PHARMACEUTICAL FORMULATIONS

Abstract

The present invention relates to a pharmaceutical composition comprising a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains 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

PHARMACEUTICAL FORMULATIONS QPfr7 ίη / 77Π7 / E / YΙΛΙ Field of Invention The present invention relates to a pharmaceutical composition of a radiohybrid agent containing silicon fluoride and a chelating group, wherein the fluorine is fluorine-18 (18F) 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; 1-100 mg / mL ethanol; and 5-10 mg / mL sodium chloride. Background of the Invention Prostate cancer. Prostate cancer (PCa) has remained the most common malignancy in men for decades, with a high incidence and low survival rates. Due to their overexpression in prostate cancer, prostate-specific membrane antigen (PSMA) or glutamate carboxypeptidase II (GCP II) have proven to be excellent targets for the development of highly sensitive radiolabeled agents for endorphin therapy and imaging of PCa. Prostate-specific membrane antigen is an extracellular hydrolase whose catalytic center comprises two zinc(II) ions with a bridging hydroxide ligand. It is highly upregulated in metastatic prostate carcinomas and Ref. 338804 is hormone-resistant, but its physiological expression has also been reported in the kidneys, salivary glands, small intestine, brain, and, to a lesser extent, in healthy prosthetic tissue. In the intestine, PSMA facilitates folate absorption by converting pteroylpoly-L-glutamate to pteroylglutamate (folate). In the brain, it hydrolyzes N-acetyl-L-glutamate (NAAG) to N-acetyl-L-glutamate and glutamate. Prosthetic specific membrane antigen (PSMA) Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly overexpressed in the epithelial cells of prostate cancer. Despite its name, PSMA is also expressed, to varying degrees, in the neovasculature of a wide variety of non-prostate cancers. Among the most common non-prostate cancers that demonstrate PSMA expression are renal cell carcinoma, colorectal cancer, lung cancer, and breast cancer. The general structures required for PSMA-targeting molecules comprise a binding unit encompassing a zinc-binding group (such as urea, phosphinate, or phosphoramidate) connected to a Pl' glutamate moiety, which ensures high affinity and specificity for PSMA and is typically more closely linked to an effector function. The effector portion is more flexible and, to some extent, tolerant of structural modifications. Currently, two categories of PSMA targeting inhibitors are used in clinical settings. On the one hand, there are tracers with chelating units for the complexation of radionuclides such as PSMA I&T or related compounds. On the other hand, there are small molecules, which comprise a targeting unit and effector molecules. Score 18F Recently, several groups have focused on developing novel 18F-labeled urea-based inhibitors for prostate cancer (PCa) diagnosis. The 18F-labeled urea-based PSMA inhibitor 18F-DCFPyl has shown promising results in detecting primary and metastatic PCa. Based on the structure of PSMA-617, the 18F-labeled analog PSMA-1007 was recently developed, which showed comparable tumor-to-organ ratios. An attractive approach for introducing 18F markers is the use of silicon fluoride acceptors (SIFAs). Silicon fluoride acceptors are described, for example, in Lindner et al., Bioconjugate Chemistry 25, 738-749 (2014). To preserve the silicon-fluoride bond, the use of silicon fluoride acceptors introduces the need for spherically demanding groups around the silicon atom. This, in turn, makes silicon fluoride acceptors highly hydrophobic. In terms of binding to the target molecule, particularly the target molecule that is a PSMA, the hydrophobic moiety provided by the silicon fluoride acceptor can be exploited to establish interactions of the radiodiagnostic or therapeutic compound with the hydrophobic pocket described in Zhang et al., Journal of the American Chemical Society 132, 12711-12716 (2010).However, prior to binding, the increased degree of lipophilicity introduced into the molecule poses a serious problem with regard to the development of radiopharmaceuticals with adequate in vivo biodistribution, i.e., low nonspecific binding in non-target tissue. Despite numerous attempts, the problem of hydrophobicity caused by silicon fluoride acceptors has recently been resolved through the use of agents with a hydrophilic chelating moiety. Application WO2019 / 020831 describes a novel type of radiohybrid agent having a SIFA moiety and a metal chelator. By developing the compounds described therein, the inventors have identified improved pharmaceutical formulations for patient administration. The formulations described herein exhibit improved radiostability and shelf life compared to previously described formulations. In view of the foregoing, the technical problem underlying the present invention can be seen as providing improved radiodiagnostic formulations containing a silicon fluoride acceptor and a metal chelator that, at the same time, are characterized by favorable pharmacological stability properties. Brief Description of the Invention As will become evident below, the present invention establishes a proof of principle using specific conjugates, formulated in specific ways, that bind with high affinity to the prostate-specific antigen (PSMA) as the target. The composition in which the compounds are prepared and stored affects the chemical and radiochemical stability of the agents. Consequently, another underlying technical problem of the present invention can be seen in providing improved diagnostics for the medical indication of cancer, preferably prostate cancer. These technical problems are solved by the subject matter of the claims. Accordingly, in the first aspect, the present invention relates to a pharmaceutical composition comprising a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is fluorine-18 (18F) or the chelating group contains a chelated radioactive metal, wherein the composition has a pH of 4.0-6.0 and further comprises: (a) citrate buffer 0.1-200 mM; and (b) 1-100 mg / ml of ethanol; and (c) 5-10 mg / mL of sodium chloride. The alternative compositions described herein relate to pharmaceutical compositions of a radiohybrid agent containing a silicon fluoride and a chelating group wherein the fluorine is 18F 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 4.06.0. The formulation 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 solution). A method for producing a composition as described herein is described, the method comprising preparing a formulation of a radiohybrid agent containing a silicon fluoride and a chelating group wherein the fluorine is 18F 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. The pharmaceutical composition may comprise 50-200 mM citrate buffer. The pharmaceutical composition may comprise 10-100 mg / ml of ethanol. The pharmaceutical composition may have a pH of 4.0 to 6.0. The pharmaceutical composition may comprise a chelated radioactive metal or fluorine-18F. The pharmaceutical composition may comprise a chelated radioactive metal selected from the cations of: Se, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Ac, Th or Er. The pharmaceutical composition may comprise a fluorine-18F and a non-radioactive chelated metal ion. The pharmaceutical composition may comprise fluorine19F and a chelated radioactive metal ion. The pharmaceutical composition can be a composition where the metal is radioactive and the fluorine is 19F. The pharmaceutical composition can be a composition where the fluorine is 18F and the metal is not radioactive. The pharmaceutical composition may comprise a chelated radioactive metal cation selected from: n7Lu,90Y,225Ac,68Ga or67Ga. The pharmaceutical composition may comprise 60-120 mM citrate buffer. The pharmaceutical composition may include a buffer QPfrZ Ln / Zznz / E / YIAI citrate 0.1-200 mM. The pharmaceutical composition may comprise citrate buffer 0.1-120 mM. The pharmaceutical composition may comprise citrate buffer 0.1-50 mM. The pharmaceutical composition may comprise citrate buffer 0.1-20 mM. The pharmaceutical composition may comprise citrate buffer 1-15 mM. The pharmaceutical composition may comprise 10 mM citrate buffer (+15%). The pharmaceutical composition may comprise citrate buffer 10 mM (±10%). The pharmaceutical composition may comprise 10 mM citrate buffer (+5%). The pharmaceutical composition may comprise citrate buffer 10 mM (±2%). The pharmaceutical composition may comprise 10 mM citrate buffer (+1%). The pharmaceutical composition may comprise 10 mM citrate buffer. The pharmaceutical composition may comprise 1-10 mM citrate buffer. The pharmaceutical composition may comprise citrate buffer 1-10 mM (+15%). The pharmaceutical composition may comprise citrate buffer 1-10 mM (+10%). QQfr7 ίη / 77Π7 / E / YΙΛΙ The pharmaceutical composition may comprise citrate buffer 1-10 mM (+5%). The pharmaceutical composition may comprise citrate buffer 1-10 mM (±2%). The pharmaceutical composition may comprise citrate buffer 1-10 mM (±1%). The pharmaceutical composition may be formulated with anhydrous citric acid or, alternatively, citric acid monohydrate, or salts thereof (including sodium citrate). The pharmaceutical composition may be formulated using citric acid monohydrate. The pharmaceutical composition can be formulated with 1.5-2.5 mg / ml of citric acid (anhydrous base). The pharmaceutical composition can be formulated with 1.9 mg / ml (±10%) of citric acid (anhydrous base). The pharmaceutical composition can be formulated with 1.9 mg / mL (±5%) of citric acid (anhydrous base). The pharmaceutical composition can be formulated with 1.9 mg / mL (±2%) of citric acid (anhydrous base). The pharmaceutical composition can be formulated with 1.9 mg / mL (±1%) of citric acid (anhydrous base). The pharmaceutical composition can be formulated with 1.9 mg / mL of citric acid (anhydrous base). The pharmaceutical composition may have a pH of 4.5-5.5. The pharmaceutical composition may have a pH of 5 (±15%). The pharmaceutical composition may have a pH of 5 (±10%). 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%). 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. The pharmaceutical composition may comprise 5-100 mg / ml of ethanol. The pharmaceutical composition may comprise 10-100 mg / ml of ethanol. The pharmaceutical composition may comprise 10-70 mg / ml of ethanol. The pharmaceutical composition may comprise 40-60 mg / ml of ethanol. The pharmaceutical composition may comprise 50mg / mL (±15%) of ethanol. The pharmaceutical composition may comprise 50mg / mL (±10%) of ethanol. The pharmaceutical composition may comprise 50mg / mL (±5%) of ethanol. The pharmaceutical composition may comprise 50mg / mL (±2%) of ethanol. QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ The pharmaceutical composition may include mg / mL QPfrZ Ln / Zznz / E / YIAI (+1%) ethanol. The pharmaceutical composition may comprise 50 mg / mL of ethanol. The pharmaceutical composition may comprise 5 (±15%) of ethanol. The pharmaceutical composition may comprise 5 (±10%) of ethanol. The pharmaceutical composition may comprise 5 (±5%) of ethanol. The pharmaceutical composition may comprise 5 (±2%) of ethanol. The pharmaceutical composition may comprise 5 (±1%) of ethanol. The pharmaceutical composition may comprise 5% ethanol. The pharmaceutical composition may comprise 5 of sodium chloride. The pharmaceutical composition may comprise 6-9 sodium chloride. The pharmaceutical composition may comprise (±15%) sodium chloride. The pharmaceutical composition may comprise (±10%) sodium chloride. The pharmaceutical composition may comprise mg / mL mg / mL mg / mL mg / mL mg / mL mg / mL mg / ml mg / ml mg / ml of 0.2 mg / mL 0.2 mg / mL 0.2 mg / mL (±5%) of sodium chloride. The pharmaceutical composition may comprise 7.2 mg / mL (±2%) of sodium chloride. The pharmaceutical composition may comprise 7.2 mg / mL (±1%) of sodium chloride. The pharmaceutical composition may comprise 7.2 mg / mL of sodium chloride. In pharmaceutical formulations, citrate buffer can be prepared from citric acid and sodium hydroxide. Alternatively, citrate buffer can be prepared using appropriate amounts of sodium citrate and HCl. In the pharmaceutical composition, 1-3 mg / ml of citric acid (anhydrous base) and 0.5-1.0 mg / ml of sodium hydroxide can be used to prepare the citrate buffer solution. In the pharmaceutical composition, 1.9 mg / mL (±15%) of citric acid (anhydrous base) and 0.75 mg / mL (±15%) of sodium hydroxide can be used to prepare the citrate buffer. In the pharmaceutical composition, 1.9 mg / mL (±10%) of citric acid (anhydrous base) and 0.75 mg / mL (±10%) of sodium hydroxide can be used to prepare the citrate buffer. In the pharmaceutical composition, 1.9 mg / mL (±5%) of citric acid (anhydrous base) and 0.75 mg / mL (±5%) of sodium hydroxide can be used to prepare the citrate buffer. In the pharmaceutical composition, 1.9 mg / mL (±2%) of citric acid (anhydrous base) and 0.75 mg / mL (±2%) of sodium hydroxide can be used to prepare the citrate buffer. In the pharmaceutical composition, 1.9 mg / mL (+1%) of citric acid (anhydrous base) and 0.75 mg / mL (+1%) of sodium hydroxide can be used to prepare the citrate buffer. In the pharmaceutical composition, 1.9 mg / mL of citric acid (anhydrous base) and 0.75 mg / mL of sodium hydroxide can be used to prepare the citrate buffer. The pharmaceutical composition may have a radioactive concentration (RAC) at the end of synthesis (EOS) of 5-500 mCi / ml. The pharmaceutical composition may have a radioactive concentration (RAC) at the end of synthesis (EOS) of 5-200 mCi / ml. The pharmaceutical composition may have a radioactive concentration (RAC) at the end of synthesis (EOS) of 50-100 mCi / ml. The pharmaceutical composition may have a radioactive concentration (RAC) at the end of synthesis (EOS) of 10-100 mCi / mi. The term end of synthesis refers to the moment when the labeled compound is collected in the product collection vial. The pharmaceutical composition may have a radioactive concentration (RAC) at the end of the QQfrZ ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ synthesis (EOS) of 20-90 mCi / ml. The pharmaceutical composition may have a radioactive concentration (RAC) at the end of synthesis (EOS) of at least 35 mCi / ml. The pharmaceutical composition may comprise 10 mM citrate buffer (±15%), 50 mg / ml ethanol (±15%), 7.2 mg / ml sodium chloride (±15%) and have a pH of 5 (±15%). The pharmaceutical composition may comprise 10 mM citrate buffer (±10%), 50 mg / ml ethanol (±10%), 7.2 mg / ml sodium chloride (±10%) and have a pH of 5 (±10%). The pharmaceutical composition may comprise 10 mM citrate buffer (±5%), 50 mg / ml ethanol (±5%), 7.2 mg / ml sodium chloride (±5%) and have a pH of 5 (±5%). The pharmaceutical composition may comprise 10 mM citrate buffer (±2%), 50 mg / ml ethanol (±2%), 7.2 mg / ml sodium chloride (±2%) and have a pH of 5 (±2%). The pharmaceutical composition may comprise 10 mM citrate buffer (±1%), 50 mg / ml ethanol (±1%), 7.2 mg / ml sodium chloride (±1%) and have a pH of 5 (±1%). The pharmaceutical composition may comprise 10 mM citrate buffer, 50 mg / ml ethanol, 7.2 mg / ml sodium chloride and have a pH of 5. The pharmaceutical composition may comprise a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal wherein the composition has a pH of 5.0 (±15%) and further comprises: (a) 10 mM citrate buffer (±15%); and (b) 50 mg / mL (±15%) of ethanol; and (c) 7.2 mg / ml (±15%) of sodium chloride. The pharmaceutical composition may comprise a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal wherein the composition has a pH of 5.0 (±10%) and further comprises: (a) 10 mM citrate buffer (±10%); and (b) 50 mg / mL (±10%) of ethanol; and (c) 7.2 mg / ml (±10%) of sodium chloride. The pharmaceutical composition may comprise a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal wherein 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. The pharmaceutical composition may comprise a radiohybrid agent containing a silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal wherein the composition has a QPfrZ Ln / Zznz / E / YIAI pH of 5.0 (+2%) and also comprises: (a) 10 mM citrate buffer (+2%); and (b) 50 mg / mL (±2%) of ethanol; and (c) 7.2 mg / ml (+2%) of sodium chloride. The pharmaceutical composition may comprise a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal wherein 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. The pharmaceutical composition may comprise a radiohybrid agent containing silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal wherein 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. The pharmaceutical composition can be diluted with sodium chloride solution before administration. The pharmaceutical composition can be diluted up to 10 times or more with sodium chloride solution before administration. The solution of QPfrZ ίη / ZZΖΠZ / E / YΙΛΙ sodium chloride used as a diluent before administration may be an aqueous solution of 9 mg / ml (+5%) sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM citrate buffer (+15%). After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM citrate buffer (+10%). After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM (± 5%) citrate buffer. After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM citrate buffer (+2%). After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM citrate buffer (+1%). After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM citrate buffer. After dilution with sodium chloride solution, the pharmaceutical composition may contain 5.3 mg / ml (±15%) of ethanol. After dilution with sodium chloride solution, the pharmaceutical composition may contain 5.3 mg / ml (+10%) of QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ ethanol. After dilution with sodium chloride solution, the pharmaceutical composition may comprise 5.3 mg / ml (±5%) of ethanol. After dilution with sodium chloride solution, the pharmaceutical composition may comprise 5.3 mg / ml (±2%) of ethanol. After dilution with sodium chloride solution, the pharmaceutical composition may contain 5.3 mg / ml (+ 1%) of ethanol. After dilution with sodium chloride solution, the pharmaceutical composition may contain 5.3 mg / ml of ethanol. After dilution with sodium chloride solution, the pharmaceutical composition may comprise 5-10 mg / ml of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain 8.8 mg / ml (+15%) of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain 8.8 mg / ml (±10%) of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain 8.8 mg / ml (±5%) of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain 8.8 mg / ml (±2%) of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain 8.8 mg / ml (+1%) of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain 8.8 mg / ml of sodium chloride. After dilution with sodium chloride solution, the pharmaceutical composition may contain citrate buffer 1.1 mM (±15%), ethanol 5.3 mg / ml (±15%), sodium chloride 8.8 mg / ml (±15%) and have a pH of 5.1 (±15%). After dilution with sodium chloride solution, the pharmaceutical composition may contain citrate buffer 1.1 mM (±10%), ethanol 5.3 mg / ml (±10%), sodium chloride 8.8 mg / ml (±10%) and have a pH of 5.1 (±10%). After dilution with sodium chloride solution, the pharmaceutical composition may contain citrate buffer 1.1 rrM (±5%), ethanol 5.3 mg / ml (±5%), sodium chloride 8.8 mg / ml (±5%) and have a pH of 5.1 (±5%). After dilution with sodium chloride solution, the pharmaceutical composition may contain citrate buffer 1.1 mM (±2%), ethanol 5.3 mg / ml (±2%), sodium chloride 8.8 mg / ml (±2%) and have a pH of 5.1 (±2%). After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM (±1%) citrate buffer, 5.3 mg / ml (±1%) ethanol, 8.8 mg / ml (+1%) sodium chloride and have a pH of 5.1 (±1%). After dilution with sodium chloride solution, the pharmaceutical composition may comprise 1.1 mM citrate buffer, 5.3 mg / ml ethanol, 8.8 mg / ml sodium chloride and have a pH of 5.1. The pharmaceutical composition can improve product stability by lowering the pH. During testing, it was identified that the product is less stable under basic conditions, resulting in the hydrolyzed silanol product (displacement of F- by OH-). Lowering the pH helped stabilize the product, and citrate was selected at pH 5. Ethanol can be used as a shield against radiolysis. Optimizing the amount of ethanol leads to the development of the stabilized material as described in this document. Different quantities of components can be combined. For example, the buffer solution can be a 0.1–200 mM citrate buffer with a pH of 4.5 to 5.5 and up to 70 mg / mL of ethanol. The composition may contain additional salts to maintain blood isotonicity. The composition contains sodium chloride. The pharmaceutical composition may bind to PSMA. The pharmaceutical composition may comprise a radiohybrid agent selected from: QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ and isomers and salts thereof where M3+ is a radioactive or non-radioactive chelated metal. The agents may be in the form of pharmaceutically acceptable salts so that, QQF7 ίη / ZZΖΠZ / E / YΙΛΙ for example, the groups one or more of the groups shown as QPfrZ Ln / Zznz / E / YIAI COOH can be salts of the same. The pharmaceutical composition may comprise a radiohybrid agent comprising: or an isomer or salt of the same. The pharmaceutical composition can be used as a cancer diagnostic or imaging agent. The pharmaceutical composition can be used in a method for obtaining cancer imaging and / or diagnosis in a patient in need thereof. Therefore, a method for obtaining cancer imaging and / or diagnosis comprising administering a conjugate, compound, or composition of the invention to a patient in need thereof is also presented herein. The pharmaceutical composition can be used in the treatment of cancer. The pharmaceutical composition can be used for the diagnosis, imaging, or prevention of neoangiogenesis / angiogenesis. The pharmaceutical composition can be used as a cancer diagnostic or imaging agent or for use in the treatment of cancer where the cancer is prostate, breast, lung, colorectal, or renal cell carcinoma. The pharmaceutical composition comprises a radiohybrid agent having three separate fractions. The three separate residues are (a) one or more ligands capable of binding to PSMA, (b) a silicon fluoride acceptor residue (SIFA) comprising a covalent bond between a silicon and fluorine atom, and (c) one or more chelating groups containing a chelated radioactive or non-radioactive cation. While certain ligands capable of binding to a disease-relevant target molecule may be cyclic peptides, cyclic peptides are not chelating groups as envisaged herein, since the problem of the hydrophobic SIFA moiety is not resolved in the absence of an additional chelating group. Thus, the radiohybrids of the compositions of the invention require a hydrophilic chelating group in addition to the ligands capable of binding to PSMA. The hydrophilic chelating group is necessary to reduce the hydrophobic nature of the radiohybrids of the compositions caused by the presence of the SIFA moiety. The ligand in relation to the first aspect of the invention is defined in functional terms. This is because the present invention does not depend on the specific nature of the ligand in structural terms. Rather, a key aspect of the invention is the combination, within a single molecule, of a silicon fluoride acceptor and a chelating agent or chelate. These two structural elements, SIFA and the chelating agent, exhibit spatial proximity. Preferably, the shortest distance between any 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 furthermore, it is preferred that no more than 25 covalent bonds separate an atom of the SIFA moiety and an atom of the chelating agent, preferably no more than 20 chemical bonds, and even more preferably no more than 15 chemical bonds. The cation according to point (c) can be either radioactive or non-radioactive. Examples are given later. Consequently, the conjugates can be radioactively labeled in the SIFA residue or not radiolabeled in the SIFA residue. In the first case, the chelating group can be a complex of a cold (non-radioactive) ion or it can be devoid of any ion. In the latter case, the chelating agent will contain a radioactive cation. The present inventors discovered that placing the silicon fluoride acceptor in the vicinity of a hydrophilic chelating agent such as, but not limited to, DOTAGA or DOTA efficiently protects or compensates for the lipophilicity of the SIFA residue to an extent that changes the overall hydrophobicity of the compound within a range that makes the compound suitable for in vivo administration. An additional advantage of the radiohybrid compositions, especially the PSMA-targeted radiohybrids of the present invention, is their surprisingly low accumulation in the kidneys of mice compared to other PSMA-targeted radiopharmaceuticals, such as PSMA I&T. Without wishing to limit ourselves to a particular theory, it appears to be the combination of the SIFA structural element with a chelating agent that provides the unexpected reduction in kidney accumulation. In a preferred embodiment, a ligand according to the invention comprises or consists of a peptide, a peptidomimetic, or a substituted urea, the substituents including amino acids. It is understood that a ligand comprising a peptide or peptidomimetic also comprises a non-peptide and non-peptidomimetic portion. In terms of molecular weight, preference is given to molecular weights below 15 kDa, below 10 kDa, or below 5 kDa. Accordingly, small proteins are also included within the term ligand. Target molecules are not particularly limited and include enzymes, receptors, epitopes, transporters, cell surface molecules, and extracellular matrix proteins. Targets that are relevant to the disease are preferred.Targets that are causally involved in a given disease, or that are highly overexpressed in a given disease, and / or whose inhibition may have a beneficial effect in a patient with a given disease, are particularly preferred. The ligands are preferably high-affinity ligands with a preferred affinity, expressed as IC50, below 50 nM, below 20 nM, or below 5 nM. Ligands that bind with high affinity to prostate-specific membrane antigen (PSMA) are especially preferred. Preferably, the silicon fluoride acceptor moiety (SIFA) has the structure represented by formula (I): Where F is understood to encompass both 19F and 18F, Rlsy R2S is independently a linear or branched C3 to C10 alkyl group, preferably R1S and R2S are selected from isopropyl and tert-butyl, and more preferably R1S and R2S are tert-butyl; R3S is a C1 to C20 hydrocarbon group that may comprise one or more aromatic units and one or more aliphatic units and / or up to 3 heteroatoms selected from O and S, preferably R3S is a C6 to C10 hydrocarbon group comprising an aromatic ring and that may comprise one or more aliphatic units; more preferably, R3S is a phenyl ring, and most preferably, R3S is a phenyl ring wherein the Si-containing substituent and the bond marked with ?vwww are in a para position, and wherein the SIFA moiety is attached to the conjugate retarder via the bond marked with ,lllllllllllll More preferably, the silicon fluoride acceptor residue (SIFA) has the structure represented by the formula (la): QPfr7 ίη / 77Π7 / E / YΙΛΙ where t-Bu indicates a tere-butyl group; and it is understood that F encompasses both 19F and 18F. A preferred chelating group comprises at least one of the following (i), (ii) or (iii). (i) A macrocyclic ring structure with 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 especially preferred that 3 or 4 ring atoms be nitrogen or oxygen atoms. Between the oxygen and nitrogen atoms, nitrogen atoms are preferred. In combination with the macrocyclic ring structure, the preferred chelating group may comprise 2 or more, such as 2 to 6, preferably 2 to 4, carboxyl and / or hydroxyl groups. Between the carboxyl and hydroxyl groups, carboxyl groups are preferred. (ii) An open-chain, acyclic chelating structure with 8 to 20 backbone atoms, of which 2 or more, more preferably 3 or more, are heteroatoms selected from oxygen or nitrogen atoms. Preferably, 6 or fewer backbone atoms are selected from oxygen or nitrogen atoms. Between the oxygen and nitrogen atoms, nitrogen atoms are preferred. More preferably, the open-chain chelating structure comprises a combination of 2 or more, more preferably 3 or more, heteroatoms selected from oxygen or nitrogen atoms, and 2 or more, such as 2 to 6, preferably 2 to 4, carboxyl and / or hydroxyl groups. Between the carboxyl and hydroxyl groups, carboxyl groups are preferred. (iii) A branched chelating structure 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 groups may comprise an amide. The substituted chelating groups may comprise an aromatic group. The substituted chelating groups may comprise a hydroxypyridinone. In preferred specific examples, the chelating group is a residue of a chelating agent selected from 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-hydroxybutandiamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetracyclododecane-N,N',N ,N'-tetraacetic acid (DOTA), a(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-l, 4,7,10tetraacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane Ν,Ν',Ν'' N'''-1,4,7,10-tetra(methylene)phosphonic acid (DOTMP), N,N'dipyridoxyethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) (DPDP), diethylenetriamine-N,Ν',Ν'' penta(methylene)phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine acid N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2aminoethyl)-Ν,Ν,Ν',N'-tetraacetic acid (EGTA), Ν,Νbis(hydroxybenzyl)-ethylenediamine-N,Ν'-diacetic acid (HBED), hydroxyethyldiaminotriacetic acid (HEDTA), l-(p-nitrobenzyl)1<4,7,10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 6hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), tetra 3-hydroxy-N-methyl-2-pyridinone chelators, acid (4-((4-(3-(bis(2(3-hydroxy-l-methyl-2-oxo-l,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-l-methyl-2-oxo1,2-dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), abbreviated as Me-3,2-HOPO, 1,4,7-triazacyclononan-l-succinic-4,7-diacetic acid (NODASA), 1(l-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,ll-bis(carboxymethyl)1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), acid 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridinebis(methyleneaminetetraacetic acid) (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP), 1,4,7,10-tetraazacyclotridecan-N,N',N'',N'''tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazonan-11]methyl-hydroxy-phosphoryl]propanoic acid and triethylenetetraaminohexaacetic acid (TTHA), the residue of which is QPfrZ ίη / ZZΖΠZ / E / YΙΛΙ provides by means of the covalent bonding of a carboxyl group contained in the chelating agent to the rest of the conjugate through an ester or amide bond. The specific chelating agents are shown below: DOTA DOTPI OH NOTE CO2H THP EITHER X OH Me-3,2-HOPO Among the examples of chelating agents above, particular preference is given to a chelating agent selected from QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ TRAP, DOTA and DOTAGA. Macrocyclic and acyclic compounds that chelate metals or cations are well known in the art and are available from various manufacturers. While the chelating moieties according to the present invention are not particularly limited, it is understood that a person skilled in the art can use numerous moieties commercially without further ado. The chelating group may comprise a chelated cation that is not radioactive. The preferred examples of cations that can be chelated by the chelating group are the non-radioactive cations of Se, Cr, Mn, Co, Fe, Ni, Cu, Ga, Zr, Y, Te, 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 cations of Se, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th, and Er. The cation can be Ga. The cation can be Lu. The chelating group may comprise a chelating cation that is radioactive. Preferred examples of cations that can be chelated by the chelating group are the cations of 43Sc, 44Sc, 47Sc, 51Cr, 52mMn, 58Co, 52Fe, 56Ni, 57Ni, 62Cu, 64Cu, 67Cu, 66Ga, 67ga, 68Ga, 89Zr, 90Y, 89Y, <Tc,99mTc,97Ru,105Rh,109Pd,141Ag,110In, niln, n3In, n4in,117mSn,121Sn,127Te,142Pr,143Pr,149Pm,154Pm,149Tb,152Tb,155Tb,161Tb,153Sm,157Gd,161Tb,166Ho,165Dy,169Er,169Yb, i^Yb,172Tm,177Lu,186Re,188Re,191Pt,197Hg,198Au,199Au,212Pb,203Pb,211At,212Bi,213Bi,223Ra,225Ac,227Th, una molécula catiónica que comprende18F o un catión tal como18F-[AIF]2+; más preferiblemente los cationes de44Sc,47Sc,64Cu,68Ga,90Y,X11ln,161Tb,166Ho,177Lu,188Re,212Pb,212Bi,225Ac, y227Th o una molécula catiónica que comprende18F. Los cationes se pueden seleccionar de Lu-177, Y-90 o Ac-225. Los cationes preferidos pueden ser isótopos emisores de positrones tales como68Ga. Therefore, the ligand is preferentially able to bind to the prostate-specific membrane antigen (PSMA). More preferably, the ligand has the structure represented by formula (II): HOOC .r!52L,R^ RCH2)n--5 R < i ii |0COOH (II) wherein m is an integer from 2 to 6, preferably from 2 to 4, more preferably 2; n is an integer from 2 to 6, preferably from 2 to 4, more preferably 2 or 3; R1Les CH2, NH or O, preferably NH; R3Les CH2, NH or O, preferably NH; R2Les C or P (OH), preferably C; and wherein the ligand is attached to the remainder of the conjugate through the bond marked by awww. The ligand can have the structure represented by the formula (lia): COOH (Ha) where n is an integer from 2 to 6; and where the ligand is attached to the rest of the conjugate through the bond marked by ιΛΛΛΛΛΛΛΛ . Several PSMA binders are known in the art, all of which are suitable according to the invention. The above preferred embodiment is a structural definition of a preferred group of PSMA binders. It is particularly preferred that the conjugate of the first aspect be a compound of formula (III): SIFA HOOC 2L-Rt / (CH2)n—X —i1—X—R—X—RCH And ^RY HOOC^*01^2^ °COOH(III) or a pharmaceutically acceptable salt thereof, wherein: SIFA is a silicon fluoride acceptor residue (SIFA) comprising a covalent bond between a silicon atom and a fluorine atom and labelled with 18F; preferably SIFA is the SIFA residue of formula (I) and more preferably of formula (la) defined above; m is an integer from 2 to 6, preferably 2 or 3, more preferably 2; n is an integer from 2 to 6, preferably 2 or 3, more preferably 2 or 4; R1Les CH2, NH or O, preferably NH; R3les CH2, NH or O, preferably NH; R2les C or P (OH), preferably C; X1 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; X2 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; L1 is a divalent bonding group with a structure selected from 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 with a structure QPfrZ Ln / Zznz / E / YIAI selected from an oligoamide and an oligo(ester-amide). L1 may be optionally substituted with one or more substituents selected independently of -OH, -OCH3, -COOH, -COOCH3, NH2 and NHC(NH)NH2. X3 is selected from an amide bond and an ester bond, an ether, an amine, and a bonding group of formula: QPfrZ Ln / Zznz / E / YIAI wherein the bond marked with « / wwvwv· in the NH group is attached to RBy and the other bond marked with άλλλλλλλ is attached to SIFA; preferably X3 is an amide bond; RB is a trivalent coupling group. X4 is selected from an amide bond, an ether bond, a thioether bond and an ester bond, a thioester bond, a urea bridge, an amine bond, a bonding group of formula: wherein the amide bond marked with WAWW is formed with the chelating group, and the other bond marked with rtvwvw is attached to RB; and a bonding group of the formula: EITHER QPfrZ ίη / ZZΖΠZ / E / YΙΛΙ where the bond marked with Mww^ney end carbonyl is formed with the chelating group, and the other bond marked with wwww is attached to RB; preferably X4 is an amide bond. RChEs is a chelating group containing a non-radioactive or chelated non-radioactive cation, preferably a radioactive or non-radioactive metal cation, wherein the preferred embodiments of the chelating group and the optional chelated cation are as defined above. The term oligo as 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) should preferably be understood as a group in which 2 to 20, more preferably 2 to 10 subunits are joined by the type of bonds specified in the same terms. As the expert in the technique will understand, where two different types of bonds are indicated in parentheses, both types of bonds are contained in the group in question (for example, in oligo(ester-amide), ester bonds and amide bonds are contained). It is preferred that L1 comprise a total of 1 to 5, more preferably a total of 1 to 3, and most preferably a total of 1 or 2 amide and / or ester linkages, preferably amide linkages, within its skeleton. Therefore, the term oligoamide describes a residue that has a chain of CH2 or CHR groups interspersed with groups selected from NHCO or CONH. Each occurrence of the R residue is an optional substituent selected from -OH, -OCH3, -COOH, COOCH3, NH2, and NHC(NH)NH2. It is also preferred that X1-L1-X2 represent one of the following structures (L1) and (L-2): -NH-C(O)-R6-C(O)-NH-R7-NH-C(O)- (Ll) -C (O) -NH-R8-NH-C (O) -R9-C (O) -NH-R10-NH-C (O) - (L-2) wherein R6a R10 are independently selected from C2 to CIO alkylene, preferably linear C2 to CIO alkylene, whose alkylene groups may each be substituted with one or more independently selected substituents from OH, -OCH3, -COOH, -COOCH3, NH2 and NHC(NH)NH2. It is especially preferred that the total number of carbon atoms in R6 and R7 be from 4 to 20, more preferably from 4 to 16, with no carbon atoms contained in optional substituents. It is especially preferred that the total number of carbon atoms in R8 to R10 be from 6 to 20, more preferably from 6 to 16, with no carbon atoms contained in optional substituents. It is particularly preferred that -X1-L1-X2 represent one of the following structures (L-3) and (L-4): -NH-C (O) -Rn-C (O) -NH-R12-CH (COOH) -NH-C (O) - (L-3) -C (O) -NH-CH (COOH) -R13-NH-C (O) -R14-C (O) -NH-R15-CH (COOH) -NHQQfrZ ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ C(O)- (L-4) wherein R11a R15 are independently selected from C2 to C8 alkylene, preferably linear C2 to C8 alkylene. It is especially preferred that the total number of carbon atoms in R11 and R12 or R13 to R15, respectively, be from 8 to 18, more preferably from 8 to 12, even more preferably from 9 or 10. Preferably, RB has the structure represented by formula (IV): (CH2)b|--(C^--A-* * (IV) wherein: A is selected from N, CR16, wherein R16 is H or C1-C6 alkyl, and a 5- to 7-membered carbocyclic or heterocyclic group; preferably A is selected from N and CH, and more preferably A is CH; the bond marked by mvww at (0¾¾) is formed with X2, y is an integer from 0 to 4, preferably 0 or 1, and most preferably 0; the bond marked by λλμλ / W at (CH2)b is formed with X3, yb is an integer from 0 to 4, preferably from 0 to 2, and most preferably 0 or 1; and the bond marked by λλλλμλλ at (CfVc) is formed with X4, yc is an integer from 0 to 4, preferably from 0 to 2, and most preferably 0 or 1. preferably 0 or 1. Even more preferred as a conjugate according to the invention is a compound of formula (Illa): QPfrZ Ln / Zznz / E / YIAI HOOC HOOC^ (CH2)mO (Illa) or a pharmaceutically acceptable salt thereof, wherein m, n, r1l, p2L, r3l, χA, pi, b,c, χ4 and rchson are as defined above, including all preferred modalities thereof. It is preferred for the compound of formula (Illa) than b+cb 1. It is also preferred for the compound of formula (Illa) than b+c 3. It is more preferred for the compound of formula (Illa) that b be 1 and c be 0. It is also preferred for the compound of formula (III) that -X4-RCH represent a residue of a chelating agent selected from DOTA and DOTAGA linked with one of its carboxylic groups by an amide bond to the rest of the conjugate. In a preferred embodiment of the compound of formula (III), the compound is a compound of formula (Illb): QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ (lllb) or a pharmaceutically acceptable salt thereof, wherein m, n, R1L, R2L, R3L, X1, L1, b, c, X4 and RCH are as defined above; yr is 0 or 1. It is especially preferred that -N(H)-RCH represent a residue of a chelating agent selected from DOTA and DOTAGA linked with one of its carboxylic groups via an amide bond to the rest of the conjugate. For use in PET imaging, the radiohybrid compositions require a positron-emitting atom. The radiohybrid compositions include 18F for medical use. The preferred radiohybrid compositions are those in which F includes 18F and M3+ refers to a radioactive or non-radioactive metal cation. Although the structures shown here have COOH groups, the pH of the solution affects whether the groups are salts or acids. Some of the acidic groups may be charged salts. Therefore, the compounds described herein include the carboxylate salts of the compounds shown. Compositions of the following compounds, or salts thereof, are included herein: PSMA-SIFA1 (5) QPfr7 ίη / 77Π7 / E / YΙΛΙ QQfr7 ίη / 77Π7 / Ε / ΥΙΛΙ and isomers thereof QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ QPfr7 ίη / 77Π7 / E / YΙΛΙ QQfr7 ίη / 77Π7 / E / YΙΛΙ QPfr7 ίη / 77Π7 / E / YΙΛΙ PSMA-SIFA4(8) QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ QPfr7 ίη / 77Π7 / E / YΙΛΙ and isomers of the same QPfrZ in / ZZPZ / E / YILI OH QQfr7 in / 77P7 / E / YILI PSMA-SIFA 10 QPfrZ Ln / Zznz / E / YIAI QPfr7 in / 77P7 / E / YILI QPfrZ in / ZZPZ / E / YILI PSMA-SIFA 11 QPfrZ Ln / Zznz / E / YIAI and isomers of the same: QPfr7 in / 77P7 / E / YILI QPfrZ Ln / Zznz / E / YIAI The preferred marking schemes for the most preferred radio hybrids of the compositions are defined here previously. The term pharmaceutical composition refers to a composition comprising a pharmaceutical product together with a biocompatible carrier in a form suitable for administration to mammals. A biocompatible carrier is a fluid, especially a liquid, in which a pharmaceutical product is suspended or dissolved, such that the composition is physiologically tolerable, i.e., it can be administered to the body of a mammal without toxicity or undue discomfort. The biocompatible carrier is appropriately an injectable liquid carrier such as sterile, pyrogen-free water for injection or an aqueous solution such as saline solution. The pharmaceutical composition may further comprise pharmaceutically acceptable carriers, excipients, and / or diluents. Examples of suitable pharmaceutical carriers, excipients, and / or diluents are well known in the art and include phosphate-buffered saline solutions, water, emulsions such as oil-in-water emulsions, various types of wetting agents, sterile solutions, etc. Compositions comprising such carriers can be formulated using well-known conventional methods. These pharmaceutical compositions can be administered to the subject in an appropriate dose. Administration of suitable compositions can be effected by different routes, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal, or intrabronchial administration.It is particularly preferred that administration be carried out by injection and / or delivery, for example, into a site in the pancreas or a cerebral artery, or directly into brain tissue. The compositions can also be administered directly to the target site, e.g., by biolytic 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 medical practice, the dosage for any patient depends on many factors, including the patient's size, body surface area, age, the specific compound to be administered, sex, timing and route of administration, general health status, and other drugs being administered concurrently. The pharmaceutically active ingredient may be present in quantities between 0.1 mg and 10 mg / kg of body weight per dose; however, doses below or above this exemplary range are foreseen, especially considering the factors mentioned above. In another aspect, the present invention provides one or more compositions of the invention, as described above in this document, for use in diagnostic medicine. The preferred uses in medicine are in nuclear medicine such as nuclear diagnostic imaging, also called nuclear molecular imaging, and / or targeted radiotherapy of diseases associated with overexpression, preferably of PSMA in diseased tissue. In a further aspect, the present invention provides compositions of the invention as defined herein for use in a method for the diagnosis and / or staging of cancer, preferably prostate cancer. Prostate cancer is not the only cancer that expresses PSMA. Non-prostate cancers that demonstrate PSMA expression include breast, lung, colorectal, and renal cell carcinomas. Therefore, any composition containing a radiohybrid described herein having a PSMA-binding residue can be used in the diagnosis, imaging, or treatment of a cancer that expresses PSMA. The preferred indications are cancer screening or staging, including but not limited to high-grade gliomas, lung cancer, and especially prostate cancer and metastatic prostate cancer; detection of metastatic disease in patients with intermediate- to high-risk primary prostate cancer; and detection of metastatic sites, even with low serum PSA levels, in patients with biochemically recurrent prostate cancer. Another preferred indication is imaging and visualization of neoangiogenesis. In terms of medical indications for undergoing therapy, especially radiotherapy, cancer is a preferred indication. Prostate cancer is a particularly preferred indication. In another aspect, the present invention provides a composition comprising a conjugate or compound of the radiohybrids as defined herein above for use in a method of diagnosing and / or staging cancer, preferably prostate cancer. Detailed Description of the Invention Example 1: The gallium chelate of compound rh-PSMA-7.3 was prepared as described above in WO2019 / 020831 and EP19154500.3: rhPSMA-7.3 (D-Dap, (S)-DOTA-GA): QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 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. Deprotection of orthogonal Dde was performed using imidazole and hydroxylamine hydrochloride dissolved in a mixture of NMP and DMF for 3 h. SiFABA (1.5 eq.) with the free side-chain amine was reacted with HOAt (1.5 eq.), TBTU (1.5 eq.), and DIPEA (4.5 eq.) as activation reagents in DMF for 2 h. After deprotection with Fmoc (piperidine 20% in DMF (v / v, 8 ml / g resin) for 5 min and subsequently for 15 min, after which the resin was thoroughly washed with DMF (8 × 5 ml / g resin)), (R)-DOTAGA(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.The resin cleavage with simultaneous deprotection of the acid-labile protecting groups was performed in TFA (the fully protected resin-bound peptide was dissolved in a mixture of TFA / TIPS / water (v / v / v; 95 / 2.5 / 2.5) and stirred for 30 min. The solution was filtered, and the resin was treated in the same manner for another 30 min. Both filtrates were combined, stirred for an additional 5 h, and concentrated under a stream of nitrogen. After dissolving the residue in a mixture of tert-butanol and water and subsequent lyophilization, the crude peptide was obtained). Complexation of the peptide with natGa was carried out. The peptide (1.0 eq.) was dissolved in a 3:1 (v / v) mixture of tBuOH in H2O, and an aqueous solution of Ga(NOa)3 (3.5 eq.) was added. After heating the resulting mixture for 30 min at 75°C, the peptide was purified by RP-HPLC. Marked with 18F Aqueous 18F was passed through a SAX cartridge (Sep-Pak Accell Plus QMA Carbonate light), which was 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. The 18F was eluted with 100 pmol of [K+c2.2.2]OH- dissolved in 500 pL of anhydrous acetonitrile. Before labeling, 30 pmol of oxalic acid were added to anhydrous acetonitrile (1 M, 30 pL). This mixture was used whole or in aliquots for the fluoridation of 10–25 nmol of PSMA-SiFA (1 mM in anhydrous DMSO). The resulting reaction mixture was incubated for 5 minutes at room temperature. For tracer purification, a Sep-Pak C18 light cartridge was used, preconditioned with 10 mL of EtOH, followed by 10 mL of H2O. The labeling mixture was diluted with 9 mL of PBS (pH 3) and passed through the cartridge followed by 10 mL of H2O. The peptide was eluted with 500 µL of a 4:1 (v / v) mixture of EtOH in water.The radiochemical purity of the labeled compound was determined by radio RP-HPLC and radio-TLC (silica gel 60 RP-18 F254s, mobile phase: 3:2 (v / v) mixture of MeCN in H2O supplemented with 10% aqueous 2M NaOAc and 1% TFA). Alternatively, [18F]rhPSMA-7.3 can be prepared in an automated synthesis module by isotopic exchange between the [18F] fluoride ion and [19F] rhPSMA-7.3 as follows: Fluorine-18 in the form of the [18F] fluoride ion is prepared from the nuclear reaction 18O(p,n)18F in a cyclotron by irradiating [18F]-enriched water with protons. The [18F] fluoride is first immobilized on an ion-exchange resin to allow for the recovery of the [18F]-enriched water. The [18F] fluoride is then eluted with a solution of Cryptand 222 and potassium carbonate in acetonitrile and water. The eluate is transferred to the reaction vessel and evaporated by heating under a nitrogen flow. [19F] rhPSMA-7.3 in a solution of DMSO, acetonitrile, and acetic acid is added to the reaction vessel and reacted with the nucleophilic [18F] fluoride for at least 1 min to form [18F]rhPSMA-7.3. The crude [18F]rhPSMA-7.3 solution is diluted with water and purified by hydrophobic solid-phase extraction. Impurities are removed by washing the cartridge with water. [18F]rhPSMA-7.3 is eluted with an ethanol and water solution and formulated by diluting it with an isotonic buffer solution. The formulated solution is sterilized by filtration through a 0.2 µm filter. Dilution, if applicable, is performed using an isotonic sodium chloride injectable solution. The batches of material were prepared in a citrate buffer made of sodium citrate + HCl or in a citrate buffer made of citric acid + NaOH. Radiostability was measured in phosphate and citrate buffer solutions at various pH levels to compare the level of the correct 18F-Si compound and the decomposed free 18F: QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ QPfrZ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ O Ξ o § LL <O oo ΣΤΓ T— θ'- <1 2.9 CXI LO 0.4 0.9 cxi HPLC G-49 T=6h Impureza @ 2.6 min [Área] 0.406 0.314 CO co o 0.119 0.131 0.084 TLC t=6h O Z5 O ___ — o~ co- 8'9 CO 3.75 2.7 2.5 4.3 [18F][natGa]· RhPSMA7.3 [%] 93.2 8'96 96.25 97.3 97.5 95.7 _cz o II. o ______1 1— [%] ojnjon|j[d8J 3.9 σ> 2.3 2.3 cq 2.2 [18F][natGa]RhPSMA7.3 [%] 96.1 98.1 97.7 97.7 98.4 97.8 pH T=0h 8.0 6.5 7.5 5.0 6.0 7.5 Diluent None 0.6 ml of 0.23 M phosphate buffer solution pH 6.0 0.6 ml of phosphate buffer solution pH 7.0 0.6 ml of 0.2 M citrate buffer solution pH 5.0 0.6 ml of 0.2 M citrate buffer solution pH 6.0 0.6 ml of 0.2 M citrate buffer solution pH 7.0 '8FrhPSMA in 50% ethanol 0.5 ml E 0.1 ml 0.1 ml EE o # Sample — CXI CO LO co or ΓM The most stable formulation was at pH 5.0 in citrate buffer. Increasing the pH in the citrate buffer resulted in an increase in the amount of free 18F (which is presumably displaced by OH). At the same pH (6.0), the phosphate buffer solution yielded a less stable product than the citrate buffer. The chemical and radiochemical purity of several formulations containing citrate buffer or citrate-buffered saline solution was evaluated (Table 1). Table 1: Radiochemical and chemical purity of various formulations Input Radioactivity Concentration at EOS (mCi / mL) Formulation pH Radiochemical Purity by HPLC (%) [,8F]fluoride Impurity by TLC (%) Chemical Purity (%) T0 T= 10h T0 T = 10 h T0 T = 10 h 1 27 Citratol buffer solution 00 mM, 5% ethanol 5.0 98.6 98.7 1.6 1.5 98.6 96.9 2 26 Citrate buffer solution 100 mM, 5% ethanol 5.5 99.5 99.5 1.9 2.5 99.1 36.7 3 12 Citratol buffer solution 00 mM, 5% ethanol 6.0 99.5 >99.5 1.2 1.5 N / AM / A 4 51 Citrate buffer solution 100 mM, 5% ethanol 6.5 99.5 >99.5 <1.0 1.4 N / A Xl / A 5 56 Saline solution buffered with 10 mM citrate, 5% ethanol 5.0 98.7 98.9 1.2 1.1 98.3 36.7 6 34 Saline solution buffered with 10 mM citrate, 5% ethanol 6.0 99.3 99.6 1.0 1.9 99.6 98.8 QPfrZ Ln / Zznz / E / YIAI After dilution with sodium chloride injection solution (0.9% w / v), the pH of the formulation is maintained (inlet 5, Table 1: 10 mM citrate buffered saline solution, 5% ethanol): Table 2: Formulation after dilution of Table 1, inlet 5 with sodium chloride solution Input Dilution Factor Citrate Buffer Solution (mM) Sodium Chloride (mg / mL) Ethanol (mg / mL) pH 1 1 10 7.2 50.0 5.0 2 1.8 5.6 8.0 27.8 5.0 3 3 3.3 8.4 16.7 5.0 4 5 2.0 8.6 10.0 5.0 5 7 1.4 8.7 7.1 5.1 6 9.4 1.1 8.8 5.3 5.1 It is noted that the method known by the aforementioned invention, which in relation to the applicant is the one that is, as of this date, the best to put into practice, is clear from the present description of the invention.

Claims

1. A pharmaceutical composition, characterized in that it comprises a radiohybrid agent containing a silicon fluoride and a chelating group wherein the fluorine is 18F or the chelating group contains a chelated radioactive metal, wherein the composition has a pH of 4.0-6.0 and further comprises: a) 0.1-200 mM citrate buffer; and b) 1-100 mg / ml of ethanol; and c) 5-10 mg / mL of sodium chloride.

2. The pharmaceutical composition according to claim 1, characterized in that it comprises 1-15 mM citrate buffer.

3. The pharmaceutical composition according to claim 1, characterized in that it comprises 1-10 mM (± 10%) of citrate buffer.

4. The pharmaceutical composition according to any of claims 1 to 3, characterized in that it comprises 5-50 mg / mL (±10%) of ethanol.

5. The pharmaceutical composition according to claim 4, characterized in that it comprises 5-50 mg / mL of ethanol.

6. The pharmaceutical composition according to any of claims 1 to 5, characterized in that it has a pH of 4.5 to 5.

5.

7. The pharmaceutical composition according to any of claims 1 to 6, characterized in that it comprises 6-9 mg / mL of sodium chloride.

8. The pharmaceutical composition according to any of claims 1 to 7, characterized in that the citrate buffer is prepared from citric acid and sodium hydroxide, or sodium citrate and hydrochloric acid.

9. The pharmaceutical composition according to claim 8, characterized in that 1-3 mg / ml of citric acid and 0.5-1.0 mg / ml of sodium hydroxide are used to prepare the citrate buffer solution.

10. The pharmaceutical composition according to claim 8, characterized in that 1.9 mg / mL of citric acid and 0.75 mg / mL of sodium hydroxide are used to prepare the citrate buffer solution.

11. The pharmaceutical composition according to any of claims 1 to 10, characterized in that the metal is radioactive and the fluoride is 19F.

12. The pharmaceutical composition according to any of claims 1 to 11, characterized in that the chelated metal is selected from the cations of: Se, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Th or Er.

13. The pharmaceutical composition according to any of claims 1 to 10, characterized in that the fluoride is 18F and the metal is not radioactive.

14. The pharmaceutical composition according to claim 12, characterized in that the chelated radioactive metal cation is a positron-emitting isotope.

15. The pharmaceutical composition according to any of claims 1-14, characterized in that it has a radioactive concentration (RAC) at the end of synthesis (EOS) of 5-200 mCi / mL.

16. The pharmaceutical composition according to any of the preceding claims, characterized in that it comprises 1-10 mM (+10%) citrate buffer, 5-50 mg / mL (+10%) ethanol, 6-9 mg / mL sodium chloride and having a pH of 4.5 to 5.

5.

17. The pharmaceutical composition according to any of the preceding claims, characterized in that it comprises 10 mM citrate buffer, 50 mg / mL ethanol, 7.2 mg / mL sodium chloride and a pH of 5.

18. The pharmaceutical composition according to any of claims 1 to 17, characterized in that it is diluted with sodium chloride solution prior to administration.

19. The pharmaceutical composition according to claim 18, characterized in that it comprises citrate buffer solution 1.1 mM (+10%), ethanol 5.3 mg / mL (+10%), sodium chloride 8.8 mg / mL (±10%), and having a pH of 4.5 to 5.

5.

20. The pharmaceutical composition according to any of claims 1 to 19, characterized in that the radiohybrid agent is selected from: QQF7 ίη / ZZΖΠZ / E / YΙΛΙ QPfrZ Ln / Zznz / E / YIAI and salts or isomers thereof wherein M3+ is a chelated radioactive or non-radioactive metal.

21. The pharmaceutical composition according to claim 20, characterized in that the radiohybrid agent is: or an isomer thereof.

22. The pharmaceutical composition according to any of claims 1-21, for use as a cancer diagnostic or imaging agent.

23. A method for imaging and / or diagnosing cancer, characterized in that it comprises administering a composition according to any of claims 1-21 to a patient in need thereof.

24. The pharmaceutical composition according to any of claims 1-21, characterized in that it is for the diagnosis, imaging or prevention of neoangiogenesis / angiogenesis.

25. The pharmaceutical composition according to any of claims 1-21, for use as a cancer diagnostic or imaging agent, wherein the cancer is prostate, breast, lung, colorectal or renal cell carcinoma.

26. A method for producing a composition according to any of claims 1-25, characterized in that it comprises preparing a formulation of a radiohybrid agent containing a silicon fluoride and a chelating group wherein the fluorine is 18F 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.