RU2804349C2 - Paraminohypuric acid (pah) as a kidney protector - Google Patents

Abstract

FIELD: medicines.

SUBSTANCE: group of inventions relates to the to the use of para-aminohyppuric acid (PAH), to a pharmaceutical composition intended for protecting the kidneys during imaging or treatment using radiolabeled compounds, to a method (variants) and a set for reduction of nephrotoxic side effects in the subject. The use of PAH or a pharmaceutically acceptable salt thereof, in a method of reduction of the nephrotoxic side effects of radioactively labeled and therapeutic and diagnostic compounds in a subject as radiopharmaceuticals in the treatment or diagnosis using a radioligand, is characterized by the following: the radiopharmaceutical is a conjugated molecule containing a radioactive isotope, a molecule carrier, a chelating agent, and a radioactive isotope, wherein the radioactive isotope is a trivalent radioactive isotope.

EFFECT: provision of a method of improving the biological distribution of therapeutic and diagnostic compounds containing radioactive isotopes, changing the clearance of nephrotoxic chemotherapeutic substances or radiopharmaceuticals in a subject, such as [¹⁷⁷Lu-DOTA⁰-Tyr3]-octreotide, inhibitors of ¹⁷⁷Lu-PSMA or others, the use of PAHs to suppress reabsorption of the drug by the kidneys, improve the bioavailability of the drug and allow the accumulation of imaging agents, such as those intended for SPECT and PET, in tissues.

27 cl, 14 dwg, 34 tbl, 8 ex

Description

The present invention relates to the use of para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic (eg, imaging) compounds in a subject. The present invention also relates to a pharmaceutical composition for protecting the kidneys during imaging or treatment using radiolabeled and/or non-radiolabeled compounds, wherein the composition contains a radiolabeled and/or non-radiolabeled pharmaceutical compound in combination with para -aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof, or a carboxy derivative and a pharmaceutically acceptable excipient, diluent, carrier or combination thereof. The present invention also provides a method for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject, the method comprising administering para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof in combination with radiolabeled or unlabeled a radioactive isotope therapeutic or diagnostic compound, wherein the administration of PAG is carried out before and/or during and/or after the administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, and the method includes administering to the subject a pharmaceutical composition of the present invention during imaging or treatment performed using a radiolabeled and/or non-radiolabeled compound.

In particular, the present invention relates to the use of PAG or a pharmaceutically acceptable salt or carboxy derivative thereof for inhibiting the renal accumulation and improving the in vivo biological distribution of radiolabeled molecules that may cause renal damage, particularly therapeutic radiopharmaceuticals, and/or for improving contrast in the case of diagnostic radiopharmaceuticals by using para-aminohippuric acid (PAH) or its salt or carboxy derivative (eg sodium aminohippurate).

New medical treatments expose patients to an increasing number of drugs for diagnosis and treatment. Some of these drugs cause side effects due to systemic toxicity, including impaired renal function. The kidneys clear most of these compounds and reabsorb them and partially remain in the proximal tubules, causing dose-dependent nephrotoxicity. Nephrotoxicity causes severe clinical syndromes, including acute kidney injury (AKI). Nephrotoxic agents, as etiological factors, are involved in 17-26% of cases of nosocomial AKI. Drug-induced renal failure is caused by various classes of drugs and includes prescription drugs as well as commonly used over-the-counter drugs.

The toxicity of therapeutic and potential diagnostic agents may be related to the pharmacological compound itself, and the degree of toxicity may be increased in the renal microenvironment. For example, the goal of chemotherapy is to destroy malignant cells through the use of various mechanisms of action aimed at stopping cell division. Since benign cells undergo the normal cell cycle, healthy tissues, including renal parenchyma cells, are also affected. The kidneys, as a filtering organ, are especially susceptible to toxic compounds. Because the kidneys receive a significant proportion of the minute volume of blood, high blood flow through the kidneys causes the kidneys to be exposed to drugs and drug metabolites. Some of these agents have the charge and size necessary for filtration in the glomerulus and subsequent passage into the epithelial cells of the renal tubules by pinocetosis or endocytosis. Other drugs are transported along peritubular capillaries and gain access to the basolateral surface of renal tubular epithelial cells, where they are taken up by organic anion and organic cation transporters (OAT and OCT, respectively) and leak into the tubular lumens, where they can cause clinically significant nephrotoxicity.

Some anticancer therapeutics, such as cisplatin, are known to be nephrotoxic. Cisplatin ((SP-4-2)-diaminideplatinum(II) chloride) is a complex of a platinum atom with NH ₃ and Cl (flat square complex). Its nephrotoxicity is due to its accumulation in kidney cells and its binding to DNA (deoxyribonucleic acid) in cells, thereby inhibiting cellular mechanisms, particularly cell replication. Nephrotoxicity of cisplatin is described in Natochin et al. (Comp. Biochem Biochem. Physiol Vol. 94C, No. 1 pp 115-120, 1989). Choline chloride, PAG, furosemide, and ethacrynic acid have been reported to attenuate the nephrotoxic effects of cisplatin in rats.

Nephrotoxicity is also known to be an undesirable side effect of radioactive isotope based therapeutics/diagnostics.

Diagnostic agents, because they are not administered as frequently to a given subject, are rarely highly nephrotoxic to that subject. However, when using such diagnostic imaging tools (particularly SPECT (single photon emission computed tomography) or PET (positron emission tomography) imaging), effective biological distribution and contrast are required.

In particular, renal clearance, accumulation and retention in the kidneys of radiolabeled peptides, peptidomimetics, antibody fragments, knotans or labeled inhibitors and other compounds occurs, leading, for example, to high dose irradiation of the kidneys and thus an increased risk of radiotoxicity to kidney In addition, rapid renal clearance of, for example, radiopharmaceuticals results in suboptimal biological distribution and low accumulation of the drug in target organs. Radioactive isotope-induced nephrotoxicity is based on a mechanism that is fundamentally different from the mechanism of nephrotoxicity caused by other anticancer drugs, such as cisplatin. Radioactive isotopes, due to their radioactivity, usually cause cellular oxidative stress without entering the cells.

Thus, nephrotoxicity is a well-known side effect of radioligand therapy (RLT), with the kidney, for example, being the dose-limiting organ. Prior art patent publications EP 1196154 B1, EP 0094378, EP 2021012 B1 and US 2016/0143926 A1 describe that co-administration of amino acids such as lysine and arginine or mixtures thereof, and other compounds such as amifostine or gelatin, may reduce the accumulation and retention of [ ¹⁷⁷ Lu-DOTA ⁰ ,Tyr3]-octreotate, [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide and [ ¹¹¹ In-DTPA-D-Phel]-octreotide. Using kidney protection products is extremely important. Lutathera, the first ¹⁷⁷ Lu-labeled drug approved by the FDA, is administered only in combination with an infused amino acid mixture (Receptor-mediated radionuclide therapy with ⁹⁰ Y-DOTATOC in association with amino acid infusion: a phase I study; Lisa Bodei et al. Eur J Nucl Med (2003) 30: 207-216; ⁸⁶ Y-DOTA ⁰ )-D-Phel-Tyr3-octreotide (SMT487) - a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Jamar F et al., Eur J Nucl Med Mol Imaging. 2003 Apr; 30(4): 510-8).

The dose of radiation absorbed by the kidneys can be reduced by co-infusion of agents that competitively inhibit the reabsorption of the radiolabeled compound, such as positively charged amino acids, gelofusin, trypsinized albumin, or FRALB-C (Albumin derived peptides efficiently reduce renal uptake of radiolabeled peptides, Vegt E et al., Eur J Nucl Med Mol Imaging (2010) 37: 226).

Other publications claim that a much greater reduction in renal accumulation can be achieved by using lysine/arginine solutions in combination with compounds such as amifostine and gelatin (EP 1196154 B1, EP 2021012 B1). To more effectively reduce the reabsorption of radiolabeled peptides in the kidney, the use of a combination of two or more competitive endocytosis inhibitors and other approaches have been explored.

Another approach for kidney protection is the administration of radiolabeled PSMA (prostate-specific membrane antigen) inhibitors and co-treatment with binding molecules related to PSMA, such as 2-(phosphonomethyl)pentanedicarboxylic acid (PMPA), which improves the ratio of the amounts of the compound in the kidneys and tumors. This approach is based on the specificity of the kinetics of accumulation of the compound in the kidneys and tumors, respectively (PMPA for nephroprotection in PSMA-targeted radionuclide therapy of prostate cancer, Kratochwil et al., JNM 2015 Feb; 56(2): 293; US 2018/207299).

The mechanism of action of currently developed and clinically used renal protective agents intended for co-treatment, such as amino acid solution or PMPA, is based on accelerated clearance of radiopharmaceuticals from the kidneys. Their similarity with radiopharmaceuticals is used, consisting in the similarity of binding ability. Therefore, when used in clinical practice, these protective agents must be combined with radiopharmaceuticals that have similar renal binding properties. In addition, infusion of amino acids used as a means of protecting the kidneys from radioactive exposure may result in clinically adverse side effects. Vomiting and nausea caused by infusion of large volumes of non-isotonic amino acid solutions are common. A severe life-threatening side effect of such infusions described in the literature is hyperkalemia (Effect of amino acid infusion on potassium serum levels in neuroendocrine tumor patients treated with targeted radiopeptide therapy. Giovacchini G et al., Eur J Nucl Med Mol Imaging. 2011 Sep ; 38(9): 1675-82). Therefore, the amount of amino acids intended to be administered is usually limited to 25 g lysine and 25 g arginine. Rolleman EJ et al. describes the reduction of renal accumulation as follows: "(1) with a commercially available amino acid (AA) solution (21 ± 14%, P < 0.02), (2) with 25 g (17 ± 9%, P <0.04), 50 g (15±13%, P<0.04) or 75 g (44±11%, P<0.001) lysine and (3) using a combination of 25 g lysine and 25 g arginine (LysArg ) (33 ± 23%, P < 0.01). Infusion of solution alone (500, 1000 or 2000 ml of saline/glucose mixture) did not change the accumulation of radioactive substance. In patients who were injected with 75 g of lysine (Lys75) and LysArg, serum potassium concentrations significantly increased" (Safe and effective inhibition of renal uptake of radiolabeled octreotide by a combination of lysine and arginine. Rolleman EJ et al., Eur J Nucl Med Mol Imaging. 2003 Jan; 30(1): 9 -15). In this renal protection approach, hyperkalemia still remains a challenge since high concentrations of lysine and arginine are used as a component of the mixture (Giovacchini G et al., cited above).

Lysine and arginine are reabsorbed in the proximal tubule by sodium-independent amino acid transporters (SCL3A1). The mechanism of clearance of radiopharmaceuticals such as [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide is not fully understood. Published results indicate that the amino acid transporter SCL3A1 may play some role in the clearance of radiopharmaceuticals, but it is certain that this is not the main mechanism, much less the only mechanism involved.

Therefore, the object of the present invention is to develop a novel method for suppressing renal accumulation, intended for use as a means of co-treatment with a wide range of (radio)pharmaceuticals, regardless of the mechanism on which their accumulation in the kidneys is based, and thereby reducing nephrotoxic side effects. effects of (radio)pharmaceuticals used as therapeutic or, less commonly, diagnostic compounds. However, for diagnostic imaging in medicine, it is imperative to improve their in vivo biological distribution and improve contrast by increasing their accumulation in the area targeted for imaging, such as accumulation in any tissue.

These problems are achieved by the main objects disclosed in the present invention, in particular, as defined in the claims.

The basis of the present invention is the discovery that para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof may be suitable for use, for example, to improve the biological distribution of therapeutic and diagnostic compounds, in particular those containing radioactive isotopes. Using the novel method of the present invention, it is possible to change the clearance in a subject of drugs such as chemotherapeutic agents or radiopharmaceuticals such as [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide, ¹⁷⁷ Lu-PSMA inhibitors or others. which can cause kidney damage. In addition, according to the invention, it has been found that the administration of PAG can be used to suppress the reabsorption of a drug by the kidneys. Thus, the concentration of drug in serum can (but does not have to) be increased, this provides improved bioavailability of the drug.

Thus, the present invention is particularly suitable for inhibiting the accumulation in the kidney of a variety of protein-like molecules, such as proteins and peptides or fragments thereof, or antibody fragments, which are nephrotoxic in nature. Moreover, this is true regardless of whether such protein-like molecules are conjugated to a toxin, radioactive isotope, cytostatic agent, or other potentially toxic agents to cells. In particular, according to the invention, it has surprisingly been found that the nephrotoxicity of radiopharmaceuticals, due to their radioactivity, is also reduced when they are co-administered with the PAG proposed in the present invention. This finding was even more surprising because the mechanism underlying the action of radiolabeled therapeutics/diagnostics is unique (radioactivity) and different from other mechanisms of action, such as those observed with anticancer drugs such as cisplatin.

In addition, the present invention allows imaging agents (particularly those intended for SPECT and PET) to accumulate in tissues that need to be identified (for example, target areas of a tumor), and thus reduce their content in non-target tissues . Thus, with the present invention, it is possible to improve image contrast, for example, for a given conjugated molecule containing a radioactive isotope, since its renal clearance is reduced.

Para-aminohippuric acid (PAH)

Aminohippuric acid or para-aminohippuric acid (PAH), a derivative of hippuric acid, is an amide derivative of (a) the amino acid glycine and (b) para-aminobenzoic acid, which is not present in humans. They are covalently linked by an amide bond. The sodium salt of PAG, sodium aminohippurate, is a diagnostic agent that is widely used for diagnostic testing of renal function, particularly for testing renal plasma flow. In the following description, aminohippuric acid, para-aminohippuric acid and aminohippurate (particularly an alkali or alkaline earth metal), particularly sodium, are used interchangeably and are referred to as "PAG".

para-aminohippuric acid (PAH):

sodium aminohippurate:

PAG is usually supplied as a sterile, preservative-free 20% aqueous solution for injection. PAG is filtered by the glomeruli and actively secreted in the proximal tubules. At low plasma concentrations (1.0 to 2.0 mg/100 mL) in the subject's kidneys, approximately 90% of the PAG contained in the renal circulation is cleared in a single circulation cycle. PAG is also used to determine the functional capacity of the renal tubular secretion mechanism or maximum transport (Tm PAG). This is done by increasing the plasma concentration to values (40-60 mg/100 ml) sufficient to saturate the maximum capacity of tubular cells for PAG secretion. PAG practically does not cause any side effects and has negligible toxicity (when administered intravenously to female mice, the LD ₅₀ (semi-lethal dose) is 7.22 g/kg). Events such as vomiting and nausea or hyperkalemia have not been described or, if they have been described, they have been reported in rare cases.

In contrast to established co-treatments of the prior art (eg, the use of mixtures of amino acids), para-aminohippuric acid (aminohippurate) provides the ability to non-specifically modulate the clearance of (radio)pharmaceuticals because it is a substrate and/or functional inhibitor of a variety of transporters. PAG is actively secreted by carriers into the urine. PAG is now known to be a substrate or inhibitor of 14 different transporters, including transmembrane organic cation transporters (e.g., OCT1, OCT1A, OCT2, OCT3, OCTN1, OCTN2, OCTN3) and transmembrane organic anion transporters (e.g., OAT1, OAT2, OAT3 , OAT4, OAT5, OATP, URAT1). PAG substrates also include hMRPs (histone methylation read proteins), ATP-dependent (ATP = adenosine triphosphate) flux transporters.

Therefore, para-aminohippuric acid or a pharmaceutically acceptable salt or carboxy derivative thereof can be used as a co-treatment agent with a wide range of radiolabeled or non-radiolabeled therapeutic and diagnostic compounds, regardless of the nature of the carrier molecule (i.e., peptide, antibody fragment , peptidomimetic, small molecule, etc.). It has been established that modulation of renal clearance by PAG leads to an increase in the duration of circulation of the administered drug in the blood and to an increase in its bioavailability. Aminohippuric acid or a salt thereof can be administered before and/or during and/or after administration of (radio)pharmaceuticals cleared by the kidneys, for example by infusion or injection.

General provisions

Although the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methodologies, protocols and reagents described in the present invention, as they may vary. It should also be understood that the terminology used in the present invention is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art.

Elements of the present invention are described below. These elements are provided for specific embodiments, but it should be understood that they can be combined in any manner and in any quantity to form additional embodiments. The various examples and preferred embodiments described should not be construed as limiting the present invention to only those embodiments expressly described. This description is to be understood as supporting and covering embodiments that combine the expressly described embodiments with any number of disclosed and/or preferred elements. In addition, any permutations and combinations of all elements described herein are to be considered as disclosed in the specification of this application unless the context otherwise requires.

In the description and claims below, unless the context otherwise requires, the term “comprise” and its variants such as “comprises” and “comprising” are to be understood as including, but not excluding, the specified element, integer or step. any other unspecified element, integer or stage. The term "consist of" is a specific embodiment of the term "comprise" whereby any other unspecified element, integer, or step is excluded. In the context of the present invention, the term "comprise" covers the term "consist of". Thus, the term “comprising” covers “including” as well as “consisting of,” for example, a composition “comprising” X may consist of only X, or may include something additional, such as X+Y.

Terms in the singular in the context of the description of the present invention (especially in the context of the claims) include terms in the singular and in the plural, unless otherwise indicated in the present invention or clearly inconsistent with the context. The indications of ranges of values in the present invention are merely intended to briefly indicate individually each individual value within the range. Unless otherwise specified in the present invention, each individual value is included in the description as if it were individually stated in the present invention. Nothing in the specification should be construed as indicating any unstated element essential to the practice of the present invention.

The term "about" for a numerical value of x means x±10%.

The term "subject" as used herein generally includes humans and non-human animals, and preferably includes mammals (e.g., non-human primates, including marmosets, tamarins, spider monkeys, night monkeys, green monkeys, squirrel monkeys and baboons, macaques , chimpanzees, orangutans, gorillas; cows; horses; sheep; pigs; chickens; cats; dogs; mice; rats; rabbits; guinea pigs, etc.), including chimeric and transgenic animals, and animals for used disease models. In the context of the present invention, the term "subject" preferably means a non-human primate or human, most preferably a human.

A first object of the present invention is the use of para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof for reducing the unwanted nephrotoxic effects of radiolabeled or non-radiolabeled therapeutic and diagnostic compounds in a subject being treated with such compounds.

As noted above, PAG or its salt is a substrate and/or inhibitor of various transporters in the kidneys. Therefore, it can be used in conjunction with a wide range of radiolabeled or non-radiolabeled therapeutic and diagnostic compounds that are thought to enter renal tubular cells, for example through uptake by organic anion transporters (OATs) and organic cation transporters (OCTs), thereby exhibiting their potential nephrotoxicity. It can also be used to protect kidney cells from radioactive effects of radiolabeled therapeutic or diagnostic agents, for example, if they cause oxidative stress due to radioactivity. Protection against nephrotoxicity may also specifically include protection against glomerulotoxicity.

Examples of therapeutic nephrotoxic compounds include, without limitation, non-steroidal anti-inflammatory drugs, which are widely used to relieve pain and signs of inflammation; which, however, can cause a variety of kidney-related complications, such as prerenal azotemia, acute tubular necrosis, acute papillary necrosis, acute interstitial nephritis, chronic tubulointerstitial nephritis (analgesic nephropathy), minimal change disease, membranous nephropathy, hyperkalemia and metabolic acidosis (hyporeninemia and aldosteronopenia, hyponatremia, hypertension); angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, which are used to treat hypertension and congestive heart failure, and to slow the progression of diabetic nephropathy, and which may lead to a high risk of acute kidney injury (AKI) and hyperkalemia; antimicrobial agents such as neomycin, gentamicin, tobramycin, amikacin and streptomycin, which are commonly used to treat infections caused by gram-negative bacteria, and the intracellular accumulation of which leads either to the death of tubular cells or to functional changes in transporters across the cell membrane, leading to electrolyte disturbances balance (hypokalemia, hypomagnesemia and hypocalcemia); sulfur-containing antibiotics such as sulfamethoxazole-trimethoprim, which can cause hyperkalemia due to inhibition of the epithelial sodium channel located in the distal convoluted tubule, leading to sodium excretion, and sulfadiazine, which can cause acute interstitial nephritis and crystalline nephropathy; glycopeptide antibiotics such as vancomycin, which can cause nephrotoxicity due to acute tubular necrosis; fluoroquinolone antibiotics such as cyprofloxacin, which can cause acute interstitial nephritis and crystalluria; other antibiotics such as penicillins and cephalosporins, which cause acute interstitial nephritis and acute tubular necrosis; and polymyxins such as colistin and polymyxin B, which cause acute interstitial nephritis due to toxic tubular damage; antivirals such as acyclovir, which can cause acute kidney injury due to crystal deposition in the renal tubules, foscarnet, which can cause acute tubular necrosis, acute kidney injury, electrolyte disturbances such as hypocalcemia, hypomagnesemia, hypokalemia, and hypo- or hyperphosphatemia ; antiretroviral agents such as tenofovir, which is toxic to kidney cells and causes acute kidney injury with or without proximal tubulopathy, which causes chronic kidney disease, and protease inhibitors such as indinavir, abacavir, ritonavir and atazanavir, which may crystallize in the renal tubules and cause crystal-related kidney damage and nephrolithiasis; fungicidal agents such as amphotericin B, which can cause acute tubular necrosis and tubular dysfunction, which manifests as renal tubular acidosis, urine concentration problems and electrolyte imbalances; immunosuppressive agents such as calcineurin inhibitors (eg, tacrolimus, cyclosporine), which are particularly used for immunosuppressive treatment after solid organ transplantation and which can cause acute kidney injury; lithium, which is the mainstay of treatment for patients suffering from bipolar disorder and which can cause various types of nephrotoxicity such as nephrogenic diabetes insipidus (NIDI), chronic kidney disease and chronic tubulointerstitial nephritis. Other therapeutic agents associated with acute kidney injury include proton pump inhibitors; acetaminophen; HMG-CoA reductase inhibitors and osmotic agents.

Therapeutic nephrotoxic compounds also include chemotherapeutic agents, which play a major role in the treatment of various neoplasias and can cause many different kidney-related complications, such as renal syndromes associated with acute kidney injury or chronic kidney disease, and renal syndromes associated with electrolyte disturbances. Examples of such chemotherapeutic agents include cisplatin (acute tubular necrosis, proximal tubulopathies, hypernatremia, hypomagnesemia, hypocalcemia, distal renal tubular acidosis, thrombotic microangiopathy), pemetrexed (acute tubular necrosis), streptozocin (also called streptozotocin) (acute tubular necrosis, proximal tubulopathies), mitromycin (acute tubular necrosis), zoledronate (acute tubular necrosis), interferon (acute interstitial nephritis), allopurinol (acute interstitial nephritis), hemcitabin (thrombotic microangiopathies), mitomycin C (thrombotic microangiopathy), anti -angiogenic drugs (thrombotic microangophy), methothestrexate ( crystalline nephropathy) ifosfamide (proximal tubulopathies, hypernatremia), cyclophosphamide (hyponatremia), vincristine (hyponatremia), cetuximab (hypomagnesemia), methotrexate (acute kidney injury).

For example, cisplatin and ifosfamide, which are standard components used in treatment regimens for various solid organ tumors, including those affecting children, are known to enter proximal tubule cells via organic cation transporters (OCT2) ( Shirali A, Perazella M, Advances in Chronic Kidney Disease, Vol 21, No 1 (January), 2014: pp 56-63). Therefore, it is believed that coadministration of PAG can effectively reduce the nephrotoxic side effects of these chemotherapeutic agents.

Other nephrotoxic compounds include radiocontrast agents, such as iodinated radiocontrast agents, which are required for some diagnostic and invasive radiology procedures, and the use of which can lead to contrast agent-induced nephropathy (CINE) and acute kidney injury. Examples of iodinated ionic contrast agents are diatrizoate (Hypaque 50), metrizoate (Isopaque 370), iothalamate (Copgau), ioxaglate (Hexabrix); Non-ionic contrast agents include iopamidol (Isovue 370), iohexol (Omnipaque 350), yoxilan (Oxilan 350), iopromide (Ultravist 370), iodixanol (Visipaque 320), ioversol.

In a preferred embodiment of the present invention, PAG is used to reduce the nephrotoxic side effects of radiopharmaceuticals that are used as diagnostic and therapeutic agents.

Radiopharmaceuticals may contain non-metallic (organic) radioactive isotopes ( ¹⁸ F, ¹¹ C, ¹³ N, ¹⁵ O, ¹²⁴ I, etc.) or radiometals (for example, ⁹⁰ Y, ^99m Tc, ¹¹¹ In, ¹³¹ l, ⁶⁷ Ga , ⁶⁸ Ga, ⁶⁴ Cu, ¹⁶¹ Tb, ²²⁵ Ac, ⁴⁴ Sc, ⁴⁷ Sc, ⁶⁷ Cu, ⁸⁹ Zr, ¹⁷⁷ Lu, etc.). Although some radioactive metals, in the form of a metal salt or metal complex, can target a specific tissue, most often it is necessary to conjugate the radioactive isotope/metal to a targeted biomolecule to ensure delivery of the radioactive isotope to the target site, such as tumor tissue, in the necessary way. Biomolecules can be, for example, small organic molecules, peptides, monoclonal antibodies (mAbs) or fragments of mAbs. They act as a means of transport ("carrier") designed to transfer the radioactive isotope to the target tissue.

Commercially available small complex radiopharmaceuticals include, for example, ^99m Tc-sestamibi (Cardiolite®), which is used for myocardial perfusion imaging; ^99m Tc-tetrofosmin (Myoview®), which is used for imaging myocardial perfusion; ^99m Tc-pentetate (DTPA) (Technescan®), which is used for renal imaging and functional studies; ^99m Tc-bicisate (ECD) (Neurolite®), which is used for brain perfusion imaging; ^99m Tc-MDP (Medronate®), which is used for skeletal scintigraphy; ^99m Tc-teboroxime (Cardiotec®), which is used for imaging myocardial perfusion; ¹¹¹ In-hydroxyquinoline (indium-111-oxin®), which is used for scintigraphy with leukocytes; ¹¹¹ In-pentetate (indium-111-DTPA®), which is used to visualize CSF (cerebrospinal fluid) kinetics; ¹⁵³ Sm-EDTMP (Quadramet®), which is used to treat bone pain (therapy); ¹⁸⁸ Re-HEDP, which is used to treat metastatic bone pain.

The most attractive approach to achieve conjugation of a radioactive isotope to a targeted biomolecule (carrier) is the use of a suitable bifunctional chelating agent or chelating agent that binds or coordinates tightly to the radioisotope and at the same time contains functional moieties designed to conjugate it to the biomolecule.

Examples of commercially available peptide conjugates or immunoconjugates include, for example, ^99m Tc-depreotide (NeoTect®), which is used to study certain lung lesions; ^99m Tc-arcitumomab (CEA-Scan® ^99m Tc-mAb), which is used for imaging colorectal cancer; ¹¹¹ In-capromabpendetide (ProstaScint®), which is used for imaging prostate cancer; ¹¹¹ In-pentetreotide (Octreoscan®), which is used for neuroendocrine tumor imaging; ¹¹¹ In-imciromabpentetate (MyoScint®), which is used to visualize chest pain thought to be caused by myocardial infarction; ¹¹¹ In-satumomabpendetide (OncoScint®), which is used for imaging of metastatic disease associated with colorectal and ovarian cancer; ⁹⁰ Y-ibritumomabtiuxetan (Zevalin®), which is used to treat non-Hodgkin's lymphoma (NHL); ⁶⁸ Ga-edotreotide or ⁶⁸ Ga-DOTATE, intended for imaging of neuroendocrine tumors; ¹⁷⁷ Lu-B DOTATETE (Lutatera), intended for the treatment of neuroendocrine tumors.

Thus, in a particularly preferred embodiment of the present invention, PAG is used to reduce the nephrotoxic side effects of radiopharmaceuticals, such as those mentioned above, in treatment and/or diagnosis with radiochemicals/radioligands.

In radioligand therapy (also known as PRT - peptide receptor radionuclide therapy), radiopharmaceuticals are labeled with a radioligand that specifically binds to a target contained in a (tumor) cell, such as a tumor cell surface protein or marker. Once the compound binds to the target site of the tumor, such as a receptor, the radioactive isotope emits high-energy beta radiation to target cells in the target site.

In radioligand diagnostics, a radiolabeled compound binds to a target contained in a (tumor) cell, such as a receptor. The decay of a radioactive isotope can be studied using positron emission tomography (PET) or single photon emission computed tomography (SPECT).

Therefore, in a preferred embodiment of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used to reduce the nephrotoxic side effects of a pharmaceutical agent that is labeled with a radioactive isotope ("radiopharmaceutical"). Preferably, the radiopharmaceutical is a conjugated molecule that contains (i) a carrier molecule that binds to a target structure contained in a (tumor) cell (for example, a receptor or antigen), (ii) a chelating agent (or chelating agent) and (iii) a radioactive isotope. The chelating agent typically coordinates with a radioactive isotope, thereby forming a radiolabeled complex that is conjugated to the carrier molecule.

Radioactive isotope

The term “radioactive isotope” (or “radioisotope”) means isotopes of natural or artificial origin having an unstable ratio of neutrons to protons that decay by emitting corpuscular radiation (i.e. proton (alpha) or electron (beta) radiation)) or electromagnetic radiation (gamma radiation)). In other words, radioactive isotopes undergo radioactive decay. In a radiolabeled complex contained in a radiopharmaceutical, any known radioactive isotope may be included in the complex with the chelating agent. Such radioactive isotopes may include, without limitation, ¹⁸ F, ¹³¹ I, ⁹⁴ Tc, ^99m Tc, ⁹⁰ In, ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁹⁰ Y, ¹⁷⁷ Lu, ¹⁶¹ Tb, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁵ Co, ⁵⁷ Co, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac, ²¹³ Bi, ²¹² Bi, ²¹² Pb, ²²⁷ Tn, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁵² Gd, ¹⁵³ Gd, ¹⁵⁷ Gd or ¹⁶⁶ Dy, preferably ⁶⁸ Ga, ¹⁷⁷ Lu or ^99m Tc.

The selection of suitable radioactive isotopes depends, in particular, on the chemical structure and chelating ability of the chelating agent and, most significantly, depends on the purpose of the resulting (bound) conjugated molecule (for example, depending on its use for diagnosis or treatment and, for example, on the person being treated diseases). For example, beta radiation sources such as ⁹⁰ Y, ¹³¹ I, ¹⁶¹ Tb and ¹⁷⁷ Lu can be used to accompany systemic treatment with radioactive isotopes. The use of DOTA, DOTAGA or DOTAM as a chelating agent can successfully provide the possibility of using any of the following as radioactive isotopes: ⁶⁸ Ga, ^43,44,47 Sc, ¹⁷⁷ Lu, ¹⁶¹ Tb, ²²⁵ Ac, ²¹³ Bi, ²¹² Bi, ²¹² Pb.

In some preferred embodiments, the radioactive isotope may be ¹⁷⁷ Lu. In some preferred embodiments, the radioactive isotope may be ¹¹¹ In. In some preferred embodiments, the radioactive isotope may be ⁹⁰ Y. In some preferred embodiments, the radioactive isotope may be ⁶⁸ Ga.

Chelating agent

As noted above, a carrier molecule, eg a compound that targets a (cancer) cell, is preferably associated with a chelating agent or chelating agent that coordinates with a radioactive isotope.

The terms "chelating agent" or "chelating agent" are used interchangeably in the present invention. They mean polydentate (multi-bonded) ligands capable of forming two or more separate coordination bonds (“coordinated”) with a central (metal) ion. More precisely, such molecules or molecules that share one pair of electrons can also be called “Lewis bases.” The central (metal) ion is usually coordinated to the chelating agent through two or more electron pairs. The terms "bidentate chelating agent", "tridentate chelating agent" and "tetradentate chelating agent" are known in the art and mean chelating agents containing two, three or four electron pairs available for simultaneous donation to a metal ion coordinated with the chelating agent. The electron pairs of the chelating agent usually form coordination bonds with one central (metal) ion; however, in some cases, the chelating agent can form coordination bonds with more than one metal ion, and different types of binding are possible.

The terms “coordinating” and “coordinating” mean an interaction in which one donor containing multiple electron pairs is coordinated (“coordinated”) preferably with one central (metal) ion, i.e. two or more lone electron pairs become shared.

The chelating agent or chelating agent is preferably a macrocyclic bifunctional chelating agent containing a metal chelating group at one end and a reactive functional group at the other end that is capable of binding to other molecules, such as peptides. Preferably, the chelating agent is selected such that when complexed with a radioactive isotope, the chelating agent forms a square bipyramidal complex. In another embodiment, the chelating agent does not form a planar or planar square complex.

The chelating agent is preferably selected based on its ability to coordinate with the desired central (metal) ion, typically a radioactive isotope as defined above in the present invention.

Accordingly, the chelating agent may be described by one of the following formulas (4a)-(4jj):

Preferably, the chelating agent may be DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, which may be represented by formula (4a)), HBED-CC (N,N''-bis [2-Hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N''-diacetic acid, which can be described by formula (4e)), DOTAGA (2-[1,4,7,10-tetraazacyclododecane-4,7 ,10-tris(acetate)]pentanedicarboxylic acid), DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane) or their derivatives.

Advantageously, DOTA effectively complexes with radioactive isotopes used for diagnosis (e.g. ⁶⁸ Ga) and therapy (e.g. ⁹⁰ Y or ¹⁷⁷ Lu), and thus allows the same conjugate to be used for imaging (diagnostics). ), and for treatment, i.e. as a theragnostic agent. Derivatives of DOTA capable of forming complexes with radioactive isotopes of scandium ( ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc), including DO3AP (which can be described by formula (4hh)), DO3AP ^PrA (which can be described by formula (4ii)) or DO3AP ^ABn (which can be described by formula (4ii)) described by formula (4jj)), may also be preferred and are described in Kerdjoudj et al. (Dalton Trans, 2016, 45, 1398-1409).

It is advantageous that HBED-CC effectively forms complexes with radioactive isotopes used for diagnostics (eg, ⁶⁸ Ga, ^99m Tc).

In the context of the present invention, other preferred chelating agents include (2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedicarboxylic acid (NODAGA), 1,4,7-triazacyclononane-1, 4,7-triacetic acid (NOTA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedicarboxylic acid (DOTAGA), 1,4,7- triazacyclononanphosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis-[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3.6 ,9,15-tetra-azabicyclo[9,3,1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PTA), N'-{5-[acetyl(hydroxy )amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA) and hydrazinonicotinamide (HYNIC).

The chelating agent, eg DOTA, can preferably form a complex with a central (metal) ion, preferably a radioactive isotope as defined in the present invention. Alternatively, the chelating agent, for example, DOTA, may not form a complex with the central (metal) ion, preferably a radioactive isotope as defined in the present invention, and thus may be in an uncomplexed form. If the specified chelating agent (eg, DOTA) does not form a complex with the specified metal ion, then the carboxy groups contained in the specified chelating agent may be free or form a salt.

One skilled in the art, based on his or her skill and knowledge, can select suitable combinations of chelating agent and radioactive isotopes. Thus, for example, in some preferred embodiments, the chelating agent may be DOTA and the radioactive isotope may be ¹⁷⁷ Lu. In other preferred embodiments, the chelating agent may be DOTA and the radioactive isotope may be ⁶⁸ Ga. In other preferred embodiments, the chelating agent may be HYNIC and the radioactive isotope may be ^99m Tc.

Carrier molecule

A carrier molecule can be any molecule that binds to a target contained in a (tumor) cell, such as a receptor or other molecule located on the cell surface. In a preferred embodiment of the present invention, the carrier molecule is selected from the group consisting of peptide, peptidomimetic, antibody fragment, antibody mimetic, small molecules and knotans.

The cell-contained target may be any target that is present in the target cells, or preferably on the surface of the target cells, to which the radioactive isotope-containing conjugated molecule for radiotherapy or diagnostic purposes is intended to bind.

For example, the action of a carrier molecule may be directed at a receptor or at a cell surface molecule contained in a diseased cell, such as a tumor cell. Examples of receptors and cell surface molecules contained in tumor cells that may be a target structure for a carrier molecule are described in detail below. However, target structures are not limited to receptors and cell surface molecules described below. Other receptors and cell surface molecules found in cancerous or other diseased cells are considered as target structures for carrier molecules. In addition, other carrier molecules that target receptors and cell surface molecules found in cancerous or other diseased cells are being considered.

Compounds that target the somatostatin receptor

In accordance with the present invention, PAG or a salt or carboxy derivative thereof can be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting the somatostatin receptor (SSTR).

For the treatment of well to moderately differentiated neuroendocrine tumors (NETs), for example, peptides targeting the somatostatin receptor (SSTR) can be used. Treatment of NETs with radioligands is generally accepted and can provide high rates of long-term remission and tumor stabilization. Peptides that specifically target the somatostatin receptor are, for example, the somatostatin analogs Tyr3-octreotide (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) and Tyr3-octreotate (D -Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr) (Capello A et al.: Tyr3-octreotide and Tyr3-octreotate radiolabeled with ¹⁷⁷ Lu or ⁹⁰ Y: peptide receptor radionuclide therapy results in vitro, Cancer Biother Radiopharm, 2003 Oct;18(5):761-8). Other examples of somatostatin agonists are the peptides, octreotide (D-Phe-cyclo(Cys-Phe-D-Trp-Lys-Thr-Cys)Thr(ol)) and NOC (D-Phe-cyclo(Cys-1-Nal-D -Trp-Lys-Thr-Cys)Thr(ol)).

Other examples of compounds that target the somatostatin receptor are somatostatin antagonist peptides such as JR10 (p-NO ₂ -Phe-c(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)D- Tyr-NH ₂ ); JR11 (Cpa-c(D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH ₂ ); BASS (p-NO ₂ -Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH ₂ ; LM3 (p-Cl-Phe-cyclo(D-Cys-Tyr- D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH ₂ .

In a particularly preferred embodiment of the present invention, PAG is used to reduce the nephrotoxic side effects of (radio)pharmaceuticals based on somatostatin analogues; examples include: ¹⁷⁷ Lu-DOTATOC ( ¹⁷⁷ Lu-DOTA ⁰ -[Tyr3]-octreotide) ( ¹⁷⁷ Lu-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys]-Thr( ol), ¹⁷⁷ Lu-DOTANOC ( ¹⁷⁷ Lu-DOTA-D-Phe-cyclo(Cys-1-Nal-D-Trp-Lys-Thr-Cys)Thr(ol)), ¹⁷⁷ Lu-DOTATATE ( ¹⁷⁷ Lu-DOTA -D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr), ⁶⁸ Ga-DOTATOC ( ⁶⁸ Ga-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys- Thr-Cys)Thr(on)), ⁶⁸ Ga-DOTANOC ( ⁶⁸ Ga-DOTA-D-Phe-cyclo(Cys-1-Nal-D-Trp-Lys-Thr-Cys)Thr(ol)), ⁹⁰ Y -DOTATOC ( ⁹⁰ Y-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol)), ⁹⁰ Y-DOTATATE ( ⁹⁰ Y-DOTA-D-Phe-cyclo( Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr), ¹¹¹ In-DTPA-octreotide ( ¹¹¹ In-DTPA-D-Phe-cyclo(Cys-Phe-D-Trp-Lys-Thr-Cys)Thr (ol)).

In another preferred embodiment, PAG or a salt or carboxy derivative thereof is used to reduce the nephrotoxic side effects of (radio)pharmaceuticals based on somatostatin antagonist compounds; their examples include: ¹¹¹ In-DOTA-BASS ( ¹¹¹ In-DOTA-p-NO ₂ -Phe-cyclo-(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH ₂ , ¹¹¹ In-DOTA-JR11 ( ¹¹¹ In-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ), ⁶⁸ Ga-DOTA- JR11 (Ga-OpS201) ( ⁶⁸ Ga-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ), ⁶⁸ Ga-DODAGA -JR11 (Ga-OPS202) ( ⁶⁸ Ga-NODAGA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ), ¹⁷⁷ Lu- DOTA-JR11 (Lu-OPS201) ( ¹⁷⁷ Lu-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ).

Compounds that target PSMA

PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of prostate-specific membrane antigen (PSMA)-targeting (radio)pharmaceuticals.

Human prostate-specific membrane antigen (PSMA) (also called glutamate carboxypeptidase II (GCPII), folate hydrolase 1, folipoly-gamma-glutamate carboxypeptidase (FGCP), and N-acetylated alpha-linked acid dipeptidase I (NAALADase I)) is a type II transmembrane zinc-containing metallopeptidase. which is highly expressed in the nervous system, prostate, kidney and small intestine. It is also commonly considered a tumor marker in prostate cancer.

In the prior art, various agents containing therapeutic or diagnostic fragments have been developed that specifically target PSMA.

More recently, various small molecule PSMA targeting agents capable of binding to the extracellular domain of PSMA have been developed for PET/CT (computed tomography) and SPECT/CT imaging, including radiolabeled N-[N -[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[ ^11C ]methyl-L-cysteine (DCFBC) and several urea-based peptidomimetic PSMA inhibitors (see Bouchelouche et al. Discov Med. 2010 Jan; 9(44): 55-61), including MIP-1095 (Hillier et al. Cancer Res. 2009 Sep 1; 69(17):6932-40), a PSMA ligand currently used in clinical trials, and DOTA-conjugated PSMA inhibitor, PSMA-617, developed by Benesova et al. (JNM 2015, 56: 914-920 and EP 2862857 A1).

Urea-based PSMA ligands typically include three components: a binding motif (Glu-urea-Lys), a bridge, and a radiolabeled moiety (a chelating molecule for radiolabeling or a prosthetic group for fluorinated agents). Examples of the most commonly used low molecular weight PSMA ligands are ¹²³ I-MIP-1072 and ¹²³ I-MIP-1095 (Barrett JA et al. J Nucl Med. 2013;54:380-387); ^99m Tc-MIP-1404 and ^99m Tc-1405 (Hillier SM et al. J Nucl Med. 2013;54:1369-1376), designed for SPECT imaging, used in clinical studies. N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl] ^-4-18 E-fluorobenzyl-L-cysteine ( ¹⁸ F-DCFBC) (Cho SY et al., J Nucl. Med. 2012; 53 : 1883-1891) and ⁶⁸ Ga-PSMA-11 ( ⁶⁸ Ga-PSMA-N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) (Eder M et al, Pharmaceuticals (Basel) 2014;7:779-796) are PET imaging agents. Other theragnostics include, for example, ¹³¹ I-MIP-1095 (Zechmann et al., Eur J Nucl Med Mol Imaging. 2014;41:1280-1292), PSMA-617 chelating agent (Afshar-Oromieh A et al., J Nucl Med. 2015;56:1697-1705) and PSMA-I&T (I&T = imaging and treatment) (Weineisen M et al., J Nucl Med. 2015;56:1169-1176), PSMA-I&S (Robu S et al., J Nucl Med. 2017;58:235-242). Other ¹⁸ F-labeled small molecule urea derivatives described include ¹⁸ F-DCFPyL (Chen Y et al., Clin Cancer Res. 2011; 17:7645-7653) and ¹⁸ F-PSMA-1007 (Giesel FL et al. , Eur J Nucl Med Molecular Imaging 2017;44:678-688).

Recently, Kelly et al. (J Nucl Med. 2017 pii: jnumed. 116.188722. doi: 10.2967/jnumed. 116.188722. [published online ahead of official publication]) investigated agents with affinity for both PSMA and human serum albumin (HSA). The ligands developed by Kelly et al. contain a p-(iodophenyl)butyric acid moiety that binds HSA and a urea moiety that binds PSMA. The radiotherapy-targeted iodine ( ^131I ) contained in the compounds developed by Kelly et al. is covalently linked to the HSA binding moiety, which in turn is directly linked to the PSMA binding moiety via a hydrocarbyl chain. Another example is a ¹⁷⁷ Lu-labeled phosphoamidate-based PSMA inhibitor containing an albumin-binding moiety (Choy et al. Theranostics 2017; 7(7): 1928-1939). The DOTA-based chelating agent, which forms a complex with the radioactive isotope ¹⁷⁷ Lu, is linked by an ether bond to the irreversible PSMA inhibitor, CTT1298 (EP 2970345 A1).

Thus, in a preferred embodiment of the present invention, PAG or a salt or carboxy derivative thereof is used to reduce the nephrotoxic side effects of (radio)pharmaceuticals containing a PSMA-targeting ligand bound to a chelating agent molecule as defined above complexed with a radioactive an isotope as defined above, for example selected from the group consisting of ⁶⁸ Ga, ¹⁷⁷ Lu, ²²⁵ Ac, ¹¹¹ In, ^99m Ic.

In a particularly preferred embodiment, PAG is used to reduce the nephrotoxic side effects of ⁶⁸ Ga-PSMA-11.

Folate conjugates

FR-α (folate receptor alpha) is of greatest interest as a tumor-related target for imaging and targeted therapies. A number of research groups have demonstrated targeting of FR-containing tumor cells in vitro and in vivo using folic acid conjugates and various therapeutic probes. In summary, the folate receptor (FR) has been shown to be a valuable target for radionuclide imaging using radioisotope-containing folic acid conjugates.

However, the use of folate-based radiopharmaceuticals for treatment has long been considered unfeasible because they accumulate in significant quantities in the kidneys. With respect to other radioactive isotope-containing conjugates described in the present invention, by using the method of the present invention, the present invention enables the off-target accumulation of radiopharmaceuticals to be reduced in vivo, thereby improving the kidney to tumor ratio.

Preferred examples of folate conjugate radiopharmaceuticals use ^99m Tc (Guo et al., J Nucl Med. 1999; 40: 1563-1569; Mathias et al., Bioconjug Chem. 2000; 11:253-257; Leamon et al., Bioconjug Chem 2002;13:1200-1210;Reddyet al J Nucl Med 2004;45:857-866;Müller et al J Nucl Med Mol Imaging 2006;33:1007-1016;Müller et al. , Bioconjug Chem. 2006;17:797-806), ¹¹¹ In (Siegel et al., J Nucl Med. 2003;44:700-707), ^66/67/68 Ga (Mathias et al., Nucl Med Biol. 1999;26:23-25; Mathias et al., Nucl Med Biol. 2003;30:725-731) and ¹⁸ F (Bettio et al., J Nucl Med. 2006;47:1153-1160).

Typical folate conjugates are, for example, ¹¹¹ In-DTPA-folate, ¹⁷⁷ Lu-EC0800, ¹⁷⁷ Lu-cm09, ^149/161 Tb-cm09, ^99m Tc(CO) ₃ , ^99m Tc-EC20, ¹¹¹ In-DTPA-folate, ¹¹¹ In/ ¹⁷⁷ Lu-DOTA-folate obtained using click chemistry, ⁶⁷ Ga-DOTA-Bz-folate ( ⁶⁷ Ga-EC0800), ⁶⁸ Ga-NODAGA-folate and compounds targeting the CCK2 receptor.

PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting the CCK2 receptor.

The CCK2 (cholecystokinin) receptor is located in regions of the central and peripheral nervous system and is overexpressed in several types of human cancers, such as medullary thyroid carcinomas, small cell lung cancers, and ovarian stromal carcinomas. Specific studies have been conducted to develop suitable radioligands that specifically target the CCK2 receptor in vivo. A number of radiolabeled CCK/gastrin-related peptide systems have been synthesized and characterized. All peptides contain a common C-terminal CCK receptor binding tetrapeptide sequence Trp-Met-Asp-Phe-NH ₂ or derivatives thereof. Peptides can be categorized based on the sequence of their primary peptides (gastrin or CCK) and based on their shape (ie, linear, cyclic, multimeric).

Examples of CCK receptor ligands are gastrin analogs such as sargastrin (Gln-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH ₂ ), minigastrin 0 (MG-0) D-Glu-(Glu) ₅ -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH ₂ ), minigastrin 11 (MG-11) (D-Glu-Ala-Tyr- Gly-Trp-Met-Asp-Phe-NH ₂ ), cyclo-minigastrin 1 (cyclo-MG1) (cyclo[γ-D-Glu-Ala-Tyr-D-Lys]-Trp-Met-Asp-Phe-NH ₂ ), cyclo-minigastrin 2 (cyclo-MC2) (cyclo[γ-D-Glu-Ala-Tyr-D-Lys]-Trp-Nle-Asp-Phe-NH ₂ , demogastrin 1 (D-Glu-(Glu ) ₅ -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH ₂ ), demogastrin 2 (D-Glu-(Glu) ₅ -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH ₂ , H ₂ -Met (His-His-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH ₂ ), H ₂ -Nle (His-His-Glu-Ala-Tyr-Gly-Trp-Nle- Asp-Phe-NH ₂ ), H ₆ -Met (His) ₆ -Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH ₂ ); and CCK8 analogues such as CCK8 (D-Asp-Tyr -Met-Gly-Trp-Met-Asp-Phe-NH ₂ ), CCK8(Nle) (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH ₂ ), sCCK8 (D-Asp- Tyr(OSO ₃ H)-Met-Gly-Trp-Met-Asp-Phe-NH ₂ ), sCCK8[Phe ² (p-CH ₂ SO ₃ H), Nle ^3.6 ] (D-Asp-Phe(p -CH ₂ SO ₃ H)-Nle-Gly-Trp-Nle-Asp-Phe-NH ₂ ), sCCK8[Phe ² (p-CH ₂ SO ₃ H), HPG ^3.6 ] (D-Asp-Phe( p-CH ₂ SO ₃ H)-HPG-Gly-Trp-HPG-Asp-Phe-NH ₂ ).

Preferably, the peptides targeting the CCK receptor are labeled with radioactive isotopes for imaging or therapeutic purposes. Suitable radioactive isotopes include those described above and preferably include the following radioisotopes: ^99m Tc, ¹¹¹ In, ¹⁸ F, ⁶⁸ Ga, ¹³¹ I, ⁹⁰ Y and ¹⁷⁷ Lu. To ensure the introduction of the radioactive isotope, it is preferable to use a chelating agent conjugated to the peptide. As the chelating agent, the chelating agents described above can be used, with DOTA, DOTAGA, DOTAM, DTPA and HYNIC being preferred.

Therefore, in a preferred embodiment of the present invention, PAG is used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting the CCK2 receptor, including, but not limited to, ¹⁷⁷ Lu-DOTA-sargastrin, ¹¹¹ In-DTPA-MG0, ¹¹¹ In- DOTA-MG11, ¹¹¹ In-DOTA-MG11(Nle), ¹¹¹ In-DOTA-H ₂ -Met, ¹¹¹ In-DOTA-H2-Nle, ¹¹¹ In-DOTA-H ₆ -Met, [ ^99m Tc] ₂ N ₄ ⁰ , D-Glu ¹ -MG ( ^99m Tc-demogastrin 1), [ ^99m Tc] ₂ N ₄ ^0-1 , Gly ⁰ , D-Glu ¹ -MG ( ^99m Tc-demogastrin 2), ^99m Tc-HYNIC-MG11 , ^99m Tc-HYNIC-cyclo-MS1, ^99m Tc-HYNIC-cyclo-MG2; and CCK8 analogs such as ¹¹¹ In-DTPA-CCK8, ¹¹¹ In-DTPA-CCK8(Nle), ^99m Tc-HYNIC-CCK8, ^99m Tc-HYNIC-sCCK8, ¹¹¹ In-DOTA-sCCK8[Phe ² (p-CH ₂ SO ₃ H), Nle ^3.6 ] and ¹¹¹ In-DOTA-sCCK8[Phe ² (p-CH ₂ SO ₃ H), HPG ^3.6 ].

Integrin binding molecules

PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals that target integrins.

Integrins are heterodimeric glycoproteins consisting of α- and β-subunits. There are 24 known combinations of 8 β-subunits and 18 α-subunits. Integrins mediate cell-cell and cell-matrix interactions and transduce signals across the plasma membrane through inside-out and outside-in signal transduction. Some of the integrins play an important role during the movement of endothelium as well as tumor cells during tumor-induced angiogenesis and the formation of tumor metastases. Angiogenesis, the formation of new blood vessels outside the primary vasculature, is a critical stage in the development and spread of various human tumors. Many therapeutic approaches used in oncology are aimed at suppressing tumor-induced angiogenesis. With regard to integrins, considerable attention has been paid to the role of α _v β ₃ and α _v β ₅ integrins, since they are the most important in the proliferation of vascular endothelial cells. Thus, one of the most important target structures used for the development of radiopharmaceuticals intended for imaging angiogenesis is the α _v β ₃ integrin.

Tumor-induced angiogenesis can be blocked in vivo by antagonizing the effects of α _v β ₃ integrin using small peptides containing the amino acid sequence Arg-Gly-Asp (RGD). This tripeptide sequence, found in extracellular matrix proteins, is the primary α _v β ₃ integrin binding site. Due to the selective expression of α _v β ₃ integrin in tumors, radiolabeled RGD peptides are attractive candidates for targeting α _v β ₃ integrin in tumors. Over the past decade, a variety of radiolabeled linear and cyclic RGD peptides have been investigated for use as radiotracers for tumor imaging with SPECT or PET, and as therapeutic agents.

Therefore, PAG or a salt or carboxy derivative thereof may be particularly suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals containing radiolabeled RGD peptides.

Preferably, RGD peptides are radiolabeled for imaging or therapeutic purposes. Suitable radioactive isotopes include those described above and preferably include the following radioisotopes: ¹⁸ F, ^99m Tc, ⁶⁸ Ga, ¹¹¹ In, ¹³¹ I, ⁹⁰ Y, ⁶⁷ Cu and ¹⁷⁷ Lu. To ensure the introduction of the radioactive isotope, it is preferable to use a chelating agent conjugated to the peptide. The chelating agent may be any suitable chelating agent, such as those described above, with NOTA, DOTA, DOTAGA, DOTAM, DTPA, HYNIC being preferred.

Thus, for example, PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of ¹⁸ F-galacto-RGD, ^99m Tc-NC100692 ( ^99m Tc-maracyclatide), ¹⁸ F-AH11185 ( ¹⁸ F-flucyclatide), ¹⁸ F-RGD-K5, ⁶⁸ Ga-NOTA-RGD, ¹⁸ F-FPPRGD2, ¹⁸ F-AlF-NOTA-PRGD2 ( ¹⁸ F-alfatide), ¹⁸ F-NOTA-E[PEG4-c(RGDfk)] ₂ ( ¹⁸ F-alphatide II), ⁶⁸ Ga-NOTA-PRGD2, ⁶⁷ Cu-cyclam-RAFT-c(-RGDfK-) ₄ , ¹¹¹ In-DOTA-E-[c(RGDfK)] ₂ , ^99m Tc-HYNIC-E -[c(RGDfK)] ₂

Compounds that target the neurotensin receptor

Neurotensin receptor 1 (NTR1) is overexpressed in pancreatic ductal adenocarcinoma, which is one of the deadliest cancers. Several NTR1 antagonists have been developed, such as SR142948A and SR48692, and ¹⁷⁷ Lu-3BP-2273, which is a ¹⁷⁷ Lu labeled DOTA-conjugated NTR1 antagonist that was developed from SR142948A. It has been used to treat pancreatic ductal adenocarcinoma (Baum RP et al., The Journal of Nuclear Medicine, Vol.59, No. 5, May 2018).

Therefore, PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of neurotensin 1 receptor-targeting (radio)pharmaceuticals, in particular radiolabeled NTR1 antagonists intended for the diagnosis or treatment of cancers, preferably labeled using ¹⁷⁷ Lu or ⁶⁸ Ga NTR1 antagonists, more preferably ¹⁷⁷ Lu-3BP-2273, although other radioactive isotopes, such as the radioactive isotopes described above, as well as other chelating agents, such as the chelating agents described above, may be considered.

Compounds that target the glucagon-like peptide-1 (GLP-1) receptor

The GLP-1 receptor is overexpressed in almost all benign insulinomas, as well as in gastrinomas. Benign insulinomas, which arise from β-cells of the pancreas and are contained in small nodules, produce insulin, which leads to potentially life-threatening hypoglycemia.

Therefore, PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting the GLP-1 receptor. Non-limiting examples thereof include ¹¹¹ In, ^99m Tc and ⁶⁸ Ga labeled peptides based on the 39-mer exendin-4 peptide, such as Lys ⁴⁰ (Ahx-DOTA- ¹¹¹ In)NH ₂ -exendin-4. However, other radioactive isotopes may be contemplated, such as the radioactive isotopes described above, as well as other chelating agents, such as the chelating agents described above.

Compounds that target the gastrin-releasing peptide (GRP) receptor

PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting the GRP receptor.

GRP receptors have been found in important human tumors such as breast and prostate cancer. Bombesin is a tetradecapeptide neurohormone and an amphibian homolog of mammalian GRP (27-mer peptide). Various analogues of bombesin have been developed for administration of the ^99m Tc label and examination using SPECT. Specifically, trimmed bombesin was linked to a N ₃ S-containing chelating agent via a Gly-5-aminovaleric acid bridge ( ^99m Tc-RP527). In addition, several bombesin analogues and bombesin antagonists have been developed and incorporated with various radioactive isotopes (eg, ⁶⁸ Ga, ⁶⁴ Cu, ¹⁸ F) using various chelating agents. Examples include the pan-bombesin analog, ⁶⁸ Ga-BZH3 (Zhang H et al., Cancer Res 2004; 64: 6707-6715), and ^{the 177} Lu-labeled bombesin derivative (7-14) linked to DOTA by Gly -4-aminobenzoyl bridge (Bodei L et al., Eur J Nucl Med Mol Imaging 2007: 34(suppl 2): S221.

However, PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of GRP receptor-targeting (radio)pharmaceuticals containing other radioactive isotopes, e.g. the radioisotopes described above, as well as other chelating agents, e.g. , chelating agents described above.

Compounds that target neurokinin type 1 receptor

Neurokinin receptor type 1 is constitutively overexpressed in glioma cells and tumor vessels (Hennig IM et al., Int J Cancer 1995; 61: 786-792). A radiolabeled 11 amino acid peptide, substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), acting through the neurokinin receptor type 1 can be suitably used to target malignant gliomas . Specifically, substance P was conjugated to the chelating agent DOTAGA and ^{a 90} Y labeled DOTAGA-substance P conjugate was used in clinical studies (Kneifel S et al., Eur J Nucl Med Mol Imaging. 2007; 34: 1388-1395). Another study determined the feasibility and effectiveness of α-emitting radioactive isotope treatment of a brain tumor using the α-emitting conjugate 213Bi-DOTA-[THi8,Met(O ₂ )11]-substance P (Cordier et al., Eur J Nucl Med Mol Imaging 2010;37:1335-1344).

Therefore, PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of therapeutic and diagnostic compounds targeting the neurokinin type 1 receptor, in particular substance P conjugates containing a radioactive isotope intended for diagnosis or treatment and a chelating agent. agent that coordinates a radioactive isotope.

Affiliates

PAG or a salt or carboxy derivative thereof can also be suitably used to reduce the nephrotoxic side effects of antibody mimetics used as therapeutic and diagnostic compounds.

Affilins are artificial proteins designed to selectively bind antigens. Affin proteins are structural derivatives of human ubiquitin or gamma-B crystallin, respectively. Affilin proteins are produced by modifying the surface-exposed amino acids contained in these proteins and are isolated using reproduction techniques such as phage display and screening. They are similar to antibodies in their affinity and specificity for antigens, but not in structure; they makes them a type of antibody mimetics. Affilins were developed by Scil Proteins GmbH as potential biopharmaceuticals, diagnostics and affinity ligands. Affilin molecules can be easily modified and are suitable for introducing as a label into tumor cells for diagnosis or for killing tumor cells, especially by irradiation.

It is possible to obtain polyvalent affilin molecules that simultaneously bind different targets. Radioactive isotopes or cytotoxins can be conjugated to affilin proteins, making them potential therapeutics and diagnostic tools. Radioisotope-chelating agent-affin conjugates, such as ¹⁷⁷ Lu-DOTA-affin and ⁶⁸ Ga-DOTA-affin, have been developed for imaging and treatment. PAG can be used to effectively reduce the nephrotoxic side effects of these affilin-containing conjugates. It can also be used to reduce the nephrotoxic side effects of other affilin-containing conjugates containing other radioactive isotopes (eg, those described above) and chelating agents (eg, those described above), respectively.

Thus, in a preferred embodiment, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used to reduce the nephrotoxic side effects (radiolabeled) of therapeutic and diagnostic compounds intended for the treatment or imaging of cancers, such as, for example, neuroendocrine tumors, prostate cancer gland cancer, pancreatic cancer, kidney cancer, bladder cancer, medullary thyroid carcinomas, small cell lung cancer, ovarian stromal carcinomas, pancreatic ductal adenocarcinoma, insulinomas, gastrinomas, breast cancer, etc.

For example, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used to reduce the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds used for the treatment or imaging of prostate cancer, such as (radio)pharmaceuticals targeting the somatostatin receptor, or radiolabeled therapeutic and diagnostic compounds that target prostate-specific membrane antigen (PSMA). In a preferred embodiment, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used to reduce the nephrotoxic side effects of ¹⁷⁷ Lu-DOTATOC ( ¹⁷⁷ Lu-DOTA ⁰ -[Tyr3]-octreotide).

In one embodiment of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used in combination with another substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds. Examples of other substances that reduce the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds are amino acids such as lysine and arginine and mixtures thereof, gelatin, amifostine, albumin-derived peptides, trypsinized albumin, PSMA-binding molecules such such as FMPK, vitamins, gelofusin or FRALB-C (cyanbromobromide-fragmented bovine serum albumin).

In a particularly preferred embodiment of the present invention, the pharmaceutically acceptable salt of PAG is sodium aminohippurate. Preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered as a solution in saline, preferably water for injection (WFI) or NaCl solution, more preferably 20% NaCl solution.

In the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is used in an amount that is sufficient to effectively reduce the nephrotoxic side effects of the therapeutic and/or diagnostic compound(s). The effective amount of PAG can be determined by standard experiments, for example, using animal models. Such animal models include, without limitation, rabbit, sheep, mouse, rat, dog and non-human primate models.

Thus, for example, the amount of PAG administered may range from about 0.1 mg/kg to 10 g/kg, preferably from about 0.5 mg/kg to 5 g/kg, more preferably from about 1 mg/kg up to 1 g/kg (calculated per 1 kg of body weight).

In a preferred embodiment of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is used in an amount of from about 5 to about 500 mg/(kg body weight), for example, in an amount of about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg/(kg body weight) and up to 500 mg/(kg body weight ). More preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is used in an amount of from about 50 to about 500 mg/(kg body weight), more preferably from about 50 to about 250 mg/(kg) body weight), for example, in an amount of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, PO, 120, 130, 140, 150, 160, 170, 180, 190 , 200, 210, 220, 230, 240 or 250 mg/(kg body weight). More preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used in an amount of from about 75 to about 200 mg/(kg body weight), for example, in an amount of about 75, 80, 85, 90, 95, 100 , 105, PO, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 and up to 200 mg/(kg body weight), or 200 mg/(kg body weight). Most preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is used in an amount of from about 80 to about 160 mg/(kg body weight), for example, in an amount of about 80, 85, 90, 95, 100, 105 , 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 and up to 160 mg/(kg body weight), or equal to 160 mg/(kg body weight).

PAG or a pharmaceutically acceptable salt or carboxy derivative thereof is typically used in an amount (molar and/or weight) greater than the amount of therapeutic or diagnostic compound (co-administered).

Thus, for example, the therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are used in an amount ratio of from about 1/1,000,000 to 1/10 (w/w), preferably from about 1 /500,000 to 1/100 (w/w), more preferably from about 1/250,000 to about 1/500 (w/w).

In a preferred embodiment of the present invention, the therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are used at an amount ratio of from about 1/250,000 to about 1/5,000 (w/w), e.g. , in an amount ratio of from about 1/250,000, 1/200,000, 1/150,000, 1/100,000, or 1/50,000 to about 1/5000 (w/w), more preferably in an amount ratio of about 1 /240,000 to about 1/8,000 (w/w), for example, at ratios of about 1/240,000, 1/230,000, 1/220,000, 1/210,000, 1/200,000, 1/190,000, 1/180,000 , 1/170000, 1/160000, 1/150000, 1/140000, 1/130000, 1/120000, 1/110000, 1/100000, 1/90000, 1/80000, 1/70000, 1/60000, 1 /50000, 1/40000, 1/30000, 1/20000, 1/19000, 1/18000, 1/17000, 1/16000, 1/15000, 1/14000, 1/13000, 1/12000, 1/11000 , 1/10000, 1/9000 or 1/8000 (w/w). In another preferred embodiment, the therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are used at an amount ratio of from about 1/100,000 to about 1/10,000 (wt/wt). .), for example, with an amount ratio of about 1/100000, 1/95000, 1/90000, 1/85000, 1/80000, 1/75000, 1/70000, 1/65000, 1/60000 1/55000, 1/50000, 1/45000, 1/40000, 1/35000, 1/30000, 1/25000, 1/20000, 1/15000, 1/10000 (w/w). In another preferred embodiment, the therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are used at an amount ratio of from about 1/50,000 to about 1/40,000 (wt/wt). .), for example, at ratios of about 1/50000, 1/49000, 1/48000, 1/47000, 1/46000, 1/45000, 1/44000, 1/43000, 1/42000, 1/41000 , 1/40000 (w/w).

The second object of the present invention is a pharmaceutical composition containing (a) radiolabeled and/or non-radiolabeled pharmaceutical compound(s) in combination with para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof and a pharmaceutically acceptable excipient, diluent, carrier or combination thereof.

The radiolabeled or non-radiolabeled pharmaceutical compound may be any nephrotoxic therapeutic or diagnostic compound described above having the potential to cause nephrotoxic side effects, preferably it is a radiolabeled diagnostic and/or therapeutic compound. Preferably, the pharmaceutical composition contains a radiolabeled pharmaceutical compound, which is a radioisotope-containing complex conjugated to a carrier molecule, thereby containing a carrier molecule, a chelating agent and a radioisotope.

Preferably, the carrier molecule for the radioactive isotope-containing complex is selected from among the carrier molecules described above, more preferably from the group consisting of small organic molecules, peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules and knotanes, and more preferably, if selected from the group consisting of somatostatin analogs, PSMA inhibitors, gastrin analogs, integrin binding molecules and antigen binding proteins described above, for example, from the group consisting of Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, sargastrin, RGD , affilin or folate conjugates. In a particularly preferred embodiment, the carrier molecule is selected from the group consisting of Tyr3-octreotide and Tyr3-octreotate.

Preferably, the chelating agent for the radioactive isotope-containing complex is selected from among the chelating agents described above, more preferably, it is selected from the group consisting of DOTA, DOTAM, DOTAG, HBED-CC, NOTA, NODAGA, DOTAGA, TRAP, NOPO, PCT , DFO, DTPA, DO3AP, DO3AP ^PrA , DO3AP ^ABn , HYNIC or their derivatives.

Preferably, the radioactive isotope for the radioisotope-containing complex is selected from among the radioactive isotopes described above, and more preferably, it is selected from the group consisting of ⁹⁴ Tc, ^99m Tc, ⁹⁰ In, ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y , ⁹⁰ Y, ¹⁸ F, ¹³¹ I, ¹⁷⁷ Lu, ¹⁶¹ Tb, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁵ Co, ⁵⁷ Co, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac, ²¹³ Bi, ²¹² Bi, ²¹² Pb, ²²⁷ Th, ¹⁵³ Sm, ¹⁶⁶ Ho, ²²⁵ Ac and ¹⁶⁶ Dy. Even more preferably, the radioactive isotope for the radioactive isotope-containing complex contained in the pharmaceutical composition is selected from the group consisting of ¹⁷⁷ Lu, ⁶⁸ Ga, ¹¹¹ In, ⁹⁰ Y, ^99m Ic, ¹⁸ F, ¹³¹ I, ²²⁵ Ac and ¹⁶¹ Tb, or, most preferably, if it is selected from the group consisting of ¹⁷⁷ Lu, ⁶⁸ Ga, ¹¹¹ In, ⁹⁰ Y, ^99m Tc, ²²⁵ Ac and ¹⁶¹ Tb. In one embodiment, the radioactive isotope is specifically selected from divalent radioactive isotopes, preferably selected from the group consisting of ⁶⁴ Cu, ⁶⁷ Cu and ²¹² Pb, trivalent radioisotopes, preferably selected from the group consisting of ¹⁷⁷ Lu, ⁹⁰ Y, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ²²⁵ Ac, ¹⁶¹ Tb, ⁴⁴ Sc and ⁴⁷ Sc, or among the tetravalent radioactive isotopes, ²²⁷ Th is preferred. In another embodiment, the radioactive isotope is ^99m Ic, which can be di-, tetra-, or pentavalent. More preferably, the radioactive isotope may be selected from among trivalent radioactive isotopes.

In addition, it is preferable if the radioactive isotope is adapted to form a complex with DOTATOC (DOTA). In particular, ⁹⁰ In, ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁹⁰ Y, ¹⁷⁷ Lu, ¹⁶¹ Tb, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁵ Co, ⁵⁷ Co, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac , ²¹³ Bi, ²¹² Bi, ²¹² Pb, ¹⁵³ Sm, ¹⁶⁶ Ho, ²²⁵ Ac and ¹⁶⁶ Dy can be combined with DOTATOC used as a chelating agent.

As noted above, one skilled in the art can appropriately select suitable combinations of carrier molecules, chelating agent and radioactive isotopes. Thus, for example, the complex containing a radioactive isotope can be selected from the group including [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide, ¹⁷⁷ Lu-DOTA-JA11, ¹⁷⁷ Lu-RGD, ¹⁷⁷ Lu-DOTA-affin 2, ¹⁷⁷ Lu- DOTA-sargastrin, ⁶⁸ Ga-HBED-CC-PSMA-11. Preferably, the radioactive isotope-containing complex is selected from the group consisting of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide and [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotate.

Preferably, the pharmaceutical composition contains a radiolabeled or non-radiolabeled therapeutic or diagnostic compound in a safe and effective amount.

As used herein, the term “safe and effective amount” means an amount of agent(s) that is sufficient to enable diagnosis and/or result in a significant beneficial change in the course of the disease being treated. However, at the same time, a "safe and effective amount" is small enough to avoid severe side effects, in other words providing a reasonable benefit/risk ratio. In addition, the "safe and effective amount" will vary depending on the particular condition being diagnosed or treated, as well as the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the type of concomitant treatment used, the particular pharmaceutically acceptable excipient or carrier and similar factors.

In a particularly preferred embodiment of the present invention, the pharmaceutical composition contains sodium aminohippurate as a pharmaceutically acceptable salt of PAG.

PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is typically contained in the pharmaceutical composition in an amount greater than the amount of (co-administered) therapeutic or diagnostic compound contained in the pharmaceutical composition.

Thus, for example, the therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are contained in the pharmaceutical composition in an amount ratio of about 1/1,000,000 to 1/10 (w/w), preferably from about 1/500,000 to 1/100 (w/w), more preferably from about 1/250,000 to about 1/500 (w/w).

In a preferred embodiment of the present invention, the therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are contained in the pharmaceutical composition in an amount ratio of from about 1/250,000 to about 1/5,000 (wt/wt). ), for example, at an amount ratio of from about 1/250,000, 1/200,000, 1/150,000, 1/100,000 or 1/50,000 to about 1/5000 (w/w), more preferably at an amount ratio of from about 1/240,000 to about 1/8,000 (w/w), for example, at ratios of about 1/240,000, 1/230,000, 1/220,000, 1/210,000, 1/200,000, 1/190,000, 1/180000, 1/170000, 1/160000, 1/150000, 1/140000, 1/130000, 1/120000, 1/110000, 1/100000, 1/90000, 1/80000, 1/70000, 1/ 60000, 1/50000, 1/40000, 1/30000, 1/20000, 1/19000, 1/18000, 1/17000, 1/16000, 1/15000, 1/14000, 1/13000, 1/12000, 1/11000, 1/10000, 1/9000 or 1/8000 (w/w). More preferably, the therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are contained in the pharmaceutical composition in an amount ratio of from about 1/100,000 to about 1/10,000 (wt. /wt.), for example, at an amount ratio of about 1/100000, 1/95000, 1/90000, 1/85000, 1/80000, 1/75000, 1/70000, 1/65000, 1/60000 1/ 55000, 1/50000, 1/45000, 1/40000, 1/35000, 1/30000, 1/25000, 1/20000, 1/15000, 1/10000 (w/w). In another preferred embodiment, the therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are contained in the pharmaceutical composition in an amount ratio of from about 1/50,000 to about 1/40,000 (wt. ./wt.), for example, at an amount ratio of about 1/50000, 1/49000, 1/48000, 1/47000, 1/46000, 1/45000, 1/44000, 1/43000, 1/42000, 1/41000, 1/40000 (w/w).

In one embodiment of the present invention, the pharmaceutical composition, in addition to the PAG, contains another substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds, wherein the substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds compounds other than PAG are preferably selected from the group consisting of amino acids, for example, lysine and arginine, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules such as PMPA, vitamins.

A pharmaceutical composition containing PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, (a) radiolabeled and/or non-radiolabeled pharmaceutical compound(s) and optionally containing another substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutics and diagnostic compounds, further contains a pharmaceutically acceptable excipient, diluent, carrier, or a combination thereof. Preferably, the pharmaceutical composition is a liquid or semi-liquid composition, which is more preferably a liquid or semi-liquid composition, which is more preferably an aqueous solution, which may be buffered and/or has isotonic characteristics.

The term "pharmaceutically acceptable" means a compound or agent that is compatible with the components of the pharmaceutical composition proposed in the present invention, in particular with the diagnostic or therapeutic pharmaceutical compound(s), and does not interfere with and/or significantly reduce its diagnostic or therapeutic activity . Pharmaceutically acceptable carriers preferably have sufficiently high purity and sufficiently low toxicity that they can be administered to the subject being treated.

Preparations, carriers and excipients

Pharmaceutically acceptable excipients can serve a variety of functions and include, without limitation, diluents, fillers, bulking agents, carriers, disintegrants, binders, lubricants, glidants, coatings, solvents and cosolvents, buffering agents, preservatives, excipients, antioxidants, wetting agents, antifoaming agents, thickening agents, sweeteners, flavoring agents and humectants.

Suitable pharmaceutically acceptable excipients are generally selected based on the composition of the pharmaceutical composition.

Pharmaceutically acceptable excipients useful for pharmaceutical compositions in liquid form generally include solvents, diluents or carriers such as (pyrogen-free) water, (isotonic) saline solutions such as phosphate or citrate buffered saline, fixed oils, vegetable oils such as, for example, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, ethanol, polyols (for example, glycerin, propylene glycol, polyethylene glycol, etc.); lecithin; surfactants; preservatives such as benzyl alcohol, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.; isotonic agents such as sugars, polyhydric alcohols such as mannitol, sorbitol, or sodium chloride; aluminum monostearate or gelatin; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates; and agents to adjust tonicity such as sodium chloride or dextrose. The pH value can be adjusted using acids or bases such as hydrochloric acid or sodium hydroxide. Compared to a specific reference medium, buffers can be hypertonic, isotonic or hypotonic, i.e. Compared to a particular reference medium, the buffer may have a higher, the same, or lower salt content, and it is preferable to use concentrations of the above salts that do not cause cell damage due to osmosis or other concentration effects. Reference media are, for example, fluids used in in vivo procedures, such as blood, lymph, cytosolic fluid, or other body fluids, or, for example, fluids that can be used as reference media in in vivo procedures, such as ordinary buffers or liquids. Such conventional buffers or liquids are known to one skilled in the art.

Liquid pharmaceutical compositions administered by injection and preferably by intravascular, more preferably intravenous (IV) injection should preferably be sterile and stable under the conditions of preparation and storage. Such compositions are typically formulated as parenterally acceptable aqueous solutions that are pyrogen-free, have a suitable pH, are isotonic, and maintain stability of the active ingredient(s).

For liquid pharmaceutical compositions, suitable pharmaceutically acceptable excipients and carriers include water, typically pyrogen-free water; isotonic solution or buffered (aqueous) solutions, for example, solutions buffered with phosphate, citrate, etc. In particular, for injection of the (pharmaceutical) compositions proposed in the present invention, water or preferably a buffer can be used, more preferably an aqueous buffer, which may contain a sodium salt, for example, at least 50 mm sodium salt, a calcium salt, for example, at least 0 .01 mM calcium salt, and optionally a potassium salt, for example, at least 3 mM potassium salt.

The sodium, calcium and optionally potassium salts may be in the form of halides, for example chlorides, iodides or bromides, in the form of hydroxides, carbonates, bicarbonates or sulfates and the like. Examples of sodium salts include, but are not limited to, NaCl, Nal, NaBr, Na ₂ CO ₃ , NaHCO ₃ , Na ₂ SO ₄ , examples of optional potassium salts include, for example, KCl, KI, KBr, K ₂ CO ₃ , KHCO ₃ , K ₂ SO ₄ , and examples of calcium salts include, for example, CaCl ₂ , CaI ₂ , CaBr ₂ , CaCO ₃ , CaSO ₄ , Ca(OH) ₂ . In addition, the buffer may contain organic anions of the above cations.

Buffers suitable for injection as defined above may contain salts selected from the group consisting of sodium chloride (NaCl), calcium chloride (CaCl ₂ ) and optionally potassium chloride (KCl), where other anions may be contained in addition to chloride anions. CaCl ₂ can also be replaced with another salt such as KCl. Salts contained in the injection buffer are typically contained at a concentration of at least 50 mM in the case of sodium chloride (NaCl), at least 3 mM in the case of potassium chloride (KCl), and at least 0.01 mM in the case of calcium chloride (CaCl ₂ ). Compared to a specific reference medium, the injection buffer may be hypertonic, isotonic, or hypotonic, i.e. Compared to a particular reference medium, the buffer may have a higher, the same, or lower salt content, and it is preferable to use concentrations of the above salts that do not cause cell damage due to osmosis or other concentration effects.

For pharmaceutical compositions in (semi-)liquid form, suitable pharmaceutically acceptable excipients and carriers include binders such as microcrystalline cellulose, gum tragacanth or gelatin; starch or lactose; sugars such as, for example, lactose, glucose and sucrose; starches such as, for example, corn starch or potato starch; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; disintegrants such as alginic acid; lubricants such as magnesium stearate; glidifiers such as stearic acid, magnesium stearate; calcium sulfate, colloidal silicon dioxide, etc.; sweeteners such as sucrose or saccharin; and/or flavoring agents such as peppermint, methyl salicylate or orange flavor.

Pharmaceutical compositions intended for topical administration are usually prepared in the form of creams, ointments, gels, pastes or powders. Pharmaceutical compositions for oral administration may be formulated as tablets, capsules, liquids, powders, or sustained release forms. However, in preferred embodiments, the pharmaceutical composition of the present invention is administered parenterally, preferably by intravenous or intratumoral injection, and is suitably formulated in a liquid or lyophilized form for parenteral administration, as described elsewhere in the present invention. Parenteral formulations are typically stored in vials, IV bags, ampoules, cartridges, or prefilled syringes and can be administered as injections, inhalations, or aerosols, with injections being preferred.

The pharmaceutical composition may be in lyophilized form. Lyophilized pharmaceutical compositions are preferably reconstituted in a suitable buffer, preferably based on an aqueous carrier, prior to administration.

The pharmaceutical compositions of the present invention are also intended for use in the preparation of a medicament intended to reduce the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds.

Pharmaceutical compositions or medicaments are preferably intended for reducing the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds intended for the imaging and treatment of diseases, preferably neoplastic diseases, such as neuroendocrine tumors, prostate cancer, pancreatic cancer, kidney cancer, bladder cancer , brain cancer, gastrointestinal cancer, medullary thyroid carcinomas, small and non-small cell lung cancers, and ovarian stromal carcinomas, pancreatic ductal adenocarcinoma, insulinomas, gastrinomas, breast cancer or sarcoma.

Sets

Another aspect of the present invention is a kit comprising pharmaceutical components useful in accordance with the present invention, for example, para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof, radiolabeled or non-radiolabeled therapeutic or diagnostic compound described above , and/or the pharmaceutical composition proposed in the present invention. Thus, for example, in one embodiment, a kit may include para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof in one component of the kit, and may include a pharmaceutical composition of the present invention described above in another component of the kit, or a solution, for example, for dissolving PAG or a pharmaceutically acceptable salt or carboxy derivative thereof in another component of the kit. The solution may be an isotonic or hypertonic solution, and may be a buffered solution, for example, optionally a buffered aqueous solution, such as an aqueous NaCl solution or water for injection (WFI). In another embodiment of the present invention, the kit may include para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof in one component of the kit, and a radiolabeled and/or non-radiolabeled therapeutic or diagnostic compound described above in another component. set.

The kit may optionally include at least one other agent as defined herein in relation to the pharmaceutical composition, including, for example, amino acids such as lysine and arginine and mixtures thereof, gelatin, amifostine, albumin-derived peptides, PSMA binding molecules such as PMPC, vitamins, radioactive isotopes, antimicrobial agents, solubilizing agents, etc.

The kit may be a collection of two or more components, including any of the above exemplified components, contained in suitable containers. Thus, for example, all containers may be vials, bottles, soft bottles, jars, sealed bags or bags, tubes or blister packs, or they may be in any other suitable form, provided that the container preferably prevents premature mixing of the components. Each of the different components can be located separately, or several different components can be located together (i.e., in the same container).

A container may also be a compartment or chamber contained within a vial, tube, jar or envelope or bag or blister pack or bottle, provided that the contents of one compartment do not physically come into contact with the contents of another compartment until they are deliberately mixed by a pharmacist or physician .

In addition, the kit or set of components may include technical instructions with information regarding the administration and dosage of any of its components.

Methods of treatment and diagnosis, and cases of application

Another object of the present invention is the use of para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof and/or a pharmaceutical composition described above and/or a kit described above for the preparation of a medicament comprising para-aminohippuric acid ( PAG) or a pharmaceutically acceptable salt or carboxy derivative thereof, and/or a pharmaceutical composition described above, intended to reduce in a subject the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds.

The present invention also provides a pharmaceutical composition as described above, or a kit as described above, for use in a method of reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject.

Another aspect of the present invention is also a method of reducing in a subject the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds, the method comprising administering to the subject a pharmaceutical composition described above, or a kit described above, during imaging or treatment performed using radiolabeled and/or non-radiolabeled compound.

Another aspect of the present invention is also a method for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject, the method comprising administering to the subject para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof in combination with a radiolabeled compound. or a non-radiolabeled therapeutic or diagnostic compound, wherein administration of the PAG is carried out before and/or during and/or after administration of the radiolabeled or non-radiolabeled therapeutic or diagnostic compound.

In a preferred embodiment, the method is intended to reduce in a subject the nephrotoxic side effects of radiopharmaceuticals during treatment or diagnosis using a radioligand. Preferably, the radiopharmaceutical is a radioisotope-containing complex comprising a carrier molecule, a chelating agent and a radioisotope as defined above. In a more preferred embodiment, the carrier molecule is selected from the group consisting of peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules, knotans, which may be agonistic or antagonistic ligands of a cell receptor, in particular a cell surface receptor. In a particularly preferred embodiment, the carrier molecule is selected from the group consisting of somatostatin analogs, PSMA inhibitors, gastrin analogs, integrin binding molecules described above, and, for example, selected from the group consisting of Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA- 11, sargastrin, RGD.

In another preferred embodiment, the chelating agent contained in the radiopharmaceutical compound used in the method of the present invention is selected from the group consisting of DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, DFO, DTPA , DO3AP, DO3AP ^PrA , DO3AP ^ABn , HYNIC or their derivatives.

In another preferred embodiment, the radioactive isotope contained in the radiopharmaceutical compound used in the method of the present invention is selected from the group consisting of ⁹⁴ Tc, ^99m Tc, ⁹⁰ In, ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁹⁰ Y , ¹⁷⁷ Lu, ¹⁶¹ Tb, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁵ Co, ⁵⁷ Co, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac, ²¹³ Bi, ²¹² Bi, ²¹² Pb, ²²⁷ Th, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁶⁶ Dy, ¹⁸ F and ¹³¹ I, and more preferably selected from the group consisting of ¹⁷⁷ Lu, ²²⁵ Ac and ⁶⁸ Ga.

In another preferred embodiment of the present invention, the radioactive isotope-containing conjugated molecule used in the method of the present invention is selected from the group consisting of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide, ¹⁷⁷ Lu-DOTA-JA11, ¹⁷⁷ Lu-DOTA -RGD, ¹⁷⁷ Lu-DOTA-sargastrin, ⁶⁸ Ga-HBED-CC-PSMA-11, PSMA11, ¹⁷⁷ Lu-PSMA I&T and ^99m Tc-etarfolatide.

In a particularly preferred embodiment of the present invention, the pharmaceutically acceptable salt of PAG used in the method of the present invention is sodium aminohippurate.

In the method of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is preferably administered in an amount that is sufficient to effectively reduce the nephrotoxic side effects of the therapeutic and/or diagnostic compound that is typically administered to the subject in parallel. The effective amount of PAG can be determined by standard experiments, for example, using animal models. Such animal models include, without limitation, rabbit, sheep, mouse, rat, dog and non-human primate models.

Thus, for example, the amount of PAG administered may range from about 0.1 mg/kg to 10 g/kg, preferably from about 0.5 mg/kg to 5 g/kg, more preferably from about 1 mg/kg up to 1 g/kg (calculated per 1 kg of body weight).

In a preferred method of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered in an amount of from about 5 to about 500 mg/(kg body weight), typically administered in parallel (e.g., up to during or after administration of a nephrotoxic therapeutic or diagnostic compound), for example, in an amount of about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350 , 400, 450, 500 mg/(kg body weight). Thus, the exemplary amounts provided herein can be administered on the same day (eg, as a diagnostic/therapeutic nephrotoxic compound). The modes of administration of PAG or its salt or carboxy derivative are usually the same as the modes of administration of the nephrotoxic compound. More preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered in an amount of from about 50 to about 500 mg/(kg body weight), more preferably from about 50 to about 250 mg/(kg) body weight), for example, in an amount of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, PO, 120, 130, 140, 150, 160, 170, 180, 190 , 200, 210, 220, 230, 240 or 250 mg/(kg body weight). More preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered in an amount of from about 75 to about 200 mg/(kg body weight), for example, in an amount of about 75, 80, 85, 90, 95, 100, 105, PO, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 mg/(kg weight body). Most preferably, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered in an amount of from about 80 to about 160 mg/(kg body weight), for example, in an amount of about 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160 mg/(kg body weight).

PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is typically administered in an amount greater than that of the (co-administered) therapeutic or diagnostic compound.

Thus, for example, the therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are administered in an amount ratio of from about 1/1,000,000 to 1/10 (wt/wt), preferably from about 1 /500,000 to 1/100 (w/w), more preferably from about 1/250,000 to about 1/500 (w/w).

In a preferred method of the present invention, the therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are administered in an amount ratio of from about 1/250,000 to about 1/5,000 (w/w). ), for example, at an amount ratio of from about 1/250,000, 1/200,000, 1/150,000, 1/100,000 or 1/50,000 to about 1/5000 (w/w), more preferably at an amount ratio of from about 1/240,000 to about 1/8,000 (w/w), for example, at ratios of about 1/240,000, 1/230,000, 1/220,000, 1/210,000, 1/200,000, 1/190,000, 1/180000, 1/170000, 1/160000, 1/150000, 1/140000, 1/130000, 1/120000, 1/110000, 1/100000, 1/90000, 1/80000, 1/70000, 1/ 60000, 1/50000, 1/40000, 1/30000, 1/20000, 1/19000, 1/18000, 1/17000, 1/16000, 1/15000, 1/14000, 1/13000, 1/12000, 1/11000, 1/10000, 1/9000 or 1/8000 (w/w). In another preferred method, the therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are administered at an amount ratio of from about 1/100,000 to about 1/10,000 (wt/wt). ), for example, at an amount ratio of about 1/100000, 1/95000, 1/90000, 1/85000, 1/80000, 1/75000, 1/70000, 1/65000, 1/60000 1/55000, 1 /50000, 1/45000, 1/40000, 1/35000, 1/30000, 1/25000, 1/20000, 1/15000, 1/10000 (w/w). In another preferred method, the therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, are administered at an amount ratio of from about 1/50,000 to about 1/40,000 (wt/wt). ), for example, at ratios of about 1/50,000, 1/49,000, 1/48,000, 1/47,000, 1/46,000, 1/45,000, 1/44,000, 1/43,000, 1/42,000, 1/41,000, 1/40000 (w/w).

In another embodiment of the present invention, in the method of the present invention, para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered in combination with another substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds. In a preferred embodiment, the substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds other than PAG is selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules such as PMPA, vitamins. Substance(s) that reduce the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds other than PAG may be administered before and/or during and/or after administration of PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably aminohippurate sodium

The pharmaceutical compositions or kits of the present invention can be administered to a subject in need thereof several times a day, once a day, every other day, once a week or once a month. Preferably, treatment, diagnosis or prophylaxis is carried out using an effective dose of the pharmaceutical compositions or kits proposed in the present invention.

In the method of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, can be administered to a subject before and/or during and/or after administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, pharmaceutical composition or set accordingly. Thus, for example, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered prior to administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, pharmaceutical composition or kit. In a preferred method of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is administered prior to administration of the pharmaceutical composition or kit of the present invention as defined above. Alternatively, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, can be administered before and during or before and after administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound. Pre-administration of PAG can be carried out approximately 60 minutes, 30 minutes, 10 minutes or 5 minutes before administration of the therapeutic or diagnostic compound, pharmaceutical composition or kit, preferably if PAG is administered approximately 0.5-5 hours or 10-60 minutes before administration a therapeutic or diagnostic compound, pharmaceutical composition or kit, respectively. In some embodiments, PAG may be administered before and after administration of the therapeutic or diagnostic compound, for example, 0.5-5 hours or 10-60 minutes, or before, during and after.

In the method of the present invention, PAG or a pharmaceutically acceptable salt or carboxy derivative thereof, preferably sodium aminohippurate, is preferably administered as a solution in a buffered aqueous solution, for example, an isotonic or hypertonic solution, for example, water for injection (WFI) or in a NaCl solution, for example, in a 20% NaCl solution.

In the method of the present invention, PAG, pharmaceutical compositions or kits are typically administered parenterally. Preferably, administration is systemic, for example by intravascular, intravenous (IV), subcutaneous, intramuscular or intradermal injection. Alternatively, administration can be done locally, for example by intratumoral injection.

Brief description of drawings

In fig. Figure 1 shows the accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the kidneys over time during co-infusion of amino acids and PAG, where a 0.9% NaCl solution was used as a control.

In fig. Figure 2 shows a % decrease in the accumulation of [ ¹⁷⁷ Lu-OOTA ⁰ -Tyr3]-octreotide in the kidneys over time compared to the initial value (infusion of 0.9% NaCl solution), with joint infusion of amino acids and PAG.

In fig. Figure 3 shows the amount of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the kidneys at an early time point of 0.5 hours after injection, expressed as a percentage of the administered dose, with co-administration of a 0.9% solution of NaCl, Lys/Arg and PAG .

In fig. Figure 4 shows the amount of [ ¹⁷⁷ Lu-DOTA-Tyr3]-octreotide in the kidneys at a late time point of 24 hours after injection, expressed as a percentage of the administered dose, with the co-administration of a 0.9% solution of NaCl, Lys/Arg and PAG.

In fig. Figure 5 shows the accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the organ ex vivo 5 and 60 minutes after injection (N=5). PAG significantly reduced accumulation in the kidneys even at an early time point (**P≤0.005, ****P≤0.0005).

In fig. Figure 6 shows the concentration of radioactive substance in the kidneys, expressed as a % of the concentration of the administered radioactive substance, at different time points after injection (0.5, 1, 4, 24 hours) for various radiolabeled agents ( ¹⁷⁷ Lu) (DOTA-RGD, affilin, DOTA-sargastrin, DOTA-JR11) with co-administration of PAG (200 mg/ml) and 0.9% NaCl solution, respectively.

In fig. Figure 7 shows the concentration of a radioactive substance in the blood, expressed as a % of the concentration of the administered radioactive substance, at different time points after injection (0.5, 1, 4, 24 hours) for various radiolabeled agents ( ¹⁷⁷ Lu) (DOTA-RGD, affilin, DOTA-sargastrin, DOTA-JR11) with co-administration of PAG (200 mg/ml) and 0.9% NaCl solution, respectively.

In fig. Figure 8 shows the concentration of the radioactive substance in the kidneys (upper diagram) and in the blood (lower diagram), expressed as % of the concentration of the administered radioactive substance at different points in time after injection (0.1, 0.5, 1, 2, 4 hours) for labeled with ⁶⁸ Ga HBED-CC-PSMA-11 upon co-administration of PAG (200 mg/ml) and 0.9% NaCl solution, respectively.

In fig. Figure 9 graphically presents the results of a study of the biological distribution of ¹⁷⁷ Lu-DOTATOC administered intravenously to mice after intraperitoneal injection of PAG or saline.

In fig. 10 graphically presents the results of a study of the biological distribution of ^99m Ic-etarfolatide administered intravenously to mice after intraperitoneal injection of PAG or saline.

In fig. 11 is a comparative bar graph for the radioactive concentration in the kidneys, expressed as a % of the administered radioactive concentration, obtained using rats of three groups that were administered ¹⁷⁷ Lu-PSMA I&T and that were administered saline-OOP (volume-providing solution) probenecid- FFP2 (FFP = kidney protectant) or PAG-FFP1 solution.

In fig. 12 shows a comparative bar graph for the concentration of radioactive substance in blood taken from the left ventricle of the heart, expressed as a % of the concentration of the administered radioactive substance, obtained using rats of three groups that were administered ¹⁷⁷ Lu-PSMA I&T and that were administered saline-OOP probenecid -SZP2 or PAG-SZP1 solution.

In fig. 13 is a comparative bar graph for the concentration of radioactive substance in the renal medulla, expressed as a % of the concentration of the administered radioactive substance, obtained using rats of three groups that were administered ¹⁷⁷ Lu-PSMA I&T and that were administered saline-OOP probenecid-FFP2 or solution PAG-SZP1.

In fig. 14 is a comparative bar graph for the concentration of radioactive substance in the renal cortex, expressed as a % of the concentration of the administered radioactive substance, obtained using rats of three groups that were administered ¹⁷⁷ Lu-PSMA I&T and that were administered saline-OOP probenecid-FFP2 or solution PAG-SZP1.

Examples

The results below indicate that co-treatment with sodium aminohippurate (SAH) solutions provides a significant reduction in the renal retention and accumulation of various radiopharmaceuticals containing different carrier molecules, different chelating agents and different radioisotopes, respectively, and that administration of PAH is much more more effective than infusion of lysine and arginine. In addition, it has been found that co-treatment with PAG increases the bioavailability of radiopharmaceuticals and increases the accumulation of radiopharmaceuticals in the tumor.

Experimental protocols (examples 1 and 2):

Experiments using SPECT/CT:

Biological distribution in the kidneys was examined using single photon emission computed tomography (SPECT) by defining volumes of interest (VOIs) on radioactive 3D images obtained from 6 animal groups to study each kidney protectant and [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide was used in 3 animals; healthy Wistar rats were used. 50 MBq [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide was administered together with a solution of amino acids (L-Arg and L-Lys) - 200 mg/ml in water for injection, with a solution of sodium para-aminohippurate - 200 mg/ml in water for injection (PAG) and 0.9% NaCl solution used as a standard. Images were acquired at 0.5 h, 1 h, 4 h, 8 h, and 24 h after injection.

Ex vivo organ distribution

All animals were pre-injected with 1.0 ml of NaCl, Arg-Lys or PAG 10 min before the administration of the radiopharmaceutical by injection. Injection solutions intended for biological distribution studies were prepared as a mixture of 12 μl [ ¹⁷⁷ Lu]Lu-DOTA-TOC, 1.5 ml NaCl or Arg-Lys, or PAG.

Injection solutions for SPECT animals were prepared as a mixture of 80 μl [ ¹⁷⁷ Lu]Lu-DOTA-TOC, 1.5 ml NaCl or Arg-Lys, or PAG. Animals were injected with substances and killed after 5 minutes or 60 minutes. The necessary organs and tissues were collected and the concentration of the radioactive substance was determined. Male Wistar rats had an average body weight of 210±12 g (after 5 min) and 218±13 g (after 60 min). The average concentration of the administered radioactive substance was 4.49 ± 0.38 MBq/(kg body weight) (after 5 min) and 159 ± 13 MBq/(kg body weight) (after 5 min) in the case of animals studied using SPECT , and 4.19 ± 0.57 MBq/(kg body weight) (after 60 min) or 139 ± 8 MBq//(kg body weight) (after 60 min) in the case of animals that were studied using SPECT.

Microsoft Excel 2010 and Graphpad Prism 6.05 software were used to perform statistical analysis. Results were presented as medians and 25th and 75th percentiles, and means with standard deviation (SD) or standard error of the mean (SEM). For comparisons, ordinary one-way ANOVA and Tukey's multiple comparison test, two-sample two-tailed t-test were used. The significance level was taken to be P<0.05.

Example 1: Accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the kidneys

The accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the kidneys of rats during co-infusion of 0.9% NaCl solution (control), Lys/Arg (250 mg Lys/250 mg Arg) and PAG (500 mg), respectively, was determined using designed for the study of small animals quantitative SPECT. The results are presented in tables 1-3.

The values given in Tables 1-3 are graphically presented in FIG. 1-4.

From the above results, it is clear that co-infusion of Lys/Arg leads to a reduction in renal accumulation of 21 and 26% at 8 and 24 hours, respectively, with significantly different values obtained for different individuals (Table 2, Figs. 1, 2 and 4). The result obtained with amino acid infusion is similar to that described in the literature (33±23%, publication by Rolleman EJ et al., cited above). In contrast, co-infusion of PAG resulted in a reduction of 56% and a reduction of 50% at the same time points with a low standard deviation (Table 3, Figs. 1 and 2). PAG infusions also result in low levels of renal accumulation at early time points. 0.5 h after injection of the Lys/Arg mixture, only a slight decrease of 10% is observed, in contrast to PAG, in which a decrease of 50% is observed (Tables 2 and 3, Figs. 1-3).

Example 2: Accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in an organ ex vivo

The concentration of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the ex vivo organ was determined at early time points, 5 min and 60 min after injection, in accordance with the above protocol. The results are graphically presented in Fig. 5. Compared with the case of co-treatment with Lys/Arg infusion, the use of PAN infusion, even at early time points, significantly reduced (P≤0.005) the accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide compared to the values obtained with NaCl infusion.

Thus, the above results indicate that the use of sodium aminohippurate solutions provides a more significant reduction in the retention and accumulation of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide in the kidneys than the use of a combination of lysine and arginine known in the prior art.

Experimental protocols (examples 3-5)

The imaging study was designed to determine the effectiveness of PAG in reducing the renal accumulation of ¹⁷⁷ Lu or ⁶⁸ Ga labeled peptides that are coordinated by chelating agents having different structures and binding scaffolds. Radioisotope distribution studies of radiolabeled test compounds were performed in two different cohorts of healthy Wistar rats, focusing on renal accumulation/renal clearance and blood concentrations. Animals in one cohort were treated with ¹⁷⁷ Lu/ ⁶⁸ Ga labeled peptide in combination with a saline control (MBq/kg and mg/kg values must be determined on a case-by-case basis), while animals in the other cohort were first treated with intraperitoneal injection. PAG before administration of ^{the 177} Lu/ ⁶⁸ Ga labeled peptide (10 min before injection) along with two intravenous injections of PAG solution. Renal clearance and overall pharmacokinetic parameters for each ¹⁷⁷ Lu/ ⁶⁸ Ga labeled peptide (administered without or with PAG pre-administration) were determined by PET or SPECT. Each cohort included at least 3 rats to allow statistical analysis.

^177Lu -labeled peptides: The radiochemical purity (RPP) of ^177Lu -labeled compounds obtained from ITG was determined after preparation by MTLC (instantaneous thin layer chromatography). For each compound, the results of the study are attached, the RCC was >95%. The nominal dose level, concentration, and volume for each ¹⁷⁷ Lu-labeled peptide tested are shown in Table 4.

^68Ga -labeled peptides: ^68Ga -labeled compounds were prepared immediately before use and their radiochemical purity was determined by MTLC. (Tagging data and QC results are provided for each compound; RCN was >95%). The nominal dose level, concentration, and volume for each ¹⁶⁸ Ga-labeled peptide tested are shown in Table 5.

Example 3: Reduction of Renal Accumulation of Various Radiolabeled Compounds by Concomitant Administration of PAG

Mice were injected with 4 different molecules conjugated to the cyclic chelating agent, DOTA, and labeled with the therapeutic radioactive isotope, lutetium-177: ¹⁷⁷ Lu-DOTA-RGD, ¹⁷⁷ Lu-DOTA-affin, ¹⁷⁷ Lu-DOTA-sargastrin, and ¹⁷⁷ Lu- DOTA-JR11, respectively, and PAG (200 mg/ml) or saline (0.9% NaCl solution) was co-injected as a control. The time dependence of the concentration of the radioactive substance in the kidneys, in % of the concentration of the administered radioactive substance, was determined in accordance with the protocol described above. The results are graphically presented in Fig. 6.

According to FIG. 6, with concomitant administration of PAG, a significant decrease in the accumulation of radioactive substance in the kidneys is observed in the case of all studied compounds, in particular in the case of small peptides such as DOTA-RGD, DOTA-JR11 and DOTA-sargastrin. From those shown in FIGS. 6 results it is also clear that a decrease in accumulation in the kidneys occurs already at early time points, ranging from 0.5 to 1 hour after administration.

Therefore, the above experimental results show that the administration of PAG leads to a decrease in the accumulation of radiolabeled compounds of various types in the kidneys, i.e. DOTA-related peptides, peptidomimetics, etc., the accumulation of which in the kidneys occurs through various mechanisms.

Example 4: Effect of PAG on the concentration of various radiolabeled compounds in the blood

Mice were injected with 4 different molecules conjugated to the cyclic chelating agent, DOTA, and labeled with the therapeutic radioactive isotope, lutetium-177: ¹⁷⁷ Lu-DOTA-RGD, ¹⁷⁷ Lu-DOTA-affin, ¹⁷⁷ Lu-DOTA-sargastrini ¹⁷⁷ Lu-DOTA -JR11, respectively, and PAG (200 mg/ml) or saline (0.9% NaCl solution) was co-injected as a control. The dependence of the concentration of a radioactive substance in the blood, in % of the concentration of the administered radioactive substance, on time was determined in accordance with the protocol described above. The results are graphically presented in Fig. 7.

According to FIG. 7, with the joint administration of PAG, a significant increase in the concentration of affilin in the blood is observed. Therefore, although the reduction in renal accumulation of Affilin by PAG is less pronounced than with other compounds tested (see Fig. 6), the results indicate that at the same time, blood concentrations of Affilin increase with co-administration of PAG, leading to to improved bioavailability of the radiopharmaceutical.

Example 5: Effect of PAG on the accumulation of ⁶⁸ Ga-labeled PSMA-11 in the kidneys and its concentration in the blood

Mice were injected with diagnostic ⁶⁸ Ga labeled PSMA-11 conjugated to the acyclic chelating agent, HBED-CC, and co-injected with PAG (200 mg/ml) or saline (0.9% NaCl) as a control. . The time dependence of the concentration of the radioactive substance in the kidneys (top diagram) and in the blood (bottom diagram), as a percentage of the concentration of the administered radioactive substance, was determined in accordance with the protocol described above. The results are graphically presented in Fig. 8.

As shown in FIG. 8, with concomitant administration of PAG, a significant decrease in the accumulation of ⁶⁸ Ga-labeled HBED-CC conjugated to PSMA-11 in the kidneys was observed. From those shown in FIGS. 8 results also show that a decrease in renal accumulation occurs already at early time points of 0.1, 0.5 and 1 hour after administration.

Accordingly, the above experimental results obtained in Examples 3-5 show that the administration of PAG leads to a decrease in the accumulation in the kidneys of radiolabeled compounds of various types containing various carrier molecules (peptide, peptidomimetics, recombinant proteins), various chelating agents ( cyclic chelating agent, acyclic chelating agent) and various radioactive isotopes (therapeutic radioactive isotope, diagnostic radioactive isotope), respectively, and therefore can be suitably used to reduce the nephrotoxic side effects of a variety of radiolabeled and non-radiolabeled diagnostic and therapeutic compounds.

Example 6: Comparative study of the biological distribution of ¹⁷⁷ Lu-DOTATOC administered intravenously to mice after intraperitoneal injection of PAG or saline

CD1 nude mice harboring a somatostatin receptor-containing pancreatic tumor (AR24J) were injected by IP injection with 50 μl of 0.9% NaCl solution (group A) or 50 μl of 20% PAG solution (group B) exactly 10 min before IV. injections of ¹⁷⁷ Lu-DOTATOC/NaCl (group A) or ¹⁷⁷ Lu-DOTATOC/PAG (group B) through the retro-orbital venous sinus. The nominal dose level, concentration and volume are given in Table 6.

Mice (3 animals per group) were sacrificed after 0.5, 1, 2 and 4 hours, respectively. The organs were quickly washed with 0.9% NaCl and dried, then weighed and read to exclude possible contaminating blood. The following organs/tissues were sampled or removed, weighed and read to determine ¹⁷⁷ Lu concentration: blood, tumor, kidney, liver, bladder (empty), heart, spleen, lungs, brain, muscle, stomach (empty) , small intestine (without contents), large intestine (without contents), remaining skeleton. The results obtained for the organ/tissue were expressed as a percentage of the administered dose (percentage of ID/g, %)). The results of the distribution of ¹⁷⁷ Lu-DOTATOC in 0.9% NaCl solution (group A) in organs/tissues, as well as the results of the distribution of ¹⁷⁷ Lu-DOTATOC with the addition of PAG (group B) in organs/tissues are graphically presented in Fig. 9.

According to FIG. 9 there is a significant decrease in the accumulation of ¹⁷⁷ Lu-DOTATOC in the kidneys of animals of group B (lower diagram), which were administered ¹⁷⁷ Lu-DOTATOC with the addition of PAG, compared with the accumulation in the case of animals of group A (upper diagram), which were administered ¹⁷⁷ Lu-DOTATOC in NaCl solution. The decrease in the accumulation of radiolabeled compound in the kidneys is particularly pronounced at early time points (0.5 h, 1 h) after administration of ¹⁷⁷ Lu-DOTATOC. At the same time, the concentrations of ¹⁷⁷ Lu-DOTATOC in the tumor and in the blood of animals of group B are significantly higher than in animals of group A. Without being limited to any specific theoretical considerations, it can be assumed that the blocking of the excretion of ¹⁷⁷ Lu-DOTATOC provided by PAG is DOTATOC via the kidneys leads to an increase in the duration of blood circulation with ¹⁷⁷ Lu-DOTATOC and thus to an increase in the accumulation of the radiolabeled compound also in the tumor area. Thus, the presented results indicate an improved bioavailability of ¹⁷⁷ Lu-DOTATOC in the case of animals of the group that were administered ¹⁷⁷ Lu-DOTATOC with the addition of PAG, compared to the case of animals in group A that were administered ¹⁷⁷ Lu-DOTATOC in NaCl solution.

Example 7: Comparative study of the biological distribution ^{of 99m} Tc-etarfolatide administered in combination with PAG or saline

7.1. Introduction of a radioactive isotope into etarfolatide

^99m Tc-etarfolatide has the following chemical structure:

The introduction of the radioactive isotope was carried out according to the method described in the publication by Kim et al. (Ann Nucl Med 2016;30:369-379). A ligand exchange technique was used using tartrate as a coligand. 100 μg of etharfolatide, 50 μl of tartrate solution (20 mg/50 ml in water from Millipore) and 80 μl of SnCl ₂ dihydrate solution (1 mg/ml in 0.01 M HCl solution) were added to an Eppendorf tube. In a lead-shielded fume hood, approximately 750 MBq (20 mCi) of freshly eluted ^99m Tc-pertechnetate was added to the reaction vessel and the vessel was heated in a water bath at 100°C for 30 minutes and cooled to room temperature.

Radioactive isotope introduction efficiency and stability were determined using: (i) flash thin layer chromatography using silica gel (MTLC-SG) using water as mobile phases (R _f ^99m Tc-etharfolatide and free pertechnetate = 0.9-1.0 ; _Rf colloidal solution = 0.0-0.1) and acetone ( _Rf free pertechnetate = 0.9-1.0; _Rf colloidal solution and ^99m Tc-etarfolatide = 0.0-0.1), and (ii) RP-HPLC (reverse phase high performance liquid chromatography): solvent A: 0.1% TFA (trifluoroacetic acid) in H ₂ O. solvent B: 0.1% TFA in AcCN; elution in gradient mode, flow rate 1 ml/min.

On each day of the experiment, a new procedure for introducing a radioactive isotope was carried out to ensure approximately the same activity of ^99m Tc. The RCP determined using RP-HPLC was ~100%, while the formation of a colloidal solution was detected using TLC at a maximum amount of 5% or less. The stability ^{of 99m} Tc-etarfolatide was examined by HPLC 24 hours after preparation and the concentration of the radioactive isotope did not decrease.

The measured volume of radiolabeled folate was 1300 μl, whereas the activity was 734 MBq (experiment date: March 4). A sample corresponding to a dose of 300 MBq (ie 15 MBq x 20 mice) was prepared. 531 μl of radiolabeled folate was collected and diluted with 1469 μl saline or 1469 μl PAG (2000 μl ^99m Tc-etarfolatide, 100 μl/15 MBq/mouse). Before injection, the sample was filtered through a sterile filter with a pore size of 0.22 μm. The administered dose of 15 MBq/mouse corresponded to an amount of 2.04 μg etarfolatide/mouse (the administered amount of etarfolatide remained constant throughout the experiment).

Samples of ^99m Tc-etarfolatide, diluted with saline or using PAG, were examined immediately after preparation, as well as 24 hours after dilution, and when studied using HPLC, no signs of a decrease in the concentration of the radioactive isotope were found (the radioactive concentration was 100%), however, when Using TLC, it was found that ^{the 99m} Tc-etarfolatide/PAG system was stable (RCC was 100%), while in the ^99m Tc-etarfolatide/saline system, 14% of the colloidal solution was formed.

7.2. Preparation of PAG solution

2 g of PAG sodium salt was weighed into a Corning tube; added 4 ml H ₂ O; shook - partial dissolution of PAG occurred; 20 μl of NaOH (obtained from ITG) was added, shaken - partial dissolution of PAG occurred; added 20 μl of NaOH, shook - complete dissolution of PAG occurred; 2 ml of H ₂ O were added, the pH value was 10; 80 μl of 37% HCl was added (in portions of 20 μl), the pH value was ~6. The final volume of the resulting solution was determined and was 7100 µl; 2900 µl was added to the solution (in another Corning tube) to obtain a final solution of 2 g of PAG in 10 ml of H ₂ O, i.e. 200 mg PAG/ml. After filtration through a 0.22 µm filter, the Corning tube was sealed with aluminum foil and cooled.

7.3. Biological distribution study

30 Mice (male and female) were randomly divided into two groups.

Group A: After IP injection of PAG, given 10 min before radiopharmaceutical administration, mice were injected with ^99m Tc-etarfolatide diluted with PAG (2.04 μg etarfolatide/mouse). Studies were carried out at 5 time points: after 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours (3 mice were studied at each time point).

Doses administered at each time point:

Group B: After IP saline injection 10 min before radiopharmaceutical administration, mice were injected with ^99m Tc-etarfolatide diluted in saline (2.04 μg etarfolatide/mouse). Studies were carried out at 5 time points: after 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours (3 mice were studied at each time point). Doses administered at each time point:

The results of the biological distribution study are presented in Fig. 10. After 30 minutes, a decrease in the accumulation of ^99m Tc-etarfolatide in the kidneys became noticeable due to the protective effect of PAG. Thus, the results obtained using the ¹⁷⁷ Lu-based conjugated molecule are confirmed by the results of the study containing ^{the 99m} Tc conjugated molecule, in which ^99m Tc has a valency different from the valency of ¹⁷⁷ Lu, which is three.

Example 8: Study of the biological distribution of ¹⁷⁷ Lu-labeled PSMA I&T

The chemical structure of "PSMA 1&T" is as follows

Compounds of interest (CIs) intended for imaging experiments

Research systems and parameter values for imaging experiments

PROTOCOL EXECUTION

The protocol was carried out to determine the concentration of radioactive substance in the kidneys of animals, which were divided into 3 separate groups and administered one IS, but three different FFPs. Thus, the following scheme of experimental groups was formed.

1. Results of an imaging experiment for PSMA I&T - probenecid

1.1. Rat 1

1.2. Rat 2

1.3. Rat 3

2. Results of the imaging experiment for PSMA I&T - PAG

2.1. Rat 4

2.2. Rat 5

2.3. Rat 6

3. Results of the imaging experiment for PSMA 1&T -saline 3.1. Rat 7

3.2. Rat 8

3.3. Rat 9

RESULTS

PE1: Toxicity Observations

Result: no signs of acute immediate or acute delayed toxicity were detected.

PE2: Accumulation of radioactive substance in organs over time

Result: the tables below show the relative concentrations of the radioactive substance, adjusted for decay, in both kidneys, as a percentage of the concentration of the radioactive substance introduced into the entire body.

Results Table I.

Concentration of radioactive substance in the kidneys, as a % of the concentration of the administered radioactive substance, adjusted for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were administered a suspension of probenecid PO (orally)

Results table II.

Concentration of radioactive substance in the kidneys, as a % of the concentration of the administered radioactive substance, adjusted for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were injected with PAG solution by IP and IV

Results table III.

Concentration of radioactive substance in the kidneys, as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were injected with saline solution.

Results table IV.

Concentration of radioactive substance in the blood (left ventricle), as a % of the concentration of the administered radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and which were injected with probenecid suspension

Results table V.

Concentration of radioactive substance in the blood (left ventricle), as a % of the concentration of the administered radioactive substance, adjusted for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were injected with PAG solution by IP and IV

Results Table VI.

Concentration of radioactive substance in the blood (left ventricle), as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were injected with saline solution.

Table of results VII.

Concentration of radioactive substance in the renal medulla, as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T and that were injected with probenecid suspension.

Table of results VIII.

Concentration of radioactive substance in the renal medulla, as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were injected with PAG solution by IP and IV

Results Table IX.

Concentration of radioactive substance in the renal medulla, as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals injected with ¹⁷⁷ Lu-PSMA I&T and in which IP and IV were injected with saline

Results table X.

Concentration of radioactive substance in the renal cortex, as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T and that were injected with probenecid suspension.

Table of results XI.

Concentration of radioactive substance in the renal cortex, as a % of the concentration of the injected radioactive substance, adjusted for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T, and that were injected with PAG solution by IP and IV

Table of results XII.

Concentration of radioactive substance in the renal cortex, as a % of the concentration of the injected radioactive substance, corrected for decay, in the group of animals that were injected with ¹⁷⁷ Lu-PSMA I&T and that received IP and IV saline

The results are presented in Fig. 11-14. The results obtained in all experiments indicate a pronounced decrease in the concentration of the radioactive substance in the kidney cells when PAG was administered compared to the case of administration of saline solution used as a control, as well as compared to the case of a control experiment in which probenecid was administered (Fig. 11) . With the introduction of PAG at all points during the experiment, a decrease in the concentration of the radioactive substance was observed both in the renal cortex (Fig. 13) and in the renal medulla (Fig. 14).

Probenecid was tested as an additional control. It is known that probenecid is a strong inhibitor of the release of OA ^- (organic anions) by the cells of the proximal tubules of the kidneys. It inhibits organic anion transporter type 1 (OAT1) in the basolateral part of the cell. OAT1 is known to transport organic anions from the blood into renal tubular cells in exchange for dicarboxylates such as succinate or 2-oxoglutarate. The results of all experiments carried out in accordance with Example 8 (see FIGS. 11-14) indicate no effect on OAT1 by the probenecid-based inhibition mechanism. Thus, we can conclude that the effect of PAG, leading to a decrease in the concentration of the radioactive substance in kidney cells, is based on a mechanism that differs from the mechanism known for probenecid.

Claims (30)

1. The use of para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof in a method of reducing in a subject the nephrotoxic side effects of radiolabeled and therapeutic and diagnostic compounds as radiopharmaceuticals in treatment or diagnosis using a radioligand, where the radiopharmaceutical is a radioactive isotope containing a conjugated molecule containing a carrier molecule, a chelating agent and a radioactive isotope, where the radioactive isotope is a trivalent radioisotope. 2. Use according to claim 1, wherein the carrier molecule is selected from the group consisting of peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules and knotans, wherein the carrier molecule is preferably selected from the group consisting of somatostatin analogues, PSMA inhibitors ( prostate-specific membrane antigen), gastrin analogues, integrin binding molecules and folate, wherein the carrier molecule is most preferably selected from the group consisting of Tyr3-octreotide, Tyr3-octreotate, NOC, JR10, JR11, BASS, LM3, PSMA-11, sargastrin, RGD and folate. 3. Application according to any one of paragraphs. 1 or 2, wherein the chelating agent is a macrocyclic chelating agent, preferably selected from the group consisting of DOTA, HBED-CC, NOT A, NODAGA, DOTAGA, DOT AM, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3AP ^PrA , DO3AP ^Abn and HYNIC or their derivatives. 4. Application according to any one of paragraphs. 1-3, where the radioactive ^isotope is selected from the group consisting of ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, 90 Y, ¹⁷⁷ Lu, ¹⁶¹ Tb, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac, ²²⁷ Th, ¹⁵³ Sm , ¹⁶⁶ Ho, ¹⁵² Gd, ¹⁵³ Gd, ¹⁵⁷ Gd or ¹⁶⁶ Dy, preferably from the group consisting of ¹⁷⁷ Lu, ⁹⁰ Y, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ²²⁵ Ac, ¹⁶¹ Tb, ⁴⁴ Sc, and ⁴⁷ Sc, most preferably from the group consisting of ¹⁷⁷ Lu, ²²⁵ Ac and ⁶⁸ Ga. 5. Application according to any one of paragraphs. 1-4, wherein the radioactive isotope containing conjugated molecule is selected from the group consisting of [¹⁷⁷Lu-DOTA⁰-Tyr3]-octreotide,¹⁷⁷Lu-DOTANOC (¹⁷⁷Lu-DOTA-D-Phe-cyclo(Cys-1-Nal-D-Trp-Lys-Thr-Cys)Thr(ol)),¹⁷⁷Lu-DOTATE (¹⁷⁷Lu-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr),⁶⁸Ga-DOTATOC (⁶⁸Ga-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol)),⁶⁸Ga-DOTANOC (⁶⁸Ga-DOTA-D-Phe-cyclo(Cys-1-Nal-D-Trp-Lys-Thr-Cys)Thr(ol)),⁹⁰Y-DOTATOC (⁹⁰Y-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol)),⁹⁰Y-DOTATATE(⁹⁰Y-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr),¹¹¹In-DTPA-octreotide (¹¹¹In-DTPA-D-Phe-cyclo(Cys-Phe-D-Trp-Lys-Thr-Cys)Thr(ol)),¹¹¹In-DOTA-BASS (¹¹¹In-DOTA-p-NO₂-Phe-cyclo-(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH₂,¹¹¹In-DOTA-JR11 (¹¹¹In-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH₂),⁶⁸Ga-DOTA-JR11 (Ga-OpS201) (⁶⁸Ga-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH₂),⁶⁸Ga-DODAGA-JR11 (Ga-OPS202) (⁶⁸Ga-NODAGA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH₂),¹⁷⁷Lu-DOTA-JR11,¹⁷⁷Lu-DOTA-RGD,¹⁷⁷Lu-DOTA-sargastrin,⁶⁸Ga-HBED-CC-PSMA-11, and¹⁷⁷Lu-PSMA I&T. 6. Application according to any one of paragraphs. 1-5, wherein para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof is administered in combination with another substance that reduces the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds, wherein the other substance is preferably selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides that bind PSMA molecules such as PMPA (2-(phosphonomethyl)pentanedicarboxylic acid), and vitamins. 7. Application according to any one of paragraphs. 1-6, wherein PAG or a pharmaceutically acceptable salt thereof is administered in an amount ranging from 5 to 500 mg/(kg body weight), and/or a therapeutic or diagnostic compound and PAG or a pharmaceutically acceptable salt thereof is administered at an amount ratio ranging from 1 /240000 to 1/8000 (w/w). 8. Application according to any one of paragraphs. 1-7, where the pharmaceutically acceptable salt of PAG is sodium aminohippurate. 9. Application according to any one of paragraphs. 1-8, wherein the treatment or diagnosis using the radioligand is the therapy or diagnosis of cancers, in particular neuroendocrine tumors, prostate cancer, pancreatic cancer, kidney cancer, bladder cancer, medullary thyroid carcinomas, small cell lung cancer, stromal carcinomas ovarian, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma and breast cancer. 10. A pharmaceutical composition for reducing nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds, containing a radiolabeled pharmaceutical compound and para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, carrier or a combination thereof wherein the radiolabeled pharmaceutical compound is a radioisotope-containing conjugated molecule comprising a carrier molecule, a chelating agent and a radioisotope, wherein the radioisotope is a trivalent radioisotope. 11. The pharmaceutical composition according to claim 10, wherein the carrier molecule is selected from the group consisting of peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules and knotans, wherein the carrier molecule is preferably selected from the group consisting of somatostatin analogues, PSMA inhibitors, gastrin analogues, integrin binding molecules and folate conjugates, wherein the carrier molecule is most preferably selected from the group consisting of Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, sargastrin, RGD and folate. 12. Pharmaceutical composition according to any one of paragraphs. 10 or 11, wherein the chelating agent is selected from the group consisting of DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3AP ^PrA , DO3AP ^Abn and HYNIC or derivatives thereof. 13. Pharmaceutical composition according to any one of paragraphs. 10-12, in which the radioactive isotope is selected from the group consisting of ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁹⁰ Y, ¹⁷⁷ Lu, ¹⁶¹ Tb, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac, ¹⁵³ Sm, ¹⁶⁶ Ho, or ¹⁶⁶ Dy, preferably from the group consisting of ¹⁷⁷ Lu, ⁹⁰ Y, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ²²⁵ Ac, ¹⁶¹ Tb, ⁴⁴ Sc, and ⁴⁷ Sc, most preferably from the group consisting of ¹⁷⁷ Lu, ²²⁵ Ac and ⁶⁸ Ga. 14. Pharmaceutical composition according to any one of paragraphs. 10-13, in which the radioactive isotope-containing conjugated molecule is selected from the group consisting of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide, ¹⁷⁷ Lu-DOTA-JR11, ¹⁷⁷ Lu-DOTA-RGD, ¹⁷⁷ Lu-DOTA-sargastrine, ⁶⁸ Ga-HBED-CC-PSMA-11, and ¹⁷⁷ Lu-PSMA I&T. 15. Pharmaceutical composition according to any one of paragraphs. 10-14, wherein the composition, in addition to PAG, contains another substance that reduces the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds. wherein the additional substance that reduces the nephrotoxic side effects of therapeutic and diagnostic compounds other than PAG is optionally selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules such as PMPA, and vitamins. 16. Pharmaceutical composition according to any one of paragraphs. 10-15, wherein the therapeutic or diagnostic compound and the PAG are contained in the pharmaceutical composition in an amount ratio of 1/240,000 to 1/8,000 (w/w). 17. Pharmaceutical composition according to any one of paragraphs. 10-16, in which the pharmaceutically acceptable salt of PAG is sodium aminohippurate. 18. A kit for reducing the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds, comprising para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof in one component of the kit, and further comprising a radiolabeled therapeutic or diagnostic compound as a radiopharmaceutical, described in any of paragraphs. 1-5 in another component of the set. 19. A method of reducing the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds in a subject, comprising administering to the subject a pharmaceutical composition according to any one of claims. 10-17 or the kit of claim 18 before, during or after imaging or treatment using a radiolabeled compound. 20. A method of reducing the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds in a subject, comprising administering to the subject para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof in combination with a radiolabeled therapeutic or diagnostic compound, wherein administration of PAG is carried out before and/or or during and/or after administration of a radiolabeled therapeutic or diagnostic compound, preferably (i) before, during or after, or (ii) before and after administration of a radiolabeled therapeutic or diagnostic compound as a radiopharmaceutical in treatment or diagnosis using a radioligand, wherein the radiopharmaceutical is a radioactive isotope-containing conjugated molecule comprising a carrier molecule, a chelating agent and a radioactive isotope, wherein the radioactive isotope is a trivalent radioisotope. 21. The method of claim 20, wherein the carrier molecule is selected from the group consisting of peptides, peptidomimetics, small molecules and knotanes, wherein the carrier molecule is preferably selected from the group consisting of somatostatin analogs, PSMA inhibitors, gastrin analogs, integrin binding molecules and folates, wherein the carrier molecule is most preferably selected from the group consisting of Tyr3-octreotide, Tyr3-octreotate, NOC, JR10, JR11, BASS, LM3, PSMA-11, sargastrin, RGD and folate. 22. Method according to any one of paragraphs. 20 or 21, wherein the chelating agent is selected from the group consisting of DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PTA, DFO, DTPA, DO3AP, DO3AP ^PrA , DO3AP ^ABn and HYNIC or derivatives thereof. 23. Method according to any one of paragraphs. 20-22, in which the radioactive isotope is selected from the group consisting of ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁹⁰ Y, ¹⁷⁷ Lu, ¹⁶¹ Tb, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ²²⁵ Ac, ¹⁵³ Sm, ¹⁶⁶ But, or ¹⁶⁶ Dy, preferably from the group consisting of ¹⁷⁷ Lu, ⁹⁰ Y, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ²²⁵ Ac, ¹⁶¹ Tb, ⁴⁴ Sc, and ⁴⁷ Sc, most preferably from the group consisting of ¹⁷⁷ Lu, ²²⁵ Ac and ⁶⁸ Ga. 24. Method according to any one of paragraphs. 20-23, in which the conjugated molecule containing a radioactive isotope is selected from the group consisting of [ ¹⁷⁷ Lu-DOTA ⁰ -Tyr3]-octreotide, ¹⁷⁷ Lu-DOTANOC ( ¹⁷⁷ Lu-DOTA-D-Phe-cyclo(Cys-1-Nal- D-Trp-Lys-Thr-Cys)Thr(ol)), ¹⁷⁷ Lu-DOTATATE ( ¹⁷⁷ Lu-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr), ⁶⁸ Ga-DOTATOC ( ⁶⁸ Ga-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol)), ⁶⁸ Ga-DOTANOC ( ⁶⁸ Ga-DOTA-D-Phe-cyclo (Cys-1-Nal-D-Trp-Lys-Thr-Cys)Thr(ol)), ⁹⁰ Y-DOTATOC ( ⁹⁰ Y-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr -Cys)Thr(ol)), ⁹⁰ Y-DOTATATE ( ⁹⁰ Y-DOTA-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr), ¹¹¹ In-DTPA-octreotide ( ¹¹¹ In-DTPA-D-Phe-cyclo(Cys-Phe-D-Trp-Lys-Thr-Cys)Thr(ol)), ¹¹¹ In-DOTA-BASS ( ¹¹¹ In-DOTA-p-NO ₂ -Phe-cyclo -(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH ₂ , ¹¹¹ In-DOTA-JR11 ( ¹¹¹ In-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)- D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ), ⁶⁸ Ga-DOTA-JR11 (Ga-OpS201) ( ⁶⁸ Ga-DOTA-Cpa-cyclo[D-Cys-Aph(Hor) -D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ), ⁶⁸ Ga-DODAGA-JR11 (Ga-OPS202) ( ⁶⁸ Ga-NODAGA-Cpa-cyclo[D-Cys-Aph(Hor )-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH ₂ ), ¹⁷⁷ Lu-DOTA-JR11, ¹⁷⁷ Lu-DOTA-RGD, ¹⁷⁷ Lu-DOTA-sargastrine, ⁶⁸ Ga-HBED-CC -PSMA-11, and ¹⁷⁷ Lu-PSMA I&T. 25. Method according to any one of paragraphs. 19-24, wherein para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof is used in combination with another substance that reduces the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds, wherein the additional substance that reduces the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds therapeutic and diagnostic compounds other than PAG, optionally selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides, PSMA binding molecules such as PMPA, and vitamins. 26. Method according to any one of paragraphs. 19-25, in which PAG or a pharmaceutically acceptable salt thereof is administered in an amount ranging from 5 to 500 mg/(kg body weight) and/or therapeutic and/or diagnostic compound(s) and PAG or a pharmaceutically acceptable salt thereof is used at a ratio amounts ranging from 1/240,000 to 1/8,000 (w/w). 27. Method according to any one of paragraphs. 19-26, in which the pharmaceutically acceptable salt of PAG is sodium aminohippurate.

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