Radiolabelled compounds

Abstract

The present invention relates to methods for the synthesis of radiolabelled compounds. The invention also relates to use of the radiolabelled compounds obtained by said methods in medicine.

Description

[0001] RADIOLABELLED COMPOUNDS

[0002] TECHNICAL FIELD

[0003] The present invention relates to methods for the synthesis of radiolabelled compounds. The invention also relates to use of the radiolabelled compounds obtained by said methods in medicine.

[0004] BACKGROUND OF THE INVENTION

[0005] Radiolabelled compounds are useful in diagnosis and therapy. The present invention relates to a method for synthesis of radiohalogenated compounds which enables incorporation of radiohalogens in a facile manner.

[0006] Using prosthetic groups (i.e. small radiolabelled organic molecules which can then be coupled to the main pharmacophore of interest) is the strategy generally employed when labelling peptides or other macromolecules to overcome the limitations of radioactive halogens, for example, basicity and poor reactivity in the case of18F. The approaches used to date all vary in the number of steps involved, the overall reaction time, isolated yield and method of isolation.

[0007] A problem associated with radiohalogenated compounds in vivo is the removal of the halogen by the body (dehalogenation) from those compounds and localisation of the free halide in tissues such as the thyroid and stomach. This results in lower bioavailability of the compounds and leads to non-specific physiologic uptake. This impacts the ability to use the radiolabelled compounds for diagnostic and therapeutic use. Thus a facile radiohalogenation method that prevents or reduces the degree of in vivo dehalogenation is desired.

[0008] SUMMARY OF THE INVENTION

[0009] The present invention provides a method that proceeds through a synthetic intermediate that enables versatile incorporation of radiohalogens into building blocks via a click reaction.

[0010] Accordingly, in a first aspect, described herein is method for the preparation of a radiolabelled compound of Formula 2:

[0011] Formula 2 or a salt or solvate thereof; said method comprising reaction of a compound of Formula 1 :

[0012] Formula 1 or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:

[0013] R1is selected from Ce-ioary I , C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen;

[0014] A is selected from R2aor R2b; wherein:

[0015] R2ais a functional group capable of undergoing a click reaction;

[0016] R2bis a group of formula: wherein:

[0017] Y is a functional group that results from a click reaction;

[0018] L is a linker group; and

[0019] B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule; each Rzis independently -CH2OC1-6 alkyl, -CH2OH, -COOH or -COO-; or each Rzmay be taken together with the atom to which they are attached to form a 6- to 8- membered heterocycle comprising 2 O atoms; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; and where each Rzis COO-, the compound of Formula 2 may be a compound of Formula X:

[0020] (Ligand)x

[0021] Formula X where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

[0022] The compound of Formula 2 may be a compound of Formula II or Formula X: (Ligand)x

[0023] Formula IIorFormula X

[0024] The compound of Formula 1 may be a compound of Formula I or Formula Y:

[0025] Also described herein is method for the preparation of a radiolabelled compound of Formula II or

[0026] Formula X:

[0027] (Ligand)x

[0028] Formula IIorFormula X or a salt or solvate thereof; said method comprising reaction of a compound of Formula I or Formula Y: or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:

[0029] R1is selected from Ce-ioary I , C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen; A is selected from R2aor R2b; wherein:

[0030] R2ais a functional group capable of undergoing a click reaction;

[0031] R2bis a group of formula: wherein:

[0032] Y is a functional group that results from a click reaction;

[0033] L is a linker group; and

[0034] B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule;

[0035] R3is C1-6 alkyl or H;

[0036] R4is C1-6 alkyl or H; or

[0037] R3and R4are taken together with the atoms to which they are attached to form a 6- to 8- membered heterocycle; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

[0038] The reaction of a compound of Formula I or Formula X, or a salt or solvate thereof, with a nucleophilic radioactive halide source may be carried out in the presence of a phase transfer catalyst.

[0039] The compound of Formula II may be a compound of Formula Ila:

[0040] Formula Ila or a salt or solvate thereof; and said method may comprise reaction of a compound of Formula la:

[0041] Formula la or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:

[0042] R2ais a functional group capable of undergoing a click reaction; optionally wherein R2ais an azide or C2-8 alkynyl. Alternatively, the compound of Formula II or Formula X may be a compound of Formula III or Formula Z:

[0043] (Ligand)x

[0044] Formula IIIorFormula Z or a salt or solvate thereof; and said method may comprise reaction of a compound of Formula lb of Formula Yb: or a salt or solvate thereof; with a nucleophilic radioactive halide source.

[0045] The compound of Formula Yb:

[0046] Formula Yb may be prepared by oxidation and complexation of a compound of Formula lb:

[0047] Formula lb In a second aspect, described herein is a compound obtained by the method of synthesis of the first aspect of the invention. Said compound may be useful in therapy. In a third aspect, described herein is a compound described herein for use in therapy. The compound described herein may be for use in therapy or may be for use in treating cancer; or proliferative diseases, for example pulmonary arterial hypertension.

[0048] In a fourth aspect, described herein is a method of treatment, comprising administering a compound described herein to a subject. The method may be a method of treating cancer; or proliferative diseases, for example pulmonary arterial hypertension.

[0049] In a fifth aspect, described herein is a compound described herein for use in diagnosis of a disease or disorder in a subject. The disease or disorder may be cancer or a proliferative disease, such as pulmonary arterial hypertension.

[0050] In a sixth aspect, described herein is a method of diagnosing a disease or disorder in a subject, comprising administering a compound described herein to the subject. The disease or disorder may be cancer or a proliferative disease, such as pulmonary arterial hypertension.

[0051] In a seventh aspect, described herein is a compound described herein for use in treating cancer; or proliferative diseases, for example pulmonary arterial hypertension, in a subject, wherein the treatment is a theranostic therapy.

[0052] In a eighth aspect, described herein is a method of treatment, comprising administering a compound described herein to a subject, wherein the method is a theranostic method. The disease or disorder may be cancer or a proliferative disease, such as pulmonary arterial hypertension.

[0053] Embodiments described herein in relation to the first aspect of the present invention apply mutatis mutandis to the second to eighth aspects of the present invention.

[0054] DETAILED DESCRIPTION

[0055] Described herein is a synthetic method in which sulfonate compounds of Formula 1 undergo nucleophilic substitution reaction with radioactive halide in the presence of a phase transfer catalyst. The methods described herein enable provision of radiohalide-tagged pharmaceutically-active compounds (e.g., of Formula III or Formula Z).

[0056] Sulfonate compounds of Formula 1 , Formula I and Formula Y are surprisingly stable, can be stored for long periods of time under normal laboratory conditions and are easy to handle. The sulfonate-bearing compounds also feature a functional group which is capable of undergoing a click reaction to facilitate click chemistry.

[0057] The resulting radiolabelled compounds of Formula 2, Formula II and Formula X can be used as radiolabelled prosthetic groups that are incorporated into biologically or pharmaceutically active molecules, for example a targeting motif, or, alternatively, the sulfonate starting material can be coupled with a biologically or pharmaceutically acceptable molecule prior to radiohalogenation. The radiolabelled compounds can be coupled with biologically or pharmaceutically active molecules using click chemistry, e.g. to form compounds of Formula III.

[0058] The radiolabelled compounds of Formula 2, Formula II and Formula X are surprisingly stable to in vivo dehalogenation. Without being bound by theory, it is thought that this is, at least in part, due to the presence of the 1 ,3-diol moiety.

[0059] Reactions of the invention enable synthesis of radiohalogenated compounds which do not readily undergo dehalogenation in vivo. This is beneficial because it improves bioavailability of the compounds and improves specificity of physiological uptake. This provides for improved therapeutic and diagnostic compounds.

[0060] Various aspects and embodiments are disclosed herein. It will be recognised that features specified in each embodiment may be combined with other specified features to provide further embodiments.

[0061] Described herein is a method for the synthesis of a radiolabelled compound of Formula 2:

[0062] Formula 2 or a salt or solvate thereof; said method comprising reaction of a compound of Formula 1 :

[0063] Formula 1 or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:

[0064] R1is selected from Ce-ioary I , C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen;

[0065] A is selected from R2aor R2b; wherein:

[0066] R2ais a functional group capable of undergoing a click reaction;

[0067] R2bis a group of formula: wherein:

[0068] Y is a functional group that results from a click reaction;

[0069] L is a linker group; and

[0070] B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule; each Rzis independently -CH2OC1-6 alkyl, -CH2OH, -COOH or -COO-; or each Rzmay be taken together with the atom to which they are attached to form a 6- to 8- membered heterocycle comprising 2 O atoms; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; and where each Rzis COO-, the compound of Formula 2 may be a compound of Formula X:

[0071] (Ligand)x

[0072] Formula X where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

[0073] Also described herein is a method for the synthesis of a radiolabelled compound of Formula II or Formula X:

[0074] (Ligand)x

[0075] Formula IIorFormula X or a salt or solvate thereof; said method comprising reaction of a compound of Formula I or Formula Y: or a salt or solvate thereof; with a nucleophilic radioactive halide source (optionally in the presence of a phase transfer catalyst); wherein: R1is selected from Ce-ioary I , C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen;

[0076] A is selected from R2aor R2b; wherein:

[0077] R2ais a functional group capable of undergoing a click reaction;

[0078] R2bis a group of formula: wherein:

[0079] Y is a functional group that results from a click reaction;

[0080] L is a linker group; and

[0081] B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule;

[0082] R3is C1-6 alkyl or H;

[0083] R4is C1-6 alkyl or H; or

[0084] R3and R4are taken together with the atoms to which they are attached to form a 6- to 8- membered heterocycle; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

[0085] The method may preferably comprise radiohalogenation of a compound of Formula I, comprising hydroxy groups that are optionally protected as an acetal group, i.e. R3and R4are each independently C1-6 alkyl or H, or R3and R4are taken together with the atoms to which they are attached to form a 6- to 8-membered heterocycle; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups.

[0086] Alternatively, the method may comprise radiohalogenation of a metal complex of Formula Y. In compounds of Formula Y the moiety CH2OR3and CH2OR4are each oxidised and complexed with a metal ion to form a metal for example a platinum complex of the formula below:

[0087] The diol moiety in Formula I may be oxidised to a di-acid and then complexed to form a metal complex of Formula Y. The methods described herein may involve a radiohalogenation reaction step and a click reaction step. The radiohalogenation reaction step may be carried out first, followed by the click reaction (see, e.g. Scheme 1A). Accordingly, the compounds of Formula Ila described herein are radiolabelled intermediates that may be use to radiolabel biological molecules or pharmaceutically active molecules.

[0088] Alternatively, the click reaction step may be carried out first and the resulting compound may be subjected to the radiohalogenation reaction step (see, e.g., Scheme 1 B).

[0089] Scheme 1: synthetic methods described (variables defined herein)

[0090] Radiohalogenation Click reaction step

[0091] Formula lastepFormula Ila Formula III

[0092] Formula la Click reaction step Formula lb Radiohalogenation step Formula III

[0093] Accordingly, also described herein is a method of synthesising a compound of Formula Ila:

[0094] Formula Ila or a salt or solvate thereof; and said method comprises reaction of a compound of Formula la:

[0095] Formula la or a salt or solvate thereof; with a nucleophilic radioactive halide source (optionally in the presence of a phase transfer catalyst); wherein: R2ais a functional group capable of undergoing a click reaction.

[0096] The method may further comprise reaction of the compound of Formula Ila:

[0097] Formula Ila or a salt or solvate thereof; with a compound of Formula IV:

[0098] R6— L— B

[0099] Formula IV or a salt or solvate thereof; to form a radiolabelled compound of Formula III:

[0100] Formula III or a salt or solvate thereof; wherein the reaction is a click reaction; and wherein:

[0101] R6is a functional group capable of undergoing a click reaction with R2a.

[0102] Alternatively, also disclosed herein is a method of synthesising a compound of Formula III:

[0103] Formula III or a salt or solvate thereof; and said method comprises reaction of a compound of Formula lb:

[0104] Formula lb or a salt or solvate thereof; with a nucleophilic radioactive halide source (optionally in the presence of a phase transfer catalyst).

[0105] The method may further comprise preparation of the compound of Formula lb:

[0106] Formula lb or a salt or solvate thereof; by reaction of a compound of Formula la:

[0107] Formula la or a salt or solvate thereof; with a compound of Formula IV:

[0108] R6— L— B

[0109] Formula IV or a salt or solvate thereof; wherein the reaction is a click reaction.

[0110] Each Rz(e.g., including R3and R4) is independently -CH2OC1-6 alkyl, -CH2OH, -COOH or -COO-, or each Rzmay be taken together with the atom to which they are attached to form a 6- to 8-membered heterocycle comprising 2 O atoms; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups.

[0111] It will be appreciated that where each Rzis taken together with the atom to which they are attached to form a 6- to 8-membered heterocycle, this may enable protection of the oxygen atoms to which each Rzare attached. These groups may be deprotected after the radiohalogenation step to form the diol compound, i.e. , where each Rzis -CH2OH.

[0112] Radiohaloqenation reaction step

[0113] The methods described herein comprise a reaction of a compound of Formula I or Formula Y, or a salt or solvate thereof, with a nucleophilic radioactive halide source, to form a radiohalide-labelled compound of Formula II or Formula X. This reaction may be described as a radiohalogenation reaction step. The reaction may be carried out in the presence of a phase transfer catalyst.

[0114] The radiohalogenation reaction may proceed by SN2-type nucleophilic substitution reaction. A nucleophilic substitution reaction is a reaction in which a nucleophile displaces a leaving group from a compound. The reaction may follow a concerted mechanism, for example as described herein. A SN2- type reaction is generally bimolecular. In the processes described here, the reaction occurs between a compound of Formula I or Formula Y and a nucleophilic radioactive halide source. The reaction may proceed with inversion of stereochemistry at the reaction site. The radiohalogenation reaction may be carried out prior to a click reaction step. The product of the radiohalogenation reaction may subsequently be subjected to a click reaction. Alternatively, the radiohalogenation reaction step may be subsequent to a click reaction step, in which case the compound of Formula I or Formula Y may comprise a functional group that results from a click reaction.

[0115] In the methods described herein, the nucleophilic radioactive halide source acts as the nucleophile in the radiohalogenation reaction. The radioactive halide source is a reagent capable of delivering a radioactive halide ion, i.e. [X*]- under the reaction conditions. The radiohalide source may be an alkali metal salt or an alkaline earth metal salt. The radiohalide source may be an alkali metal salt. The radiohalide source may be a sodium salt. The radiohalide source may be a potassium salt.

[0116] In the compounds described herein, X* is a radioactive halide, i.e. a radiohalide. “Radioactive” describes an atom or ion that undergoes spontaneous nuclear transformation accompanied by the emission of radiation. The radiation may be in the form of alpha particles, beta particles or gamma radiation. “Radiohalide” means an radioactive anion with -1 charge derived from a radioactive halogen atom. “Halogen” means fluorine, chlorine, bromine, iodine or astatine. “Halide” means an anion derived from a halogen atom with -1 charge. Thus, the nucleophile may be a radiohalide ion.

[0117] The radiohalide source may deliver a radioactive iodide ion, a radioactive bromide ion, a radioactive astatide ion or a radioactive fluoride ion. The radiohalide source may deliver a fluoride-18 ion, an iodide-123 ion, an iodide-124 ion, an iodine-125 ion, an iodide-131 ion, an astatide-21 1 ion, a bromide-75 ion, a bromide-76 ion or a bromide-80 ion.

[0118] X* may be selected from radioactive iodide, radioactive bromide, radioactive astatide and radioactive fluoride. X* may be selected from fluoride-18, iodide-123, iodide-124, iodine-125, iodide-131 , astatide-21 1 , bromide-75, bromide-76 and bromide-80. Preferably, X* is iodide-123, iodide-124 or iodide-131. Thus, preferably, the compounds described herein are radioiodine-labelled.

[0119] In the compounds described herein, R1-S(O)2-O- represents a substituent that acts as a leaving group in the radiohalogenation reaction. As used herein, “leaving group” refers to an atom or group of atoms which, under the reaction conditions, becomes detached from an atom in what is considered to the residual or main part of the reaction substrate. A leaving group may be charged or uncharged. Thus, in the radiohalogenation reaction step described herein, the leaving group may be a sulfonate, [R1- S(O)2-O]-. For example, the leaving group may be a tosylate.

[0120] In the compounds described herein, R1is selected from Ce-ioaryl, C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen; R1may be selected from the group consisting of Ce-ioaryl and 5- to 10-membered heteroaryl; and wherein Ce-ioaryl, 5- to 10-membered heteroaryl may be further substituted with C1-6 alkyl, halogen or -NO2. R1may be Ce-ioaryl optionally substituted with C1-6 alkyl, halogen or -NOo. R1may be Ce-ioaryl, optionally substituted with one or more Ci-ealky I. R1may be Ce-ioaryl, substituted with one or more C1- ealky I. R1may be Ce-ioaryl, substituted with one or more methyl. R1may be phenyl substituted with one methyl group.

[0121] The radiohalogenation reaction step may be carried out in the presence of a phase transfer catalyst.

[0122] A phase transfer catalyst is a compound that facilitates the transition of one or more reactants from one phase to another. A phase transfer catalyst may facilitate the transfer of an ionic reagent from an aqueous phase to an organic solvent phase. A phase transfer catalyst may facilitate the solvation of an ionic reagent or salt in an organic solvent.

[0123] In the reactions described herein, the phase transfer catalyst may be used to facilitate the radiohalogenation reaction with the nucleophilic radioactive halide source.

[0124] Examples of phase transfer catalysts that may be used in the present radiohalogenation reaction include, but are not limited to quaternary ammonium salts. A quaternary ammonium salt may have the structure: [NR4]+[counterion]_, wherein each R is independently alkyl or aryl, for example Ci-ioalkyl or Ce-ioaryl. Counter ions include halides, hydrogen sulfates, and thiosalicylates. A quaternary ammonium salt may be a methyltrioctylammonium or benzyltriethylammonium salt. Quaternary ammonium salts include, for example methyltrioctylammonium halide; for example methyltrioctylammonium chloride or methyltrioctylammonium bromide; methyltrioctylammonium hydrogen sulfate, methyltrioctylammonium bis(trifluoromethylsulfonyl)imide, methyltrioctylammonium thiosalicylate; benzyltriethylammonium halide; for example benzyltriethylammonium chloride or benzyltriethylammonium bromide.

[0125] The radiohalogenation reaction step may further be carried out in the presence of an ionic liquid. An ionic liquid is a salt that is in the liquid state at room temperature and pressure (e.g., 20 °C and 101 kPa).

[0126] The phase transfer catalyst itself may be an ionic liquid and therefore may function as the ionic liquid in the radiohalogenation reaction step. A compound may be considered to be both a phase transfer catalyst and an ionic liquid. A compound may act as both a phase transfer catalyst and an ionic liquid under the radiohalogenation reaction conditions.

[0127] Examples of ionic liquids that may be used in the radiohalogenation reaction described herein include, but are not limited to, 1-butyl-3-methylimidazolium salts, quaternary ammonium salts, pyridinium salts, pyrrolidinium salts, imidazolium salts or phosphonium salts. Examples of 1-butyl-3-methylimidazolium salts may have formula [1-butyl-3-methylimidazolium][counterion]; where [counterion] is a halide, tetrafluoroborate, bis(trifluoromethylsulfonyl)imide, trifluoromethanesulfonate, hexafluorophosphate, octyl sulfate, hydrogen sulfate. For example, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid ([bmim][NTf2]) may be used.

[0128] When the phase transfer catalyst does not also act as an ionic liquid, preferably the radiohalogenation reaction step is preferably also carried out in the presence of base.

[0129] The radiohalogenation reaction may be carried out in the presence of base. The radiohalogenation reaction may be carried out in the absence of base. Suitable bases that may be used in the reaction include but are not limited to alkaline metal hydroxides, for example, sodium hydroxide and potassium hydroxide.

[0130] Preferably, when the radiohalogenation reaction does not comprise an ionic liquid, the reaction is carried out in the presence of base. When the radiohalogenation reaction does not comprise an ionic liquid, the reaction may be carried out at a temperature of at least about 100°C, at least about 1 10°C, at least about 120°C, at least about 130°C, at least about 140°C, at least about 150°C. The reaction may be carried out at a temperature of up to about 300°C, up to about 250°C or up to about 200°C. The reaction may be carried out at a temperature of from about 100°C to about 200°C. For example, the reaction may be carried out at about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160°C, about 170°C, about 180°C, about 190°C, about 200°C. Preferably, when the radiohalogenation reaction does not comprise an ionic liquid, the reaction may be carried out at about 150°C.

[0131] The radiohalogenation reactions described herein may be carried out neat, i.e. in the absence of an additional reaction solvent. When the reaction is carried out neat, the reaction mixture may consist of the compound of Formula I, the nucleophilic radioactive halide source, the phase transfer catalyst, the compound of Formula II and optionally, an ionic liquid (and optionally a base). When present, the ionic liquid may act as the reaction solvent.

[0132] The radiohalogenation reaction described herein may be carried out in the presence of an additional reaction solvent. The reaction solvent may be an organic solvent. When the reaction is carried out in the presence of an organic solvent, the reaction mixture may consist of the compound of Formula I, the nucleophilic radioactive halide source, the phase transfer catalyst, the compound of Formula II, an organic solvent and optionally, an ionic liquid (and optionally a base). Examples of organic solvents include, but are not limited to, dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), diethyl ether, ethyl acetate, acetone, dichloromethane, chloroform, toluene, xylene, light petroleum ether (b.p. 40-60°C), hexane, and pentane. Preferably, the radiohalogenation reaction is carried out in dimethylformamide (DMF) or dimethylsulfoxide (DMSO). The radiohalogenation reaction may be carried out under basic pH conditions. The nucleophilic radioactive halide source may be provided in a solution with a base, for example as described herein.

[0133] The radiohalogenation reactions described herein may be carried out at a range of temperatures. The radiohalogenation reactions described herein may be carried out at elevated temperature. The radiohalogenation reactions described herein may be carried out at room temperature. The radiohalogenation reaction may be carried out at a temperature of at least about 20°C, at least about 30°C, at least about 40°C, at least about 50°C, at least about 75°C, at least about 100°C. The reaction may be carried out at a temperature of up to about 300°C, up to about 250°C or up to about 200°C. The reaction may be carried out at a temperature of from about 20°C to about 200°C. For example, reactions described herein may be carried out at about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160°C, about 170°C, about 180°C, about 190°C, about 200°C. Preferably, the radiohalogenation reactions described herein is carried out at about 100°C.

[0134] Click reaction step

[0135] In the compounds of Formula I or Formula Y, A is selected from R2aor R2b. A is a functional group capable of undergoing a click reaction or A comprises a functional group that results from a click reaction.

[0136] The methods described herein therefore may comprise a click reaction step. The use of click chemistry enables the attachment of a group derived from a biological molecule or pharmaceutically active molecule to the radiohalide-labelled compound.

[0137] A click reaction is an atom economical means of joining two functional groups. Click reactions are typically high yielding and generate few by-products. Click reactions may be conducted under aqueous conditions. Click reactions may be characterised by a high thermodynamic driving force. Click reactions may be irreversible. Click reactions may produce a single reaction product with high reaction specificity. Click reactions may be used to attach a probe, reporter molecule or substrate of interest to a specific biomolecule.

[0138] Click reactions may involve cycloaddition. An example of a click reaction is the 1 ,3-dipolar cycloaddition between a 1 ,3-dipole and a dipolarophile. A 1 ,3-dipole is a dipolar compound with delocalized electrons and a separation of charge over three atoms. Dipolar compounds are those that exhibit a dipole moment. Examples of 1 ,3-dipoles include but are not limited to azides; ozones; nitro compounds; diazo compounds; oxides such as azoxides, nitrile oxides, nitrous oxide, nitrones; imines such as azomethine imines, nitrilimines, carbonyl imines; ylides such as azomethine ylides, nitrile ylides, carbonyl ylide, thiosulfines. A dipolarophile is a compound that readily reacts with a dipolar compound. In a 1 ,3-dipolar cycloaddition reaction, the dipolarophile is typically an alkene or alkyne, but can be other ir systems. The alkene may be cyclooctene. Heteroatom-containing dipolarophiles such as carbonyls and imines can also undergo

[0139] 1 .3-dipolar cycloaddition. When the dipolarophile is an alkyne, aromatic rings are generally produced. The alkyne may be terminal. The alkyne may be non-terminal. The alkyne may form part of a carbocyclic ring. The alkyne may be cyclooctynyl. The alkyne containing reactant may be a strained system.

[0140] When the 1 ,3-dipole is an azide and the dipolarophile is an alkyne, a 1 ,2,3-triazole ring is produced. The 1 ,3-dipolar cycloaddition between an azide and an alkyne is an example of a click reaction and is also known as the Huisgen cycloaddition.

[0141] Further examples of click reactions include [3+2] cycloaddition of an azide and an alkyne, 1 ,3-dipolar cycloaddition, strain-promoted azide-alkyne cycloaddition (SPAAC), copper-catalysed azide-alkyne cycloaddition (CuAAC), copper-catalysed azide-alkyne cycloaddition (RuAAC), strain-promoted alkyne-nitrone cycloaddition (SPANC), strain-promoted azide-alkene [3+2] cycloaddition, [4+2] cycloaddition of a conjugated diene and an alkene (Diels Alder reaction), and [4+1] cycloaddition between isonitriles and tetrazines. Click reactions may also include thiol-ene reactions, thiol-yne reactions, nucleophilic substitution, nucleophilic ring opening of aziridines and epoxides, addition to carbon-carbon double bonds, and non-Aldol type carbonyl reactions.

[0142] Click reactions involve reaction of two functional groups, for example FG1 and FG2, to generate a product which contains P, a functional group that results from a click reaction. FG1 and FG2 are functional groups capable of undergoing a click reaction. FG1 and FG2 are complementary, that is FG1 and FG2 react with each other to undergo a click reaction. In the compounds and processes described herein, FG1 and FG2 are moieties present on compounds of Formula la or Formula Ila and compounds of Formula IV.

[0143] FG1 and FG2 may be a dipole and a dipolarophile. P may be a cyclic moiety. P may be aromatic. P may be a hetero aromatic ring. P may be an aromatic ring. P may be a heterocyclic ring.

[0144] FG1 and FG2 may be an azide and an alkyne. FG1 may be an azide. FG2 may be an alkyne. FG2 may be a terminal alkyne. When FG1 is an azide and FG2 is an terminal alkyne, P is a substituted

[0145] 1 .2.3-triazole.

[0146] FG1 and FG2 may form part of separate molecules. FG1 and FG2 may undergo an intermolecular click reaction. The reaction described herein is an example of an intermolecular click reaction.

[0147] Alternatively, a click reaction may be an intramolecular click reaction, i.e. where FG1 and FG2 are part of the same molecule. Described herein is an intermolecular click reaction between an azide and an alkyne. The azide may be a 1 ,3-dipole and the alkyne may be a dipolarophile. Described herein is an 1 ,3-dipolar cycloaddition reaction between an azide and an alkyne. The resulting product features a 1 ,2,3-triazole moiety. The 1 ,2,3-triazole moiety may be substituted.

[0148] Described herein are compounds that undergo a click reaction. For example, compounds of Formula la undergo a click reaction with a compound of Formula IV to form compound of Formula lb. Compounds of Formula Ila may undergo a click reaction with a compounds of Formula IV to form a compound of Formula III. Compounds of Formula G may undergo a click reaction with a compounds of Formula F to form compound of Formula A.

[0149] In the compounds described herein, R2ais a functional group capable of undergoing a click reaction. R2amay be an azide or an alkyne. R2amay be an alkyne. R2amay be a terminal alkyne.

[0150] R6is a functional group capable of undergoing a click reaction with R2a. R6may be a terminal group, attached via L to B, i.e. R6-L-B. Alternatively, R6may be a non-terminal group, for example taken with L to form a cyclic moiety (e.g. a cycloalkyl or heterocycloalkyl ring or ring system). For example, when R6is a non-terminal group (for example, alkyne), the compound may have structure:

[0151] R6may be an azide or an alkyne. R6may be a terminal azide or an alkyne.

[0152] Accordingly, R2amay be an azide and R6may be a C2-6 alkyne. Alternatively, R2amay be a C2-6 alkyne and R6may be an azide.

[0153] The click reactions described herein may be carried out in vivo. The click reactions described herein may be biorthogonal. The click reactions described herein may be used for in vivo labelling. The click reactions described herein may be used to install a therapeutic moiety. The click reactions described herein may be used to install a diagnostic moiety. The click reactions described herein may be used to install a detectable moiety. The click reactions described herein may be used to couple a therapeutic moiety to a targeting moiety. The click reactions described herein may be used to couple a diagnostic moiety to a targeting or therapeutic moiety.

[0154] The click reactions described herein may be carried out in the presence of a metal catalyst. The metal catalyst may be ligated, i.e. have ligands bound to the metal. Alternatively, the metal catalyst may not be ligated. The click reactions described herein may be carried out in the presence of a copper catalyst. For example, a copper catalyst may be used in the reaction of an azide with an alkyne to form a triazole ring. The copper catalyst may be a copper(l) catalyst. The catalyst may be generated in situ, for example by combining copper and the ligand compounds in situ. Examples of copper(l) catalysts include, but are not limited to: tetrakis(acetonitrile)copper(l) hexafluorophosphate ([Cu(CH3CN)4]PFe); copper(l) acetate (Cu(OAc)); imidazoline(mesythyl)copper bromide ((Imes)CuBr); copper(l) iodide; copper(l) bromide; copper(l) chloride; tris(triazolylmethyl)amine copper(l); copper(l) oxide (CU2O); and copper(0) / copper(ll) sulfate mixture (Cu(0) / CuSO4). The ligand compounds may be selected from: bathophenanthroline disulfonic acid, disodium salt BPS); tris-[(1-benzyl-1 H-1 ,2,3-triazol-4-yl)methyl] amine (TBTA); tris[(1-(2-ethoxy-2-oxoethyl)-1 H-1 ,2,3-triazol-4-yl)methyl]amine (TEOTA); tris[(1- hydroxypropyl-1 H-1 ,2,3-triazol-4-yl) methyl] amine (THPTA); 2-[4-{(bis [(1 -tert-butyl-1 H-1 ,2,3-triazol-4- yl)methyl] amino) methyl}-1 H-1 ,2,3- triazol- 1-yl] ethyl hydrogen sulfate (BTTES); 2-[4-{(bis[(1 -tert-butyl- 1 H1 ,2,3-triazol-4-yl)methyl]amino)methyl}-1 H-1 ,2,3-triazol-1-yl]-acetic acid (BTTAA); 3-[4-({bis[(1 -tert- butyl-1 H-1 ,2,3-triazol-4-yl)methyl]amino}methyl)-1 H-1 ,2,3-triazol1-yl]propanol (BTTP); and 3-[4- ({bis[(1 -tert-butyl-1 H-1 ,2,3-triazol-4-yl)methyl]amino} methyl)-1 H- 1 , 2 , 3-tri azo I- 1 -y I] pro py I hydrogen sulfate (BTTPS). The catalyst ligand may be BTA or BTTAA. For example, the ligand may be:

[0155] Bathophenanthrolinedisulfonic acid

[0156] BPDS The click reactions described herein may be carried out neat, i.e. in the absence of an additional solvent. The click reactions described herein may be carried out in the presence of an aqueous solvent, for example, water. The click reactions described herein may by carried out in organic solvent. The click reactions described herein may be carried out under aqueous conditions. Examples of organic solvents include, but are not limited to, dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), diethyl ether, ethyl acetate, acetone, diclholoromethane, chloroform, toluene, xylene, light petroleum ether (b.p. 40-60°C), hexane, pentane.

[0157] In the compounds described herein, R2bis a group of formula -Y-L-B; wherein: Y is a functional group that results from a click reaction; L is a linker group; and B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule.

[0158] In the compounds described herein, Y is therefore the moiety that results from the click reaction step, e.g. between R2aand R6. One of R2aor R6is selected from the group consisting of (i) or (ii) and the other of R2aor R6is selected from the group consisting of the other of (i) or (ii):

[0159] (i) a dipolarophile, for example, an azide; ozone; nitro compound; diazo compound; oxide such as azoxide, nitrile oxide, nitrous oxide, nitrone; imine such as azomethine imine, nitrilimine, carbonyl imine; ylide such as an azomethine ylide, nitrile ylide, carbonyl ylide, or thiosulfine.

[0160] (ii) a 1 ,3-dipole, for example, an alkyne, an alkene, or other ir system.

[0161] Y may be selected from the group consisting of: Cs-sheteroaryl ring or Cs-sheterocyclyl ring, wherein heterocyclyl may be partially unsaturated or fully saturated. Y may form part of a fused ring system. Y may be a C5-heteroaryl ring. Y may be a C5-heterocyclyl ring. Y may be a triazole. Preferably Y is a 1 ,2,3-triazole.

[0162] The click reaction described herein is a 1 ,3-dipolar cycloaddition. The click reaction described herein is a [3+2] cycloaddition. In the click reaction described herein, one of R2aand R6is an azide and the other of R2aand R6is an alkyne.

[0163] When one of R2aand R6is an azide and the other of R2aand R6is an alkyne in the click reaction described herein, Y is a 1 ,2,3-triazole.

[0164] Linker L

[0165] In the compounds described herein, L is a bond or linker group of formula -(Z)m-, wherein each Z is independently selected from -(CR72)-, -CEC-, -CR2C(O)O-, -NR7C(O)-, -C(O)NR-, -NR7C(O)NR7- , - NR7C(S)NR7-, -SO2NR7-, -NR7SO2-, -CR72OCR72-, -CR72SCR72-, -CR72NR7CR72- Cs-sheterocycloalkyl, Cs-scycloalkyl, Ce -ioaryl, 5- to 10-membered heteroaryl, an amino acid, a peptide, a sugar or polyethyleneglycol (PEG); each R7is independently selected from hydrogen, - C(O)NH(phenyl), hydroxy, Ci-salkyl, Ci-ealkoxy, C2-4alkenyl, C2-4alkynyl, hydroxyCi-ealkyl; and wherein phenyl may be further substituted with -CH2OC(O)O(p-NO2CeH4); and m is an integer of value 1 to 20. L may be hexanoyl-Val-Cit-PAB-PNP. The linking group hexanoyl-Val-Cit-PAB-PNP may be degraded by the lysosome.

[0166] L may have the following structure: wherein the attachment point of B is denoted by the grey circle and the attachment point of R6or Y is denoted by the grey square.

[0167] L may have the following structure: wherein the attachment point of B is denoted by the grey circle and the attachment point of R6or Y is denoted by the grey square.

[0168] Substituent derived from biological or pharmaceutically active molecule B

[0169] Compounds described herein may bear substituent B. B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule by removal of a hydrogen atom from a carbon, nitrogen or oxygen atom. As would be appreciated, the radiolabelling processes described herein may be used in conjunction with a wide range of biological or pharmaceutically active molecules. The processes described herein therefore represent a platform technology.

[0170] B may be derived from a therapeutic compound; a targeting compound; or a conjugate of therapeutic compound and a targeting compound.

[0171] B may be derived from a targeting compound or a conjugate of therapeutic compound and a targeting compound; and wherein the targeting compound is a DNA-targeting compound. B may be derived from a drug, peptide, or antibody; optionally a transporter substrate, transporter inhibitor, hexose compound, a tumour accumulating compound, a lysosomotropic drug, or histone deacetylase inhibitors; further optionally TOCA, chloroquine, sucrose, bafilomycin A1 , or histone deacetylase inhibitors C1 A and C1 B.

[0172] In the context of the invention, a therapeutic compound is a compound or chemical entity that binds to a target and causes a therapeutic effect when administered to a subject. A therapeutic compound may modulate a particular receptor, enzyme, protein, kinase, cell, tissue type or organ. A therapeutic compound may bind to an intracellular or extracellular receptor, an enzyme, a protein or a kinase.

[0173] The substituent derived from a therapeutic compound may facilitate transportation of the compounds described herein to the cell, tissue or organ of interest. A substituent derived from a therapeutic compound may facilitate transportation of the compounds described herein into a cell.

[0174] In the context of the invention, a targeting compound is a compound that targets and binds to a target, for example, an intracellular component.

[0175] An intracellular component is a structure or organelle within a cell, for example and intracellular organelle or DNA. The targeting compound may modulate an intracellular organelle or DNA. The targeting compound may modulate one or more intracellular organelles. The targeting compound may modulate the lysosome. The targeting compound may bind to DNA. The targeting compound may bind to the minor groove of DNA.

[0176] The substituent derived from a targeting compound may interact with an intracellular component, for example an intracellular organelle. The substituent derived from a targeting compound may interact with the lysosome. The substituent derived from a targeting compound may interact with DNA. The substituent derived from a targeting compound may bind to DNA. The substituent derived from a targeting compound may bind to the minor groove of DNA.

[0177] The substituent derived from a targeting compound may facilitate transportation of the compounds described herein to an intracellular component, for example, the lysosome or DNA. The substituent derived from a targeting compound may bring the compounds described herein into close proximity with an intracellular component, for example, the lysosome or DNA.

[0178] The targeting moiety is a univalent substituent derived from a biological molecule or a univalent substituent derived from a pharmaceutically active molecule. The univalent substituent of a biological molecule or a pharmaceutically active molecule is derived from the biological molecule or a pharmaceutically active molecule by removal of a proton. The biological molecule or a pharmaceutically active molecule may be a drug, peptide, antibody, transporter substrate, transporter inhibitor, hexose compound, and / or other tumour accumulating compound.

[0179] The substituent B may be derived from a drug, a peptide or an antibody. The substituent B may be derived from a transporter substrate, a transporter inhibitor, a hexose compound, and / or a tumour accumulating compound, a lysosomotropic drug, or a histone deacetylase (HDAC) inhibitor. The substituent B may be derived chloroquine, sucrose, bafilomycin A1 , and or histone deacetylase (HDAC) inhibitors C1A and C1 B. The substituent B may be derived from a lysosomotropic drug. Incorporation of substituent derived from a lysosomotropic drug may enable endosomal release. Incorporation of substituent derived from a lysosomotropic drug may disrupt endosomal localisation. Examples of lysosomotrpoic drugs include but are not limited to chloroquine, sucrose, bafilomycin A1 , and histone deacetylase (HDAC) inhibitors C1 A and C1 B (Br J Cancer, 119, 2018,1278-1287).

[0180] The substituent B may have structure: wherein W is somatostatin or an analogue thereof, for example, octreotide, lanreotide or pAG-TOCA; and Z is a bond or linker group of formula -(Z)m-, wherein each Z is independently selected from - (CR72)-, — C=C— , -CR2C(O)O-, -NR7C(O)-, -C(O)NR-, -NR7C(O)NR7-, - NR7C(S)NR7-, -SO2NR7-, -NR7SO2-, -CR72OCR72-, -CR72SCR72-, -CR72NR7CR72-, Cs-sheterocycloalkyl, Cs-scycloalkyl, Ce- ioaryl, 5- to 10-membered heteroaryl, an amino acid, a peptide, a sugar or a monodisperse polyethyleneglycol (PEG); each R7is independently selected from hydrogen, -C(O)NH(phenyl), hydroxy, Ci-salkyl, Ci-ealkoxy, C2-4alkenyl, C2-4alkynyl, hydroxyCi-ealkyl; and wherein phenyl may be further substituted with -CH2OC(O)O(p-NO2CeH4); and m is an integer of value 1 to 20. pAG-TOCA has the following structure, wherein the wavy line denotes the point of attachment:

[0181] Platinum motifs may be incorporated in substituent B. The substituent B may be derived from a platinum-containing therapeutic compound. The substituent B may be derived from cisplatin. The platinum-containing therapeutic compound may target and bind to DNA to cause a therapeutic effect. The platinum-containing therapeutic compound may target and bind to the minor groove of DNA to cause a therapeutic effect. The substituent B may be a Hoechst dye. Hoechst dyes are blue fluorescent dye compounds that may be used, for example, to stain DNA. Hoechst dyes may have the structure: wherein R may be one of the following:

[0182] Hoechst 332581 R = -OH

[0183] Hoechst 33342 | R = -OCH^CH

[0184] Hoechst 34580 | R = -NfCH,),.

[0185] Additional exemplary compounds of Formula IV include: wherein R6is an alkynyl group.

[0186] Radiohalogens

[0187] Radiolabelled compounds are useful in diagnosis and therapy. Radiolabelling may be carried out by incorporation of the corresponding radiohalide into a molecule of interest. The molecule of interest may be a biological molecule or a pharmaceutically active compound. Radiohalogens that may be employed include radioiodine, radioastatine, radiofluorine and radiobromine. Radiohalogens are typically incorporated as their anionic equivalents, radiohalides. Radiohalides that may be employed include radioiodide, radioastatide, radiofluoride and radiobromide. Radioisotopes that may be used in reactions and compounds of the invention include iodine-123, iodine-124, iodine-125, iodine-131 , fluorine-18, astatine-211 , bromine-75, bromine-76 and bromine-80. Thus, radiohalides that may be used in reactions and compounds of the invention include iodide-123, iodide-124, iodide-131 , fluoride-18, astatide-211 , bromide-75, bromide-76 and bromide-80.

[0188] Radiohalides that may be useful in methods of diagnosing disease include, but are not limited to, iodide-123, iodide-124, fluoride-18, bromide-75 and bromide-76.

[0189] Radiohalides that may be useful in methods of therapy include, but are not limited to, iodine-123, iodine- 131 , astatine-211 and bromide-80.

[0190] Iodide-123 is a radioactive isotope of iodide which undergoes radioactive decay by electron capture and emits a gamma ray. Iodide-123 may be used in nuclear medicine imaging, for example, single-photon emission computed tomography (SPECT). Iodide-123 may be used in methods of treatment. Iodide-123 may be used in methods of radiotherapy. Iodide-123 may be used in methods of treatment for cancer.

[0191] Iodide-124 is a radioactive isotope of iodide which undergoes radioactive decay by electron capture or positron emission. Iodide-124 may be used in nuclear medicine imaging, for example, positron emission tomography (PET).

[0192] Fluoride-18 is a radioactive isotope of fluoride which undergoes radioactive decay by positron emission or electron capture. Fluoride-18 may be used in nuclear medicine imaging, for example, positron emission tomography (PET).

[0193] Iodide-131 is a radioactive isotope of iodide which undergoes radioactive decay by beta decay. Iodide-131 may be used in methods of treatment. Iodide-131 may be used in methods of radiotherapy. Iodide-131 may be used in methods of treatment for cancer. Iodide-131 may also be used in nuclear medicine imaging.

[0194] Bromide-75 is a radioactive isotope of bromide which undergoes radioactive decay by beta decay and electron capture. Bromide-75 may be used in methods of treatment. Bromide-75 may be used in methods of radiotherapy. Bromide-75 may be used in nuclear medicine imaging, for example, positron emission tomography (PET).

[0195] Bromide-76 is a radioactive isotope of bromide which undergoes radioactive decay by beta decay and electron capture. Bromide-76 may be used in methods of treatment. Bromide-76 may be used in methods of radiotherapy. Bromide-76 may be used in nuclear medicine imaging, for example, positron emission tomography (PET). Bromide-80 is a radioactive isotope of bromide which undergoes radioactive decay by beta decay and electron capture. Bromide-80 may be used in methods of treatment. Bromide-80 may be used in methods of radiotherapy. Bromide-80 may be used in nuclear medicine imaging.

[0196] Exemplary synthetic methods

[0197] In the synthetic methods and compounds described herein, R1is selected from Ce -ioaryl, C1-6 alkyl and

[0198] 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen.

[0199] R1may be a phenyl substituted with methyl; R2amay be azide; R3and R4may be taken together with the atoms to which they are attached to form a 6-membered heterocycle, further substituted with a gem / na / -dimethyl group; and X* may be radioactive iodide.

[0200] R1may be phenyl substituted with methyl; R2amay be C2-alkyne; R3and R4may be taken together with the atoms to which they are attached to form a 6-membered heterocycle, further substituted with a gem / na / -dimethyl group; and X* may be radioactive iodide.

[0201] In the synthetic methods and compounds described herein, R2ais a functional group capable of undergoing a click reaction. R2amay be an azide. R2amay be a C2-8 alkynyl. R2amay be ethynyl.

[0202] In the synthetic methods and compounds described herein, R2bis a group of formula: wherein Y is a functional group that results from a click reaction; L is a linker group; and

[0203] B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule, as described herein. Y may be a heteroaryl ring. Y may be 1 ,2,3-triazole.

[0204] R3may be C1-6 alkyl or H; R4may be C1-6 alkyl or H; or R3and R4may be taken together with the atoms to which they are attached to form a 6- to 8-membered heterocycle; and the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups.

[0205] R3and R4may be taken together with the atoms to which they are attached to form a 6-membered heterocycle. The 6-membered heterocycle may be substituted by one or more C1-6 alkyl group. The

[0206] 6-membered heterocycle may be substituted by a geminal di-methyl group. Preferably the 6-membered heterocycle may be 1 ,3-dioxane. Preferably, the 6-membered heterocycle may be 1 ,3-dioxane substituted by a geminal di-methyl group at the 2-position.

[0207] R6is a functional group capable of undergoing a click reaction with R2a. R6may be an azide or C2-8 alkynyl. R6may be ethynyl. X* is a radioactive halide. X* may be fluoride-18, iodide-123, iodide-124, iodide-131 , astatide-211 , bromide-75, bromide-76 or bromide-80.

[0208] R1may be phenyl substituted at the para position with methyl; R2amay be azide; R3and R4may be taken together with the atoms to which they are attached to form a a 1 ,3-dioxane ring substituted by a geminal di-methyl group at the 2-position; and X* may be radioactive iodide, preferably iodide-123; R6may be ethynyl; Y may be 1 ,2,3-triazole.

[0209] Scheme 2: Exemplary synthetic method 1

[0210] Described herein is a method of synthesising a compound of Formula A in which the radiohalogenation reaction is carried out first, followed by the click reaction step, as shown in Scheme 2. The radiohalogenation reaction step comprises reaction of a compound of Formula C, or a salt or solvate thereof, with [123l]Nal in the presence of methyltrioctylammonium chloride to form the compound of Formula G (see Scheme 2). The click reaction step comprises reaction of a compound of Formula G with a compound of Formula F to form the compound of Formula A (see Scheme 2).

[0211] The compound of Formula A may then be deprotected to form the diol compound. Alternatively, the compound of Formula G may be deprotected before the click reaction step to form the diol compound which may then undergo the click reaction step.

[0212] Scheme 3: Exemplary synthetic method 2

[0213] Also described herein is a method of synthesising a compound of Formula A in which the click reaction step, followed by the radiohalogenation reaction step, as shown in Scheme 3. The click reaction step comprises reaction of a compound of Formula C with a compound of Formula F to form the compound of Formula E (see Scheme 3). The radiohalogenation reaction step comprises reaction of a compound of Formula E, or a salt or solvate thereof, with [123l]Nal in the presence of methyltrioctylammonium chloride to form the compound of Formula A (see Scheme 3).

[0214] The compound of Formula A may then be deprotected to form the diol compound.

[0215] The compound of Formula I or Formula C may be prepared from penta erythritol (C(C2HsOH)4).

[0216] The methods described herein may be for preparation of a compound of Formula X:

[0217] (Ligand)x

[0218] Formula X where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2. The metal may preferably be platinum. Ligand may be a bidentate ligand, in which case, x is preferably 1. Ligand may be a monodentate ligand, in which case x may be 2.

[0219] Ligand is preferably an amine ligand, for example a diamine. Ligand may be a C2-8 1 ,2-diamino alkyl or

[0220] C2-8 1 ,2-diamino cycloalkyl, for example selected from one of the following:

[0221] Accordingly, also described herein is a method of synthesising a compound of structure: which may then undergo a radiohalogenation reaction step, as shown in Scheme 4. The compound may be prepared starting with the acetal protected neopentylglycol tosyl intermediate, e.g. of Formula E. Said intermediate may be deprotected to form the diol, which can then be oxidised to form the corresponding acid. The acid may then be conjugated with platinum, for example as described in Liu et al., Oncotarget, 2017, vol. 8, (No. 24), pp: 39476-39496, the entire contents of which are herein incorporated by reference. Scheme 4: Further exemplary synthetic method

[0222] [123l]Nal methyltrioctylammonium chloride radiohalogenation step

[0223] In the methods described herein, R6may be a non-terminal group, for example taken with L to form a cyclic moiety (e.g. a cycloalkyl, cycloalkynyl, heterocycloalkyl or heterocycloalkynyl ring or ring system). For example, a compounds of Formula IV may have structure: wherein R6and L are taken together to form a cyclic alkyne. Exemplary reactions where R6forms a cyclic alkyne are set out in Scheme 5 below.

[0224] Scheme 5: Exemplary synthetic method 3

[0225] Each of the radiolabelled compounds produced by the above reactions may be conjugated to an antibody or fragment thereof to form compound of Formula II.

[0226] Also provided herein are compounds obtained by the methods of synthesis provided herein.

[0227] Definitions

[0228] As used herein, the term “biorthogonal” refers to any chemical reaction that can occur inside of a living system without interfering with native biochemical processes.

[0229] As used herein, the term “dipole” refers to a pair of separated opposite charges.

[0230] As used herein, the term “1 ,3-dipole” refers to an organic molecule that can be represented as either an allyl-type or a propargyl / allenyl-type zwitterionic octet / sextet structures. Both types of 1 ,3-dipoles share four electrons in the ir-system over three atoms.

[0231] As used herein, the term “dipolarophile” means any compound that reacts with a dipole. A dipolarophile may react with a 1 ,3-dipole in a cycloaddition reaction. Dipolarophiles are often alkenes or alkynes.

[0232] As used herein, the term “moiety” means a characteristic part of a molecule.

[0233] As used herein, the term “diagnostic moiety” or “detectable moiety” refers to a portion of a compound of the invention that provides a diagnostic effect in connection with a disease or disorder and permits visualisation of cells or tissues in which compounds of the invention accumulate.

[0234] As used herein, the term “isotope” refers to each of two or more forms of the same element that have the same number of protons but different numbers of neutrons in their nuclei.

[0235] As used herein, the term “radioisotope” means a radioactive isotope of an element.

[0236] As used herein, the term “halogen” means fluorine, chlorine, bromine, iodine or astatine. The term “halide” means an anion derived from a halogen atom with -1 charge.

[0237] As used herein, the term “radiohalide” means a radioactive anion with -1 charge derived from a radioactive of a halogen atom.

[0238] As used herein, the term “halogenation” means a chemical reaction in which a halide ion or halogen atom is introduced into a compound. As used herein, the term “aryl” refers to a substituent derived from an aromatic ring by removal of a proton. The term “aromatic ring” refers to an aromatic carbocyclic ring system. An aromatic ring system may be monocyclic or polycyclic. An aromatic ring may be fused to a heteroaromatic ring or a cycloalkyl group. An aromatic ring may have from 6 to 14 ring atoms. An aromatic ring may be a 6-membered aromatic ring, i.e. a phenyl ring.

[0239] As used herein, the term “heteroaryl” refers to a substituent derived from an heteroaromatic ring by removal of a proton. The term “heteraromatic ring” refers to an aromatic ring system wherein one or more of the ring-forming atoms is a heteroatom such as nitrogen, oxygen or sulfur. A heteroaromatic ring may be fused to an aromatic ring. A heteroaromatic ring may have from 5 to 14 ring atoms. A heteroaromatic ring may be a 5-membered heteroaromatic ring that contains one to three heteroatoms selected from O, S and N, for example, triazole.

[0240] Unless otherwise defined, the term “alkyl” as used herein refers to a saturated hydrocarbon which may be straight-chain, branched, cyclic or a combination thereof. Alkyl groups include linear, branched or cyclic alkyl groups and hybrids thereof, such as (cycloalky l)alky I. The term “C1-6 alkyl” as used herein means an alkyl group having 1-6 carbon atoms, which may be branched or unbranched. Examples of C1-6 alkyl include hexyl, pentyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

[0241] As used herein, the term “alkenyl” refers to a unsaturated hydrocarbon featuring a carbon-carbon double bond, which may be straight-chain, branched, cyclic or a combination thereof. The term “C2-6 alkenyl” as used herein means an alkyl group having 2-6 carbon atoms, which may be branched or unbranched. Examples of C2-6 alkenyl include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl and isohexenyl.

[0242] As used herein, the term “alkynyl” refers to a unsaturated hydrocarbon featuring a carbon-carbon triple bond, which may be straight-chain, branched, cyclic or a combination thereof. The carbon-carbon triple bond may be terminal, i.e. -C=CH, located at the end of a carbon chain. The term “C2-8 alkynyl” as used herein means an alkyl group having 2-8 carbon atoms, which may be branched or unbranched. Examples of C2-8 alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, and cyclooctynyl.

[0243] As used herein, the term “cycloalkyl” refers to a cyclic alkyl group, for example cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. A cycloalkyl group may be monocyclic or polycyclic. A cycloalkyl group may be fused to an aromatic ring. A cycloalkyl group may have from 3 to 15 ring carbon atoms. A “cycloakyl” ring may be saturated or partially unsaturated.

[0244] As used herein, the term “heterocycloalkyl ring” refers to a ring system with may be saturated, partially unsaturated or aromatic and wherein one or more of the ring-forming atoms is a heteroatom such as O, S or N. A “heterocycloalkyl ring” may be saturated or partially unsaturated. A heterocycloalkyl group may be monocyclic or polycyclic. A heterocycloalkyl group may have from 3 to 15 ring atoms.

[0245] As used herein, the term “alkoxy” means -O-alkyl wherein alkyl has the meaning as defined above. Examples of O-ealkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tertiary butoxy, pentyloxy, hexyloxy. Alkoxy is attached to the rest of the molecule by the “oxy” moiety.

[0246] As used herein, the term “amino acid” refers to an organic compound which features a carboxyl and an amino group attached to the same carbon. An amino acid may be selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0247] As used herein, the term “peptide” refers to a compound comprising two or more amino acids linked by peptide bonds between a carboxyl and an adjacent amino group.

[0248] As used herein “polyethyleneglycol” refers to a group of structure -(O-CH2-CH2)n-, wherein n is an integer from 2 to 100, preferably 2-50, preferably 2-20, preferably 2-10.

[0249] As used herein, the term “geminal” or “gem” denotes two functional groups attached to the same atom in a compound.

[0250] As used herein, the term “sugar” refers to saccharide compound. Sugars include monosaccharide compounds such as glucose, galactose, fructose, xylose as well as di- and oligo-saccharide compounds for example formed from said monosaccharide subunits. A sugar may be a polyol such as sorbitol or mannitol.

[0251] As used herein, the terms “compound of the invention”, “compound of the disclosure” “compound described herein” and “compound of Formula II”, etc, include pharmaceutically acceptable salts and derivatives thereof and polymorphs, isomers (e.g. stereoisomers and tautomers) and isotopically labelled variants thereof. For example, reference to compounds of Formula II includes pharmaceutically acceptable salts thereof. Reference to compounds of Formula Ila includes pharmaceutically acceptable salts thereof. Reference to compounds of Formula III includes pharmaceutically acceptable salts thereof. Reference to compounds of Formula A includes pharmaceutically acceptable salts thereof. Reference to compounds of Formula G includes pharmaceutically acceptable salts thereof.

[0252] A compound described herein may be provided as a solvate, for example a hydrate.

[0253] Pharmaceutically acceptable derivatives of a compound described herein include pharmaceutically acceptable esters, amides, prodrugs (e.g. a pyridine N-oxide) or isotopically labelled variants thereof. Described herein are pharmaceutical compositions comprising a compound described herein, including a pharmaceutically acceptable salt, solvate, ester, hydrate or amide thereof, in admixture with a pharmaceutically acceptable excipient(s), and optionally other therapeutic agents. The term “acceptable” means being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, intranasal, pulmonary, topical, local, or rectal administration, and the like, typically in unit dosage forms for administration.

[0254] The term “pharmaceutically acceptable salt” includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids and bases. Compounds which contain basic, e.g. amino, groups are capable of forming pharmaceutically acceptable salts with acids. Examples of pharmaceutically acceptable acid addition salts of the compounds described herein include acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.

[0255] Compounds which contain acidic, e.g. carboxyl, groups are capable of forming pharmaceutically acceptable salts with bases. Pharmaceutically acceptable basic salts of the compounds described herein include, but are not limited to, metal salts such as alkali metal or alkaline earth metal salts (e.g. sodium, potassium, magnesium or calcium salts) and zinc or aluminium salts and salts formed with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines (e.g. diethanolamine), benzylamines, N-methyl-glucamine, amino acids (e.g. lysine) or pyridine.

[0256] Hemisalts of acids and bases may also be formed, e.g. hemisulphate salts.

[0257] Pharmaceutically acceptable salts of compounds described herein may be prepared by methods well- known in the art. For a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0258] Solvates

[0259] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compounds described herein, which may be used in the any one of the uses / methods described. The term solvate is used herein to referto a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di- hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.

[0260] Isomers

[0261] It will be appreciated that the compounds described herein may exist in various isomeric forms and the compounds described herein include all stereoisomeric forms and mixtures thereof, including enantiomers and racemic mixtures. The present invention includes within its scope the use of any such stereoisomeric form or mixture of stereoisomers, including the individual enantiomers ofthe compounds described herein as well as wholly or partially racemic mixtures of such enantiomers. Where appropriate, isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate, isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis). In addition, it will be appreciated that in some instances, compounds described herein may exist in tautomeric forms and the compounds described herein include all tautomers and mixtures thereof.

[0262] Pharmaceutical compositions

[0263] A pharmaceutical composition may comprise any compound or a pharmaceutically acceptable salt or derivative as described herein, and a pharmaceutically acceptable excipient. A pharmaceutical composition as described herein may comprise one or more pharmaceutically acceptable excipients, for example pharmaceutically acceptable carriers, diluents, preserving agents, solubilising agents, stabilising agents, disintegrating agents, binding agents, lubricating agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts, buffers, coating agents and antioxidants. Suitable excipients and techniques for formulating pharmaceutical compositions are well known in the art (see, e.g. Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000). Suitable excipients include, without limitation, pharmaceutical grade starch, mannitol, lactose, corn starch, magnesium stearate, stearic acid, alginic acid, sodium saccharin, talcum, cellulose, cellulose derivatives (e.g. hydroxypropylmethylcellulose, carboxymethylcellulose) glucose, sucrose (or other sugar), sodium carbonate, calcium carbonate, magnesium carbonate, sodium phosphate, calcium phosphate, gelatin, agar, pectin, liquid paraffin oil, olive oil, alcohol, detergents, emulsifiers or water (preferably sterile).

[0264] A pharmaceutical composition may further comprise an adjuvant and / or one or more additional therapeutically active agent(s).

[0265] A pharmaceutical composition may be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

[0266] A pharmaceutical composition may be adapted for administration by any appropriate route, for example by oral, buccal or sublingual routes or parenteral routes, including subcutaneous, intramuscular, intravenous, intraperitoneal, and intradermal, rectal and topical administration, and inhalation. Such compositions may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with a excipient(s) under sterile conditions. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.

[0267] Formulations suitable for oral administration may also be designed to deliver the compounds described herein in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds. Means to deliver compounds in a ratesustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.

[0268] Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.

[0269] Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0270] The compounds described herein may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents 2001 , 1 1 (6): 981- 986.

[0271] The formulation of tablets is discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).

[0272] For administration intranasally or by inhalation, the active ingredient may be presented in the form of a dry powder from a dry powder inhaler or in the form of an aerosol spray of a solution or suspension from a pressurised container, pump, spray, atomiser or nebuliser.

[0273] For parenteral administration, the pharmaceutical composition described herein ion may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use. For parenteral administration, the compounds described herein may be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable means for administration include intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0274] Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, mannitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9) may be used. For some applications, the compounds described herein may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water (WFI).

[0275] Parenteral formulations may include implants derived from degradable polymers such as polyesters (e.g. polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.

[0276] The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0277] The solubility of compounds described herein used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and / or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.

[0278] Mixed with such pharmaceutically acceptable excipients, e.g. as described in the standard reference, Gennaro, A.R. et al, Remington: The Science and Practice of Pharmacy (21st Edition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules, suppositories or patches. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation or as an aerosol spray, in the form of a solution, suspension, or emulsion.

[0279] For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent described herein can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and / or wetting agents, such as propylene glycol or butylene glycol.

[0280] Described herein is a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.

[0281] The one or more compounds described herein may be used in combination therapies for the treatment of the described conditions i.e., in conjunction with other therapeutic agents. For the case of active compounds combined with other therapies the two or more treatments may be given in individually varying dose schedules and via different routes.

[0282] The combination of the agents listed above with a compound described herein would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.

[0283] Where a compound described herein is administered in combination therapy with one, two, three, four or more, preferably one or two, preferably one other therapeutic agents, the compounds can be administered simultaneously or sequentially. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer period apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

[0284] Described herein is a product comprising a compound described herein and another therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. Products provided as a combined preparation include a composition comprising a compound described herein and the other therapeutic agent together in the same pharmaceutical composition, or the compound described herein and the other therapeutic agent in separate form, e.g. in the form of a kit.

[0285] Described herein is a pharmaceutical composition comprising a compound of the invention and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.

[0286] Described herein is a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound described herein. The kit may comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

[0287] The kit described herein may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit described herein typically comprises directions for administration.

[0288] In the combination therapies described herein, the compound described herein and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Moreover, the compound described herein and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound described herein and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound described herein and the other therapeutic agent.

[0289] Treatment

[0290] By "treatment" herein is meant the treatment by therapy, whether of a human or a non-human animal (e.g., in veterinary applications) typically a non-human mammal, in which some desired therapeutic effect on the condition is achieved; for example, the inhibition of the progress of the disorder, including a reduction in the rate of progress, a halt in the rate of progress, amelioration of the disorder or cure of the condition. Treatment as a prophylactic measure is also included. References herein to prevention or prophylaxis do not indicate or require complete prevention of a condition; its manifestation may instead be reduced or delayed via prophylaxis or prevention according to the present invention.

[0291] Compounds or compositions as described herein, when used for preventing or treating a disorder, may be administered in an "effective amount", which may also be referred to as a “therapeutically effective amount”. By a "therapeutically effective amount" herein is meant an amount of the one or more compounds described herein or a pharmaceutical formulation comprising such one or more compounds, which is effective for producing such a therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0292] It will be appreciated that appropriate dosages of the compounds described herein may vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention. The selected dosage level will depend on a variety of factors including the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination and the age, sex, weight, condition, general health and prior medical history of the patient. The amount of compound(s) and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action so as to achieve the desired effect. Administration in vivo can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to a person skilled in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.

[0293] Methods of treatment

[0294] Compounds as described herein may be used for treating or preventing a disease or disorder. The disease may be cancer. The disease may be a proliferative disorder. The disease may be pulmonary arterial hypertension.

[0295] In a further aspect, compounds described herein may be for use in a method of treating a disease. Compounds described herein may be for use in a method of treating cancer. Compounds described herein may be for use in a method of treating a proliferative disorder. Compounds described herein may be for use in a method of treating pulmonary arterial hypertension.

[0296] Compounds as described herein may be used for treating or preventing a disease or disorder that can be ameliorated by bringing a radiohalide into close proximity with a biological target. The radiohalide may emit radiation once it reaches the target. The radiohalide may emit radiation that kills cells.

[0297] The invention also provides a method of treating or preventing a disease or disorder in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound described herein.

[0298] Methods of diagnosis

[0299] Compounds described herein may be used for diagnosing or identifying a disease or disorder. The disease may be cancer. The disease may be a proliferative disorder. The disease may be pulmonary arterial hypertension.

[0300] In a further aspect, compounds described herein may be used in a method of diagnosing a disease. Compounds described herein may be for use in a method of diagnosing cancer. Compounds described herein may be for use in a method of diagnosing a proliferative disorder. Compounds described herein may be for use in a method of diagnosing pulmonary arterial hypertension.

[0301] The method of diagnosing or identifying a disease or disorder may involve a compound as described herein which features a targeting moiety and a radiohalide. The targeting moiety may enable the compound to be transported to a site of interest in the body. The site of interest may be an organ, tumour, tissue, cell, cell membrane, receptor, protein or subcellular organism. The radiohalide may be identifiable in vivo using nuclear imaging. The radiohalide may be identifiable in vivo by positron emission topography (PET) or single-photon emission computed tomography (SPECT). Theranostic methods

[0302] As used herein, the term “theranostic” refers to the combination of using one radioactive drug to diagnose (identify) a disease and a second radioactive drug to treat the disease. Theranostics is a field of medicine that combines nuclear medical imaging and radiation therapy. Theranostics may be used to develop personalised therapies for cancer or proliferative diseases.

[0303] Compounds described herein may be for use in a theranostic method of diagnosing and treating a disease. Compounds described herein may be for use in a theranostic method of diagnosing and treating cancer. Compounds described herein may be for use in a theranostic method of diagnosing and treating a proliferative disease. Compounds described herein may be for use in a theranostic method of diagnosing and treating pulmonary hypertension.

[0304] Method of manufacture & method of treatment

[0305] Also described herein is the use of a compound described herein in the manufacture of a medicament for the treatment or prevention of a disease or disorder. A compound described herein in the manufacture of a medicament for the treatment or prevention of cancer. A compound described herein in the manufacture of a medicament for the treatment or prevention of a proliferative disorder. A compound described herein in the manufacture of a medicament for the treatment or prevention of pulmonary arterial hypertension.

[0306] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other components. In any of the embodiment described herein, reference to “comprising” also encompasses “consisting essentially of’.

[0307] Features described above in relation to each aspect of the present invention also represent features of each other aspect of the present invention subject to a technical incompatibility that would prevent such a combination of preferred features. Furthermore, it will be evident to the skilled person that advantages set out above with respect to each aspect of the present invention are also offered by each other aspect of the present invention.

[0308] EXAMPLES

[0309] The following examples are merely illustrative examples of the invention described herein and are not intended to be limiting upon the scope of the invention. Example 1 : Preparation of 2, 2-dimethv5,5-bis-(hvdroxymethyl)-1 ,3-dioxane.

[0310] Pentaerythritol (50 g, 0.36 mol) and p-toluenesulfonic acid monohydrate (0.61 g) were dissolved in 500 ml N,N-dimethylformamide (DMF, dried by molecular sieve at room temperature) at about 80°C, and then the mixture was allowed to cool undisturbed. When the solution cooled to about 40°C , stirring was started and 55.4 ml 2,2-dimethoxypropane (0.36 mol) was added. After 24 hours of stirring at room temperature, the solution was stirred at room temperature with 9.0 g of base treated DOWEX 1XZ-100 ion-exchange resin for 1 hour, filtered and then the solvent was evaporated under reduced pressure at 85°C. The base-treated DOWEX 1XZ-100 ion exchange was prepared by washing 30 g twice with 200 ml of deionized water, then washed with 300 ml of 4% aq. NaOH and then washed three times with 200 ml of water, filtered and then air-dried in a hood. After the treatment with this resin as noted above, the dry product was ground and extracted (Soxhlet), first with light petroleum ether (b.p. 40-60°C.) for 6 hours, then with diethyl ether for 12 hours, collected and dried. White crystals, yield 40.0 g, 61 .9%. M.P 124.5°-125.5°C ;

[0311] Example 2: Preparation of 1 ,3-Dioxane-5,5-dimethanol, 2,2-dimethyl-, 5,5-bis(4- methylbenzenesulfonate)

[0312] 1 ,3-Dioxane-5,5-dimethanol, 2,2-dimethyl-, 5,5-bis(4-methylbenzenesulfonate) was synthesized by the toslyation of the hydroxyl group on 2, 2-dimethy5,5-bis-(hydroxymethyl)-1 ,3-dioxane. p-Toluenesulfonyl chloride (78.7 g, 0.42 mol) and triethylamine (120 ml) were added to a 500 ml round-bottomed flask. 2,2-dimethy5,5-bis-(hydroxymethyl)-1 ,3-dioxane (24.7 g, 0.14 mol) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at S4 0 °C for 2 h. Chloroform was added, and extraction was conducted with chloroform. The organic layer was washed with aq. NaHCOs and water, then was concentrated by rotary evaporation to yield 1 ,3-Dioxane-5,5-dimethanol, 2,2-dimethyl-, 5,5-bis(4- methylbenzenesulfonate) as a white solid (95.3 g, 98%). This product was used in the next step without purification.

[0313] Example 3: Preparation of (5-(azidomethyl)-2,2-dimethyl-1 ,3-dioxan-5-yl)methyl 4- methylbenzenesulfonate

[0314] In a round-bottom flask, 60 g of product 1 ,3-Dioxane-5,5-dimethanol, 2,2-dimethyl-, 5,5-bis(4- methylbenzenesulfonate) (124 mmol) was added, followed by the addition of 100mL of dimethylformamide. Next, 11 g of sodium azide (169 mmol, 1.36 equiv.) was added. The reaction mixture was kept under reflux at 60 °C for 6 h. The crude reaction mixture was then diluted in hexane (500 mL) and washed twice with a saturated aqueous solution of NaCI (2 x 300 mL). The organic phase was then dried under reduced pressure and further purification by column chromatography (silica gel) employing isocratic eluent 1 :9 ethyl acetate / hexane was carried out. Example 4:lodination of (5-(azidomethyl)-2,2-dimethyl-1 ,3-dioxan-5-yl)methyl 4- methylbenzenesulfonate Radioiodination of (5-(azidomethyl)-2,2-dimethyl-1 ,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate was achieved via adding Methyltriooctylammonium chloride and DMF containing Radioactive Sodium Iodide (1-123, 1-124, 1-125, 1-131) to a solution of (5-(azidomethyl)-2,2-dimethyl-1 ,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate in dried acetonitrile. To allow iodination, the mixture was stirred and reacted at 100°C for 2hrs in a sealed vial. Then, the acetonide group was deprotected by 2M HCI. Then the product was purified by chromatography.

[0315] Example 5: Iodination in the absence of a phase transfer catalyst

[0316] 1231-Nal / NaOH was added to a reaction v-vial with anhydrous ethanol. The solvents were evaporated under a stream of N2 until dry (multiple times). The tosylate precursor dissolved in acetonitrile in a concentration of was added to the vial, and heated at 120°C to obtain intermediate which was further processed.

[0317] Example 6: Exemplary synthesis of a radiolabelled platinum complex

[0318]

[0319] Example 7: additional synthetic examples according to exemplary synthetic method 1 (Scheme 2)

[0320] = - L— B

[0321] Followed by deprotection to form the diol. Method A is with phase transfer catalyst. Method B is without phase transfer catalyst. Click reaction steps:

[0322] Preparation of

[0323]

[0324] Example 8: additional synthetic examples according to exemplary synthetic method 2 (Scheme 3) click reaction step radiohalogenation step Method A is with phase transfer catalyst. Method B is without phase transfer catalyst. Example 9: preparation of Hoescht compound 4 Synthesis of Compound 2

[0325] To a solution of compound 1 (200 mg, 0.43 mmol) in anhydrous DMF (3 mL) was added N,N- diisopropylethylamine (DIEA) (224 pL, 1.29 mmol, 3.0 equiv) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 minutes before 4-nitrophenyl chloroformate (118 mg, 0.60 mmol, 1.4 equiv) dissolved in 1 mL of DMF was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and monitored by LC-MS.

[0326] Upon completion, the reaction was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was analyzed by LC- MS, which indicated the formation of the desired product 2 (50% conversion), along with 25% of unreacted starting material 1. The crude material was purified by silica gel column chromatography (eluent: DCM / MeOH, gradient 0-5%) to afford compound 2 as a yellow solid.

[0327] Synthesis of Compound 3 (Amide Coupling Approach)

[0328] To a solution of compound 2 (150 mg, 0.24 mmol) and propiolamide (25 mg, 0.30 mmol, 1.25 equiv) in anhydrous DMF (2 mL) was added HATU (114 mg, 0.30 mmol, 1.25 equiv) and DIPEA (104 pL, 0.60 mmol, 2.5 equiv) at room temperature under nitrogen. The mixture was stirred at room temperature for 4 hours and monitored by LC-MS.

[0329] After completion, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (or reversephase column chromatography) to afford compound 3 as a pale solid.

[0330] LC-MS (ESI): m / z [M+H]+calcd for C37H32N8O6: 685.25, found: 685.3.

[0331] Example 10: preparation of compound JQ1

[0332] ADDITIONAL DISCLOSED EMBODIMENTS

[0333] Aspects and features of the present invention are also described in the following numbered clauses.

[0334] 1 . A method for the preparation of a radiolabelled compound of Formula II or Formula X:

[0335] (Ligand)x

[0336] Formula IIorFormula X or a salt or solvate thereof; said method comprising reaction of a compound of Formula I or Formula Y:

[0337] (Ligand)x Formula IorFormula Y or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:

[0338] R1is selected from Ce-ioaryl, C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen;

[0339] A is selected from R2aor R2b; wherein:

[0340] R2ais a functional group capable of undergoing a click reaction;

[0341] R2bis a group of formula: wherein:

[0342] Y is a functional group that results from a click reaction;

[0343] L is a linker group; and B is a univalent substituent derived from a biological molecule or pharmaceutically active molecule;

[0344] R3is C1-6 alkyl or H;

[0345] R4is C1-6 alkyl or H; or

[0346] R3and R4are taken together with the atoms to which they are attached to form a 6- to 8- membered heterocycle; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; or where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

[0347] 2. The method of clause 1 , wherein the reaction of a compound of Formula I, or a salt or solvate thereof, with a nucleophilic radioactive halide source is carried out in the presence of a phase transfer catalyst.

[0348] 3. The method of clause 1 or 2 wherein the compound of Formula II is a compound of Formula

[0349] Ila:

[0350] Formula Ila or a salt or solvate thereof; and said method comprises reaction of a compound of Formula la:

[0351] Formula la or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:

[0352] R2ais a functional group capable of undergoing a click reaction; optionally wherein

[0353] R2ais an azide or C2-8 alkynyl; optionally ethynyl.

[0354] 4. The method of clause 3, further comprising reaction of the compound of Formula Ila:

[0355] Formula Ila or a salt or solvate thereof; with a compound of Formula IV:

[0356] R6— L— B

[0357] Formula IV or a salt or solvate thereof; to form a radiolabelled compound of Formula III:

[0358] Formula III or a salt or solvate thereof; wherein the reaction is a click reaction; and wherein:

[0359] R6is a functional group capable of undergoing a click reaction with R2a; optionally wherein R6is an azide or C2-8 alkynyl; optionally ethynyl. The method of clause 4 further comprising the steps of: when R3and R4are not H, deprotecting the compound of Formula III to form a compound of Formula Za:

[0360] Formula Za or a salt or solvate thereof; followed by oxidation to form a compound of Formula Zb:

[0361] Formula Zb or a salt or solvate thereof; and complexation to form the compound of Formula Z:

[0362] (Ligand)x

[0363] Formula Z or a salt or solvate thereof. The method of clause 1 or 2 wherein the compound of Formula II is a compound of Formula

[0364] III or Formula Z:

[0365] (Ligand)x

[0366] Formula IIIorFormula Z or a salt or solvate thereof; and said method comprises reaction of a compound of Formula lb or Formula Yb: or a salt or solvate thereof; with a nucleophilic radioactive halide source. The method of clause 6, wherein the compound of Formula lb:

[0367] Formula lb or a salt or solvate thereof; is prepared by reaction of a compound of Formula la:

[0368] Formula la or a salt or solvate thereof; with a compound of Formula IV:

[0369] R6— L— B

[0370] Formula IV or a salt or solvate thereof; wherein the reaction is a click reaction.

[0371] 8. The method of clause 6 or 7, wherein the compound of Formula Yb:

[0372] Formula Yb or a salt or solvate thereof; is prepared by oxidation of a compound of Formula la:

[0373] Formula lb or a salt or solvate thereof; followed by complexation with metal reagent, for example Pt(DACH)SO4.

[0374] 9. A method for the preparation of radiolabelled compound of Formula Xa:

[0375] (Ligand)x

[0376] Formula Xa or a salt or solvate thereof; said method comprising the steps: when R3and R4are not H, deprotecting the compound of Formula Ila:

[0377] Formula Ila or a salt or solvate thereof; to form a compound of Formula Xb:

[0378] Formula Xb or a salt or solvate thereof; followed by oxidation to form a compound of Formula Xc:

[0379] Formula Xc or a salt or solvate thereof; and complexation to form the compound of Formula Xa.

[0380] 10. The method of any preceding clause, wherein R2ais an azide and R6is a C2-6 alkyne; or R2ais a C2-6 alkyne and R6is an azide.

[0381] 11 . The method of any preceding clause, wherein L is a bond or linker group of formula -(Z)m-, wherein each Z is independently selected from -(CR72)-, -C=C-, -CR2C(O)O-, -NR7C(O)-, -C(O)NR-, -NR7C(O)NR7-, - NR7C(S)NR7-, -SO2NR7-, -NR7SO2-, -CR72OCR72-, - CR72SCR72-, -CR72NR7CR72-, Cs-sheterocycloalkyl, Cs-scycloalkyl, Ce-ioary I, 5- to 10-membered heteroaryl, an amino acid, a peptide, a sugar or a monodisperse polyethyleneglycol (PEG); each R7is independently selected from hydrogen, -C(O)NH(phenyl), hydroxy, Ci-oalkyl, Ci-ealkoxy, C2-4alkenyl, C2-4alkynyl, hydroxyCi-ealkyl; and wherein phenyl may be further substituted with -CH2OC(O)O(p-NO2CeH4); and m is an integer of value 1 to 20.

[0382] 12. The method of any preceding clause, wherein Y is heteroaryl; optionally wherein Y is 1 ,2,3-triazole.

[0383] 13. The method of any preceding clause, wherein the click reaction is a 1 , 3-di polar cycloaddition or a [3+2] cycloaddition.

[0384] 14. The method of any preceding clause, wherein the click reaction is copper-catalysed.

[0385] 15. The method of any preceding clause, wherein B is derived from: a therapeutic compound; a targeting compound; or a conjugate of therapeutic compound and a targeting compound. 16. The method of any preceding clause, wherein B is derived from a targeting compound or a conjugate of therapeutic compound and a targeting compound; and wherein the targeting compound is a DNA-targeting compound.

[0386] 17. The method of any preceding clause, wherein B is derived from a drug, peptide, or antibody; optionally a transporter substrate, transporter inhibitor, hexose compound, a tumour accumulating compound, a lysosomotropic drug, or histone deacetylase inhibitors; further optionally TOCA, chloroquine, sucrose, bafilomycin A1 , or histone deacetylase inhibitors C1 A and C1 B.

[0387] 18. The method of any preceding clause, wherein B is selected from: wherein W is somatostatin or an analogue thereof, for example, octreotide, lanreotide or pAG-TOCA; and

[0388] E is a bond or linker group of formula -(Z)m-, wherein each Z is independently selected from Cs-scycloalkyl, Ce- aryl, 5- to 10-membered heteroaryl, an amino acid, a peptide, a sugar or a monodisperse polyethyleneglycol (PEG); each R7is independently selected from hydrogen, -C(O)NH(phenyl), hydroxy, Ci-salkyl, Ci-ealkoxy, C2-ealkenyl, C2-ealkynyl, hydroxyCi-ealkyl; and wherein phenyl may be further substituted with -CH2OC(O)O(p-NO2CeH4); and m is an integer of value 1 to 20.

[0389] 19. The method of any preceding clause, wherein L has structure: wherein the attachment point of B is denoted by the grey circle and the attachment point of R6or Y is denoted by the grey square. 20. The method of any preceding clause, wherein R1is selected from the group consisting of Ce- ioaryl and 5- to 10-membered heteroaryl; and wherein each of the Ce- aryl, 5- to 10- membered heteroaryl may be further substituted with C1-6 alkyl, halogen or -NO2.

[0390] 21 . The method of any preceding clause, wherein R1is Ce -ioaryl substituted with one or more Ci- ealkyl.

[0391] 22. The method of any preceding clause, wherein R1is phenyl substituted with one methyl group.

[0392] 23. The method of any preceding clause, wherein the radioactive halide source comprises an alkali metal salt or an alkaline earth metal salt; optionally an alkali metal salt.

[0393] 24. The method of any preceding clause, wherein the radioactive halide source comprises radioactive iodide, radioactive bromide, radioactive astatide or radioactive fluoride.

[0394] 25. The method of any preceding clause, wherein the radioactive halide source comprises fluoride-18, iodide-123, iodide-124, iodine-125, iodide-131 , astatide-211 , bromide-75, bromide-76 or bromide-80.

[0395] 26. The method of any preceding clause, wherein the radioactive halide source comprises radioactive iodide.

[0396] 27. The method of any preceding clause, wherein the radioactive halide source comprises iodide-123, iodide-124 or iodide-131 .

[0397] 28. The method of any preceding clause, wherein the radioactive halide source comprises a sodium salt.

[0398] 29. The method of any preceding clause, wherein the reaction further comprises a base.

[0399] 30. The method of any preceding clause, wherein the radioactive halide source comprises iodide-123, iodide-124 or iodide-131 and R1is phenyl substituted with methyl.

[0400] 31 . The method of any preceding clause, wherein the phase transfer catalyst is a quaternary ammonium salt.

[0401] 32. The method of any preceding clause, wherein the phase transfer catalyst is methyltrioctylammonium halide, for example methyltrioctylammonium chloride or methyltrioctylammonium bromide; benzyltriethylammonium halide, for example benzyltriethylammonium chloride or benzyltriethylammonium bromide; methyltrioctylammonium thiosalicylate, methyltrioctylammonium hydrogen sulfate, Methyl- trioctylammonium bis(trifluoromethylsulfonyl)imide.

[0402] 33. The method of any preceding clause, wherein the method further comprises an ionic liquid.

[0403] 34. The method of any preceding clause, wherein the ionic liquid is a quaternary ammonium salt or a substituted imidazolium salt.

[0404] 35. The method of any preceding clause, wherein the ionic liquid is [1 -butyl-3- methylimidazolium][X], where X is a halide, tetrafluoroborate, bis(trifluoromethylsulfonyl)imide, trifluoromethanesulfonate, hexafluorophosphate, octyl sulfate, hydrogen sulfate.

[0405] 36. The method of any preceding clause, wherein R3and R4are taken together with the atoms to which they are attached to form a 6-membered heterocycle, optionally further substituted by one or more C1-6 alkyl group.

[0406] 37. The method of any preceding clause, wherein the nucleophilic radioactive halogen source comprises radioactive iodide and the phase transfer catalyst is a quaternary ammonium salt; optionally wherein the phase transfer catalyst is methyltrioctylammonium chloride.

[0407] 38. The method of any preceding clause, wherein:

[0408] R1is phenyl substituted with methyl;

[0409] R2ais azide;

[0410] R3and R4are taken together with the atoms to which they are attached to form a 6-membered heterocycle, further substituted with a gem / na / -dimethyl group;

[0411] X* is radioactive iodide.

[0412] 39. The method of any preceding clause, wherein:

[0413] R1is phenyl substituted with methyl;

[0414] R2ais C2-alkyne;

[0415] R3and R4are taken together with the atoms to which they are attached to form a 6-membered heterocycle, further substituted with a gem / na / -dimethyl group;

[0416] X* is radioactive iodide.

[0417] 40. The method of any of preceding clause, wherein the compound of Formula II is a compound of Formula G:

[0418] Formula G or a salt or solvate thereof; and said method comprises reaction of a compound of Formula C:

[0419] Formula C or a salt or solvate thereof; with [123l]Nal in the presence of methyltrioctylammonium chloride. The method of clause 40, further comprising reaction of the compound of Formula G:

[0420] Formula G or a salt or solvate thereof; with a compound of Formula F:

[0421] Formula F or a salt or solvate thereof; to prepare a radiolabelled compound of Formula A:

[0422] Formula A or a salt or solvate thereof; wherein the reaction comprises a click reaction. 42. The method of any preceding clause, wherein the compound of Formula II or III is a compound of Formula A:

[0423] Formula A or a salt or solvate thereof; and said method comprises reaction of a compound of Formula E:

[0424] Formula E or a salt or solvate thereof; with [123l]Nal in the presence of methyltrioctylammonium chloride. 43. The method of clause 42, wherein the compound of Formula E:

[0425] Formula E or a salt or solvate thereof; is prepared by reaction of a compound of Formula C:

[0426] Formula C or a salt or solvate thereof; with a compound of Formula F:

[0427] = - L— B

[0428] Formula F or a salt or solvate thereof; wherein the reaction is a click reaction. The method of any preceding clause, wherein the compound of Formula II or III is a compound of formula: or a salt or solvate thereof; and said method comprises deprotection and oxidation of a compound of formula: or a salt or solvate thereof; to form a compound of formula: or a salt or solvate thereof; followed by reacting the compound with [123l]Nal in the presence of methyltrioctylammonium chloride. The method of claim 44, wherein the compound of formula: or a salt or solvate thereof, is a compound of Formula E:

[0429] Formula E or a salt or solvate thereof. 46. The method of any one of the preceding clauses, wherein the compound of Formula I or Formula C is prepared from pentaerythritol (C(C2H5OH)4).

[0430] 47. The compound obtained by the method of synthesis of any of the preceding clauses.

[0431] 48. The compound of clause 47 for use in therapy.

[0432] 49. The compound of clause 47 for use in treating cancer or a proliferative disease, for example pulmonary arterial hypertension.

[0433] 50. A method of treating cancer or a proliferative disease, for example pulmonary arterial hypertension, in a subject, comprising administering a compound of clause 45 to a subject.

[0434] 51 . The method of clause 50, wherein the method is a theranostic method.

[0435] 52. The compound of clause 47 for use in diagnosing a disease or disorder in a subject, optionally wherein the disease or disorder may be cancer or a proliferative disease, such as pulmonary arterial hypertension.

[0436] 53. A method of diagnosing a disease or disorder in a subject, comprising administering a compound described herein to the subject, optionally wherein the disease or disorder is cancer or a proliferative disease, such as pulmonary arterial hypertension.

[0437] Embodiments described herein in relation to the first aspect of the present invention apply mutatis mutandis to the second to eighth aspects of the present invention.

[0438] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It will be appreciated that variations to the foregoing embodiments of the invention can be made while still falling within the scope of the invention. Each feature disclosed in this specification, unless stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0439] All of the features disclosed in this specification may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. In particular, the preferred features of the invention are applicable to all aspects of the invention and may be used in any combination. Likewise, features described in non-essential combinations may be used separately (not in combination). It will be appreciated that many of the features described above, particularly of the preferred embodiments, are inventive in their own right and not just as part of an embodiment of the present invention. Independent protection may be sought for these features in addition to or alternative to any invention presently claimed.

Claims

CLAIMS1. A method for the preparation of a radiolabelled compound of Formula 2:Formula 2 or a salt or solvate thereof; said method comprising reaction of a compound of Formula 1 :Formula 1 or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:R1is selected from Ce-ioary I , C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen;A is selected from R2aor R2b; wherein:R2ais a functional group capable of undergoing a click reaction;R2bis a group of formula:wherein:Y is a functional group that results from a click reaction;L is a linker group; andB is a univalent substituent derived from a biological molecule or pharmaceutically active molecule; each Rzis independently -CH2OC1-6 alkyl, -CH2OH, -COOH or -COO-; or each Rzmay be taken together with the atom to which they are attached to form a 6- to 8- membered heterocycle comprising 2 O atoms; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; and where each Rzis COO-, the compound of Formula 2 may be a compound of Formula X:(Ligand)xFormula X where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

2. The method for the preparation of a radiolabelled compound according to claim 1 , wherein the compound of Formula 2 is a compound of Formula II or Formula X:(Ligand)xFormula IIorFormula X or a salt or solvate thereof; said method comprising reaction of a compound of Formula I or Formula Y:Formula IorFormula Y or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:R1is selected from Ce-ioary I , C1-6 alkyl and 5- to 10-membered heteroaryl; and wherein each of aryl, heteroaryl may be substituted with one or more C1-6 alkyl, halogen or -NO2 and C1-6 alkyl may be substituted with one or more halogen;A is selected from R2aor R2b; wherein:R2ais a functional group capable of undergoing a click reaction;R2bis a group of formula:wherein:Y is a functional group that results from a click reaction;L is a linker group; andB is a univalent substituent derived from a biological molecule or pharmaceutically active molecule;R3is C1-6 alkyl or H;R4is C1-6 alkyl or H; orR3and R4are taken together with the atoms to which they are attached to form a 6- to 8- membered heterocycle; and wherein the 6- to 8-membered heterocycle may be further substituted by one or more C1-6 alkyl groups; or where M is a metal ion, Ligand a coordinating ligand and x is 1 or 2; and X* is a radioactive halide.

3. The method of claim 1 , wherein the reaction of a compound of Formula I or Formula X, or a salt or solvate thereof, with a nucleophilic radioactive halide source is carried out in the presence of a phase transfer catalyst.

4. The method of any one of claims 1-3, wherein the compound of Formula II is a compound ofFormula Ila:Formula Ila or a salt or solvate thereof; and said method comprises reaction of a compound of Formula la:Formula la or a salt or solvate thereof; with a nucleophilic radioactive halide source; wherein:R2ais a functional group capable of undergoing a click reaction; optionally whereinR2ais an azide or C2-8 alkynyl; optionally ethynyl.

5. The method of claim 4, further comprising reaction of the compound of Formula Ila:Formula Ilaor a salt or solvate thereof; with a compound of Formula IV:R6— L— BFormula IV or a salt or solvate thereof; to form a radiolabelled compound of Formula III:Formula III or a salt or solvate thereof; wherein the reaction is a click reaction; and wherein:R6is a functional group capable of undergoing a click reaction with R2a; optionally wherein R6is an azide or C2-8 alkynyl; optionally ethynyl.

6. The method of any one of claims 1-3, wherein the compound of Formula II or Formula X is a compound of Formula III or Formula Z:(Ligand)xFormula IIIorFormula Z or a salt or solvate thereof; and said method comprises reaction of a compound of Formula lb or Formula Yb:or a salt or solvate thereof; with a nucleophilic radioactive halide source.

7. The method of claim 6, wherein the compound of Formula lb:Formula lb or a salt or solvate thereof; is prepared by reaction of a compound of Formula la:Formula la or a salt or solvate thereof; with a compound of Formula IV:R6— L— BFormula IV or a salt or solvate thereof; wherein the reaction is a click reaction.

8. The method of any preceding claim, wherein R2ais an azide and R6is a C2-6 alkyne; or R2ais a C2-6 alkyne and R6is an azide.

9. The method of any preceding claim, wherein L is a bond or linker group of formula -(Z)m-, wherein each Z is independently selected from -(CR72)-, -C=C-, -CR2C(0)0-, -NR7C(O)-, - C(O)NR-, -NR7C(O)NR7-, - NR7C(S)NR7-, -SO2NR7-, -NR7SO2-, -CR72OCR72-, - CR72SCR72-, -CR72NR7CR72-, Cs-sheterocycloalkyl, Cs-scycloalkyl, Ce-ioaryl, 5- to 10-membered heteroaryl, an amino acid, a peptide, a sugar or a monodisperse polyethyleneglycol (PEG); each R7is independently selected from hydrogen, -C(O)NH(phenyl), hydroxy, Ci-salkyl, Ci-ealkoxy, C2-4alkenyl, C2-4alkynyl, hydroxyCi-ealkyl; and wherein phenyl may be further substituted with -CH2OC(O)O(p-NO2CeH4); and m is an integer of value 1 to 20.

10. The method of any preceding claim, wherein Y is heteroaryl; optionally wherein Y is 1 ,2,3-triazole.11 . The method of any preceding claim, wherein the click reaction is a 1 ,3-dipolar cycloaddition or a [3+2] cycloaddition.

12. The method of any preceding claim, wherein the click reaction is copper-catalysed.

13. The method of any preceding claim, wherein B is derived from: a therapeutic compound; a targeting compound; or a conjugate of therapeutic compound and a targeting compound, optionally wherein the targeting compound is a DNA-targeting compound.

14. The method of any preceding claim, wherein B is derived from a drug, peptide, or antibody; optionally a transporter substrate, transporter inhibitor, hexose compound, a tumour accumulating compound, a lysosomotropic drug, or histone deacetylase inhibitors; further optionally TOCA, chloroquine, sucrose, bafilomycin A1 , or histone deacetylase inhibitors C1A and C1 B.

15. The method of any preceding claim, wherein B is selected from:wherein W is somatostatin or an analogue thereof, for example, octreotide, lanreotide or pAG-TOCA; andE is a bond or linker group of formula -(Z)m-, wherein each Z is independently selected from -Cs-scycloalkyl, Ce-ioaryl, 5- to 10-membered heteroaryl, an amino acid, a peptide, a sugar or a monodisperse polyethyleneglycol (PEG); each R7is independently selected from hydrogen, -C(O)NH(phenyl), hydroxy, Ci-salkyl, Ci-ealkoxy, C2-ealkenyl, C2-ealkynyl, hydroxyCi-ealkyl; and wherein phenyl may be further substituted with -CH2OC(O)O(p-NO2CeH4); and m is an integer of value 1 to 20.

16. The method of any preceding claim, wherein L has structure:wherein the attachment point of B is denoted by the grey circle and the attachment point of R6or Y is denoted by the grey square.

17. The method of any preceding claim, wherein R1is selected from the group consisting of Ce- ioaryl and 5- to 10-membered heteroaryl; and wherein each of the Ce-ioaryl, 5- to 10-membered heteroaryl may be further substituted with C1-6 alkyl, halogen or -NO2, optionally wherein R1is Ce-ioaryl substituted with one or more Ci-salky I, optionally wherein R1is phenyl substituted with one methyl group.

18. The method of any preceding claim, wherein the radioactive halide source comprises an alkali metal salt or an alkaline earth metal salt; optionally an alkali metal salt (for example, a soduim salt), and / or wherein the radioactive halide source comprises radioactive iodide, radioactive bromide, radioactive astatide or radioactive fluoride, optionally wherein the radioactive halide source comprises fluoride-18, iodide-123, iodide-124, iodide-131 , astatide-211 , bromide-75, bromide-76 or bromide-80, optionally wherein the radioactive halide source comprises radioactive iodide, optionally wherein the radioactive halide source comprises iodide-123, iodide-124 or iodide-131 .

19. The method of any preceding claim, wherein the reaction further comprises a base.

20. The method of any preceding claim, wherein: a) the phase transfer catalyst is a quaternary ammonium salt, optionally wherein the phase transfer catalyst is methyltrioctylammonium halide, for example methyltrioctylammonium chloride or methyltrioctylammonium bromide; benzyltriethylammonium halide, for example benzyltriethylammonium chloride or benzyltriethylammonium bromide; methyltrioctylammonium thiosalicylate, methyltrioctylammonium hydrogen sulfate, Methyl-trioctylammonium bis(trifluoromethylsulfonyl)imide; and / or b) the method further comprises an ionic liquid, optionally wherein the ionic liquid is a quaternary ammonium salt or a substituted imidazolium salt, optionally wherein the ionic liquid is [1-butyl-3-methylimidazolium][X], where X is a halide, tetrafluoroborate,bis(trifluoromethylsulfonyl)imide, trifluoromethanesulfonate, hexafluorophosphate, octyl sulfate, or hydrogen sulfate.

21. The method of any preceding claim, wherein the nucleophilic radioactive halogen source comprises radioactive iodide and the phase transfer catalyst is a quaternary ammonium salt; optionally wherein the phase transfer catalyst is methyltrioctylammonium chloride.

22. The method of any preceding claim, wherein: a) R3and R4are taken together with the atoms to which they are attached to form a 6-membered heterocycle, optionally further substituted by one or more C1-6 alkyl group;or b) R1is phenyl substituted with methyl;R2ais azide;R3and R4are taken together with the atoms to which they are attached to form a 6-membered heterocycle, further substituted with a gem / na / -dimethyl group;X* is radioactive iodide; or c) R1is phenyl substituted with methyl;R2ais C2-alkyne;R3and R4are taken together with the atoms to which they are attached to form a 6-membered heterocycle, further substituted with a gem / na / -dimethyl group;X* is radioactive iodide.

23. The method of any preceding claims, wherein the compound of Formula II is a compound of Formula G:Formula G or a salt or solvate thereof; and said method comprises reaction of a compound of Formula C:Formula C or a salt or solvate thereof;with [123l]Nal in the presence of methyltrioctylammonium chloride, optionally further comprising reaction of the compound of Formula G:Formula G or a salt or solvate thereof; with a compound of Formula F:= - L— BFormula F or a salt or solvate thereof; to prepare a radiolabelled compound of Formula A:Formula A or a salt or solvate thereof; wherein the reaction comprises a click reaction.

24. The method of any preceding claim, wherein the compound of Formula II or III is a compound of Formula A:Formula A or a salt or solvate thereof; and said method comprises reaction of a compound of Formula E:Formula E or a salt or solvate thereof;with [123l]Nal in the presence of methyltrioctylammonium chloride, optionally wherein the compound of Formula E:Formula E or a salt or solvate thereof; is prepared by reaction of a compound of Formula C:Formula C or a salt or solvate thereof; with a compound of Formula F:_ _ L— BFormula F or a salt or solvate thereof; wherein the reaction is a click reaction.

25. The compound obtained by the method of any preceding claim for use in: a) therapy, optionally for use in treating cancer, or a proliferative disease, for example pulmonary arterial hypertension; or b) diagnosing a disease in a subject, wherein said compound has been administered to the subject, optionally wherein the disease is cancer or a proliferative disease, such as pulmonary arterial hypertension; or c) a theranostic method.

Images