Targeted radioligand compounds and uses thereof

Abstract

The present disclosure provides a compound comprising a radiolabeling moiety, a targeting moiety, and a DNA intercalating agent and complexes thereof For example, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof. Methods of making and uses thereof, such as cancer theranostic applications, are also included. (I)

Description

TARGETED RADIOLIGAND COMPOUNDS AND USES THEREOFRELATED APPLICATIONS

[0100] The present application claims the benefit of priority of co-pending United States provisional patent application no. 63 / 569,534 filed on March 25, 2024 the contents of which are incorporated herein by reference in their entirety.FIELD

[0101] The present disclosure relates to the field of radiopharmaceuticals, and in particular, to targeted radioligand compounds and methods of making and uses thereof.BACKGROUND

[0102] Prostate cancer (PC) accounts for 29% of all cancer cases among men and is the second most common cancer after breast cancer, thus stimulating a large academic interest for its therapeutic development.1

[0103] Apart from traditional cancer therapies, targeted radiotherapy (TRT) has emerged as a promising new strategy for targeted cancer treatment.177Lu-PSMA-617 (Pluvicto®), a PC targeting radiopharmaceutical, has recently been approved by the FDA, demonstrating the potential of TRT for PC treatment.2It consists of two primary parts:177Lu, a therapeutic [3 -emitting radioisotope; and glutamate-ureido-lysine (GUL).34GUL is a prostate specific membrane antigen (PSMA) antagonist, which allows GUL based compounds to target and localize in PC tissue.5Interestingly, it has been found that GUL can additionally identify PSMA-negative PC tumours by targeting alternative, PSMA-like targets that may be expressed over the disease’s progression, making it a powerful targeting probe.6PSMA is a transmembrane protein that functions as an ideal target because it can be 100-1 ,000 times overexpressed in PC tissues — with limited expression in non-PC tissues — and it naturally undergoes clathrin mediated endocytosis.47-9Through endocytosis, PSMA can internalize bound ligands; it is also reported that the binding of PSMA to ligands can increase the rate of PSMA internalization, thus making PSMA an effective target for PC therapy.10’11

[0104] Auger-emitting TRT shows promising potential as a novel therapeutic strategy for cancer treatment.4Similar to Pluvicto®,125l-DCIBzL is a pre-clinical drug which makes use of the Auger-emitting radioisotope,125l, as an alternative to177Lu. Auger-emission refers to the low energy electrons released from radioisotopes which decay by electron capture or internal conversion often leading to a cascade of emitted Auger electrons, such as in the case of125l.12These Auger electrons have very short emission ranges — of less than 10 pm and often within nanometers ranges — allowing for a high linear energy transfer and extremely limited damage to neighbouring cells.4 13 14Over its decay and subsequent relaxation,125l releases an average of 13.3 electrons,79% of which with energies below 400 eV, in addition to one gamma photon at 35.5 keV.12In contrast,177Lu emits high energy, 497 keV, electrons with high penetration depths of 670 pm that can damage surrounding healthy tissue, leaving125l as a safer option.3The high linear energy transfer of Auger electrons are more conducive to double-stranded DNA breaks when compared to P- particles; however, it is reported that Auger-emitters cause very little cellular damage compared to p -emitters unless directly near the DNA due to their severely limited range.4 15 16

[0105] To circumvent this issue, radiolabeling a DNA intercalator, like acridine orange, with an Auger-emitting radioisotope has demonstrated significant nuclear uptake and localization to cell DNA inducing higher yields of double-stranded breaks and greater cytotoxicity.14 16DNA intercalators like acridine orange place themselves within the DNA superstructure between nucleotide pairs.17Such intercalators are polyaromatic and planar, taking advantage of the favourable electrostatic interaction between aromatic pi systems — also known as TT-TT stacking — allowing them to be retained within the DNA.18This interaction can be used to “anchor” an Augeremitting radioisotope to the DNA and increase their cytotoxicity.

[0106] The combination of a radioligand with a DNA intercalator been shown using99mTc, however,99mTc is a poor Auger electron emitter for TRT due to its relatively low Auger electron yield19and are only suited for imaging applications.

[0107] Alternative radioligands that can be used with p -emitting and / or Auger emitting therapeutic radioisotopes are needed in the field of TRT.

[0108] The background herein is included solely to explain the context of the disclosure. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge as of the priority date.SUMMARY

[0109] The present application includes compound comprising a radiolabeling moiety, a targeting moiety, and a DNA intercalating agent.

[0110] The present application also includes a compound of Formula I,RL - LRL- LinkerwhereinDI is DNA intercalating agent;TM is a targeting moiety;RL is a radiolabeling moiety; and- is a central linker,LRL, LDIand LTMare independently selected from a direct bond and a spacer linker, or a pharmaceutically acceptable salt and / or solvate thereof.

[0111] The present application also includes a radioisotope complex or a pharmaceutically acceptable salt and / or solvate thereof, comprising a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof and a radioisotope.

[0112] The present application also includes a pharmaceutical composition comprising a compound of Formula I or a complex thereof with a radioisotope or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

[0113] The present application also includes a method of treating a disease, disorder or condition comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof, wherein the disease, disorder or condition is cancer.

[0114] The present application also includes a method of imaging a tissue in a subject in need thereof by administering an imaging effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to the subject and applying an imaging technique to detect emitted radiation.

[0115] The present application also includes a method of diagnosing cancer in subject by administering a diagnostic effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof and applying an imaging technique to detect emitted radiation.

[0116] The present application also includes a method of theranostic treatment comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof and performing a medical diagnostic method on the subject.

[0117] In an embodiment, the present application comprises, consists or consists essentially of the stated features, elements, components, groups, integers, and / or steps.

[0118] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the disclosure, are given by way ofillustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole.DRAWINGS

[0119] Certain embodiments of the disclosure will now be described in greater detail with reference to the attached drawings in which:

[0120] Figure 1 shows an ESI+ MS spectrum of purified PSMA-Glu-DOTA (C-1) in an exemplary embodiment of the disclosure.

[0121] Figure 2 shows an HPLC analysis of free68Ga (top) and the crude [68Ga]Ga-PSMA- Glu-DOTA (bottom) of a reaction perform with 100pg of precursor in exemplary embodiments of the disclosure. Crude sample taken prior to Sep-Pak reformulation. Solvent A: H2O (0.1% trifluoroacetic acid (TFA)); Solvent B: ACN (0.1% TFA). Gradient: 0-5 min: 95% A 5% B; 5-22 min: 60% A 40%B; 22-30 min: 5% A 95% B; 30-33 min: 95% A 5% B. Column Gemini Analytical C18, 250x4.6mm.

[0122] Figure 3 shows A: Radio-TLC of free68Ga and B: crude sample of [68Ga]Ga-PSMA- Glu-DOTA after 20min reaction (reaction perform with 100pg of precursor) in exemplary embodiments of the disclosure. Mobile phase: MeOH:NH4OAc (1 :1); Stationary phase: iTLC silica gel plate.

[0123] Figure 4 shows ESI- and ESI+ spectra of the supernatant sample (crudenatGa- PSMA-Glu-DOTA,natGa-C-1) in exemplary embodiments of the disclosure.

[0124] Figure 5 shows an analytical HPLC spectrum of the crudenatGa-PSMA-Glu-DOTA (natGa-C-1) in an exemplary embodiment of the disclosure. The peak corresponding tonatGa-PSMA- Glu-DOTA was collected during several runs and combined, lyophilized and dispensed into 100pg vials for later in vitro studies.

[0125] Figure 6 shows LC-MS DAD and TIC spectra of purifiednatGa-PSMA-Glu-DOTA (natGa-C-1) in exemplary embodiments of the disclosure. The DAD and TIC results are not conclusive of purity. The product was observed very early in the chromatogram when run with formic acid. Similar early retention times were observed by Muskaan when running PSMA-Glu- DOTA with formic acid conditions. In TFA, the retention time was usually around 10min.

[0126] Figure 7 shows a TLC of crude DCIBzL after overnight reaction. Eluent: Hexane:Ethyl acetate (2:1). Silica gel 60. Left: TLC stained with permanganate, Right: UV.

[0127] Figure 8 shows an ESI+MS spectrum of the pure DCIBzL.

[0128] Figure 9 shows an HPLC spectrum of low concentrated sample of DCIBzL precursor.Solvent A: H2O (0.1% TFA); Solvent B: ACN (0.1% TFA). HPLC gradient: 1mL / min. Solvent A:Water + 0.1% Trifluoroacetic acid (TFA), Solvent B: Acetonitrile + 0.1% TFA. Gradient: 0-3 min 95% A, 3-18 min 95-5% A, 18-20 min 5% A, 20.01 - 25min 95% A. Column Gemini Analytical C18, 250x4.6mm.

[0129] Figure 10 shows TLC optimization and analysis of l-DCIBzL. a) Optimization TLC of crude product after overnight reaction. Eluent: Hexane:Ethyl acetate (10:7) was the optimal, b) TLC of deprotected product l-DCIBzL after reaction with TFA. Eluent: Hexane:Ethyl acetate (10:7). Silica gel 60.

[0130] Figure 11 shows HPLC analysis of l-DCIBzL non-radioactive standard. Solvent A: H2O (0.1% TFA); Solvent B: ACN (0.1% TFA). HPLC gradient: 1 mL / min. Solvent A: Water + 0.1% Trifluoroacetic acid (TFA), Solvent B: Acetonitrile + 0.1% TFA. Gradient: 0-3 min 95% A, 3-18 min 95-5% A, 18-20 min 5% A, 20.01 - 25min 95% A. Column Gemini Analytical C18, 250x4.6mm.

[0131] Figure 12 shows LC-MS analysis of l-DCIBzL non-radioactive standard in an exemplary embodiment of the disclosure.

[0132] Figure 13 shows HPLC spectra of crude sample after TFA deprotection of carboxylic groups. Solvent A: H2O (0.1% TFA); Solvent B: ACN (0.1 % TFA). HPLC gradient: 1 mL / min. Solvent A: Water + 0.1% Trifluoroacetic acid (TFA), Solvent B: Acetonitrile + 0.1% TFA. Gradient: 0-3 min 95% A, 3-18 min 95-5% A, 18-20 min 5% A, 20.01 - 25min 95% A. Column Gemini Analytical C18, 250x4.6mm.

[0133] Figure 14 shows co-injection of purified125l-DCIBzL with the non-radioactive standard l-DCIBzL. Solvent A: H2O (0.1% TFA); Solvent B: ACN (0.1% TFA). HPLC gradient: 1 mL / min. Solvent A: Water + 0.1% Trifluoroacetic acid (TFA), Solvent B: Acetonitrile + 0.1% TFA. Gradient: 0-3 min 95% A, 3-18 min 95-5% A, 18-20 min 5% A, 20.01 - 25min 95% A. Column Gemini Analytical C18, 250x4.6mm.

[0134] Figure 15 shows an ESI+ MS spectrum of PSMA2-Glu(AO)-Tyr (H-1-4).

[0135] Figure 16 shows a 1 H-NMR of PSMA2-Glu(AO)-Tyr (H-1-4).

[0136] Figure 17 shows an ESI+ MS spectrum ofnatl- PSMA2-Glu(AO)-Tyr (natl-1-4).

[0137] Figure 18 shows an in vitro competition binding assay using125l-DCIBzL as radioligand and different concentrations of PMPA, PSMA-Glu-DOTA (C-1) ,natGa-PSMA-Glu-DOTA (natGa-C-1), Glu-AO-DOTA (1-1) and PSMA2-Glu-AO-Tyr127 (natl-l-4). in an exemplary embodiment of the disclosure.

[0138] Figure 19 shows the results of internalization assays with exemplary compound I-4 under block conditions (black, left most bar in each set of three bars), ice-cold conditions (middlebar in each set of three bars), and no-cell control (white, right most bar is each set of three bars). Error bars represent SD (n=3).

[0139] Figure 20 shows the results % internalization and % surface bound from internalization assays with exemplary compound I-4. Error bars represent SD (n=3).

[0140] Figure 21 shows results of the absorbance scan for acridine AO (left panel) and DNA blank (right panel). In the left panel graph, 0 urn is the left most and topmost line. In the right panel graph, 0 urn is the topmost line.

[0141] Figure 22 are graphs showing the saturation binding curves derived from fluorescence data to calculate dissociation constants for acridine orange (left panel) and DNA blanks (right panel). Fluorescence reading was taken at 530 nm with DNA serial dilutions ranging from 3.13 uM to 200 uM. Error bars indicate range of triplicates.

[0142] Figure 23 are graphs showing the absorbance scan results of PSMA-Glu(AO)-DOTA (1-1) (left most panel), PSMA2-Glu(AO)-DOTA (I-2) (middle panel), and PSMA2-Glu-AO-Tyr (natl-l- 4) (left most panel). All measurements taken in triplicateFigure 24 are graphs showing saturation binding curves derived from fluorescence data. Fluorescence was read at 525 nm for PSMA-Glu(AO)-DOTA (1-1) (left most panel), and PSMA2- Glu(AO)-DOTA (I-2) (middle panel), and 523 nm for PSMA2-Glu-AO-Tyr (natl-l-4) (left most panel) depending on emission maxima. Excitation ranged from 498-500 nm, depending on absorbance maxima. Error bars indicate range of triplicates.

[0143] DETAILED DESCRIPTION i. Definitions

[0144] Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to be applicable to all embodiments and aspects of the present disclosure herein described for which they are suitable as would be understood by a person skilled in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0145] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0146] In understanding the scope of the present disclosure, the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives. The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0147] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies. In addition, all ranges given herein include the end of the ranges and also any intermediate range points, whether explicitly stated or not.

[0148] As used in this disclosure, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0149] In embodiments comprising an “additional” or “second” component, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0150] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present.

[0151] The abbreviation, “e.g.” is derived from the Latin exempli gratia and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.” The word “or” is intended to include “and” unless the context clearly indicates otherwise.

[0152] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed or composition to be prepared, the identity of the molecule(s) to be transformed and / or the specificuse for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0153] The terms "about", “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0154] The term "compound(s) of the application" or "compound(s) of the present application" and the like as used herein refers to a compound of Formula I and includes pharmaceutically acceptable salts, solvates and / or prodrugs thereof as well as all stereoisomers and regioisomers.

[0155] The term “complex of the application” or “complexes of the application” and the like as used herein refers to a complex comprising one or more compounds of Formula I or pharmaceutically acceptable salts and / or solvates thereof and one or more radioisotopes.

[0156] The term “composition(s) of the application” or “composition(s) of the present application” and the like as used herein refers to a composition, such a pharmaceutical composition, comprising one or more compounds or complexes of the application.

[0157] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term Ci- iOalkyl means an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0158] The term “alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term C2-6alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0159] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix“Cni-n2”. For example, the term C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0160] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 20 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as selected from O, S and N and the remaining atoms are C. Heterocycloalkyl groups are optionally benzofused.

[0161] The term “aryl” as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring and contains either 6, 9 or 10 carbon atoms, such as phenyl, indanyl or naphthyl.

[0162] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring containing 5-20 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. When a heteroaryl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heteroaryl groups are optionally benzofused.

[0163] The suffix “ene” at the end of a group (for example “alkylene” or “alkenylene”) means that the group is bivalent, that is that it is bonded to two variables each on a different end of the group.

[0164] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups, contain one or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged or spirofused.

[0165] All cyclic groups, including aryl and cyclo groups, and hetero versions thereof, contain one or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged or spirofused.

[0166] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.

[0167] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0168] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0169] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.

[0170] When a group is substituted with one or more substituents, it understood that the selection of those substituents is independent of each other. That is, the one or more substituents may be the same or different.

[0171] The term “substituted” as used herein means that the referenced atom contains at least one substituent group other that a hydrogen atom.

[0172] The term “substituent” as used herein refers to any chemical grouping, including groups comprising carbon atoms and / or heteroatoms that is compatible with the reaction conditions of the processes of the application.

[0173] The term “optionally substituted” refers to groups, structures, or molecules that are either unsubstituted or are substituted with one or more substituents.

[0174] The symbol when drawn perpendicularly across a bond indicates a point of covalent attachment of a chemical group.

[0175] As used herein, the term “one or more” item includes a single item selected from the list as well as mixtures of two or more items selected from the list.

[0176] The term “linker group” as used herein refers to any molecular structure that connects two or more other molecular structures together.

[0177] The term “targeting moiety" are used herein refers to a moiety that is recognized by a target site to which it binds.

[0178] The term “target” or “target site” as used herein means a receptor, for example a cell surface receptor, antigen, or other protein on a cell surface to which a target moiety can bind.

[0179] The term “amino acid residue” are used herein refers to a molecular structure comprising a carboxylic acid group without the “ — OH” of the carboxylic acid group and an amino group without the “H” portion of the amino group.

[0180] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0181] The term “treating” or “treatment” and the like as used herein, and as is well understood in the art, refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to alleviation oramelioration of one or more symptoms or conditions, arresting development of disease, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, including regression of the disease, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” may also refer to prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of affecting a partial or complete cure for a disease and / or symptoms of the disease. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated to prevent recurrence. Prophylactic treatment includes preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease).

[0182] Treating may refer to any indicia of success in the treatment or amelioration or prevention of an infection, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms; or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician. Accordingly, the term "treating" includes the administration of the methods of the present disclosure to prevent, delay, alleviate, arrest or inhibit development of the symptoms or conditions associated with diseases.

[0183] “Palliating” a disease, disorder or condition means that the extent and / or undesirable clinical manifestations of a disease, disorder or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0184] The term “subject” as used herein includes all members of the animal kingdom including mammals such as a mouse, a rat, a dog and a human. Thus, the methods and uses of the present disclosure are applicable to both human therapy and veterinary applications.

[0185] The term “pharmaceutically acceptable” as used herein means compatible with the treatment of subjects, for example humans.

[0186] The term “pharmaceutically acceptable carrier” as used herein means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0187] The term “pharmaceutically acceptable salt” as used herein means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0188] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0189] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0190] The term “solvate” as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0191] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0192] The term “administering” or “administration” and the like as used herein refers to the placement of a compound, one of more compounds or a pharmaceutical composition thereof, as disclosed herein into a cell, either in cell culture or in a subject, by a method or route which results in at least partial delivery to a desired site. The compounds and compositions disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject. Possible routes of administration of the compounds and pharmaceutical compositions disclosed herein include, but are not limited to, topical, intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal, oral, buccal, sublingual, intranasal, or rectal routes of administration, or a combination thereof.

[0193] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the disclosure that is effective, at dosages and for periods of time necessary to achieve the desired result.

[0194] The term “theranostic” as used herein refers to an agent that can be used for both diagnosis and therapy.

[0195] The term “theranostic application” as used herein means using a radioactive drug to diagnose and treat a disease, disorder or condition.

[0196] The term “imaging effective amount” when used in connection with a radioligand, complex or one or more complexes of the application, is an amount of the radioligand, complex to produce a visible image when the complex is administered to a subject and the radiation emitted by the complex is detected using positron-emission tomography (“PET”), single photon emission tomography (SPECT), autoradiography, ex vivo and / or in vitro binding assays.

[0197] As used herein, the term “diagnostic effective amount” means an amount of a compound, or one or more compounds, of the application or complex, or one or more complexes of the application, that is effective, at dosages and for periods of time to achieve a desired diagnostic effect including, for example, diagnosing a particular disease, disorder or condition being assessed.

[0198] The term “administered” as used herein means administration of a therapeutically effective amount of one or more compounds, complexes or compositions of the application to a cell, tissue, organ or subject.

[0199] The term “cancer” as used herein refers to cellular-proliferative disease states.

[0200] It will be understood that any component defined herein as being included may be explicitly excluded by way of proviso or negative limitation, such as any specific compounds or method steps, whether implicitly or explicitly defined herein.

[0201] The term “Pluvicto” or “177Lu-PSMA-617” as used herein refers to a compound having the generic name lutetium (177Lu) vipivotide tetraxetan and having the chemical formula:

[0202] The term “125l-DCIBz” or “l125-PSMA” as used herein refers to a compound having the chemical name 2-[3-[1-carboxy-5-(4-(125)l-iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid and having the chemical formula

[0203] The term "DNA intercalating agent" as used herein refers to a chemical moiety which insert themselves between successive DNA base pairs causing distortions and potentially interfering with DNA replication, transcription, and repair, leading to cell death or mutations.

[0204] The term “acridine orange” as used herein refers to a compound having the chemical name / V, / V, / V, / V'-Tetramethylacridine-3,6-diamine, and the chemical structure:II. Compounds, Complexes and Compositions of the Application

[0205] Disclosed herein are compounds for use as theranostic radiopharmaceuticals made by combining a radiolabeling moiety, such as a chelator for a radioisotope including, for example, |3-emitting and Auger-emitting radiometals, or a radiolabeling moiety comprising an Auger-emitting radioisotope, and a targeting moiety, such as for targeting PSMA, with a DNA intercalating agent, such as acridine orange, to enhance potency and specificity of the compound to allow for a more targeted and safer approach to cancer therapy. In some embodiments, compounds or complexes comprising a radiolabeling moiety, a targeting moiety such as a PSMA targeting moiety and a DNA intercalating agent such as acridine orange were developed wherein the radiolabeling moiety comprises a chelator such as DOTA for chelating radiometals such as68Ga,177Lu,161Tb or225Ac or comprises a tyrosine or a derivative thereof radiolabeled with a radioisotope such as I125. The compounds and complexes of the application are improved over comparator compounds, such as corresponding comparator compounds without a DNA intercalator. The DNA intercalator targets DNA and thus brings radioisotopes within range of sensitive cellular regions necessary for function which increases their destructiveness to cells, thereby increasing the cytotoxic effects of radioisotopes making them more useful therapeutically. This is especially beneficial for short range radioisotopes such as Auger-emitting radioisotopes.

[0206] Accordingly, there is provided a compound comprising a radiolabeling moiety, a targeting moiety, and a DNA intercalating agent. In some embodiments, there is provided a radioligand compound comprising a radiolabeling moiety, a targeting moiety, and a DNA intercalating agent.

[0207] In some embodiments, the radiolabeling moiety binds or chelates a radioisotope. In some embodiments, the radioisotope is selected from the group consisting of11C,43Sc,44sSc,47Sc,18F,51Cr,55Co,58mCo,67Ga,68Ga,111ln,99mTc,186Re,188Re,139La,140La,149Tb,152Tb,161Tb,175Yb,153Sm,166Ho,88Y, "Y,149Pm,165Dy,169Er,177Lu,47Sc,142Pr,159Gd,212Bi,213Bi,72As,72Se,97Ru,109Pd,105Rh,101mRh,119Sb,128Ba,123l,124l,131l,197Hg,211At,151Eu,153Eu,169Eu,201TI,203Pb,212Pb,64Cu,67Cu,188Re,186Re,198Au,225Ac,227Th and199Ag.

[0208] In some embodiments, the radiolabeling moiety comprises a radioisotope chelator. In some embodiments, the radiolabeling moiety comprises a radiometal chelator.

[0209] In some embodiments, the radiometal chelator comprises 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1 ,4,7-triazacyclononanetriacetic acid (NOTA) or desferrioxamine (DFO).

[0210] In some embodiments, the radiometal chelator comprises DOTA.

[0211] In some embodiments, the radioisotope comprises an Auger electron emitting radioisotope.

[0212] In some embodiments, the radiolabeling moiety comprises tyrosine or a derivative thereof.

[0213] In some embodiments, the radiometal chelator further comprises a click chemistry attachment moiety.

[0214] In some embodiments, the targeting moiety comprises a small molecule, peptide or antibody selected for high affinity to a target receptor.

[0215] In some embodiments, the target receptor is a prostate-specific membrane antigen (PSMA) receptor.

[0216] In some embodiments, the DNA intercalating agent comprises an acridine molecule.

[0217] In some embodiments, the acridine molecule comprises acridine orange.

[0218] In some embodiments, the DNA intercalating agent comprises an anthracycline molecule.

[0219] In some embodiments, the radiolabeling moiety acts as a linker between the targeting moiety and the DNA intercalating agent.

[0220] In some embodiments, the compound further comprises a central linker connecting the radiolabeling moiety, the targeting moiety, and the DNA intercalating agent.

[0221] In some embodiments, the compound is a compound of Formula I,RL LRLLinkerwhereinDI is DNA intercalating agent;TM is a targeting moiety;RL is a radiolabeling moiety; and- is a central linker,LRL, LDIand LTMare independently selected from a direct bond and a spacer linker, or a pharmaceutically acceptable salt and / or solvate thereof.

[0222] In some embodiments, the central linker is at least trivalent.

[0223] In some embodiments, each a spacer linker is divalent.

[0224] In some embodiments, the DNA intercalating agent comprises any suitable antiproliferative agent known the art which inserts itself between successive DNA base pairs. In some embodiments, the DNA intercalating agent inhibits protein synthesis.

[0225] In some embodiments, the DNA intercalating agent comprises an acridine molecule. In some embodiments, the acridine molecule comprises acridine orange.

[0226] In some embodiments, the DNA intercalating agent comprises an anthracycline molecule. In some embodiments, the DNA intercalating agent is bound via LDIto the central linker (optionally the DNA intercalating agent is bound the central linker when LDIis a direct bond). In some embodiments, the DNA intercalating agent is acridine orange, propidium iodide, DAPI (4',6- diamidino-2-phenylindole), berberine, ethidium bromide, proflavine, thalidomide, doxorubicin, daunorubicin, or dactinomycin, each of which is bound via LDIto the central linker. In some embodiments, the DNA intercalating agent is acridine orange, propidium iodide, DAPI (4',6- diamidino-2-phenylindole), berberine, ethidium bromide, proflavine, or thalidomide, each of which is bound via LDIto the central linker. In some embodiments, the DNA intercalating agent is acridine orange which is bound via LDIto the central linker.

[0227] In an exemplary embodiment, the DNA intercalating agent is acridine orange which is bound via LDIto the central linker having the following chemical structure

[0228] Therefore, in an exemplary embodiment, the compound of Formula I is a compound of Formula l-A^LDIRL - LRL- Linker^L™— TM (|-A) or a pharmaceutically acceptable salt and / or solvate thereof.

[0229] In some embodiments, the targeting moiety comprises a small molecule, peptide or antibody selected for high affinity to a target receptor.

[0230] In some embodiments, the target receptor is an antigen or other protein on a cell surface, for example a cell surface receptor.

[0231] In some embodiments, the targeting moiety is a moiety selected from prostate specific membrane antigen (PSMA) binding group , a glucagon-like peptide-1 receptor (GLP-1 R) binding group, a glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R) binding group, a folate receptor (FR) binding group, a cholecystokinin-2 receptor (CCK2R) binding group, a gastrin releasing peptide receptor (GRPR) binding group, a somatostatin receptor 2 (SSTR2) binding group, a neurotensin receptor 1 (NTR1 ) binding group, a neuropeptide Y receptor type 1 (Y1 R) binding group, a nectin-4 binding group, a Delta-like ligand 3 (DLL3) binding group, an epithelial cell adhesion molecule (EpCAM) binding group, herceptin, arginyl- glycyl-aspartic acid (RGD), epidermal growth factor (EGF), platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), hyaluronan, AS-1411 , GBI-10, biotin, vitamin H, vitaminB-7, folates, lectins, Lactoferrin, transferrin, integrin, mannose derivates, bombesin, bradykinin, mesothelin, hepsin, mucin, estrogen receptor, milk fat globulin, telomerases, nuclear matrix proteins, prostatic acid phosphatase, squamous cell carcinoma antigen (SCCA), oculocutaneous albinism (OCA), pancreas cancer associated antigen (PaA), or antibodies, antibody fragments or antigenic fragments of EGFR, human epidermal growth factor receptor (HER2, HER3, HER4), breast cancer type 1 susceptibility protein (BRCA1), cancer antigen (CA19-9, CA59, CA-125), cluster of differentiation glycoprotein( CD4, CD19, CD20, CD22, CD23, CD276, CD30, CD32, CD324, CD33, CD34, CD44, CD5, CD52, CD70, CD71 , CD79b, CDH1 , CDH6, CDH19, CDH17) carcinoembryonic antigen (CEA), cytotoxic T-lymphocyte associated protein 4 (CTLA4), delta-like 3 (DLL3), ephrin type-A receptor 2 (EphA2), fms-like tyrosine kinase 3 (FLT3), glucose-regulated protein (GRP78), insulin receptor, insulin like growth factor-1 (IGFR), vascular endothelial growth factor (VEGFR1 , VEGFR2, VEGFR3), Ly1 antibody reactive (Ly1 R), Lym1 , Lym2, MPL, c-MET, Mucin (MUC1 , MUC2, MUC3, MUC16, MUC18), neuropilin-1 (NRP1), programmed cell death protein 1 (PD1 , PD-L1), tyrosine-protein kinase-like 7 (PTK7), Transforming growth factor beta-3 (TGF3), tumor necrosis factor (TNF), tumor-associated calcium signal transducer 2 (TROP2), TATA element modulatory factor (TFM1), lysosome-associated membrane protein 1 (LAMP1), a4|31 integrin (VLA4), melanoma antigen recognized by T cells 1 (MART1 / MelanA), glycoprotein 100 (gp100), tyrosinase, tyrosinase-related protein 1 (TRP1), tyrosinase-related protein 2 (TRP2), New York esophageal squamous cell carcinoma 1 (NY-ESO-1), Cyclin-dependent kinase 4 (CDK-4), 13- catenin, melanoma associated antigen (mutated) 1 (MUM1), Caspase-8, lysophosphatidylglycerol acyltransferase 1 (LPGAT1 , KIAA0205), Human papillomavirus (HPVE7), Spliceosome Associated Factor 1 (SART1), preferentially expressed antigen of melanoma (PRAME), multiple tumor suppressor 2 (p15), B melanoma antigen 1 (BAGE1), dystrophin-associated glycoproteins (DAG1), receptor for advanced glycation end products (RAGE1), N-acetylglucosamine (NAG), Tumor- associated glycoprotein 72 (TAG72), cancer antigen (CA125), RAS p21 protein activator 1 (p21 ras), protein 53 (p53), human papillomavirus type 16 (HPV16-E7), Synovial sarcoma, X breakpoint (SSX), human tumor antigen (HOM-MEL55), Type II Collagen (NY-COL2), HOM- HD397, HOM-RCC-1 .14, HOM-HD21 , HOM-NSCLC11 , HOM-MEL-2.4, HOM-TES11 , RCC-3.1.3, cancer-testis antigen (NY-ESO-1), Melanoma Antigen (MAGE1 , MAGE2, MAGE3, MAGE4 MAGE- 11), G antigen (GAGE1 , GAGE6), harvey rat sarcoma (Ha-ras), serine / threonine protein (RAF), disialoganglioside (GD2, GD3), GM2 ganglioside activator (GM2), transcription factors (TF), salmonella protein (sTn), glycoprotein 75 (gp75), latent membrane protein (EBV-LMP1 , EBV- LMP2), human papillomavirus type 16 (HPV-F4, HPV-F6, HPV-F7), prostate-specific antigen (PSA), alpha-fetoprotein (AFP), monoclonal antibody (CO17-1A), epithelial cell adhesion molecule (GA733), glycoprotein 72 (gp72), placental protein 13 (13-HCG), glycoprotein 43 (gp43), heat shock protein (HSP-70), protein 17 (p17 mel), high-molecular-weight proteins (HMW), carcinoma- associated protein (HOJ-1), melanoma gangliosides, tumor-associated glycoprotein (TAG-72),melanoma-associated antigen 1 (MZ2-E), homeodomain-containing protein (PEM), trophoblast and ovarian cancer antigen (LK26), Thomsen-Friedenreich (T) antigen, Human chorionic gonadotropin (HCG), pancreatic oncofetal antigen, cancer antigens (15-3, 19-9, 549, 195), PROTACs, topoisomerase inhibitor, leukemia inhibitory factor and any combination thereof, each of which is bound via LTMto the central linker (or optionally, bound to the central linked when LTMis a direct bond).

[0232] In some embodiments, the target receptor is a prostate-specific membrane antigen (PSMA) receptor bound via LTMto the central linker (or optionally, bound to the central linked when LTMis a direct bond). Therefore, in some embodiments, the targeting moiety comprises a PSMA binding group. In some embodiments, the PSMA binding group is a peptide analogue selected from quisqualic acid, aspartate-glutamate (Asp-Glu), Glu-Glu, glycine-glutamate (Gly-Glu), y-glutamate- glutamate (y-Glu-Glu) and beta-N-acetyl-L-aspartate-L-glutamate (P-NAAG), each of which is bound via LTMto the central linker. In some embodiments, the PSMA binding group comprises a phosphorus, thiol, or urea derivative attached to a glutamate moiety.

[0233] In some embodiments, the targeting moiety comprises glutamate-ureido-lysine (GUL) bound via LTMto the central linker. In some embodiments, the targeting moiety is a PSMA binding group which comprises glutamate-ureido-lysine (GUL):

[0234] Therefore, in an exemplary embodiment, the compound of Formula I is a compound of Formula l-Bor a pharmaceutically acceptable salt and / or solvate thereof.

[0235] In some embodiments, the DNA intercalating agent is acridine orange bound via LDIto the central linker and the targeting moiety is a PSMA binding group which comprises glutamate- ureido-lysine (GUL) bound via LTMto the central linker. Therefore, in an exemplary embodiment, the compound of Formula I is a compound of Formula l-Cor a pharmaceutically acceptable salt and / or solvate thereof.

[0236] In some embodiments, the radiolabeling moiety comprises a radioisotope chelator or an Auger emitting moiety, bound via l_RLto the central linker.

[0237] In some embodiments, the radiolabeling moiety comprises a radioisotope chelator bound via l_RLto the central linker. In some embodiments, the radiolabeling moiety comprises a radiometal chelator. In some embodiments, the radioisotope chelator is a cyclic or an acyclic bifunctional chelating agent that binds with and / or complexes one or more radioisotopes. In some embodiments, the radioisotope chelator is 1 ,4,7- triazacyclononane (TACN); 1 ,4,7- triazacyclononane-triacetic acid (NOTA); 1 ,4,7-triazacyclononane-N-succinic acid-N',N"-diacetic acid (NOTASA); 1 ,4,7-triazacyclononane-N-glutamic acid-N',N"-diacetic acid (NODAGA); 1 ,4,7- triazacyclononane-N,N',N"-tris (methylenephosphonic) acid (NOTP); 1 ,4,7,10- tetraazacyclododecane (

[0012] aneN4) (cyclen); 1 ,4,7,10-tetraazacyclotridecane (

[0013] aneN4); 1 ,4, 7,11-tetraazacyclotetradecane (iso-cyclam); 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10- tetraacetic acid (DOTA); 2-(1 ,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A); 2,2'-(1 ,4,7,10- tetraazacyclododecane-1 ,7-diyl) diacetic acid (DO2A); 2,2',2"-(1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl) triacetic acid (DO3A); 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10- tetra(methanepnosphonic acid) (DOTP); 1 ,4,7,10-tetraazacyclododecane-1 ,7- di(methanephosphoriic acid) (DO2P); 1 ,4,7,10- tetraazacyclododecane- 1 ,4,7- tri(methanephosphonic acid) (DO3P); 1 ,4,7,10-tetraazacyclo-decane-1 -glutamic acid-4,7,10-triacetic acid (DOTAGA); 1 ,4,7,10-tetraazacyclodecane-1 -succinic acid-4,7,10- triacetic acid (DOTASA); 1 ,4, 8,11-tetraazacyclotetradecane (

[0014] aneN4) (cyclam); 1 ,4,8,12- tetraazacyclopentadecane (

[0015] aneN4); 1 ,5,9,13-tetraazacyclohexadecane (

[0016] aneN4); 1 ,4- ethano-1 ,4,8,11 -tetraazacyclo-tetradecane (et-cyclam); 1 ,4,8,11-tetraazacyclotetradecane- 1 ,4,8,1 1-tetraacetic acid (TETA); 2-(1 ,4,8,11-tetraazacyclotetradecane- 1-y I) acetic acid (TE1A); 2,2'- (1 ,4,8,11-tetraazacyclotetradecane-1 ,8-diyl) diacetic acid (TE2A); 4,11-bis(carboxy methyl)- 1 ,4,8,11 -tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19- hexaazabicyclo[6.6.6]icosane (Sar); 1 ,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanines; porphyrins; PCTA (3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-1 (15),11 ,13-triene-3,6,9-triacetic acid); DEPA (7-[2-(biscarboxymethylamino)ethyl]-4,10-biscarboxymethyl-1 ,4,7,10- tetraazacyclododec-1-yl-acetic acid); DTPA (1 ,1 ,4,7,7-diethylenetriaminepentaacetic acid); CHX- DTPA (cyclohexane-1 ,2-diamineN,N,N',N'-tetraacetate); BATPA (1 ,2-bis[2-aminophenoxy]ethane- N,N,N',N'-tetraacetic acid); TTHA (triethylenetetramineN,N,N',N",N"',N"'-hexaacetic acid); HBED (N,N'-bis[2-hydroxybenzyl]ethylenediamine-N,N'-diacetic acid); EGTA (ethylene glycol bis[2- aminoethyl ether]-N,N,N',N'-tetraacetic acid); EDTMP (ethylenediamine tetra- [methylene phosphonic acid]); TRAP (triazacyclononate phosphinic acids); SHBED (N,N'-bis[2-hydroxy-5- sulfobenzyl]ethylenediaminediacetic acid); H6Sbbpen(N,N'-bis-[2-hydroxy-5-sulfonylbenzyl]-N,N'- bis[2-methylpyridyl]ethylenediamine); THP (Tris(3,4-hydroxypyridinone); DFO (deferoxamine); FSC (Fusarinine); 6SS (N,N'-bis[2,2-dimethyl-2- mercaptoethyl]ethylenediamine-N,N'-diacetic acid); ECO (ethylenecysteamine cysteine); ECD (ethyl cysteinate dimer); NETA ([2-{4,7- biscarboxymethyl(1 ,4,7)triazacyclonona-1-yl-ethyl}carbonylmethylamino] acetic acid; THPN (Tetrakis(3-Hydroxy-4-Pyridinone)); H2dedpa (1 ,2-[{6-(carboxylato-)pyridin-2-yl}methylamino]- ethane); H4octapa (N,N'-bis[6-carboxy-2-pyridylmethyl]-ethylenediamine-N,N'-diacetic acid); H2bispa2 (6,6'-[{9-hydroxy-1 ,5-bis- (methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7- diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid); DOTMP(1 ,4,7,10- Tetraazacyclododecane-1 ,4,7,10-tetrayl-tetrakis(methylphosphonic acid)); PEPA (1 ,4,7,10,13- pentaazocyclopentadecane pentaacetic acid); HEHA (1 ,4,7,10,13,16-hexaazocyclooctadecane hexaacetic acid); H2hox; H2CHXhox; H2octox; H2pyhox; H4neunopa; TETPA; H4pypa; H4py4pa; DTPAm; EGTAm; ampam; Me-3,2-HOPO; 3,4,3-(LI-1 ,2-HOPO); macrocyclic tetrapthalimide; or desferrioxamine (DFO) or any derivatives thereof, each of which is bound via l_RLto the central linker. In some embodiments, the radioisotope chelator comprises 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1 ,4,7-triazacyclononanetriacetic acid (NOTA) or desferrioxamine (DFO), each of which is bound via l_RLto the central linker. In some embodiments, radioisotope chelator is DOTA or NOTA, each of which is bound via l_RLto the central linker. In some embodiments, the radioisotope chelator comprises DOTA which is bound via l_RLto the central linker.

[0238] Therefore, in an exemplary embodiment, the compound of Formula I is a compound of Formula l-Dor a pharmaceutically acceptable salt and / or solvate thereof.

[0239] In some embodiments, the radiolabeling moiety (optionally, radioisotope chelator) binds or chelates a radioisotope.

[0240] In some embodiments, the radioisotope is a radioactive isotope of C, N, F, S, Br, Ru, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, a lanthanide, or an actinide.

[0241] In some embodiments, the radioisotope is a radioactive isotope of C, N, O, F, P, S, Cl, Br, I, As, Se, At, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, TI, Pb, Bi, Po, Fr, Pm, a lanthanide (such as La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), an actinide (such as Ac, Th, U), Mg, Al, Ca, Cd, or Ba.

[0242] In some embodiments, the lanthanide is Lu, Sm, Ho, or Tb.

[0243] In some embodiments, the actinide is Ac, Th, or U.

[0244] In some embodiments, the radioisotope is selected from11C,14C ,15N ,18F,32P,33P,

[0245] In some embodiments, the radioisotope is selected from11C,43Sc,44sSc,47Sc,18F,51Cr,55Co,58mCo,67Ga,68Ga,111ln,99mTc,186Re,188Re,139La,140La,149Tb,152Tb,161Tb,175Yb,153Sm,166Ho,88Y, "Y,149Pm,165Dy,169Er,177Lu,47Sc,142Pr,159Gd,212Bi,213Bi,72As,72Se,97Ru,109Pd,105Rh,101 mRh,119Sb,128Ba,123l,124l,131l,161Tb,197Hg,211At,151Eu,153Eu,169Eu,201TI,203Pb,212Pb,64Cu,67Cu,188Re,186Re,198Au,225Ac,227Th and199Ag.

[0246] In some embodiments, the radioisotope is any radioisotope for use in imaging or for use in therapy.

[0247] In some embodiments, the radioisotope for use in imaging is selected from99mTc,

[0248] In some embodiments, the radioisotope for use in therapy is selected from188Re,

[0249] In some embodiments, the radioisotope for use in therapy is selected from177Lu,212Pb, and225Ac. In some embodiments, the radioisotope for use in therapy is177Lu or225Ac. In some embodiments, the radioisotope for use in therapy is177Lu. In some embodiments, the radioisotope for use in therapy is225Ac.

[0250] In some embodiments, the radiolabeling moiety comprises an Auger emitting moiety. Therefore, in some embodiments, the compound of Formula I is a radioligand compound.

[0251] In some embodiments, the Auger emitting moiety comprises an Auger electron emitting radioisotope. In some embodiments, the Auger electron emitting radioisotope is selected from125l,68Ga,18F,161Tb and177Lu. In some embodiments, the Auger electron emitting radioisotope is125l.

[0252] In some embodiments, the Auger emitting moiety is a tyrosine derivative comprising an Auger emitting isotope. In some embodiments, the radiolabeling moiety comprises tyrosine or|125 a derivative thereof. In some embodiments, the Auger emitting moiety is:or

[0253] Therefore, in an exemplary embodiment, the compound of Formula I is a compound of Formula l-E(i) or Formula l-E(ii)or a pharmaceutically acceptable salt and / or solvate thereof.

[0254] As used herein “DNA intercalating agent is bound via LDIto the central linker” or “ “targeting moiety is a moiety bound via LTMto the central linker", radiolabeling moiety comprises a radioisotope chelator bound via l_RLto the central linker” and the likes, means that that the DNA intercalating agent, targeting moiety and radioisotope chelator have been chemically modified to bind to the LDI, LTM, RRLrespectively, or the central linker. In some embodiments, the DNA intercalating agent, targeting moiety and radioisotope chelator rare is bound via LDI, LTM, RRLrespectively to the central linker (optionally, the DNA intercalating agent, targeting moiety and radioisotope chelator are bound to the central linker) by reacting a functional group on the DNA intercalating agent, targeting moiety and radioisotope chelator with a complementary functional group on LDI, LTM, RRLrespectively or the central linker.

[0255] In some embodiments, the central linker comprises a carbon chain.

[0256] In some embodiments, the central linker comprises an amino acid.

[0257] In some embodiments, the central linker is at least trivalent.

[0258] It would be appreciated by a person skilled in the art that the central linker comprises a functional group on each of the termini that reacts with complementary functional groups of each of the molecules to be linked.

[0259] In some embodiments, the central linker is a trivalent amino acid. In some embodiments, the amino acid is a naturally occurring amino acid, a modified amino acid, a D enantiomer of a naturally occurring amino acid, a D enantiomer of a modified amino acid, an unnatural amino acid, a |3- amino acid or a y-amino acid, and combinations thereof.

[0260] In some embodiments, the trivalent amino acid is glutamate, lysine, ornithine, homolysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), cysteine, homo-cysteine, or glutamine. In some embodiments, the amino acid comprises glutamate. In some embodiments, the trivalent amino acid is glutamate.

[0261] Therefore, in some embodiments, the compound of Formula I is a compound of Formula l-F or a pharmaceutically acceptable salt and / or solvate thereof, or a compound of Formula l-G, or a pharmaceutically acceptable salt and / or solvate thereof,

[0262] In some embodiments, l_RL, LDIand LTMare independently selected from a direct bond and a spacer linker. In some embodiments, each spacer linker is independently a cleavable linker or a non-cleavable linker. In some embodiments, each spacer linker is independently a non- cleavable linker. In some embodiments, each spacer linker independently and optionally comprises a group which is obtained by click chemistry,

[0263] In some embodiments, a cleavable linker allows the release of TM, RL and / or DI from the compound of Formula I under cleaving conditions, selected from, but not limited to acids, bases, reducing agents, oxidizing agents, light, radiation and enzymes. In some embodiments, the cleavable linker is a biodegradable linker, a biocompatible linker, an enzymatic cleavable linker, a pH sensitive linker, a photo sensitive linker, a radiation sensitive linker, or any combination thereof.

[0264] In some embodiments, each spacer linker independently comprises one or more groups selected from amino acid residues, Ci.2oalkylene, C2-2oalkenylene, and C2.20alkynylene, wherein each Ci.2oalkylene, C2.2oalkenylene and C2.2oalkynylene, is independently and optionally interrupted by one or more of a / an cycloalkylene, heterocycloalkylene, arylene, heteroarylene, ester, ethioester, carbamate, carbonate, amino, imido, ether, thioether, carbonyl, thiocarbonyl, sulfonyl, sulfoxide, urea, thiourea and amido group. In some embodiments, each spacer linker independently comprises one or more groups selected from amino acid residues, Ci.20alkylene, C2.20alkenylene, and C2.20alkynylene, wherein each Ci.20alkylene, and C2.20alkenylene is independently and optionally interrupted by one or more of a cycloalkylene, a heterocycloalkylene, an arylene, a heteroarylene, an amino, an ether, a thioether, a carbonyl, a thiocarbonyl, a sulfonyl, a sulfoxidyl an urea, a thiourea and an amido group.

[0265] In some embodiments, each spacer linker independently comprises one to eight groups selected from an amino acid residue, Wa, Ra, Ra-Wa, Wa-Rb, Ra-Wa-Rband Wa-Rb-Wb, wherein each Waand Wbis independently selected from O, S, S(O), SO2, NR1, C(O), C(S), C(O)O, C(S)O, OC(O)NR1, NR1C(O)O, OC(O)O, O-N=C, S-S, NR1C(O), NR1C(S), C(O)NR1, C(S)NR1, (Ci.6alkyleneY)p, Y-(Ci-6alkyleneY')p, Z1-C3.i5cycloalkylene-Z2, Z1-C6-i5arylene-Z2, Z1-C5.2oheteroarylenel-Z2and Z1-C3.2oheterocycloalkylene-Z2, each Raand Rbis independently selected from Ci.2oalkylene, C2.2oalkenylene, and C2.2oalkynylene, each Y and Y' is independently selected from O, S, C(O) and NR2; each Z1and Z2are independently selected from a direct bond, O, S, C(O) and NR3;R1, R2and R3are independently selected from H and Ci-3alkyl; and; p is an integer selected from 1 to 8.

[0266] In some embodiments, each Waand Wbis independently selected from O, S, S(O), SO2, NR1, C(O), C(S), NR1C(O), NR1C(S), C(O)NR1, C(S)NR1, (Ci.6alkyleneY)p, Y-(Ci.6alkyleneY')p, Z1-C3.i5cycloalkylene-Z2, Z1-C6-i5arylene-Z2, Z1-C5-2oheteroarylenel-Z2and Z1-C3. 2oheterocycloalkylene-Z2.

[0267] Therefore, in some embodiments, each spacer linker independently comprises one to eight groups selected from an amino acid residue, Wa, Ra, Ra-Wa, Wa-Rb, Ra-Wa-Rband Wa- Rb-Wb, wherein each Waand Wbis independently selected from O, S, S(O), SO2, NR1, C(O), C(S), C(O)O, C(S)O, OC(O)NR1, NR1C(O)O, OC(O)O, O-N=C, S-S, NR1C(O), NR1C(S), C(O)NR1, C(S)NR1, (Ci.6alkyleneY)p, Y-(Ci-6alkyleneY')p, Z1-C3.i5cycloalkylene-Z2, Z1-C6-i5arylene-Z2, Z1-C5. 2oheteroarylenel-Z2and Z1-C3.2oheterocycloalkylene-Z2, each Raand Rbis independently selected from Ci.2oalkylene, C2-2oalkenylene, and C2-2oalkynylene, each Y and Y' is independently selected from O, S, C(O) and NR2; each Z1and Z2are independently selected from a direct bond, O, S, C(O) and NR3;R1, R2and R3are independently selected from H and Ci_3alkyl; and; p is an integer selected from 1 to 8.

[0268] In some embodiments, each spacer linker independently comprises one to eight groups selected from an amino acid residue Wa, Ra-Wa, Wa-Rb, and Wa-Rb-Wb.

[0269] In some embodiments, each Raand Rbis independently selected from Ci-iOalkylene, C2-ioalkenylene and C2-ioalkynylene. In some embodiments, each Raand Rbis independently selected from Ci.2oalkylene. In some embodiments, each Raand Rbis independently selected from Ci-i2alkylene. In some embodiments, each Raand Rbis independently selected from O-ioalkylene.

[0270] In some embodiments, each Waand Wbis independently selected from O, S, S(O), SO2, NR1, C(O), C(S), NR1C(O), NR1C(S), C(O)NR1, C(S)NR1, (Ci.6alkyleneY)p, Y-(Ci.6alkyleneY')p, Z1-C3.i5cycloalkylene-Z2, Z1-C6-i5arylene-Z2, Z1-C5-2oheteroarylenel-Z2and Z1-C3. 2oheterocycloalkylene-Z2. In some embodiments, each Waand Wbis independently selected from O, NR1, C(O), NR1C(O), C(O)NR1, (Ci.6alkyleneY)p, Y-(Ci.6alkyleneY')p, Z1-C3.i5cycloalkylene-Z2, Z1-C6-i5arylene-Z2, Z1-C5-2oheteroarylene-Z2and Z1-C3.2oheterocycloalkylene-Z2.

[0271] In some embodiments, each C3.i5cycloalkylenyl in Waor Wbis independently selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene.

[0272] In some embodiments, each Ce-isarylene in Waor Wbis independently selected from phenylene, naphthylene, dihydronaphthylene, tetrahydronaphthylene, indanylene, anthracylene, dihydroindenylene, indenylene, fluroenylene, phenanthrenylene and dihydrophenanthrenylene.

[0273] In some embodiments, each C5-2oheteroarylene in Waor Wbis independently selected from furylene, imidazolylene , isothiazolylene, thiazolylene, pyridylene, pyrazinylene, pyrazolylene, pyrrolylene, triazolylene (including 1 ,2,3 triazolylene, and 1 ,2,4 triazolylene) thiophenylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, tetrazolylene, pyrimidinylene, pyridazinylene, triazinylene, adeninylene, guaninylene, benzofuranylene, indolylene, isoindolylene, indolizinylene, indazolylene, benzodioxolylene, benzimidazolylene, azaindolylene, purinylene, isobenzofuranylene, benzothiazolylene, quinolinylene, isoquinolinylene, benzothiophenylene, benzoisothiazolylene, benzoxazolylene, quinoxalinylene, phthalazinylene, cinnolinylene, naphthyridinylene, pyridoyrimidinylene, pyridopyrazinylene, pyridopyrazinylene, pteridinylene, quinuclidinylene, azaadamantanylene, carbazolylene, dibenzofuranylene, acridinylene, phenazinylene, phenoxazinylene, phenothiazinylene and phenoxathiinyenel.

[0274] In some embodiments, each C3-2oheterocycloalkylene2oheteroarylene in Waor Wbis independently selected from aziridinylene, oxiranylene, thiiranylene, oxaxiridinylene, dioxiranylene, azetidinylene, oxetanylene, theitanylene, diazetidinylene, dioxetanylene, dithietanylene, tetrahydrofuranylene, tetrahydrothiophenylene, pyrrolidinylene, pyrrolinylene, 2H-pyrrolylene, imidazolinylene, imidazolidinylene, pyrazolidinylene, oxothiazolidinylene, thiazolidinylene, isothiazolidinylene, dioxolanylene, dithiolanylene, dioxazolylene, dithiazolylene, tetrahydropyranylene, tetrahydrothiopyranylene (thianylene), tetrahydrothiopyranylene oxide (thianylene oxide), tetrahydrothiopyranylene dioxide (thianylene dioxide), dithianylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxanylene, indolinylene, 3H- indolyl,dihydroquinolinylene, tetrahydroquinolinylene, decahydroquinolinylene, chromenylene, benzoxazinylene, quinolinonylene, azaspiroundecanylene, diazaspiroundecanylene, azaspirodecanylene, diazaspirodecanylene, azaspirononanylene, diazaspirononanylene, azaspirooctanylene, diazaspirooctanylene, azaspiroheptanylene, diazaspiroheptanylene, diazaspirooctanylene, azaspirohexanylene, diazaspirohexanylene, azaspiropentanylene and diazaspiropentanylene.

[0275] In some embodiments, one or more of the C3-2oheterocycloalkylene in Waor Wbis optionally and independently obtained by click chemistry.

[0276] In some embodiments, the C3.2oheterocycloalkylene obtained by click chemistry is any suitable C3.2oheterocycloalkylene obtained by click chemistry known in art. For example, in some embodiments, the at least one C3.2oheterocycloalkylene obtained by click chemistry is a C3. 2oheterocycloalkylene obtained by click chemistry as described in Zagidullin A, Milyukov V, Rizvanov A, Bulatov E.; Explor Target Antitumor Then 2020;1 :381-90; Troup R.I., et al. Explor Target Antitumor Then 2020;1 :273-312; and references cited therein. In some embodiment, the click chemistry is azide-alkyne click chemistry (e.g., a cycloaddition reaction between an azide and an alkyne) or strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry.

[0277] In some embodiments, each Z1and Z2are independently selected from a direct bond, O, C(O) and NR3. In some embodiments, each Z1and Z2are independently selected from a direct bond, C(O) and NR3. In some embodiments, each Z1and Z2are independently selected from a direct bond.

[0278] In some embodiments, each Waand Wbis independently selected from O, NR1, C(O), NR1C(O), C(O)NR1, (Ci.6alkyleneY)pand Y-(Ci-6alkyleneY')p. In some embodiments, each Waand Wbis independently selected from NR1, C(O), (Ci-6alkyleneY)pand Y-(Ci-6alkyleneY')p.

[0279] In some embodiments, each Y and Y' is independently selected from O, S, C(O) and NR2. In some embodiments, each Y and Y' is independently selected from O, C(O) and NR2. In some embodiments, each Y and Y' is O.

[0280] In some embodiments, each Wa-Rbis independently selected from NR1Ci-i2alkylene and C(O)Ci-i2alkylene.

[0281] In some embodiments, each Ra-Wais independently selected from Ci. i2alkyleneNR1, and Ci-i2alkyleneC(O).

[0282] In some embodiments, each Wa-Rb-Wbis independently selected from NR1Ci. i2alkyleneC(O), NR1Ci-i2alkyleneNR1, C(O)-Ci-i2alkyleneC(O), C(O)Ci-i2alkyleneNR1, NR2-(Ci. 6alkyleneO)pCi-6alkyleneNR1, NR2-(Ci-6alkyleneO)pCi-6alkyleneC(O), C(O)-(Ci-6alkyleneO)pCi.6alkyleneNR1and C(O)-(Ci-6alkyleneO)pCi-6alkyleneC(O),

[0283] In some embodiments, each R1, R2and R3are independently selected from H, CH3and CH2CH3. In some embodiments, each R1, R2and R3are independently selected from H and CH3.

[0284] In some embodiments, each Z1and Z2are independently selected from a direct bond, C(O) and NR3.

[0285] In some embodiments, p is an integer selected from 1 to 6, 1 to 4 or 1 to 3.

[0286] In some embodiments, the one to eight amino acid residues in each spacer linker are independently selected from a naturally occurring amino acid residue, a modified amino acid residue, a D enantiomer of a naturally occurring amino acid, a D enantiomer of a modified amino acid, an unnatural amino acid, a |3- amino acid residue or a y-amino acid residue, and combinations thereof.

[0287] In some embodiments, the naturally occurring amino acid residue in each spacer linker is selected from, but not limited to, alanine (A, Ala), arginine (R, Arg), asparagine (N, Asn), aspartic acid (D, Asp), cysteine (C, Cys), glutamine (Q, Gin), glutamic acid (E, Glu), glycine (G, Gly), histidine (H, His), isoleucine (I, lie), leucine (L, Leu), Lysine (K, Lys), methionine (M, Met),phenylalanine (F, Phe), proline (P, Pro), serine (S, Ser), threonine (T, Thr), tryptophan (W, Trp), tyrosine (Y, Tyr), valine (V, Vai), pyrrolysine (Pyl), selenocycleine (Sec) and pyrroline-carboxy- lysine (PCL).

[0288] In some embodiments, the modified amino acid residue in each spacer linker is selected from, but not limited to, 4-carboxy-L-phenylalanine (Cbp), hydroxyproline, y- carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3- aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6- aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2- aminopimelic acid, tertiary-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'- diaminopimelic acid, 2,3-diaminoproprionic acid (Dap), N-ethylglycine, N-methylglycine, N- ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4- hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N- methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid, thioproline, hydroxyproline, and 4- (aminomethyl)cyclohexane-l -carboxylic acid (e.g. tranezamic acid), and combinations thereof.

[0289] In some embodiments, the modified amino acid residue in each spacer linker is o selected from naphthalaninyl:carboxyl:(e.g. derived from tranezamic acid):.or combinations thereof.

[0290] In an exemplary embodiment, LDIis a direct bond or a spacer linker comprising one to four groups selected from Wa, Ra, Ra-Wa, Wa-Rb, Ra-Wa-Rband Wa-Rb-Wb. In an exemplary embodiment, LDIis a direct bond or a spacer linker comprising one to four Wa-Rb-Wb. In an exemplary embodiment, LDIis a direct bond or a spacer linker comprising one Wa-Rb. In some embodiments, LDIis Wa-Rb. In some embodiments, the Wa-Rbin LDIis selected from NR1O. i2alkylene and C(O)Ci-i2alkylene.In an exemplary embodiment, l_RLis a direct bond or a spacer linker comprising one to four groups selected from Wa, Ra, Ra-Wa, Wa-Rb, Ra-Wa-Rband Wa-Rb-Wb. In an exemplary embodiment, LRLis a direct bond or a spacer linker comprising one to four Wa-Rb-Wbgroups. In an exemplary embodiment, l_RLis a direct bond. In an exemplary embodiment, LTMis a direct bond or comprises one to four groups selected from an amino acid residue, Wa, Ra, Ra-Wa, Wa-Rb, Ra-Wa-Rband Wa— Rb— Wb. In an exemplary embodiment, LTMis a direct bond or comprises one to four groups selected from an amino acid residue and Wa-Rb-Wb. In an exemplary embodiment, LTMis a directbond or comprises one to two amino acid residues. In an exemplary embodiment, LTMis a direct bond or comprises two amino acid residues and the two amino acid residues are naphthalaninyl:p y , pFormula I is:

[0291] In an exemplary embodiment, LTMis a direct bond.

[0292] In an exemplary embodiment, theportion of the compound of Formula I is selected from

[0293] In some embodiments, the compound of Formula I is selected from the following list of compounds, or a pharmaceutically acceptable salt and / or solvate thereof:or a pharmaceutically acceptable salt and / or solvate thereof.

[0294] In some embodiments, the compound is

[0295] In some embodiments, the radiolabeling moiety comprises a radioisotope chelator that binds with and / or complexes a radioisotope. Therefore, in some embodiments, the compound of Formula I further comprises a radioisotope complexed to the radioisotope chelator.

[0296] Accordingly, the present application also includes a radioisotope complex or a pharmaceutically acceptable salt and / or solvate thereof, comprising a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof and a radioisotope, wherein the radiolabelling moiety is a radioisotope chelator.

[0297] In some embodiment, the radioisotope is as defined above including embodiments thereof.

[0298] In an embodiment the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19).

[0299] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non- pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0300] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt maybe useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0301] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0302] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0303] The compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0304] The compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.III. Compositions and Kits of the Application

[0305] The compounds and complexes of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds or complexes of the application and a carrier. The compounds or complexes of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds or complexes of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.

[0306] The present application also includes a kit comprisingone or more compounds of Formula I as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, and instructions for administration of the one or more compounds of Formula I, or a pharmaceutically acceptable salt and / or solvate thereof, to a subject in need thereof.

[0307] The present application also includes a kit comprising one or more compounds of Formula I as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radioisotope as defined above, and optionally instructions for administration of the one or more compounds of Formula I, or a pharmaceutically acceptable salt and / or solvate thereof, to a subject in need thereof and the radioisotope to a subject in need thereof.

[0308] The present application also includes a kit comprising one or more complexes of the application as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, and instructions for administration of the one or more compounds complexes to a subject in need thereof.

[0309] In some embodiments, the one or more compounds of Formula I or a pharmaceutically acceptable salt and / or solvate thereof as defined above, the one or more complexes or a pharmaceutically acceptable salt and / or solvate thereof as defined above, or the one or more radioisotope as defined above and are each present in the kits in one or more pharmaceutical compositions.

[0310] In some embodiments, the pharmaceutical compositions comprising the one or more compounds of Formula I or a pharmaceutically acceptable salt and / or solvate thereof as defined above, the one or more complexes or a pharmaceutically acceptable salt and / or solvate thereof as defined above, or the one or more radioisotope as defined above are formulated for parenteral administration as described below. In some embodiments, the parenteral administration is by injection.

[0311] In some embodiments, the kit further comprises a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate- buffered saline, Ringer’s solution or dextrose solution. In some embodiments, the pharmaceutically acceptable buffer is present in the kits in one or more containers such as vial or ampoule.

[0312] In some embodiments, the kits are for use in imaging. In some embodiments, the kits are for use in therapy. In some embodiments, the kits are for use in treating cancer. In someembodiments, the kits are adapted and / or arranged to carry out any method of the present application. Therefore, the present application also includes pharmaceutical packages or kits adapted and arranged to carry out any method of the present application.

[0313] The compounds or complexes of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical ortransdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20thedition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0314] Parenteral administration includes systemic delivery routes other than the gastrointestinal (Gl) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0315] In some embodiments, a compound or complex of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the formof a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed- release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0316] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0317] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0318] In some embodiments, a compound or complex of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiments, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonaryadministration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0319] In some embodiments, a compound or complex of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds or complexes of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0320] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, solutions, gels and powders.

[0321] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound or complex of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.

[0322] Suppository forms of the compounds or complexes of the application are useful for vaginal, urethral and rectal administrations.

[0323] In some embodiments a compound or complex of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy- ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0324] A compound or complex of the application including pharmaceutically acceptable salts and / or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.IV. Methods and Uses of the Application

[0325] In some embodiments, the compound is for use in medical imaging and / or radiotherapy.

[0326] The present application includes a method of treating a disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds or complexes of the application or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof. The present application also includes a use of one or more compounds or complexes of the application or a pharmaceutically acceptable salt and / or solvate thereof for treatment of a disease or disorder as well as a use of one or more compounds or complexes of the application or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treatment of a disease or disorder. The application further includes one or more compounds or complexes of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a disease or disorder.

[0327] In some embodiments, a target of the target binding group of the compound or complex is present on disease cells. Indeed, the presence and / or overexpression of receptors on the cell surface is a hallmark of many diseases associated cells including cancer cells. According, in another embodiment, a target of the target binding group (for example a cell surface receptor) is present on cancer cells and the disease or disorder is cancer. For example, in one embodiment, the target of the target binding group is PSMA and the disease or disorder is prostate cancer.

[0328] In some embodiments, the disease, disorder or condition is cancer.

[0329] In some embodiments, the cancer is selected from, but not limited to: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma / Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma / Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas / Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; CerebralAstrocytoma / Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing’s Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin’s Lymphoma, Adult; Hodgkin’s Lymphoma, Childhood; Hodgkin’s Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi’s Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin’s, Adult; Lymphoma, Hodgkin’s, Childhood; Lymphoma, Hodgkin’s During Pregnancy; Lymphoma, NonHodgkin’s, Adult; Lymphoma, Non-Hodgkin’s, Childhood; Lymphoma, Non-Hodgkin’s During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom’s; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma / Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin’s Lymphoma, Adult; Non-Hodgkin’s Lymphoma, Childhood; Non- Hodgkin’s Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma / Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell T umor; Ovarian Low Malignant Potential T umor; Pancreatic Cancer; Pancreatic Cancer, Childhood;Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm / Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin’s Lymphoma; Pregnancy and NonHodgkin’s Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing’s Family of Tumors; Sarcoma, Kaposi’s; Sarcoma (Osteosarcoma) / Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; medullary thyroid carcinoma; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom’s Macro globulinemia; Wilms’ T umor and a neuroendocrine tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein.

[0330] In some embodiments, the cancer is prostate cancer or a neuroendocrine tumor.

[0331] In some embodiments, the cancer is a PSMA-positive cancer. In an embodiment, the PSMA positive cancer is prostate cancer.

[0332] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the disease, disorder or condition is metastasis.

[0333] Efficaciousness of treatment is determined in association with any known method for diagnosing or treating the particular cancer. Alleviation of one or more symptoms of the cancer indicates that the compound or complex confers a clinical benefit.

[0334] In some embodiments, the compound or complex is administered in combination with at least one additional cancer therapy, including chemotherapy, radiation and / or immunooncology therapy. The other cancer therapy is administered in any order with the at least one additional cancer therapy, for example simultaneously, sequentially or separately.

[0335] As used herein, “treating a cancer” includes, but is not limited to, reversing, alleviating or inhibiting the progression of the cancer or symptoms or conditions associated with the cancer. “Treating the cancer” also includes extending survival in a subject. Survival is optionally extended by at least 1 , 2, 3, 6 or 12 months, or at least 2, 3, 4, 5 or 10 years over the survival that would be expected without treatment with a compound or complex as described herein. “Treating the cancer” also includes reducing tumour mass and / or reducing tumour burden. Optionally, tumour mass and / or tumour burden is reduced by at least 5, 10, 25, 50, 75 or 100% following treatment with a compound or complex as described herein. “Treating the cancer” also includes reducing the aggressiveness, grade and / or invasiveness of a tumour.

[0336] The application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds or complexes of the application to the cell. The present application also includes a use of one or more compounds or complexes of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds one or more compounds or complexes of the application for the preparation of a medicament for inhibition of proliferative activity in a cell. The application further includes one or more compounds one or more compounds or complexes of the application for use in inhibiting proliferative activity in a cell. In some embodiments, the one or more compounds or complexes comprises a radioisotope for use in therapy, optionally a radioisotope selected from188Re,186Re,

[0337] In some embodiments, the proliferative activity is a tumour. The application also includes a method of treating a tumour in a cell, comprising administering an effective amount of one or more compounds or complexes of the application to the cell. The present application also includes a use of one or more compounds or complexes of the application treating a tumour in a cell as well as a use of one or more compounds one or more compounds or complexes of the application for the preparation of a medicament for treating a tumour in a cell. The application further includes one or more compounds one or more compounds or complexes of the application for use in treating a tumour in a cell.

[0338] The present application also includes a method of imaging a tissue in a subject in need thereof by administering an imaging effective amount of one or more compounds or complexes of the application to the subject and applying an imaging technique to detect emitted radiation. The present application also includes a use of one or more compounds or complexes of the application for use in imaging a tissue as well as a use of one or more compounds or complexes of the application comprising a radioisotope for preparation of a medicament for imaging a tissue.The application further includes one or more compounds or complexes of the application comprising a radioisotope for use in imaging a tissue. In some embodiments, the use further includes application of an imaging technique to detect emitted radiation. In some embodiments, the one or more compounds or complexes comprises a radioisotope for use in imaging, optionally99mTc,188Re,

[0339] The present application also includes a method of diagnosing cancer in subject by administering a diagnostic effective amount of one or more compounds or complexes of the application to a subject in need thereof and applying an imaging technique to detect emitted radiation. The present application also includes a use of one or more compounds or complexes of the application for diagnosing cancer as well as a use of one or more compounds or complexes of the application for diagnosing cancer. The application further includes one or more compounds or complexes of the application comprising a radioisotope for use in diagnosing cancer. In some embodiments, the use further includes application of an imaging technique to detect emitted radiation. In some embodiments, the one or more compounds or complexes comprises a radioisotope for use in imaging, optionally99mTc,188Re,186Re,153Sm,66Ga,67Ga,68Ga,111ln,59Fe,63Zn,52Fe,52Mn,45Ti,60Cu,61Cu,67Cu,64Cu,62Cu,82Rb,198Au,199Au,195mpt,19lTIPt,193mPt, n7mSri i89Zr,177Lu,18F,203Pb,44Sc,51Cr,101mRh,166Ho, or123l.

[0340] In some embodiments, diagnosing cancer comprises identifying and localizing a primary tumour mass as well as potential local and distant metatheses. In some embodiments, diagnosing cancer comprises determining tumour volume.

[0341] The present application also includes a method of radioisotope treatment comprising administering an effective amount of one or more compounds or complexes of the application to a subject in need thereof.

[0342] The present application also includes a use of one or more compounds or complexes of the application for radioisotope treatment or a use of one or more complexes of the application for preparation of a medicament for radioisotope treatment.

[0343] The present application also includes a method of theranostic treatment comprising administering an effective amount of one or more compounds or complexes of the application to a subject in need thereof and performing a medical diagnostic method on the subject.

[0344] The present application also includes a use of one or more compounds or complexes of the application for theranostic treatment or a use of one or more compounds or complexes of the application for preparation of a medicament for theranostic treatment.

[0345] In an embodiment, the subject is a mammal. In another embodiment, the subject is human. In an embodiment, the subject is a non-human animal. In an embodiment, the subject is canine. In an embodiment, the subject is feline. Accordingly, the compounds, methods and uses of the present application are directed to both human and veterinary diseases, disorders and conditions.

[0346] In some embodiments, the subject in need is a subject having the disease, disorder or condition. In some embodiments, the subject in need is a subject in need of imaging. In some embodiments, the subject in need of imaging is a subject in need of diagnosis, in need of locating a position for a therapeutic intervention, in need of assessment of the functioning of a body part, and / or in need of assessment of the presence of absence of a disease, disorder or condition.

[0347] In some embodiments, the type of imaging that is used in the methods and uses of the application are positron emission tomography (PET), single photon emission computerized tomography (SPECT), or radioisotope renography and scintigraphy. Methods of performing such imaging techniques are well known to those skilled in the art.

[0348] In some embodiments, for use in diagnostic or therapeutic methods, the one or more compounds and / or complexes are comprised in a pharmaceutical composition as described above.

[0349] In some embodiments, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject. In a further embodiment, the amount of a given compound or complex that will correspond to an effective amount will vary depending upon factors, such as the given compound or complex, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. In an embodiment, the effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.

[0350] In some embodiments, the compound or complex is administered at least once a week. However, in some embodiments, the compound or complex is administered to the subject from about one time per two weeks, three weeks or one month. In some embodiments, the compound or complex is administered about one time per week to about once daily. In some embodiments, the compound or complex is administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the compounds or complexes of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound or complex used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administrationis required. For example, the compound or complex is administered to the subject in an amount and for duration sufficient to treat the subject.

[0351] The dosage of a compound or complex of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, a compound or complex of the application is administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the compound of the application from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg.V. Methods of Preparing the Compounds of the Application

[0352] Compounds and / or complexes of the present application or comparator compounds can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound and / or complex of the present application or comparator compounds is within the purview of the person of skill in the art. Some starting materials for preparing compounds or complexes of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0353] In some embodiments, the compound of Formula I or comparator compound is prepared all or in part using solid phase peptide synthesis (SPPS) or solution phase coupling techniques known in the art, for example, using the synthetic procedures found in Stewart and Young, 1984, Solid Phase Synthesis, Second Edition, Pierce Chemical Co., Rockford, III.; Fields and Noble, 1990, “Solid phase peptide synthesis utilizing 9-fluorenylmethyloxycarbonyl aminoacids,” Int. J. Pept. Protein Res. 35:161-214; Geysen et al., 1987, J. Immunol. Methods 102:259- 274.

[0354] Accordingly, in some embodiments, in SPPS, an Na -protected linker group, such as a tert-butoxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc) amino acid linker group, is activated at the a-carbonyl and coupled with the deprotected Na functionality of the solid phase support. The newly added Na-protected linker group is then deprotected and coupled to the next Na -protected linker group if necessary until the final cleavage step. It would be appreciated by the person skilled in the art the chemistry of the coupling, deprotection, and final cleavage step of the linker from the solid phase support depends on choice of a N-protecting group. In some embodiments, the cleavage is accomplished by treatment with acid, for example trifluoro acetic acid (TFA) optionally in the presence of scavenger reagents such as triisopropylsilane. In some embodiments, when the a N-protecting group is Fmoc, cleavage in acid will also result in deprotection of the side chains.

[0355] In an exemplary embodiment, the compounds of Formula I or comparator compounds are prepared using fluorenylmethyloxycarbonyl (Fmoc) solid-phase peptide synthesis chemistry known in the art. Accordingly, in some embodiments, the compounds of Formula I or fragments therefore are prepared, manually or by using automated multiple solid-phase peptide synthesizer, using a Wang resin, Rink Amide-MBHA or equivalent resin and Fmoc-protected linker group derivatives with suitable side-chain protections such as Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc- Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-lle-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)- OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc- Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(ivDde)-OH, Fmoc- Nle-OH, Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH), Fmoc-Glu-OtBu. The resin is swelled using a suitable solvent such as combination of dichloromethane (DCM) and dimethylformamide (DMF). Prior to each coupling step the base-labile Na-protecting group Fmoc is cleaved from the Fmoc protected linker groups using a suitable base such as diisopropylethylamine (DIPEA) in a suitable solvent such as DMF for time to cleave to cleave the Fmoc protecting group, for example, about 10-15 min. The resin is then subsequently washed with a suitable solvent such as the DMF. An excess amount of the Fmoc-linker group (e.g., 4 to 8 molar equivalent) is then coupled using coupling agents known in the art, for example, hexafluorophosphate azabenzotriazole tetramethyl uranium) (HATU) N,N’-diisopropylcarbodiimide (DIC) and ethyl cyanohydroxyiminoacetate (Oxyma, e.g Oxyma Pure®) or (Benzotriazol- 1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and (1 -Hydroxybenzotriazole (HOBt), in a suitable solvent such as DMF for about 30 minutes to about 2 hours and then furtherwashed with a suitable solvent, such as DMF. The coupling step is repeated once for each linker group.

[0356] When necessary, the methyltrityl (Mtt) group of the Fmoc-Lys(Mtt)-OH (i.e., N-a- Fmoc-N-E-4-methyltrityl-L-lysine) linker group or the deprotected Lys(Mtt)-residue in the linker fragment is removed by treating the group or residue with hexafluoroisopropanol (HFIP) in a suitable solvent such as dichloromethane (DCM) (e.g. about 30% v / v) for suitable amount of time, for example, about 1 hour, followed by washing the resin with the suitable solvent and repeating the treatment with HFIP in DCM with a final washing with DCM after treatment.

[0357] After coupling, the compound of Formula I, comparator compound or fragment thereof is cleaved from the solid phase by treatment with a suitable acid for example, trifluoroacetic acid (TFA) and optionally in the presence of a trialkylsilane such as triisopropylsilane (TIP) and water and then precipitated with a suitable solvent such as diethyl ether. The product is dissolved in a suitable solvent such as water and acetonitrile and purified using high-performance liquid chromatography (HPLC) such as reversed phase HPLC using a suitable solvent or solvent mixture such as water with acetonitrile and TFA with an increasing gradient of acetonitrile. Relevant fractions are checked by analytical UPLC. Fractions containing the pure target compounds are pooled and freeze-dried.

[0358] The chelating group such as DOTA is conjugated to the linker fragment, for example, E-amine of a lysine residue of the linker fragment or the linker fragment attached to the tumour binding group and / or circulation enhancing group using active ester chemistry known in the art. For example, DOTA is combined with the linker fragment in the presence of a base such as an amine.

[0359] The chelating groups can be synthesized through methods known in the art or are commercially available. For example, DOTA is available from Sigma-Aldrich (St. Louis, Missouri, United States).

[0360] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[0361] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”. The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvateby cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0362] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry", March, 4thed. McGraw Hill (1992) or, “Organic Synthesis" , Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquidliquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0363] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

[0364] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.VI. Numbered Embodiments of the Application

[0365] The present application includes the following embodiments:

[0366] 1. A radioligand compound comprising a radiolabeling moiety, a targeting moiety, and a DNA intercalating agent.

[0367] 2. The radioligand compound of embodiment 1 , wherein the radiolabeling moiety binds or chelates a radioisotope.

[0368] 3. The radioligand compound of embodiment 1 , wherein radioisotope is selected from the group consisting of11C,43Sc,44sSc,47Sc,18F,51Cr,55Co,58mCo,67Ga,68Ga,111ln,99mTc,

[0369] 4. The radioligand compound of embodiment 1 , wherein the radioisotope comprises an Auger electron emitting radioisotope.

[0370] 5. The radioligand compound of any one of embodiments 1 to 4, wherein the targeting moiety comprises a small molecule, peptide or antibody selected for high affinity to a target receptor.

[0371] 6. The radioligand compound of embodiment 5, wherein the target receptor is a prostate-specific membrane antigen (PSMA) receptor.

[0372] 7. The radioligand compound of embodiment 5, wherein the targeting moiety comprises glutamate-ureido-lysine (GUL).

[0373] 8. The radioligand compound of any one of embodiments 1 to 7, wherein the DNA intercalating agent comprises an acridine molecule.

[0374] 9. The radioligand compound of embodiment 8, wherein the acridine molecule comprises acridine orange.

[0375] 10. The radioligand compound of any one of embodiments 1 to 7, wherein the DNA intercalating agent comprises an anthracycline molecule.

[0376] 1 1. The radioligand compound of any one of embodiments 1 to 10, wherein radiolabeling moiety comprises a radiometal chelator.

[0377] 12. The radioligand compound of embodiment 1 1 , wherein the radiometal chelator comprises 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1 ,4,7- triazacyclononanetriacetic acid (NOTA) or desferrioxamine (DFO).

[0378] 13. The radioligand compound of embodiment 12, wherein the radiometal chelator comprises DOTA.

[0379] 14. The radioligand compound of embodiment 1 1 , wherein the radiometal chelator further comprises a click chemistry attachment moiety.

[0380] 15. The radioligand compound of any one of embodiments 1 to 10, wherein radiolabeling moiety comprises tyrosine or a derivative thereof.

[0381] 16. The radioligand compound of any one of embodiments 1 to 15, wherein the radioligand compound further comprises a central linker connecting the radiolabeling moiety, the targeting moiety, and the DNA intercalating agent.

[0382] 17. The radioligand compound of embodiment 16, wherein the central linker comprises a carbon chain.

[0383] 18. The radioligand compound of embodiment 16, wherein the linker comprises an amino acid.

[0384] 19. The radioligand compound of embodiment 19, wherein the amino acid comprises glutamate.

[0385] 20. The radioligand compound of embodiment 1 , wherein the radioligand compound is

[0386] 21. The radioligand compound of any one of embodiments 1 to 16, wherein the radiolabeling moiety acts as a linker between the targeting moiety and the DNA intercalating agent.

[0387] 22. The radioligand compound of any one of embodiments 1 to 21 , wherein the radioligand compound is for use in medical imaging and / or radiotherapy.

[0388] 23. The application comprises a method making the compound of any one of embodiments 1 to 22.EXAMPLES

[0389] The following non-limiting examples are illustrative of the present disclosure:A. ChemistryA. Synthesis of compounds containing a radiometal chelator.General

[0390] In some embodiments, compounds containing a DOTA chelator for radiolabeling with radio isotopes such as68Ga,177Lu,161Tb and / or225Ac were developed. The general structures of the PSMA-targeting, DOTA-containing compounds are shown in Scheme 1 , with and without a DNA intercalator domain. Synthesis of PSMA-Glu-DOTA (C-1) and PSMA-Glu(AO)-DOTA (1-1) was then optimized and radiolabeled with68Ga. Scheme 1 shows the structure of PSMA-targeting compounds containing a DOTA chelator and PSMA targeting vector, without a DNA intercalator (PSMA-Glu-DOTA) and with a DNA intercalator (PSMA-Glu(AO)-DOTA).(PSMA-Glu(AO)-DOTA, 1-1) (PSMA-Glu-Dota, C-1)Scheme 1

[0391] PSMA-Glu-DOTA (C-1) and PSMA-Glu(AO)-DOTA (1-1) were synthesized, purified, and characterized. PSMA-Glu-DOTA (C-1) was used as a control of the impact of acridine orange on the binding, internalization and DNA intercalation of the PSMA-Glu(AO)-DOTA (1-1).Example 1 :Synthesis of PSMA-Glu-DOTA (C-1)Solid phase peptide synthesis for PSMA-Glu-DOTA (C-1):Scheme 2

[0392] 100mg of Fmoc-Glu(OBut)-Wang resin was added to a reactor and was allowed to swell for 1 h in a 9:1 dichloromethane (DCM):DMF solution in a shaker at r.t.. The DCM:DMF solution was drained and 5ml_ of 20% piperidine in DMF was added to the resin to deprotect the Fmoc. The solution was shaken for 15 minutes at r.t., was drained into an empty glass vial, and this step was repeated to form intermediate 2 (Scheme 2). Once completed, 5ml_ of 20% piperidine in DMF was directly added to the glass vial containing the first 10ml_ of deprotection solution. This deprotection solution containing Fmoc was used to prepare the following UV absorbance (300nm) sample: 10pL of the Fmoc deprotection solution + 990pL of MeOH. A blank was prepared using 10pL of 20% piperidine in DMF + 990pL of MeOH. Next, a Kaiser test was done and the resin in the column was washed with DMF followed by DCM. Subsequently, the first coupling reaction was started usingN, / V-disuccinimidyl carbonate (DSC, 95.5mg, 10 equiv.) and DIPEA (0.13ml_, 20 equiv.) dissolved in 5ml_ of DMF for 40 minutes in the shaker at r.t. to form intermediate 3. Once completed, a Kaiser test was performed, and the resin was washed with dichloromethane (DCM) and dimethyl formamide (DMF). Next, intermediate 3 was reacted with H-Lys(Fmoc)-OtBu.HCI (85.98mg, 5 equiv.) and DIPEA (0.065ml_, 5 equiv.) dissolved in 5ml_ of DMF, for 1 ,5h in a shaker at r.t. to form intermediate 4. The column was drained, and the wash steps were repeated. Intermediate 4 was deprotected using 20% piperidine in DMF to form intermediate 5. UV absorbance readings were measured, and a Kaiser test was performed. Wash steps were repeated and intermediate 5 was reacted with Fmoc-L-glutamic acid-5-tertbutyl ester (148mg, 5 equiv.), HATU (132.3mg, 5 equiv.), and 2,4,6-trimethylpyridine (0.091 ml, 10 equiv.) dissolved in 5ml_ of DMF (Fig.8), for 40 minutes in a shaker at r.t. to form intermediate 6. Upon completion, a Kaiser test was performed. The resin in the column was then drained, washed, and deprotected using 20% piperidine in DMF to form intermediate 7. Intermediate 7 was reacted with 1 ,4,7,10-Tetraazacyclododecane-1 ,4,7,10- tetraacetic acid mono- / V-hydroxysuccinimide ester (DOTA-NHS-ester, 106mg, 2 equiv.) and DIPEA (0.06ml_, 5 equiv.) dissolved in 5ml_ of DMF overnight, in the shaker at r.t. to form intermediate 8. Upon completion, the column was drained, a Kaiser test was performed, and the resin was washed thoroughly.Cleavage and deprotection to provide PSMA-Glu-DOTA (C-1):

[0393] Intermediate 8 was deprotected and cleaved from the resin using 5ml_ of 95%TFA: 2.5%H2O: 2.5% Triisopropyl silane (TIPS) deprotection solution for 3h in a shaker at r.t. to form PSMA-Glu-DOTA (Scheme 2). PSMA-Glu-DOTA (C-1) was crashed out in cold diethyl ether and the precipitate was isolated using gravity filtration. The precipitate was then dissolved in 1 ml_ of H2O and dried in a lyophilizer to obtain crude PSMA-Glu-DOTA (47.9mg). PSMA-Glu-DOTA (C-1) was successfully characterized via ESI+MS and Liquid chromatography (LC)-MS. HPLC was performed using two different solvent systems. The first solvent system and gradient used was- Solvent A: H2O (0.1% TFA); Solvent B: Acetonitrile (ACN) (0.1 % TFA); solvent gradient: 0-5 min: 95% A 5% B; 5-22 min: 60% A 40%B; 22-30 min: 5% A 95% B; 30-33 min: 95% A 5% B. The second solvent was- Solvent A: H2O (0.1% Formic Acid (FA)); Solvent B: ACN (0.1% FA); solvent gradient: 0-5 min: 95% A 5% B; 5-22 min: 60% A 40%B; 22-30 min: 5% A 95% B; 30-33 min: 95% A 5% B. 131.2 Solid Phase Synthesis of PSMA-Glu-DOTA (C-1):

[0394] 100 mg of Fmoc-Glu (OtBu)-Wang resin was added to a 10 mL plastic column. The resin was allowed to swell in 5 mL of DCM:DMF (9:1) for 1 hour in the shaker at 400 rpm. The liquid was eluted and an Fmoc deprotection was performed and the column was washed. The Kaiser test was performed, a blue solution was obtained indicating Fmoc deprotection. Then, DSC (186 mg,0.7 mmol) and DIPEA (187 mg, 1.5 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, H- lys(Fmoc)-Otbu (168 mg, 0.4 mmol) and DIPEA (187 mg, 1.5 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 90 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, Fmoc-L-Glu(OtBu)-OH (50 mg, 0.1 mmol), DIPEA (30 mg, 0.2 mmol), and HATU (44 mg, 0.1 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, DOTA(OtBu)3 (100 mg, 0.2 mmol), DIPEA (45 mg, 0.3 mmol), and HATU (66 mg, 0.2 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. The product (C-1) was then cleaved off of the resin using 5 mL of TFA solution (95% TFA, 2.5% TIPS, 2.5% water); the column was shaken for 3 hours at 400 rpm. After cleavage, the solution was collected in cold ether and the white fluffy precipitate was filtered out and collected.Purification of PSMA-Glu-DOTA (C-1) using HPLC:

[0395] 3mg of crude was dissolved in 1 ,4mL of H2O and was purified via HPLC by collecting the product peak observed at 7-8 mins in FA. The fractions were combined and lyophilized to obtain pure PSMA-Glu-DOTA (C-1) (2.59mg), which was analyzed via ESI+MS shown in Figure 1.Example 2: Radiolabeling experiments with PSMA-Glu-DOTA (C-1):68Ga radiolabeling experiments using 50pg of PSMA-Glu-DOTA (C-1):

[0396] Radiolabeling was performed on a 50pg and 100pg purified PSMA-Glu-DOTA (C-1) separately. 500pL of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES, 2.4M) buffer was added to an eppendorf containing purified PSMA-Glu-DOTA (C-1) and this mixture was transferred to a MW vial. 1 mL of68Ga (activity) was eluted from a68Ge / 68Ga generator using 0.6M hydrochloric acid (HCI) and 500pL of the eluted activity was then transferred to the MW vial. The pH was then checked to ensure that it is approximately 4. The MW vial was then placed in an oil bath and the68Ga coordination reaction was incubated at 97°C for 20 minutes. The HPLC was carried out using the following solvent system and gradient: Solvent A- H2O (0.1% TFA); Solvent B- ACN (0.1% TFA); solvent gradient: 0-5 min: 95% A 5% B; 5-22 min: 60% A 40%B; 22-30 min:5% A 95% B; 30-33 min: 95% A 5% B. TLC were also carried out using MeOH:NH4OAc (1 :1) as eluent.

[0397] After HPLC and radio-TLC,68Ga-PSMA-Glu-DOTA (68Ga-C-1) was separated from free68Ga using a preactivated C18 Sep-Pak cartridge. The activation of the C18 Sep-Pak cartridge was done by washing the column with 3ml_ of MeOH followed by 3ml_ of H2O. After activation, the reaction mixture was passed through the column and washed with 1 ml_ of water. 0.5ml_ of 50:50 ethanol (EtOH): saline solution was used to elute formulated68Ga-PSMA-Glu-DOTA, and was analyzed through radio-HPLC and radio-TLC (Figure 2 and Figure 3).68Ga radiolabeling experiments using 100ug of PSMA-Glu-DOTA (C-1):

[0398] To avoid the need for reformulation with SeP-Pak, the reaction was performed with 100pg of purified PSMA-Glu-DOTA (C-1) to facilitate the68Ga coordination reaction to completion. This was necessary to shorten the preparation time because the generator was providing low activity. HPLC analysis for this radiolabeling attempt was done in TFA to provide better resolution between the free 68Ga and [68Ga] Ga-PSMA-Glu-DOTA peaks. Free68Ga had a RT of 3 minutes on the HPLC chromatogram. Once this was established, the reaction was stopped and HPLC was performed. The chromatogram showed a sharp symmetrical peak representing68Ga-PSMA-Glu- DOTA (68Ga-C-1) with a RT of 11 minutes (Figure 2). The reaction reached full conversion to the product68Ga-PSMA-Glu-DOTA. The reaction using 100pg of PSMA-Glu-DOTA was able to produce the desired product,68Ga-PSMA-Glu-DOTA (68Ga-C-1), in relatively higher yield as compared to the 50pg radiolabeled sample however at a cost of decreasing specific activity.Preparation ofnatGa-PSMA-Glu-DOTAatGa-C-1):

[0399] 4.9 mg of crude PMSA-Glu-DOTA (C-1) (5.9 pmol) was combined with 4.8mg ofGa(NO3)3(17.5 pmol, 2.96eq.) in 1 mL ascorbic acid buffer of 50mg / mL concentration and pH = 4.5. The reaction was placed at 95°C for 20 min. Soon after starting heating, a white precipitate appeared. The precipitate was insoluble in H2O, MeOH and ACN, therefore, it was believed to be Ga(OH)3. The supernatant (measured by ESI as shown in Figure 4) was filtered and a C18 Sep- Pak light was used to remove any excess of salts including ascorbic acid. After reformulation, the sample was dried, redissolved in water and lyophilized. ESI confirmed the formation of the product. Molecular weight 900.26. The ESI did not show the presence of PSMA-Glu-DOTA precursor. ThenatGa-PSMA-Glu-DOTA (natGa-C-1) was better observed on the negative mode due to the deprotonation of the carboxylic acids of PSMA. The product was purified by collecting the peak with the analytical HPLC and later lyophilized (Figure 5 and Figure 6).Example 3: Synthesis of PSMA-Glu(AO)-DOTA (1-1)Synthesis of DN A intercalator moiety:

[0400] Acridine orange (AO) was used as the DNA intercalator. Acridine orange (AO) derivative 10-(4-Amino-butyl)-3,6-bis-dimethylamino-acridinium was synthesized according to Scheme 3.Scheme 3. Reaction scheme for the synthesis of 10-(4-Amino-butyl)-3,6-bis-dimethylamino- acridinium.Synthesis of 3,6-bis(dimethylamino)-10-(4- (1,3-dioxoisoindolin-2-yl)butyl)acridinium (A1):

[0401] 15 mL of dry acetonitrile was added to a flask containing Acridine orange (1 g, 3.78 mmol) and N-(4-Bromobutyl)phthalimide (3.27 g, 11.58 mmol). The mixture was refluxed with stirring overnight under an inert atmosphere. It was then filtered and washed with 3x5 mL of p- xylene and 3x5 mL of acetone to yield A1 (1.65 g, 3.53 mmol, 93%) as a brick red solid.1H NMR (600 MHz, CDCI3): 58.68 (s, 1 H), 7.83 (d, J= 9 Hz, 2H), 7.32 (dd, J= 5.16, 3.06 Hz 2H), 7.72 (dd,J= 5.16, 3.06 Hz 2H), 6.96 (d, J= 8.70 Hz, 2H), 6.61 (s, 2H), 4.97 (t, J= 7.32 Hz, 2H), 3.76 (t, J= 6.54 Hz, 2H), 3.27 (s, 12H), 2.05 (p, J= 6.78 Hz, 2H), 1.93 (p, J= 7.32 Hz, 2H).Synthesis of 10-(4-Amino-butyl)-3,6-bis-dimethylamino-acridinium (A2):

[0402] 10 mL of methanol was added to A1 (25 mg, 0.53 mmol) and hydrazine monohydrate(175 mg, 5.5 mmol) and was refluxed with stirring for 5 hours. The phthallic hydrazide precipitate was filtered out and the filtrate was rotary evaporated to dryness. The solid was resuspended in 15 mL of water and washed with 3x10 mL chloroform. The aqueous phase was evaporated to yield A2 (110 mg, 0.33 mmol, 61%) as an orange solid.1H NMR (600 MHz, D2O): 07.81 (s, 1 H), 7.26 (d, J= 9 Hz, 2H), 6.74 (d, J= 7.38 Hz, 2H), 5.75 (s, 2H), 3.89 (t, J= 7.02 Hz, 2H), 2.99 (s, 12H), 3.76 (t, J= 7.50 Hz, 2H), 1.57 (p, J= 7.62 Hz, 2H), 1.49 (p, J= 6.96 Hz, 2H).Synthesis of A3:

[0403] 5 mL of ACN was added to a round bottom flask containing 150 mg of A2, 150 mg of Fmoc-Glu-Otbu, and 0.375 mL of DIPEA. The mixture was sonicated for 30 minutes and then dried by rotary evaporation. The dried mixture was loaded onto a silica plug and eluted with DCM:MeOH (19:1). Rf = 0.4 DCM:MeOH (19:1). ESI+ m / z 745 (M+, 100%).Synthesis of A4:

[0404] 6 mL of DCM:TFA (5:1) was added to a scintillation vial containing 0.4 g of A3. The mixture was shaken for 90 minutes and then dried by rotary evaporation. DCM:MeOH (19:1). Rf = 0.0 DCM:MeOH (19:1). ESI+ m / z 689 (M+, 100%).Kaiser Test:

[0405] ~5 Resin beads were collected from the column by micropipette and placed into a clean Eppendorf tube. The beads were then washed with 3x15 pL MeOH to remove excess solvent and dried. Then, 25 pL each of 3 mg / mL ascorbic acid in pyridine, 4 g / mL phenol in MeOH, and 50 mg / mL ninhydrin in MeOH were added to the Eppendorf tube for a total volume of 75 pL. The tube was then heated at 95 °C for 5 minutes to produce a blue oryellow solution. A blue solution indicates free amines, and a yellow solution indicates no free amines.Fmoc Deprotection (Solid Phase synthesis):

[0406] 5 mL of piperidine solution (20% piperidine in DMF) was added to the column and the column was shaken for 15 minutes at 400 rpm. After eluting the liquid, this was repeated once more. One additional 5 mL wash with piperidine solution was performed.Solid Phase Synthesis of PSMA-Glu(AO)-DOTA (1-1):

[0407] The column is washed with 5x5 mL DMF and then 5x5 mL DCM.

[0408] The AO derivative, A2, was attached to the PMSA-Glu-DOTA (C-1) complex during solid phase synthesis to make PSMA-Glu(AO)-DOTA (1-1) as shown in Scheme 4.Scheme 4. General solid phase peptide synthesis of PSMA-Glu(AO)-DOTA (1-1).

[0409] 100 mg of Fmoc-Glu (OtBu)-Wang resin was added to a 10 mL plastic column. The resin was allowed to swell in 5 mL of DCM:DMF (9:1) for 1 hour in the shaker at 400 rpm. The liquid was eluted and an Fmoc deprotection was performed and the column was washed. The Kaiser test was performed, a blue solution was obtained indicating Fmoc deprotection. Then, DSC (186 mg, 0.7 mmol) and DIPEA (187 mg, 1.5 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed, and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, H- lys(Fmoc)-Otbu (168 mg, 0.4 mmol) and DIPEA (187 mg, 1.5 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 90 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmocdeprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, Fmoc-L-Glu(ODmab)-OH (79 mg, 0.1 mmol), DIPEA (30 mg, 0.2 mmol), and HATU (44 mg, 0.1 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, DOTA(OtBu)3(100 mg, 0.2 mmol), DIPEA (45 mg, 0.3 mmol), and HATU (66 mg, 0.2 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. The column was eluted and then a Dmab deprotection was performed by the addition of 5 mL of 2% Hydrazine in DMF, left to shake for 15 minutes at 400 rpm. The column was then eluted and then washed. Then, A2 (105 mg, 0.3 mmol), DIPEA (80 mg, 0.6 mmol), and HATU (119 mg, 0.3 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. The product was then cleaved off of the resin using 5 mL of TFA solution (95% TFA, 2.5% TIPS, 2.5% water); the column was shaken for 3 hours at 400 rpm. After cleavage, the solution was collected in cold ether and the orange fluffy precipitate was filtered out and collected. ESI- m / z 1154 (M+, 21%).Example 4: Solid Phase Synthesis of PSMA2-Glu(A0)-D0TA (1-2) :Scheme 5

[0410] 100 mg of Fmoc-Glu (OtBu)-Wang resin was added to a 10 mL plastic column. The resin was allowed to swell in 5 mL of DCM:DMF (9:1) for 1 hour in the shaker at 400 rpm. The liquid was eluted and an Fmoc deprotection was performed and the column was washed. The Kaiser test was performed, a blue solution was obtained indicating Fmoc deprotection. Then, DSC (115 mg, 0.5 mmol) and DIPEA (116 mg, 0.9 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, H- lys(Fmoc)-Otbu (104 mg, 0.2 mmol) and DIPEA (116 mg, 0.9 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 90 minutes at 400 rpm. A kaiser test was performedand a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, Fmoc-2-Nal-OH (99 mg, 0.2 mmol), DIPEA (58 mg, 0.5 mmol), and HATU (86 mg, 0.2 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, trans-4-[[[[(9H-Fluoren- 9-yl)methoxy]carbonyl]amino]methyl]cyclohexanecarboxylic Acid (86 mg, 0.2 mmol), DIPEA (58 mg, 0.5 mmol), and HATU (86 mg, 0.2 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, A4 (155 mg, 0.2 mmol), DIPEA (58 mg, 0.5 mmol), and HATU (86 mg, 0.2 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, DOTA(OtBu)3(129 mg, 0.2 mmol), DIPEA (58 mg, 0.5 mmol), and HATU (86 mg, 0.2 mmol) dissolved in 5 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. The product was then cleaved off of the resin using 5 mL of TFA solution (95% TFA, 2.5% TIPS, 2.5% water); the column was shaken for 3 hours at 400 rpm. After cleavage, the solution was collected in cold ether and the orange fluffy precipitate was filtered out and collected (ESI+ m / z 745 (M2+, 100%).Example 5: Radiolabeling experiments with 1-1 and 1-2Radiolabeling of PSMA-Glu(AO)-DOTA (1-1):

[0411] Lu177-I-1 : 5 pL of [Lu177]LuCI3(500 pCi) was added to a vial containing 295 pL of0.1 M NaOAc (pH 5.5) and 50 pg of 1-1. This mixture was heated and stirred at 85 °C for 30 minutes. A radiochemical conversion of 91% was achieved verified through iTLC; Eluent NH4(OH):EtOH:H2O (1 :5:10).Radiolabeling of PSMA-2-Glu(AO)-DOTA (1-2):

[0412] Lu177-l-2: 5 pL of [Lu177]LuCI3(500 pCi) was added to a vial containing 295 pL of0.1 M NaOAc (pH 5.5) and 50 pg of I-2. This mixture was heated and stirred at 85 °C for 30 minutes. A radiochemical conversion of 95% was achieved verified through iTLC; Eluent NH4(OH):EtOH:H2O (1 :5:10).Radiolabeling of PSMA-Glu-DOTA (C-1):

[0413] Lu177-C-1 : 10 pL of [Lu177]LuCI3(1 mCi) was added to a vial containing 290 pL of0.1 M NaOAc (pH 5.5) and 100 pg of C-1. This mixture was heated and stirred at 95 °C for 15 minutes. A radiochemical conversion of 99% was achieved verified through iTLC; Eluent NH4(OH):EtOH:H2O (1 :5:10).B: Synthesis of compounds containing an isotope-comprising agent

[0414] A variation of the complex contains a tyrosine amino acid to allow for radioiodination. The compounds radiolabeled with125l may also be in Auger radiotherapy, especially for micrometastases. DCIBzL, PSMA-Glu(AO)-Tyr (I-3) and PSMA-Glu-Tyr (C-2) compounds (shown in Scheme 5) will be synthesized, purified and characterized and125l radiolabeled.125l-DCIBzL is known to show good in vitro and in vivo results for auger radiotherapy of micrometastasis and can be used as a standard to compare and validate the performance of these compounds.125I-PSMA- Glu-Tyr (C-2) can be used to assess the impact of the DNA intercalator, AO, on the binding, internalization and DNA intercalation of125l-PSMA-Glu(AO)-Tyr (I-3).

[0415] Scheme 6 shows exemplary structure of PSMA-targeting compounds:125l-DCIBzL (an iodine radiolabeling motif and PSMA targeting vector without a DNA intercalator),125l PSMA- Glu-tyr (an iodine radiolabeling motif and PSMA targeting vector and central linked without a DNA intercalator, C-2), and125l-PSMA-Glu(AO)-Tyr, I-3 (a DNA intercalator, an iodine radiolabeling motif and PSMA targeting vector).(125l-DCIBzL, l125-PSMA), (125l-PSMA-Glu(AO)-Tyr (I-3))Scheme 6Example 6: Synthesis of125l-DCIBzL

[0416] As a control / standard for comparison, DCIBzL was prepared and radiolabeled.Preparation ofDCIBzL precursor (Scheme 7):Scheme 7

[0417] To a solution of PSMA (2mg, 4.1pmol) in dry DCM (2ml_) was added triethylamine (5.2pL, 37pmol), followed by / V-hydroxysuccinimidyl-4-tributylstannylbenzoate (2.7 mg, 5.3pmol) as shown in Scheme 6. After stirring for overnight at room temperature, the reaction mixture was analyzed by TLC and ESI. After confirmation of product formation, the solvent was removed under air flow. The crude product was purified in a silica column using Hexane / Ethyl acetate (2:1). A silica column was prepared with 0.5g of silica in a Pasteur pipette. The slurry was prepared with Hexane:Ethyl acetate (2:1) and the column was properly compacted. The crude product was added in the smallest volume as possible (TLC shown in Figure 7). 35 fractions of about 150 - 200uL were collected. The product eluted in the last fractions. Three main groups of fractions were collected. Mass of product obtained: 1.69 mg. The pure product was dissolved in MeOH and transferred to 3 eppendorf tubes and dried under high vacuum (ESI-MS and HPLC shown in Figure 8 and Figure 9, respectively). The masses transferred to each vial was around 400pg.Preparation ofl-DCIBzL non-radioactive standard (Scheme 8):Scheme 8

[0418] To a solution of PSMA (12.7 mg, 26pmol) in DCM (5ml_) was added triethylamine (33pL, 234pmol), followed by / V-succinimidyl 4-iodobenzoate (13 mg, 37.6pmol) as shown in Scheme 7. After stirring for overnight at room temperature, the reaction mixture was analyzed by TLC and ESI. The dried crude product was then redissolved in Hex:EtOAc (10:7) and purified by conventional column chromatography. 9.8 mg of l-DCIBzL(tBu) was obtained. 20% of I- DCIBzL(tBu) was left as reference for HPLC, NMR and mass and 80% of the crude was moved to the deprotection step in TFA:DCM (1 :1) for 2h. After deprotection reaction, TLC showed only one spot with Rf = 0, different from the protected form (Figure 10). The product was dried and redissolved in water. A C18 Sep-Pak purification was used to remove the excess of TFA and protecting groups. The product was reformulated in MeOH (1 mL) and later dried to give 8mg (Figure 11 and Figure 12).Preparation of125l-DCIBzL (Scheme 9):Scheme 9. Preparation of125l-DCIBzL

[0419] 1 mg / mL of iodogen was prepared in CHCh. 20pL of the solution was transferred into an 1.5mL eppendorf vial. The solution was dried under air flow. Around 1 m Ci of activity (few pLdepending on concentration) was added as shown in Scheme 8. The activity was kept for couple of minutes until the precursor was added in solution (50pL of MeOH and 1 pL of HAc). The mixture was stirred for 20min. After the reaction was completed, the solvent was evaporated with air flow. 200pL of TFA:DCM (1 :1) was added and the mixture stirred for 1 h. After that, the solution is dried again. The crude product is redissolved in ACN (100uL) and 1 uL is transferred to an eppendorf containing 100uL of H2O (0.1%TFA) for an HPLC sample. After the HPLC is performed (Figure 13), the crude product is dried and stored at -20oC. HPLC showed incomplete deprotection if only run for 10min but showed mainly product when the deprotection reaction was performed for 1 h.

[0420] The product was purified using analytical C18 column on HPLC. Solvent A: H2O (0.1% TFA); Solvent B: ACN (0.1% TFA). HPLC gradient: 1 mL / min. Solvent A: Water + 0.1% Trifluoroacetic acid (TFA), Solvent B: Acetonitrile + 0.1% TFA. Gradient: 0-3 min 95% A, 3-18 min 95-5% A, 18-20 min 5% A, 20.01 - 25min 95% A. Column Gemini Analytical C18, 250x4.6mm. Two runs were performed and the fractions corresponding to the product collected and combined. The purified product was co-injected with the l-DCIBzL non-radioactive standard to confirm the formation of the product (Figure 14).Example 7a: Solid Phase Synthesis of PSMA2-Glu(AO)-Tyr, (H-l-4 ) andnatl-PSMA2-Glu(AO)-Tyr (model of 1-4 comprising natural I,nat1-1-4):Scheme 10

[0421] 200 mg of Fmoc-Glu (OtBu)-Wang resin was added to a 50 mL plastic column. The resin was allowed to swell in 10 mL of DCM:DMF (9:1) for 1 hour in the shaker at 400 rpm. The liquid was eluted and an Fmoc deprotection was performed and the column was washed. The Kaiser test was performed, a blue solution was obtained indicating Fmoc deprotection. Then, DSC (230 mg, 0.9 mmol) and DIPEA (232 mg, 0.18 mmol) dissolved in 10 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, H-lys(Fmoc)-Otbu (208 mg, 0.45 mmol) and DIPEA (232 mg, 0.18 mmol) dissolved in 10 mL DMF was added to the resin and allowed to shake for 90 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, Fmoc-2-Nal-OH (198 mg, 0.45 mmol), DIPEA (116 mg, 0.9 mmol), and HATU (172 mg, 0.45 mmol) dissolved in 10 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, trans- 4-[[[[(9H-Fluoren-9-yl)methoxy]carbonyl]amino]methyl]cyclohexanecarboxylic Acid (172 mg, 0.45mmol), DIPEA (116 mg, 0.9 mmol), and HATU (172 mg, 0.45 mmol) dissolved in 10 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. Then, A4 (310 mg, 0.45 mmol), DIPEA (116 mg, 0.9 mmol), and HATU (172 mg, 0.45 mmol) dissolved in 10 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. The resin was then split into two 100 mg portions, A and B. Then, Fmoc-3-iodo-Tyr-OH (143 mg, 0.45 mmol) for A or Fmoc-Tyr- OH (109 mg, 0.45 mmol) for B, DIPEA (116 mg, 0.9 mmol), and HATU (172 mg, 0.45 mmol) dissolved in 10 mL DMF was added to the resin and allowed to shake for 40 minutes at 400 rpm. A kaiser test was performed and a yellow solution was obtained indicating coupling. After eluting the column, an Fmoc deprotection was performed and the column was washed. Another Kaiser test was performed returning a blue solution. The products were then cleaved off of the resin using 5 mL of TFA solution (95% TFA, 2.5% TIPS, 2.5% water) each; the columns were shaken for 3 hours at 400 rpm. After cleavage, the solutions were collected in cold ether and orange fluffy precipitates was filtered out and collected.

[0422] Figure 15and Figure 16 show an ESI+ MS spectrum and an 1 H-NMR spectrum of PSMA2-Glu(AO)-Tyr (H-1-4), respectively. Figure 17 shows an ESI+ MS spectrum ofnatl- PSMA2- Glu(AO)-Tyr (natl-1-4).Example 7b: I125lodination / labeling protocol to provide1251-1-4

[0423] 1 mg / mL of iodogen (1 ,3,4,6-tetrachloro-3a,6a-diphenylglucoluril) was prepared in CHCI3. 20pL of the solution was transferred into an 1.5mL Eppendorf vial. The solution was dried under air flow. Around 0.5 Ci of activity (few pL depending on concentration) was added and 5pL of a 1 mg / mL solution of H-l-4 in PBS buffer (pH 7) was added shortly after. The reaction was shaken for 2 minutes, and the mixture was then transferred into another 1.5mL Eppendorf and diluted to 1 mL with PBS buffer. This solution was then purified by C18 sep-Pak.C. BiologyExample 8. Competitive binding assays of exemplary compounds.Methods

[0424] The evaluation of PSMA affinity (IC50) values was determined in a competitive binding assay using LNCaP cells (3 x 105 cells in 24 well-plate and125l- benzoyl PSMA (125l- DCIBzL) as radioligand. Cells were seeded two days before the assay then culture medium wasremoved and washed with (HBSS + 10 mM HEPES + 0.1 % BSA). Afterwards, concentration of 0.2nM 1251- benzoyl PSMA was incubated with different concentration of the unlabeled tested compounds. Each condition was performed in triplicates. Followed by washing three times and the bound activity was quantified using gamma counter. IC50 values were calculated by Graphpad™ 10 software.Results and Discussion

[0425] In vitro binding (IC50) of the targeted radioligand complexes were assessed using125l-DCIBzL.125l-DCIBzL was used as radiotracer and different concentrations of PMPA ([(phosphonomethyl)pentanedioic acid]; a known inhibitor of PSMA), PSMA-Glu-DOTA (C-1 ,natGa- PSMA-Glu-DOTA (natGa.C-1) were used to calculate IC50. Similarly, the IC5o of PSMA-Glu-AO- DOTA (1-1) and PSMA2-Glu-AO-Tyr127 (natl-l-4) were calculated (Figure 18). Figure 18 shows the results of the in vitro competition binding assay using125l-DCIBzL as radioligand and different concentrations of PMPA, PSMA-Glu-DOTA (C-1) andnatGa-PSMA-Glu-DOTA (natGa.C-1) in an exemplary embodiment of the disclosure. Figure 18 shows the results of the in vitro competition binding assay using PSMA-Glu-AO-DOTA (1-1) and PSMA2-Glu-AO-Tyr127 (natl-l-4).

[0426] natGa-PSMA-Glu-DOTA (natGa.C-1) was used to assess the effect of a chelated metal on the IC50 of the compounds. The data in Figure 18 shows that chelation decreases binding affinity. However, the IC50s of each remain within the same order of magnitude. While not being bound by theory, innatGa.C-1 the DOTA chelator is very close to the targeting vector and as such its effect on binding is more pronounced. Such differences may be mitigated by using a longer spacer linker region like the naphthalaninyl - tranezamic acid spacer linker used innatl-l-4. Similarly, while not being bound by theory, the difference in the affinity observed between PSMA-Glu-AO- DOTA (1-1) and PSMA2-Glu-AO-Tyr127 (natl-l-4) shown in Figure 18 may be attributable to the naphthalaninyl - tranezamic acid derived linker in PSMA2-Glu-AO-Tyr127 (natl-l-4) which is known to enhance binding to PSMA.Example 9. Internalization assay.Methods

[0427] A concentration of 1 nM PSMA2-Glu-AO-Tyrl125(I-4) was prepared using binding buffer (incomplete culture medium RPMI 1640 with 0.5% BSA) and incubated with approximately 0.3 million LNCaP cells at 37 °C for 0.5, 2, 4, or 6 hours. Following incubation, the cells were washed three times and treated with citrate buffer (pH 3) for 5 minutes. The supernatant was collected to measure the surface-bound fraction. The cells were then lysed, and the lysates were collected to quantify the internalized fraction. Radioactivity in each tube was measured using a gamma counter (CPM). For the blocking condition, 10 pM PMPA was added along with 1 nMPSMA2-Glu-AO-Tyrl125 (I-4), and the mixture was incubated for 6 hours at 37 °C. For the ice-cold condition, 1 nM PSMA2-Glu-AO-Tyrl125 (i-4) was incubated on ice for 6 hours. As a no-cell control, the binding buffer alone was incubated at 37 °C for 6 hours. The total percentage binding was calculated by dividing the sum of the internalized and surface-bound fractions by the standard counts, representing the total activity applied to each sample, and multiplying by 100. The percentage of internalized activity was determined by dividing the internalized fraction by the standard counts, while the percentage of surface-bound activity was calculated by dividing the surface-bound fraction by the standard counts. Error bars represent the standard deviation (n = 3).Internalization of PSMA2-Glu-AO-Tyrl125 (1-4)

[0428] As described above, 1 nM PSMA2-Glu-AO-Tyrl125 (I-4) was incubated for 0.5, 2,4 or 6 hour at 37 °C with =0.3 million LnCaP cells then washed 3x, incubated with citrate buffer(pH3) for 5min and supernatant collected to tubes (surface-bound fraction). Cells lysed and collected to tubes (Internalized fraction) then the radioactivity in the tubes were measured via gamma counter (CPM).

[0429] For blocking condition, 10 pM of PMPA was added with 1 nM PSMA2-Glu-AO- Tyrl 125 (I-4) and incubated for 6 hr at 37 °C.

[0430] For Ice cold condition, 1nM PSMA2-Glu-AO-Tyrl125 (I-4) was incubated on Ice for 6 hr. For no-cell control, binding buffer was incubated at 37 °C for 6 hr.

[0431] For no-cell control, binding buffer was incubated at 37 °C for 6 hr.Results and Discussion

[0432] Figure 19 and Figure 20 show the results of the internalization assays.

[0433] Figure 19 shows the results of the internalization assays with exemplary compoundI-4 under block conditions (black, left most bar in each set of three bars), ice-cold conditions (middle bar in each set of three bars), and no-cell control (white, right most bar is each set of three bars). Error bars represent SD (n=3).

[0434] Blocking, ice-cold, and no-cell trials all serves as negative controls to demonstrate specificity of the ligand and verify the internalization mechanism.

[0435] Blocking using a different high affinity ligand (PMPA) to saturate the binding site, making the ligand of interest unable to bind. Block conditions indicate that ligand of interest is specific for that site since it cannot bind / internalize to / in the cell when the binding sites are saturated.

[0436] Ice-cold conditions greatly slow cell metabolism. Therefore, active cell processes are largely halted / slowed making natural internalization mechanisms inoperable. Ice-cold conditions help verify a mechanism for internalization.

[0437] No cell conditions does not comprise cells, 0 binding is expected to be observed.

[0438] Figure 20 shows the % internalized and the % surface binding. Total % binding was calculated by dividing the sum of two fractions by standard counts representing the total activity applied to each sample *100. % internalized was calculated by dividing internalized fraction by standard counts representing the total activity applied to each sample. % surface bound was calculated by dividing surface bound fraction by standard counts representing the total activity applied to each sample

[0439] As can be seen Figures 19 and 20, it was observed that a large majority of what binds to the cell was internalized within the cell. This is advantageous for efficacy of therapy with short, ranged isotopes.Example 10. DNA intercalation assay.

[0440] A DNA intercalation assay was developed to investigate the binding of exemplary compounds of the application to double stranded calf thymus DNA both qualitatively using absorbance and quantitatively using fluorescence.Methods

[0441] 3.025 g of TRIS was dissolved in milli-Q water. 1 M HCI was used to adjust the pH to 7.4. Additional milli-Q was used to total the volume at 250 ml_. Particulates were removed via vacuum filtration to filter the solution into a sterile bottle, which was then autoclaved and stored in the fridge. Milli-Q water, and sometimes DMSO to aid solubility, was used to dissolve and dilute dye compounds. The final dilution was made with the TRIS-HCI buffer at a dye concentration of 16 uM. Calf thymus DNA from Sigma-Aldrich (CAS #91080-16-9) was diluted with TRIS-HCI buffer to a concentration of 1 mg / ml_. Initial stock solution of DNA was serially diluted with TRIS-HCI buffer to concentrations of 400, 200, 100, 50, 25, 12.5, 6.25, 3.13, and 0 uM. A repeater pipette was used to plate 125 uL of the 16-uM dye solution, in triplicate, into a black, clear bottom, 96 well plate. A pipette was used to plate an additional 125 uL of the DNA Serial Dilutions, in triplicate, into those wells. An absorbance scan was conducted from 520-550 nm and a fluorescence scan was conducted from 515-580 nm, with excitation being at 505 or the peak of absorbance for DNA-dye complex. Excel and GraphPad PRISM were used to analyze and visualize the data.Result s / Discussion

[0442] Acridine Orange (AO) was used as the control compound. Evaluated compounds included PSMA-Glu(AO)-DOTA (1-1), which comprises a custom spacer linker between the chelating moiety DOTA (dodecane tetraacetic acid), the PSMA (prostate specific membrane antigen) targeting vector GUL (glutamate-ureido-lysine), and the DNA intercalating moiety acridine orange; PSMA2-Glu(AO)-DOTA (I-2), which used a naphthalaninyl - tranezamic acid linker to the targeting vector, GUL, similar to that found in Pluvicto™, a trademarked and FDA-approved drug, and also further included a linked acridine orange moiety for DNA binding; and PSMA2-Glu-AO- Tyr (natl-l-4), which again used a phthalaninyl - tranezamic acid linker, similar to that found in Pluvicto™ and acridine orange as the DNA binder, however,natl-l-4 also comprised the amino acid Tyrosine which was synthetically modified to comprise iodine rather than another radionuclide. PSMA2-Glu-AO-Tyr (natl-l-4) is expected to behave exactly like the radioactive version (containing 1-125, I-4) in the intercalation experiments, and thus served as a model compound for I-4 and effectively allowed for the study of I-4.

[0443] The first 2 runs of the assay were carried out to establish an expected standard in AO, and to establish a baseline using DNA blanks. Figure 21 shows results of the absorbance scan for AO (left panel), note the characteristic redshift in the peak intensity having moved to larger wavelengths, and the decrease in peak intensity for the 200 uM DNA compared to 0 uM DNA, and thus the delta in intensity corresponds to binding. This is further shown when using the DNA blanks (Figure 21 right panel) which contains no dye. Thus, no peak was observed. The signals observed at a low magnitude are residuals left over from DNA’s absorbance at 280 nm.

[0444] Furthermore, a fluorescence scan was conducted, and the peak emission wavelength was used to construct a Scatchard plot from the results of the saturation binding experiment and a Kd was determined. For AO, Figure 22 (left panel) shows the Scatchard plot with an R2of 0.98 resulting in a Kd of 31 uM. Figure 22 (right panel) shows the random and indeterminate results of the DNA blank stemming from noise fluctuations. No Kd was calculated from this data.

[0445] Figure 23 shows the absorbance results of PSMA-Glu(AO)-DOTA (1-1), PSMA2- Glu(AO)-DOTA (I-2), and PSMA2-Glu-AO-Tyr (natl-l-4), from left to right. For PSMA-Glu(AO)-DOTA (1-1) and PSMA2-Glu(AO)-DOTA (I-2), a slight red shift was observed as well as an intensity decrease upon binding. However, this was not to the same magnitude as with AO alone. PSMA2- Glu-AO-Tyr (natl-l-4) it resembles the DNA blank absorbance scan in Figure 20, thus indicating no dye is being detected by absorbance. Furthermore, Figure 24 shows fluorescence data which was used to create a Scatchard plot for PSMA-Glu(AO)-DOTA (1-1), PSMA2-Glu(AO)-DOTA (I-2), and PSMA2-Glu-AO-Tyr (natl-l-4). None of these plots were observed to resemble the random shape of the DNA blank in Figure 20, but rather they showed the characteristic increase and plateau expected of a saturation binding experiment. AO-RLT2 reports The lowest Kd of 131 pM was observed with PSMA2-Glu(AO)-DOTA (I-2) , followed by PSMA-Glu(AO)-DOTA (1-1) at 231 pM,and PSMA2-Glu-A0-Tyr (natl-l-4) at 387 pM. Note that the assay was optimized for AO alone, and thus all 3 compounds report R2values between 0.67 and 0.91.

[0446] Therefore, from absorbance alone, AO was found to exhibit strong binding whilst PSMA-Glu(AO)-DOTA (1-1) and PSMA2-Glu(AO)-DOTA (I-2) were found to exhibit weak binding while preliminary results with PSMA2-Glu-AO-Tyr (natl-l-4) were inconclusive. Therefore, the peak intensity from a fluorescence scan was used to derive a saturation binding and a dissociation constant for each compound as noted above. Each test compound was shown to be positive for binding to DNA, albeit with less affinity than AO alone.

[0447] While the present disclosure has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples but should be given the broadest interpretation consistent with the description as a whole.All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present disclosure is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION

[0448] A number of publications are cited herein. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference

[0449] (1) Siegel, R. L; Miller, K. D.; Wagle, N. S.; Jemal, A. Cancer Statistics, 2023.CA Cancer J Clin 2023, 73 (1), 17-48.

[0450] (2) Fallah, J.; Agrawal, S.; Gittleman, H.; Fiero, M. H.; Subramaniam, S.; John,C.; Chen, W.; Ricks, T. K.; Niu, G.; Fotenos, A.; Wang, M.; Chiang, K.; Pierce, W. F.; Suzman, D. L.; Tang, S.; Pazdur, R.; Amiri-Kordestani, L.; Ibrahim, A.; Kluetz, P. G. FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer. Clinical Cancer Research 2023, 29 (9) 1651-1657.

[0451] (3) Dash, A.; Pillai, M. R. A.; Knapp, F. F. Production of 177Lu for TargetedRadionuclide Therapy: Available Options. Nuclear Medicine and Molecular Imaging. 2015, 49(2):85-107.

[0452] (4) Kiess, A. P.; Minn, I.; Chen, Y.; Hobbs, R.; Sgouros, G.; Mease, R. C.;Pullambhatla, M.; Shen, C. J.; Foss, C. A.; Pomper, M. G. Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen. Journal of Nuclear Medicine 2015, 56 (9): 1401- 1407.

[0453] (5) Neels, O. C.; Kopka, K.; Liolios, C.; Afshar-Oromieh, A. Radiolabeled PSMAInhibitors. Cancers. 2021 , 13(24):6255.

[0454] (6) Bakht, M. K.; Hayward, J. J.; Shahbazi-Raz, F.; Skubal, M.; Tamura, R.;Stringer, K. F.; Meister, D.; Venkadakrishnan, V. B.; Xue, H.; Pillon, A.; Stover, M.; Tronchin, A.; Fifield, B. A.; Mader, L; Ku, S. Y.; Cheon, G. J.; Kang, K. W.; Wang, Y.; Dong, X.; Beltran, H.; Grimm, J.; Porter, L. A.; Trant, J. F. Identification of Alternative Protein Targets of Glutamate- Ureido-Lysine Associated with PSMA Tracer Uptake in Prostate Cancer Cells. Proc Natl Acad Sci U S A 2022, 119 (4).

[0455] (7) Bostwick, D. G.; Pacelli, A.; Blute, M.; Roche, P.; Murphy, G. P. ProstateSpecific Membrane Antigen Expression in Prostatic Intraepithelial Neoplasia and Adenocarcinoma: A Study of 184 Cases. Cancer 1998 Jun 1 ;82(11):2256-61.

[0456] (8) Goodman, O. B.; Barwe, S. P.; Ritter, B.; McPherson, P. S.; Vasko, A. J.;Keen, J. H.; Nanus, D. M.; Bander, N. H.; Rajasekaran, A. K. Interaction of Prostate Specific Membrane Antigen with Clathrin and the Adaptor Protein Complex-2. Int J Oncol 2007 Nov;31 (5): 1199-203.

[0457] (9) Rajasekaran, A. K.; Anilkumar, G.; Christiansen, J. J. Is Prostate-SpecificMembrane Antigen a Multifunctional Protein? Am. J. Physiol. Cell Physiol. 2005288(5), C975-C981.

[0458] (10) Liu, H.; Rajasekaran, A. K.; Moy, P.; Xia, Y.; Kim, S.; Navarro, V.; Rahmati,R.; Bander, N. H. Constitutive and Antibody-Induced Internalization of Prostate-Specific Membrane Antigen. Cancer Res 1998, 58(18):4055-60.

[0459] (11) Evans, J. C.; Malhotra, M.; Cryan, J. F.; O’Driscoll, C. M. The Therapeutic and Diagnostic Potential of the Prostate Specific Membrane Antigen / Glutamate Carboxypeptidase II (PSMA / GCPII) in Cancer and Neurological Disease. British Journal of Pharmacology. 2016, 173(21):3041-3079.

[0460] (12) Pomplun, E.; Booz, J.; Charlton, D. E. A Monte Carlo Simulation of AugerCascades. Radiat Res 1987, 111 (3):533-52.

[0461] (13) Ku, A.; Facca, V. J.; Cai, Z.; Reilly, R. M. Auger Electrons for Cancer Therapy- a Review. EJNMMI Radiopharmacy and Chemistry. 4, 27 (2019).

[0462] (14) Pereira, E.; Quental, L.; Oliveira, M. C.; Raposinho, P.; Belchior, A.; Di Maria,S.; Correia, I.; Lavrado, J.; Mendes, F.; Vaz, P.; Santos, I.; Paulo, A. Radiolabeled Acridine Orange (AO) Derivatives as DNA-Targeted Probes for Auger Therapy. Radiotherapy and Oncology 2016, 118:S83.

[0463] (15) Narra, V. R.; Howell, R. W.; Harapanhalli, R. S.; Sastry, K. S. R.; Rao, D. V.Radiotoxicity of Some lodine-123, lodine-125 and lodine-131-Labeled Compounds in Mouse Testes: Implications for Radiopharmaceutical Design. Journal of Nuclear Medicine 1992, 33 (12), 2196-201.

[0464] (16) Neshasteh-Riz, A.; Mairs, R. J.; Angerson, W. J.; Stanton, P. D.; Reeves, J.R.; Rampling, R.; Owens, J.; Wheldon, T. E. Differential Cytotoxicity of [123l]IUdR, [125l]IUdR and [131 l]IUdR to Human Glioma Cells in Monolayer or Spheroid Culture: Effect of Proliferative Heterogeneity and Radiation Cross-Fire. Br J Cancer 1998, 77 (3), 385-390.

[0465] (17) Lerman, L. S. Structural Considerations in the Interaction of DNA andAcridines. J Mol Biol 1961 , 3 (1), 18-33.

[0466] (18) Lewis, M.; Bagwill, C.; Hardebeck, L.; Wireduaah, S. CHAPTER 1 : ModernComputational Approaches to Understanding Interactions of Aromatics. In Monographs in Supramolecular Chemistry, 2017; Vol. 2017-January.

[0467] (19) Fernandes, C.; Palma, E.; Silva, F.; Belchior, A.; Pinto, C.I.G.; Guerreiro,J.F.; Botelho, H.M.; Mendes, F.; Raposinho, P.; Paulo, A. Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and / orthe Cell Nucleus. Int. J. Mol. Sci. 2022, 23, 7238.

Claims

Claims:

1. A compound comprising a radiolabeling moiety, a targeting moiety, and a DNA intercalating agent.

2. The compound of claim 1 , wherein the radiolabeling moiety comprises a radioisotope chelator and the targeting moiety comprises a small molecule, peptide or antibody selected for high affinity to a target receptor.

3. The compound of claim 1 or claim 2, wherein the radiolabeling moiety acts as a linker between the targeting moiety and the DNA intercalating agent.

4. The compound of claim 1 , wherein the compound is a compound of Formula I,RL LRL- LinkerwhereinDI is DNA intercalating agent;TM is a targeting moiety;RL is a radiolabeling moiety; and- is a central linker,LRL, LDIand LTMare independently selected from a direct bond and a spacer linker, or a pharmaceutically acceptable salt and / or solvate thereof.

5. The compound of claim 4, wherein the central linker is at least trivalent.

6. The compound of claim 4 or claim 5, wherein the DNA intercalating agent comprises any suitable antiproliferative agent known the art which inserts itself between successive DNA base pairs.

7. The compound of claim 6, wherein the DNA intercalating agent is acridine orange, propidium iodide, DAPI (4',6-diamidino-2-phenylindole), berberine, ethidium bromide, proflavine, thalidomide, doxorubicin, daunorubicin, or dactinomycin, each of which is bound via LDIto the central linker.

8. The compound of claim 7, wherein the DNA intercalating agent is acridine orange which is bound via LDIto the central linker.

9. The compound of any one of claims 4 to 8, wherein the targeting moiety comprises a small molecule, peptide or antibody selected for high affinity to a target receptor and the target receptor is an antigen or other protein on a cell surface.

10. The compound of claim 9, wherein the targeting moiety is a moiety selected from prostate specific membrane antigen (PSMA) binding group , a glucagon-like peptide-1 receptor (GLP- 1 R) binding group, a glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R) binding group, a folate receptor (FR) binding group, a cholecystokinin-2 receptor (CCK2R) binding group, a gastrin releasing peptide receptor (GRPR) binding group, a somatostatin receptor 2 (SSTR2) binding group, a neurotensin receptor 1 (NTR1 ) binding group, a neuropeptide Y receptor type 1 (Y1 R) binding group, a nectin-4 binding group, a Delta-like ligand 3 (DLL3) binding group, an epithelial cell adhesion molecule (EpCAM) binding group, herceptin, Arginyl-Glycyl-Aspartic acid (RGD), epidermal growth factor (EGF), platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), hyaluronan, AS-1411 , GBI-10, biotin, vitamin H, vitamin B-7, folates, lectins, Lactoferrin, transferrin, integrin, mannose derivates, bombesin, bradykinin, mesothelin, hepsin, mucin, estrogen receptor, milk fat globulin, telomerases, nuclear matrix proteins, prostatic acid phosphatase, squamous cell carcinoma antigen (SCCA), oculocutaneous albinism (OCA), pancreas cancer associated antigen (PaA), or antibodies, antibody fragments or antigenic fragments of EGFR, human epidermal growth factor receptor (HER2, HER3, HER4), breast cancer type 1 susceptibility protein (BRCA1), cancer antigen (CA19-9, CA59, CA-125), cluster of differentiation glycoprotein( CD4, CD19, CD20, CD22, CD23, CD276, CD30, CD32, CD324, CD33, CD34, CD44, CD5, CD52, CD70, CD71 , CD79b, CDH1 , CDH6, CDH19, CDH17) carcinoembryonic antigen (CEA), cytotoxic T-lymphocyte associated protein 4 (CTLA4), delta-like 3 (DLL3), ephrin type-A receptor 2 (EphA2), fms-like tyrosine kinase 3 (FLT3), glucose-regulated protein (GRP78), insulin receptor, insulin like growth factor-1 (IGFR), vascular endothelial growth factor (VEGFR1 , VEGFR2, VEGFR3), Ly1 antibody reactive (Ly1 R), Lym1 , Lym2, MPL, c-MET, Mucin (MUC1 , MUC2, MUC3, MUC16, MUC18), neuropilin-1 (NRP1), programmed cell death protein 1 (PD1 , PD-L1), tyrosine-protein kinase- like 7 (PTK7), Transforming growth factor beta-3 (TGF3), tumor necrosis factor (TNF), tumor- associated calcium signal transducer 2 (TROP2), TATA element modulatory factor (TFM1), lysosome-associated membrane protein 1 (LAMP1), a4|31 integrin (VLA4), melanoma antigen recognized by T cells 1 (MART1 / MelanA), glycoprotein 100 (gp100), tyrosinase, tyrosinase- related protein 1 (TRP1), tyrosinase-related protein 2 (TRP2), New York esophageal squamous cell carcinoma 1 (NY-ESO-1), Cyclin-dependent kinase 4 (CDK-4), 13-catenin, melanoma associated antigen (mutated) 1 (MUM1), Caspase-8, lysophosphatidylglycerol acyltransferase 1 (LPGAT1 , KIAA0205), Human papillomavirus (HPVE7), SpliceosomeAssociated Factor 1 (SART1), preferentially expressed antigen of melanoma (PRAME), multiple tumor suppressor 2 (p15), B melanoma antigen 1 (BAGE1), dystrophin- associated glycoproteins (DAG1), receptor for advanced glycation end products (RAGE1), N- acetylglucosamine (NAG), Tumor-associated glycoprotein 72 (TAG72), cancer antigen (CA125), RAS p21 protein activator 1 (p21 ras), protein 53 (p53), human papillomavirus type 16 (HPV16-E7), Synovial sarcoma, X breakpoint (SSX), human tumor antigen (HOM-MEL55), Type II Collagen (NY-COL2), HOM-HD397, HOM-RCC-1.14, HOM-HD21 , HOM-NSCLC11 , HOM-MEL-2.4, HOM-TES11 , RCC-3.1.3, cancer-testis antigen (NY-ESO-1), Melanoma Antigen (MAGE1 , MAGE2, MAGE3, MAGE4 MAGE-11), G antigen (GAGE1 , GAGE6), harvey rat sarcoma (Ha-ras), serine / threonine protein (RAF), disialoganglioside (GD2, GD3), GM2 ganglioside activator (GM2), transciprtion factors (TF), salmonella protein (sTn), glycoprotein 75 (gp75), latent membrane protein (EBV-LMP1 , EBV-LMP2), human papillomavirus type 16 (HPV-F4, HPV-F6, HPV-F7), prostate-specific antigen (PSA), alpha-fetoprotein (AFP), monoclonal antibody (C017-1A), epithelial cell adhesion molecule (GA733), glycoprotein 72 (gp72), placental protein 13 (13-HCG), glycoprotein 43 (gp43), heat shock protein (HSP-70), protein 17 (p17 mel), high-molecular-weight proteins (HMW), carcinoma-associated protein (HOJ-1), melanoma gangliosides, tumor-associated glycoprotein (TAG-72), melanoma- associated antigen 1 (MZ2-E), homeodomain-containing protein (PEM), trophoblast and ovarian cancer antigen (LK26), Thomsen-Friedenreich (T) antigen, Human chorionic gonadotropin (HOG), pancreatic oncofetal antigen, cancer antigens (15-3, 19-9, 549, 195), PROTACs, topoisomerase inhibitor, leukemia inhibitory factor and any combination thereof, each of which is bound via LTMto the central linker.11 . The compound of claim 10, wherein the targeting moiety comprises a PSMA binding group.

12. The compound of claim 11 , wherein the PSMA binding group is a peptide analogue selected from quisqualic acid, aspartate-glutamate (Asp-Glu), Glu-Glu, glycine-glutamate (Gly- Glu), y-glutamate-glutamate (y-Glu-Glu) and beta-N-acetyl-L-aspartate-L-glutamate (|3- NAAG), each of which is bound via LTMto the central linker13. The compound of claim 11 , wherein the PSMA binding group comprises glutamate-ureido- lysine (GUL):(GUL).

14. The compound of any one of claims 1 to 13, wherein the radiolabeling moiety comprises a radioisotope chelator or an Auger emitting moiety, bound via l_RLto the central linker.

15. The compound of claim 14, wherein the radioisotope chelator is 1 ,4,7- triazacyclononane(TACN); 1 ,4,7-triazacyclononane-triacetic acid (NOTA); 1 ,4,7-triazacyclononane-N-succinic acid-N',N"-diacetic acid (NOTASA); 1 ,4,7-triazacyclononane-N-glutamic acid-N',N"-diacetic acid (NODAGA); 1 ,4,7-triazacyclononane-N,N',N"-tris (methylenephosphonic) acid (NOTP); 1 ,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen); 1 ,4,7,10-tetraazacyclotridecane ([13]aneN4); 1 ,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA); 2-(1 , 4,7,10-tetraazacyclododecan- 1-yl)acetate (DO1A); 2, 2'-(1 ,4,7,10- tetraazacyclododecane-1 ,7-diyl) diacetic acid (DO2A); 2,2',2"-(1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triyl) triacetic acid (DO3A); 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetra(methanepnosphonic acid) (DOTP); 1 ,4,7,10- tetraazacyclododecane-1 ,7- di(methanephosphoriic acid) (DO2P); 1 ,4,7,10- tetraazacyclododecane-1 ,4,7-tri(methanephosphonic acid) (DO3P); 1 ,4,7,10-tetraazacyclo- decane-1 -glutamic acid-4,7, 10-triacetic acid (DOTAGA); 1 ,4,7,10-tetraazacyclodecane-1 - succinic acid-4,7,10- triacetic acid (DOTASA); 1 ,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam); 1 ,4,8,12-tetraazacyclopentadecane ([15]aneN4); 1 ,5,9,13- tetraazacyclohexadecane ([16]aneN4); 1 ,4-ethano- 1 ,4, 8, 11 -tetraazacyclo-tetradecane (et- cyclam); 1 ,4,8,11-tetraazacyclotetradecane-1 ,4,8,1 1-tetraacetic acid (TETA); 2-(1 ,4,8,11- tetraazacyclotetradecane- 1-y I) acetic acid (TE1A); 2,2'-(1 ,4,8,11-tetraazacyclotetradecane- 1 ,8-diyl) diacetic acid (TE2A); 4,11-bis(carboxy methyl)- 1 ,4,8,11-tetraazabicyclo[6.6.2]- hexadecane (CB-TE2A); 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (Sar); 1 ,4,7,10-tetra- (2-carbamoyl-methyl)-cyclododecane (TCMC); N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13- diaza-18-crown-6 (macropa), phthalocyanines; porphyrins; PCTA (3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-1(15),11 ,13-triene-3,6,9-triacetic acid); DEPA (7-[2- (biscarboxymethylamino)ethyl]-4, 10-biscarboxymethyl- 1 ,4,7, 10-tetraazacyclododec-1 -yl- acetic acid); DTPA (1 ,1 ,4,7,7-diethylenetriaminepentaacetic acid); CHX-DTPA (cyclohexane- 1 ,2-diamineN,N,N',N'-tetraacetate); BATPA (1 ,2-bis[2-aminophenoxy]ethane-N,N,N',N'- tetraacetic acid); TTHA (triethylenetetramineN,N,N',N",N"',N"'-hexaacetic acid); HBED (N,N - bis[2-hydroxybenzyl]ethylenediamine-N,N'-diacetic acid); EGTA (ethylene glycol bis[2- aminoethyl ether]-N,N,N',N'-tetraacetic acid); EDTMP (ethylenediamine tetra- [methylene phosphonic acid]); TRAP (triazacyclononate phosphinic acids); SHBED (N,N'-bis[2-hydroxy- 5- sulfobenzyl]ethylenediaminediacetic acid); H6Sbbpen(N,N'-bis-[2-hydroxy-5- sulfonylbenzyl]-N,N'-bis[2-methylpyridyl]ethylenediamine); THP (Tris(3,4-hydroxypyridinone); DFO (deferoxamine); FSC (Fusarinine); 6SS (N,N'-bis[2,2-dimethyl-2- mercaptoethyl]ethylenediamine-N,N'-diacetic acid); ECO (ethylenecysteamine cysteine); ECD(ethyl cysteinate dimer); NETA ([2-{4,7-biscarboxymethyl(1 ,4,7)triazacyclonona-1-yl- ethyl}carbonylmethylamino] acetic acid; THPN (Tetrakis(3-Hydroxy-4-Pyridinone)); H2dedpa (1 ,2-[{6-(carboxylato-)pyridin-2-yl}methylamino]- ethane); H4octapa (N,N'-bis[6-carboxy-2- pyridylmethyl]-ethylenediamine-N,N'-diacetic acid); H2bispa2 (6,6'-[{9-hydroxy-1 ,5-bis- (methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7- diyl}bis(methylene)]dipicolinic acid); DOTMP(1 , 4,7,10-Tetraazacyclododecane- 1 ,4, 7,10- tetrayl-tetrakis(methylphosphonic acid)); PEPA (1 ,4,7,10,13-pentaazocyclopentadecane pentaacetic acid); HEHA (1 ,4,7, 10,13, 16-hexaazocyclooctadecane hexaacetic acid); H2hox; H2CHXhox; H2octox; H2pyhox; H4neunopa; TETPA; H4pypa; H4py4pa; DTPAm; EGTAm; ampam; Me-3,2-HOPO; 3,4,3-(LI-1 ,2-HOPO); macrocyclic tetrapthalimide; or desferrioxamine (DFO) or any derivatives thereof, each of which is bound via l_RLto the central linker.

16. The compound of claim 15, wherein the radioisotope chelator is DOTA which is bound via LRLto the central linker.

17. The compound of any one of claims 1 to 16, wherein the compound of Formula I is a compound of Formula l-Dor a pharmaceutically acceptable salt and / or solvate thereof.

18. The compound of any one of claims 14 to 17, wherein the radioisotope chelator binds or chelates a radioisotope and the radioisotope is selected from11C,14C ,15N ,18F,32P,33P,35S,19. The compound of claim 18, wherein the radioisotope is any radioisotope for use in imaging or for use in therapy.

20. The compound of claim 14, wherein the radiolabeling moiety comprises an Auger emitting moiety21. The compound of claim 20, wherein the Auger emitting moiety comprises an Auger electron emitting radioisotope selected from125l,68Ga,18F,161Tb and177Lu.

22. The compound of claim 21 , wherein the Auger electron emitting radioisotope is125l.|12523. The compound of any one of claims 20 to 22, wherein the Auger emitting moiety is24. The compound of any one of claims 20 to 22, wherein the compound of Formula I is a compound of Formula l-E(i) or l-E(ii),or a pharmaceutically acceptable salt and / or solvate thereof.

25. The compound of any one of claims 4 to 24, wherein the central linker is a trivalent amino acid.

26. The compound of claim 25, wherein the trivalent amino acid is glutamate.

27. The compound of any one of claims 4 to 26, wherein l_RL, LDIand LTMare independently selected from a direct bond and a spacer linker.

28. The compound of claim 27, wherein each spacer linker independently comprises one or more groups selected from amino acid residues, Ci-2oalkylene, C2-2oalkenylene, and C2- 2oalkynylene, wherein each Ci.2oalkylene, C2-2oalkenylene and C2-2oalkynylene, is independently and optionally interrupted by one or more of a / an cycloalkylene, heterocycloalkylene, arylene, heteroarylene, ester, ethioester, carbamate, carbonate, amino, imido, ether, thioether, carbonyl, thiocarbonyl, sulfonyl, sulfoxide, urea, thiourea and amido group.

29. The compound of claim 27, wherein each spacer linker independently comprises one to eight groups selected from an amino acid residue, Wa, Ra, Ra-Wa, Wa-Rb, Ra-Wa-Rband Wa- Rb-Wb, wherein each Waand W13is independently selected from O, S, S(O), SO2, NR1, C(O), C(S), C(O)O, C(S)O, OC(O)NR1, NR1C(O)O, OC(O)O, O-N=C, S-S, NR1C(O), NR1C(S), C(O)NR1, C(S)NR1, (Ci-6alkyleneY)p, Y-(Ci-6alkyleneY')p, Z1-C3-i5cycloalkylene-Z2, Z1-Ce-i5arylene-Z2, Z1-C5-2oheteroarylenel-Z2and Z1-C3-2oheterocycloalkylene-Z2, each Raand Rbis independently selected from Ci.2oalkylene, C2-2oalkenylene, and C2. 2oalkynylene, each Y and Y' is independently selected from O, S, C(O) and NR2;each Z1and Z2are independently selected from a direct bond, O, S, C(O) and NR3;R1, R2and R3are independently selected from H and Ci-3alkyl; and; p is an integer selected from 1 to 8.

30. The compound of claim 29, wherein each Waand Wbis independently selected from O, S, S(O), SO2, NR1, C(O), C(S), C(O)O, C(S)O, OC(O)NR1, NR1C(O)O, OC(O)O, O-N=C, S-S, NR1C(O), NR1C(S), C(O)NR1, C(S)NR1, (Ci.6alkyleneY)p, Y-(Ci.6alkyleneY')p, Z1-C3. i5cycloalkylene-Z2, Z1-Ce-i5arylene-Z2, Z1-C5-2oheteroarylenel-Z2and Z1-C3. 2oheterocycloalkylene-Z2.

31. The compound of claim 30, wherein each Waand Wbis independently selected from O, NR1, C(O), NR1C(O), C(O)NR1, (Ci.6alkyleneY)p, Y-(Ci.6alkyleneY')p, Z1-C3.i5cycloalkylene-Z2, Z1-C6-isarylene-Z2, Z1-C5-2oheteroarylene-Z2and Z1-C3.2oheterocycloalkylene-Z2.

32. The compound of any one of claims 29 to 31 , wherein each Raand Rbis independently selected from Ci.^alkylene.

33. The compound of any one of claims 29 to 32, wherein each Y and Y' is independently selected from O, S, C(O) and NR2.

34. The compound of claim 33, wherein each Y and Y' is independently selected from O, C(O) and NR2.

35. The compound of any one of claims 29 to 34, wherein each Z1and Z2are independently selected from a direct bond, O, S, C(O) and NR3.

36. The compound of claim 35, wherein each Z1and Z2are independently selected from a direct bond, C(O) and NR3.

37. The compound of any one of claims 29 to 36, wherein each Wa-Rbis independently selected from NR1Ci-i2alkylene and C(O)Ci-i2alkylene.

38. The compound of any one of claims 29 to 36, wherein each R / V3is independently selected from Ci-i2alkyleneNR1, and Ci-i2alkyleneC(O).

39. The compound of any one of claims 29 to 38, wherein R1, R2and R3are independently selected from H and CH3.

40. The compound of any one of claims 29 to 37, wherein the amino acid residue in each spacer linker are independently selected from a naturally occurring amino acid residue, a modified amino acid residue, a D enantiomer of a naturally occurring amino acid, a D enantiomer of a modified amino acid, an unnatural amino acid, a |3- amino acid residue or a y- amino acid residue, and combinations thereof.

41. The compound of claim 40, wherein the modified amino acid residue is selected from, 4- carboxy-L-phenylalanine (Cbp), hydroxyproline, y-carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2- aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tertiary-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3- diaminoproprionic acid (Dap), N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo- hydroxylysine, 3-hydroxyproline, 4- hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N- methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid, thioproline, hydroxyproline, and 4-(aminomethyl)cyclohexane- 1 -carboxylic acid (e.g. tranezamic acid), and combinations thereof.

42. The compound of claim 41 , wherein the modified amino acid residue is selected from o naphthalaninyl:4-(aminomethyl)cyclohexane-1 -carboxyl: oor combinations thereof.

43. The compound of claim 29, wherein LDIis a direct bond or a spacer linker comprising one Wa-Rband the Wa-Rbin LDIis selected from NR1Ci-i2alkylene and C(O)Ci-i2alkylene.

44. The compound of claim 29, wherein l_RLis a direct bond.

45. The compound of claim 29, wherein LTMis selected from a direct bond and46. The compound of claim 4, wherein compound of Formula I is selected from the following list of compounds,or a pharmaceutically acceptable salt and / or solvate thereof.

47. A radioisotope complex or a pharmaceutically acceptable salt and / or solvate thereof, comprising a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof as defined in any one of claims 4 to 17 and a radioisotope as defined in claim 18.

48. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 46 or a pharmaceutically acceptable salt and / or solvate thereof or the complex of claim 47 or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

49. A kit comprising a compound as defined in any one of claims 1 to 46 or a pharmaceutically acceptable salt and / or solvate thereof or the complex of claim 47 or a pharmaceutically acceptable salt and / or solvate thereof, and instructions for administration of the compound or complex or a pharmaceutically acceptable salt and / or solvate thereof, to a subject in need thereof.

50. A method of treating a disease, disorder or condition comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 46 or a pharmaceutically acceptable salt and / or solvate thereof or the complex of claim 47 or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof, wherein the disease, disorder or condition is cancer.51 . The method of claim 50, wherein the cancer is prostate cancer or a neuroendocrine tumor.

52. The method of claim 50, wherein the cancer is a PSMA-positive cancer.

53. A method of imaging a tissue in a subject in need thereof by administering an imaging effective amount of a compound as defined in any one of claims 1 to 46 or a pharmaceutically acceptable salt and / or solvate thereof or the complex of claim 47 or a pharmaceutically acceptable salt and / or solvate thereof to the subject and applying an imaging technique to detect emitted radiation.

54. A method of diagnosing cancer in subject by administering a diagnostic effective amount of a compound as defined in any one of claims 1 to 46 or a pharmaceutically acceptable salt and / or solvate thereof or the complex of claim 47 or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof and applying an imaging technique to detect emitted radiation.

55. A method of theranostic treatment comprising administering an effective amount of a compound as defined in any one of claims 1 to 46 or a pharmaceutically acceptable salt and / or solvate thereof or the complex of claim 47 or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof and performing a medical diagnostic method on the subject.

Images