Pharmaceutical Compounds

Abstract

The present invention relates to a pharmaceutical composition comprising a silicon fluoride and a radioconjugate containing a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 4.0 to 6.0 and further comprises 0.1 to 200 mM citrate buffer; 1 to 100 mg / mL ethanol; and 5 to 10 mg / mL sodium chloride.

Description

[Technical Field]

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

[0002] Prostate cancer Prostate cancer (PCa) remains the most common malignant disease in men, with a low survival rate and high incidence rate over the past several decades. Due to its overexpression in prostate cancer, prostate-specific membrane antigen (PSMA), or glutamate carboxypeptidase II (GCP II), has proven its suitability as an excellent target for the development of highly sensitive radiolabeled agents for internal radiotherapy and imaging of PCa. Prostate-specific membrane antigen (PSMA) is an extracellular hydrolase whose catalytic center contains two zinc(II) ions with bridging hydroxide ligands. It is highly upregulated in metastatic and hormone-refractory prostate cancer, but its physiological expression has also been reported in the kidney, salivary gland, small intestine, brain, and, to a lesser extent, healthy prostate tissue. In the intestine, PSMA facilitates folate absorption by converting pteroylpoly-γ-glutamate to pteroylglutamate (folate). In the brain, it hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and glutamate.

[0003] Prostate-specific membrane antigen (PSMA) 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 various degrees in the neovasculature of a wide range of non-prostate cancers.The most common non-prostate cancers that demonstrate PSMA expression include breast cancer, lung cancer, colorectal cancer and renal cell carcinoma.

[0004] The generally required structure of a PSMA targeting molecule includes a linking unit containing a zinc-binding group (e.g., urea, phosphinate, or phosphoramidate) attached to a P1' glutamate moiety, ensuring high affinity and specificity for PSMA, and is usually further attached to an effector functional group, which is more flexible and, to some extent, resistant to structural modification.

[0005] Two categories of PSMA-targeted inhibitors are currently used in clinical settings: on the one hand, tracers with chelating units for radionuclide conjugation, e.g., PSMA I&T or related compounds, and on the other hand, small molecules containing a targeting unit and an effector molecule.

[0006] 18 F labeling In recent years, several groups have developed novel immunotherapeutic agents for PCa diagnosis. 18 We focus on the development of inhibitors based on F-labeled urea. 18 F-labeled urea-based PSMA inhibitors 18 F-DCFPyl demonstrated promising results for the detection of primary and metastatic PCa. Based on the structure of PSMA-617, 18 A F-labeled analog, PSMA-1007, was recently developed, which showed comparable tumor-to-organ ratios.

[0007] 18An attractive approach for introducing F labels is the use of silicon fluoride acceptors (SIFAs). Silicon fluoride acceptors are described, for example, in Lindner et al., Bioconjugate Chemistry, vol. 25, pp. 738-749 (2014). The use of silicon fluoride acceptors creates the need for sterically bulky groups around the silicon atom to maintain the silicon fluoride bond. This, in turn, makes the silicon fluoride acceptor highly hydrophobic. For binding to target molecules, particularly PSMA, the hydrophobic moiety provided by silicon fluoride acceptors can be utilized to establish interactions with radiodiagnostic or radiotherapeutic compounds with hydrophobic pockets, as described in Zhang et al., Journal of the American Chemical Society, vol. 132, pp. 12711-12716 (2010). Furthermore, the higher extent of lipophilicity introduced into the molecule prior to conjugation poses serious problems for the development of radiopharmaceuticals suitable for in vivo biodistribution, i.e., with low non-specific binding in non-target tissues.

[0008] Despite numerous attempts, the hydrophobicity problem caused by silicon fluoride acceptors has only recently been solved by using drugs with hydrophilic chelator moieties. Application WO2019 / 020831 describes a new type of radioconjugate containing both a SIFA moiety and a metal chelator. In developing the compounds described therein, the inventors have identified improved pharmaceutical formulations for delivery to patients. The formulations described herein exhibit improved radiation stability and shelf life compared to previously described formulations.

[0009] In view of the above, the technical problem underlying the present invention can be stated in providing improved radiodiagnostic formulations containing a silicon fluoride acceptor and a metal chelator, which are simultaneously characterized by favorable drug-stability properties. Summary of the Invention

[0010] As will be seen below, the present invention has established proof of principle using a specific conjugate formulated in a specific way that binds with high affinity to prostate-specific antigen (PSMA) as a target. The composition in which the compounds are prepared and stored affects the chemical and radiochemical stability of these drugs. Therefore, a further technical problem underlying the present invention can be presented in providing improved diagnosis for medical indications that are cancer, preferably prostate cancer.

[0011] These technical problems are solved by the subject matter of the claims. Thus, in a first aspect, the present invention relates to a pharmaceutical composition comprising a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is fluorine-18 ( 18 F), or the chelating group contains a chelated radiometal, and the composition has a pH of 4.0 to 6.0; (a) 0.1 to 200 mM citrate buffer; and (b) 1 to 100 mg / mL ethanol; and (c) 5-10 mg / mL sodium chloride Further includes:

[0012] An alternative composition disclosed herein relates to a pharmaceutical composition of a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition comprises (a) 50 to 200 mM citrate buffer and / or; (b) 10 to 100 mg / mL ethanol and / or; and (c) a pH of 4.0 to 6.0.

[0013] The formulation can be prepared in a high concentration 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).

[0014] A method of producing the compositions described herein is described, the method comprising the steps of preparing a formulation of a silicon fluoride and a radiation complex containing a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, the composition has a pH of 4.0 to 6.0 and a citric acid concentration of at least 10 mM, and diluting the citric acid concentration with a solution of sodium chloride.

[0015] The pharmaceutical composition may contain 50 to 200 mM citrate buffer. The pharmaceutical composition may contain 10 to 100 mg / ml ethanol. The pharmaceutical composition may have a pH of 4.0 to 6.0.

[0016] The pharmaceutical composition may comprise a chelated radiometal or 18 F may contain fluorine. The pharmaceutical composition may comprise a chelated radiometal selected from the cations of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Ac, Th, or Er.

[0017] The pharmaceutical composition comprises 18 It can contain F fluorine and a non-radioactive chelated metal ion. The pharmaceutical composition comprises 19 It may contain F fluorine and a radioactive chelated metal ion.

[0018] The pharmaceutical composition is a compound in which the metal is radioactive and the fluorine is 19 F. The pharmaceutical composition contains fluorine. 18 F, and the metal is non-radioactive. The pharmaceutical composition comprises 177 Lu, 90 Y, 225 Ac, 68 Ga or 67 The radioactive metal cation may comprise a chelated radioactive metal cation selected from Ga.

[0019] The pharmaceutical composition may contain 60 to 120 mM citrate buffer. The pharmaceutical composition may contain 0.1 to 200 mM citrate buffer. The pharmaceutical composition may contain 0.1 to 120 mM citrate buffer.

[0020] The pharmaceutical composition may contain 0.1 to 50 mM citrate buffer. The pharmaceutical composition may contain 0.1 to 20 mM citrate buffer.The pharmaceutical composition may contain 1 to 15 mM citrate buffer.

[0021] The pharmaceutical composition may contain 10 mM (±15%) citrate buffer. The pharmaceutical composition may contain 10 mM (±10%) citrate buffer. The pharmaceutical composition may contain 10 mM (±5%) citrate buffer.

[0022] The pharmaceutical composition may contain 10 mM (±2%) citrate buffer. The pharmaceutical composition may contain 10 mM (±1%) citrate buffer. The pharmaceutical composition may contain 10 mM citrate buffer.

[0023] The pharmaceutical composition may contain 1 to 10 mM citrate buffer. The pharmaceutical composition may contain 1-10 mM (±15%) citrate buffer. The pharmaceutical composition may contain 1-10 mM (±10%) citrate buffer.

[0024] The pharmaceutical composition may contain 1-10 mM (±5%) citrate buffer. The pharmaceutical composition may contain 1-10 mM (±2%) citrate buffer. The pharmaceutical composition may contain 1-10 mM (±1%) citrate buffer.

[0025] Pharmaceutical compositions can be formulated with anhydrous citric acid, or citric acid monohydrate, or salts thereof (including sodium citrate). Pharmaceutical compositions can be formulated with citric acid monohydrate.

[0026] The pharmaceutical composition may be formulated with 1.5 to 2.5 mg / mL citric acid (anhydrous basis). The pharmaceutical composition can be formulated with 1.9 mg / mL (±10%) citric acid (anhydrous basis).

[0027] The pharmaceutical composition can be formulated with 1.9 mg / mL (±5%) citric acid (anhydrous basis). The pharmaceutical composition can be formulated with 1.9 mg / mL (±2%) citric acid (anhydrous basis).

[0028] The pharmaceutical composition can be formulated with 1.9 mg / mL (±1%) citric acid (anhydrous basis). The pharmaceutical composition can be formulated with 1.9 mg / mL citric acid (anhydrous basis).

[0029] The pharmaceutical composition may have a pH of 4.5 to 5.5. The pharmaceutical composition may have a pH of 5 (±15%). The pharmaceutical composition may have a pH of 5 (±10%).

[0030] The pharmaceutical composition may have a pH of 5 (±5%). The pharmaceutical composition may have a pH of 5 (±2%). The pharmaceutical composition may have a pH of 5 (±1%).

[0031] The pharmaceutical composition may have a pH of 5. The pharmaceutical composition may have a pH of 5.1. The pharmaceutical composition may have a pH of 4.9.

[0032] The pharmaceutical composition may contain 5 to 100 mg / mL ethanol. The pharmaceutical composition may contain 10 to 100 mg / mL ethanol. The pharmaceutical composition may contain 10 to 70 mg / mL ethanol.

[0033] The pharmaceutical composition may contain 40 to 60 mg / mL ethanol. The pharmaceutical composition can contain 50 mg / mL (±15%) ethanol. The pharmaceutical composition can contain 50 mg / mL (±10%) ethanol.

[0034] The pharmaceutical composition can contain 50 mg / mL (±5%) ethanol. The pharmaceutical composition can contain 50 mg / mL (±2%) ethanol. The pharmaceutical composition can contain 50 mg / mL (±1%) ethanol.

[0035] The pharmaceutical composition can contain 50 mg / mL ethanol. The pharmaceutical composition may contain 5-50 mg / mL (±15%) ethanol. The pharmaceutical composition may contain 5 to 50 mg / mL (±10%) ethanol.

[0036] The pharmaceutical composition may contain 5 to 50 mg / mL (±5%) ethanol. The pharmaceutical composition may contain 5 to 50 mg / mL (±2%) ethanol. The pharmaceutical composition may contain 5 to 50 mg / mL (±1%) ethanol.

[0037] The pharmaceutical composition may contain 5 to 50 mg / mL ethanol. The pharmaceutical composition may contain 5-10 mg / mL sodium chloride. The pharmaceutical composition may contain 6-9 mg / mL sodium chloride.

[0038] The pharmaceutical composition can contain 7.2 mg / mL (±15%) sodium chloride. The pharmaceutical composition can contain 7.2 mg / mL (±10%) sodium chloride. The pharmaceutical composition can contain 7.2 mg / mL (±5%) sodium chloride.

[0039] The pharmaceutical composition can contain 7.2 mg / mL (±2%) sodium chloride. The pharmaceutical composition can contain 7.2 mg / mL (±1%) sodium chloride. The pharmaceutical composition can contain 7.2 mg / mL sodium chloride.

[0040] In the pharmaceutical composition, the citrate buffer can be prepared from citric acid and sodium hydroxide. Alternatively, the citrate buffer can be prepared with an appropriate content of sodium citrate and HCl.

[0041] In the pharmaceutical composition, a citrate buffer can be prepared using 1-3 mg / mL citric acid (anhydrous basis) and 0.5-1.0 mg / mL sodium hydroxide. In the pharmaceutical composition, a citrate buffer can be prepared using 1.9 mg / mL (±15%) citric acid (anhydrous basis) and 0.75 mg / mL (±15%) sodium hydroxide.

[0042] In the pharmaceutical composition, a citrate buffer can be prepared using 1.9 mg / mL (±10%) citric acid (anhydrous basis) and 0.75 mg / mL (±10%) sodium hydroxide.

[0043] In the pharmaceutical composition, a citrate buffer can be prepared using 1.9 mg / mL (±5%) citric acid (anhydrous basis) and 0.75 mg / mL (±5%) sodium hydroxide.

[0044] In the pharmaceutical composition, a citrate buffer can be prepared using 1.9 mg / mL (±2%) citric acid (anhydrous basis) and 0.75 mg / mL (±2%) sodium hydroxide.

[0045] In the pharmaceutical composition, a citrate buffer can be prepared using 1.9 mg / mL (±1%) citric acid (anhydrous basis) and 0.75 mg / mL (±1%) sodium hydroxide.

[0046] In the pharmaceutical composition, a citrate buffer can be prepared using 1.9 mg / mL citric acid (anhydrous basis) and 0.75 mg / mL sodium hydroxide. The pharmaceutical composition may have an end of synthesis (EOS) radioactivity concentration (RAC) of 5 to 500 mCi / mL.

[0047] The pharmaceutical composition may have an end of synthesis (EOS) radioactivity concentration (RAC) of 5 to 200 mCi / mL. The pharmaceutical composition may have an end of synthesis (EOS) radioactivity concentration (RAC) of 50-100 mCi / mL.

[0048] The pharmaceutical composition may have an end of synthesis (EOS) radioactivity concentration (RAC) of 10-100 mCi / mL. The term "end of synthesis" refers to the point at which the labeled compound is collected in a product collection vial.

[0049] The pharmaceutical composition may have an end of synthesis (EOS) radioactivity concentration (RAC) of 20-90 mCi / mL. The pharmaceutical composition may have an end of synthesis (EOS) radioactivity concentration (RAC) of at least 35 mCi / mL.

[0050] The pharmaceutical composition can contain 10 mM (±15%) citrate buffer, 50 mg / mL (±15%) ethanol, 7.2 mg / mL (±15%) sodium chloride, and has a pH of 5 (±15%).

[0051] The pharmaceutical composition can contain 10 mM (±10%) citrate buffer, 50 mg / mL (±10%) ethanol, 7.2 mg / mL (±10%) sodium chloride, and has a pH of 5 (±10%).

[0052] The pharmaceutical composition can contain 10 mM (±5%) citrate buffer, 50 mg / mL (±5%) ethanol, 7.2 mg / mL (±5%) sodium chloride, and has a pH of 5 (±5%).

[0053] The pharmaceutical composition can contain 10 mM (±2%) citrate buffer, 50 mg / mL (±2%) ethanol, 7.2 mg / mL (±2%) sodium chloride, and has a pH of 5 (±2%).

[0054] The pharmaceutical composition can contain 10 mM (±1%) citrate buffer, 50 mg / mL (±1%) ethanol, 7.2 mg / mL (±1%) sodium chloride, and has a pH of 5 (±1%).

[0055] The pharmaceutical composition can contain 10 mM citrate buffer, 50 mg / mL ethanol, 7.2 mg / mL sodium chloride, and has a pH of 5. The pharmaceutical composition may comprise a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 5.0 (±15%) and further comprises: (a) 10 mM (±15%) citrate buffer; and (b) 50 mg / mL (±15%) ethanol; and (c) 7.2 mg / mL (±15%) sodium chloride.

[0056] The pharmaceutical composition may comprise a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 5.0 (±10%) and further comprises: (a) 10 mM (±10%) citrate buffer; and (b) 50 mg / mL (±10%) ethanol; and (c) 7.2 mg / mL (±10%) sodium chloride.

[0057] The pharmaceutical composition may comprise a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18F, or the chelating group contains a chelated radiometal, and the composition has a pH of 5.0 (±5%) and further comprises: (a) 10 mM (±5%) citrate buffer; and (b) 50 mg / mL (±5%) ethanol; and (c) 7.2 mg / mL (±5%) sodium chloride.

[0058] The pharmaceutical composition may comprise a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 5.0 (±2%) and further comprises: (a) 10 mM (±2%) citrate buffer; and (b) 50 mg / mL (±2%) ethanol; and (c) 7.2 mg / mL (±2%) sodium chloride.

[0059] The pharmaceutical composition may comprise a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 5.0 (±1%) and further comprises: (a) 10 mM (±1%) citrate buffer; and (b) 50 mg / mL (±1%) ethanol; and (c) 7.2 mg / mL (±1%) sodium chloride.

[0060] The pharmaceutical composition may comprise a radioconjugate containing silicon fluoride and a chelating group, wherein the fluorine is 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 5.0 and further comprises: (a) 10 mM citrate buffer; and (b) 50 mg / mL ethanol; and (c) 7.2 mg / mL sodium chloride.

[0061] The pharmaceutical composition can be diluted with sodium chloride solution before administration. The pharmaceutical composition can be diluted up to 10-fold or more with sodium chloride solution before administration. The sodium chloride solution used as a diluent before administration can be an aqueous solution of 9 mg / mL (±5%) sodium chloride.

[0062] After dilution with sodium chloride solution, the pharmaceutical composition may contain 1.1 mM (±15%) citrate buffer. After dilution with sodium chloride solution, the pharmaceutical composition may contain 1.1 mM (±10%) citrate buffer.

[0063] After dilution with sodium chloride solution, the pharmaceutical composition may contain 1.1 mM (±5%) citrate buffer. After dilution with sodium chloride solution, the pharmaceutical composition may contain 1.1 mM (±2%) citrate buffer.

[0064] After dilution with sodium chloride solution, the pharmaceutical composition may contain 1.1 mM (±1%) citrate buffer. After dilution with sodium chloride solution, the pharmaceutical composition may contain 1.1 mM citrate buffer.

[0065] After dilution with sodium chloride solution, the pharmaceutical composition can contain 5.3 mg / mL (±15%) ethanol. After dilution with sodium chloride solution, the pharmaceutical composition can contain 5.3 mg / mL (±10%) ethanol.

[0066] After dilution with sodium chloride solution, the pharmaceutical composition can contain 5.3 mg / mL (±5%) ethanol. After dilution with sodium chloride solution, the pharmaceutical composition can contain 5.3 mg / mL (±2%) ethanol.

[0067] After dilution with sodium chloride solution, the pharmaceutical composition can contain 5.3 mg / mL (±1%) ethanol. After dilution with sodium chloride solution, the pharmaceutical composition can contain 5.3 mg / mL ethanol.

[0068] After dilution with sodium chloride solution, the pharmaceutical composition may contain 5-10 mg / mL sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition can contain 8.8 mg / mL (±15%) sodium chloride.

[0069] After dilution with sodium chloride solution, the pharmaceutical composition can contain 8.8 mg / mL (±10%) sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition can contain 8.8 mg / mL (±5%) sodium chloride.

[0070] After dilution with sodium chloride solution, the pharmaceutical composition can contain 8.8 mg / mL (±2%) sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition can contain 8.8 mg / mL (±1%) sodium chloride.

[0071] After dilution with sodium chloride solution, the pharmaceutical composition can contain 8.8 mg / mL sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition can contain 1.1 mM (±15%) citrate buffer, 5.3 mg / mL (±15%) ethanol, 8.8 mg / mL (±15%) sodium chloride, and has a pH of 5.1 (±15%).

[0072] After dilution with sodium chloride solution, the pharmaceutical composition can contain 1.1 mM (±10%) citrate buffer, 5.3 mg / mL (±10%) ethanol, 8.8 mg / mL (±10%) sodium chloride, and has a pH of 5.1 (±10%).

[0073] After dilution with sodium chloride solution, the pharmaceutical composition can contain 1.1 mM (±5%) citrate buffer, 5.3 mg / mL (±5%) ethanol, 8.8 mg / mL (±5%) sodium chloride, and has a pH of 5.1 (±5%).

[0074] After dilution with sodium chloride solution, the pharmaceutical composition can contain 1.1 mM (±2%) citrate buffer, 5.3 mg / mL (±2%) ethanol, 8.8 mg / mL (±2%) sodium chloride, and has a pH of 5.1 (±2%).

[0075] After dilution with sodium chloride solution, the pharmaceutical composition can contain 1.1 mM (±1%) citrate buffer, 5.3 mg / mL (±1%) ethanol, 8.8 mg / mL (±1%) sodium chloride, and has a pH of 5.1 (±1%).

[0076] After dilution with sodium chloride solution, the pharmaceutical composition can contain 1.1 mM citrate buffer, 5.3 mg / mL ethanol, 8.8 mg / mL sodium chloride, and has a pH of 5.1.

[0077] Pharmaceutical compositions can improve product stability by lowering the pH. During testing, it was determined that the product was unstable under basic conditions, generating hydrolyzed silanol products (replacement of F- with OH-). Lowering the pH helped stabilize the product, and citric acid pH 5 was selected.

[0078] Ethanol can be used as a radiolytic protectant. Optimization of the amount of ethanol leads to the development of stabilized materials as described herein. Different contents of components can be combined. For example, the buffer solution can be 0.1 to 200 mM citrate buffer with a pH of 4.5 to 5.5 and up to 70 mg / mL ethanol. The composition can contain additional salts for blood isotonicity. The composition contains sodium chloride.

[0079] The pharmaceutical composition is capable of binding to PSMA The pharmaceutical composition comprises

[0080] [ka]

[0081] [ka]

[0082] [ka]

[0083] [In the formula, M 3+ is a chelated radioactive or non-radioactive metal] and isomers and salts thereof. These agents can be in the form of a pharmaceutically acceptable salt, for example, as one or more of these groups shown as the group COOH can be salts thereof.

[0084] The pharmaceutical composition comprises

[0085] [ka]

[0086] or an isomer or salt thereof. The pharmaceutical composition can be used as a cancer diagnostic or imaging agent. The pharmaceutical composition can be used in a method for imaging and / or diagnosing cancer in a patient in need thereof. Accordingly, also provided herein is a method for imaging and / or diagnosing cancer, comprising administering a conjugate, compound, or composition of the present invention to a patient in need thereof.

[0087] The pharmaceutical composition can be used in the treatment of cancer. The pharmaceutical compositions can be used for the diagnosis, imaging or prevention of angiogenesis / vasculogenesis.

[0088] The pharmaceutical composition may be used as a cancer diagnostic or imaging agent or for use in the treatment of cancer, wherein the cancer is prostate cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma. The pharmaceutical composition includes a radioconjugate having three separate moieties: (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 comprising a chelated non-radioactive or radioactive cation.

[0089] Some ligands capable of binding to disease-related target molecules may be cyclic peptides, which are not chelating groups as envisioned herein because the hydrophobic SIFA moiety problem is not solved in the absence of an additional chelating moiety. Thus, the radioconjugates of the compositions of the present invention require a hydrophilic chelating group in addition to a ligand capable of binding to PSMA. The hydrophilic chelating group is required to reduce the hydrophobic nature of the radioconjugates of the compositions caused by the presence of the SIFA moiety.

[0090] The ligand associated with the first aspect of the present invention is defined in functional terms. This is why the present invention does not depend on the specific nature of the ligand in structural terms. Rather, an important aspect of the present invention is the combination of a silicon fluoride acceptor and a chelating agent or chelate in a single molecule. These two structural elements, SIFA and chelating agent, are in close spatial proximity. Preferably, the shortest distance between two atoms of the two elements is less than or equal to 25 Å, more preferably less than 20 Å, and even more preferably less than 15 Å. Alternatively, or in addition, it is preferred that 25 or fewer covalent bonds separate the atoms of the SIFA moiety and the atoms of the chelating agent, preferably 20 or fewer chemical bonds, and even more preferably 15 or fewer chemical bonds.

[0091] The cation according to item (c) can be a radioactive or non-radioactive cation. Examples are further shown below. As a result, the conjugate can be radiolabeled with a SIFA moiety or not radiolabeled with a SIFA moiety. In the former case, the chelating group can either be a complex of a cold (non-radioactive) ion or lack any ion. In the latter case, the chelating agent contains a radioactive cation.

[0092] The inventors have discovered that placing a silicon fluoride acceptor adjacent to a hydrophilic chelator, such as, but not limited to, DOTAGA or DOTA, effectively masks or compensates for the lipophilicity of the SIFA moiety to the extent that it alters the overall hydrophobicity of the compound, rendering the compound suitable for in vivo administration.

[0093] A further advantage of the radioconjugates of the composition, and in particular the PSMA-targeted radioconjugates of the present invention, is their surprisingly low accumulation in the kidneys of mice when compared to other PSMA-targeted radiopharmaceuticals, such as PSMA I&T. Without wishing to be bound by any particular theory, it is believed to be the combination of the structural element SIFA with the chelator that unexpectedly reduces accumulation in the kidneys.

[0094] In a preferred embodiment, the ligand according to the present invention comprises or consists of a peptide, a peptidomimetic, or a substituent including a substituted urea, an amino acid. It is understood that a ligand comprising a peptide or a peptidomimetic also includes non-peptidic and non-peptidomimetic moieties. In terms of molecular weight, a molecular weight of less than 15 kDa, less than 10 kDa, or less than 5 kDa is preferred. Accordingly, small proteins are also encompassed by the term "ligand." Target molecules include, but are not limited to, enzymes, receptors, epitopes, transporters, cell surface molecules, and proteins of the extracellular matrix. Disease-related targets are preferred. Particularly preferred are targets that are inevitably involved in a given disease or are highly overexpressed in a given disease and / or whose inhibition can have a beneficial effect in patients suffering from a given disease. The ligand preferably has an IC of less than 50 nM, less than 20 nM, or less than 5 nM. 50 It is a high affinity ligand with a favorable affinity expressed as

[0095] Particularly preferred are ligands that bind with high affinity to prostate-specific membrane antigen (PSMA). Preferably, the silicon fluoride acceptor (SIFA) moiety has the formula (I):

[0096] [ka]

[0097] [Wherein F is 19 F and 18 It is understood that F encompasses both 1S and R 2S are independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl; R 3Sis a C1-C20 hydrocarbon group which may contain one or more aromatic and one or more aliphatic units and / or up to three heteroatoms selected from O and S, preferably R 3S is a C6-C10 hydrocarbon group that contains an aromatic ring and may contain one or more aliphatic units; more preferably, R 3S is a phenyl ring, and most preferably R 3S is a phenyl ring, containing an Si-containing substituent and

[0098] [ka]

[0099] The bond marked with is in the para position, and the SIFA moiety is

[0100] [ka]

[0101] is attached to the rest of the conjugate by the bond marked with ]. More preferably, the silicon fluoride acceptor (SIFA) moiety has the formula (Ia):

[0102] [ka]

[0103] [wherein t-Bu represents a tert-butyl group; F is 19 F and 18 It is understood that F is also included.

[0104] Preferred chelating groups include at least one of the following: (i), (ii) or (iii): (i) A macrocyclic ring structure having 8 to 20 ring atoms, of which 2 or more, more preferably 3 or more, are selected from oxygen or nitrogen atoms. Preferably, 6 or fewer ring atoms are selected from oxygen or nitrogen atoms. It is particularly preferred that 3 or 4 ring atoms are nitrogen or oxygen atoms. Of oxygen and nitrogen atoms, nitrogen atoms are particularly preferred. In combination with the macrocyclic ring structure, a preferred chelating group can contain 2 or more, for example, 2 to 6, preferably 2 to 4, carboxyl and / or hydroxyl groups. Of carboxyl and hydroxyl groups, carboxyl groups are particularly preferred. (ii) An acyclic, open-chain chelating structure having 8 to 20 main chain (skeletal) atoms, of which 2 or more, more preferably 3 or more, are heteroatoms selected from oxygen atoms or nitrogen atoms. Preferably, 6 or fewer of the skeletal atoms are selected from oxygen atoms or nitrogen atoms. Of oxygen and nitrogen atoms, nitrogen atoms are particularly preferred. More preferably, the open-chain chelating structure is a structure containing 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 carboxyl groups and hydroxyl groups, carboxyl groups are particularly preferred. (iii) Branched chelating structures containing a quaternary carbon atom. Preferably, the quaternary carbon atom is substituted with three identical chelating groups in addition to the SIFA / ligand moiety. The substituted chelating group can comprise an amide. The substituted chelating group can comprise an aromatic group. The substituted chelating group can comprise a hydroxypyridinone.

[0105] In preferred specific examples, the chelating group is bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), 4,11- ...b), 4-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2c), 4-(1,4,8,11-tetraazabicyclotetradec-1-yl)-methylbenzoic acid (CPTA), 4-(1,4,8,11-tetraazabicyclotetradec-1-yl)-methylbenzoic acid (CPTA), 4-(1,4,8,11-tetraazabicyclotetradec-1-yl)-methylbenzoic acid (CPTA), 4-(1,4,8,11-tetraaz2] Hexadecane (DO2A), 1,4,7,10-tetracyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(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'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphatase) 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), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7, 10-Tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), abbreviated as Me-3,2-HOPO, is a tetra-3-hydroxy-N-methyl-2-pyridinone chelating agent (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-( ... Hydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxoxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethylphosphinic acid)] (TRAP), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TR The residue of a chelating agent selected from 4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazonan-1-yl]methyl-hydroxy-phosphoryl]propanoic acid, and triethylenetetraminehexaacetic acid (TTHA) is provided by covalently linking a carboxyl group contained in the chelating agent to the remainder of the conjugate via an ester or amide bond.

[0106] Specific chelating agents are listed below.

[0107] [ka]

[0108] Among the above exemplary chelating agents, chelating agents selected from TRAP, DOTA, and DOTAGA are particularly preferred. Metal- or cation-chelating macrocyclic and acyclic compounds are well known in the art and are available from numerous manufacturers. The chelating moieties according to the present invention are not particularly limited, and it will be understood that numerous moieties can be used in a routine manner by those skilled in the art without difficulty.

[0109] The chelating group can include a chelated cation that is non-radioactive. Preferred examples of cations that can be chelated by the chelating group include non-radioactive cations of 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, and Th; more preferably, cations of 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.

[0110] The chelating group can include a chelated cation that is radioactive. Preferred examples of cations that can be chelated by the chelating group are: 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 cation, 18 F-containing cationic molecules, or e.g., 18 F-[AlF] 2+ and more preferably, 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 cation or 18 A cationic molecule containing F. The cation can be selected from Lu-177, Y-90, or Ac-225. Preferred cations are positron-emitting isotopes, such as 68 It can be Ga.

[0111] Thus, the ligand is preferably capable of binding to prostate-specific membrane antigen (PSMA). More preferably, the ligand has the formula (II):

[0112] [ka]

[0113] [wherein m is an integer of 2 to 6, preferably 2 to 4, and more preferably 2; n is an integer of 2 to 6, preferably 2 to 4, and more preferably 2 or 3; R 1L is CH, NH or O, preferably NH; R 3L is CH, NH or O, preferably NH; R 2L is C or P(OH), preferably C; the ligand is

[0114] [ka]

[0115] is attached to the rest of the conjugate by the bond marked with ]. The ligand has the formula (IIa):

[0116] [ka]

[0117] wherein n is an integer of 2 to 6; and the ligand is

[0118] [ka]

[0119] The conjugate may have a structure represented by the formula: Many PSMA binding agents are known in the art, which are all suitable in accordance with the present invention. The preferred embodiments described above are structural definitions of preferred groups of PSMA binding agents.

[0120] The conjugate of the first aspect has the formula (III):

[0121] [ka]

[0122] [In the formula, SIFA is a silicon fluoride acceptor (SIFA) moiety containing a covalent bond between a silicon and a fluorine atom; 18 is labeled with F; preferably, the SIFA is a SIFA moiety of formula (I), more preferably formula (Ia) as defined above; m is an integer of 2 to 6, preferably 2 or 3, and more preferably 2; n is an integer of 2 to 6, preferably 2 or 3, and more preferably 2 or 4; R 1L is CH, NH or O, preferably NH; R 3L is CH, NH or O, preferably NH; R 2L is C or P(OH), preferably C; 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; 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; L 1is a divalent linking group having a structure selected from 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), preferably a divalent linking group having a structure selected from oligoamide and oligo(ester-amide).

[0123] L 1 can be optionally substituted with one or more substituents independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, and -NHC(NH)NH2.

[0124] X 3 is an amide bond, and an ester bond, an ether, an amine, and a group of the formula:

[0125] [ka]

[0126] [wherein, in the NH group

[0127] [ka]

[0128] Bonds marked with R B is combined with

[0129] [ka]

[0130] The other bond marked with is attached to SIFA; preferably, X 3 is an amide bond; R B is a trivalent coupling group. X 4 is an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond,

[0131] [ka]

[0132] [In the formula,

[0133] [ka]

[0134] The amide bond marked with is formed with a chelating group,

[0135] [ka]

[0136] Other bonds marked with R B and a linking group of the formula:

[0137] [ka]

[0138] [Wherein, at the carbonyl terminal

[0139] [ka]

[0140] The bonds marked with are formed with chelating groups,

[0141] [ka]

[0142] Other bonds marked with R B preferably, X 4 is an amide bond. R CH is a chelating group comprising a chelated non-radioactive or non-radioactive cation, preferably a non-radioactive or radioactive metal cation, wherein preferred embodiments of said chelating group and optional chelated cation are as defined above.

[0143] The term "oligo", as used herein as 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 as referring to a group in which 2 to 20, more preferably 2 to 10, subunits are linked by the type of bond specified in the same term. As will be understood by the skilled reader, two different types of bonds are indicated in parentheses and both types of bonds are included in the relevant group (e.g., in "oligo(ester-amide)", ester and amide bonds are included).

[0144] L 1preferably contains 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 an amide bond, in its skeleton.

[0145] Thus, the term oligoamide describes a moiety having a chain of CH or CHR groups interrupted by groups selected from NHCO or CONH, where each occurrence of the R moiety is an optional substituent selected from -OH, -OCH, -COOH, -COOCH, -NH, and -NHC(NH)NH.

[0146] -X 1 -L 1 -X 2 - has the following structures (L-1) and (L-2): -NH-C(O)-R 6 -C(O)-NH-R 7 -NH-C(O)- (L-1) -C(O)-NH-R 8 -NH-C(O)-R 9 -C(O)-NH-R 10 -NH-C(O)- (L-2) [In the formula, R 6 ~R 10 are independently selected from C2-C10 alkylene, preferably straight-chain C2-C10 alkylene, and the alkylene groups can each be substituted with one or more substituents independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, and -NHC(NH)NH2.

[0147] Particularly preferred is R 6 and R 7 The total number of carbon atoms in R is 4 to 20, more preferably 4 to 16, and no carbon atoms are contained in the optional substituents. 8 ~R 10 The total number of carbon atoms in the alkyl group is 6 to 20, more preferably 6 to 16, and no carbon atoms are included in the optional substituents.

[0148] -X 1 -L 1 -X 2 - has the following structures (L-3) and (L-4): -NH-C(O)-R 11 -C(O)-NH-R 12 -CH(COOH)-NH-C(O)- (L-3) -C(O)-NH-CH(COOH)-R 13 -NH-C(O)-R 14 -C(O)-NH-R 15 -CH(COOH)-NH-C(O)- (L-4) [In the formula, R 11 ~R 15 are independently selected from C2-C8 alkylene, preferably straight-chain C2-C8 alkylene. R 11 and R 12 or R 13 ~R 15 It is particularly preferred that the total number of carbon atoms therein is 8 to 18, more preferably 8 to 12, and even more preferably 9 or 10.

[0149] Preferably, R B is represented by formula (IV):

[0150] [ka]

[0151] [Wherein A represents N, CR 16 Selected from R 16 is H or C1-C6 alkyl, and 5- to 7-membered carbocyclic or heterocyclic groups; preferably, A is selected from N and CH, more preferably, A is CH; (CH2) a in

[0152] [ka]

[0153] Bonds marked with X 2 where a is an integer from 0 to 4, preferably 0 or 1, most preferably 0; (CH2) b in

[0154] [ka]

[0155] Bonds marked with X 3 where b is an integer of 0 to 4, preferably 0 to 2, more preferably 0 or 1; (CH2) c in

[0156] [ka]

[0157] Bonds marked with X 4 and c is an integer of 0 to 4, preferably 0 to 2, and more preferably 0 or 1. Even more preferred conjugates according to the present invention are those of formula (IIIa):

[0158] [ka]

[0159] [where m, n, R 1L , R 2L , R 3L , X 1 , L 1 , b, c, X 4 and R CH is as defined above, including all preferred embodiments thereof, or a pharmaceutically acceptable salt thereof.

[0160] Compounds of formula (IIIa) where b+c≧1 are preferred. Also preferred are compounds of formula (IIIa) where b+c≦3. Compounds of formula (IIIa) in which b is 1 and c is 0 are more preferred.

[0161] -X 4 -R CH Also preferred are compounds of formula (III) in which represents the residue of a chelator selected from DOTA and DOTAGA linked to one of its carboxyl groups by an amide bond to the rest of the conjugate.

[0162] In a preferred embodiment of the compound of formula (III), said compound has the formula (IIIb):

[0163] [ka]

[0164] [where m, n, R 1L , R 2L , R 3L , X 1 , L 1 , b, c, X 4 and R CH is as defined above; and r is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0165] -N(H)-R CH It is particularly preferred that represents the residue of a chelator selected from DOTA and DOTAGA linked with one of its carboxyl groups by an amide bond to the rest of the conjugate.

[0166] For use in PET imaging, the radioconjugate of the composition requires a positron-emitting atom. The radioconjugate of the composition may include a positron-emitting atom for medical use. 18 The most preferred radioactive conjugates of the present invention include F, wherein F is 18 Contains F, M 3+ means a non-radioactive or radioactive metal cation.

[0167] The structures shown herein are shown to have COOH groups, and the pH of the solution will affect whether these groups are salts or acids. Some of the acid groups may be charged salts. Thus, the compounds disclosed herein include carboxylate salts of the compounds shown. Included herein are compositions of the following compounds, or salts thereof: PSMA-SIFA1(5)

[0168] [ka]

[0169] and their isomers:

[0170] [ka]

[0171] [ka]

[0172] PSMA-SIFA2(6)

[0173] [ka]

[0174] and their isomers

[0175] [ka]

[0176] [ka]

[0177] PSMA-SIFA3(7)

[0178] [ka]

[0179] and their isomers

[0180] [ka]

[0181] [ka]

[0182] [ka]

[0183] [ka]

[0184] [ka]

[0185] [ka]

[0186] PSMA-SIFA4(8)

[0187] [ka]

[0188] and their isomers

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] [ka]

[0193] [ka]

[0194] [ka]

[0195] PSMA-SIFA5(9)

[0196] [ka]

[0197] and their isomers

[0198] [ka]

[0199] [ka]

[0200] [ka]

[0201] PSMA-SIFA10

[0202] [ka]

[0203] and their isomers:

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] PSMA-SIFA11

[0208] [ka]

[0209] and their isomers:

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] The preferred labeling schemes for these most preferred radioconjugates of the composition are as defined herein above. The term "pharmaceutical composition" refers to a composition comprising a pharmaceutical agent together with a biocompatible carrier in a form suitable for mammalian administration. A "biocompatible carrier" is a fluid, particularly a liquid in which a pharmaceutical agent is suspended or dissolved, so that the composition is physiologically tolerable, i.e., can be administered to the mammalian body without toxicity or undue discomfort. The biocompatible carrier is suitably an injectable carrier liquid, for example, sterile pyrogen-free water or aqueous solution for injection, such as physiological saline.

[0214] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, and / or diluent. Examples of suitable pharmaceutical carriers, excipients, and / or diluents are well known in the art and include phosphate-buffered saline, water, emulsions (e.g., oil / water emulsions), various types of wetting agents, sterile solutions, etc. Compositions containing such carriers can be formulated using well-known, conventional methods. These pharmaceutical compositions can be administered to a subject at an appropriate dose. The appropriate composition can be administered in different ways, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly, topically, intradermally, intranasally, or intrabronchially. It is particularly preferred that the administration be by injection and / or delivery to a site in the pancreas, a cerebral artery, or directly into brain tissue. The composition 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 brain. The dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical field, the dosage for any one patient depends on many factors, including the patient's size, body surface area, age, the particular compound being administered, sex, time and route of administration, general health, and other drugs being administered concomitantly. The pharmaceutically active substance can be present in an amount between 0.1 ng and 10 mg / kg of body weight per dose; however, doses below or above this exemplary range are envisioned, particularly considering the factors mentioned above.

[0215] In a further aspect, the present invention provides one or more compositions of the invention as disclosed hereinabove for use in diagnostic medicine. A preferred use in medicine is in nuclear medicine, such as nuclear imaging, also called nuclear molecular imaging, and / or in targeted radiotherapy of diseases with overexpression, preferably PSMA, in diseased tissue.

[0216] In a further aspect, the present invention provides the composition of the present invention as defined herein above for use in a method for diagnosing and / or staging cancer, preferably prostate cancer.Prostate cancer is not the only cancer that expresses PSMA.Non-prostate cancer that demonstrates PSMA expression includes breast cancer, lung cancer, colorectal cancer and renal cell carcinoma.Therefore, any composition that contains a radioconjugate as described herein that has a PSMA binding moiety can be used in the diagnosis, imaging or treatment of cancer that has PSMA expression.

[0217] Preferred applications include the detection or staging of cancer, including but not limited to high-grade glioma, lung cancer, and particularly prostate cancer and metastatic prostate cancer, the detection of metastatic disease in patients with intermediate-risk to high-risk primary prostate cancer, and the detection of metastatic sites, as well as low serum PSA levels in patients with biochemically recurrent prostate cancer. Another preferred application is the imaging and visualization of neoangiogenesis.

[0218] With regard to medical indications subject to therapy, particularly radiation therapy, cancer is a preferred indication, with prostate cancer being a particularly preferred indication. In a further aspect, the present invention provides a composition comprising a radioconjugate conjugate or compound as defined herein above for use in a method of diagnosing and / or staging cancer, preferably prostate cancer. Scope of claims at the time of international application [Item 1] A pharmaceutical composition comprising a radioactive complex containing silicon fluoride and a chelating group, wherein the fluorine is: 18 F, or the chelating group contains a chelated radiometal, and the composition has a pH of 4.0 to 6.0; a) 0.1 to 200 mM citrate buffer; and b) 1 to 100 mg / mL ethanol; and c) A pharmaceutical composition further comprising 5 to 10 mg / mL sodium chloride. [Item 2] The pharmaceutical composition according to claim 1, comprising a 1 to 15 mM citrate buffer. [Item 3] The pharmaceutical composition according to claim 1, comprising a 1 to 10 mM (±10%) citrate buffer. [Item 4] The pharmaceutical composition according to any one of claims 1 to 3, comprising 5 to 50 mg / mL (±10%) ethanol. [Item 5] The pharmaceutical composition according to claim 4, comprising 5 to 50 mg / mL of ethanol. [Item 6] The pharmaceutical composition according to any one of claims 1 to 5, which has a pH of 4.5 to 5.5. [Item 7] The pharmaceutical composition according to any one of claims 1 to 6, comprising 6 to 9 mg / mL sodium chloride. [Item 8] The pharmaceutical composition according to any one of claims 1 to 7, wherein the citrate buffer is prepared from citric acid and sodium hydroxide, or sodium citrate and hydrochloric acid. [Item 9] The pharmaceutical composition according to claim 8, wherein the citrate buffer solution is prepared using 1 to 3 mg / mL citric acid and 0.5 to 1.0 mg / mL sodium hydroxide. [Item 10] The pharmaceutical composition according to claim 8, wherein the citrate buffer is prepared using 1.9 mg / mL citric acid and 0.75 mg / mL sodium hydroxide. [Item 11] The metal is radioactive and the fluoride is 19 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein F. Item 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the chelated metal is selected from the group consisting of cations of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th, and Er. [Item 13] Fluoride 18 11. The pharmaceutical composition of claim 1, wherein F is F and the metal is non-radioactive. [Item 14] The pharmaceutical composition of claim 12, wherein the chelated radioactive metal cation is a positron-emitting isotope. [Item 15] The pharmaceutical composition according to any one of claims 1 to 14, wherein the radioactivity concentration (RAC) at the end of synthesis (EOS) is 5 to 200 mCi / mL. [Item 16] The pharmaceutical composition according to any one of claims 1 to 15, comprising 1 to 10 mM (±10%) citrate buffer, 5 to 50 mg / mL (±10%) ethanol, and 6 to 9 mg / mL sodium chloride, and having a pH of 4.5 to 5.5. [Item 17] The pharmaceutical composition according to any one of claims 1 to 16, comprising 10 mM citrate buffer, 50 mg / mL ethanol, and 7.2 mg / mL sodium chloride, at pH 5. [Item 18] The pharmaceutical composition according to any one of claims 1 to 17, which is diluted with sodium chloride solution before administration. [Item 19] The pharmaceutical composition according to item 18, comprising 1.1 mM (±10%) citrate buffer, 5.3 mg / mL (±10%) ethanol, and 8.8 mg / mL (±10%) sodium chloride, and having a pH of 4.5 to 5.5. [Item 20] The radiocomplex agent is

change

change

change

change

[0219] Example 1: The gallium chelate of compound rh-PSMA-7.3 was prepared as previously described in WO2019 / 020831 and EP19154500.3: rhPSMA-7.3(D-Dap, (S)-DOTA-GA):

[0220] [ka]

[0221] Fmoc-D-Dap(Dde)-OH (2.0 equiv.) was preactivated in a mixture of HOAt (2.0 equiv.), TBTU (2.0 equiv.), and 2,4,6-trimethylpyridine (6.7 equiv.) in DMF and added to the resin-bound peptide for 2.5 h. Orthogonal Dde-deprotection was performed using imidazole and hydroxylamine hydrochloride dissolved in a mixture of NMP and DMF for 3 h. SiFA-BA (1.5 equiv.) was reacted with the free amine of the side chain with HOAt (1.5 equiv.), TBTU (1.5 equiv.), and DIPEA (4.5 equiv.) as the activating reagent in DMF for 2 h. After Fmoc-deprotection (20% piperidine in DMF (v / v, 8 mL / g of resin) for 5 min, followed by 15 min, after which the resin was extensively washed with DMF (8 × 5 mL / g of resin)), (R)-DOTA-GA(tBu) (2.0 equiv.) was conjugated with HOAT (2.0 equiv.), TBTU (2.0 equiv.), and 2,4,6-trimethylpyridine (6.7 equiv.) in DMF for 2.5 h. Cleavage from the resin with simultaneous deprotection of the acid-labile protecting groups was carried out in TFA (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 and the resin was treated in the same way for another 30 min. Both filtrates were combined, stirred for another 5 h and concentrated under a stream of nitrogen. The crude peptide was obtained after dissolving the residue in a mixture of tert-butanol and water and then lyophilizing). nat Ga-complexation was performed. The peptide (1.0 equiv.) was dissolved in a 3:1 (v / v) mixture of tBuOH in HO, and an aqueous solution of Ga(NO) (3.5 equiv.) was added. After heating the resulting mixture at 75 °C for 30 min, the peptide was purified by RP-HPLC.

[0222] 18 F-labeling aqueous 18 F -was passed through a SAX cartridge (Sep-Pak Accell Plus QMA Carbonate light), which had been preconditioned with 10 mL of water. After drying with 10 mL of air, the water was removed by rinsing the cartridge with 10 mL of anhydrous acetonitrile, followed by 20 mL of air. 18 F was dissolved in 500 μL of anhydrous acetonitrile [K + ⊂2.2.2]OH - The peptide was eluted with 100 μmol of oxalic acid. Prior to labeling, 30 μmol of oxalic acid in anhydrous acetonitrile (1 M, 30 μL) was added. This mixture was used either as a whole or as an aliquot for the fluorination of 10–25 nmol of PSMA-SiFA (1 mM in anhydrous DMSO). The resulting reaction mixture was incubated at room temperature for 5 min. For tracer purification, a Sep-Pak C18 light cartridge preconditioned with 10 mL of EtOH and then 10 mL of HO was used. The labeling mixture was diluted with 9 mL of PBS (pH 3), passed through the cartridge, and then diluted with 10 mL of HO. The peptide was eluted with 500 μL of a 4:1 mixture (v / v) of EtOH in water. The radiochemical purity of the labeled compound was confirmed by radio-RP-HPLC and radio-TLC (silica gel 60 RP-18 F). 254 s, determined with mobile phase: a 3:2 mixture (v / v) of MeCN in H2O supplemented with 10% 2 M aqueous NaOAc and 1% TFA).

[0223] or,[ 18 F]rhPSMA-7.3 18 F] fluoride ion and [ 19 It can be prepared in an automated synthesis module by isotope exchange between [F]rhPSMA-7.3 as follows: 18 F] fluorine-18 in the form of fluoride ion, along with a proton 18 O-enriched water is irradiated by the cyclotron. 18 O(p,n) 18 Prepared from F nuclear reactions.

[0224] [ 18[F] fluoride is first immobilized on an ion exchange resin, 18 O-Enriched water can then be collected. 18 [F] fluoride is eluted with a solution of cryptand 222 and potassium carbonate in acetonitrile and water. The eluate is transferred to a reaction vessel and evaporated by heating under a stream of nitrogen. [F] fluoride in a solution of DMSO, acetonitrile, and acetic acid is eluted. 19 F]rhPSMA-7.3 was added to the reaction vessel and reacted with the nucleophilic [ 18 F] fluoride, and [ 18 F]rhPSMA-7.3 is formed. 18 The crude solution of [F]rhPSMA-7.3 is diluted with water and purified by hydrophobic solid-phase extraction. Impurities are removed by washing the cartridge with water. 18 [F]rhPSMA-7.3 is formulated by elution with an ethanol-water solution and dilution with an isotonic formulation buffer. The formulated solution is sterilized by filtration through a 0.2 μm filter.

[0225] Where applicable, dilutions are made with isotonic saline for injection. Batches of material were prepared either in citrate buffer made from sodium citrate + HCl or in citrate buffer made from citric acid + NaOH.

[0226] Radiation stability was measured in phosphate and citrate buffers at various pH levels to compare the exact 18F-Si compound with the level of 18F without degradation:

[0227] [Table A]

[0228] The most stable formulation was at pH 5.0 in citrate buffer. As the pH in the citrate buffer increased, the amount of 18F (presumably displaced by OH) increased. Phosphate buffer at the same pH (6.0) yielded a product that was less stable than citrate buffer.

[0229] Radiochemistry and chemical purity were evaluated for various formulations containing citrate buffer or citrate buffered saline (Table 1).

[0230] [Table 1]

[0231] Maintain the pH of the formulation (Entry 5, Table 1: 10 mM citrate buffered saline, 5% ethanol) after dilution with sodium chloride solution for injection (0.9% w / v).

[0232] [Table 2]

Claims

1. A pharmaceutical composition comprising a silicon fluoride and a radioconjugate containing a chelating group, wherein the fluorine is １８ F, or the chelating group contains a chelated radiometal; The radiation complex 【Chemistry 1】 wherein M 3+ is a chelated radioactive or non-radioactive metal, or an isomer or salt thereof; the composition has a pH of 4.0 to 6.0; a) 0.1 to 200 mM citrate buffer; and b) 1-100 mg / mL ethanol; and c) A pharmaceutical composition further comprising 5-10 mg / mL sodium chloride.

2. 10. The pharmaceutical composition of claim 1, comprising 1 to 15 mM citrate buffer.

3. 10. The pharmaceutical composition of claim 1, comprising 1 to 10 mM citrate buffer.

4. 4. The pharmaceutical composition according to any one of claims 1 to 3, comprising 5 to 50 mg / mL ethanol.

5. 5. The pharmaceutical composition of claim 4, comprising 5 to 50 mg / mL ethanol.

6. The pharmaceutical composition according to any one of claims 1 to 5, having a pH of 4.5 to 5.

5.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, comprising 6 to 9 mg / mL sodium chloride.

8. 8. The pharmaceutical composition of claim 1, wherein the citrate buffer is prepared from citric acid and sodium hydroxide, or sodium citrate and hydrochloric acid.

9. 9. The pharmaceutical composition of claim 8, wherein the citrate buffer solution is prepared using 1 to 3 mg / mL citric acid and 0.5 to 1.0 mg / mL sodium hydroxide.

10. 9. The pharmaceutical composition of claim 8, wherein the citrate buffer is prepared using 1.9 mg / mL citric acid and 0.75 mg / mL sodium hydroxide.

11. The metal is radioactive and the fluoride １９ The pharmaceutical composition according to any one of claims 1 to 10, wherein the compound is F.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, 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.

13. Fluoride １８ 11. The pharmaceutical composition of claim 1, wherein the metal is F and the metal is non-radioactive.

14. 13. The pharmaceutical composition of claim 12, wherein the chelated radioactive metal cation is a positron-emitting isotope.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the radioactivity concentration (RAC) at the end of synthesis (EOS) is 5 to 200 mCi / mL.

16. 16. The pharmaceutical composition according to any one of claims 1 to 15, comprising 1 to 10 mM citrate buffer, 5 to 50 mg / mL ethanol, and 6 to 9 mg / mL sodium chloride, and having a pH of 4.5 to 5.

5.

17. 17. The pharmaceutical composition of claim 1, comprising 10 mM citrate buffer, 50 mg / mL ethanol, 7.2 mg / mL sodium chloride, at pH 5.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, which is diluted with sodium chloride solution before administration.

19. 19. The pharmaceutical composition of claim 18, comprising 1.1 mM citrate buffer, 5.3 mg / mL ethanol, and 8.8 mg / mL sodium chloride, and having a pH of 4.5 to 5.5.

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