solid-phase coupling protocols based on Fmoc (9- flurorenylmethyl chloroforomate) and tert-butyl (tBu) protecting group chemistry.

[0444] Example 1: Preparation of ligands

[0445] Unless otherwise specified, all the reagents and solvents were obtained from general commercial vendors. Diacetyl nicotinic acid was prepared from previously reported methods [Zhi-Wei et al., 2020],

[0446] 2,6-diacetylpyridine bis(thiosemicarbazone) [H2daptsc] (1)

[0447] Thiosemicarbazide (0.39 g, 4.3 mmol) and diacetylpyridine (0.34 g, 2.1 mmol) were dissolved in ethanol (25 mL) at room temperature and the solution was stirred under reflux for 5 hours. A pale-yellow precipitate formed, which was cooled in ice and filtered and dried under vacuum. The reaction afforded a pale-yellow solid (0.43 g, 66% yield).

[0448] 2,6-diacetylpyridine bis(N4-phenyl-3-thiosemicarbazone) [H2dapbptsc] (2)

[0449] 4-Phenyl-3-thiosemicarbazide (2.05 g, 12.27 mmol) and 2,6-diacetylpyridine (1.00 g, 6.13 mmol) were dissolved in ethanol (50 mL) at room temperature with a few drops of glacial acetic acid. A pale-yellow precipitate formed gradually. The suspension was stirred at reflux for 1 hour, cooled in an ice bath, and filtered, affording a pale-yellow solid (2.03 g, 72% yield).

[0450] 1 H NMR (500 MHz, DMSO-D6) 5 10.71 (s, 2H), 10.23 (s, 2H), 8.58 (d, J = 7.9 Hz, 2H), 7.84 (t, J = 7.9 Hz, 1 H), 7.58 (d, J = 7.2 Hz, 4H), 7.40 (t, J = 7.9 Hz, 4H), 7.24 (t, J = 7.4 Hz, 2H), 2.55 (s, 6H).

[0451] HRMS: calculated m / z = 462.1534, found m / z = 462.1527.

[0452] 2,6-diacetylnicotinic acid bis(thiosemicarbazone) [H2natsc] (3)

[0453]

[0454] Thiosemicarbazide (0.10 g, 1.08 mmol) and 2,6-diacetylnicotinic acid (0.12 g, 0.54 mmol) were dissolved in ethanol (50 mL) at room temperature with a few drops of cone. HCI. A pale-yellow precipitate formed quickly. The suspension was stirred at reflux for 1 hour, cooled in an ice bath, and filtered, affording a pale-yellow solid (0.16 g, 68% yield).

[0455] 1H NMR (500 MHz, DMSO-D6) 5 10.37 (s, 2H), 8.61 (s, 2H), 8.43 (s, 2H), 8.23 (d, J = 4.5 Hz, 2H), 2.45 (s, 6H).

[0456] A crystal structure of 3 was obtained by SC-XRD (Figure 1).

[0457] 2,6-diacetylnicotinic acid bis(N4-phenyl-3-thiosemicarbazone) [H2nabptsc] (4)

[0458] 4-Phenyl-3-thiosemicarbazide (0.32 g, 1.93 mmol) and 2,6-diacetylnicotinic acid (0.2 g, 0.97 mmol) were dissolved in ethanol (50 mL) at room temperature with a few drops of cone. HCI. A pale-yellow precipitate formed quickly. The suspension was stirred at room temperature for 1 hour, cooled in an ice bath, and filtered, affording a pale-yellow solid (0.38 g, 78% yield).

[0459] 1 H NMR (500 MHz, DMSO-D6) 5 10.73 (s, 2H), 10.35 (s, 2H), 8.75 (s, 2H), 7.54 (d, J = 7.5 Hz, 4H), 7.40 (t, J = 8.1 Hz, 4H), 7.24 (t, J = 7.4 Hz, 2H), 2.56 (s, 6H). Ligands 2,6-diacetylpyridine b / s(N4-(4-chlorophenyl)-3-thiosemicarbazone) (17) and

[0460] 2,6-diacetylpyridine b / s(N4-(4-methoxyphenyl)-3-thiosemicarbazone (18) where prepared under similar conditions starting from 4-(4-chlorophenyl)-3-thisemicarbazide and 4-(4-methoxyphenyl)-3-thiosemicarbazie, respectively.

[0461] 2,6-diacetylpyridine mono(thiosemicarbazone) [Hdapmtsc] (5)

[0462] Thiosemicarbazide (0.75 g, 8.16 mmol) in ethanol (10 mL) was added dropwise to a solution of excess diacetylpyridine (2.68 g, 16.54 mmol) in ethanol (25 mL) with a few drops of cone. HCI at room temperature. The solution was stirred under reflux for 1 hour. A pale-yellow precipitate formed, which was cooled in ice, filtered, washed with cold ethanol and dried under vacuum. The reaction afforded a pale-yellow solid (1.65 g, 85% yield).

[0463] 1H NMR (500 MHz, DMSO-D6) 5 10.40 (s, 1 H), 8.70 (dd, J = 8.0, 1.2 Hz, 1 H), 8.47 (s, 1 H), 8.24 (s, 1 H), 7.96 (t, J = 7.9 Hz, 1 H), 7.90 (dd, J = 7.7, 1.2 Hz, 1 H), 2.67 (s, 3H), 2.46 (s, 3H).

[0464] 2,6-diacetylpyridine-(thiosemicarbazone)-(N4-phenyl-3-thiosemicarbazone) [H2daptscptsc] (PhTSC) (6)

[0465] Hdapmtsc (5) (0.064 g, 0.27 mmol) was dissolved in DMF (3 mL). 5 drops of acetic acid were added and the mixture was stirred at room temperature. 4-Phenyl-3- thiosemicarbazide (0.045 g, 0.27 mmol) was added and the reaction was stirred at room temperature for 72 hours. Water was added and a yellow precipitate formed. The precipitate was filtered and dried under vacuum, yielding a pale-yellow solid (0.10 g, 43% yield).

[0466] This ligand is also abbreviated as PhTSC.

[0467] 2,6-diacetylpyridine mono(N4-phenyl-3-thiosemicarbazone) [Hdapmptsc] (7)

[0468] 2,6-Diacetylpyridine (1.00 g, 6.10 mmol) was dissolved in a 4:1 ethanol / water mixture (50 mL). 10 drops of acetic acid were added, and the solution was cooled to 0°C. 4-Phenyl-3-thiosemicarbazide (1.02 g, 6.10 mmol) was dissolved in a 4:1 ethanol / water mixture (100 mL) and added dropwise to the 2,6-diacetylpyridine solution over the course of 1 hour. The reaction was stirred at 0°C for a further hour after addition. A pale-yellow precipitate formed, which was filtered and dried (1.62 g, 81 % yield).

[0469] 1H NMR (500 MHz, DMSO-D6) 5 10.77 (s, 1 H), 10.27 (s, 1 H), 8.83 (dd, J = 8.0, 1.2 Hz, 1 H), 8.01 (t, J = 7.8 Hz, 1 H), 7.95 (dd, J = 7.6, 1.1 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 8.1 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1 H), 2.70 (s, 3H), 2.56 (s, 3H).

[0470] 2,6-diacetylpyridine N4-phenyl-3-thiosemicarbazone N4’-(4-carboxyphenyl)-3- thiosemicarbazone [H2dapptsc-4cptsc] (8) [Hdapmbptsc] (7) (0.50 g, 1.60 mmol) was dissolved in DMF (20 mL). 10 drops of acetic acid were added, and the solution was cooled to 0 °C. 4-(4-carboxyphenyl)-3- thiosemicarbazide (0.34 g, 1.60 mmol) was dissolved in DMF (10 mL) and added dropwise to the Hdapmbptsc solution over the course of 1 hour. After addition, the reaction was allowed to warm to room temperature and stirred overnight. Water was added to the solution until a yellow precipitate formed. The solid was isolated by filtration and washed with ethanol (3 x 20 mL) and diethyl ether (3 x 20 mL). The solid was dissolved in methanol acidified with HCI, and diethyl ether was added to afford a vibrant yellow powder, which was filtered and dried under vacuum (0.32 g, 37% yield).

[0471] 1 H NMR (500 MHz, DMSO-D6) 5 12.89 (s, 1 H), 10.92 (s, 1 H), 10.71 (d, J = 1.8 Hz, 1 H), 10.36 (s, 1 H), 10.23 (s, 1 H), 8.63 - 8.50 (m, 2H), 7.95 (d, J = 8.6 Hz, 2H), 7.86 (t, J = 7.9 Hz, 1 H), 7.82 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1 H), 2.56 (s, 3H), 2.54 (s, 3H).

[0472] Example 2: Preparation of complexes

[0473] Antimony(lll) 2,6-nicotinic acid bis(N4-phenyl-3-thiosemicarbazone) chloride [Sb(nabtsc)CI] (9)

[0474] SbCh (0.048 g, 0.20 mmol) was added to a solution of H2natsc (3) (0.075 g, 0.20 mmol) in methanol (10 mL). The solution immediately turned red. The reaction was stirred at room temperature for 45 minutes. Water was added to the solution, which precipitated a red powder. Antimony(lll) 2,6-diacetylpyridine bis(N4-phenyl-3-thiosemicarbazone) chloride [Sb(nabptsc)CI] (10)

[0475] SbCh (0.15 g, 0.65 mmol) was added to a solution of H2dapbptsc (2) (0.3 g, 0.65 mmol) in ethanol (20 mL). Triethylamine (0.2 mL) was added to promote deprotonation. The solution immediately turned deep-red and a precipitate slowly formed. The reaction was stirred at room temperature for 1 hour. The suspension was cooled in ice, filtered, and dried under vacuum, yielding a deep-red solid (0.31 g, 78% yield).

[0476] 1 H NMR (500 MHz, DMSO-D6) 5 9.65 (m, 2H), 8.33 (t, J = 7.9 Hz, 1 H), 8.19 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.1 Hz, 4H), 7.30 (t, J = 7.7 Hz, 4H), 7.00 (t, J = 7.2 Hz, 2H), 2.67 (s, 6H).

[0477] A crystal structure of 10 was obtained by SC-XRD (Figure 2).

[0478] Antimony(lll) 2,6-diacetylnicotinic acid bis(N4-phenyl-3-thiosemicarbazone) chloride [Sb(nabptsc)CI] (11)

[0479] SbCh (0.045 g, 0.19 mmol) was added to a solution of H2nabptsc (4) (0.075 g, 0.15 mmol) in methanol (10 mL). The solution immediately turned brick-red and a precipitate slowly formed. The reaction was stirred at room temperature for 1 hour. Water was then added to the solution to precipitate any dissolved complex. The precipitate was filtered and dried under vacuum, yielding a red solid. 1 H NMR (500 MHz, DMSO-D6) 5 9.81 (s, 2H), 8.43 (s, 2H), 7.73 (d, J = 7.5 Hz, 4H), 7.31 (t, J = 7.9 Hz, 4H), 7.01 (tt, J = 7.3, 1.1 Hz, 4H), 2.73 (s, 6H).

[0480] A crystal structure of 11 was obtained by SC-XRD (Figure 3).

[0481] Antimony(lll) 2,6-diacetylpyridine bis(thiosemicarbazone) hydroxide [Sb(nabtsc)OH] (12)

[0482] Sb(lll) complex 9 was dissolved in a methanol / water mixture. The methanol evaporated, leaving orange crystals of 12 suspended in water. These were collected and characterized by SC-XRD. The crystal structure is shown in Figure 4.

[0483] Antimony(lll) 2,6-diacetylpyridine bis(N4-phenyl-3-thiosemicarbazone) hydroxide [Sb(nabptsc)OH] (13)

[0484] Sb(lll) complex 10 was dissolved in DMF with HBF4 (50% in water) resulting in the formation of 13 which was characterized by SC-XRD. The crystal structure is shown in Figure 5A. Antimony(lll) 2,6-diacetylpyridine-(thiosemicarbazone)-(N4-phenyl-3- thiosemicarbazone) chloride [Sb(daptscptsc)CI] (14)

[0485] [H2daptscptsc] (6) (0.035 g. 0.09 mmol) was dissolved in ethanol (3 mL). SbCh (0.027 g, 0.12 mmol) was dissolved in ethanol (3 mL) and added dropwise to the ligand solution. The mixture was heated under reflux for 1 hour. The resulting orange solid was collected by filtration (0.048 g).

[0486] Antimony(lll) 2,6-diacetylpyridine b / s(N4-(4-chlorophenyl)-3-thiosemicarbazone) hydroxide (20)

[0487] 2,6-diacetylpyridine b / s(N4-(4-chlorophenyl)-3-thiosemicarbazone) (17) (2.66 g, 5.02 mmol) and SbCh (1.26 g, 5.52 mmol) were mixed in ethanol (25 mL). Triethylamine (0.2 mL) was added, and the solution was stirred for 1 hour. The solvent was evaporated under pressure and the red solid was washed with ethanol (3 x 10 mL). A red solid was obtained (3.17 g, 97% yield). Crystals were obtained by vapor diffusion from DMF / acetone at 5°C. The product was characterized by HRMS, NMR and XRD. The crystal structure is shown in Figure 5B.

[0488] 1H NMR (500 MHz, DMSO-D6) 6 8.88 (s, 2H), 7.51 (dd, J = 8.4, 7.5 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 9.0 Hz, 4H), 6.50 (d, J = 8.9 Hz, 4H), 1.83 (s, 6H).

[0489] Antimony(lll) 2,6-diacetylpyridine b / s(N4-(4-methoxyphenyl)-3- thiosemicarbazone) hydroxide (21)

[0490] 2,6-diacetylpyridine b / s(N4-(4-methoxyphenyl)-3-thiosemicarbazone (18) (0.202 g, 0.387 mmol) and SbCh (0.110g, 0.482mmol) were mixed in ethanol (25 mL). Triethylamine (0.2 mL) was added and the solution was stirred for 1 hour at room temperature. The solvent was evaporated under pressure and the solid was washed with ethanol (3 x 10mL). A red solid was obtained (0.24 g, 93% Yield). Crystals suitable for SC-XRD were obtained by vapor diffusion from DMF / Ethanol at 5°C. Product was characterized by high resolution mass spectrometry (HRMS) and NMR and XRD. The crystal structure is shown in Figure 5C.

[0491] 1H NMR (500 MHz, DMSO-D6) 6 9.49 (s, 2H), 8.32 (dd, J = 8.3, 7.7 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 9.0 Hz, 4H), 6.89 (d, J = 9.1 Hz, 4H), 3.74 (s, 6H), 2.66 (s, 6H).

[0492] Conclusion

[0493] Complexes with Sb(lll) and the ligands of the present disclosure were readily obtained and characterized.

[0494] Example 2A: One-pot synthesis

[0495] Aim

[0496] Formation of the complexes by combining a diacetylpyridine (DAP) precursor, a thiosemicarbazide moiety, and an antimony source in one pot synthesis was studied.

[0497] Materials

[0498] 4-phenylthiosemicarbazide (20 mg) in DMSO (0.5 mL) and diacetylpyridine (20 mg) in DMSO (0.5 mL) was added to a solution of SbCh (1.4 mg) in 2M HCI (5 mL, 1 mmol of SbCh). Upon mixing, the colourless solutions turned immediately orange, which is indicative of antimony complex formation.

[0499] Results

[0500] Upon mixing of the reagents, the colourless solution turned immediately orange, thereby indicating formation of the antimony complex.

[0501] This indicates that the complexes can be prepared with a greater level of modularity by combining different thiosemicarbazide derivatives and diacetylpyridine derivatives.

[0502] Conclusion

[0503] Preparation of the complexes from ligand precursors in one pot synthesis was achieved. Example 3: Test experiments with Sb(lll) complexes using different ligand systems

[0504] Attempts to study Sb(lll) complexes made from pyridyl-mono(thiosemicarbazone) ligands and a source of Sb(lll) (SbCh) showed that said complexes were not stable in most solutions, making them unsuitable for application in radiopharmacy.

[0505] Two different ligands L1 and L2 were studied:

[0506] With L2, different conditions, were attempted using different solvents (methanol, ethanol, and absolute ethanol), with and without acidification, using different temperatures and both 1 :1 and 2:1 molar ratios of Sb(lll) to L2. Under these conditions, no formation of a complex could be observed.

[0507] With L1 , it was possible to isolate a complex. However, said complex proved unstable in solution, dissociating back to their respective ligands upon dissolution. This was confirmed spectroscopically by the orange (characteristic absorption of the antimony complexes) solids turning yellow on dissolution. The complex was unstable in acetone, DCM, chloroform, DMF, DMSO, methanol and ethanol respectively. Further confirmation was obtained through X-ray crystallography, as the resulting yellow solid yielded crystals which confirmed their structure to be that of the free ligands L1 and L2 without complexed Sb(lll).

[0508] Another ligand system studied was the Sb(lll) complex with hydrotris(methimazolyl)borate (TMe) [Dodds et al. 2006], Said system is able to form complexes with Sb(lll), but these are not stable in water above pH 3, and are therefore not applicable for use in radiopharmacy. Conclusion

[0509] Complexes with Sb(lll) and pyridyl-mono(thiosemicarbazone) or TMe proved to have low stability and are therefore not suitable for use in radiopahramacy.

[0510] Example 4: Preparation of peptide-ligand conjugate

[0511] Synthesis of H2nabptsc-PEG2-Angiopep-2

[0512] Fmoc-Tyr(tBu)-functionalized Wang Resin (0.10 mmol) in dimethylformamide (DMF) (10 mL) was loaded into an automated solid-phase peptide synthesizer. The Angiopep-2 peptide was synthesized using standard Fmoc / tBu protocols [Subiros-Funosas et al., 2009], In short, Fmoc deprotection was carried out using 20% piperidine in DMF. Then, amino acid residues were added sequentially using N,N'-Diisopropylcarbodiimide (DIG) and Ethyl cyanohydroxyiminoacetate (Oxyma) coupling reagents in a microwave reactor at 90 °C for 2 minutes. Fmoc-NH-PEG2-CH2COOH was added after Fmoc deprotection of Angiopep-2 and coupled at 50 °C for 10 minutes. After a final Fmoc deprotection step, the resin was removed from the peptide synthesizer. The resin was transferred to a frit- fitted syringe along with DIC / Oxyma, and [FLnabptsc] (4) (0.05 g, 0.1 mmol). The solution was made up to ~8 mL with DMF and agitated at room temperature for 2 hours. The resin was then isolated from the solution and washed with DMF (3 x 5 mL) and dichloromethane (DCM) (3 x 5 mL). The resin was dried under vacuum. Then, a trifluoroacetic acid(TFA) / triisopropylsilane(TIPS) / H2O cleavage cocktail solution (95 / 2.5 / 2.5, 6 mL) was added to the resin, and stirred at room temperature for 90 minutes. The solution was collected in a pre-weighed falcon tube and the resin washed with more cleavage cocktail (4 mL). The solution was reduced under a flow of nitrogen at room temperature. When the solution was < 0.5 mL, diethyl ether (20 mL) was added, which precipitated a pale-yellow solid. The suspension was vortexed, centrifuged, and solvent decanted. Diethyl ether (20 mL) was again added to the solid, and these steps were repeated 5 times. The resultant solid was dried under vacuum yielding a paleyellow powder (0.25 g, 84% yield).

[0513] MALDI: calculated m / z = 2934, found m / z = 2934.

[0514] The MALDI mass spectrum of H2nabptsc-PEG2-Angiopep-2 is shown in Figure 6.

[0515] Example 5: Radiolabelling

[0516] Aim

[0517] To obtain radiolabeled Sb(lll)-ligand complexes by complexing purified radioantimony with any ligand according to the present disclosure.

[0518] Materials and Methods

[0519] 119Sb was produced via the119Sn(p,n)119Sb nuclear reaction and117Sb was produced via the117Sn(p,n)117Sb nuclear reaction as described in literature. The desired1xxSb was produced via the1xxSn(p,n)1xxSb nuclear reaction using naturalNatSn. The targets were prepared by electroplatingNatSn on a rhodium backing (diameter of 28 mm and thickness of 1 mm) or silver backing (diameter of 30 mm and thickness of 5 mm) as described previously [Thisgaard & Jensen, 2008], The electroplated tin targets were mounted in an irradiation capsule and pneumatically transferred to the cyclotron using the ARTMS QLIANTM Irradiation System® (“QIS”, ARTMS, Vancouver, Canada) on a GE PETtrace Cyclotron. The GE PETtrace cyclotron was equipped with a GE aluminium energy degrader of 0.8 or 0.5 mm, reducing the proton beam energy to either -10.8 MeV or -13.1 MeV.NatSn targets were irradiated with either 10.8 or 13.1 MeV proton beams with a beam current of 20 pA for 60-90 min. Dissolution of irradiated tin targets and radiochemical separation of1xxSb from the target material was performed as described previously [Thisgaard & Jensen, 2009],

[0520] Compound 6 (PhTSC) dissolved in DMSO was added to the 0.8M HCI solution containing radioactive Sb and the mixture was allowed to react for 10 min at room temperature. Results

[0521] The radiolabelling of 6 (PhTSC) was indirectly confirmed by the formation of a reddish radioactive precipitate in suspension. The precipitate was centrifuged for 10 min and a radioactive pellet was obtained. This pellet was subsequently washed with Milli-Q water (3 x 2 mL) and the wash water was found to be free of any radioactive element, only the pellet remaining radioactive.

[0522] This result is consistent with those obtained using non-radioactive Sb and with the published literature on other antimony complexes.

[0523] Conclusion

[0524] Radiolabeled Sb(lll) complexes from purified radioantimony and compounds according to the present disclosure have been successfully prepared following the presented method.

[0525] Example 6: pH stability

[0526] Aim

[0527] To determine the pH-range within which Sb(l I l)-ligand complexes according to the present disclosure are stable.

[0528] Materials and Methods

[0529] 2.5 mg of (11) was dissolved in a 1 :1 dimethylsulfoxide (DMSO) / water mixture (100 mL). 1 M HCI was added until the pH was ~1. 10M NaOH was then added in 10 pL portions, and a UV / vis spectrum was recorded at various pH values. When close to equivalence point, saturated NaHCCh was instead used to titrate. The stability of 11 was monitored by the change in absorption at specific wavelengths as a function of pH.

[0530] The 24-hour stability of complex 11 was examined at pH 7.4. Here, 2.5 mg of (11) was dissolved in a DMSO / water mixture (100 mL). Then, the pH was adjusted to 7.4 with saturated NaHCCh solution. A UV / vis spectrum was immediately recorded, and then another spectrum was recorded after 24 hours.

[0531] Results

[0532] The absorption of 11 at 330, 370, and 470 nm as a function of pH is shown in Figure 7. Complex 11 was identified to be stable within the pH-range within which the absorbance at 330, 370, and 470 nm is stable. As shown in Figure 7, this range is approximately from pH = 3.5 - 12.

[0533] The UV / vis spectra of complex 11 at pH = 7.4 recorded at 0 hours and 24 hours after preparation are shown in Figure 8. The lack of change in absorption, as evident from the two overlaid spectra, confirms the stability of complex 11 at pH 7.4 and within this time frame.

[0534] Conclusion

[0535] Sb(l I l)-ligand complexes as prepared in Example 2 are stable within a pH-range of 3.5 - 12.

[0536] Example 6A: Further stability studies

[0537] Materials and Methods

[0538] The complexes were individually dissolved in a 9:1 DMSO / PBS buffer solution (pH 7.4). A UV / vis spectrum was recorded immediately, and again every 24 hours for 3 days. The compounds tested were 11 , 20 and 21.

[0539] Results

[0540] Complexes were retained in all tests for up to 72 hours in the studied conditions. Partial dissociation of the complex into ligand was observed for complexes 20 and 21 , while complex 11 was the most stable in the studied conditions with almost 100% complex retained after 72 hours. The UV-vis spectra are shown in Figure 10.

[0541] Conclusion

[0542] The stability of Sb(lll) complexes at relevant pH conditions was confirmed.

[0543] Example 7 Transmetallation study

[0544] Aim

[0545] To determine the stability of the complexes towards transmetallation with other metal ions.

[0546] Materials and Methods

[0547] Complex 10 (6 mg, 0.01 mmol) was dissolved in 9:1 DMSO / water solution (100 mL). 10 mL portions were taken, and either 1 or 2 equivalents of Ca(NC>3)2.4H2O, MgCh.6H2O or ZnCh were added. The solutions were allowed to stand at room temperature for 24 hours. Then, HRMS and UV / vis spectra were recorded for each of the solutions to probe for the occurrence of transmetallation.

[0548] Results HRMS showed no evidence of transmetallation with Ca2+or Mg2+using Ca(NC>3)2.4H2O or MgCh.6H2O, respectively. HRMS showed a small degree of transmetallation with Zn2+using ZnCh. The HRMS for (10) doped with 2 equivalents of ZnCh is shown in the ESI mass spectrum in Figure 9.

[0549] The UV / vis spectra of all solutions showed no change in curve shape detected for any of the solutions.

[0550] Conclusion

[0551] The Sb(lll)-ligand complexes according to the present disclosure are stable towards transmetallation with Ca2+, Mg2+, and Zn2+. Example 8: Preparation of PSMA-ligand conjugate and complex formation

[0552] The preparation of Sb(lll)-complexes with a prostate cancer target moiety is described below. The PSMA targeting moiety used is based on the same moiety used in known DOTA-based chelator vipivotide tetraxetan (also known as PSMA-617). Preparation of diacetylpyridine pentafluorphenylester (DAP-PFP) precursor Diacetylnicotinic acid (DANA, 0.2 g, 1 mmol) was dissolved in dichloromethane (DCM, 10 mL) with pentafluorophenol (PFP, 0.18 g, 1 mmol). N,N'-Dicyclohexylcarbodiimide (DCC, 0.2 g, 1 mmol) in DCM (5 mL) was added dropwise to the mixture and a precipitate slowly formed. The reaction was stirred at room temperature for 1 hour, whereby thin- layer chromatography (TLC) showed a complete reaction. The precipitate was removed by vacuum filtration and the solvent was removed from the filtrate. The crude product was recrystallised from hot ethyl acetate, leaving diacetylpyridine pentafluorophenylester (DAP-PFP) as a white solid (0.25 g, 67% yield).

[0553] Preparation of di acetyl pyridine with PSMA targeting moiety (DAP-PSMA)

[0554] DAP-PFP (10 mg) and PSMA-precursor (17.6 mg, (((S)-5-((S)-2-((1r,4S)-4- (aminomethyl)cyclohexane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)-1- carboxypentyl)carbamoyl)-L-glutamic acid) was dissolved in DMF (2 mL). N,N-Diisopropylethylamine (DIPEA, 4.67 pL) in dimethylformamide (DMF, 100 pL) was added. The reaction was stirred at room temperature for 2 days. Cold diethyl ether (10 mL) was added to the solution and a white powder precipitated. The precipitate was centrifuged (4000 rpm for 3 minutes), solvent decanted, and more cold diethyl ether (5 mL) was added. This step was repeated 5 times to ensure removal of all DMF. The product was dried under a flow of nitrogen, leaving a white powder (20 mg, 88% yield).

[0555] Characterization by MALDI (m / z 845.102) confirmed the formation of the desired product.

[0556] Formation of PSMA-ligand conjugate (19) and complex formation

[0557] Conjugation of DAP-PSMA with 4-Phenyl-3-thiosemicarbazide preformed in analogous conditions as described in Example 1. Briefly, DAP-PSMA (10 mg) and 4-phenyl-3- thiosemicarbazide (4 mg) was dissolved in DMF (0.5 mL). HCI (3 M, 15 pL) was added and the solution turned yellow. Stirred at room temperature for 1 hour and then analysed using MALDI. The formation of PSMA-ligand conjugate 19 was confirmed by MALDI, where it was seen the major signal of m / z 1144.716 expected for C57H67N12O10S2T

[0558] Subsequently, formation of Sb(lll) complex starting from ligand 19 was confirmed qualitatively by the formation of the expected deep red color upon mixing the chelator with antimony chloride. References

[0559] Filosofov D, Kurakina E, Radchenko V. Potent candidates for Targeted Auger Therapy: Production and radiochemical considerations. Nuclear Medicine and Biology. 2021 ;94- 95:1-19.

[0560] Thisgaard H, Jensen M. 119Sb--a potent Auger emitter for targeted radionuclide therapy. Med Phys. 2008;35(9):3839-46.

[0561] Ku A, Facca VJ, Cai Z, Reilly RM. Auger electrons for cancer therapy - a review. EJNMMI Radiopharmacy and Chemistry. 2019;4(1):27.

[0562] Chen C, Sommer C, Thisgaard H, McKee V, McKenzie CJ. Facile transmetallation of [SbIH(DOTA)]- renders it unsuitable for medical applications. RSC Advances.

[0563] 2022; 12(10):5772-81.

[0564] Brahmachari UN. Chemotherapy of antimonial compounds in kala-azar infection. Part IV. Further observations on the therapeutic values of urea stibamine. By U.N.

[0565] Brahmachari, 1922. Indian J Med Res. 1989;89:393-404.

[0566] Haidar AK, Sen P, Roy S. Use of Antimony in the T reatment of Leishmaniasis: Current Status and Future Directions. Molecular Biology International. 2011 ;2011:571242.

[0567] Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, et al. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Am J Trop Med Hyg. 2017;96(1):24-45.

[0568] Thakur ML, Clark JC, Silvester DJ. The Production of 117Sb-labelled potassium antimonyl tartrate for medical use. The International Journal of Applied Radiation and Isotopes. 1970;21(1):33-6.

[0569] Sun H, Yan SC, Cheng WS. Interaction of antimony tartrate with the tripeptide glutathione. European Journal of Biochemistry. 2000;267(17):5450-7.

[0570] Olson AP, Ma L, Feng Y, Najafi Khosroshahi F, Kelley SP, Aluicio-Sarduy E, et al. A Third Generation Potentially Bifunctional Trithiol Chelate, Its nat,1XXSb(lll) Complex, and Selective Chelation of Radioantimony (119Sb) from Its Sn Target. Inorganic Chemistry. 2021 ;60(20): 15223-32. Thisgaard H, Jensen M. Production of the Auger emitter 119Sb for targeted radionuclide therapy using a small PET-cyclotron. Applied Radiation and Isotopes. 2009;67(1):34-8.

[0571] Li, Zhi-Wei; Wang, Xin; Wei, Lian-Qiang; Ivanovic-Burmazovic, Ivana; Liu, Gao-Feng [Journal of the American Chemical Society, 2020, vol. 142, # 16, p. 7283 - 7288]

[0572] Dodds CA, Reglinski J, Spicer MD. Lower Main-Group Element Complexes with a Soft Scorpionate Ligand: The Structural Influence of Stereochemically Active Lone Pairs. Chemistry - A European Journal. 2006;12(3):931-9.

[0573] R. Subiros-Funosas, R. Prohens, R. Barbas, A. El-Faham and F. Albericio, Oxyma: An Efficient Additive for Peptide Synthesis to Replace the Benzotriazole-Based HOBt and HOAt with a Lower Risk of Explosion Chem. - Eur. J., 2009, 15, 9394.

Claims

1. Claims1 . A metal complex or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof, wherein the metal complex comprises formula I(formula I), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, whereinM is antimony (Sb) or a radioisotope of Sb, optionally bound to one or more ligands (Z);R2and R2’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle, each of which may be optionally substituted;R4and R4’ are each individually, H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, -L-RT, or R4and R4’ are together forming a cycle, each of which may be optionally substituted;X and X’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, (=0), or aryl;R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT, or two R1groups are together forming a cycle, each of which may be optionally substituted; n is an integer from 0 to 3; each dashed line individually represents a double or a single bond;Ra, Rb, Rb’, are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT, each of which may be optionally substituted;L is a linker; and RTis a targeting moiety.

2. The metal complex according to claim 1 , wherein M is Sb, such as121Sb,123Sb, 117Sb,119Sb, or any combination thereof.

3. The metal complex according to any one of claims 1 or 2, wherein M is a radioisotope of Sb.

4. The metal complex according to claim 3, wherein M is117Sb, and / or119Sb.

5. The metal complex according to any one of the preceding claims, wherein the complex is according to formula IItautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;Z is -OH, H2O, -F, -Cl, -Br, -I, -ORd, -OOCRd, SCN-, OCN-, -CN, NH3, -N(Rd)3, CO, RdCN-, RdNC-, or -P(Rd)3; each instance of Rdis individually selected from an alkyl, cycloalkyl, aryl or heteroaryl group, each of which may be optionally substituted;X and X’ are each individually -H, Ci-Ce alkyl, C3-Ce cycloalkyl, (=0), or aryl;R1is -H, halogen, -COORa, -CON(Rb)(Rb), Ci-C6alkyl, C3-C6cycloalkyl, aryl, -L-RT; or two R1groups are together forming a cycle; each of which may be optionally substituted;R2and R2’ are each individually, -H, Ci-Ce alkyl, C3-Ce cycloalkyl, aryl, heteroaryl, -L-RT, or R2and R2’ are together forming a cycle; each of which may be optionally substituted;R4and R4’ are each individually, -H, Ci-Ce alkyl, C3-Ce cycloalkyl, aryl, heteroaryl, -L-RT, or R4and R4’ are together forming a cycle; each of which may be optionally substituted; each dashed line individually represents a double or a single bond; n is an integer from 0 to 3;Ra, Rb, Rb’ are each individually -H, Ci-Ce alkyl, C3-Ce cycloalkyl, aryl, heteroaryl, or-L-RT, each of which may be optionally substituted;L is a linker; andRTis a targeting moiety.1.

6. The metal complex according to claim 5, wherein Z is -Cl or -OH.

7. The metal complex according to any one of claims 1 to 6, wherein X and X’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, or (=0).

8. The metal complex according to any one of claims 1 to 6, wherein X and / or X’ areCi-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl, each of which may be optionally substituted.

9. The metal complex according to any one of claims 1 to 6, wherein X and / or X’ are CH3.

10. The metal complex according to any one of claims 1 to 6, wherein X and X’ are the same.11 . The metal complex according to any one of claims 1 to 6, wherein the metal complex is according to any one of formulas lla-1 , lla-2, or lla-3:Formula lla-2Formula lla-1Formula lla-3 or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof, whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb; andZ, R1, R2, R2’, R4, R4’, n, are each as defined in claim 1.

12. The metal complex according to any one of claims 1 to 11 , wherein R1is halogen, -COORa, -CON(Rb)(Rb), Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, two R1are together forming a forming a cycle, or -L-RT.

13. The metal complex according to any one of claims 1 to 11 , wherein R1is H.

14. The metal complex according to any one of claims 1 to 11 , wherein R1is -L-RT.

15. The metal complex according to any one of claims 1 to 11 , wherein R1is Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3 , or C4 alkyl, each of which may be optionally substituted.

16. The metal complex according to any one of claims 1 to 11 , wherein R1is C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

17. The metal complex according to any one of claims 1 to 11 , wherein R1is -COORa, or -CON(Rb)(Rb), wherein Ra, Rb, Rb’, are each individually -H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl.

18. The metal complex according to claim 17, wherein R1is -COOH or -CONH2.

19. The metal complex according to any one of claims 1 to 18, wherein n is 1.

20. The metal complex according to any one of claims 1 to 19, wherein the metal complex is according to any one of formulas lla-4, lla-5, lla-6:Formula lla-6 or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;Z, R1, R2, R2’, R4, R4’ X, X’ and each dashed line are each respectively as defined in any one of claims 1 to 20.21 . The metal complex according to any one of claims 1 to 20, wherein R2, R2’, R4and R4’ are each individually H, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or -L-RT.

22. The metal complex according to any one of claims 1 to 20, wherein R2and / or R2’ are each individually Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3, or C4 alkyl.

23. The metal complex according to any one of claims 1 to 20, wherein R2and / or R2’ are -CH3.

24. The metal complex according to any one of claims 1 to 20, wherein R2and / or R2’ are aryl or heteroaryl.

25. The metal complex according to claim 24, wherein R2and R2, whereinReis selected from halogen and alkoxy, preferably Reis Cl or -O-CH3.

26. The metal complex according to any one of claims 1 to 20, wherein R2and / or R2’ are phenyl.

27. The metal complex according to any one of claims 1 to 20, wherein R2and R2’ are each individually C3-C6 cycloalkyl, such as C3, C4, C5, or Ce cycloalkyl.

28. The metal complex according to any one of claims 1 to 20, wherein R2and R2’are the same.

29. The metal complex according to any one of claims 1 to 28, wherein R4and / or R4’ are each individually Ci-Ce alkyl, such as C1-C4 alkyl, such as Ci , C2, C3, or C4 alkyl.

30. The metal complex according to any one of claims 1 to 28, wherein R4and / or R4’ are -CH3.

31. The metal complex according to any one of claims 1 to 28, wherein R4and / or R4’ are aryl or heteroaryl.

32. The metal complex according to any one of claims 1 to 28, wherein R4and / or R4’ are, wherein Rfis selected from halogen and alkoxy, preferably RfisCl or -O-CH3.

33. The metal complex according to any one of claims 1 to 28, wherein R4and / or R4’ are phenyl.

34. The metal complex according to any one of claims 1 to 28, wherein R4and R4’are the same.

35. The metal complex according to any one of claims 1 to 34, wherein one of R1, R2,R2, R4, or R4is -L-RT36. The metal complex according to any one of claims 1 to 34, wherein the metal complex is according to any one of formulas llb-1 , llb-2, llb-3, llb-4, or llb-5:Formula llb-4Formula llb-3Formula llb-5 or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof; whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;L is a linker,RTis a targeting moiety, andZ, R1, R2, R2’, R4, R4’, X, X’, n and each dashed line are respectively as defined in any one of claims 1 to 34.

37. The metal complex according to any one of claims 1 to 36, wherein RTis a peptide, an antibody, or an antigen-binding fragment thereof.

38. The metal complex according to claim 37, wherein RTbinds to a cell surface protein, such as a receptor.

39. The metal complex according to any one of claims 36 to 38, wherein RTbinds to a cell surface protein, such as a receptor which is overexpressed in cancer, particularly in glioblastoma.

40. The metal complex according to any one of claims 36 to 39, wherein RTbinds to the epidermal growth factor receptor (EGFR).41 . The metal complex according to any one of claims 1 to 38, wherein RTbinds to low-density lipoprotein receptor-related protein 1 (LRP1).

42. The metal complex according to claim 41 , wherein RTis a peptide from the angiopep family, particularly angiopep-2.

43. The metal complex according to any one of claims 41 to 42, wherein RTcomprises or consist of:TFFYGGSRGKRNNFKTEEY (SEQ ID NO.:1)44. The metal complex according to any one of claims 41 to 43, wherein the metal complex comprises formula lie:l_— TFFYGGSRGKRNNFKTEEY (SEQ ID NO. : 1 ) (formula I Ic) or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119SbL is a linker, andR2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of claims 1 to 34.

45. The metal complex according to any one of claims 1 to 37, wherein RTbinds to prostate-specific membrane antigen (PSMA) on prostate cancer cells.

46. The metal complex according to claim 45, wherein RTconsists of47. The metal complex according to any one of claims 45 to 46, wherein the metal complex comprises formula llc-1(formula llc-1), or an isomer, stereoisomer, tautomer, acid-base form thereof; or a pharmaceutically acceptable salt thereof; whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119SbL is a linker, andR2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of claims 1 to 34.

48. The metal complex according to any one of claims 1 to 47, wherein L comprises or consists of a linear bivalent, saturated or unsaturated, C1-C50 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)- , -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, -S-, -S(=O)-, -S(=O)2- , -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle,whereinRL1is selected from the group consisting of C1-C5 alkyl and the moiety ‘A’ comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle.

50. The metal complex according to any one of claims 48 to 49, wherein L comprises, wherein m is an integer from 1 to 30.51 . The metal complex according to any one of claims 48 to 50, wherein L comprises or consists of:, wherein m is an integer from 1 to 30.

52. The metal complex according to any one of claims 48 to 51 , wherein m is an integer from 1 to 20, or 1 to 10.

53. The metal complex according to any one of claims 48 to 52, wherein L comprises or consists54. The metal complex according to any one of claims 48 to 53, wherein the metal complex is according to formula lid:(formula lid), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;Z, R2, R2’, R4, R4’, X, X’ and each dashed line are respectively as defined in any one of claims 1 to 34.

55. The metal complex according to any one of claims 1 to 54, wherein the complex is:; or a pharmaceutically acceptable salt thereof.

56. The metal complex according to any one of claims 1 to 47, wherein the metal complex is according to formula lld-1 :(formula lld-1), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof; whereinSb is an isotope of antimony such as121Sb,123Sb,117Sb, or119Sb, or any combination thereof; preferably117Sb, or119Sb;Z, R2, R2’, R4, R4’, X, X’ and each dashed line are respectively as defined in any one of claims 1 to 34.

57. The metal complex according to any one of claims 1 to 56, wherein the metal complex is according to any one of(22); or a pharmaceutically acceptable salt thereof.

58. A compound according to any one of any one of formulas lllb-1, lllb-2, lllb-3, lllb-4, or lllb-5:Formula lllb-4Formula lllb-3Formula lllb-5 whereinL is a linker,RTis a targeting moiety that binds to a cell surface protein, such as a receptor; andR1, R2, R2’, R4, R4, X, X’, and each dashed line are respectively as defined in any one of claims 1 to 34.

59. The compound according to claim 58, wherein RTis as defined in any one of claims 37-43, and 45-46.

60. The compound according to any one of claims 58 to 59, wherein the compound is according to formula I lie or lllc-1 :(formula 11 lc-1 ), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof; whereinR2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of claims 1 to 34.61 . The compound according to any one of claims 58 to 60, wherein L is as defined in any one of claims 48 to 53.

62. The compound according to any one of claims 58 to 61 , wherein the compound is according to formula Hid or llld-1 :a11 Id-1), or an isomer, stereoisomer, tautomer, acid-base form thereof, or a pharmaceutically acceptable salt thereof; whereinR1, R2, R2’, R4, R4’, X, X’, and each dashed line are respectively as defined in any one of claims 1 to 34.

63. The compound according to any one of claims 58 to 62, wherein the compound is64. A composition comprising the metal complex according to any one of claims 1 to57.

65. The composition according to claim 64, wherein the metal complex is formulated in an isotonic saline buffer or PBS buffer.

66. A metal complex according to any one of claims 1 to 57, or the composition according to claims 64 to 65, for use as a medicament.

67. A metal complex according to any one of claims 1 to 57, or the composition according to claims 64 to 65, for use in the treatment, prevention, or alleviation of cancer in a subject.

68. The metal complex or the composition for use according to claim 67, wherein the cancer is brain cancer.

69. The metal complex or the composition for use according to any one of claims 67 to 68, wherein the brain cancer is a brain tumour or an intracerebral neoplasm.

70. The metal complex or the composition for use according to any one of claims 67 to 69, wherein the metal complex or composition is administered intravenously.71 . The metal complex or the composition for use according to claim 70, wherein the metal complex or composition is administered by convection-enhanced delivery (CED).

72. The metal complex or the composition for use according to claim 67, wherein the cancer is prostate cancer.

73. The metal complex or the composition for use according to claim 72, wherein the prostate cancer is a PSMA-positive prostate cancer.

74. The metal complex or the composition for use according to any one of claims 67 to 73, wherein the subject is a mammal.

75. The metal complex or the composition for use according to any one of claims 67 to 74, wherein the subject is a human.

76. A metal complex according to any one of claims 1 to 57, or the composition according to any one of claims 64 to 65, for use in a method of diagnosis of a disease or condition.

77. A method of treatment, prevention or alleviation of cancer, said method comprising administration of a metal complex according to any one of claims 1 to 57, or the composition according to any one of claims 64 to 65, to a subject in need thereof.

78. Use a metal complex according to any one of claims 1 to 57, or the composition according to any one of claims 64 to 65, in the manufacture of a medicament for the treatment, prevention or alleviation of cancer.

Images