Para-aminohippuric acid (PAH) as a renal protective substance

Abstract

The present application discloses para-aminohippuric acid (PAhI) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof for use in methods for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject. Also disclosed are pharmaceutical compositions comprising a radiolabeled and / or non-radiolabeled pharmaceutical compound and para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof and a pharmaceutically acceptable excipient, diluent, carrier, or combination thereof. Another subject of the present application is a method for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject, comprising administering to the subject para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof in combination with a radiolabeled or non-radiolabeled therapeutic or diagnostic compound.

Description

[0001] The present invention relates to the use of p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof for reducing the nephrotoxic side effects of radiolabeled or non-radiolabeled therapeutic and diagnostic (e.g., for imaging purposes) compounds in a subject. It also relates to pharmaceutical compositions for kidney protection during imaging or therapy using radiolabeled and / or non-radiolabeled compounds, wherein the composition comprises a radiolabeled and / or non-radiolabeled pharmaceutical compound in combination with p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, and a pharmaceutically acceptable excipient, diluent, carrier, or a combination thereof. The present invention also relates to a method of reducing the nephrotoxic side effects of radiolabeled or non-radiolabeled therapeutic and diagnostic compounds in a subject, which method comprises administering para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof in combination with the radiolabeled or non-radiolabeled therapeutic or diagnostic compound, wherein the PAH is administered before and / or during and / or after the administration of the radiolabeled or non-radiolabeled therapeutic or diagnostic compound, and methods comprising administering a pharmaceutical composition according to the present invention to a subject during imaging or therapy using the radiolabeled and / or non-radiolabeled compound.

[0002] In particular, the present application relates to the use of PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof for inhibiting renal uptake and improving the in vivo biodistribution of radiolabeled molecules that are potentially damaging to the kidney, in particular for therapeutic radiopharmaceuticals, and / or to improving contrast in the context of diagnostic radiopharmaceuticals by using para-aminohippuric acid (PAH) or a salt or carboxylic acid derivative thereof (such as sodium aminohippurate).

[0003] In the context of advanced medical treatment, patients are exposed to an increasing variety of drugs for diagnostic and therapeutic purposes. Some of these agents cause adverse drug effects associated with systemic toxicity, including impairment of renal function. Most of these compounds are cleared by the kidneys and reabsorbed and partially retained in the proximal tubules, resulting in dose-limiting nephrotoxicity. Nephrotoxicity leads to serious clinical syndromes, including acute kidney injury (AKI). Nephrotoxic agents are believed to be the causative factor in 17-26% of hospitalized AKI. Drug-induced renal damage involves various classes of drugs and includes prescription agents as well as common over-the-counter drugs.

[0004] The toxicity of therapeutic and potential diagnostic agents may be inherent to the pharmacological compounds themselves, and the potential for toxicity may be elevated in the renal microenvironment. For example, the goal of chemotherapy is to kill malignant cells through various mechanisms designed to prevent cell division. Because the cell cycle operates normally in non-malignant cells, healthy tissues, including renal parenchymal cells, can also be affected. The kidney, as a filtering organ, is particularly exposed to targets for toxic compounds. Because it receives a large proportion of cardiac output, the strong blood flow through the kidneys exposes the kidneys to drugs and drug metabolites. Some of these agents have the charge and size required for glomerular filtration and subsequently enter the renal tubular epithelial cells through pinocytosis or endocytosis. Other drugs are transported through the peritubular capillaries and enter the renal tubular epithelial cells on the basolateral surface, where they are taken up by organic anion and organic cation transporters (OAT and OCT, respectively) and effluxed into the tubular lumen, where they can cause clinically significant nephrotoxicity.

[0005] Some anticancer therapeutics, such as cisplatin, are known to have nephrotoxic effects. Cisplatin (SP-4-2) - diamminedichloroplatinum (II)) is a platinum atom complexed by NH3 and Cl (a square planar complex). Its nephrotoxicity is based on its uptake by renal cells and its binding to the cell's DNA, thereby inhibiting cellular mechanisms, particularly cell replication. Natochin et al. reported the nephrotoxicity of cisplatin (Comp. Biochem. Physiol Vol. 94C, No. 1 pp 115-120, 1989). Choline chloride, PAH, furosemide, and ethacrynic acid have been described as reducing the nephrotoxic effects of cisplatin in rats.

[0006] Nephrotoxicity is also known as an adverse side effect when administering radionuclide-based therapeutic / diagnostic agents.

[0007] Diagnostic agents—due to their infrequent administration to a given subject—are rarely highly nephrotoxic to that subject.However, use of such diagnostic agents for imaging purposes, particularly for SPECT or PET imaging purposes, requires favorable biodistribution and contrast.

[0008] In some embodiments, the present invention relates to the treatment of nephrotoxicity of radioactive nuclides.In ...

[0009] Nephrotoxicity is therefore a well-known side effect of radioligand therapy (RLT), wherein for example the kidney is the dose-limiting organ. In the prior art patent publications EP 1196154 B1, EP 0094378, EP 2021012 B1 and US 2016 / 0143926 A1 it has been described that the co-administration of amino acids such as lysine and arginine or mixtures thereof with other compounds such as amifostine or gelatin can reduce [ 177 Lu-DOTA 0 ,Tyr3]octranate, [ 177 Lu-DOTA°-Tyr3]-octreotide and [ 111 In-DTPA-D-Phe1] octreotide absorption and retention. The use of renal protective agents is very critical. LUTATHERA is the first FDA-approved 177 Lu-labeled drug, administered only in combination with an amino acid mixture for infusion (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-Phe1-Tyr3-octreotide(SMT487)-a phase 1 clinical study:pharmacokinetics, biodistribution and renal protective effect of different regimens of aminoacid co-infusion. Jamar F et al., Eur J Nucl Med Mol Imaging. 2003Apr; 30(4):510-8.)

[0010] The radiation dose absorbed by the kidney can be reduced by co-infusion of agents that competitively inhibit the reabsorption of radiolabeled compounds, such as positively charged amino acids, Gelofusine, trypsinized albumin, or FRALB-C (bovine serum albumin fragmented with cyanogen bromide) (Albumin derived peptides efficiently reduce renal uptake of radiolabeled peptides, Vegt E et al., Eur J Nucl Med Mol Imaging (2010) 37:226).

[0011] Others claim that renal absorption can be reduced more significantly by combining lysine / arginine solutions with compounds such as amifostine and gelatin (EP 1196154 B1, EP 2021012 B1). In order to more effectively reduce renal reabsorption of radiolabeled peptides, the combination of two or more competitive endocytosis inhibitors and other approaches has been envisioned.

[0012] Another approach to nephroprotection is to use a combination of radiolabeled PSMA inhibitors and structurally related PSMA-binding molecules, such as 2-(phosphomethyl)glutaric acid (PMPA), to improve the kidney-to-tumor ratio. This concept is based on the specific kinetics of compound uptake in the kidney and tumor, respectively (PMPA for nephroprotection in PSMA-targeted radionuclide therapy of prostate cancer, Kratochwil et al., JNM 2015 Feb;56(2):293; US 2018 / 207299).

[0013] The mechanism of action of the renal protective combination drugs currently under development and clinical use (such as amino acid solutions or PMPA) is based on the accelerated clearance of radiopharmaceuticals from the kidneys. Their similarity to radiopharmaceuticals in terms of their binding properties is used. Therefore, the clinical use of these protective agents must be combined with radiopharmaceuticals that exhibit similar binding properties in the kidneys. In addition, the infusion of amino acids as renal radioprotectants may lead to clinically adverse side effects. Vomiting and nausea caused by large-scale infusion of non-isotonic amino acid solutions are often observed. A serious life-threatening side effect of such infusions reported 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 used for administration is usually limited to 25g lysine and 25g arginine. Rolleman EJ et al. reported decreased renal uptake as follows: "(1) commercial amino acid solution (AA) (21% + / - 14%, P < 0.02), (2) 25 g (17% + / - 9%, P < 0.04), 50 g (15% + / - 13%, P < 0.04), or 75 g of lysine (44% + / - 11%, P < 0.001), and (3) a combination of 25 g of lysine plus 25 g of arginine (LysArg) (33% + / - 23%, P < 0.01). Fluid infusion alone (500, 1,000, or 2,000 ml of saline / dextrose) did not alter renal uptake of radioactivity. Serum potassium levels were significantly increased in patients studied with 75 g of lysine (Lys75) and LysArg." (Safe and effective inhibition of renal uptake of radiolabeled octreotide by a combination of lysine andarginine. Rolleman EJ et al., Eur J Nucl Med Mol Imaging. 2003 Jan;30(1):9-15). Hyperkalemia remains an unresolved issue with this renoprotective approach because high concentrations of lysine and arginine are used as part of the mixture (Giovacchini G et al., supra).

[0014] Lysine and arginine are reabsorbed by the sodium-independent amino acid transporter (SCL3A1) in the proximal tubule. 177 The clearance mechanism of radiopharmaceuticals such as [Lu-DOTA°-Tyr3]-octreotide has not been fully elucidated. Published data suggest that the SCL3A1 amino acid transporter may play a role in radiopharmaceutical clearance, but this observation clearly does not represent the primary, let alone the only, mechanism involved.

[0015] Therefore, the object of the present invention is to provide an innovative method for inhibiting renal uptake to be used as a combination therapy for a broader spectrum of (radio)pharmaceuticals, regardless of the underlying mechanism of their renal accumulation, thereby reducing the nephrotoxic side effects of (radio)pharmaceuticals as therapeutic or, more rarely, diagnostic compounds. However, diagnostics in medical imaging are highly desired to improve their biodistribution in vivo and to enhance contrast by increasing their uptake at the site to be imaged, such as any tissue.

[0016] These objectives are solved by the subject matter disclosed herein and defined in particular by the claims.

[0017] The present invention is based on the discovery that p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof can be suitably used, for example, to improve the biodistribution of therapeutic and diagnostic compounds, particularly including radionuclides. Potentially renal-damaging agents, such as chemotherapeutic agents or radiopharmaceuticals, such as [ 177 Lu-DOTA°-Tyr3]-octreotide, 177 The clearance of Lu PSMA-inhibitors and the like can be improved by the innovative methods according to the present invention. Furthermore, it has been found that PAH administration can be used to downregulate renal drug reabsorption. This can (but need not) increase drug serum levels, leading to enhanced drug bioavailability.

[0018] Thus, the present invention is particularly suitable for inhibiting renal uptake of all types of protein molecules, such as proteins and peptides or fragments thereof or antibody fragments that exhibit inherent nephrotoxicity. This is especially true regardless of whether such protein molecules are combined with toxins, radionuclides, cytostatics or other potentially cytotoxic agents. In particular, it was unexpectedly found that co-administration of the present invention with PAH also reduced the nephrotoxicity of radiopharmaceuticals due to their radioactivity. This finding is even more surprising because the underlying mechanism of radionuclide-based therapy / diagnosis is unique (radioactivity) and distinct from other mechanisms observed in anticancer drugs such as cisplatin.

[0019] Furthermore, the present invention allows the imaging agent (particularly for SPECT and PET purposes) to accumulate in the tissue to be identified (e.g. at the tumor target site) and thus reduces its presence in off-target tissues. Thus, the present invention allows the image contrast of a given molecule, such as a conjugate molecule, comprising a radionuclide to be improved, since its clearance by the kidney is reduced.

[0020] Para-aminohippuric acid (PAH)

[0021] Aminohepik 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 does not occur naturally in humans. They are covalently linked via an amide bond. The sodium salt of PAH, sodium aminohippurate, is a diagnostic reagent widely used in diagnostic tests for renal function, particularly for measuring renal plasma flow. Hereinafter, aminohippuric acid, para-aminohippuric acid, and aminohippuric acid salts (particularly, alkali or alkaline earth salts), particularly the sodium salt, are used synonymously and referred to as "PAH."

[0022] Para-aminohippuric acid (PAH):

[0023]

[0024] Sodium p-aminohippurate:

[0025]

[0026] Typically, PAH is provided as a sterile, unpreserved 20% aqueous solution for injection. PAH is filtered by the glomerulus and actively secreted by the proximal tubules. At low plasma concentrations (1.0 to 2.0 mg / 100 mL), the kidneys of the subject clear an average of 90% of PAH from the renal bloodstream in a single cycle. PAH is also used to measure the functional capacity of the renal tubular secretion mechanism or the maximum transport capacity (TmPAH). This is achieved by raising the plasma concentration to a level sufficient to saturate the maximum capacity of the renal tubular cells to secrete PAH (40-60 mg / 100 mL). PAH has essentially no side effects and negligible toxicity (LD50 for intravenous injection in female mice is 7.22 g / kg). Phenomena such as vomiting and nausea or hyperkalemia are not reported, or if present, are only rarely reported.

[0027] In contrast to the combination therapy of the prior art (e.g., by using amino acid mixtures), para-aminohippuric acid (aminohippurate) allows for the nonspecific modulation of (radio)drug clearance because it is a substrate and / or functional inhibitor of various transporters. PAH is actively secreted into the urine by transporters. To date, PAH has been implicated as a substrate or inhibitor of 14 different transporters, including organic cation transmembrane transporters (e.g., OCT1, OCT1A, OCT2, OCT3, OCTN1, OCTN2, OCTN3) and organic anion transmembrane transporters (e.g., OAT1, OAT2, OAT3, OAT4, OAT5, OATP, URAT1). PAH is also a substrate for hMRP, an ATP-dependent efflux transporter.

[0028] Therefore, para-aminohippuric acid or a pharmaceutically acceptable salt or carboxylic acid derivative thereof can be used in combination with a broad spectrum of radiolabeled or non-radiolabeled therapeutic or diagnostic compounds, regardless of the nature of the carrier molecule (i.e., peptide, antibody fragment, peptidomimetic, small molecule, etc.). Modulation of renal clearance by PAH is believed to result in prolonged blood circulation of the administered drug and increased bioavailability thereof. For example, aminohippuric acid or a salt thereof can be administered before and / or during and / or after administration of a (radioactive) drug to be cleared by the kidneys, for example by infusion or injection.

[0029] General Comments

[0030] Although the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as they may vary. It should also be understood that the terminology used herein 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 herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0031] The key elements of the present invention will be described below. These key elements are listed together with specific embodiments, however, it should be understood that they can be combined in any way and in any number to form other embodiments. The examples and preferred embodiments of the different descriptions should not be interpreted as limiting the present invention to only the embodiments clearly described. This description should be understood to support and include embodiments that combine the embodiments clearly described with any number of disclosures and / or preferred elements. In addition, unless the context indicates otherwise, any arrangement and combination of all described key elements in this application should be considered to be disclosed by the specification sheet of the application.

[0032] Throughout this specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprising" and "containing" will be understood to imply the inclusion of stated members, integers or steps but not the exclusion of any other non-stated members, integers or steps. The term "consisting of is a specific embodiment of the term "comprising" in which any other non-stated members, integers or steps are excluded. In the context of the present invention, the term "comprising" encompasses the term "consisting of". Thus, the term "comprising" encompasses "including" as well as "consisting of", for example, a composition "comprising" X may consist solely of X or may also contain other contents, such as X+Y.

[0033] Unless otherwise indicated herein or clearly contradicted by context, the terms "a" and "an" and "the" and similar references used in the context of describing the present invention (especially in the context of the claims) are to be interpreted as covering both the singular and the plural. Reference to ranges of values herein is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0034] The term "about" in relation to a value x refers to x ± 10%.

[0035] The term "subject" as used herein generally includes humans and non-human animals, preferably mammals (e.g., non-human primates, including marmosets, tamarins, spider monkeys, owl monkeys, long-tailed 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 disease models. In the context of the present invention, the term "subject" preferably refers to a non-human primate or a human, most preferably a human.

[0036] In a first aspect, the present invention relates to the use of p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof to reduce the undesirable nephrotoxic properties of radiolabeled or non-radiolabeled therapeutic and diagnostic compounds in a subject treated with the compound.

[0037] As mentioned above, PAH or its salt is a substrate and / or inhibitor of various transport proteins in the kidney. Therefore, it can be used for a wide spectrum of radiolabeled or non-radiolabeled therapeutic and diagnostic compounds, which are expected to enter renal tubular cells, such as via absorption by organic anion transporters (OAT) and organic cation transporters (OCT), and therefore exert their potential nephrotoxicity. It can also be used to protect renal cells from the radioactivity of radiolabeled therapeutic agents or diagnostic agents, such as when oxidative stress is caused by radioactivity. In addition, protection against nephrotoxicity may particularly mean protection against glomerular toxicity.

[0038] Examples of therapeutic nephrotoxic compounds include, but are not limited to, nephrotoxic agents that are widely used to relieve signs of pain and inflammation. Nonsteroidal Anti-inflammatory drugs Despite this, they can still cause a wider variety of renal 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 (hyporeninemic hypoaldosteronism, hyponatremia, hypertension); Tight blood vessels Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers , which is used to treat hypertension and congestive heart failure, as well as to slow the progression of diabetic nephropathy, and which can lead to a higher risk of acute kidney injury (AKI) and hyperkalemia; anti- microbial agents , such as neomycin, gentamicin, tobramycin, amikacin, and streptomycin, which are commonly used to treat Gram-negative bacterial infections, and whose intracellular accumulation leads to tubular cell death or altered function of cell membrane transporters, resulting in electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia); Sulfonamide antibiotics , such as sulfamethoxazole-trimethoprim, which can cause hyperkalemia by inhibiting the distal tubule epithelial sodium channel, which powers potassium excretion, and sulfadiazine, which can cause acute interstitial nephritis and crystalline nephropathy; Glycopeptide antibiotics , such as vancomycin, which can cause acute tubular necrosis; Fluoroquinolone antibiotics , such as ciprofloxacin, which can cause acute interstitial nephritis and crystalluria; Other anti Vitamins , such as penicillins and cephalosporins, which can cause acute interstitial nephritis and acute tubular necrosis; and polymyxins, such as colistin and polymyxin B, which cause acute interstitial nephritis through toxic tubular damage; antiviral drugs , such as acyclovir, which can induce acute kidney injury secondary to tubular crystal precipitation, except foscarnet, which can cause acute tubular necrosis, acute kidney injury, and electrolyte abnormalities such as hypocalcemia, hypomagnesemia, hypokalemia, and hypo- or hyperphosphatemia; antiretroviral drugs, such as tenofovir, which is toxic to tubular cells, causing acute kidney injury with or without proximal tubulopathy, which can lead to chronic kidney disease, and protease inhibitors, such as indinavir, abacavir, ritonavir, and atazanavir, which can crystallize in the renal tubules, causing crystal-related kidney injury and kidney stones; Anti-factual Fungal drugs , such as amphotericin B, which can cause acute tubular necrosis and tubular dysfunction, manifested by renal tubular acidosis, urine concentration defects, and electrolyte imbalances; Immunosuppressants , such as calcineurin inhibitors (e.g., tacrolimus, cyclosporine), which are particularly used for immunosuppressive therapy after solid organ transplantation and may cause acute kidney injury; lithium (Lithium) , which is the main treatment for patients with bipolar disorder and can cause various forms of nephrotoxicity, such as nephrogenic diabetes insipidus (NDI), chronic kidney disease, and chronic tubuloenteropathy. Other therapeutic agents that cause acute kidney injury are proton pump inhibitors; acetaminophen; HMG-CoA reductase inhibitors; and osmotic agents.

[0039] Therapeutic nephrotoxic compounds also include Chemotherapeutic agents They play a central role in the treatment of various tumors and can cause a wide spectrum of renal complications, such as renal syndrome associated with acute kidney injury or chronic kidney disease, and renal syndrome associated with electrolyte imbalance. Examples of these chemotherapeutic agents include cisplatin (acute tubular necrosis, proximal tubular disease, hypernatremia, hypomagnesemia, hypocalcemia, distal renal tubular acidosis, thrombotic microangiopathy), pemetrexed (acute tubular necrosis), streptozotocin (also known as streptozotocin) (acute tubular necrosis, proximal tubular disease), mithramycin (acute tubular necrosis), zoledronic acid (acute tubular necrosis), interferon (acute interstitial nephritis), allopurinol (acute interstitial nephritis), gemcitabine (thrombotic microangiopathy), mitomycin C (thrombotic microangiopathy), anti-angiogenic agents (thrombotic microangiopathy), methotrexate (crystalline nephropathy), ifosfamide (proximal tubular disease, hypernatremia), cyclophosphamide (hyponatremia), vincristine (hyponatremia), cetuximab (hypomagnesemia), methotrexate (acute kidney injury).

[0040] For example, cisplatin and ifosfamide, which are standard components of treatment regimens for various solid organ tumors, including those affecting children, are known to be absorbed by cells in the proximal tubules via the organic cation transporter (OCT2) (Shirali A, Perazella M, Advances in Chronic Kidney Disease, Vol 21, No 1 (January), 2014: pp56-63). Therefore, it is speculated that co-injection with PAH may effectively reduce the nephrotoxic side effects of these chemotherapeutic drugs.

[0041] Additional nephrotoxic compounds include radiocontrast agents, such as iodinated radiocontrast agents, which are necessary for several diagnostic and interventional radiology procedures and can lead to contrast-induced nephropathy (CIN) and acute kidney injury. Examples of iodinated ionic contrast agents are diatrizoate (Hypaque 50), metronidazole (Isopaque 370), iothalamate (Conray), iodixanol (Hexabrix); non-ionic contrast agents include iopamidol (Isovue 370), iohexol (Omnipaque 350), ioxilan (Oxilan 350), iopromide (Ultravist 370), iodixanol (Visipaque 320), ioversol.

[0042] In a preferred embodiment of the present invention, PAH is used to reduce the nephrotoxic side effects of radiopharmaceuticals used as diagnostic and therapeutic agents.

[0043] Radiopharmaceuticals can include non-metallic (organic) radionuclides ( 18 F. 11 C. 13 N. 15 O. 124 I, etc.) or radioactive metals (such as 90 Y. 99m Tc, 111 In, 131 1. 67 Ga, 68 Ga, 64 Cu, 161 Tb, 225 Ac, 44 Sc, 47 Sc, 67 Cu, 89 Zr, 177Lu, etc.). Although some radioactive metals can be targeted to specific tissues in the form of metal salts or metal complexes, it is usually necessary to combine the radionuclide / radiometal with a targeting biomolecule in order to deliver the radionuclide to the target site, such as tumor tissue, in a targeted manner. The biomolecule can be, for example, a small organic molecule, a peptide, a monoclonal antibody (mAb), or a mAb fragment. They act as a carrier ("vehicle") to transport the radionuclide to the target tissue.

[0044] Commercially available small complex radiopharmaceuticals include, for example 99m Tc-Sestamibi It is used for myocardial perfusion imaging; 99m Tc-Tetrofosmin It is used for myocardial perfusion imaging; 99m Tc-Pentetate(DTPA) It is used for renal imaging and functional studies; 99m Tc-Bicisate(ECD) It is used for brain perfusion imaging; 99m Tc-MDP It is used for bone scintigraphy; 99m Tc-Teboroxime It is used for myocardial perfusion imaging; 111 In-Oxyquinoline(Indium-111 ), which is used for leukocyte scintigraphy; 111 In-Pentetate(Indium-111 ), which is used for CSF dynamics imaging; 153 Sm-EDTMP It is used in the treatment (therapy) of bone pain; 188 Re-HEDP, which is used for the treatment of metastatic bone pain.

[0045] The most elegant approach to establishing a stable conjugation of a radionuclide and a targeting biomolecule (carrier) is to use a suitable bifunctional chelator or chelating agent that tightly binds or coordinates the radionuclide while providing a functional moiety for its conjugation to the biomolecule.

[0046] Examples of commercially available peptide or immunoconjugates include 99m Tc-Depreotide(Neo ), which is used to evaluate certain lung lesions; 99m Tc-Arcitumumab (CEA- 99m Tc-mAb), which is used for colorectal cancer imaging; 111In-Capromab pendetide It is used for prostate cancer imaging; 111 In-Pentetreotide It is used for imaging neuroendocrine tumors; 111 In-Imciromab pentetate It is used for imaging of chest pain suspected to be caused by myocardial infarction; 111 In-Satumomab pendetide Its use in imaging metastatic disease associated with colorectal and ovarian cancers; 90 Y-Ibritumomab tiuxetan It is used in the treatment of non-Hodgkin lymphoma (NHL); 68 Ga-Edotreotide or 68 Ga-DOTATE, which is used for imaging of neuroendocrine tumors; 177 Lu-B DOTATETE (Lutathera), which is used in the treatment of neuroendocrine tumors.

[0047] Therefore, in a particularly preferred embodiment of the present invention, PAH is used to reduce the nephrotoxic side effects of radiopharmaceuticals, as described above, in radiochemotherapy / ligand therapy and / or diagnostics.

[0048] In radioligand therapy (also known as PRRT - peptide-receptor radionuclide therapy), the radiopharmaceutical is labeled with a radioligand that specifically binds to a (tumor) cell target, such as a tumor cell surface protein or marker. After the compound binds to the tumor target (e.g., to a receptor), the radionuclide releases high-energy beta particle radiation to precisely target the cells at the target site.

[0049] In radioligand diagnostics, a radiolabeled compound binds to a target cell, such as a receptor. The decay of the radioisotope can be measured by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0050] Therefore, in a preferred embodiment of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used to reduce the nephrotoxic side effects of radiolabeled drugs ("radiopharmaceuticals"). The radiopharmaceutical is preferably a conjugate molecule comprising (i) a carrier that binds to a target structure (e.g., a receptor or antigen) on a (tumor) cell, (ii) a chelating agent (or chelators), and (iii) a radionuclide. The chelating agent typically coordinates with the radionuclide, thereby forming a radiolabeled complex that is conjugated to the carrier molecule.

[0051] Radionuclides

[0052] The term "radionuclide" (or "radioisotope") refers to an isotope of natural or artificial origin that has an unstable neutron to proton ratio and that disintegrates with the emission of particles, i.e., protons (α-radiation) or electrons (β-radiation) or electromagnetic radiation (γ-radiation). In other words, the radionuclide undergoes radioactive decay. In the radiolabeled complex of the radiopharmaceutical, any known radionuclide can be complexed by a chelating agent. Such radionuclides may include, but are not limited to, 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 Th, 153 Sm, 166 Ho, 152 Gd, 153 Gd, 157 Gd or 166 Dy, especially 68 Ga, 177 Lu or 99m Tc.

[0053] The choice of a suitable radionuclide depends, among other things, on the chemical structure and chelating capacity of the chelating agent and, most importantly, on the intended application (e.g. diagnostics and therapy, and, e.g., treatment of diseases) of the resulting (complex) conjugate molecule. For example, beta-emitters, such as 90 Y. 131 I. 161 Tb and 177 Lu can be used for simultaneous systemic radionuclide therapy. Providing DOTA, DOTAGA or DOTAM as a chelating agent can advantageously enable the use of either 68Ga, 43,44,47 Sc, 177 Lu, 161 Tb, 225 Ac, 213 Bi, 212 Bi, 212 Pb as a radionuclide.

[0054] In some preferred embodiments, the radionuclide may be 177 Lu. In some preferred embodiments, the radionuclide may be 111 In. In some preferred embodiments, the radionuclide may be 90 In some preferred embodiments, the radionuclide may be 68 Ga.

[0055] chelating agents

[0056] As mentioned above, the carrier molecule, such as the (cancer) cell targeting compound, is preferably linked to a chelating agent or chelator that coordinates the radionuclide.

[0057] The terms "chelating agent" or "chelating agent" are used interchangeably herein. They refer to polydentate (multi-bonded) ligands that are capable of forming two or more separate coordination bonds with ("coordinate") a central (metal) ion. Specifically, such molecules or molecules that share one electron pair may also be referred to as "Lewis bases." The central (metal) ion is typically coordinated to the chelating agent via two or more electron pairs. The terms "bidentate chelating agent," "tridentate chelating agent," and "quadrant chelating agent" are recognized in the art and refer to chelating agents having two, three, and four electron pairs, respectively, which are readily available simultaneously to the metal ion coordinated by the chelating agent. Typically, the electron pairs of the chelating agent form coordination bonds with a single central (metal) ion; however, in some instances, the chelating agent may form coordination bonds with more than one metal ion, and a variety of binding modes are possible.

[0058] The terms "coordinating" and "coordination" refer to an interaction in which a multi-electron pair donor is coordinatively bonded ("coordinated") to, i.e., shares two or more unshared electron pairs with, preferably a central (metal) ion.

[0059] The chelating agent or chelating agent is preferably a macrocyclic bifunctional chelating agent having a metal chelating group at one end and a reactive functional group at the other end, which can bind other moieties, such as peptides. Preferably, the chelating agent can be selected so that the chelating agent forms a square bipyramidal complex for complexing radionuclides. In another embodiment, the chelating agent is not derived from a planar or square planar complex.

[0060] The chelating agent is preferably selected for its ability to coordinate the desired central (metal) ion, typically a radionuclide as specified herein.

[0061] Thus, the chelating agent may be characterized by one of the following formulas (4a)-(4jj):

[0062]

[0063]

[0064]

[0065]

[0066] Preferably, the chelating agent can be DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, which may be characterized by formula (4a)), HBED-CC (N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, which can be characterized by formula (4e)), DOTAGA (2-[1,4,7,10-tetraazacyclododecane-4,7,10-tri(acetate)]-pentanedioic acid), DOTAM (1,4,7,10-tetra(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane) or its derivatives.

[0067] Advantageously, DOTA is combined with diagnostics (e.g. 68 Ga) and therapeutic (eg 90 Y or 177 Lu) radionuclides and thus enable the use of the same conjugate for both imaging (diagnostic) and therapeutic purposes, i.e. as a theranostic agent. 43 Sc, 44 Sc, 47 Sc) DOTA derivatives - including DO3AP (characterized by formula (4hh)), DO3AP PrA (characterized by formula (4ii)) or DO3AP ABn (characterized by formula (4jj)) - may also be preferred and is described in Kerdjoudj et al. (Dalton Trans., 2016, 45, 1398-1409).

[0068] Advantageously, HBED-CC is combined with diagnostic radionuclides such as 68 Ga, 99mTc) effectively forms a complex.

[0069] Other preferred chelating agents in the context of the present invention include (2-(4,7-bis(carboxymethyl)-1,4,7-triazanon-1-yl-pentanedioic acid ( NODAGA )、1,4,7-triazacyclo-nonane-1,4,7-triacetic acid ( NOTA )、2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetra-azacyclododecane-1-yl)-pentanedioic acid ( DOTAGA )、1,4,7-triazacyclononanephosphinic acid ( TRAP )、1,4,7-triazacyclo-nonane-1-[methyl(2-carboxyethyl)-phosphinic acid]-4,7-bis-[methyl(2-hydroxymethyl)-phosphinic acid]( NOPO )、3,6,9,15-tetra-azabicyclo[9,3,1]-pentadecan-1(15),11,13-triene-3,6,9-triacetic acid ( PCTA ), N'-{5-[acetyl(hydroxy)amino]-pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}-amino)pentyl]-N-hydroxysuccinamide ( DFO ), diethylene triamine pentaacetic acid ( DTPA ), and hydrazine nicotinamide ( HYNIC ).

[0070] The chelating agent group, such as a DOTA group, may preferably be complexed with a central (metal) ion, in particular with a radionuclide as defined herein. Alternatively, the chelating agent group, such as DOTA, may not be complexed with a central (metal) ion, in particular a radionuclide as defined herein, and may therefore be present in an uncomplexed form. If the chelating agent (such as DOTA) is not complexed with the metal ion, the carboxylic acid group of the chelating agent may be in the form of a free acid or a salt.

[0071] It is within the skill and knowledge of those skilled in the art to select a suitable combination of chelating agent and radionuclide. For example, in some preferred embodiments, the chelating agent may be DOTA and the radionuclide may be 177 In other preferred embodiments, the chelating agent may be DOTA and the radionuclide may be 68 In other preferred embodiments, the chelating agent may be HYNIC and the radionuclide may be 99m Tc.

[0072] Carrier molecules

[0073] The carrier molecule may be any molecule that binds to a (tumor) cell target, such as a receptor or another cell (surface) molecule. In a preferred embodiment of the invention, the carrier molecule is selected from the group consisting of a peptide, a peptidomimetic, an antibody fragment, an antibody mimetic, a small molecule and a binding site.

[0074] The cellular target may be any target cell present in, or preferably present on, the target cell to which the radionuclide conjugate molecule is intended to bind for radiotherapy or diagnosis.

[0075] For example, the carrier molecule can be directed against a receptor or cell surface molecule present on a disease cell (such as a tumor cell). Hereinafter, examples of receptors and cell surface molecules present on tumor cells are described in detail, which can be target structures of the carrier molecule. However, the target structure is not limited to the receptors and cell surface molecules described below. Other receptors and cell surface molecules present on cancer or other disease cells are considered to be target structures of the carrier molecule. In addition, other carrier molecules targeting receptors and cell surface molecules present on cancer or other disease cells are contemplated.

[0076] Somatotropin inhibitor receptor-targeted compounds

[0077] According to the present invention, PAH or a salt or carboxylate derivative thereof can be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting somatostatin receptors (SSTRs).

[0078] For the treatment of well to moderately differentiated neuroendocrine tumors (NET), for example, peptides targeting somatostatin receptors (SSTRs) can be used. In NETs, radioligand therapy has been established and can achieve long-term tumor remission and stabilization at a high rate. Peptides targeting somatostatin receptors are, for example, 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 90Y: peptide receptor radionuclide therapy results in vitro, Cancer Biother Radiopharm, 2003 Oct; 18(5): 761-8). Further examples of somatotropin inhibitor 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)).

[0079] Other examples of compounds targeting somatostatin receptors are somatostatin antagonist peptides, such as JR10 (p-NO2-Phe-c(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2); JR11 (Cpa-c(D-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2); BASS (p-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2); LM3 (p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2).

[0080] In a particularly preferred embodiment of the invention, PAH is used to reduce the nephrotoxic side effects of (radio)pharmaceuticals based on somatostatin analogs; examples of which include: 177 Lu-DOTATOC( 177 Lu-DOTA°-[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(ol)), 68Ga-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-ring(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol)), 90 Y-DOTATATE( 90 Y-DOTA-D-Phe-ring (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)).

[0081] In another preferred embodiment, PAH or a salt or carboxylic acid derivative thereof is used to reduce the nephrotoxic side effects of (radio)pharmaceuticals based on somatostatin inhibitor antagonist compounds; examples include: 111 In-DOTA-BASS( 111 In-DOTA-p-NO2-Phe-ring-(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2, 111 In-DOTA-JR11( 111 In-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH2), 68 Ga-DOTA-JR11(Ga-OpS201)( 68 Ga-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH2), 68 Ga-DODAGA-JR11(Ga-OPS202)( 68 Ga-NODAGA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH2), 177 Lu-DOTA-JR11(Lu-OPS201)( 177 Lu-DOTA-Cpa-cyclo[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]D-Tyr-NH2).

[0082] PSMA-targeting compounds

[0083] PAH or a salt or carboxylic acid derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)drugs targeting prostate-specific membrane antigen (PSMA).

[0084] Human prostate-specific membrane antigen (PSMA) (also known as glutamate carboxypeptidase II (GCPII), folate hydrolase 1, folylpoly-γ-glutamate carboxypeptidase (FGCP), and N-acetylated-α-linked acid dipeptidase I (NAALADase I)) is a type II transmembrane zinc metallopeptidase that is highly expressed in the nervous system, prostate, kidney, and small intestine. It is also commonly considered a tumor marker for prostate cancer.

[0085] In earlier technologies, various PSMA-targeting agents carrying therapeutic or diagnostic moieties have been developed.

[0086] Recently, various small-molecule PSMA-targeting agents capable of binding to the extracellular domain of PSMA have been developed for PET / CT and SPECT / CT imaging, including radiolabeled N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine (DCFBC) and several urea-based peptide mimetic 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), PSMA ligands currently under clinical evaluation, and et al. developed a DOTA-conjugated PSMA-inhibitor PSMA-617 (JNM 2015, 56:914-920 and EP2862857A1).

[0087] Urea-based PSMA ligands generally consist of three components: a binding motif (Glu-urea-Lys), a linker, and a radiolabel-bearing moiety (a chelator molecule for radiolabeling or a prosthetic group for fluorination reagents). 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 NuclMed. 2013;54:380-387); 99m Tc-MIP-1404 and 99mTc-1405 (Hillier SM et al. J Nucl Med. 2013; 54: 1369-1376), which is used in clinical trials for SPECT imaging. N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4- 18 F-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) is an agent for PET imaging. Further theranostic agents are, for example 131 I-MIP-1095 (Zechmann et al., Eur J Nucl Med Mol Imaging. 2014; 41: 1280-1292), chelator-based PSMA-617 (Afshar-Oromieh A et al., J Nucl Med. 2015; 56: 1697-1705) and PSMA-I&T (Weineisen Met al., J Nucl Med. 2015; 56: 1169-1176), PSMA-I&S (Robu S et al., J Nucl Med. 2017; 58: 235-242). Further, it is mentioned that 18 F-labeled small molecule urea derivatives 18 F-DCFPyL (Chen Y et al., ClinCancer Res. 2011;17:7645-7653) and 18 F-PSMA-1007 (Giesel FL et al., Eur J Nucl Med Molecular Imaging. 2017; 44:678-688).

[0088] Recently, Kelly et al. (J Nucl Med. 2017 pii:jnumed.116.188722.doi:10.2967 / jnumed.116.188722.[Epub ahead of print]) evaluated agents that exhibit affinity for both PSMA and human serum albumin (HSA). The ligands developed by Kelly et al. include p-(iodophenyl)butyric acid entities for HSA binding and urea-based PSMA binding entities. Among the compounds developed by Kelly et al., radioactive therapeutic iodine ( 131 1) covalently attached to a HAS binding moiety which in turn is directly linked to a PSMA binding entity via a hydrocarbon chain. Another example is a PSMA binding entity with an albumin binding entity. 177 Lu-labeled phosphoramidate PSMA inhibitors (Choy et al. Theranostics 2017; 7(7): 1928-1939). 177 The DOTA chelator ether of the Lu radionuclide was linked to the irreversible PSMA inhibitor CTT1298 (EP2970345A1).

[0089] Therefore, in a preferred embodiment of the present invention, PAH or a salt or carboxylic acid derivative thereof is used to reduce the nephrotoxic side effects of a (radio)pharmaceutical comprising a PSMA targeting ligand bound to a chelator molecule as defined above, which chelator molecule is bound to a radionuclide as described above (e.g. selected from 68 Ga, 177 Lu, 225 Ac, 111 In, 99m Tc) complexation.

[0090] In a particularly preferred embodiment, PAH is used to reduce 68 Nephrotoxic side effects of Ga-PSMA-11.

[0091] Folate conjugate

[0092] FR-α has attracted the greatest interest as a tumor-associated target for imaging purposes and targeted therapy concepts. Many research groups have used folate conjugates with various therapeutic probes to target FR-positive tumor cells in vitro and in vivo as an example. Therefore, the folate receptor (FR) has been shown to be a valuable target for nuclear imaging using folate radioconjugates.

[0093] However, treatment with folate-based radiopharmaceuticals has long been considered an unattainable goal due to their extensive renal accumulation. As with other radioconjugates, the present invention, as described herein, allows for the reduction of ectopic accumulation of radiopharmaceuticals in vivo through the strategies of the present invention, thereby improving the tumor-to-kidney ratio.

[0094] Preferred Examples of Use of Folate Conjugated Radiopharmaceuticals 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; Reddy et 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).

[0095] Representative folate conjugates are e.g. 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-click-folate, 67 Ga-DOTA-Bz-folate ( 67 Ga-EC0800), 68 Ga-NODAGA-folate and

[0096]

[0097] CCK2 receptor-targeting compounds

[0098] PAH or a salt or carboxylic acid derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting the CCK2 receptor.

[0099] The CCK2 receptor (cholecystokinin) is located in the central and peripheral nervous system regions and is overexpressed in various types of human cancers, such as medullary thyroid carcinoma, small cell lung cancer and stromal ovarian cancer. Extensive research has been conducted on suitable radioligands for developing in vivo targeting of the CCK2 receptor. A variety of radiolabeled CCK / gastrin-related peptides have been synthesized and characterized. All peptides have a common C-terminal CCK receptor binding tetrapeptide sequence Trp-Met-Asp-Phe-NH2 or its derivatives. Peptides can be classified based on the sequence of their parent peptide (gastrin or CCK) and its form (i.e., linear, cyclic, polyploid).

[0100] 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-NH2), Minigastrin 0 (MG-0) D-Glu-(Glu)5-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), Minigastrin 11 (MG-11) (D-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), cyclo-Minigastrin 1 (cyclo-MG1) (cyclo[γ-D-Glu-Ala-Tyr-D-Lys]-Trp-Met-Asp-Phe-NH2), cyclo-Minigastrin 1 (cyclo-MG1) (cyclo[γ-D-Glu-Ala-Tyr-D-Lys]-Trp-Met-Asp-Phe-NH2), cyclo- 2(cyclo-MG2)(cyclo[γ-D-Glu-Ala-Tyr-D-Lys]-Trp-Nle-Asp-Phe-NH2, Demogastrin 1(D-Glu-(Glu)5-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), Demogastrin 2(D-Glu-(Glu)5-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2, H2-Met(His-His-Glu-Ala-Tyr-Gly-Trp-Met-Asp-P he-NH2), H2-Nle(His-His-Glu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2), H6-Met(His)6-Glu-Ala-Tyr-Gly-Trp -Met-Asp-Phe-NH2); and CCK8 analogs, such as CCK8(D-Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2), CCK8(Nle)(D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2), sCCK8(D-Asp-Tyr(OSO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2), sCCK8[Phe 2 (p-CH2SO3H), Nle 3,6 ](D-Asp-Phe(p-CH2SO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2), sCCK8[Phe 2 (p-CH2SO3H), HPG 3,6](D-Asp-Phe(p-CH2SO3H)-HPG-Gly-Trp-HPG-Asp-Phe-NH2).

[0101] The CCK receptor targeting peptide is preferably radiolabeled with a radionuclide for imaging or therapeutic applications. Suitable radionuclides include those specified above, and in particular include the radionuclide 99m Tc, 111 In, 18 F. 68 Ga, 131 I. 90 Y and 177 Lu. For radiolabeling with radionuclides, preferably a chelating agent conjugated to a peptide is used. As chelating agents, the above-specified chelating agents can be used, with DOTA, DOTAGA, DOTAM, DTPA and HYNIC being preferred.

[0102] Therefore, in a preferred embodiment of the present invention, PAH is used to reduce the nephrotoxic side effects of CCK2 receptor-targeted (radioactive) drugs, 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-H2-Met, 111 In-DOTA-H2-Nle, 111 In-DOTA-H6-Met, [ 99m Tc]2N4 0 、D-Glu 1 -MG( 99m Tc-Demogastrin 1), [ 99m Tc]2N4 0-1 ,Gly 0 ,D-Glu 1 -MG( 99m Tc-Demogastrin 2), 99m Tc-HYNIC-MG11, 99m Tc-HYNIC-ring-MG1, 99m Tc-HYNIC-cyclo-MG2; and CCK8 analogs such as 111 In-DTPA-CCK8, 111 In-DTPA-CCK8(Nle), 99m Tc-HYNIC-CCK8, 99mTc-HYNIC-sCCK8, 111 In-DOTA-sCCK8[Phe 2 (p-CH2SO3H),Nle 3,6 ],and 111 In-DOTA-sCCK8[Phe 2 (p-CH2SO3H),HPG 3 ,6 ].

[0103] Integrin-binding molecules

[0104] PAH or a salt or carboxylic acid derivative thereof can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting integrins.

[0105] Integrins are heterodimeric glycoproteins composed of α- and β-subunits. There are 24 known combinations of eight β- and eighteen α-units. Integrins mediate cell-cell and cell-matrix interactions and transduce signals across the plasma membrane through inside-out and outside-in signaling. Some integrins play an important role in the migration of endothelial cells and tumor cells during tumor-induced angiogenesis and tumor metastasis. Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a key step in the development and spread of various human tumors. Various therapeutic strategies in oncology have focused on inhibiting tumor-induced angiogenesis. Among integrins, the roles of integrins αVβ3 and αVβ5 have received significant attention due to their prominent role in the proliferation of vascular endothelial cells. Therefore, one of the most prominent target structures for the development of radiopharmaceuticals for imaging angiogenesis is integrin αVβ3.

[0106] By antagonizing α v β3 integrin can block tumor-induced angiogenesis in vivo. This tripeptide sequence naturally present in extracellular matrix proteins is α v The main binding site of β3 integrin. v β3 integrin is selectively expressed in tumors, and radiolabeled RGD peptide is a v Attractive candidates for β3 integrin targeting. Over the past decade, a number of radiolabeled linear and cyclic RGD peptides have been evaluated as radiotracers for tumor imaging by SPECT or PET as well as therapeutic agents.

[0107] Therefore, PAH or a salt or carboxylic acid derivative thereof may be particularly suitable for reducing the nephrotoxic side effects of (radio)pharmaceuticals including radiolabeled RGD peptides.

[0108] The RGD peptide is preferably radiolabeled with a radionuclide for imaging or therapeutic applications. Suitable radionuclides include those specified above, and in particular include the radionuclide 18 F. 99m Tc, 68 Ga, 111 In, 131 I. 90 Y. 67 Cu, and 177 Lu. For radiolabeling with radionuclides, preferably a chelating agent conjugated to a peptide is used. As a chelating agent, any suitable chelating agent specified above can be used, wherein NOTA, DOTA, DOTAGA, DOTAM, DTPA, HYNIC are preferred.

[0109] For example, PAH or its salts or carboxylic acid derivatives can be suitably used to reduce the nephrotoxic side effects of the following drugs: 18 F-Galacto-RGD, 99m Tc-NC100692( 99m Tc-maracilatide), 18 F-AH11185( 18 F-Fluciclatide), 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-Alfatide 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.

[0110] Neurotensin receptor-targeted compounds

[0111] Neurotensin receptor 1 (NTR1) is overexpressed in pancreatic ductal adenocarcinoma, one of the most lethal cancers. Several NTR1 antagonists have been developed, such as SR142948A and SR48692, and 177Lu-3BP-2273, which has been developed based on SR142948A 177 Lu-labeled DOTA-conjugated NTR1 antagonist. It has been used to treat pancreatic ductal adenocarcinoma (Baum RP et al., The Journal of Nuclear Medicine, Vol. 59, No. 5, May 2018).

[0112] Therefore, PAH or its salt or carboxylic acid derivative can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting neurotensin receptor 1, in particular radiolabeled NTR1 antagonists for cancer diagnosis or therapy, preferably 177 Lu- or 68 Ga-labeled NTR1 antagonist, more preferably 177 Lu-3BP-2273, although other radionuclides, such as those mentioned above, and other chelators, such as those mentioned above, are contemplated.

[0113] Glucagon-like peptide-1 (GLP-1) receptor-targeted compounds

[0114] The GLP-1 receptor is overexpressed in virtually all benign insulinomas and gastrinomas. Benign insulinomas, which arise from the beta cells of the pancreas as small nodules, secrete insulin, leading to potentially life-threatening hypoglycemia.

[0115] Therefore, PAH or its salt or carboxylic acid derivative may also be suitable for reducing the nephrotoxic side effects of (radio)pharmaceuticals targeting the GLP-1 receptor. Non-limiting examples include those based on the 39-mer peptide exendin-4. 111 In-、 99m Tc- and 68 Ga-labeled peptides, such as Lys 40 (Ahx-DOTA- 111 In) NH2-Exendin-4. However, other radionuclides, such as those mentioned above, and other chelating agents, such as those mentioned above, are contemplated.

[0116] Gastrin-releasing peptide (GRP) receptor-targeted compounds

[0117] PAH or its salt or carboxylic acid derivative can also be suitably used to reduce the nephrotoxic side effects of (radio)pharmaceuticals targeting GRP receptors.

[0118] GRP receptors have been identified in major human tumors, such as breast and prostate cancer. Bombesin is a tetradecapeptide neurohormone and amphibian homolog of mammalian GRP (a 27mer peptide). Various bombesin analogs have been developed for99m Tc labeling and SPECT. In particular, via the Gly-5-aminovaleric acid spacer ( 99m In addition, several bombesin analogs and bombesin antagonists have been developed and have been synthesized using different chelators with different radioisotopes (e.g. 68 Ga, 64 Cu, 18 F) is labeled. Examples include pan-bombesin analogs 68 Ga-BZH3 (Zhang H et al., Cancer Res 2004; 64: 6707-6715), and coupled to DOTA via a Gly-4-aminobenzoyl spacer. 177 Lu-labeled bombesin (7-14) derivatives (Bodei L et al., Eur J Nucl Med Mol Imaging 2007: 34 (suppl 2): S221.

[0119] However, PAH or its salts or carboxylic acid derivatives can also be suitably used to reduce the nephrotoxic side effects of GRP receptor-targeted (radio)pharmaceuticals, which include other radionuclides, such as the radionuclides mentioned above, and other chelators, such as the chelators mentioned above.

[0120] Neurokinin type 1 receptor targeting compounds

[0121] Neurokinin type 1 receptors are consistently overexpressed on glioma cells and tumor blood vessels (Hennig IM et al., Int J Cancer 1995; 61: 786-792). Radiolabeled 11-amino acid peptide substance P (Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met) acting via neurokinin type 1 receptors can be suitably used to target malignant gliomas. In particular, substance P has been conjugated to the chelator DOTAGA, and 90Y-labeled DOTAGA-substance P has been used in clinical studies (Kneifel S et al., Eur J Nucl Med Mol Imaging. 2007; 34: 1388-1395. In another study, the feasibility and effectiveness of targeted α-radiation radionuclide therapy for brain tumors were evaluated using the α-radiation emitting conjugate 213Bi-DOTA-[THi8,Met(O2)11]-substance P (Cordier et al., Eur J Nucl Med Mol Imaging. 2010; 37: 1335-1344).

[0122] Therefore, PAH or its salts or carboxylic acid derivatives can also be suitably used to reduce the nephrotoxic side effects of therapeutic and diagnostic compounds targeting neurokinin type 1 receptors, in particular substance P conjugates comprising a radionuclide for diagnosis or treatment and a chelator that coordinates the radionuclide.

[0123] Affilins

[0124] PAH or its salts or carboxylic acid derivatives may also be suitably used to reduce the nephrotoxic side effects of antibody mimetics used as therapeutic and diagnostic compounds.

[0125] Affilins are artificial proteins designed to selectively bind antigens. Affilin proteins are structurally derived from human ubiquitin or γ-B crystallin. Affilins are constructed by modifying the surface-exposed amino acids of these proteins and isolated through display technologies such as phage display and screening. They resemble antibodies in their affinity and specificity for antigens but differ in structure, making them antibody mimics. Developed by ScilProteins GmbH as potential biopharmaceutical drugs, diagnostics and affinity ligands, Affilin molecules can be easily modified and are suitable for marking tumor cells for diagnostic purposes or for specific killing of tumor cells by radiation.

[0126] Multispecific Affilin molecules can be generated that bind to different targets simultaneously. Radionuclides or cytotoxins can be conjugated to Affilin proteins, making them potential tumor therapeutics and diagnostics. Radionuclide-chelator-Affilin conjugates, such as 177 Lu-DOTA-Affilin and 68 Ga-DOTA-Affilin has been designed for imaging and therapeutic purposes. PAH can effectively reduce the nephrotoxic side effects of these Affilin conjugates. It can also be used to reduce the nephrotoxic side effects of other Affilin conjugates containing other radionuclides (such as those specified above) and chelating agents (such as those specified above).

[0127] Thus, in a preferred embodiment, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used to reduce the nephrotoxic side effects of (radiolabeled) therapeutic and diagnostic compounds used in the therapy or imaging of cancers such as, for example, neuroendocrine tumors, prostate cancer, pancreatic cancer, kidney cancer, bladder cancer, medullary thyroid cancer, small cell lung cancer, stromal ovarian cancer, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, breast cancer, etc.

[0128] For example, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used to reduce the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds used for prostate cancer therapy or imaging, such as (radio)pharmaceuticals targeting somatostatin receptors or (radio)pharmaceuticals targeting prostate specific membrane antigen (PSMA). In a preferred embodiment, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used to reduce 177 Lu-DOTATOC( 177 Nephrotoxic side effects of Lu-DOTA°-[Tyr3]-octreotide).

[0129] In an embodiment of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used in combination with other substances that reduce 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 as PMPA), vitamins, Gelofusine, or FRALB-C (cyanogen bromide-cleaved bovine serum albumin).

[0130] In a particularly preferred embodiment of the present invention, the pharmaceutically acceptable salt of PAH is sodium aminohippurate. Preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, preferably sodium aminohippurate, is used in a saline solution, preferably in water for injection (WFI) or a NaCl solution, more preferably in a 20% NaCl solution.

[0131] In the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is used in an amount sufficient to effectively reduce the nephrotoxic side effects of the therapeutic and / or diagnostic compound. This effective amount of PAH can be determined by routine experimentation, such as by using an animal model. Such models include, but are not limited to, rabbit, sheep, mouse, rat, dog, and non-human primate models.

[0132] For example, the amount of PAH administered may range from about 0.1 mg / kg to 10 g / kg (per kilogram body weight), preferably from about 0.5 mg / kg to 5 g / kg, and more preferably from about 1 mg / kg to 1 g / kg.

[0133] In a preferred embodiment of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is used in an amount of about 5 mg to about 500 mg per 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 up to 500 mg per kg body weight. More preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is used in an amount of about 50 mg to about 500 mg per kg body weight, more preferably about 50 mg to about 250 mg per kg body weight, for example about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg per kg body weight. More preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used in an amount of about 75 mg to about 200 mg per kg body weight, for example, in an amount of about 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, up to 200 mg per kg body weight, or 200 mg per kg body weight. More preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof is used in an amount of about 80 mg to about 160 mg per 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, up to 160 mg per kg body weight, or in an amount of 160 mg per kg body weight.

[0134] Typically, the PAH, or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, is used in a greater (molar and / or w / w) amount than the (co-administered) therapeutic or diagnostic compound.

[0135] For example, the therapeutic or diagnostic compound is used in a ratio of about 1 / 1,000,000 to 1 / 10 (w / w) to PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate), preferably about 1 / 500,000 to 1 / 100 (w / w), more preferably about 1 / 250,000 to about 1 / 500 (w / w).

[0136] In a preferred embodiment of the present invention, the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are used in a ratio of about 1 / 250,000 to about 1 / 5,000 (w / w), for example, about 1 / 250,000, 1 / 200,000, 1 / 150,000, 1 / 100,000, or 1 / 50,000 to about 1 / 5,000 (w / w), more preferably about 1 / 240,000 to about 1 / 8,000 (w / w), for example, about 1 / 240,000, 1 / 230,000, 1 / 220,000, 1 / 210,000, 1 / 200,000, 1 / 190,000, 1 / 180,000 000, 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) ratio. In a further preferred embodiment, the therapeutic and / or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are used in a ratio of about 1 / 100,000 to about 1 / 10,000 (w / w), for example, about 1 / 100,000, 1 / 95,000, 1 / 90,000, 1 / 85,000, 1 / 80,000, 1 / 75,000, 1 / 70,000, 1 / 65,000, 1 / 60,000, 1 / 55,000, 1 / 50,000, 1 / 45,000, 1 / 40,000, 1 / 35,000, 1 / 30,000, 1 / 25,000, 1 / 20,000, 1 / 15,000, 1 / 10,000 (w / w). In a further preferred embodiment, the therapeutic and / or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are used in a ratio of about 1 / 50,000 to about 1 / 40,000 (w / w), for example, 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 / 40,000 (w / w).

[0137] In a second aspect, the present invention relates to a pharmaceutical composition comprising (a) a radiolabeled and / or non-radiolabeled drug compound in combination with para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, and a pharmaceutically acceptable excipient, diluent, carrier or combination thereof.

[0138] The radiolabeled or non-radiolabeled pharmaceutical compound may be any nephrotoxic therapeutic or diagnostic compound specified above that potentially exhibits nephrotoxic side effects, preferably a radiolabeled diagnostic and / or therapeutic compound. Preferably, the pharmaceutical composition comprises a radiolabeled pharmaceutical compound that is a radionuclide complex conjugated to a carrier molecule, thereby comprising a carrier molecule, a chelating agent and a radionuclide.

[0139] Preferably, the carrier molecule of the radionuclide complex is selected from the carrier molecules specified above, in particular from small organic molecules, peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules and binding agents, and more preferably from the somatostatin analogs, PSMA-inhibitors, gastrin analogs, integrin binding molecules and antigen binding proteins specified above, such as Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD, Affilin or folate conjugates. In a particularly preferred embodiment, the carrier molecule is selected from Tyr3-octreotide and Tyr3-octreotate.

[0140] Preferably, the chelating agent of the radionuclide complex is selected from the chelating agents specified above, more preferably selected from DOTA, DOTAM, DOTAG, HBED-CC, NOTA, NODAGA, DOTAGA, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3AP PrA 、DO3AP ABn , HYNIC or its derivatives.

[0141] Preferably, the radionuclide of the radionuclide complex is selected from the radionuclides specified above, and more preferably selected from 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, 67Cu, 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 Even more preferably, the radionuclide of the radionuclide complex included in the pharmaceutical composition is selected from 177 Lu, 68 Ga, 111 In, 90 Y. 99m Tc, 18 F. 131 I. 225 Ac and 161 Tb, or most preferably selected from 177 Lu, 68 Ga, 111 In, 90 Y. 99m Tc, 225 Ac and 161 In one embodiment, the radionuclides are specifically selected from divalent radionuclides, in particular from 64 Cu, 67 Cu and 212 Pb, selected from trivalent radionuclides, in particular 177 Lu, 90 Y. 67 Ga, 68 Ga, 111 In, 225 Ac, 161 Tb, 44 Sc and 47 Sc, or selected from tetravalent radionuclides, in particular 227 Th. In another embodiment, the radionuclide is 99m Tc, which may be divalent, tetravalent, or pentavalent. More particularly, the radionuclide may be selected from trivalent radionuclides.

[0142] It is also preferred that the radionuclide is suitable for complexation by 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 is bound to DOTATOC which acts as a chelating agent.

[0143] As mentioned above, suitable combinations of carrier molecules, chelating agents and radionuclides can be appropriately selected by those skilled in the art. For example, the radionuclide complex can be selected from [ 177 Lu-DOTA°-Tyr3]-octreotide, 177 Lu-DOTA-JA11, 177 Lu-RGD, 177 Lu-DOTA-Affilin 2, 177 Lu-DOTA-Sargastrin, 68 Ga-HBED-CC-PSMA-11. Preferably, the radionuclide complex is selected from [ 177 Lu-DOTA°-Tyr3]-octreotide and [ 177 Lu-DOTA°-Tyr3]-octranate.

[0144] The pharmaceutical composition preferably includes a safe and effective amount of a radiolabeled or non-radiolabelled therapeutic or diagnostic compound.

[0145] As used herein, a "safe and effective amount" refers to an amount of an agent sufficient to allow diagnosis and / or significantly induce a positive change in the disease to be treated. However, at the same time, a "safe and effective amount" is small enough to avoid serious side effects, that is, to allow a reasonable relationship between advantages and risks. In addition, the "safe and effective amount" will vary depending on the specific condition to be diagnosed or treated, the age and physical condition of the patient to be treated, the severity of the condition, the duration of treatment, the nature of the concomitant therapy, the nature of the specific pharmaceutically acceptable excipient or carrier used, and similar factors.

[0146] In a particularly preferred embodiment of the present invention, the pharmaceutical composition comprises sodium aminohippurate as a pharmaceutically acceptable salt of PAH.

[0147] Typically, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is present in a greater amount than the (co-administered) therapeutic or diagnostic compound contained in the pharmaceutical composition.

[0148] For example, the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are present in the pharmaceutical composition in a ratio of about 1 / 1,000,000 to 1 / 10 (w / w), preferably about 1 / 500,000 to 1 / 100 (w / w), more preferably about 1 / 250,000 to about 1 / 500 (w / w).

[0149] In a preferred embodiment of the present invention, the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are present in the pharmaceutical composition in a ratio of about 1 / 250,000 to about 1 / 5,000 (w / w), for example, about 1 / 250,000, 1 / 200,000, 1 / 150,000, 1 / 100,000, or 1 / 50,000 to about 1 / 5,000 (w / w), more preferably about 1 / 240,000 to about 1 / 8,000 (w / w), for example, about 1 / 240,000, 1 / 230,000, 1 / 220,000, 1 / 210,000, 1 / 200,000, 1 / 190,000, 1 / 200,000, 1 / 250,000, 1 / 260,000, 1 / 300,000, 1 / 400,000, 1 / 500,000, 1 / 600,000, 1 / 700,000, 1 / 800,000 00, 1 / 180,000, 1 / 170,000, 1 / 160,000, 1 / 150,000, 1 / 140,000, 1 / 130,000, 1 / 120,000, 1 / 110,000, 1 / 100,000, 1 / 90,000, 1 / 80,000, 1 / 70,000, 1 / 60,000, 1 / 50,000, 1 / 40,000, 1 / 30,000, 1 / 20,000, 1 / 19,000, 1 / 18,000, 1 / 17,000, 1 / 16,000, 1 / 15,000, 1 / 14,000, 1 / 13,000, 1 / 12,000, 1 / 11,000, 1 / 10,000, 1 / 9,000 or 1 / 8,000 (w / w ratio). More preferably, the therapeutic and / or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are present in the pharmaceutical composition in a ratio of about 1 / 100,000 to about 1 / 10,000 (w / w), for example, about 1 / 100,000, 1 / 95,000, 1 / 90,000, 1 / 85,000, 1 / 80,000, 1 / 75,000, 1 / 70,000, 1 / 65,000, 1 / 60,000, 1 / 55,000, 1 / 50,000, 1 / 45,000, 1 / 40,000, 1 / 35,000, 1 / 30,000, 1 / 25,000, 1 / 20,000, 1 / 15,000, 1 / 10,000 (w / w). In a further preferred embodiment, the therapeutic and / or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are present in the pharmaceutical composition in a ratio of about 1 / 50,000 to about 1 / 40,000 (w / w), for example, 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 / 40,000 (w / w).

[0150] In an embodiment of the present invention, the pharmaceutical composition comprises, in addition to PAH, additional substances that reduce the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds, wherein the substances in addition to PAH that reduce the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds are preferably selected from amino acids, such as lysine and arginine, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules (such as PMPA), vitamins.

[0151] The pharmaceutical composition comprising PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, (a) a radiolabeled and / or non-radiolabeled pharmaceutical compound, and optionally an additional substance that reduces the nephrotoxic side effects of the radiolabeled and non-radiolabeled therapeutic and diagnostic compound further comprises a pharmaceutically acceptable excipient, diluent, carrier, or combination thereof. The pharmaceutical composition is preferably a liquid or semi-liquid composition, more preferably a liquid or semi-liquid composition, more preferably an aqueous solution, which may be buffered and / or exhibit isotonic properties.

[0152] The term "pharmaceutically acceptable" refers to compounds or agents that are compatible with the components of the pharmaceutical compositions of the present invention, particularly with the diagnostic or therapeutic drug compounds, and do not interfere with and / or substantially reduce their diagnostic or therapeutic activity. Pharmaceutically acceptable carriers preferably have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the subject to be treated.

[0153] Formulations, carriers and excipients

[0154] Pharmaceutically acceptable excipients can perform different functional roles and include, but are not limited to, diluents, fillers, extenders, carriers, disintegrants, binders, lubricants, glidants, coatings, solvents and co-solvents, buffers, preservatives, adjuvants, antioxidants, wetting agents, antifoaming agents, thickeners, sweeteners, flavorings, and humectants.

[0155] Suitable pharmaceutically acceptable excipients are generally selected based on the formulation of the pharmaceutical composition.

[0156] For pharmaceutical compositions in liquid form, useful pharmaceutically acceptable excipients 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 peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.); lecithin; surfactants; preservatives such as benzyl alcohol, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.; isotonic agents such as sugars; polyols such as mannitol, sorbitol, sodium chloride; aluminum monostearate or gelatin; antioxidants such as ascorbic acid, sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or glucose. pH can be adjusted with acids or bases, for example, hydrochloric acid or sodium hydroxide. The buffer can be hypertonic, isotonic or hypotonic relative to a specific reference medium, i.e. the buffer can have a higher, the same or lower salt content relative to a specific reference medium, wherein preferably such concentrations of the above-mentioned salts can be used which do not result in cell damage due to osmotic or other concentration effects. The reference medium is a liquid present in in vivo methods, such as blood, lymph, cytosolic fluid or other body fluids, or a liquid such as can be used as a reference medium in in vitro methods, such as a common buffer or liquid. Such common buffers or liquids are known to the skilled person.

[0157] Liquid pharmaceutical compositions for administration via injection, especially by intravascular, more preferably intravenous (iv) injection, should preferably be sterile and stable under the conditions of manufacture and storage. Such compositions are typically formulated into parenteral acceptable aqueous solutions that are pyrogen-free, have a suitable pH, are isotonic and maintain the stability of the active ingredient.

[0158] For liquid pharmaceutical compositions, suitable pharmaceutically acceptable excipients and carriers include water, typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, such as phosphate, citrate, etc. In particular, for injections of the (pharmaceutical) composition of the present invention, water or preferably a buffer, more preferably an aqueous buffer, can be used, which may contain a sodium salt, such as at least 50 mM sodium salt, a calcium salt, such as at least 0.01 mM calcium salt, and optionally a potassium salt, such as at least 3 mM potassium salt.

[0159] Sodium salts, calcium salts, and optionally potassium salts may be present in the form of their halides, such as chlorides, iodides, or bromides, in the form of their hydroxides, carbonates, bicarbonates, or sulfates. Without limitation, examples of sodium salts include NaCl, NaI, NaBr, Na2CO3, NaHCO3, and Na2SO4, examples of potassium salts include KCl, KI, KBr, K2CO3, KHCO3, and K2SO4, and examples of calcium salts include CaCl2, CaI2, CaBr2, CaCO3, CaSO4, and Ca(OH)2. In addition, organic anions of the above-mentioned cations may be included in the buffer.

[0160] The buffer solution that is suitable for injection purpose as defined above can comprise and be selected from sodium chloride (NaCl), calcium chloride (CaCl ) and optionally potassium chloride (KCl) salt, wherein other anions can also be present except chloride radical.CaCl 2 can also be replaced with another salt, as KCl.Usually, the salt in injection buffer solution is with at least 50mM sodium chloride (NaCl), at least 3mM potassium chloride (KCl) and at least 0.01mM calcium chloride (CaCl ) concentration exists.Injection buffer solution can be hypertonic, isotonic or hypotonic with respect to specific reference medium, namely buffer solution can have higher, identical or lower salt content with respect to specific reference medium, wherein preferably can use this concentration of above-mentioned salt, it does not cause the cell damage that causes because of osmotic or other concentration effects.

[0161] For pharmaceutical compositions in (semi)solid form, suitable pharmaceutically acceptable excipients and carriers include binders such as microcrystalline cellulose, gum tragacanth or gelatin; starch or lactose; sugars such as lactose, glucose and sucrose; starches such as corn starch or potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; disintegrants such as alginic acid; lubricants such as magnesium stearate; glidants such as stearic acid, magnesium stearate; calcium sulfate, colloidal silicon dioxide and the like; sweeteners such as sucrose or saccharin; and / or flavorings such as mint, methyl salicylate or orange flavoring.

[0162] Typically, the pharmaceutical composition for topical application can be formulated into a cream, ointment, gel, paste or powder. The pharmaceutical composition for oral administration can be formulated into tablets, capsules, liquids, powders or sustained release forms. However, according to a preferred embodiment, the pharmaceutical composition of the present invention is administered parenterally, particularly by intravenous or intratumoral injection, and is therefore formulated into a liquid or lyophilized form for parenteral administration, as discussed elsewhere herein. Parenteral formulations are typically stored in bottles, IV bags, ampoules, cartridges or prefilled syringes and can be administered as injections, inhalants or aerosols, with injections being preferred.

[0163] The pharmaceutical composition may be provided in lyophilized form. The lyophilized pharmaceutical composition is preferably reconstituted in a suitable buffer, advantageously based on an aqueous carrier, before administration.

[0164] The pharmaceutical compositions of the present invention are also useful in the preparation of medicaments for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds.

[0165] The pharmaceutical composition or medicament is preferably used to reduce the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds used for imaging or treating diseases, in particular neoplastic diseases, such as neuroendocrine tumors, prostate cancer, pancreatic cancer, kidney cancer, bladder cancer, brain cancer, gastrointestinal cancer, medullary thyroid cancer, small cell or non-small cell lung cancer, and stromal ovarian cancer, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, breast cancer, or sarcoma.

[0166] Reagent test kit

[0167] According to a further aspect, the present invention provides a kit comprising a pharmaceutical ingredient for use according to the present invention, such as para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, a radiolabeled or non-radiolabeled therapeutic or diagnostic compound as specified above, and / or a pharmaceutical composition according to the present invention. For example, in an embodiment, the kit may comprise para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof in one part of the kit and a pharmaceutical composition according to the present invention as specified above in another part of the kit, or a solution for a soluble PAH or a solution of a pharmaceutically acceptable salt or carboxylic acid derivative thereof in another part of the kit. The solution may be isotonic or hypertonic, and it may be buffered, such as an optionally buffered aqueous solution, such as an aqueous NaCl solution or water for injection (WFI). In another embodiment of the invention, the kit may comprise para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof in one part of the kit and a radiolabeled and / or non-radiolabeled therapeutic or diagnostic compound as specified above in another part of the kit.

[0168] Optionally, the kit may include at least one additional agent as defined herein in the context of pharmaceutical compositions, including, for example, amino acids such as lysine and arginine and mixtures thereof, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules (e.g., PMPA), vitamins, radionuclides, antimicrobial agents, solubilizing agents, and the like.

[0169] The kit can be a two-part or more part kit of any of the components listed above contained in a suitable container. For example, each container can be in the form of a vial, bottle, squeeze bottle, jar, sealed sleeve, envelope or capsule, tube or blister pack, or any other suitable form, provided that the container preferably prevents premature mixing of the components. Each different component can be provided separately, or a number of different components can be provided together (i.e., in the same container).

[0170] The container may also be a vial, a tube, a jar, or an envelope, or a sleeve, or a blister pack, or a compartment or chamber within a bottle, provided that the contents of one compartment cannot be physically associated with the contents of another compartment prior to intentional mixing by a pharmacist or physician.

[0171] The kit or part of a kit may also comprise a technical instruction sheet containing information on the administration and dosage of any of its components.

[0172] Therapeutic and diagnostic methods and uses

[0173] According to a further aspect, the present invention relates to the use of p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof, and / or a pharmaceutical composition as described above, and / or a kit as described above for the preparation of a medicament for reducing the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject.

[0174] Also contemplated is a pharmaceutical composition as described above or a kit as described above for use in a method of reducing nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds in a subject.

[0175] In a further aspect, the present application 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 to the subject a pharmaceutical composition as described above or a kit as described above during imaging or therapy using radiolabeled and / or non-radiolabeled compounds.

[0176] In a further aspect, the present application 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 to the subject para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof in combination with a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, wherein the administration of PAH is before and / or during and / or after the administration of the radiolabeled or non-radiolabeled therapeutic or diagnostic compound.

[0177] In a preferred embodiment, the method is used to reduce the nephrotoxic side effects of radiopharmaceuticals in subjects undergoing radioligand therapy or diagnosis. Preferably, the radiopharmaceutical compartment is a radionuclide complex comprising a carrier molecule as specified above, a chelating agent, and a radionuclide. In a more preferred embodiment, the carrier molecule is selected from peptides, peptidomimetics, antibody fragments, antibody mimetics, small molecules, and binding agents, which may have the properties of an agonist or antagonist ligand for a cell receptor, particularly 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 as specified above, and for example, selected from Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD.

[0178] In a further embodiment, the chelating agent of 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 its derivatives.

[0179] In a further preferred embodiment, the radionuclide of the radiopharmaceutical compound used in the method of the present invention is selected from 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 1, and more preferably selected from 177 Lu,225 AC and 68 Ga.

[0180] In a further preferred embodiment of the present invention, the radionuclide comprising conjugate molecule used in the method of the present invention is selected from [ 177 Lu-DOTA°-Tyr3]-octreotide, 177 Lu-DOTA-JA11, 177 Lu-DOTA-RGD, 177 Lu-DOTA-Sargastrin, 68 Ga-HBED-CC-PSMA-11, PSMA11, 177 Lu-PSMAI&T and 99m Tc-Etarforlatide.

[0181] In a particularly preferred embodiment of the present invention, the pharmaceutically acceptable salt of PAH used in the method of the present invention is sodium aminohippurate.

[0182] In the methods of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is preferably administered in an amount sufficient to effectively reduce the nephrotoxic side effects of the therapeutic and / or diagnostic compound, which is typically administered in parallel to the subject. The effective amount of PAH can be determined by routine experimentation, such as by using an animal model. Such models include, but are not limited to, rabbit, sheep, mouse, rat, dog, and non-human primate models.

[0183] For example, the amount of PAH administered may range from about 0.1 mg / kg to 10 g / kg (per kilogram body weight), preferably from about 0.5 mg / kg to 5 g / kg, and more preferably from about 1 mg / kg to 1 g / kg.

[0184] In particularly preferred methods of the invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered in an amount of about 5 mg to about 500 mg per kilogram of body weight, typically in parallel (e.g., before, concurrently, or after administration of the 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 per kilogram of body weight. Thus, the amounts exemplified herein can be given on the same day (e.g., on the same day as the diagnostic / therapeutic nephrotoxic compound). The administration regimen of the PAH or its salt or carboxylic acid derivative generally follows the administration regimen of the nephrotoxic compound. More preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered in an amount of about 50 mg to about 500 mg per kilogram body weight, more preferably about 50 mg to about 250 mg per kilogram body weight, for example about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg per kilogram body weight. More preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered in an amount of about 75 mg to about 200 mg per kilogram body weight, for example, about 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg per kilogram body weight. Most preferably, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered in an amount of about 80 mg to about 160 mg per kilogram body weight, for example, about 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160 mg per kilogram body weight.

[0185] Typically, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered in a greater amount than the (co-administered) therapeutic or diagnostic compound.

[0186] For example, the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are administered in a ratio of about 1 / 1,000,000 to 1 / 10 (w / w), preferably about 1 / 500,000 to 1 / 100 (w / w), more preferably about 1 / 250,000 to about 1 / 500 (w / w).

[0187] In a preferred method of the present invention, the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are administered in a ratio of about 1 / 250,000 to about 1 / 5,000 (w / w), such as about 1 / 250,000, 1 / 200,000, 1 / 150,000, 1 / 100,000, or 1 / 50,000 to about 1 / 5,000 (w / w), more preferably about 1 / 240,000 to about 1 / 8,000 (w / w), such as about 1 / 240,000, 1 / 230,000, 1 / 220,000, 1 / 210,000, 1 / 200,000, 1 / 190,000, 1 / 1800,000 00, 1 / 170,000, 1 / 160,000, 1 / 150,000, 1 / 140,000, 1 / 130,000, 1 / 120,000, 1 / 110,000, 1 / 100,000, 1 / 90,000, 1 / 80,000, 1 / 70,000, 1 / 60,000, 1 / 50,000, 1 / 40,000, 1 / 30,000, 1 / 20,000, 1 / 19,000, 1 / 18,000, 1 / 17,000, 1 / 16,000, 1 / 15,000, 1 / 14,000, 1 / 13,000, 1 / 12,000, 1 / 11,000, 1 / 10,000, 1 / 9,000, or 1 / 8,000 (w / w) ratio. In a further preferred method, the therapeutic and / or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are administered in a ratio of about 1 / 100,000 to about 1 / 10,000 (w / w), for example, about 1 / 100,000, 1 / 95,000, 1 / 90,000, 1 / 85,000, 1 / 80,000, 1 / 75,000, 1 / 70,000, 1 / 65,000, 1 / 60,000, 1 / 55,000, 1 / 50,000, 1 / 45,000, 1 / 40,000, 1 / 35,000, 1 / 30,000, 1 / 25,000, 1 / 20,000, 1 / 15,000, 1 / 10,000 (w / w). In a further preferred method, the therapeutic and / or diagnostic compound and PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) are administered in a ratio of about 1 / 50,000 to about 1 / 40,000 (w / w), for example, 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 / 40,000 (w / w).

[0188] In another embodiment of the present invention, aminohippuric acid (PAH) or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered in the methods of the present invention in combination with a further 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 PAH is selected from amino acids, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules (such as PMPA), and vitamins. The substance that reduces the nephrotoxic side effects of radiolabeled and non-radiolabeled therapeutic and diagnostic compounds other than PAH can be administered before, during, and / or after the administration of PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate).

[0189] The pharmaceutical composition or kit of the present invention can be administered to a subject in need thereof once a day, every other day, every week or several times a month. Preferably, treatment, diagnosis or prevention is achieved with an effective dose of the pharmaceutical composition or kit of the present invention.

[0190] In the methods of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) can be administered to the subject before and / or during and / or after the administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, pharmaceutical composition or kit, respectively. For example, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered before the administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound, pharmaceutical composition or kit. In a preferred method of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is administered before the administration of the pharmaceutical composition or kit of the present invention as defined above, i.e., PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate). PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) can be administered alternately before and / or during and / or after the administration of a radiolabeled or non-radiolabeled therapeutic or diagnostic compound. The PAH can be pre-administered 60 minutes, 30 minutes, 10 minutes, or 5 minutes prior to administration of the therapeutic or diagnostic compound, pharmaceutical composition, or kit, preferably the PAH is administered about 0.5-5 hours or 10-60 minutes prior to administration of the therapeutic or diagnostic compound, pharmaceutical composition, or kit, respectively. In certain embodiments, the PAH can be administered before and after administration of the therapeutic or diagnostic compound, such as 0.5-5 hours or 10-60 minutes thereafter, or before, during, and after.

[0191] In the methods of the present invention, PAH or a pharmaceutically acceptable salt or carboxylic acid derivative thereof (preferably sodium aminohippurate) is preferably administered in a buffered aqueous solution, such as an isotonic or hypertonic solution, for example water for injection (WFI) or a NaCl solution, such as a 20% NaCl solution.

[0192] In the methods of the present invention, the PAH, pharmaceutical composition or kit is typically administered parenterally. Administration can preferably be accomplished systemically, for example, by intravascular, intravenous (iv), subcutaneous, intramuscular or intradermal injection. Alternatively, administration can be accomplished locally, for example, by intratumoral injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0193] Figure 1 The results of the co-infusion of amino acids and PAH over time were shown. 177 Renal absorption of Lu-DOTA°-Tyr3]-octreotide using 0.9% NaCl as a control.

[0194] Figure 2 The results show that the kidneys were significantly improved with co-infusion of amino acids and PAH over time compared to baseline (0.9% NaCl infusion). 177 The percentage of Lu-DOTA°-Tyr3]-octreotide absorption was reduced.

[0195] Figure 3 Co-injection of 0.9% NaCl, Lys / Arg and PAH in the kidney at an early time point of 0.5 h pi is shown [ 177 Percent injected dose of Lu-DOTA°-Tyr3]-octreotide.

[0196] Figure 4 Co-injection of 0.9% NaCl, Lys / Arg and PAH in the kidney at late time points of 24 h pi is shown [ 177 Percent injected dose of Lu-DOTA°-Tyr3]-octreotide.

[0197] Figure 5 The 5min and 60min pi times are shown [ 177 In vitro organ absorption of Lu-DOTA°-Tyr3-octreotide (N=5). PAH significantly reduced uptake in the kidney, even at early time points (**P≤0.005, ****P≤0.0005).

[0198] Figure 6Shown are the percentages of injected radioactivity present in the kidney at different time points after injection (0.5, 1, 4, 24 h) of different radiolabeled (Lu-177) agents (DOTA-RGD, Affilin, DOTA-Sargastrin, DOTA-JR11) using co-injection with PAH (200 mg / mL) and 0.9% NaCl, respectively.

[0199] Figure 7 Shown are the percentages of injected radioactivity present in the blood at different time points after injection (0.5, 1, 4, 24 h) of different radiolabeled (Lu-177) agents (DOTA-RGD, Affilin, DOTA-Sargastrin, DOTA-JR11) using co-injection with PAH (200 mg / mL) and 0.9% NaCl, respectively.

[0200] Figure 8 The results show that the coinjection of PAH (200 mg / mL) and 0.9% NaCl was effective in 68 Percentage of injected radioactivity present in kidney (upper panel) and blood (lower panel) at different times after Ga-labeled HBED-CC-PSMA-11 injection (0.1, 0.5, 1, 2, 4 h).

[0201] Figure 9 The graph shows the intraperitoneal injection of PAH or saline solution followed by intravenous administration to mice. 177 Biodistribution analysis results of Lu-DOTATOC.

[0202] Figure 10 The graph shows the intraperitoneal injection of PAH or saline solution followed by intravenous administration to mice. 99m Results of biodistribution analysis of Tc-Etarfolatide.

[0203] Figure 11 Shows the injection 177Lu - Bar graph comparing the three groups of rats injected with PSMAI&T, saline VE, 4-(dipropylsulfamoyl)benzoic acid KP2 or PAH KP1 solution, expressed as the percentage of radioactivity injected in the kidney.

[0204] Figure 12 Shows the injection 177Lu - Bar graph comparing PSMA I&T, three groups of rats injected with saline VE, 4-(dipropylsulfamoyl)benzoic acid KP2 or PAH KP1 solution, expressed as a percentage of the radioactivity injected into the left ventricle.

[0205] Figure 13Shows the injection 177Lu - PSMA I&T, comparison bar graph of three groups of rats injected with saline VE, 4-(dipropylsulfamoyl)benzoic acid KP2 or PAH KP1 solution, expressed as percentage of injected radioactivity in the left renal medulla.

[0206] Figure 14 Shows the injection 177Lu - PSMA I&T, comparison bar graph of three groups of rats injected with saline VE, 4-(dipropylsulfamoyl)benzoic acid KP2 or PAH KP1 solution, expressed as percentage of injected radioactivity in the renal cortex. Example

[0207] The following data demonstrate that co-administration with sodium aminohippurate solution (PAH) significantly reduces renal retention and absorption of various radiopharmaceuticals (including various carrier molecules, various chelators, and various radionuclides, respectively), and that PAH administration is more effective than lysine and arginine infusions. Furthermore, it was found that the bioavailability of the radiopharmaceutical was enhanced, and that tumor uptake of the radiopharmaceutical was increased by co-administration with PAH.

[0208] Experimental protocol (Examples 1 and 2):

[0209] SPECT / CT experiment:

[0210] Renal biodistribution of [177Lu-DOTA°-Tyr3]-octreotide was determined by single-photon emission computed tomography (SPECT) in healthy Wistar rats using volume-of-interest (VOI) images obtained in three groups of six animals per renoprotectant. 50 MBq of [177Lu-DOTA°-Tyr3]-octreotide was co-administered with a 200 mg / mL solution of amino acids (L-Arg and L-Lys) in water for injection, a 200 mg / mL solution of sodium p-aminohippurate (PAH) in water for injection, and a 0.9% NaCl solution as a reference. Imaging acquisition was performed 0.5, 1, 4, 8, and 24 hours post-injection.

[0211] Isolated organ distribution:

[0212] All animals were pre-injected with 1.0 mL of NaCl, Arg-Lys, or PAH 10 min before radiotracer injection. The injection solution for biodistribution was prepared as 12 μL of [ 177 Lu]Lu-DOTA-TOC, 1.5 mL of NaCl or a mixture of Arg-Lys or PAH.

[0213] The injection solution for SPECT animals was prepared as a mixture of 80 μL [177Lu]Lu-DOTA-TOC, 1.5 mL NaCl or Arg-Lys or PAH. The animals were injected and sacrificed 5 or 60 minutes later. Target organs and tissues were collected and their activity was measured. The average body weight of male Wistar rats was 210 ± 12 g (5 min) and 218 ± 13 g (60 min). The average injection activity was 4.49 ± 0.38 MBq / kg body weight (5 min) and 159 ± 13 MBq / kg body weight (5 min) for SPECT, and 4.19 ± 0.57 MBq / kg body weight (60 min) or 139 ± 8 MBq / kg body weight (60 min) for SPECT animals.

[0214] Statistical analysis was performed using Microsoft Excel 2010 and Graphpad Prism 6.05. Data are presented as medians and [25th and 75th percentiles], as well as means and standard deviations (SD) or standard errors of the mean (SEM). For comparisons, standard one-way analysis of variance with Tukey's multiple comparison test and two-sample two-tailed t-test were used. P < 0.05 was considered significant.

[0215] Example 1: 177 Renal absorption of Lu-DOTA°-Tyr3]-octreotide

[0216] [ 177 Renal absorption of Lu-DOTA°-Tyr3]-octreotide was determined by quantitative small animal SPECT in rats co-infused with 0.9% NaCl (control), Lys / Arg (250 mg Lys / 250 mg Arg) and PAH (500 mg), respectively. The results are presented in Tables 1 to 3.

[0217] Table 1: Kidney radioactivity co-infused with 0.9% NaCl (control) [expressed as percent of injected radioactivity, decay-corrected data]

[0218]

[0219] Table 2: Renal radioactivity with Lys / Arg co-infusion (250 mg Lys / 250 mg Arg) [expressed as percent of injected radioactivity, decay-corrected data]

[0220]

[0221] Table 3: Kidney radioactivity co-infused with PAH (500 mg) [expressed as percent of injected radioactivity, decay-corrected data]

[0222]

[0223] The values shown in Tables 1 to 3 are Figures 1 to 4 It is shown graphically in .

[0224] It is clear from the presented results that co-infusion of Lys / Arg resulted in a 21% and 26% reduction in renal uptake after 8 and 24 h, respectively, with large inter-individual variability ( Table 2 , Figure 1 、 2 and 4). The results of amino acid infusion were similar to those reported in the literature (33% + / - 23%, Rolleman EJ et al., supra). In contrast, co-infusion of PAH resulted in a 56% and 50% reduction at the same time points with low standard deviations (Table 3, Figure 1 and 2 Infusion of PAH also resulted in decreased renal absorption at early time points. At 0.5 h post-injection, the Lys / Arg mixture showed only a slight decrease of 10%, compared to a 50% decrease in PAH (Tables 2 and 3, Figure 1-3 ).

[0225] Example 2: 177 In vitro organ absorption of Lu-DOTA°-Tyr3-octreotide

[0226] According to the above protocol, the early time points of 5 min and 60 min pi were determined [ 177 The results were in the isolated organ concentration of Lu-DOTA°-Tyr3]-octreotide. Figure 5 Even at early time points, when PAH-infusion was used as a co-agent, [ 177 The absorption of Lu-DOTA°-Tyr3-octreotide was significantly reduced compared with NaCl infusion (P < 0.005).

[0227] In summary, the above results indicate that sodium aminohippurate solution has a significantly higher effect in reducing renal retention and absorption of [177Lu-DOTA°-Tyr3]-octreotide compared to the combination of lysine and arginine known in the prior art.

[0228] Experimental Protocol (Examples 3-5)

[0229] Imaging studies aimed to evaluate the effects of PAH on the reduction of chelators and binding scaffolds with different structures. 177 Lu or 68 The effectiveness of Ga-labeled peptides in terms of renal absorption. The tracer distribution of radiolabeled test compounds was performed in two different groups of healthy Wistar rats, focusing on renal uptake / elimination and blood levels. One group was administered 177 Lu / 68Ga tracer was combined with saline as a control (MBq / kg and mg / kg were defined individually), while another group received PAH intraperitoneal injection first (10 min before injection). 177 Lu / 68 Ga-peptide and two intravenous injections of PAH solution. PET or SPECT was used to evaluate each 177 Lu / 68 Renal clearance and overall pharmacokinetics of Ga-peptide (administered with or without pre-administration of PAH) At least 3 rats were included in each group for statistical purposes.

[0230] 177 Lu-peptide: provided by ITG 177 Lu-labeled compounds were tested for radiochemical purity using iTLC upon receipt. The test parameters are provided for each compound, with RCP > 95%. Table 4 summarizes the radiochemical purity of each compound to be studied. 177 Nominal dose levels, concentrations, and volumes of Lu-peptides.

[0231] Table 4

[0232]

[0233] 68 Ga-peptide: 68 Ga-labeled compounds were prepared directly before use and tested for radiochemical purity using iTLC. (Labeling and QC testing parameters are provided for each compound, RCP > 95%). Table 5 summarizes the radiochemical purity of each compound to be studied. 68 Nominal dose levels, concentrations, and volumes of Ga-peptide.

[0234] Table 5

[0235]

[0236] Example 3: Reduction of Renal Absorption of Various Radiolabeled Compounds by Concomitant Administration of PAH

[0237] Mice were injected with four different molecules conjugated to the cyclic chelator DOTA and radiolabeled with the therapeutic radionuclide lutetium-177: 177 Lu-DOTA-RGD, 177 Lu-DOTA-Affilin, 177 Lu-DOTA-Sargastrin and 177 Lu-DOTA-JR11 was co-injected with PAH (200 mg / mL) or saline (0.9% NaCl) as a control. The percentage of injected radioactivity present in the kidney was determined over time according to the above protocol. Figure 6 Medium graphic display.

[0238] according to Figure 6 The simultaneous administration of PAH with all tested compounds, especially small peptides such as DOTA-RGD, DOTA-JR11 and DOTA-Sargastrin, had a significant effect in reducing renal absorption. Figure 6 It is also evident that the effect of reduced renal uptake is already present at early time points between 0.5 and 1 hour after administration.

[0239] Thus, the above experimental results indicate that PAH administration reduces the renal uptake of various radiolabeled compounds, ie, DOTA-linked peptides, peptidomimetics, etc., which accumulate in the kidney by different mechanisms.

[0240] Example 4: Effect of PAH on the blood activities of different radiolabeled compounds

[0241] Mice were injected with four different molecules conjugated to the cyclic chelator DOTA and radiolabeled with the therapeutic radionuclide lutetium-177: 177 Lu-DOTA-RGD, 177 Lu-DOTA-Affilin, 177 Lu-DOTA-Sargastrin, and 177 Lu-DOTA-JR11 was co-injected with PAH (200 mg / mL) or saline (0.9% NaCl) as a control. The percentage of injected radioactivity present in the blood was determined over time according to the above protocol. Figure 7 Medium graphic display.

[0242] according to Figure 7 , PAH blood activity was significantly increased by co-injection of Affilin. Thus, although renal absorption of Affilin by PAH was not as significantly reduced as that of the other compounds tested (see Figure 6 ), but data suggest that simultaneous co-injection of PAH increases the blood activity of Affilin, thereby improving the bioavailability of the radiopharmaceutical.

[0243] Example 5: PAH 68 Effects of Ga-labeled PSMA-11 on renal uptake and blood activity

[0244] Mice were injected with a diagnostic 68 Ga-labeled PSMA-11 was co-injected with PAH (200 mg / mL) or saline (0.9% NaCl) as a control. The percentage of injected radioactivity present in the kidney (upper panel) and blood (lower panel) was determined over time according to the above protocol. Figure 8 Medium graphic display.

[0245] like Figure 8As shown, the presence of 68 Significant reduction in renal uptake of Ga-labeled HBED-CC-conjugated PSMA-11. Figure 8 It is also evident that the effect of reduced renal uptake is already present at early time points of 0.1, 0.5 and 1 hour after administration.

[0246] Therefore, the experimental results of Examples 3-5 above indicate that the administration of PAH reduces the renal absorption of various radiolabeled compounds (respectively with different carrier molecules (peptides, peptidomimetics, recombinant proteins), different chelators (cyclic chelators, acyclic chelators), and different radionuclides (therapeutic radionuclides, diagnostic radionuclides)), and therefore can be used to reduce the nephrotoxic side effects of a variety of radiolabeled and non-radiolabeled diagnostic and therapeutic compounds.

[0247] Example 6: PAH or saline solution was injected intraperitoneally and then intravenously administered to mice 177 Bioanalysis of Lu-DOTATOC Fabric Comparative Analysis

[0248] Somatostatin receptor-positive pancreatic tumor-bearing CD1 nude mice (AR2J) received an ip injection of 50 μL NaCl 0.9% (group A) or 50 μL PAH 20% (group B), and exactly 10 minutes later, an iv injection was administered via the retroorbital sinus. 177 Lu-DOTATOC / NaCl (Group A) or 177 Lu-DOTATOC / PAH (Group B). Nominal dose levels, concentrations, and volumes are summarized in Table 6

[0249] Table 6

[0250]

[0251] *Calculate individual dose volume using individual body weight recorded on the day of treatment; record individual volume and exact treatment time and keep in study files.

[0252] **Taking into account 177 Concentration and dose range of Lu radioactive decay within 3 days from the date of delivery.

[0253] Mice (3 animals per group) were sacrificed at 0.5 hours, 1 hour, 2 hours, and 4 hours. Organs were quickly rinsed in 0.9% NaCl and dried, then weighed and counted to eliminate possible contaminating blood. The following organs / tissues were sampled or taken, weighed, and counted: 177 Lu: blood, tumor, kidney, liver, bladder (empty), heart, spleen, lung, brain, muscle, stomach (no contents), small intestine (no contents), colon (no contents), residual carcass. Data from organ / tissue counts are expressed as percentage of injected dose (%ID / g). 177Organ / tissue distribution results of Lu-DOTATOC in 0.9% NaCl (Panel A), and 177 The organ / tissue distribution results of Lu-DOTATOC and PAH (Group B) Figure 9 Graphical presentation.

[0254] according to Figure 9 , compared to receiving NaCl 177 Lu-DOTATOC Group A (above), receiving 177 Lu-DOTATOC and PAH in group B (lower figure) 177 The absorption of Lu-DOTATOC was significantly reduced. 177 In the early stages (0.5 h and 1 h) after Lu-DOTATOC, the renal uptake of the radiolabeled compound was significantly reduced. 177 Without wishing to be bound by a particular theory, it is hypothesized that Lu-DOTATOC levels are significantly increased by PAH via renal clearance. 177 The blockade of Lu-DOTATOC leads to 177 The blood circulation of Lu-DOTATOC was prolonged, and thus the accumulation of radiolabeled compound in tumor site was also increased. 177 Lu-DOTATOC's Group A, receiving 177 Lu-DOTATOC and PAH 177 Enhanced bioavailability of Lu-DOTATOC.

[0255] Example 7: 99m Comparative analysis of the biodistribution of Tc-Etarfolatide co-administered with PAH or normal saline

[0256] 7.1 Radiolabeling of Etarfolatide

[0257] 99m Tc-Etarfolatide has the following chemical structure:

[0258]

[0259] Radiolabeling was performed by a method derived from the teaching of Kim et al. (Ann Nucl Med 2016; 30: 369-379). A ligand exchange method was employed using tartrate as a co-ligand. In an eppendorf tube, 100 μg of Etarfolatide, 50 μl of tartrate solution (20 mg / 50 μl in Millipore water), and 80 μl of SnCl2 dihydrate solution (1 mg / ml in 0.01 M HCl solution) were added. In a lead shielded fume hood, approximately 750 MBq (20 mCi) of freshly eluted 99m Tc-pertechnetate was added and the reaction flask was heated in a water bath at 100 °C for 30 min and then cooled to room temperature.

[0260] Radiolabeling efficiency and stability were determined using: (i) Instant Thin Layer Chromatography - Silica Gel (ITLC-SG) with water ( 99m Tc-Etarfolatide and free pertechnetate Rf = 0.9-1.0; colloid Rf = 0.0-0.1) and acetone (free pertechnetate Rf = 0.9-1.0; colloid and 99m Tc-Etarfolatide (Rf = 0.0-0.1) as mobile phase, and (ii) RP-HPLC: Solvent A: 0.1% TFA in H2O, Solvent B: 0.1% TFA in AcCN; gradient elution, flow rate 1 mL / min.

[0261] On each day of the experiment, approximately the same 99m Tc activity was subjected to a new radiolabeling procedure. RP-HPLC showed RCP = 100%, while TLC showed maximum colloid formation of 5% or less. HPLC was evaluated 24 hours after preparation. 99m The stability of Tc-Etarfolatide was investigated and no loss of radiolabel was shown.

[0262] The volume of radiolabeled folate was measured to be 1300 μL, and the activity was 734 MBq (experimental day: March 4). A sample equivalent to 300 MBq (i.e., 15 MBq x 20 mice) was prepared. 531 μL was taken from the radiolabeled folate, which was diluted with 1469 μL of saline or 1469 μL of PAH (2000 μL 99mTc-etarfolatide, 100 μL / 15 MBq / mouse). Before injection, the sample was filtered through a 0.22M sterile filter. The 15 MBq / mouse injected corresponds to 2.04 μg of Etarfolatide / mouse (the amount of Etarfolatide injected remained stable throughout the experiment).

[0263] Diluted with saline or PAH 99m Samples of Tc-Etarfolatide were evaluated immediately after preparation and 24 hours after dilution and showed no signs of loss of radiolabel when evaluated by HPLC (100% RCP), but TLC evaluation indicated 99m Tc-Etarfolatide / PAH is stable (100% RCP), while 99m Tc-Etarfolatide / saline showed 14% colloid formation.

[0264] 7.2 Preparation of PAH Solution

[0265] Weigh 2g of PAH sodium salt into a Corning tube; add 4mL of H2O; vortex—PAH partially dissolves; add 20μL of NaOH (provided by ITG), vortex—PAH partially dissolves; add 20μL of NaOH, vortex—PAH completely dissolves; add 2mL of H2O, pH 10; add 80μL of 37% HCl (in 20μL increments), pH ~6. The final volume of the resulting solution was measured and found to be 7100μL, to which we added 2900μL (all in another Corning tube), ultimately resulting in 2g of PAH in 10mL of H2O, or 200mg of PAH / mL. After filtering through a 0.22μM filter, the Corning tube was covered with aluminum foil and cooled.

[0266] 7.3 Biodistribution analysis

[0267] 30 mice (male and female) were randomly assigned into two groups.

[0268] Group A: Mice were injected with PAH (2.04 μg Etarfolatide / mouse) diluted in PAH 10 min after receiving IP injection of PAH followed by tracer injection. 99m Tc Etarfolatide. Five time points were evaluated: 5 min, 30 min, 1 h, 2 h, and 4 h (3 mice / time point).

[0269] The dose injected at each time point:

[0270]

[0271] Group B: Mice were injected with Etarfolatide diluted in saline (2.04 μg Etarfolatide / mouse) after having received an IP injection of saline for 10 min followed by tracer injection. 99m Tc Etarfolatide. Five time points were evaluated: 5 min, 30 min, 1 h, 2 h, and 4 h (3 mice / time point).

[0272] The dose injected at each time point:

[0273]

[0274] The results of biodistribution analysis are as follows Figure 10 After 30 minutes, the protective effect of PAH was 99m The reduced renal absorption of Tc-etarfolatide has become prominent. 177 Another valence state of Lu 99m Tc 99m Tc chelate conjugate molecules, confirmed the 177 The effects observed on Lu conjugate molecules.

[0275] Example 8: 177 Biodistribution analysis of Lu-labeled PSMA I&T

[0276] The chemical structure of "PSMA I&T" is as follows:

[0277]

[0278] Test articles for imaging experiments

[0279]

[0280] Imaging time points 30 minutes, 1 hour, 2 hours, and 4 hours after injection

[0281] Measurement system and parameter settings for imaging experiments

[0282]

[0283] Program Implementation

[0284] The protocol was carried out in the following manner: the radioactivity concentration in the kidneys of one group of animals injected with TA and in three separate groups injected with different KP reagents was measured. Thus, the following experimental group matrix was formed:

[0285]

[0286] 1. PSMA I&T-4-(dipropylsulfamoyl)benzoic acid imaging experiment data

[0287] 1.1. Rat 1

[0288]

[0289]

[0290] 1.2. Rat 2

[0291]

[0292] 1.3. Rat 3

[0293]

[0294]

[0295] 2. Data of PSMA I&T-PAH Imaging Experiment 2.1 Rat 4

[0296]

[0297] 2.2 Rats 5

[0298]

[0299]

[0300] 2.3 Rats 6

[0301]

[0302] 3. Data of PSMA I&T-saline imaging experiment 3.1 Rat 7

[0303]

[0304] 3.2 Rats 8

[0305]

[0306] 3.3 Rats 9

[0307]

[0308] result

[0309] PE1: Toxicity observation

[0310] Results: No signs of immediate or delayed acute toxicity were observed.

[0311] PE2: Radioactivity accumulation in organs over time

[0312]

[0313] Results: The table below contains the decay-corrected ratio of radioactivity concentrations in the two kidneys combined at each time point, expressed as % of the injected whole-body radioactivity concentration.

[0314] Results - Table I:

[0315] Injection 177Lu- Kidney radioactivity expressed as a percentage of injected radioactivity in the group receiving PSMA I&T and 4-(dipropylsulfamoyl)benzoic acid suspension po

[0316]

[0317] Results - Table II: Injection 177Lu - Renal radioactivity expressed as a percentage of injected radioactivity in the group that received PSMA I&T and PAH solution ip. and iv.

[0318]

[0319] Results - Table III: After injection 177Lu - Renal radioactivity expressed as a percentage of injected radioactivity in the group that received PSMA I&T and saline ip and iv

[0320]

[0321] Results - Table IV: After injection 177Lu - Blood (left ventricle) radioactivity expressed as a percentage of injected radioactivity in the group receiving PSMA I&T and 4-(dipropylsulfamoyl)benzoic acid suspension po.

[0322]

[0323] Results - Table V: After injection 177Lu - Blood (left ventricle) radioactivity as a percentage of injected radioactivity in the group receiving PSMA I&T and PAH solution ip and iv

[0324]

[0325] Results - Table VI: After injection 177Lu - Blood (left ventricle) radioactivity as a percentage of injected radioactivity in the group that received PSMA I&T and saline ip and iv

[0326]

[0327] Results - Table VII:

[0328] Injection 177Lu - Renal medullary radioactivity expressed as a percentage of injected radioactivity in the group receiving PSMA I&T and 4-(dipropylsulfamoyl)benzoic acid suspension po.

[0329]

[0330] Results - Table VIII:

[0331] Injection 177Lu - Renal medullary radioactivity expressed as a percentage of injected radioactivity in the group that received PSMA I&T and PAH ip. and iv.

[0332]

[0333] Results - Table IX:

[0334] Injection 177Lu - Renal medullary radioactivity expressed as a percentage of injected radioactivity in the group that received PSMA I&T and saline ip. and iv.

[0335]

[0336] Results - Table X:

[0337] Injection 177Lu - Renal cortical radioactivity expressed as a percentage of injected radioactivity in the group receiving PSMA I&T and 4-(dipropylsulfamoyl)benzoic acid suspension po.

[0338]

[0339] Results - Table XI:

[0340] Injection 177Lu - Renal cortical radioactivity expressed as a percentage of injected radioactivity in the group receiving PSMA I&T and PAH solution ip. and iv.

[0341]

[0342] Results - Table XII:

[0343] Injection 177Lu - Renal cortical radioactivity expressed as a percentage of injected radioactivity in the group that received PSMA I&T and saline ip. and iv.

[0344]

[0345] The results are Figures 11 to 14 All experiments showed a significant decrease in radioactivity in kidney cells after PAH administration compared to saline controls and compared to 4-(dipropylsulfamoyl)benzoic acid control experiments ( Figure 11 After PAH administration, renal cortex ( Figure 13 ) and renal medulla ( Figure 14 ) showed reduced radioactivity at all time points during the experiment.

[0346] 4-(Dipropylsulfamoyl)benzoic acid was tested as a further control. 4-(Dipropylsulfamoyl)benzoic acid is believed to be an inhibitory agonist of proximal tubular cell OA in the kidney. - A strong inhibitor of (organic anion) secretion. It inhibits the basolateral type 1 organic anion transporter (OAT1). OAT1 is known for its absorption of organic anions from the blood into the renal tubular cells and exchange with dicarboxylates (such as succinate or 2-oxoglutarate). According to the experiment of Example 8 (see Figures 11 to 14 ), both showed that the 4-(dipropylsulfamoyl)benzoic acid-based inhibitory mechanism had no effect on OAT1. Therefore, it can be concluded that the PAH-based effect of reducing radioactivity in kidney cells is based on another mechanism than the known mechanism for 4-(dipropylsulfamoyl)benzoic acid.

Claims

1. Use of para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds as radiopharmaceuticals in radioligand therapy or diagnosis in a subject, wherein the radiopharmaceutical is a conjugate molecule containing a radionuclide, which comprises a carrier molecule, a chelating agent and a radionuclide, and wherein the radionuclide is a trivalent radionuclide; wherein the carrier molecule is selected from the group consisting of a somatostatin analog, a somatostatin antagonist, a somatostatin agonist, a PSMA-inhibitor, a gastrin analog, an integrin binding molecule, and a folate; wherein the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt thereof are administered in a weight ratio of 1 / 250,000 to 1 / 5,000; and The administration of p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof is before and / or after the administration of the radiolabeled therapeutic and diagnostic compound.

2. The use according to claim 1, wherein the carrier molecule is selected from Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD and folate.

3. The use according to any one of claims 1 to 2, wherein the chelating agent is a macrocyclic chelating agent.

4. The method according to claim 3, 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 macrocyclic chelating agents of HYNIC or its derivatives.

5. The use according to any one of claims 1 to 2, wherein the radionuclide is selected from 90 In, 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, 152 Gd, 153 Gd, 157 Gd and 166 Dy.

6. The method according to claim 5, wherein the radionuclide is selected from 177 Lu, 90 Y. 67 Ga, 68 Ga, 111 In, 225 Ac, 161 Tb, 44 Sc and 47 Sc.

7. The method according to claim 5, wherein the radionuclide is selected from 177 Lu, 225 Ac and 68 Ga.

8. The use according to any one of claims 1 to 2, wherein the conjugate molecule containing a radionuclide is selected from [ 177 Lu-DOTA°-Tyr3]-octreotide, 177 Lu-DOTANOC, 177 Lu-DOTATATE, 68 Ga-DOTATOC, 68 Ga-DOTANOC, 90 Y-DOTATOC, 90 Y-DOTATATE, 111 In-DTPA-octreotide, 111 In-DOTA-BASS, 111 In-DOTA-JR11, 68 Ga-DOTA-JR11, 68 Ga-DODAGA-JR11, 177 Lu-DOTA-JR11, 177 Lu-DOTA-RGD, 177 Lu-DOTA-Sargastrin, 68 Ga-HBED-CC-PSMA-11 and 177 Lu-PSMA I&T.

9. The use according to any one of claims 1-2, wherein p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof is administered in combination with an additional substance that reduces the nephrotoxic side effects of the radiolabeled therapeutic and diagnostic compound.

10. Use according to claim 9, wherein the additional substance is selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules and vitamins.

11. The use according to claim 10, wherein the PSMA-binding molecule is PMPA.

12. The use according to any one of claims 1-2, wherein PAH or a pharmaceutically acceptable salt thereof is administered at a concentration of 5 mg to 500 mg per kg body weight.

13. The use according to any one of claims 1-2, wherein the therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt thereof are administered in a weight ratio of 1 / 240000 to 1 / 8000.

14. The use according to any one of claims 1-2, wherein the pharmaceutically acceptable salt of PAH is sodium aminohippurate.

15. A pharmaceutical composition comprising a radiolabeled pharmaceutical compound and p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the radiolabeled drug compound is a therapeutic or diagnostic compound exhibiting nephrotoxic side effects, which is a conjugate molecule containing a radionuclide, comprising a carrier molecule, a chelating agent and a radionuclide, and wherein the radionuclide is a trivalent radionuclide; wherein the carrier molecule is selected from the group consisting of a somatostatin analog, a somatostatin antagonist, a somatostatin agonist, a PSMA-inhibitor, a gastrin analog, an integrin binding molecule, and a folate conjugate; and The therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt thereof are present in the pharmaceutical composition in a weight ratio of 1 / 250,000 to 1 / 5,000.

16. The pharmaceutical composition according to claim 15, wherein the carrier molecule is selected from Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD and folate.

17. The pharmaceutical composition according to any one of claims 15 to 16, 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 its derivatives.

18. The pharmaceutical composition according to any one of claims 15-16, wherein the radionuclide is selected from 90 In, 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, 152 Gd, 153 Gd, 157 Gd and 166 Dy.

19. The pharmaceutical composition according to claim 18, wherein the radionuclide is selected from 177 Lu, 90 Y. 67 Ga, 68 Ga, 111 In, 225 Ac, 161 Tb, 44 Sc and 47 Sc.

20. The pharmaceutical composition according to claim 18, wherein the radionuclide is selected from 177 Lu, 225 Ac and 68 Ga.

21. The pharmaceutical composition according to any one of claims 15-16, wherein the conjugate molecule containing a radionuclide is selected from [ 177 Lu-DOTA°-Tyr3]-octreotide, 177 Lu-DOTA-JR11, 177 Lu-DOTA-RGD, 177 Lu-DOTA-Sargastrin, 68 Ga-HBED-CC-PSMA-11 and 177 Lu-PSMA I&T.

22. The pharmaceutical composition of any one of claims 15-16, wherein in addition to PAH, the composition comprises an additional substance that reduces the nephrotoxic side effects of the radiolabeled therapeutic and diagnostic compound.

23. The pharmaceutical composition according to claim 22, wherein the additional substance that reduces the nephrotoxic side effects of therapeutic and diagnostic compounds other than PAH is selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules and vitamins.

24. The pharmaceutical composition of claim 23, wherein the PSMA-binding molecule is PMPA.

25. The pharmaceutical composition according to any one of claims 15-16, wherein the therapeutic or diagnostic compound and PAH are present in the pharmaceutical composition in a weight ratio of 1 / 240000 to 1 / 8000.

26. The pharmaceutical composition according to any one of claims 15-16, wherein the pharmaceutically acceptable salt of PAH is sodium aminohippurate.

27. A kit comprising para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof in one part of the kit and further comprising a radiolabeled therapeutic or diagnostic compound which is a radiopharmaceutical as defined in any one of claims 1 to 14 in another part of the kit; and The therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt thereof are present in a weight ratio of 1 / 250,000 to 1 / 5,000.

28. Use of a pharmaceutical composition according to any one of claims 15 to 26, or a kit according to claim 27, for the preparation of a medicament for reducing nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds in a subject.

29. Use of a pharmaceutical composition according to any one of claims 15 to 26, or a kit according to claim 27, in the preparation of a medicament for reducing the nephrotoxic side effects of a radiolabeled therapeutic or diagnostic compound in a subject, wherein the pharmaceutical composition or kit is administered to the subject before, during or after imaging or therapy with the radiolabeled compound.

30. Use of para-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof in combination with a radiolabeled therapeutic or diagnostic compound that is a radiopharmaceutical in radioligand therapy or diagnosis for the preparation of a medicament for reducing the nephrotoxic side effects of the radiolabeled therapeutic and diagnostic compound that is a radiopharmaceutical in radioligand therapy or diagnosis in a subject, wherein the administration of PAH is before and / or during and / or after the administration of the radiolabeled therapeutic and diagnostic compound, wherein the radiopharmaceutical is a conjugate molecule containing a radionuclide, which comprises a carrier molecule, a chelating agent and a radionuclide, and wherein the radionuclide is a trivalent radionuclide; wherein the carrier molecule is selected from the group consisting of a somatostatin analog, a somatostatin antagonist, a somatostatin agonist, a PSMA-inhibitor, a gastrin analog, an integrin binding molecule, and a folate; and The therapeutic or diagnostic compound and PAH or a pharmaceutically acceptable salt thereof are used in a weight ratio of 1 / 250,000 to 1 / 5,000.

31. The use of claim 30, wherein PAH is administered (i) before, during, and after, or (ii) before and after, the administration of the radiolabeled therapeutic and diagnostic compound.

32. The use according to claim 30, wherein the carrier molecule is selected from Tyr3-octreotide, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD and folate.

33. The use according to any one of claims 30 to 32, wherein the chelating agent is selected from DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3AP PrA 、DO3AP ABn and HYNIC or its derivatives.

34. The use according to any one of claims 30 to 32, wherein the radionuclide is selected from 177 Lu, 90 Y. 67 Ga, 68 Ga, 111 In, 225 Ac, 161 Tb, 44 Sc and 47 Sc.

35. The use according to claim 34, wherein the radionuclide is selected from 177 Lu, 225 Ac and 68 Ga.

36. The use according to any one of claims 30 to 32, wherein the conjugate molecule containing a radionuclide is selected from [ 177 Lu-DOTA°-Tyr3]-octreotide, 177 Lu-DOTA-JR11, 177 Lu-DOTA-RGD, 177 Lu-DOTA-Sargastrin, 68 Ga-HBED-CC-PSMA-11 and 177 Lu-PSMA I&T.

37. The use according to any one of claims 30 to 32, wherein p-aminohippuric acid (PAH) or a pharmaceutically acceptable salt thereof is used in combination with an additional agent that reduces the nephrotoxic side effects of the radiolabeled therapeutic and diagnostic compound.

38. The use according to claim 37, wherein the additional substance other than PAH that reduces the nephrotoxic side effects of radiolabeled therapeutic and diagnostic compounds is selected from the group consisting of amino acids, gelatin, amifostine, albumin-derived peptides, PSMA-binding molecules and vitamins.

39. The use according to claim 38, wherein the PSMA-binding molecule is PMPA.

40. The use according to any one of claims 30 to 32, wherein PAH or a pharmaceutically acceptable salt thereof is administered in an amount of 5 mg to 500 mg per kg body weight.

41. The use according to any one of claims 30 to 32, wherein the therapeutic and / or diagnostic compound is used in a weight ratio of 1 / 240,000 to 1 / 8,000 to PAH or a pharmaceutically acceptable salt thereof.

42. The use according to any one of claims 30-32, wherein the pharmaceutically acceptable salt of PAH is sodium aminohippurate.

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