Pharmaceutical preparations

Abstract

The present invention relates to a pharmaceutical composition comprising a radiohybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F, or the chelating group comprises a chelated radioactive metal, wherein the composition has a pH of 4.0-6.0 and further comprises: 0.1-200 mM citrate buffer; 1-100 mg / mL ethanol; and 5-10 mg / mL sodium chloride.

Description

[0001] The present invention relates to a pharmaceutical composition of a radiohybrid agent containing a fluorinated silicon and a chelating group, wherein either the fluorine is fluorine-18 18 F) or the chelating group contains a chelated radioactive metal. The composition has a pH of 4.0-6.0 and further comprises: 0.1-200 mM citrate buffer; and 1-100 mg / mL ethanol; and 5-10 mg / mL sodium chloride.

[0002] Prostate cancer

[0003] Over the past decades, prostate cancer (PCa) remains the most common malignancy in men, with high incidence and low survival rate. Due to its overexpression in prostate cancer, prostate-specific membrane antigen (PSMA) or glutamate carboxypeptidase II (GCP II) proved to be an excellent target for the development of highly sensitive radiolabeled drugs for intraluminal radiotherapy and PCa imaging. Prostate-specific membrane antigen is an extracellular hydrolase whose catalytic center contains two zinc(II) ions with bridging hydroxido ligands. It is highly upregulated in metastatic and hormone-refractory prostate cancer, but its physiological expression has also been reported in kidney, salivary glands, small intestine, brain, and also in healthy prostate tissue at low levels. In the intestinal tract, PSMA facilitates the absorption of folate by converting pteroyl poly-gamma-glutamate to pteroyl glutamate (folate). In the brain, it hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and glutamate.

[0004] Prostate-specific membrane antigen (PSMA)

[0005] Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly overexpressed in prostate cancer epithelial cells. Despite its name, PSMA is also expressed to varying degrees in the neovasculature of a variety of non-prostate cancers. The most common non-prostate cancers that show PSMA expression include breast cancer, lung cancer, colorectal cancer, and renal cell carcinoma.

[0006] The generally necessary structure of a PSMA-targeting molecule comprises a binding unit comprising a zinc-binding group (such as urea, phosphinates, or phosphoramidates) linked to a P1' glutamate moiety, which guarantees high affinity and specificity to PSMA and is usually further associated with an effector function. The effector moiety is more flexible and can tolerate structural modifications to some extent.

[0007] Two classes of PSMA-targeting inhibitors are currently used in clinical settings. On the one hand, there are tracers with chelating units for radionuclide complexation, such as PSMA I&T or related compounds. On the other hand, there are small molecules comprising a targeting unit and an effector molecule.

[0008] 18 F-labeling

[0009] Recently, several groups focused on the development of novel urea-based inhibitors for PCa diagnosis. 18 F-labeling 18 F-labeled urea-based PSMA inhibitors 18 F-DCFPyl showed promising results in the detection of primary and metastatic PCa. Based on the structure of PSMA-617, the F-labeled analogue PSMA-1007 was recently developed, which showed comparable tumor-to-organ ratios. 18 F-labeling

[0010] Introduction 18 An attractive approach for F-labeling is the use of fluorinated silicon acceptors (SIFA). Fluorinated silicon acceptors are described, for example, in Lindner et al., Bioconjugate Chemistry 25, 738-749 (2014). In order to preserve the fluorosilicon bond, the use of fluorosilicon acceptors poses the necessity of groups that are space demanding around the silicon atom. This in turn renders the fluorosilicon acceptors highly hydrophobic. The hydrophobic moieties provided by the fluorosilicon acceptors can serve the purpose of establishing an interaction of the radiodiagnostic or therapeutic compound with a hydrophobic pocket, such as described in Zhang et al., Journal of the American Chemical Society 132, 12711-12716 (2010), in terms of binding to a target molecule, in particular to PSMA as a target molecule. However, the more highly lipophilic introduction into the molecule before binding poses a severe problem for the development of radiopharmaceuticals with an appropriate in vivo biodistribution, i.e. low non-specific binding in non-target tissues.

[0011] Despite many attempts, the problem of hydrophobicity caused by fluorinated silicon acceptors was only recently solved by the use of agents with a hydrophilic chelator moiety. The application WO 2019 / 020831 describes novel radihybrid agents with both a SIFA moiety and a metal chelator. In the development of the compounds described therein, the inventors have identified improved pharmaceutical formulations for patient delivery. The formulations described herein show improved radio-stability and shelf life than previously described formulations.

[0012] In view of the above, the technical problem of the present application is to provide an improved radiodiagnostic preparation, which contains a fluorinated silicon receptor and a metal chelator, which at the same time have the feature of a good pharmaceutical stability. SUMMARY

[0013] As will become apparent by the following, the present application establishes a proof of principle using a specific conjugate formulated in a specific way, which binds with high affinity to the prostate specific antigen (PSMA) as a target. The composition, in which the compound is prepared and stored, influences the chemical and radiochemical stability of the pharmaceutical agent. Thus, a further technical problem of the present application is to provide an improved diagnosis for the medical indication of cancer, preferably prostate cancer.

[0014] These technical problems are solved by the subject matter of the claims. Thus, in a first aspect, the present application relates to a pharmaceutical composition comprising a radiological hybrid agent containing a fluorinated silicon and a chelating group, wherein either the fluorine is fluorine-18 18 F) or the chelating group contains a chelated radioactive metal, wherein the composition has a pH of 4.0-6.0 and further comprises:

[0015] (a) 0.1-200 mM citrate buffer; and

[0016] (b) 1-100 mg / mL ethanol; and

[0017] (c) 5-10 mg / mL sodium chloride.

[0018] An alternative composition disclosed herein relates to a pharmaceutical composition of a radiological hybrid agent containing a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group contains a chelated radioactive metal, wherein the composition comprises: (a) 50-200 mM citrate buffer and / or; (b) 10-100 mg / mL ethanol and / or; (c) has a pH of 4.0-6.0.

[0019] The preparation can be prepared in a high concentration of citrate buffer and then diluted to reduce the citrate concentration. The ethanol concentration can also be reduced by dilution. The composition can be diluted with a solution containing sodium chloride (saline).

[0020] A method of preparing a composition as described herein is described, the method comprising preparing a preparation of a radiological hybrid agent containing a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group contains a chelated radioactive metal, wherein the composition has a pH of 4.0-6.0 and a citrate concentration of at least 10 mM, and diluting the citrate concentration with a sodium chloride solution.

[0021] The pharmaceutical composition can comprise 50-200 mM citrate buffer.

[0022] The pharmaceutical composition can comprise 10-100 mg / ml ethanol.

[0023] The pharmaceutical composition can have a pH of 4.0 to 6.0.

[0024] The pharmaceutical composition can comprise a chelated radioactive metal or 18 F fluorine.

[0025] The pharmaceutical composition can comprise a chelated radioactive metal selected from the cations of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Ac, Th or Er.

[0026] The pharmaceutical composition can comprise 18 F fluorine and a non-radioactive chelated metal ion.

[0027] The pharmaceutical composition can comprise 19 F fluorine and a radioactive chelated metal ion.

[0028] The pharmaceutical composition can be one in which the metal is a radioactive metal and the fluorine is 19 F.

[0029] The pharmaceutical composition can be one in which the fluorine is 18 F and the metal is a non-radioactive metal.

[0030] The pharmaceutical composition can comprise a chelated radioactive metal cation selected from: 177 Lu, 90 Y, 225 Ac, 68 Ga or 67 Ga.

[0031] The pharmaceutical composition can comprise 60-120 mM citrate buffer.

[0032] The pharmaceutical composition can comprise 0.1-200 mM citrate buffer.

[0033] The pharmaceutical composition can comprise 0.1-120 mM citrate buffer.

[0034] The pharmaceutical composition can comprise 0.1-50 mM citrate buffer.

[0035] The pharmaceutical composition can comprise 0.1-20 mM citrate buffer. The pharmaceutical composition can comprise 1-15 mM citrate buffer.

[0036] The pharmaceutical composition can comprise 10 mM (± 15%) citrate buffer.

[0037] The pharmaceutical composition can comprise 10 mM (±10%) citrate buffer.

[0038] The pharmaceutical composition can comprise 10 mM (±5%) citrate buffer.

[0039] The pharmaceutical composition can comprise 10 mM (±2%) citrate buffer.

[0040] The pharmaceutical composition can comprise 10 mM (±1%) citrate buffer.

[0041] The pharmaceutical composition can comprise 10 mM citrate buffer.

[0042] The pharmaceutical composition can comprise 1-10 mM citrate buffer.

[0043] The pharmaceutical composition can comprise 1-10 mM (±15%) citrate buffer.

[0044] The pharmaceutical composition can comprise 1-10 mM (±10%) citrate buffer.

[0045] The pharmaceutical composition can comprise 1-10 mM (±5%) citrate buffer.

[0046] The pharmaceutical composition can comprise 1-10 mM (±2%) citrate buffer.

[0047] The pharmaceutical composition can comprise 1-10 mM (±1%) citrate buffer.

[0048] The pharmaceutical composition can be formulated with anhydrous citric acid or, alternatively, with citric acid monohydrate or a salt thereof (including sodium citrate). Citric acid monohydrate can be used to formulate the pharmaceutical composition.

[0049] The pharmaceutical composition can be formulated with 1.5-2.5 mg / mL citric acid (anhydrous basis).

[0050] The pharmaceutical composition can be formulated with 1.9 mg / mL (±10%) citric acid (anhydrous basis).

[0051] The pharmaceutical composition can be formulated with 1.9 mg / mL (±5%) citric acid (anhydrous basis).

[0052] The pharmaceutical composition can be formulated with 1.9 mg / mL (±2%) citric acid (anhydrous basis).

[0053] The pharmaceutical composition can be formulated with 1.9 mg / mL (±1%) citric acid (anhydrous basis).

[0054] The pharmaceutical composition can be formulated with 1.9 mg / mL citric acid (anhydrous base).

[0055] The pharmaceutical composition can have a pH of 4.5-5.5.

[0056] The pharmaceutical composition can have a pH of 5 (± 15%).

[0057] The pharmaceutical composition can have a pH of 5 (± 10%).

[0058] The pharmaceutical composition can have a pH of 5 (± 5%).

[0059] The pharmaceutical composition can have a pH of 5 (± 2%).

[0060] The pharmaceutical composition can have a pH of 5 (± 1%).

[0061] The pharmaceutical composition can have a pH of 5.

[0062] The pharmaceutical composition can have a pH of 5.1.

[0063] The pharmaceutical composition can have a pH of 4.9.

[0064] The pharmaceutical composition can comprise 5-100 mg / mL ethanol.

[0065] The pharmaceutical composition can comprise 10-100 mg / mL ethanol.

[0066] The pharmaceutical composition can comprise 10-70 mg / mL ethanol.

[0067] The pharmaceutical composition can comprise 40-60 mg / mL ethanol.

[0068] The pharmaceutical composition can comprise 50 mg / mL (± 15%) ethanol.

[0069] The pharmaceutical composition can comprise 50 mg / mL (± 10%) ethanol.

[0070] The pharmaceutical composition can comprise 50 mg / mL (± 5%) ethanol.

[0071] The pharmaceutical composition can comprise 50 mg / mL (± 2%) ethanol.

[0072] The pharmaceutical composition can comprise 50 mg / mL (± 1%) ethanol.

[0073] The pharmaceutical composition can comprise 50 mg / mL ethanol.

[0074] The pharmaceutical composition can comprise 5-50 mg / mL (± 15%) ethanol.

[0075] The pharmaceutical composition can comprise 5-50 mg / mL (± 10%) ethanol.

[0076] The pharmaceutical composition can comprise 5-50 mg / mL (± 5%) ethanol.

[0077] The pharmaceutical composition can comprise 5-50 mg / mL (± 2%) ethanol.

[0078] The pharmaceutical composition can comprise 5-50 mg / mL (± 1%) ethanol.

[0079] The pharmaceutical composition can comprise 5-50 mg / mL ethanol.

[0080] The pharmaceutical composition can comprise 5-10 mg / mL sodium chloride.

[0081] The pharmaceutical composition can comprise 6-9 mg / mL sodium chloride.

[0082] The pharmaceutical composition can comprise 7.2 mg / mL (± 15%) sodium chloride.

[0083] The pharmaceutical composition can comprise 7.2 mg / mL (± 10%) sodium chloride.

[0084] The pharmaceutical composition can comprise 7.2 mg / mL (± 5%) sodium chloride.

[0085] The pharmaceutical composition can comprise 7.2 mg / mL (± 2%) sodium chloride.

[0086] The pharmaceutical composition can comprise 7.2 mg / mL (± 1%) sodium chloride.

[0087] The pharmaceutical composition can comprise 7.2 mg / mL sodium chloride.

[0088] In the pharmaceutical composition, citrate buffer can be prepared from citric acid and sodium hydroxide. Alternatively, citrate buffer can be prepared using appropriate amounts of sodium citrate and HC1.

[0089] In the pharmaceutical composition, 1-3 mg / mL citric acid (anhydrous basis) and 0.5-1.0 mg / mL sodium hydroxide can be used to prepare citrate buffer.

[0090] In the pharmaceutical composition, 1.9 mg / mL (± 15%) citric acid (anhydrous basis) and 0.75 mg / mL (± 15%) sodium hydroxide can be used to prepare citrate buffer.

[0091] In the pharmaceutical composition, 1.9 mg / mL (± 10%) citric acid (anhydrous basis) and 0.75 mg / mL (± 10%) sodium hydroxide can be used to prepare citrate buffer.

[0092] In the pharmaceutical composition, 1.9 mg / mL (± 5%) citric acid (anhydrous basis) and 0.75 mg / mL (± 5%) sodium hydroxide can be used to make a citrate buffer.

[0093] In the pharmaceutical composition, 1.9 mg / mL (± 2%) citric acid (anhydrous basis) and 0.75 mg / mL (± 2%) sodium hydroxide can be used to make a citrate buffer.

[0094] In the pharmaceutical composition, 1.9 mg / mL (± 1%) citric acid (anhydrous basis) and 0.75 mg / mL (± 1%) sodium hydroxide can be used to make a citrate buffer.

[0095] In the pharmaceutical composition, 1.9 mg / mL citric acid (anhydrous basis) and 0.75 mg / mL sodium hydroxide can be used to make a citrate buffer.

[0096] The pharmaceutical composition can have a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of 5-500 mCi / mL.

[0097] The pharmaceutical composition can have a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of 5-200 mCi / mL.

[0098] The pharmaceutical composition can have a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of 50-100 mCi / mL.

[0099] The pharmaceutical composition can have a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of 10-100 mCi / mL.

[0100] The term "end of synthesis" refers to the point in time at which the labeled compound is collected into the product collection vial.

[0101] The pharmaceutical composition can have a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of 20-90 mCi / mL.

[0102] The pharmaceutical composition can have a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of at least 35 mCi / mL.

[0103] The pharmaceutical composition can comprise 10 mM (± 15%) citrate buffer, 50 mg / mL (± 15%) ethanol, 7.2 mg / mL (± 15%) sodium chloride, and have a pH of 5 (± 15%).

[0104] The pharmaceutical composition can comprise 10 mM (± 10%) citrate buffer, 50 mg / mL (± 10%) ethanol, 7.2 mg / mL (± 10%) sodium chloride, and have a pH of 5 (± 10%).

[0105] The pharmaceutical composition can comprise 10 mM (± 5%) citrate buffer, 50 mg / mL (± 5%) ethanol, 7.2 mg / mL (± 5%) sodium chloride, and have a pH of 5 (± 5%).

[0106] The pharmaceutical composition can comprise 10 mM (± 2%) citrate buffer, 50 mg / mL (± 2%) ethanol, 7.2 mg / mL (± 2%) sodium chloride, and have a pH of 5 (± 2%).

[0107] The pharmaceutical composition can comprise 10 mM (± 1%) citrate buffer, 50 mg / mL (± 1%) ethanol, 7.2 mg / mL (± 1%) sodium chloride, and have a pH of 5 (± 1%).

[0108] The pharmaceutical composition can comprise 10 mM citrate buffer, 50 mg / mL ethanol, 7.2 mg / mL sodium chloride, and have a pH of 5.

[0109] The pharmaceutical composition can comprise a radiophyl hybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal, wherein the pH of the composition is 5.0 (± 15%) and further comprising:

[0110] (a) 10 mM (± 15%) citrate buffer; and

[0111] (b) 50 mg / mL (± 15%) ethanol; and

[0112] (c) 7.2 mg / mL (± 15%) sodium chloride.

[0113] The pharmaceutical composition can comprise a radiophyl hybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal, wherein the pH of the composition is 5.0 (± 10%) and further comprising:

[0114] (a) 10 mM (± 10%) citrate buffer; and

[0115] (b) 50 mg / mL (± 10%) ethanol; and

[0116] (c) 7.2 mg / mL (± 10%) sodium chloride.

[0117] The pharmaceutical composition can comprise a radiophyl hybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal, wherein the pH of the composition is 5.0 (± 5%) and further comprising:

[0118] (a) 10 mM (± 5%) citrate buffer; and

[0119] (b) 50 mg / mL (± 5%) ethanol; and

[0120] (c) 7.2 mg / mL (± 5%) sodium chloride.

[0121] The pharmaceutical composition can comprise a radiohybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal, wherein the pH of the composition is 5.0 (± 2%) and further comprising:

[0122] (a) 10 mM (± 2%) citrate buffer; and

[0123] (b) 50 mg / mL (± 2%) ethanol; and

[0124] (c) 7.2 mg / mL (± 2%) sodium chloride.

[0125] The pharmaceutical composition can comprise a radiohybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal, wherein the pH of the composition is 5.0 (± 1%) and further comprising:

[0126] (a) 10 mM (± 1%) citrate buffer; and

[0127] (b) 50 mg / mL (± 1%) ethanol; and

[0128] (c) 7.2 mg / mL (± 1%) sodium chloride.

[0129] The pharmaceutical composition can comprise a radiohybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal, wherein the pH of the composition is 5.0 and further comprising:

[0130] (a) 10 mM citrate buffer; and

[0131] (b) 50 mg / mL ethanol; and

[0132] (c) 7.2 mg / mL sodium chloride.

[0133] The pharmaceutical composition can be diluted with a sodium chloride solution prior to administration. The pharmaceutical composition can be diluted with a sodium chloride solution prior to administration up to 10-fold or more. The sodium chloride solution used as a diluent prior to administration can be a 9 mg / mL (± 5%) sodium chloride solution in water.

[0134] The pharmaceutical composition can comprise 1.1 mM (± 15%) citrate buffer after dilution with a sodium chloride solution.

[0135] The pharmaceutical composition can comprise 1.1 mM (± 10%) citrate buffer after dilution with a sodium chloride solution.

[0136] The pharmaceutical composition can comprise 1.1 mM (± 5%) citrate buffer after dilution with a sodium chloride solution.

[0137] The pharmaceutical composition can comprise 1.1 mM (± 2%) citrate buffer after dilution with a sodium chloride solution.

[0138] The pharmaceutical composition can comprise 1.1 mM (± 1%) citrate buffer after dilution with a sodium chloride solution.

[0139] The pharmaceutical composition can comprise 1.1 mM citrate buffer after dilution with a sodium chloride solution.

[0140] The pharmaceutical composition can comprise 5.3 mg / mL (± 15%) ethanol after dilution with a sodium chloride solution.

[0141] The pharmaceutical composition can comprise 5.3 mg / mL (± 10%) ethanol after dilution with a sodium chloride solution.

[0142] The pharmaceutical composition can comprise 5.3 mg / mL (± 5%) ethanol after dilution with a sodium chloride solution.

[0143] The pharmaceutical composition can comprise 5.3 mg / mL (± 2%) ethanol after dilution with a sodium chloride solution.

[0144] The pharmaceutical composition can comprise 5.3 mg / mL (± 1%) ethanol after dilution with a sodium chloride solution.

[0145] The pharmaceutical composition can comprise 5.3 mg / mL ethanol after dilution with a sodium chloride solution.

[0146] The pharmaceutical composition can comprise 5-10 mg / mL sodium chloride after dilution with a sodium chloride solution.

[0147] The pharmaceutical composition can comprise 8.8 mg / mL (± 15%) sodium chloride after dilution with a sodium chloride solution.

[0148] The pharmaceutical composition can comprise 8.8 mg / mL (± 10%) sodium chloride after dilution with a sodium chloride solution.

[0149] The pharmaceutical composition can comprise 8.8 mg / mL (± 5%) sodium chloride after dilution with a sodium chloride solution.

[0150] The pharmaceutical composition can comprise 8.8 mg / mL (± 2%) sodium chloride after dilution with a sodium chloride solution.

[0151] The pharmaceutical composition can comprise 8.8 mg / mL (± 1%) sodium chloride after dilution with a sodium chloride solution.

[0152] The pharmaceutical composition can comprise 8.8 mg / mL sodium chloride after dilution with a sodium chloride solution.

[0153] The pharmaceutical composition can comprise 1.1 mM (± 15%) citrate buffer, 5.3 mg / mL (± 15%) ethanol, 8.8 mg / mL (± 15%) sodium chloride after dilution with a sodium chloride solution, and have a pH of 5.1 (± 15%).

[0154] The pharmaceutical composition can comprise 1.1 mM (± 10%) citrate buffer, 5.3 mg / mL (± 10%) ethanol, 8.8 mg / mL (± 10%) sodium chloride after dilution with a sodium chloride solution, and have a pH of 5.1 (± 10%).

[0155] The pharmaceutical composition can comprise 1.1 mM (± 5%) citrate buffer, 5.3 mg / mL (± 5%) ethanol, 8.8 mg / mL (± 5%) sodium chloride after dilution with a sodium chloride solution, and have a pH of 5.1 (± 5%).

[0156] The pharmaceutical composition can comprise 1.1 mM (± 2%) citrate buffer, 5.3 mg / mL (± 2%) ethanol, 8.8 mg / mL (± 2%) sodium chloride after dilution with a sodium chloride solution, and have a pH of 5.1 (± 2%).

[0157] The pharmaceutical composition can comprise 1.1 mM (± 1%) citrate buffer, 5.3 mg / mL (± 1%) ethanol, 8.8 mg / mL (± 1%) sodium chloride after dilution with a sodium chloride solution, and have a pH of 5.1 (± 1%).

[0158] The pharmaceutical composition can comprise 1.1 mM citrate buffer, 5.3 mg / mL ethanol, 8.8 mg / mL sodium chloride after dilution with a sodium chloride solution, and have a pH of 5.1.

[0159] The pharmaceutical composition can improve product stability by lowering the pH. During testing, it was found that the product was not very stable under basic conditions, producing hydrolyzed silanol products (F- displaced with OH-). Lowering the pH helped stabilize the product and citrate at pH 5 was selected.

[0160] Ethanol can be used as a radiolysis decomposition protectant. Optimization of the amount of ethanol led to the development of a stable material as described herein.

[0161] Different amounts of components can be combined. For example, the buffer can be 0.1-200 mM citrate buffer with a pH of 4.5-5.5 and up to 70 mg / mL ethanol. The composition can include additional salts for blood isotonicity. The composition contains sodium chloride.

[0162] The pharmaceutical composition can bind to PSMA.

[0163] The pharmaceutical composition can comprise a radiological hybrid selected from the group consisting of:

[0164]

[0165]

[0166]

[0167] and isomers and salts thereof, wherein M 3+ is a chelated radioactive metal or non-radioactive metal. These agents can be in the form of a pharmaceutically acceptable salt, such that for example one or more of the groups shown as COOH can be a salt thereof.

[0168] The pharmaceutical composition can comprise a radiological hybrid comprising:

[0169]

[0170] or isomers or salts thereof.

[0171] The pharmaceutical composition can be used as a cancer diagnostic or imaging agent.

[0172] The pharmaceutical composition can be used in a method of imaging and / or diagnosing cancer in a patient in need thereof. Accordingly, also provided herein is a method of imaging and / or diagnosing cancer, the method comprising administering a conjugate, compound or composition of the application to a patient in need thereof.

[0173] The pharmaceutical composition can be used to treat cancer.

[0174] The pharmaceutical composition can be used for the diagnosis, imaging or prevention of neovascularization / angiogenesis.

[0175] The pharmaceutical composition can be used as a cancer diagnostic or imaging agent or for the treatment of cancer, wherein the cancer is prostate cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma.

[0176] The pharmaceutical composition comprises a radiohybrid having three independent moieties. The three independent moieties are a) one or more ligands capable of binding to PSMA, (b) a silicon-fluoride acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom, and (c) one or more chelating groups containing a chelated non-radioactive cation or a radioactive cation.

[0177] While certain ligands capable of binding to a disease-related target molecule can be cyclic peptides, such cyclic peptides are not contemplated as chelating groups herein, as the problem of hydrophobic SIFA moieties cannot be solved without additional chelating moieties. Thus, the radiohybrid of the inventive composition requires a hydrophilic chelating group in addition to the ligand capable of binding to PSMA. The hydrophilic chelating group is required to reduce the hydrophobicity of the radiohybrid of the composition caused by the presence of the SIFA moiety.

[0178] The ligand in connection with the first aspect of the invention is defined in terms of function. This is because the invention does not rely on specific properties of the ligand in terms of structure. Rather, the key aspect of the invention is the combination of a silicon-fluoride acceptor and a chelator or chelate within a single molecule. The two structural elements, SIFA and chelator, exhibit a spatial proximity. Preferably, the shortest distance between two atoms of the two elements is less than or equal to 5 A, more preferably less than 4 A, even more preferably less than 3 A, and most preferably less than 2 A. More preferably less than 3 A Even more preferably less than 2 A Alternatively or additionally, preferably not more than 25 covalent bonds separate the atoms of the SIFA moiety and the atoms of the chelator, preferably not more than 20 chemical bonds, even more preferably not more than 15 chemical bonds.

[0179] The cation according to item (c) can be a radioactive cation or a non-radioactive cation. Examples are given further below. Thus, the conjugate can be radiolabeled at the SIFA moiety, or not. In the former case, the chelating group can be a complex of cold (non-radioactive) ions, or can be free of any ions. In the latter case, the chelator will contain a radioactive cation.

[0180] The inventors found that placing a silicon-fluoride acceptor in the vicinity of a hydrophilic chelator, such as but not limited to DOTAGA or DOTA, effectively shields or counteracts the lipophilicity of the SIFA moiety to an extent that the overall hydrophobicity of the compound is changed in a range that makes the compound suitable for in vivo administration.

[0181] Another advantage of the radiopharmaceutical compositions of the present application, especially the PSMA-targeting radiopharmaceutical compositions, compared to other PSMA-targeting radiopharmaceuticals such as PSMA I&T is that their accumulation in the mouse kidney is unexpectedly low. Without wishing to be bound to a particular theory, it appears that the combination of the structural element SIFA with the chelator provides for the unexpected reduction of accumulation in the kidney.

[0182] In preferred embodiments, the ligand according to the present application comprises or consists of a peptide, a peptidomimetic or a substituted urea, a substituent including an amino acid. It is to be understood that a ligand comprising a peptide or a peptidomimetic also comprises non-peptide moieties and non-peptidomimetic moieties. In terms of molecular weight, a molecular weight of below 15 kDa, below 10 kDa or below 5 kDa is preferred. Thus, the term “ligand” also includes small proteins. The target molecule is not particularly limited and includes enzymes, receptors, epitopes, transport proteins, cell surface molecules and proteins of the extracellular matrix. Preferred are targets that are associated with a disease. Particularly preferred are targets that are causally related to a given disease, or that are highly overexpressed in a given disease and / or whose inhibition can result in a beneficial effect for a patient suffering from a given disease. The ligand is preferably a high affinity ligand with a preferred affinity (expressed as IC 50 ) of below 50 nM, below 20 nM or below 5 nM.

[0183] Particularly preferred are those ligands that bind to prostate-specific membrane antigen (PSMA) with high affinity.

[0184] Preferably, the fluorinated silicon acceptor (SIFA) moiety has a structure represented by formula (I):

[0185]

[0186] wherein F is understood to include 19 F and 18 F, R 1S and R 2S are independently linear or branched C3 to C10 alkyl, preferably R 1S and R 2S are selected from isopropyl and tert-butyl, more preferably R 1S and R 2S are tert-butyl; R 3S is a Ci to C20 hydrocarbyl group which can contain one or more aromatic units and one or more aliphatic units and / or up to 3 heteroatoms selected from O and S, preferably R 3S is a C6 to C10 hydrocarbyl group containing an aromatic ring and can contain one or more aliphatic units; more preferably R 3S is a phenyl ring, most preferably R 3S is a phenyl ring, wherein the Si-containing substituent and the moiety The labeled bond is para to the and wherein the SIFA moiety is attached to the remainder of the conjugate by The labeled bond is para to the and wherein the SIFA moiety is attached to the remainder of the conjugate by

[0187] More preferably, the fluorinated silicon acceptor (SIFA) moiety has a structure represented by formula (la):

[0188]

[0189] wherein t-Bu represents a tert-butyl group;

[0190] and F is understood to include 19 F and 18 F.

[0191] Preferred chelating groups include at least one of the following (i), (ii), or (iii).

[0192] (i) a macrocyclic structure having 8 to 20 ring atoms, wherein 2 or more, more preferably 3 or more, of the atoms are selected from oxygen atoms or nitrogen atoms. Preferably, 6 or fewer of the ring atoms are selected from oxygen atoms or nitrogen atoms. Particularly preferred is that 3 or 4 of the ring atoms are nitrogen atoms or oxygen atoms. Of the oxygen and nitrogen atoms, nitrogen atoms are preferred. In combination with the macrocyclic structure, preferred chelating groups can comprise 2 or more, for example 2 to 6, preferably 2 to 4, carboxyl groups and / or hydroxyl groups. Of the carboxyl groups and hydroxyl groups, carboxyl groups are preferred.

[0193] (ii) an acyclic open chain chelating structure having 8 to 20 backbone (skeletal) atoms, wherein 2 or more, more preferably 3 or more, of the atoms are heteroatoms selected from oxygen atoms or nitrogen atoms. Preferably, 6 or fewer of the backbone atoms are selected from oxygen atoms or nitrogen atoms. Of the oxygen and nitrogen atoms, nitrogen atoms are preferred. More preferably, the open chain chelating structure is a structure comprising a combination of 2 or more, more preferably 3 or more, heteroatoms selected from oxygen atoms or nitrogen atoms and 2 or more, for example 2 to 6, preferably 2 to 4, carboxyl groups and / or hydroxyl groups. Of the carboxyl groups and hydroxyl groups, carboxyl groups are preferred.

[0194] (iii) a branched chelating structure containing a quaternary carbon atom. Preferably, the quaternary carbon atom is substituted with 3 identical chelating groups in addition to the SIFA / ligand moiety. The substituted chelating groups can include amides. The substituted chelating groups can include aromatic groups. The substituted chelating groups can include hydroxypyridinones.

[0195] In preferred specific examples, the chelating group is a residue of a chelator selected from: bis(carboxymethyl)-1,4,8,1 1 -tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,1 1 - tetraazacyclotetradec-1 -yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutyryl]amino]pentyl]-N- hydroxyoxal diamide (DFO), 4,1 1 -bis(carboxymethyl)-1,4,8,1 1 - tetraazabicyclo[6.6.2]hexadecane (DO2A) 1,4,7,10-tetraazacyclododecane-N,N',N",N"'- tetraacetic acid (DOTA), a-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTAGA), 1,4,7,10 tetraazacyclododecane N,N',N",N"' 1,4,7,10- tetra(methylene)phosphonic acid (DOTMP), N,N'-dipyridyloxyethylenediamine-N,N'- diacetic acid-5,5'-bis(phosphonate) (DPDP), diethylenetriamine N,N',N" penta(methylene) phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'- tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethylidene-diaminetriacetic acid (HEDTA), 1 -(p-nitrobenzyl)-1,4,7,10- tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3- carboxamide (HYNIC), tetra 3-hydroxy-N-methyl-2-pyridinone chelator (4-((4-(3-(bis(2-(3- hydroxy-1 -methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2- (bis(2-(3-hydroxy-1 -methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino) methyl)propyl)phenyl)amino)-4-oxobutanoic acid), abbreviated Me-3,2-HOPO, 1,4,7- triazacyclononane-1 -succinic acid-4,7-diacetic acid (NODASA), 1 -(1 -carboxy-3- carboxypropyl)-4,7-(carbooxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7- triazacyclononanetricetic acid (NOTA), 4,1 1 -bis(carboxymethyl)-1,4,8,1 1 - tetraazabicyclo[6.6.2] Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridine-bis(methylene aminotetraacetic acid (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP), 1,4,7,10-tetraazacyclotridecane-N,N',N",N"' -tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazolidin-1-yl]methyl-hydroxy-phosphoryl]propanoic acid, and triethylenetetraaminehexaacetic acid (TTHA), provided by covalently binding the carboxyl groups contained in the chelator to the rest of the conjugate through ester or amide linkages.

[0196] Specific chelators are as follows:

[0197]

[0198] Among the above exemplary chelators, particularly preferred are chelators selected from TRAP, DOTA and DOTAGA.

[0199] Metal or cation chelating macrocyclic and acyclic compounds are well known in the art and are available from many manufacturers. Although the chelating moiety according to the present application is not particularly limited, it will be appreciated that many moieties can be used by the skilled person off the shelf without further ado.

[0200] The chelating group can comprise a non-radioactive chelating cation.

[0201] Preferred examples of cations that can be chelated by the chelating group are the following non-radioactive cations: Sc, Cr, Mn, Co, Fe, Ni, Cu, Ga, Zr, Y, Tc, Ru, Rh, Pd, Ag, In, Sn, Te, Pr, Pm, Tb, Sm, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Re, Pt, Hg, Au, Pb At, Bi, Ra, Ac, Th; more preferably the following cations: Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th and Er. The cation can be Ga. The cation can be Lu.

[0202] The chelating group can comprise a radioactive chelating cation.

[0203] Preferred examples of cations that can be chelated by the chelating group are the following ions: 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn,58 Co、 52 Fe、 56 Ni、 57 Ni、 62 Cu、 64 Cu、 67 Cu、 66 Ga、 67 Ga 68 Ga、 89 Zr、 90 Y、 89 Y、 <Tc、 99m Tc, 97 Ru、 105 Rh、 109 Pd, 111 Ag, 110m In、 111 In、 113m In、 114m In、 117m Sn、 121 Sn、 127 Te、 142 Pr、 143 Pr、 149 Pm, 151 Pm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 153 Sm、 157 Gd, 161 Tb, 166 Ho、 165 Dy、 169 Er、 169 Yb、 175 Yb、 172 Tm、 177 Lu、 186 Re、 188 Re、 191 Pt, 197 Hg, 198 Au、 199 Au、 212 Pb, 203 Pb, 211 At、 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Th, includes 18 F or cations such as 18 F-[AlF] 2+ Cation molecules; more preferably, the following cations: 44 Sc、47 Sc, 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 161 Tb, 166 Ho, 177 Lu, 188 Re, 212 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Th or a cationic molecule comprising 18 F. The cation can be selected from Lu-177, Y-90 or Ac-225. A preferred cation can be a positron emitting isotope, such as 68 Ga.

[0204] Thus, the ligand is preferably capable of binding to prostate specific membrane antigen (PSMA).

[0205] More preferably, the ligand has a structure represented by formula (II):

[0206]

[0207] wherein m is an integer from 2 to 6, preferably 2 to 4, more preferably 2; n is an integer from 2 to 6, preferably 2 to 4, more preferably 2 or 3; R 1L is CH2, NH or O, preferably NH; R 3L is CH2, NH or O, preferably NH; R 2L is C or P(OH), preferably C; and wherein the ligand is connected to the remainder of the conjugate by the bond marked with .

[0208] The ligand can have a structure represented by formula (IIa):

[0209]

[0210] wherein n is an integer from 2 to 6; and wherein the ligand is connected to the remainder of the conjugate by the bond marked with .

[0211] A number of PSMA binders are known in the art, all of which are suitable for use in the present application. The above preferred embodiments are structural definitions of preferred groups of PSMA binders.

[0212] It is particularly preferred that the conjugate of the first aspect is a compound of formula (III):

[0213]

[0214] or a pharmaceutically acceptable salt thereof, wherein:

[0215] SIFA is a fluorinated silicon acceptor (SIFA) moiety comprising a covalent bond between a silicon and a fluorine atom and having 18 F label; preferably SIFA is a SIFA moiety of formula (I), more preferably a SIFA moiety of formula (la) as defined above;

[0216] m is an integer from 2 to 6, preferably 2 or 3, more preferably 2;

[0217] n is an integer from 2 to 6, preferably 2 or 3, more preferably 2 or 4;

[0218] R 1L is CH2, NH or O, preferably NH;

[0219] R 3L is CH2, NH or O, preferably NH;

[0220] R 2L is C or P(OH), preferably C;

[0221] X 1 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge and an amine bond, preferably an amide bond;

[0222] X 2 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge and an amine bond, preferably an amide bond;

[0223] L 1 is a divalent linking group having a structure selected from the group consisting of an oligoamide, an oligoether, an oligothioether, an oligoester, an oligothioester, an oligourea, an oligo(ether-amide), an oligo(thioether-amide), an oligo(ester-amide), an oligo(thioester-amide), an oligo(urea-amide), an oligo(ether-thioether), an oligo(ether-ester), an oligo(ether-thioester), an oligo(ether-urea), an oligo(thioether-ester), an oligo(thioether-thioester), an oligo(thioether-urea), an oligo(ester-thioester), an oligo(ester-urea) and an oligo(thioester-urea), preferably having a structure selected from the group consisting of an oligoamide and an oligo(ester-amide).

[0224] L 1 is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -OCH3, -COOH, -COOCH3, -NH2and -NHC(NH)NH2.

[0225] X 3 is selected from an amide bond, an ester bond, an ether, an amine and a linking group of the formula:

[0226]

[0227] wherein the bond marked with is bound to R B and the other bond marked with is bound to SIFA; preferably X 3 is an amide bond; R B is a trivalent coupling group.

[0228] X 4 is selected from the group consisting of an amide bond, an ether bond, a thioether bond and an ester bond, a thioester bond, a urea bridge, an amine bond, a linking group of the formula

[0229]

[0230] wherein the amide bond marked with is formed by a chelating group, the other bond marked with is bound to R B ; and a linking group of the formula

[0231]

[0232] wherein the carbonyl end is marked with the bond is formed by a chelating group, the other bond marked with is bound to R B ; preferably X 4 is an amide bond.

[0233] R CH is a chelating group containing a chelated non-radioactive or non-radioactive cation, preferably a non-radioactive or radioactive metal cation, wherein the preferred embodiments of the chelating group and the optional chelated cation are as defined above.

[0234] The term “oligo” used in oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea) and oligo(thioester-urea) is preferably understood to mean a group in which 2 to 20, more preferably 2 to 10, subgroups are connected by the bond types indicated in the same term. As will be understood by the skilled person, when two different types of bonds are indicated in brackets, both types of bonds are included in the relevant group (for example, in “oligo(ester-amide)”, both an ester bond and an amide bond are included).

[0235] Preferably L 1comprises in its backbone a total of 1 to 5, more preferably a total of 1 to 3, most preferably a total of 1 or 2 amide and / or ester bonds, preferably amide bonds.

[0236] Thus, the term oligoamide describes a moiety having a chain of CH2or CHR groups interspersed with groups selected from NHCO or CONH. Each occurrence of the moiety R is an optional substituent selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, and -NHC(NH)NH2.

[0237] Also preferred is -X 1 -L 1 -X 2 - represents one of the following structures (L-1) and (L-2):

[0238] -NH-C(O)-R 6 -C(O)-NH-R 7 -NH-C(O)- (L-1)

[0239] -C(O)-NH-R 8 -NH-C(O)-R 9 -C(O)-NH-R 10 -NH-C(O)- (L-2)

[0240] wherein R 6 to R 10 are independently selected from C2to C10alkylene, preferably straight chain C2to C10alkylene, which alkylene groups can each be substituted by one or more groups independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, and -NHC(NH)NH2.

[0241] It is particularly preferred that R 6 and R 7 have a total number of carbon atoms of 4 to 20, more preferably 4 to 16, and do not contain carbon atoms in the optional substituents. It is particularly preferred that R 8 to R 10 have a total number of carbon atoms of 6 to 20, more preferably 6 to 16, and do not contain carbon atoms in the optional substituents.

[0242] It is particularly preferred that -X 1 -L 1 -X 2 - represents one of the following structures (L-3) and (L-4):

[0243] -NH-C(O)-R 11 -C(O)-NH-R 12 -CH(COOH)-NH-C(O)- (L-3)

[0244] -C(O)-NH-CH(COOH)-R 13 -NH-C(O)-R 14 -C(O)-NH-R 15 -CH(COOH)-NH-C(O)- (L-4)

[0245] wherein R 11 to R 15 are independently selected from C2 to C8 alkylene, preferably straight chain C2 to C8 alkylene.

[0246] It is particularly preferred that R 11 and R 12 or R 13 to R 15 have a total number of carbon atoms of 8 to 18, more preferably 8 to 12, still more preferably 9 or 10, respectively.

[0247] Preferably, R B has a structure represented by formula (IV):

[0248]

[0249] wherein: A is selected from N, CR 16 (wherein R 16 is H or C1-C6 alkyl) and a 5- to 7-membered carbocyclic or heterocyclic group; preferably A is selected from N and CH, more preferably A is CH; (CH2) a the bond marked by X is formed by X 2 and a is an integer from 0 to 4, preferably 0 or 1, most preferably 0; (CH2) b the bond marked by X is formed by X 3 and b is an integer from 0 to 4, preferably 0 to 2, more preferably 0 or 1; (CH2) c the bond marked by X is formed by X 4 and c is an integer from 0 to 4, preferably 0 to 2, most preferably 0 or 1.

[0250] Even more preferred as conjugates according to the application are compounds of formula (Ilia):

[0251]

[0252] or a pharmaceutically acceptable salt thereof, wherein m, n, R 1L , R 2L , R 3L , X 1 , L 1 , b, c, X 4 and RCH as defined above, including all preferred embodiments thereof.

[0253] It is preferred for compounds of formula (IIIa) that b + c > 1.

[0254] It is further preferred for compounds of formula (IIIa) that b + c < 3.

[0255] It is more preferred for compounds of formula (IIIa) that b is 1 and c is 0.

[0256] It is further preferred for compounds of formula (III) that -X 4 -R CH represents a residue of a chelator selected from DOTA and DOTAGA, which is bound to the remainder of the conjugate via one of its carboxyl groups via an amide bond.

[0257] In a preferred embodiment of the compounds of formula (III), the compound is a compound of formula (IIIb):

[0258]

[0259] or a pharmaceutically acceptable salt thereof, wherein m, n, R 1L , R 2L , R 3L , X 1 , L 1 , b, c, X 4 and R CH are as defined above; and r is 0 or 1.

[0260] It is particularly preferred that -N(H)-R CH represents a residue of a chelator selected from DOTA and DOTAGA, which is bound to the remainder of the conjugate via one of its carboxyl groups via an amide bond.

[0261] For use in PET imaging, the radiopharmaceutical agent of the composition requires positron emitting atoms. The radiopharmaceutical agent of the composition includes 18 F for medical use. The most preferred radiopharmaceutical agent of the present application is one in which F comprises 18 F and M 3+ refers to a non-radioactive or radioactive metal cation.

[0262] While the structures shown herein show as having COOH groups, the pH of the solution affects whether these groups are salts or acids. Some of the acid groups can be charged salts. Thus, the compounds disclosed herein include carboxylate salts of the compounds shown. Compositions including the following compounds or salts thereof are included herein:

[0263] PSMA-SIFA1 (5)

[0264]

[0265] and isomers thereof:

[0266]

[0267]

[0268]

[0269] PSMA-SIFA2 (6)

[0270]

[0271] and isomers thereof

[0272]

[0273]

[0274] PSMA-SIFA3 (7)

[0275]

[0276] and isomers thereof

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283] PSMA-SIFA4 (8)

[0284]

[0285] and isomers thereof

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] PSMA-SIFA5 (9)

[0293]

[0294] and isomers thereof

[0295]

[0296]

[0297]

[0298] PSMA-SIFA 10

[0299]

[0300] and isomers thereof:

[0301]

[0302]

[0303]

[0304] PSMA-SIFA 11

[0305]

[0306] and isomers thereof:

[0307]

[0308]

[0309]

[0310] The preferred labeling scheme for these most preferred radiological hybrid agents of the composition is as defined above.

[0311] The term "pharmaceutical composition" refers to a composition comprising a drug and a biocompatible carrier, in a form suitable for mammalian administration. A "biocompatible carrier" is a fluid, especially a liquid, in which the drug is suspended or dissolved, such that the composition is physiologically tolerable, i.e., can be administered into the mammalian body without toxicity or undue discomfort. The biocompatible carrier is suitably an injectable carrier liquid, such as sterile, pyrogen-free water for injection or an aqueous solution, such as saline.

[0312] The pharmaceutical compositions can also comprise a pharmaceutically acceptable carrier, excipient and / or diluent. Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art, including phosphate buffered saline solution, water, emulsions (e.g. oil / water emulsions), various types of wetting agents, sterile solutions, etc. The compositions containing such carriers can be formulated by well known conventional methods. These pharmaceutical compositions can be administered to a subject in suitable dosages. The administration of suitable compositions can be achieved by different ways, for example by intravenous, intraperitoneal, subcutaneous, intramuscular, local, intradermal, intranasal or intrabronchial administration. Particularly preferred, the administration is by injection and / or delivery, for example injection and / or delivery into a site in the pancreas or into a cerebral artery or directly into brain tissue. The compositions can also be administered directly to the target site, for example by biolistic delivery to an external or internal target site, such as the pancreas or the brain. The dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any particular patient depend on many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. The pharmaceutically active substances can be present in amounts ranging from 0.1 ng to 10 mg per kg body weight per dose; however, doses below or above this exemplary range are contemplated, particularly taking into account the aforementioned factors.

[0313] In another aspect, the present application provides one or more of the inventive compositions as disclosed herein above for use in diagnostics.

[0314] A preferred use in medicine is for nuclear medicine, for example nuclear diagnostic imaging, also known as nuclear molecular imaging, and / or targeted radiotherapy of diseases associated with overexpression, preferably overexpression of PSMA on diseased tissue.

[0315] In another aspect, the present application provides the inventive compositions as defined herein above for use in a method of diagnosing and / or staging cancer, preferably prostate cancer. Prostate cancer is not the only cancer that expresses PSMA. Non-prostate cancers that show PSMA expression include breast cancer, lung cancer, colorectal cancer, and renal cell carcinoma. Thus, any composition comprising a radiological hybrid as described herein with a PSMA binding moiety can be used for the diagnosis, imaging or treatment of a cancer with PSMA expression.

[0316] A preferred indication is the detection or staging of cancer, such as but not limited to high-grade glioma, lung cancer, in particular prostate cancer and metastatic prostate cancer, detection of metastatic disease in patients with intermediate to high risk of primary prostate cancer, and detection of metastatic sites even at low serum PSA values in biochemically recurrent prostate cancer patients. Another preferred indication is the imaging and visualization of neovascularization.

[0317] Cancer is the preferred indication for a medical indication to be treated, in particular radiotherapy. Prostate cancer is a particularly preferred indication.

[0318] In another aspect, the present application provides a composition comprising a conjugate or compound of a radiological hybrid agent as defined above for use in a method of diagnosing and / or staging cancer, preferably prostate cancer.

[0319] Example 1:

[0320] The gallium chelate of the compound rh-PSMA-7.3 was prepared as described previously in WO2019 / 020831 and EP19154500.3:

[0321] rhPSMA-7.3 (D-Dap, (S)-DOTA-GA):

[0322]

[0323] Fmoc-D-Dap(Dde)-OH (2.0 eq) was pre-activated in a mixture of HOAt (2.0 eq), TBTU (2.0 eq) and 2,4,6-trimethylpyridine (6.7 eq) in DMF and added to the resin-bound peptide for 2.5 h. Dde deprotection was performed using imidazole and hydroxylamine hydrochloride dissolved in a mixture of NMP and DMF for 3 h. SiFA-BA (1.5 eq) was reacted with the free amine of the side chain with HOAt (1.5 eq), TBTU (1.5 eq) and DIPEA (4.5 eq) as activating reagents in DMF for 2 h. Fmoc deprotection (20% piperidine in DMF (v / v, 8 mL / g resin) for 5 min followed by 15 min, after which the resin was thoroughly washed with DMF (8 x 5 mL / g resin), (R)-DOTA-GA(tBu)4 (2.0 eq) was conjugated with HOAT (2.0 eq), TBTU (2.0 eq) and 2,4,6-trimethylpyridine (6.7 eq) in DMF for 2.5 h. Cleavage from the resin was performed in TFA with deprotection of the acid-labile protecting groups (the fully protected resin-bound peptide was dissolved in a mixture of TFA / TIPS / water (v / v / v; 95 / 2.5 / 2.5) and shaken for 30 min. The solution was filtered off and the resin was re-treated in the same way for 30 min. The two filtrates were combined, stirred for an additional 5 h and concentrated under a stream of nitrogen. The residue was dissolved in a mixture of tert-butanol and water and subsequently lyophilized, after which the crude peptide was obtained. Peptide purification natGa-complexation. The peptide (1.0 eq) was dissolved in a 3:1 (v / v) mixture of tBuOH in H2O and an aqueous Ga(N03)3solution (3.5 eq) was added. After heating the resulting mixture at 75 °C for 30 min, the peptide was purified by RP-HPLC.

[0324] 18 F-labeling

[0325] aqueous 18 F - by a SAX cartridge (Sep-Pak Accell Plus QMA Carbonate light) pre-treated with 10 mL water. After drying with 10 mL air, the water was removed by flushing the cartridge with 10 mL dry acetonitrile followed by 20 mL air. The 18 Fwith 100 pmol of F dissolved in 500 pL dry acetonitrile. OH elution. Prior to labeling, 30 pmol of an oxalic acid solution in dry acetonitrile (1 M, 30 pL) was added. This mixture was used as such or in aliquots for the fluorination of 10-25 nmol PSMA-SiFA (1 mM in dry DMSO). The resulting reaction mixture was incubated at room temperature for 5 min. For the purification of the tracer, a Sep-Pak C18 light cartridge pre-treated with 10 mL EtOH followed by 10 mL H2O was used. The labeling mixture was diluted with 9 mL PBS (pH 3) and passed through the cartridge followed by 10 mL H2O through. The peptide was eluted with 500 pL EtOH in water 4:1 (v / v) mixture. The radiochemical purity of the labeled compound was determined by radio-RP-HPLC and radio-TLC (silica gel 60 RP-18 F 254 s, mobile phase: MeCN in H2O 3:2 (v / v) mixture supplemented with 10% 2 M aqueous NaOAc and 1% TFA).

[0326] Alternatively, [ 18 F]fluoride ions and [ 19 F]rhPSMA-7.3 can be prepared by isotope exchange between [ 18 F]rhPSMA-7.3 as follows:

[0327] Fluorine-18 in the form of [ 18 F]fluoride ions is produced in a cyclotron by irradiation of water enriched in 18 O(p,n) 18 F nuclear reactions. 18 F]fluoride ions. 18 F]fluoride is first immobilized on an ion exchange resin in order to recover the enriched 18O. The eluate is then washed with a solution of Cryptand 222 and potassium carbonate in acetonitrile and water 18 F] fluoride. The eluate is transferred to a reaction vessel and evaporated by heating under a stream of nitrogen. A solution of 19 F] rhPSMA-7.3 is added to the reaction vessel and reacts with the nucleophilic 18 F] fluoride for at least 1 minute to form 18 F] rhPSMA-7.3. 18 The crude solution of 18 F] rhPSMA-7.3 is eluted with an ethanol-water solution and formulated by dilution with an isotonic formulation buffer. The formulated solution is sterilized by filtration through a 0.2 pm filter.

[0328] If applicable, dilution is performed using Isotonic Sodium Chloride Solution for Injection.

[0329] Each batch of material is prepared in citrate buffer made from sodium citrate + HC1 or citrate buffer made from citric acid + NaOH.

[0330] Radio-stability is measured in phosphate and citrate buffers at different pH levels to compare the levels of the correct 18F-Si compound and decomposed free 18F:

[0331]

[0332] The most stable formulation is pH 5.0 in citrate buffer. Increasing the pH in the citrate buffer increases the amount of free 18F (which is presumably substituted by OH). At the same pH (6.0), phosphate buffer produces less stable product compared to citrate buffer.

[0333] The radiochemical purity and chemical purity of various formulations containing citrate buffer or citrate buffered saline are evaluated (Table 1).

[0334] Table 1: Radiochemical purity and chemical purity of various formulations

[0335]

[0336]

[0337] After dilution with Sodium Chloride Solution for Injection (0.9% w / v), the pH of the formulation (entry 5, Table 1: 10 mM citrate buffered saline, 5% ethanol) is maintained:

[0338] Table 2: Formulations after dilution of Table 1 entry 5 with sodium chloride solution

[0339] .

Claims

1. A pharmaceutical composition comprising a radiohybrid comprising a fluorinated silicon and a chelating group, wherein either the fluorine is 18 F or the chelating group comprises a chelated radioactive metal. wherein the radiological hybrid agent is: ， wherein M 3+ is a chelated radioactive or non-radioactive metal; and wherein the pH of the composition is 4.5-6.0 and further comprising: a) 1-15 mM citrate buffer; and b) 5-50 mg / mL ethanol; and c) 6-9 mg / mL sodium chloride.

2. The pharmaceutical composition of claim 1, comprising 1-10 mM citrate buffer.

3. The pharmaceutical composition of claim 1, having a pH of 4.5 to 5.

5.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the citrate buffer is prepared from citric acid and sodium hydroxide, or sodium citrate and hydrochloric acid.

5. The pharmaceutical composition of claim 4, wherein the citrate buffer is prepared using 1-3 mg / mL citric acid and 0.5-1.0 mg / mL sodium hydroxide.

6. The pharmaceutical composition of claim 4, wherein the citrate buffer is prepared using 1.9 mg / mL citric acid and 0.75 mg / mL sodium hydroxide.

7. The pharmaceutical composition of any one of claims 1 to 3, wherein the metal is a radioactive metal and the fluorine is 19 F.

8. The pharmaceutical composition of any one of claims 1 to 3, wherein the chelated metal is selected from the cations of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th, or Er.

9. The pharmaceutical composition of any one of claims 1 to 3, wherein the fluorine is 18 F and the metal is a non-radioactive metal.

10. The pharmaceutical composition of claim 8, wherein the chelated radioactive metal cation is a positron emitting isotope.

11. The pharmaceutical composition of any one of claims 1 to 3, having a synthetic end of synthesis (EOS) radioactivity concentration (RAC) of 5-200 mCi / mL.

12. The pharmaceutical composition of any one of claims 1 to 3, comprising 1-10 mM citrate buffer, 5-50 mg / mL ethanol, 6-9 mg / mL sodium chloride, and having a pH of 4.5 to 5.

5.

13. The pharmaceutical composition of any one of claims 1 to 3, comprising 10 mM citrate buffer, 50 mg / mL ethanol, 7.2 mg / mL sodium chloride, and having a pH of 5.

14. The pharmaceutical composition of any one of claims 1 to 3, diluted with a sodium chloride solution prior to administration.

15. The pharmaceutical composition of claim 14, comprising 1.1 mM citrate buffer, 5.3 mg / mL ethanol, 8.8 mg / mL sodium chloride, and having a pH of 4.5 to 5.

5.

16. The pharmaceutical composition of any one of claims 1 to 3, for use as a cancer diagnostic or imaging agent.

17. The pharmaceutical composition of claim 16, wherein the cancer is prostate cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma.

18. The pharmaceutical composition of any one of claims 1 to 3, for use in the diagnosis, imaging, or prevention of neovascularization.

19. The pharmaceutical composition of any one of claims 1 to 3, for use in the diagnosis, imaging, or prevention of angiogenesis.

20. Use of the pharmaceutical composition of any one of claims 1-19 in the manufacture of a medicament for imaging and / or diagnosing cancer in a patient in need thereof.

21. The use of claim 20, wherein the cancer is prostate cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma.

22. Use of a pharmaceutical composition according to any one of claims 1 to 19 for the manufacture of a medicament for the diagnosis, imaging or prevention of neovascularization.

23. Use of a pharmaceutical composition according to any one of claims 1 to 19 for the manufacture of a medicament for the diagnosis, imaging or prevention of angiogenesis.

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