Pharmaceutical compositions containing 225-actinium labeled complexes and bismuth sequestering agents

Abstract

The present disclosure relates to 225 Formed by an Ac radionuclide and a target binding moiety linked to a chelator 225 Ac radiolabeled complexes and typically Bi 3+ The present disclosure also relates to a method for preparing said pharmaceutical composition.

Description

[Technical field]

[0001] This disclosure relates to the use of actinium 225 ( 225 This invention relates to the field of radiopharmaceutical compounds radiolabeled with Ac) and radiopharmaceutical compositions thereof. [Background technology]

[0002] High-energy alpha particles emitted by the decay of radioisotopes can be utilized with appropriate targeting vectors to destroy malignant cells. This therapeutic strategy, known as alpha therapy, is currently the subject of intense research. 225 The half-life of Ac is 9.9 d, which is longer than that of the main daughter. 225 Considering the high alpha particle emission energy from Ac itself and its daughters, 225 Ac was identified as a potential candidate for use in cancer therapy.

[0003] Therefore, there is great interest in the development of targeted alpha particle therapy (TAT) for the treatment of solid tumors. 225 The efficacy of Ac-PSMA-617 has been demonstrated in the treatment of prostate bone metastases. These developments have further stimulated interest in the development of novel alpha-emitting cancer therapeutics. Typically, TAT of solid tumors involves incorporating alpha particle-emitting radionuclides into a tumor-targeting scaffold and then administering intravenously to systemically target tumors and metastases. The penetration range of alpha particles into tissues is only a few cell diameters, ensuring that the maximum effect of tumor TAT remains within the tumor volume.

[0004] 225 Ac decay is stable 209 The decay cascade up to Bi produces six major radionuclide progeny. 225 The decay of Ac (t1 / 2=9.9d; 5.8 MeV α particle) results in a net of four alpha decays and three beta decays. These daughters are: 221 Fr(t1 / 2=4.8m; 6.3MeV α particles and 218keV γ radiation), 217 At(t1 / 2=32.3ms;7MeV α particle),213 Bi(t1 / 2=45.6m;6MeV α particle, 1.4MeV E max β-particles and 440keV γ-radiation), 213 Po(t1 / 2=3.7μs;8.4MeV α particle), 209 Tl(t1 / 2=2.2m; 1.8MeV E max β-particles and 1567keV γ radiation), 209 Pb(t1 / 2=3.25h; 644keV E max β-particles) and 209 Bi (stable).

[0005] 225 The main limitation of the clinical use of pharmaceutical compositions based on Ac, especially in the field of radioligand therapy (RLT), is the total body radiation of the daughter nuclides, which can cause radiation toxicity and / or radiochemical instability. 213 Bi has a tendency to accumulate in the kidney and liver, as reported, for example, in J. Singh Jaggi et al. Cancer Res; 65(11)-2005.

[0006] McDevitt et al. Applied Radiation and Isotopes 57(841-847)-2002 state that the instability is due to the high classical recoil energy of the daughter products which break the molecular bonds of the chelators.

[0007] As a result, the liberated daughter is emitted, 225 The use of pharmaceutical compositions containing radiopharmaceutical compounds radiolabeled with Ac is limited. 213 The latter may induce toxicity problems if the concentration of Bi becomes too high in the pharmaceutical composition.

[0008] Therefore, toxicity is limited and easily eliminated by the organism. 213 Bi is blocked, 225 There is a need to develop pharmaceutical compositions that contain radiopharmaceutical compounds radiolabeled with Ac. Summary of the Invention

[0009] The Applicant has surprisingly found that 225 To dramatically / substantially reduce Ac decay-induced toxicity, 225 Ac compound preparations, i.e. 225 The pharmaceutical composition comprises Ac and a target-binding (chemical or biological) moiety linked to a compound, e.g., a chelator, and at least one bismuth chelator, in particular 213 It was found that it was possible to add a Bi chelator.

[0010] The present disclosure relates to (a) 225 An Ac radiolabeled complex comprising (i) 225 Ac radionuclide, (ii) a target binding moiety linked to a chelator; Formed by 225 Ac radiolabeled complex, and (b) Typically Bi 3+ a bismuth sequestering agent capable of sequestering (c) optionally an antioxidant specifically selected from the group comprising gentisic acid and its salts, ascorbic acid and its salts, and mixtures thereof; The present invention relates to a pharmaceutical composition comprising:

[0011] The present disclosure relates to (a) 225 An Ac complex comprising (i) 225 Ac radionuclide, (ii) a target binding moiety linked to a chelator; Formed by 225 Ac complexes, and (b) Typically Bi 3+ a bismuth sequestering agent capable of sequestering (c) optionally, one or more antioxidants, preferably selected from the group consisting of gentisic acid and its salts, ascorbic acid and its salts, and mixtures thereof; The present invention further relates to a pharmaceutical composition comprising:

[0012] The present disclosure also relates to a method for preparing said pharmaceutical composition, comprising: 1) complexing a radionuclide with a chelator-linked or target-binding organic moiety; (1.1) providing an aqueous solution containing a radionuclide; (1.2) providing an aqueous solution comprising a chelating agent linked to a target-binding organic moiety; (1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; forming a 2) diluting the complex solution obtained at the end of step (1) by mixing the complex solution obtained at the end of step (1) with a diluent; wherein said bismuth sequestering agent is contained in the aqueous solution of step 1.1 and / or in the aqueous solution of step 1.2 and / or in the diluent of step 2.

[0013] The present disclosure relates to (a) 5-20MBq, especially 7-15MBq 225 Ac and (b) 0.15 to 0.80 mg, particularly 0.21 to 0.60 mg, of a bismuth sequestering agent; (c) optionally, 9 to 50 mg, in particular 12.6 to 37.5 mg, of an antioxidant; The present invention further relates to a patient dose unit including

[0014] The present disclosure relates to (a) 0.5 to 2 MBq / mL, especially 0.7 to 1.5 MBq / mL 225 Ac and (b) 0.015 to 0.08 mg / mL, particularly 0.02 to 0.06 mg / mL, of a bismuth sequestering agent; (c) optionally, 0.9 to 5 mg / mL, particularly 1.3 to 3.8 mg / mL, of an antioxidant; The present invention further relates to a pharmaceutical composition comprising: [Brief description of the drawings]

[0015] [Figure 1] 1 is an illustration of the 225Ac decay scheme. [Diagram 2] iTLC of [225Ac]Ac-PSMA-R2 DP with DMSA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] definition The use of the articles "a," "an," and "the" in both the description and the claims should be construed to include both the singular and the plural, unless otherwise indicated herein and unless clearly contradicted by context. The terms "comprising," "having," "is," "including," and "containing," e.g., in a complex of a radionuclide and a cell receptor-binding organic moiety linked to a chelating agent, should be construed as open terms (i.e., meaning "including, but not limited to"), unless otherwise noted. In addition, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0017] As used herein, the term "cancer" refers to an abnormal state or condition characterized by cells capable of autonomous proliferation, i.e., rapidly proliferating cell proliferation. Hyperproliferative and neoplastic disease states can be classified as pathological, i.e., characterizing or constituting a disease state, or non-pathological, i.e., a deviation from normal but not associated with a disease state. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness.

[0018] As used herein, the term "protecting group" refers to a chemical substituent that can be selectively removed by readily available reagents that do not attack the regenerating or other functional groups in the molecule. Suitable protecting groups are known in the art and continue to be developed. Suitable protecting groups can be found, for example, in Wutz et al. ("Greene's Protective Groups in Organic Synthesis, Fourth Edition," Wiley-Interscience, 2007). Protecting groups for the protection of carboxyl groups described by Wutz et al. (pages 533-643) are used in certain embodiments. In some embodiments, the protecting group is removable by treatment with acid.

[0019] Representative examples of protecting groups include, but are not limited to, benzyl, p-methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr). One of skill in the art will recognize appropriate situations in which protecting groups are required and will be able to select the appropriate protecting group for use in a particular situation.

[0020] As used herein, the term "aryl" refers to a polyvalent unsaturated aromatic hydrocarbon group having one or more fused aromatic rings, containing 6 to 10 ring atoms, with at least one ring being aromatic. The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto. Suitable aryl groups include phenyl, naphthyl and phenyl rings fused to heterocyclyls, such as benzopyranyl, benzodioxolyl and benzodioxanyl.

[0021] As used herein, the terms "substituted aryl" and "substituted pyridine" refer to an aryl as defined above or a pyridine substituted with one or more substituents selected from the following in a number ranging from zero to the total number of open valences on the aromatic ring structure: halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R'''', -NR''C (O)OR', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxo, and fluoro(C1-C4)alkyl; and R', R'', R''', and R'''' can be independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. When a compound of the present disclosure includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R', R'', R''', and R'''' groups are present.

[0022] As used herein, the term "alkyl," alone or as part of another substituent, refers to a straight or branched chain alkyl functional group having 1 to 6 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl).

[0023] As used herein, the term "alkylene" refers to a divalent saturated straight or branched chain hydrocarbon group having 1 to 20, particularly 1 to 12, more particularly 1 to 6 carbon atoms.

[0024] As used herein, the term "heteroalkyl" refers to a straight or branched chain alkyl functional group having from 1 to 6 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.

[0025] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic group having 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0026] As used herein, the term "halogen" refers to a fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I) group.

[0027] As used herein, the term "alkoxy" refers to an -O-alkyl group, where the alkyl group is a C1-C6 alkyl group as defined herein. Suitable alkoxy groups include methoxy, ethoxy, propoxy.

[0028] As used herein, the term "heteroaryl" refers to a polyunsaturated aromatic ring structure containing 5-10 atoms, having a single ring or multiple aromatic rings fused or covalently bonded to one another, in which at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O and S. The nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Such rings may be fused to aryl, cycloalkyl or heterocyclyl rings. Non-limiting examples of such heteroaryls include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl.

[0029] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, at least one ring atom being a heteroatom selected from N, O and S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Examples of heterocycles include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl, imidazolinyl, and 1,4-dioxanyl.

[0030] The term "about" or "approximately" is used herein (unless otherwise specified in any paragraph of this disclosure) to mean that the values ​​below may vary by ±20%, particularly ±10%, more particularly ±5%, even more particularly ±2%, and even more particularly ±1%.

[0031] Unless otherwise specified, "%" herein means weight percent (wt%), also referred to as weight percent (w / w%).

[0032] Unless otherwise specified, the indicated volumetric activities may vary by ±20%, in particular ±10%, in particular ±5%, even more in particular ±2%, even more in particular ±1%.

[0033] The term "total concentration" refers to the sum of one or more individual concentrations.

[0034] The term "aqueous solution" refers to a solution of one or more solutes in water.

[0035] (i) a radionuclide; (ii) a target binding moiety linked to a chelator; The expression "complex formed by" corresponds to a radionuclide metal ion which forms a non-covalent bond with a functional group of the chelating agent, e.g. an amine or carboxylic acid, in particular with an O atom, N atom, P atom and / or S atom of the functional group. The chelating agent has at least two such complex-forming functional groups, preferably 3, 4, 5, 6, 7 or 8 functional groups, more preferably 7 or 8 functional groups, so as to be able to form a chelate complex.

[0036] The term "sequestering agent" refers to a suitable chelating agent for complex radionuclide metal ions and / or stable metal ions.

[0037] A "pH adjuster" is a chemical that is added to a solution to adjust the pH value of the solution, thereby achieving a desired performance. The control of pH can be achieved by adding a pH adjuster to the formulation. Examples of pH adjusters include commonly used acids and bases, buffers, and mixtures of acids and bases. For example, bases that can be used include NaOH, KOH, Ca(OH)2, sodium bicarbonate, potassium carbonate, and sodium carbonate. Examples of acids that can be used include hydrochloric acid, acetic acid, citric acid, formic acid, fumaric acid, and sulfamic acid. In particular, the pH adjuster can be a base, more particularly NaOH. The pH adjuster can also be TRIS, THAM, trometamol, tromethamine. The pH range of the fluid can be any suitable range, such as from about 2 to about 14.

[0038] The term "commercial" refers to a pharmaceutical product, e.g. an aqueous pharmaceutical solution, which is capable of (and in particular has) obtaining marketing approval from a health authority, e.g. the US FDA or EMA, by complying with all pharmaceutical quality and stability requirements required by such health authority, and which may be manufactured on a commercial scale from or at a pharmaceutical manufacturing site, after which quality control testing procedures are performed, and which may (in particular is) be supplied to an end user at a remote location, e.g. a hospital or a patient.

[0039] As used herein, the phrase "target binding moiety" or "target binding organic moiety" refers to a portion of a molecule that specifically binds to a target, typically a protein or receptor, typically a receptor on the surface of a cell, particularly a cancerous cell.

[0040] The terms "polypeptide" and "peptide" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. The terms also include amino acid polymers that have been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or other manipulations, such as conjugation with a labeling component. In various embodiments, a polypeptide can be isolated from a natural source, produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be the product of a synthetic procedure.

[0041] As described above, the present disclosure provides: (a) 225 An Ac radiolabeled complex comprising (i) 225 Ac radionuclide, (ii) a target binding moiety linked to a chelator; This is formed 225 Ac radiolabeled complex, and (b) Typically Bi 3+ Bismuth sequestering agent capable of sequestering The present invention relates to a pharmaceutical composition comprising:

[0042] The present disclosure relates to (a) 225 An Ac complex comprising (i) 225 Ac radionuclide, (ii) a target binding moiety linked to a chelator; Formed by 225 Ac complexes, and (b) Typically Bi 3+ Bismuth sequestering agent capable of sequestering The present invention further relates to a pharmaceutical composition comprising:

[0043] Radiolabeled complexes Any radiolabeled complex or 225 Any complex containing an Ac radionuclide may be a component of a pharmaceutical composition according to the present disclosure. However, the pharmaceutical composition may include 225Ac radiolabeled complex or a target binding moiety linked to a chelator 225 Specially designed for Ac complexes.

[0044] especially, 225 The Ac chelator may be selected from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1-(glutamic acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), NOTAGA, in particular the chelator may be DOTA or DOTAGA.

[0045] The target binding moiety may be selected from the group consisting of a chemical entity with a molecular weight of less than 2000 g / mol, a peptide, a polypeptide, a protein such as an antibody or an antigen-binding fragment thereof, a nanobody and a consensus sequence from a fibronectin type III domain, a peptide peptidomimetic, a fusion protein / polypeptide or a low molecular weight molecule. In particular, the target binding moiety may be selected from the group consisting of a PSMA-binding ligand, a somatostatin receptor binding peptide, a gastrin releasing peptide receptor antagonist, an integrin binding ligand and a fibroblast activation protein inhibitor, more particularly a PSMA-binding ligand. In certain embodiments of the present disclosure, the target binding moiety is not an antibody. In certain embodiments of the present disclosure, the target binding moiety is a chemical entity or a peptide with a molecular weight of less than 2000 g / mol.

[0046] In general, the present disclosure also relates to pharmaceutical compositions, particularly radiopharmaceutical compositions. The pharmaceutical compositions are for intravenous (IV) use / application / administration. The solutions are stable, ready-to-use concentrates.

[0047] Target-binding moiety linked to a chelator As mentioned above, the target binding moiety may be selected from among PSMA-binding ligands, somatostatin receptor binding peptides, gastrin releasing peptide receptor antagonists, integrin binding ligands and fibroblast activation protein inhibitors, in particular PSMA-binding ligands.

[0048] PSMA-binding ligand In particular, the PSMA binding ligand linked to a chelator can be a molecule that includes (a) two ureas of amino acid residues, typically a glutamic acid-urea-lysine (GUL) moiety or a glutamic acid-urea-glutamic acid (GUG) moiety, and (b) a chelator onto which a radioisotope can be placed, preferably the chelator is [ka] wherein the chelator may be connected to the urea unit GUL or GUG via a linker, said linker may comprise a residue selected from the group Phe, Tyr, I-Tyr, 1Nal, 2Nal, Amc and cyclohexyl / cyclohexylene, each of which may be unsubstituted or substituted. Includes units of.

[0049] According to one embodiment, the PSMA binding ligand has formula (I): [ka] (where: Z is tetrazole or COOQ, in particular Z is COOQ; Q is independently H or a protecting group, in particular Q is H; m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, in particular, m is 4; q is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6, in particular, q is 1; R is a C6-C alkyl group containing 5-10 ring atoms. 10selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl being substituted one or more times by X; X is -Z 1 -Y, Z 1 is a bond or C1-C6 alkylene, in particular, V is a bond; Y is a halogen; L is C1-C6 alkylene, C3-C6 cycloalkylene and C6-C 10 a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene and arylene are optionally selected from the group consisting of: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', - substituted with one or more substituents selected from NR″C(O)OR′, —NR′-C(NR″R′′)═NR″″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —CN, and —NO2, where R′, R″, R′″, and R″″ may each independently represent hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; W is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 - and -(C=S)-NR 2 In particular, W is selected from the group consisting of -(C=O)-NR 2 - and each occurrence of L and W may be the same or different; R 2 is H or C1-C4 alkyl, in particular R 2 is H, n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent, in particular [ka] is) It is a compound of the formula:

[0050] The compounds of formula (I) include stereoisomers of formulae (Ia), (Ib), (Ic) and (Id). [ka]

[0051] The phrase "each occurrence of L and W can be the same or different" means that when the variable "n" is 2 or 3, one "L" group can be a C1-C6 alkylene and the other one or more "L" groups can be a C3-C6 cycloalkylene or arylene, or in other embodiments, each "L" group can be, for example, a C1-C6 alkylene. Similarly, when "n" is, for example, 2 or 3, one "W" group can be -(C=O)-NR 2 -, and the other "W" group or groups may be -(C=S)-NR 2 or in other embodiments, each "W" can be, for example, -(C=O)-NR 2 --It could be.

[0052] According to one embodiment, L is selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and C6-C 10 and arylene, wherein said alkylene, cycloalkylene, and arylene are optionally substituted with one or more substituents selected from: -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR'. R', R'', and R''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0053] According to one embodiment, L is a linker selected from the group consisting of C3-C6 alkylene, optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR'. R', R'' and R''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0054] According to one embodiment, R is a C-C alkyl group substituted with one or more halogens. 10 It is selected from the group consisting of aryl and pyridine substituted with one or more halogens.

[0055] According to one embodiment, R is [ka] where p is an integer selected from the group consisting of 1, 2, 3, 4 and 5, and in particular, p is 1. is selected from the group consisting of:

[0056] According to a particular embodiment, R is [ka] More particularly, R is selected from [ka] It could be.

[0057] According to a particular embodiment, X is selected from Br and I.

[0058] In particular, R is [ka] It is.

[0059] Ch is [ka] may be selected from the group consisting of:

[0060] According to a particular embodiment, Ch is [ka] It is.

[0061] According to one embodiment, W is -(C=O)-NR 2 - and Ch is [ka] It is.

[0062] According to one embodiment, m is 4, Z is COOQ and Q is H.

[0063] In a particular embodiment, according to one embodiment, R is [ka] and Ch is [ka] It is.

[0064] According to certain embodiments, the PSMA binding ligand has formula (II): [ka] (Preferably, the Glu and Lys residues are in the L configuration) It is a compound of the formula:

[0065] According to another embodiment, the PSMA binding ligand has formula (III): [ka] (Preferably, the Glu and Lys residues are in the L configuration) It is a compound of the formula:

[0066] According to another embodiment, the PSMA binding ligand has the following formula (IV): [ka] (Preferably, the Glu, Lys and 2-Nal residues are in the L configuration and the cyclohexyl unit is preferably in the trans conformation) and the following formula (IV'): [ka] (Preferably, the glutamic acid residue next to the DOTA unit is in the L configuration) Includes PSMA I&T.

[0067] According to another embodiment, the PSMA binding ligand is PSMA-617 (bipibotide tetraxetan), PSMA I&T (zadabotide glaxetan, DOTAGA-(Iy)fk(Sub-KuE)), PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, PSMA-7 I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93 and RPS-074 or antibodies or fragments thereof, such as TLX591, J591, rosopatamab, IAB2M, GCP-05, 1H8H5, SP29 or FOLHl, preferably selected from the group consisting of PSMA-617, PSMA I&T and PSMA-R2.

[0068] Synthesis of Compounds of Formulae (I), (II) and (III) Compounds of formula (I), (II) and (III) can be synthesized using the methods disclosed in WO 2017 / 165473.

[0069] In particular, compounds of formula (II) can be synthesized as disclosed in Scheme 1. The modified p-bromobenzyl group of Glu-Lys urea 2 can be prepared by reductive alkylation of Glu-Lys urea 1 with p-bromobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This procedure has been described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). An aliphatic linker, Boc-6-aminohexanoic acid, can then be coupled to the same ε-Lys amine of 2 using, for example, a base (such as N,N-diisopropylethylamine) and a coupling agent (such as N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) to give compound 3. Compound 3 can then be deprotected using an acid, such as trifluoroacetic acid, to give compound 4. Finally, conjugation with commercially available DOTA-NHS ester can be carried out to give compound (II).

[0070] Scheme 1: Synthesis of compounds of formula (II) [ka]

[0071] Somatostatin Receptor Binding Peptides Somatostatin receptor (SSTR) binding is a compound that has a specific binding affinity to the somatostatin receptor. As used herein, the term "somatostatin receptor binding peptide" refers to a peptide moiety that has a specific binding affinity to the somatostatin receptor.

[0072] In particular, the somatostatin receptor binding peptide has the formula CSP: (where: C is a chelating agent, S is an optional spacer covalently linked between C and P, P is a somatostatin receptor-binding peptide covalently linked, for example, via its N-terminus, directly or indirectly via S to C. The compound may be:

[0073] The somatostatin receptor binding peptide may be selected from octreotide, edotreotide, oxodotreotide, octreotate, lanreotide, vapreotide, satreotide and pasireotide.

[0074] The chelator C is linked to the somatostatin receptor-binding peptide either directly or via a linker molecule, in particular directly. The linking bond is either a covalent or non-covalent bond between the cell receptor-binding organic moiety (and the linker) and the chelator, in particular the bond is a covalent bond. In the context of the present disclosure, the chelator C is particularly selected in the group comprising 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), triethylenetetramineTETA, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In many embodiments of the disclosure, the chelator is DOTA.

[0075] According to many embodiments of the present disclosure, the somatostatin receptor binding peptide linked to the chelator is selected from DOTA-OC, DOTA-TOC, DOTA-NOC, DOTA-TATE, DOTA-LAN and DOTA-VAP. In many of these embodiments, the somatostatin receptor binding peptide is DOTA-TOC (edotreotide) or DOTA-TATE (oxodotreotide) or satreotide tetraxetane or satreotide trizoxetane. In many such embodiments, the somatostatin receptor binding peptide may be DOTA-TATE.

[0076] Gastrin-Releasing Peptide Receptor Antagonists In particular, the gastrin releasing peptide receptor antagonist (GRPR antagonist) linked to a chelator has the formula Ch'-S'-P' (where: Ch' is a chelator, S' is an optional spacer covalently attached between C and the N-terminus of P; P' is a GRP receptor peptide antagonist, in particular of the general formula: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z and Xaa1 is absent or is selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp and pentafluorophenylalanine (5-F-Phe) (all as the L- or D-isomer); Xaa2 is Gln, Asn, or His; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); Xaa4 is Ala, Ser or Val; Xaa5 is Val, Ser or Thr; Xaa6 is Gly, sarcosine (Sar), D-Ala or β-Ala; Xaa7 is His or (3-methyl)histidine (3-Me)His; Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2 and -O-alkyl; or Z is [ka] where X is NH (amide) or O (ester) and R1 and R2 are the same or different and are selected from a proton, an optionally substituted alkyl, an optionally substituted alkylether, an aryl, an arylether or an alkyl-, a halogen, a hydroxyl, a hydroxyalkyl, an amine, an amino, an amido or an amido-substituted aryl or heteroaryl group. is) may have:

[0077] According to one embodiment, Z has the formula: [ka] (wherein X is NH or O) is selected from one of the following:

[0078] According to one embodiment P' is DPhe-Gln-Trp-Ala-Val-Gly-His-Z, wherein Z is as defined above.

[0079] According to one embodiment, P' is DPhe-Gln-Trp-Ala-Val-Gly-His-Z, wherein Z is selected from Leu-ψ(CHN)-Pro-NH and NH-CH(CH-CH(CH)), or Z is [ka] (wherein X is NH (amide), R2 is (CH2-CH(CH3)2, and R1 is (CH2N)-Pro-NH2, which is the same as or different from R2). It is.

[0080] According to one embodiment, the chelator Ch' is selected from the following list: [ka] The chelating agent is obtained by grafting one selected from the following:

[0081] According to one embodiment, the chelator Ch' is selected from the group consisting of DOTA, DTPA, NTA, EDTA, DO3A and NOTA, in particular DOTA.

[0082] According to one embodiment, S′ is (a) Formula: [ka] (wherein PABA is p-aminobenzoic acid, PABZA is p-aminobenzylamine, PDA is phenylenediamine, and PAMBZA is (aminomethyl)benzylamine). aryl, comprising the residue of (b) a dicarboxylic acid, an ω-aminocarboxylic acid, an ω-diaminocarboxylic acid or a carboxylic acid of the formula: [ka] (where DIG is diglycolic acid and IDA is iminodiacetic acid) Diamines, (c) PEG spacers of various chain lengths, in particular: [ka] a PEG spacer selected from (d) α- and β-amino acids, either in a single chain or in homologous chains of various lengths or in heterologous chains of various lengths, in particular [ka] GRP(1-18), GRP(14-18), GRP(13-18), BBN(1-5) or [Tyr4]BB(1-5), or (e) A combination of a, b, c, and d is selected from the group consisting of:

[0083] According to one embodiment, the GRPR antagonist linked to a chelator has the following formula: [ka] (where Ch' and P' are as defined above). The compound is selected from the group consisting of:

[0084] According to one embodiment, P' is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2).

[0085] According to one embodiment, the GRPR antagonist linked to a chelator has the formula (V): [ka] (DOTA-(p-aminobenzylamine-diglycolic acid)-[D-Phe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)2]2 NeoB1.

[0086] Integrin-binding ligands Integrins are heterodimeric receptors important in cell-cell and cell-extracellular matrix (ECM) interactions and are composed of one α and one β subunit.

[0087] In embodiments, the integrin binding ligand is an αvβ3 or αvβ5 integrin antagonist.

[0088] In certain embodiments, the integrin binding ligand has the following formula (VI): [ka] It is.

[0089] Fibroblast Activation Protein Inhibitor The fibroblast activation protein inhibitor is in particular represented by formula (VII): [ka] (where: Q, R, U, V, W, Y, Z are individually present or absent, provided that at least three of Q, R, U, V, W, Y, Z are present; Q, R, U, V, W, Y, and Z are O, CH2, NR, provided that no two Os are directly adjacent to each other. 4 , C=0, C=S, C=NR 4 , H.C.R. 4 and R 4 CR 4 and in particular wherein 4 of 6 groups are present, 2 of which are C=0, 1 is CH2, and 1 is NH; more particularly wherein 4 groups are present, 2 of which are C=0, 1 is CH2, and 1 is NH; and most particularly wherein V, W, Y, and Z are present, of which V and Z are C=0 and W and Y are independently selected from CH2 and NH; ·R 1 and R 2 -H, -OH, halo, C 1~6 -Alkyl, -OC 1~6 -Alkyl, SC 1~6 -alkyl; ·R 3 is selected from the group consisting of -H, -CN, -B(OH)2, -C(O)-alkyl, -C(O)-aryl-, -C=CC(O)-aryl, -C=CS(O)2-aryl, -CO2H, -SO2H, -SON2NH2, -PO3H2 and 5-tetrazolyl; ·R 4 -H, -C 1~6 -Alkyl, -OC 1~6 -Alkyl, -SC 1~6 -alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl and -C 1~6 -aralkyl, wherein said -C 1~6each -alkyl is optionally substituted with 1-3 substituents selected from -OH, oxo, halo, optionally attached to Q, R, U, V, W, Y or Z; ·R 5 -H, halo and C 1~6 -alkyl, ·R 6 and R 7 is -H, [ka] independently selected from the group consisting of, with the proviso that R 6 and R 7 At the same time, H is not, in particular, R 6 is attached at the 7- or 8-quinolyl position, and R 7 is attached at the 5-quinolyl or 6-quinolyl position, more particularly R 6 At the 7-quinolyl position, R 7 is attached at the 6-quinolyl position, L is a linker, D, A, E and B are individually present or absent, in particular at least A, E and B are present, and if present: D is a linker, A is NR 4 , O, S, and CH2; E is [ka] (where: i is 1, 2 or 3; j is 1, 2 or 3; k is 1, 2 or 3; m is 1, 2 or 3. is selected from the group consisting of More specifically, E is C 1~6 -alkyl, most particularly E is C3 or C4 alkyl; A and E together form a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, especially heterocycloalkyl, A and E may be monocyclic, bicyclic and polycyclic, especially monocyclic, and each A and E may be -H, -C 1~6 -Alkyl, -OC 1~6 -Alkyl, -SC 1~6 -alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl and -C 1~6 -aralkyl, wherein the -C 1~6 Each -alkyl is optionally substituted with 1 to 3 substituents selected from -OH, oxo, halo, and optionally A, B, D, E, or [ka] Connected to B, S, NR 4 , N.R. 4 -O, NR 4 -C 1~6 -Alkyl, NR 4 -C 1~6 -Alkyl-NR 4 and 5-10 membered N-containing aromatic or non-aromatic monocyclic or bicyclic heterocycles, further comprising one or two heteroatoms, in particular selected from O, N and S, in particular further comprising one or two nitrogen atoms, in particular NR 4 , -C 1~6 -Alkyl-NR 4 and the N-containing heterocycle is C 1~6 -Alkyl, aryl, C 1~6 -substituted with 1 to 3 substituents selected from the group consisting of aralkyl, and R 8 is selected from the group consisting of a radioactive moiety, a chelator, a fluorescent dye, an imaging agent, and combinations thereof; [ka] is a 1-naphthyl moiety or a 5-10 membered N-containing aromatic or non-aromatic monocyclic or bicyclic heterocycle, with two ring atoms between the N atom and X, said heterocycle optionally further comprising one, two or three heteroatoms selected from O, N and S, and X is a C atom or a pharma- ceutically acceptable tautomer, racemate, hydrate, solvate or salt thereof, in particular C 1~6 -alkyl may be selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl. It is.

[0090] In certain embodiments, A and E together form a group selected from C3, C4, C5, C6, C7 and C8 monocyclic heterocycloalkyl, particularly C5 or C6 monocyclic heterocycloalkyl or C7, C8, C9, C10, C11 or C12 bicyclic heterocycloalkyl, particularly C7, C8, C9 and C10 bicyclic heterocycloalkyl, containing 1, 2, 3 or 4, particularly 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, particularly N and O, most particularly 1 or 2 N.

[0091] In certain embodiments, the fibroblast activation protein inhibitor (FAPi) is [ka] It is.

[0092] In certain embodiments, the FAPi is any one of those disclosed in International Publication No. WO 2021 / 005131, International Publication No. WO 2021 / 005125, International Publication No. WO 2022 / 148851, International Publication No. WO 2022 / 148843, or International Publication No. WO 2023 / 002045, the entire disclosures of which are incorporated by reference herein.

[0093] In particular, FAPi is FAP-2286 / 3BP-3554 (Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH) [ka] or 3BP-3940, nBu-CAyl-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH [ka] It is.

[0094] In certain embodiments of the disclosure, the target binding moiety linked to the chelator is a PSMA binding ligand and is not an SSTR binding ligand, a GRPR antagonist, or a FAPi. The disclosure is believed to be particularly useful for PSMA binding ligands, particularly PSMA-617, PSMA I&T, and PSMA-R2, particularly PSMA-617 and PSMA-R2, particularly PSMA-R2.

[0095] Bismuth Sequestering Agent The bismuth sequestering agent can be any chelating compound / chelator / chelating agent capable of stabilizing / irreversibly chelating bismuth. However, it is advantageous, although not essential, for the sequestering agent to selectively chelate bismuth over actinium.

[0096] Thus, the sequestering agents have a higher (preferably 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more higher) binding reaction rate than the corresponding binding reaction rate of, in particular, DTPA and / or DOTA, in particular DOTA. 3+ Bi, which has a binding reaction rate 3+ It is a chelating agent for

[0097] As already mentioned, the sequestering agent is particularly preferred for binding kinetic ratios of at least 80, in particular at least 90, for example 90-100, in particular 95-100, more in particular 98-100, in particular Ac 3+ Bi 3+ It is a chelating agent that has binding selectivity for

[0098] In one particular embodiment, the bismuth sequestering agent is DSMA (also called DMSA), DMPS, DOTA, DTPA, CHX-A''''-DTPA, EDTA, L py , L pyd , L pyr , L pz , NETA, 3p-C-NETA, DEPA, 3p-C-DEPA, C-DEPA, and more particularly meso-2,3-dimercaptosuccinic acid (DMSA). In certain embodiments, DTPA is not used as a bismuth sequestering agent, and preferably, in certain embodiments, DTPA is not used at all in the pharmaceutical composition.

[0099] Other features of the pharmaceutical compositions according to the present disclosure In a particular embodiment, said radionuclide is present in a concentration such that it provides a volumetric activity of at least 5 MBq / mL, particularly at least 2.5 MBq / mL, more particularly at least 1 MBq / mL (at EOP) (±10%).

[0100] In particular, (i) 225 The molar ratio of Ac radiolabeled complex to (ii) the bismuth sequestering agent may be comprised between 1:8500 and 1:80000. In a particular embodiment, the bismuth sequestering agent is present in the pharmaceutical composition at a concentration of 7-70 μg / mL.

[0101] In certain embodiments, the pharmaceutical compositions of the present disclosure have a volume activity of about 0.1 MBq / mL to about 10 MBq / mL. 225 Ac and one or more bismuth sequestrants at a total concentration of about 0.005 mg / mL to about 1 mg / mL. Preferably, in certain embodiments, the pharmaceutical compositions of the present disclosure comprise a volumetric activity of about 0.5 MBq / mL to about 5 MBq / mL. 225Ac and one or more bismuth sequestrants at a total concentration of about 0.01 mg / mL to about 5 mg / mL. More preferably, in certain embodiments, the pharmaceutical compositions of the present disclosure have a volume activity of about 0.8 MBq / mL to about 1.5 MBq / mL. 225 Ac and one or more bismuth sequestrants at a total concentration of about 0.02 mg / mL to about 2 mg / mL. Even more preferably, in certain embodiments, the pharmaceutical compositions of the present disclosure have a volume activity of about 0.9 MBq / mL to about 1.2 MBq / mL. 225 Ac and one or more bismuth sequestrants at a total concentration of about 0.03 mg / mL to about 1 mg / mL. Even more preferably, in certain embodiments, the pharmaceutical compositions of the present disclosure have a volume activity of about 1 MBq / mL. 225 Ac and one or more bismuth sequestrants at a total concentration of about 0.03 mg / mL to about 0.7 mg / mL. Even more preferably, in certain embodiments, the pharmaceutical compositions of the present disclosure have a volume activity of about 1 MBq / mL. 225 Ac and one or more bismuth sequestering agents at a total concentration of about 0.05 mg / mL. A preferred sequestering agent herein is DMSA. In certain embodiments related to the disclosure herein, the sequestering agent is not DTPA. "About" herein means ±20%, preferably ±10%, more preferably ±10% for volume activity and ±5% for bismuth chelating agents. The amount of sequestering agent referred to herein may be the sequestering agent disclosed herein as the free acid or in its salt form, e.g., sodium (Na) salt, and preferably the amount refers to the free acid.

[0102] In certain embodiments, the pharmaceutical composition further comprises at least one stabilizer against radiolysis, such as one or two stabilizers against radiolysis.

[0103] In particular, said one or more stabilizers (antioxidants) against radiolysis may be selected from the group consisting of gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g. sodium ascorbate), methionine, histidine, melatonin, ethanol and Se-methionine and mixtures thereof, in particular from gentisic acid or its salts and ascorbic acid or its salts. Preferably, only ascorbic acid or sodium ascorbate is used as stabilizer / antioxidant. Preferably, ethanol is not used as stabilizer. Preferably, in certain embodiments, ethanol is not a component of the pharmaceutical composition.

[0104] In particular, the at least two stabilizers may be gentisic acid or a salt thereof and ascorbic acid or a salt thereof.

[0105] In a particular embodiment of the pharmaceutical composition, the ratio between gentisic acid or a salt and ascorbic acid or a salt may be from 1:150 to 1:1, in particular from 1:50 to 1:2, more in particular from 1:4 to 2:5.

[0106] In particular, said gentisic acid or a salt thereof may be present in a concentration of at least 300 μg / mL, in particular from 300 μg / mL to 5000 μg / mL, even more in particular of about 1000 μg / mL.

[0107] In particular, said ascorbic acid or a salt thereof may be present in a concentration of at least 600 μg / mL, in particular from 600 μg / mL to 60000 μg / mL, even more in particular of about 2000 μg / mL.

[0108] Thus, in certain embodiments, the pharmaceutical composition comprises gentisic acid or a salt thereof and ascorbic acid or a salt thereof, wherein the gentisic acid or a salt thereof may be present at a concentration of 300 μg / mL to 5000 μg / mL, particularly about 1000 μg / mL, and the ascorbic acid or a salt thereof may be present at a concentration of 600 μg / mL to 50000 μg / mL, particularly about 2000 μg / mL.

[0109] In certain embodiments, the pharmaceutical composition may have a radiochemical purity (RCP) of greater than 90% up to 96 hours, in particular greater than 92% up to 72 hours, in particular greater than 95% up to 72 hours, preferably up to 96 hours, more preferably up to 120 hours, or even up to 144 hours.

[0110] In certain embodiments, the pharmaceutical composition further comprises a buffer, particularly an acetate buffer or a Tris buffer, particularly in amounts that provide an acetic acid concentration of 0.3 to 0.7 mg / mL, particularly about 0.48 mg / mL, and a sodium acetate concentration of 0.4 to 0.9 mg / mL, particularly about 0.66 mg / mL. In certain embodiments, the pharmaceutical composition further comprises a Tris buffer that provides a pH of about 7 to about 9, preferably a pH of about 7.5 to about 8.

[0111] Pharmaceutical compositions according to the present disclosure typically have a shelf life of at least 24 hours (h) at or below 25° C., at least 48 hours at or below 25° C., at least 72 hours at or below 25° C., between 24 and 120 hours at or below 25° C., between 24 and 96 hours at or below 25° C., between 24 and 84 hours at or below 25° C., between 24 and 72 hours at or below 25° C., and particularly a shelf life of 96 hours at or below 25° C. In certain embodiments, the pharmaceutical composition has a radiochemical purity (RCP) of 95% or greater as determined by iTLC (examples of analytical methods are provided in the Examples section herein) or as determined by HPLC over a period of at least 72 hours (3 days), more preferably at least 96 hours (4 days), even more preferably at least 120 hours (5 days), and even more preferably at least 144 hours (6 days) when stored at or below 25° C.

[0112] In certain embodiments, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) a complex having a volume activity of about 0.5 to 2 MBq / mL, preferably about 1 MBq / mL (±10%), (i) 225 Ac radionuclide, (ii) a target binding moiety linked to a chelator, preferably a PSMA binding moiety linked to a chelator, preferably a DOTA, including PSMA-R2, PSMA-617 or PSMA I&T; A complex formed by (b) Typically Bi 3+ wherein the total concentration is preferably between 0.01 and 0.1 mg / mL, preferably between 0.015 and 0.08 mg / mL, preferably about 0.05 mg / mL (±10%), and preferably only DMSA is used as the blocking agent, and preferably only DTPA is not used in the pharmaceutical composition; (c) optionally one or more stabilizers / antioxidants, preferably selected from the group consisting of gentisic acid and its salts, ascorbic acid and its salts and mixtures thereof, preferably having a total concentration of 0.5-10 mg / mL, preferably 0.9-5 mg / mL, more preferably 1.3-3.8 mg / mL, and preferably ascorbic acid or its salts are used as the only stabilizer, (d) optionally a buffer providing a pH of 7 to 9, preferably a pH of 7.5 to 8.5, more preferably a pH of 7.5 to 8.0, preferably a TRIS buffer (e.g., consisting of Tris hydrochloride, Tris and / or trometamol), preferably at a concentration of 0.5 to 5 mg / mL or 0.05 to 0.5 M, more preferably 0.1 to 0.25 M; wherein the pharmaceutical composition has a radiochemical purity (RCP) of 95% or greater as measured by iTLC or by HPLC over a period of at least 72 hours (3 days) when stored at or below 25° C., preferably for at least 120 hours (5 days).

[0113] Generally, pharmaceutical compositions according to the present disclosure are manufactured on a commercial scale, particularly in batch sizes of at least 0.1 GBq, at least 5 GBq, at least 7 GBq.

[0114] In certain embodiments, the pharmaceutical compositions according to the present disclosure are ready for use.

[0115] More specifically, the pharmaceutical compositions according to the present disclosure may be for commercial use.

[0116] According to one embodiment, the pharmaceutical composition is an aqueous solution, for example an injectable solution. According to a particular embodiment, the pharmaceutical composition is a solution for injection.

[0117] The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982) and SHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)).

[0118] The present disclosure also relates to a pharmaceutical composition as described above for use in the treatment or prevention of cancer, in particular a cancer expressing SSTR2, PSMA, GRPR, in particular a neuroendocrine tumor or prostate cancer or breast cancer.

[0119] In another aspect of the disclosure, the pharmaceutical composition is manufactured on a commercial scale, in particular in batch sizes of at least 18.5 GBq (0.5 Ci), at least 37 GBq (1 Ci) or at least 55.5 GBq (1.5 Ci) and up to 148 GBq (4 Ci), up to 129.5 GBq (3.5 Ci), up to 111 GBs (3 Ci), up to 92.5 GBq (2.5 Ci) or up to 74 GBq (2 Ci). Typically, the pharmaceutical composition is manufactured in batch sizes of 18.5 GBq (0.5 Ci) to 148 GBq (4 Ci).

[0120] In another aspect of the disclosure, the pharmaceutical composition is for commercial use.

[0121] In a further aspect, the present disclosure provides a radiolabeled PSMA-binding ligand linked to a chelator, typically a 225The present invention also relates to a pharmaceutical composition comprising an Ac]Ac-PSMA binding ligand, typically a PSMA binding ligand of formula (II) or (III), for use in the treatment or prevention of cancer in a subject in need thereof, said pharmaceutical composition being formulated with a stabilizer as described in any of the previous embodiments and administered to said subject in a therapeutically effective amount, typically comprised between 0.5 mCi and 1000 mCi, particularly between 50 mCi and 400 mCi, with a radiochemical purity (RCP) of greater than 95% upon administration.

[0122] In certain embodiments, the subject is a mammal, such as, but not limited to, a rodent, dog, cat, or primate. In certain embodiments, the subject is a human.

[0123] In a particular embodiment, a therapeutically effective amount of the composition is administered to said subject 1 to 8 times per treatment, particularly 3 times per treatment.

[0124] For example, human patients receive 2-8 cycles of 0.5 mCi-1000 mCi each administered intravenously, typically with a radiochemical purity (RCP) of >95% at the time of administration, radiolabeled PSMA-binding ligands linked to chelators, particularly chelators [ 225 The patient can be treated with the pharmaceutical composition comprising a PSMA-binding ligand, typically a PSMA-binding ligand of formula (II) or (III).

[0125] In certain cases, the pharmaceutical compositions of the present disclosure can be used in combination with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents, anti-emetic agents, agents against metal toxicity, analgesics, cytoprotective agents, and mixtures thereof.

[0126] In certain embodiments, the bismuth sequestering agent, which is an agent against metal toxicity, is selected from (or is selected from) a list of chelators, such as but not limited to the dithiol chelators 2,3-dimercapto-1-propanesulfonic acid (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or any salt of these chelators, calcium diethylenetriaminepentaacetic acid (Ca-DTPA) and zinc diethylenetriaminepentaacetic acid (Zn-DTPA) or diuretics, such as but not limited to furosemide, chlorthiazide, hydrochlorothiazide and bumex (butameni). Preferably, DMSA is used. In certain embodiments, DTPA is not used.

[0127] In certain embodiments, an agent against metal toxicity can be administered before, simultaneously with or after administration of a pharmaceutical composition according to the present disclosure, particularly after administration of a pharmaceutical composition according to the present disclosure.

[0128] Methods for preparing pharmaceutical compositions according to the present disclosure As mentioned above, the present disclosure also relates to a method for preparing said pharmaceutical composition, the method comprising: 1) complexing a radionuclide with a chelator linked to a target-binding organic moiety; (1.1) providing an aqueous solution containing a radionuclide; (1.2) providing an aqueous solution comprising a chelating agent linked to a target-binding organic moiety; (1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; forming a 2) diluting the complex solution obtained at the end of step (1) by mixing the complex solution obtained at the end of step (1) with a diluent; wherein said bismuth sequestering agent is contained in the aqueous solution of step 1.1 and / or in the aqueous solution of step 1.2 and / or in the diluent of step 2.

[0129] In certain embodiments, a bismuth sequestering agent is included in the aqueous solution of step 1.2 and / or the diluent of step 2.

[0130] In certain embodiments, a bismuth sequestering agent is included in the diluent of step 2.

[0131] In certain embodiments, the solution of step (1.2) further comprises a buffer, in particular an acetate buffer or a Tris buffer, preferably a Tris buffer, preferably providing a pH of about 7 to about 9, preferably a pH of about 7.5 to about 8.5, more preferably a pH of about 8.

[0132] In particular, in step (1.3), the resulting mixture is heated at a temperature of 70-99°C, in particular 90-98°C, for 2-59 minutes, preferably 90-98°C for 10-30 minutes, more preferably about 95°C for about 20 minutes.

[0133] In certain embodiments, the solution in step (1.1) is AcCl3, preferably 225 AcCl3, more preferably in 0.1N HCl 225 Contains AcCl3.

[0134] In particular, the solution in step (1.2) 225 In particular, the solution of step (1.2) comprises: 225 Ac radiolabeled PSMA binding complex and optionally gentisic acid.

[0135] In particular, the diluent in step (2) comprises said bismuth sequestering agent, ascorbic acid and saline.In particular, the diluent in step (2) comprises said bismuth sequestering agent, optionally ascorbic acid and optionally saline.

[0136] In certain embodiments, the process according to the present disclosure comprises: (3) filtering the solution obtained by step (2) through a 0.2 μm filter; (4) dispensing the filtrate obtained by step (3) into a dose unit container of a volume required to deliver a radiation dose of 4.0 to 15 MBq, in particular 7.0 to 8.0 MBq, more in particular 7.3 to 7.7 MBq, even more in particular 7.4 to 7.5 MBq, in particular the volume may be 5 to 50 mL, more in particular 6 to 30 mL, even more in particular 7 to 16 mL; Further includes:

[0137] In particular, the dose unit containers in step (4) are stoppered vials enclosed within a lead container. EXAMPLES

[0138] Example 1: Formulations containing [225Ac]Ac-PSMA-R2 and DTPA The PSMA-R2 compound is synthesized as described in WO 2017 / 165473.

[0139] With DTPA [ 225 A formulation containing Ac]Ac-PSMA-R2 is prepared according to the following table. This formulation is a ready-to-use 1 MBq / ml solution for injection / infusion.

[0140] [Table 1]

[0141] Example 2: 225 Formulations containing Ac]Ac-PSMA-R2 and DMSA Radiolabeling Scheme: [ka]

[0142] PSMA-R2 reconstitution To a vial containing 1 mg of PSMA-R2, 1 mL of water was added to give a 1000 ppm solution.

[0143] Preparation of Drug Substances (DS) Labeling: 120 μL in a 10 mL glass vial 225 AcCl3 0.1N HCl (calibration: day 1, 08:00, 91.49MBq, 1186μL) was added. The glass vial was crimped and measured with a dose calibrator (5.925MBq, day 7, 14:48). A solution of PSMA-R2 (47μL) was added, followed by 0.25M pH 8 Tris buffer (318μL). The pH of the resulting reaction mixture (volume 485μL) was measured with pH paper (Macherey-Nagel pH-Fix 7.5-9.5): pH 7.9. The reaction mixture was then heated at 95°C for 20 min using a heating block (Labnet, AccuBlock Digital Dry Bath). The solution was cooled to ambient temperature for 10 min. Radiolabeling was performed with a ratio of mass peptide (micrograms) to activity (MBq) of 8; mass peptide 47.4 micrograms; used MBq / microgram peptide 0.125; MBq / microgram peptide (ART) 1.270.

[0144] Preparation of DMSA solution 1.79 mg of DMSA (meso-2,3-dimercaptosuccinic acid) (Sigma Aldrich) was dispensed into a 1.5 mL centrifuge tube. 0.895 mL of water was added. The suspension was stirred using a vortex mixer until completely dissolved to obtain a homogenous DMSA solution at 2 mg / mL.

[0145] Preparation of sodium ascorbate solution L-Ascorbic acid (302.34 mg, 1.7 mmol) and sodium hydroxide (69.85 mg, 1.7 mmol) were dispensed onto a tared balance and transferred to a 50 mL Falcon vial. Water (11.72 mL) was added to give a 26.83 mg / mL sodium ascorbate solution.

[0146] Formulation of Drug Product (DP) The sodium ascorbate (596 μL) solution and the DMSA (148 μL) solution were dispensed with a pipette and transferred to a 1.5 mL centrifuge tube. The resulting solution was transferred with a 1 mL syringe to a 10 mL reaction vial ([225 [Ac]Ac-PSMAR2 DS solution). Using a syringe, 3 x 1 mL of saline (sodium chloride 0.9%) was transferred to the reaction vial. Finally, 1.695 mL of saline was added to obtain a 1 MBq / mL solution. The final volume of the formulation was 5.925 mL. The final pH of the formulation was 7.5.

[0147] A small aliquot (approximately 100 μL) was dispensed for iTLC analysis (RP-18 F254S, NHOAc 5M Aq / H2O / MeOH 3:2:7.5, described in more detail below). Acquisition of the TLC plate on an alpha scanner was performed >18 hours after development. This time was provided for 225Ac to reach long-term equilibrium and for the transferred daughter to decay. Radio-iTLC analysis showed a radiochemical purity (RCP) >99%. See Figure 2.

[0148] Stability testing DTPA formulations and equivalent DMSA 225 In order to obtain stability data for Ac]Ac-PSMA-R2 DP, we tested it with DMSA in a 5 mL solution stored at 25°C under stability conditions equivalent to those of DTPA formulations. 225 We chose to provide [Ac]Ac-PSMA-R2 DP. Therefore, the solution of the drug was withdrawn with a syringe (approximately 900 μL) to obtain a volume of 5 mL in the drug vial. The vial was then placed in a lead container and stored in a chamber at 25 °C. The radiochemical purity was analyzed by iTLC (RP-18 F254S, NHOAc 5M Aq / H2O / MeOH 3:2:7.5, plate length: 100 mm, sample run: 80 mm (10-90 mm), sample volume: 90 microliters, activity accumulation: 1.2-2.0 KBq, scan time after development >18 h, TLC scanner: MiniGita 37292, detector α: PMT+Plastic+ZnS, Rev 1.11, SN 17115, acquisition time 10 min) over a period of 7 days (time points: 24 h, 48 h, 72 h, 144 h, 168 h).

[0149] result: The following table shows stability data by iTLC analysis of DMSA formulations.

[0150] [Table 2]

[0151] The following table shows comparable RCP data for DMSA and DTPA formulations under the same conditions (5 mL solution at 25° C.). The data shows that both DTPA and DMSA provide good RCP over time. However, compared to DTPA, DMSA appears to provide good RCP over a longer period of time.

[0152] [Table 3]

Claims

1. (a) ２２５ Ac radiolabeled complex, (i) ２２５ Ac radionuclide, (ii) a target-binding moiety linked to a chelator; formed by ２２５ Ac radiolabeled complex, and (b) Typically Bi ３＋ a bismuth sequestering agent capable of sequestering (c) optionally an antioxidant specifically selected from the group comprising gentisic acid and its salts, ascorbic acid and its salts, and mixtures thereof; 10. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the antioxidant is selected from the group comprising gentisic acid and its salts, ascorbic acid and its salts, and mixtures thereof.

3. The bismuth sequestrants exhibit higher Bi binding kinetics than the corresponding binding kinetics of DTPA and / or DOTA. ３＋ Bi, having a binding kinetics relative to ３＋ The pharmaceutical composition of claim 1, which is a chelating agent for

4. The bismuth sequestering agent is particularly preferred for use with a binding reaction rate ratio of at least 90, in particular at least 90, for example 90-100, in particular 95-100, more in particular 98-100. ２２５ A.C. ３＋ More than Bi ３＋ The pharmaceutical composition of claim 1, which is a chelating agent having binding selectivity for

5. The bismuth sequestering agent is DMSA, DOTA, DTPA, CHX-A''''-DTPA, L ｐｙ , L ｐｙｄ , L ｐｙｒ , L ｐｚ , NETA, 3p-C-NETA, DEPA, 3p-C-DEPA, C-DEPA, more particularly DMSA.

6. 2. The pharmaceutical composition of claim 1, wherein the 225 Ac radionuclide is present in a concentration such that it provides a volumetric activity of at least 5 MBq / mL, particularly at least 2.5 MBq / mL, more particularly at least 1 MBq / mL (at EOP) (±10%).

7. (i) The above ２２５ 2. The pharmaceutical composition according to claim 1, wherein the molar ratio of Ac-radiolabelled complex to (ii) said bismuth sequestering agent is comprised between 1:8500 and 1:80000.

8. 2. The pharmaceutical composition of claim 1, further comprising at least one stabilizer against radiolysis, such as one or two stabilizers against radiolysis.

9. 9. The pharmaceutical composition according to claim 8, wherein the at least one stabilizer against radiolysis is selected from the group consisting of gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (e.g. sodium ascorbate), methionine, histidine, melatonin, ethanol and Se-methionine and mixtures thereof, in particular selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof.

10. 9. The pharmaceutical composition of claim 8, wherein the two stabilizers are gentisic acid or a salt thereof and ascorbic acid or a salt thereof.

11. 11. The pharmaceutical composition according to claim 10, wherein the ratio between gentisic acid or a salt and ascorbic acid or a salt is from 1:32 to 1:1, in particular from 1:16 to 1:2, more in particular from 1:4 to 2:

5.

12. 11. The pharmaceutical composition according to claim 10, wherein the gentisic acid or salt thereof is present in a concentration of at least 300 μg / mL, in particular from 300 μg / mL to 5000 μg / mL, even more in particular about 1000 μg / mL.

13. 11. The pharmaceutical composition according to claim 10, wherein the ascorbic acid or salt thereof is present in a concentration of at least 600 μg / mL, in particular from 600 μg / mL to 60000 μg / mL, even more in particular about 2000 μg / mL.

14. The aforementioned ２２５ 2. The pharmaceutical composition of claim 1, wherein the chelator of the Ac-radiolabelled complex is selected from DOTA, DTPA, NTA, EDTA, DO3A and NOTA, in particular DOTA.

15. 2. The pharmaceutical composition of claim 1, wherein the target-binding moiety is selected from among a PSMA-binding ligand, a somatostatin receptor-binding peptide, a gastrin-releasing peptide receptor antagonist and an integrin, in particular a PSMA-binding ligand.

16. 2. The pharmaceutical composition of claim 1, having a radiochemical purity of more than 90% up to 96 hours, in particular more than 92% up to 72 hours.

17. 2. The pharmaceutical composition of claim 1, further comprising a buffering agent, in particular acetate buffer or Tris buffer, in particular in an amount to provide an acetic acid concentration of 0.3 to 0.7 mg / mL (in particular about 0.48 mg / mL) and a sodium acetate concentration of 0.4 to 0.9 mg / mL (in particular about 0.66 mg / mL).

18. (d) 5 to 20 MBq, particularly 7 to 15 MBq ２２５ Ac and (e) 0.15 to 0.80 mg, particularly 0.21 to 0.60 mg, of a bismuth sequestering agent; (f) optionally 9 to 50 mg, particularly 12.6 to 37.5 mg, of an antioxidant; Patient dose units including:

19. A process for preparing the pharmaceutical composition according to any one of claims 1 to 17, comprising: (1) a 225 Ac radiolabeled complex of the 225 Ac radionuclide and a target binding moiety linked to the chelator; (1.1) providing an aqueous solution containing the 225 Ac radionuclide; (1.2) providing an aqueous solution comprising a target binding moiety linked to said chelator; (1.3) mixing the aqueous solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; forming a (2) Diluting the complex solution obtained in step (1) by mixing the complex solution obtained in step (1) with a diluent. wherein the bismuth sequestering agent is contained in the aqueous solution of step (1.1), and / or the aqueous solution of step (1.2), and / or the diluent of step (2).

20. 20. The process of claim 19, wherein the bismuth sequestering agent is included in the diluent of step (2).

21. (3) filtering the solution obtained by step (2) through a 0.2 μm filter; (4) dispensing the filtrate obtained by step (3) into dose unit containers of a volume required to deliver a radiation dose of 4.0 to 15 MBq, particularly 7.0 to 8.0 MBq, more particularly 7.3 to 7.7 MBq, even more particularly 7.4 to 7.5 MBq, wherein the volume is 5 to 50 mL, more particularly 6 to 30 mL, even more particularly 7 to 16 mL; 20. The process of claim 19, further comprising:

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