Pharmaceutical composition containing a radiolabeled GPRP antagonist and a surfactant

Abstract

One approach involves using GRPR antagonists for efficient treatment of cancer patients. To provide treatment protocols. [Solution] This disclosure relates to a radiopharmaceutical targeting the gastrin-releasing peptide receptor (GRPR). and their use. In particular, this disclosure relates to radiolabeled GRPR-antagonists and This disclosure relates to pharmaceutical compositions containing surfactants. This disclosure also relates to the use of surfactants in the treatment or prevention of cancer. Regarding radiolabeled GRPR antagonists for use.

Description

[Technical Field]

[0001] This disclosure relates to radiopharmaceuticals that target gastrin-releasing peptide receptors (GRPRs) and their Regarding the use of radiolabeled GRPR-antagonists and interfaces. In detail, this disclosure relates to the use of radiolabeled GRPR-antagonists and interfaces. This disclosure relates to a pharmaceutical composition containing an activator. This disclosure also relates to its use in the treatment or prevention of cancer. Regarding radioactively labeled GRPR antagonists. [Background technology]

[0002] gastrin-releasing peptide receptor (GRPR), also known as bombesin receptor subtype 2. It is a G protein-coupled protein expressed in various organs, including the gastrointestinal tract and the pancreas. It is a receptor (Guo M et al., Curr Opin Endocrinol Diabetes Obes. 2015; Vol. 22: 3-8, 2; Gonz alez et al., Curr Opin Enocrinol Diabetes Obes. 2008; Vol. 15: pp. 58-64). Appropriate Rigan After binding, GRPR is activated, regulating several physiological processes, such as exocrine and endocrine regulation. It induces joints, etc. (Guo M et al., Curr Opin Endocrinol Diabetes Obes. 2015; Vol. 22: 3-8, 2; Go Nzalez et al., Curr Opin Enocrinol Diabetes Obes. 2008; Vol. 15: pp. 58-64). Over the past several decades. Over time, GRPR expression has been reported in various cancer types, including prostate cancer and breast cancer. It has been reported (Gugger M and Reubi JC. Gastrin-releasing peptide receptors in non- Oplastic and neoplastic human breast. Am J Pathol. 1999; Vol. 155: 2067-2076; Markwa Ilder R and Reubi JC. Cancer Res. 1999; Vol. 59: 1152-1159). Therefore, GRPR is reception Body-mediated tumor imaging and therapy, e.g., peptide receptor scintigraphy. It has become an interesting target for radionuclide therapy and peptide receptor radionuclide therapy (Gonzalez N (Curr Opin Enocrinol Diabetes Obes. 2008; Vol. 15: pp. 58-64). Nuclear imaging and Radiolabeled somatostatin peptide analogues for therapies in neuroendocrine tumors After successful use (Brabander T et al., Front Horm Res. 2015; Vol. 44: pp. 73-87; Kwekkeboom DJ and Krenning EP. Hematol Oncol Clin North Am. 2016; Vol. 30: pp. 179-191), multiple Radiolabeled GRPR radioligands are synthesized and primarily used in prostate cancer patients. It is being studied in laboratory and clinical trials. Examples of such peptide analogs include AMBA, This includes the Demobesin series and MP2653 (Yu Z et al., Curr Pharm Des. 2013; Volume 19: 3329-3341; Lantry LE et al., J Nucl Med. 2006; Volume 47: 1144-1152; Schroeder RP et al. Eur J Nucl Med Mol Imaging. 2010; Vol. 37: 1386-1396.; Nock B et al., Eur J Nucl Med Mol Imaging. 2003; Vol. 30: pp. 247-258; Mather SJ et al., Mol Imaging Biol. 2014; Vol. 16: pp. 888-89 5) Recent studies have shown that GRPR antagonists are preferred over GRPR agonists. (Mansi R et al., Eur J Nucl Med Mol Imaging. 2011; Vol. 38: pp. 97-107; Cescato R et al.) J Nucl Med. 2008; Vol. 49: pp. 318-326). Compared to receptor agonists, antagonists are , often exhibiting higher binding and favorable pharmacokinetics (Ginj M et al., Proc Natl Acad Sci USA. 2006; Vol. 103: 16436-16441). Again, clinical trials using radiolabeled GRPR agonists... In the bed test, the patient was affected by the activation of GRPR after the peptide bound to the receptor. Unwanted side effects have been reported in (Bodei L et al., [abstract]. Eur J Nucl Med Mol Im aging. 2007; Vol. 34: S22l).

[0003] Some GRPR antagonists, such as NeoBOMB1, are radioactively targeted by different radionuclides. It can be identified, for imaging and GRPR-expressing cancers, for example, not limited to that. However, it has recently been discovered that it may potentially be used to treat prostate cancer and breast cancer. However, only in vivo distribution studies have been reported so far, and efficiency is unknown. No specific therapeutic protocols or pharmaceutical compositions have been developed.

[0004] Therefore, in this context, medical treatments that may be administered to patients, including GRPR antagonists. It would be desirable to provide a drug composition. Furthermore, using a GRPR antagonist, Providing efficient treatment protocols for patients with cancer is also desirable. It is. [Preliminary Technology Documents] [License]

[0005] [License 1] WO2014052471 [Non-licensed literature]

[0006] [Non-licensed Document 1] Guo Mら, Curr Opin Endocrinol Diabetes Obes. 2015; Volume 22: 3~8,2 [Non-licensed Document 2] Gonzalez Nら, Curr Opin Enocrinol Diabetes Obes. 2008; Volume 15: Pages 58~64 [Non-licensed Document 3] Gugger M and Reubi JC. Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human breast. Am J Pathol. 1999; 155 vol: 2067~2076 [Non-licensed Document 4] Markwalder R and Reubi JC.Cancer Res.l999;Volume 59:1152~1159 [Non-licensed Document 5] Brabander Tら, Front Horm Res. 2015; Volume 44: Pages 73~87 [Non-licensed Document 6] Kwekkeboom DJ and Krenning EP.Hematol Oncol Clin North Am.2016; Volume 30: Pages 179~191 [Non-licensed Document 7] Yu Zら, Curr Pharm Des. 2013; Volume 19: 3329~3341 [Non-licensed Document 8] Lantry LEら, J Nucl Med. 2006; Volume 47: 1144~1152. [Non-licensed Document 9] Schroeder RP, Eur J Nucl Med Mol Imaging. 2010; 37 vol: 1386~1396. [Non-licensed Document 10] Nock B, Eur J Nucl Med Mol Imaging. 2003; Volume 30: 247-258. [Non-licensed Document 11] Mather SJら, Mol Imaging Biol. 2014; Volume 16: 888~895 [Non-licensed Document 12] Mansi R, Eur J Nucl Med Mol Imaging. 2011; Volume 38: 97-107. [Non-licensed Document 13] Cescato R., J Nucl Med. 2008; Vol. 49: 318-326 [Non-licensed Document 14] Ginj Mら, Proc Natl Acad Sci USA. 2006; Volume 103: 16436~16441 [Non-licensed Document 15] Bodei Lら, [abstract]. Eur J Nucl Med Mol Imaging. 2007; Volume 34: S22l [Non-licensed Document 16] Pharmaceutics and Pharmacy Practice, JB Lippincott Company, Philadelphia, PA, edited by Banker and Chalmers., pp. 238~250 (1982) [Non-licensed Document 17] ^SHP Handbook on Injectable Drugs, Trissel, 15th Edition, pp. 622-630 (2009) [Non-licensed Document 18] Castaldi E, Muzio V, D’Angeli L, Fugazza L. 68Ga DOTATATE lyophilized ready to use kit for PET imaging in pancreatic cancer murine model. J Nucl Med 2014;55(suppl 1):1926

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Non-Patent Document 22

[0007] In the first aspect, the present disclosure is -Formula: MC-SP [In the formula, M is a radiometal, and C is a chelating agent that binds to M; S is a spacer, covalently bonded between C and the N-terminus of P; P is a general formula: It is a GRP receptor peptide antagonist for Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is either absent or contains the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Th i) 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine Nin (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo- Tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all L- or Selected from the group consisting of D-isomers; Xaa2 is Gln, Asn, or His; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); Xaa4 is Ala, Ser, or Val; Xaa5 is Val, Ser, or Thr; Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; Xaa7 is His or (3-methyl)histidine (3-Me)His; Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O-alkyl. Or, Z is, [ka] (In the formula, X is NH (amide) or O (ester), and R1 and R2 are the same or different.) Ton, optionally substituted alkyl, optionally substituted alkylalkyl, Ally aryl ether or alkyl, halogen, hydroxyl or hydroxyal Radiolabeled GRPR (selected from kill-substituted aryl or heteroaryl groups) - Antagonist; and - Surfactants comprising (i) polyethylene glycol chains and (ii) fatty acid esters This relates to pharmaceutical compositions, including those containing the above.

[0008] In a second aspect, the Disclosure relates to the use of radiation for the treatment or prevention of cancer in the subject. Regarding compositions comprising a projectile-labeled GRPR antagonist, - Radiolabeled GRPR antagonists are expressed by the following formula: MC-SP [In the formula, M is a radioactive metal, and C is a chelating agent that binds to M; S is a spacer, covalently bonded between C and the N-terminus of P; P is a general formula: It is a GRP receptor peptide antagonist for Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is either absent or contains the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Th i) 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine Nin (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo- Tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all L- or Selected from the group consisting of D-isomers; Xaa2 is Gln, Asn, or His; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); Xaa4 is Ala, Ser, or Val; Xaa5 is Val, Ser, or Thr; Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; Xaa7 is His or (3-methyl)histidine (3-Me)His; Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O-alkyl. Or, Z is, [ka] (In the formula, X is NH (amide) or O (ester), and R1 and R2 are the same or different, proto n, optionally substituted alkyl, optionally substituted alkylether, aryl aryl ether or alkyl-, halogen, hydroxyl or hydroxyalkyl It is a group that is selected from a substituted aryl or heteroaryl group; - Radiolabeled GRPR antagonists are therapeutically effective in doses between 2000 and 10000 MBq. It is administered to the aforementioned subjects. [Brief explanation of the drawing]

[0009] [Figure 1A]Figure 1A shows SPECT / CT images taken 4 and 24 hours after the first injection, and 4 hours after the second and third injections. Arrows indicate tumors. Animals were injected with 177Lu-NeoBOMB1 at 30 MBq / 300 pmol (Group 1), 40 MBq / 400 pmol (Group 2), or 60 MBq / 600 pmol. [Figure 1B] Figure 1B shows the quantified tumor uptake from the injection described in Figure 1A (n=2 per group). [Figure 2] Figure 2A shows the estimated tumor size of untreated animals and animals treated with 177Lu-NeoBOMB1 3×30MBq / 300pmol (Group 1), 3×40MBq / 400pmol (Group 2), and 3×60MBq / 600pmol (Group 3). Figure 2B shows the survival rate of untreated animals and animals treated with 177Lu-NeoBOMB1 3×30MBq / 300pmol (Group 1), 3×40MBq / 400pmol (Group 2), and 3×60MBq / 600pmol (Group 3). [Figure 3] Figure 3A shows the weight of animals before treatment and after treatment up to 12 weeks after treatment. Figure 3B shows the weight of animals before treatment and after treatment up to 24 weeks after treatment. [Figure 4] This figure shows representative hematoxylin and eosin staining of pancreatic tissue from untreated and treated animals (177Lu-NeoBOMB1 3×30 MBq / 300 pmol (Group 1), 3×40 MBq / 400 pmol (Group 2), and 3×60 MBq / 600 pmol (Group 3)). [Figure 5] This figure shows representative hematoxylin and eosin staining of kidney tissue from untreated and treated animals (177Lu-NeoBOMB1 3×30 MBq / 300 pmol (Group 1), 3×40 MBq / 400 pmol (Group 2), and 3×60 MBq / 600 pmol (Group 3)). The circled areas indicate lesions with lymphocyte infiltration (ID: D, 814, 861, 868, and 862) or atrophy and fibrosis (ID: 864). [Modes for carrying out the invention]

[0010] definition The words "treatment" and "to treat" imply that the improvement of a disease, disorder, or its symptoms is not suspended. It is included.

[0011] The phrases "prevention of" and "to prevent" include avoiding the onset of a disease, disorder, or its symptoms. It can be done.

[0012] In line with the International System of Units (SI), "MBq" is an abbreviation for "megabecquerel," the unit of radioactivity. That is the case.

[0013] In the context of this invention, "PET" refers to positron emission tomography.

[0014] In the context of this invention, "SPECT" refers to single-photon emission computed tomography.

[0015] When used in this invention, the terms "effective amount" or "therapeutably effective amount" of a compound refer to the target. To induce a biological or medical response, for example, to improve symptoms, alleviate a condition, or treat a disease. This refers to the amount of a compound that slows or delays the progression of a disease, or prevents the disease. .

[0016] When used in the present invention, the terms "substituted" or "may be substituted" mean 0 From the total number of open valencies in aromatic ring systems, to halogens, -OR', -NR 'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'' , -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR- C(NR'R''R''')=NR'''', -NR- C(NR'R'')=NR'''-S(O)R', -S(O)2R', - S(O)2NR'R'', -NRSO2R', -CN, -NO2, -R', -N3, -CH(Ph)2, Fluoro(C1~C4) Substituted with one or more substituents selected from coxo and fluoro(C1-C4)alkyl groups. It means a group that may be present; R', R'', R''' and R'''' are independently hydrogen, A Lukyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and hetero You can choose from aryl groups. If the compounds of this disclosure contain two or more R groups, for example If two or more of these groups are present, then each R', R'', R''', and R'''' group Each of the R groups is selected independently.

[0017] When used in the present invention, the term "alkyl" may refer to itself or to the term "alkyl" as part of another substituent. "Alkyl" refers to a linear or branched alkyl functional group having 1 to 12 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, s-butyl and t-butyl, pentyl and their isomers (e.g., n-pentyl, i) sopentyl, as well as hexyl and their isomers (e.g., n-hexyl, isohexyl) It includes.

[0018] As used in this invention, the term "heteroaryl" refers to a compound containing 5 to 10 atoms. A polyvalent compound having a single ring or multiple aromatic rings that are fused together or covalently bonded. This refers to a saturated aromatic ring system, where at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O, and S. Nitrogen and sulfur heteroatoms are used in some cases. It can be oxidized, and nitrogen heteroatoms can, in some cases, be quaternized. Such rings can be condensed with aryl, cycloalkyl, or heterocyclyl rings. Non-exclusive examples of such heteroaryls include furanyl, thiophenyl, pyrrolyl, and pyraryl. Zolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl Triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl Lu, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridadinyl, oxadi Nyl, dioxynyl, thiadinyl, triazinyl, indolyl, isoindolyl, benzo Furanil, isobenzofuranil, benzothiophenyl, isobenzothiophenyl, inda Zolyl, benzimidazolyl, benzoxazolyl, prinyl, benzothiadiazolyl, It contains quinolinyl, isoquinolinyl, synnolinyl, quinazolinyl, and quinoxalinyl. ru.

[0019] As used in this invention, the term "aryl" refers to a monoring containing 6 to 10 ring atoms. Alternatively, polyunsaturated aromatic hydrocarbyl having multiple aromatic rings fused together. It means a group, and at least one ring is aromatic. The aromatic ring is one or two that are condensed to it. Additional rings (as defined herein, cycloalkyl, heterocyclyl or heterocyclyl) It may contain aryl groups in some cases. Suitable aryl groups include benzopyrani. Benzodioxolil, benzodioxanil, etc., which are condensed into heterocyclines. It contains phenyl, naphthyl, and phenyl rings.

[0020] In the present invention, the term "halogen" refers to fluoro(-F), chloro(-Cl), bromo( -Br) or iodine (-I) group.

[0021] In the present invention, the term "optionally substituted aliphatic chain" means a chain of 4 to 36 carbon atoms. This refers to an aliphatic chain having elementary atoms, preferably 12 to 24 carbon atoms, which may be substituted. do.

[0022] Radiolabeled GRPR antagonist When used in the present invention, the GRPR antagonist is given by the following formula: MC-SP [In the formula, M is a radioactive metal, and C is a chelating agent that binds to M; S is a spacer, covalently bonded between C and the N-terminus of P; P is a general formula: It is a GRP receptor peptide antagonist for Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is either absent or contains the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Th i) 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine Nin (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo- Tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all L- or Selected from the group consisting of D-isomers; Xaa2 is Gln, Asn, or His; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); Xaa4 is Ala, Ser, or Val; Xaa5 is Val, Ser, or Thr; Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; Xaa7 is His or (3-methyl)histidine (3-Me)His; Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O-alkyl. Or, Z is, [ka] (In the formula, X is NH (amide) or O (ester), and R1 and R2 are the same or different, proto n, optionally substituted alkyl, optionally substituted alkylether, aryl aryl ether or alkyl-, halogen, hydroxyl or hydroxyalkyl It has [a group selected from a substituted aryl or heteroaryl group].

[0023] According to one embodiment, Z is selected from one of the following equations, and X is NH or O: [ka]

[0024] According to one embodiment, the chelating agent C is [ka] It is selected from the group consisting of the following.

[0025] In a detailed embodiment, C is [ka] It is selected from the group consisting of the following.

[0026] According to one embodiment, S is a) The following formula: [ka] [In the formula, PABA is p-aminobenzoic acid, PABZA is p-aminobenzylamine, P DA is phenylenediamine, and PAMBZA is (aminomethyl)benzylamine. Aryl containing residues; b) The following formula: [ka] [wherein DIG is diglycolic acid and IDA is iminodiacetic acid] dicarboxylic acid, ω-aminocarboxylic acid, ω-diaminocarboxylic acid, or diamine; c) PEG spacers of various chain lengths, in particular PEG spacer sele [ka] d) α- and β-amino acids, single chains or homologous chains of various chain lengths Different types of chains, especially [ka] GRP(1-18), GRP(14-18), GRP(13-18), BBN(1-5), or [Tyr4]BB(1-5); or e) combinations of a, b, c, and d It is selected from the group consisting of the following.

[0027] According to one embodiment, the GRPR antagonist is given by the following equation: [ka] The compounds are selected from the group consisting of [wherein MC and P are as defined above].

[0028] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH2-CH(CH3)2)2 ru.

[0029] According to one embodiment, the radiolabeled GRPR - antagonist has the formula (I):

Chemical formula

[0030] According to one embodiment, the radiolabeled GRPR - antagonist has the formula (II):

Chemical formula

[0031] In one embodiment, M is a radioactive metal, which is 111 In, 133m In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As,97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52m Mn, 157 Gd, 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 16 6 HO, 153 Sm, 149 PM, 151 PM, 172 Tm, 121 Sn, 117m Sn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 A u, 199 Au, 89 Zr, 225 American and 47 It can be selected from Sc. Preferably, M is 177 Lu, 6 8 Ga and 111 Selected from In.

[0032] According to one embodiment, M is 177 It is Lu. In this case, it is radioactively labeled GRPR-A. Tagonists can be used for radionuclide therapy. According to another embodiment, M teeth, 68 It is Ga. In this case, the radiolabeled GRPR antagonist is used for PET. It is possible. According to another embodiment, M is 111 In this case, radioactive label The GRPR antagonist can be used for SPECT.

[0033] Pharmaceutical composition GRPR antagonists adhere to glass and plastic surfaces via nonspecific binding (NSB). This tends to occur, which poses a challenge in formulating pharmaceutical compositions. To provide this information, several surfactants were tested. The inventors tested all tested surfactants. Among surfactants, (i) polyethylene glycol chains and (ii) fatty acid esters are particularly important. We unexpectedly found that surfactants containing the compound yielded the best results.

[0034] In a first aspect, this disclosure relates to radiolabeled GRPR-antagonisms as described herein. The compound contains (i) a polyethylene glycol chain and (ii) a fatty acid ester. The present invention relates to a pharmaceutical composition containing a surfactant. In one embodiment, the surfactant also contains free e Contains ethylene glycol.

[0035] In one embodiment, the surfactant is of formula (III) [ka] [In the formula, n is between 3 and 1000, preferably between 5 and 500, more preferably between 10 and 50] , The compound comprises a fatty acid chain, preferably an aliphatic chain that may be substituted.

[0036] In one embodiment, the surfactant is polyethylene glycol 15-hydroxystearate and free ethylene glycol.

[0037] Radiolabeled GRPR antagonists exhibit volume radioactivity. It can be present at a concentration of at least 100 MBq / mL, preferably at least 250 MBq / mL. The radiolabeled GRPR antagonist is preferably present in a concentration between 100 MBq / mL and 1000 MBq / mL. It can exist at concentrations exhibiting volume radioactivity between 250 MBq / mL and 500 MBq / mL. .

[0038] The surfactant is at least 5 μg / mL, preferably at least 25 μg / mL, more preferably It can exist at a concentration of at least 50 μg / mL. Surfactants can be present in concentrations of 5 μg / mL to 5000 μg / mL. Between L, preferably between 25 μg / mL and 2000 μg / mL, more preferably between 50 μg / mL and 1000 μg / mL. It can exist at concentrations in between.

[0039] In one embodiment, the composition comprises at least one other pharmaceutically acceptable additive. A pharmaceutically acceptable additive may be any of those used in conventional methods. , limited only by physicochemical considerations, such as the lack of solubility and reactivity of the active compound. It can be done.

[0040] In particular, one or more additives act as stabilizers against radiolytic degradation. This can be selected from buffer solutions, sequestering agents, and mixtures thereof. .

[0041] In the context of this invention, "stabilizer against radiolysis" refers to the ability to stabilize organic matter from radiolysis. It means a stabilizer that protects the organic molecule, for example, when gamma rays emitted from a radioactive nuclide are absorbed by an organic molecule. When the bonds between atoms are broken and radicals are formed, then those radicals are Removed by stabilizers that evade radicals, unwanted, potentially ineffective, and even toxic They cause any other chemical reactions that may result in molecules being released. Therefore, their stabilizers This is a "free radical scavenger," or simply "radical scavenger." It is also called a radiostabilizer. Other alternative terms for these stabilizers include "radiostabilizers (r "Adsorption stability enhancer," "radioactive stabilizer," or simply "quencher" That is the case.

[0042] In the present invention, "chelating agent" means (a complex with a radiolabeled peptide and (Not suitable for combining with free radioactive nuclide metal ions in formulations) It means.

[0043] Buffers include acetate buffer, citrate buffer, and phosphate buffer.

[0044] According to one embodiment, the pharmaceutical composition is an aqueous solution, for example, an injectable formulation. According to the application method, the pharmaceutical composition is a solution for injection.

[0045] The requirements for effective pharmaceutical carriers for injectable compositions are well known to those skilled in the art (for example). , Pharmaceuticals and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA. Banker and Chalmers (eds.), pp. 238-250 (1982), and ^SHP Handbook on Injectable Dr See ugs, Trissel, 15th edition, pp. 622-630 (2009).

[0046] This disclosure also relates to the process of combining a radiolabeled GRPR antagonist and a surfactant. The present invention relates to a method for manufacturing a pharmaceutical composition containing [a specific substance].

[0047] This disclosure also relates to the pharmaceutical compositions described above for use in the treatment or prevention of cancer. Regarding.

[0048] As used in this invention, the term "cancer" refers to autonomous proliferation, that is, rapid cell growth. This refers to cells that possess the ability to dramatically increase in number in abnormal situations or conditions. Excessive growth and neoplastic conditions are characteristic or constitutive to the pathological state, that is, the condition. It can be classified as such, or as non-pathological, that is, deviating from normal, but not in a medical condition. It can be classified as something unrelated to that. The term is an invasive histopathological type or Regardless of the stage, this refers to cancerous growth or carcinogenic processes, metastatic tissue, or cells that have transformed into malignant cells. This means including all types of tissues or organs.

[0049] In detailed embodiments, cancers include prostate cancer, breast cancer, small cell lung cancer, colon cancer, and gastrointestinal cancer. Squamous tumors, gastrinomas, renal cell carcinomas, pancreatic gastrointestinal neuroendocrine tumors, esophageal squamous cell tumors, nerve Ovarian and endometrial lesions exhibiting neoplasm-associated vascular structures such as blastoma, head and neck squamous cell carcinoma, and GRPR. and pancreatic tumors are selected. In one embodiment, the cancer is prostate cancer or breast cancer.

[0050] This disclosure also relates to, in particular, preferably PET, for use in in vivo imaging. SPECT imaging is used to detect GRPR-positive tumors in subjects where it is necessary. The present invention relates to a pharmaceutical composition as described above.

[0051] This disclosure also relates to methods for treating or preventing cancer in subjects that require it. This method involves administering a therapeutically efficient amount of the pharmaceutical composition described above to the subject. Includes the degree.

[0052] This disclosure also relates to a method for in vivo imaging, the method described above. A step of administering an effective amount of the pharmaceutical composition to a target, and the radioactive isotope present in the compound This includes a step of detecting a signal derived from the collapse.

[0053] Radiolabeled GRPR antagonists for use in cancer treatment In a second aspect, the disclosure also relates to the treatment or prevention of cancer in subjects where it is needed. Regarding compositions containing a radiolabeled GRPR-antagonist for use in radioactive Labeled GRPR antagonists are therapeutically effective in doses between 2000 and 10000 MBq. It is administered to the aforementioned subjects.

[0054] In detailed embodiments, a therapeutically efficient amount of the composition is administered to the subject 2 to 8 times per treatment. For example, the patient is given a radiolabeled substance intravenously in 2 to 8 cycles of 2000 to 10000 MBq each. The GRPR antagonist, for details, 177 Treatment can be performed using Lu-NeoBOMB1.

[0055] In some aspects, the subject is mammals, for example, rodents, though not limited to them. These are canids, felines, or primates. In some aspects, the subject is a human. ru.

[0056] The inventors of this invention, as demonstrated in animal models of cancer, 177 Lu-NeoBOMB1 is enabled. We found that, compared to untreated animals, the treatment group showed a significantly longer delay in tumor growth. Furthermore, the median survival time was significantly longer. In the non-exclusive examples described herein, animals teeth, 177 Treatment with Lu-NeoBOMB1 3×30 MBq / 300 pmol, 3×40 MBq / 400 pmol, or 3×60 MBq / 600 pmol. Despite this, there was no significant difference in tumor growth delay time and median survival. No differences were found between groups. Prior dose calculation using a linear-quadratic model. ion) predicted the difference in tumor control probability between treatment groups (tumor control probability: 3 × 30 MBq / 300 pmol). In animals treated with 3 × 40 MBq / 400 pmol and 3 × 60 MBq / 600 pmol, the percentages were 0%, 75%, and 1%, respectively. 00%), this finding was unexpected. Not bound by any theory, this means that the patient is cured. The dose required for treatment should be far lower than what was predicted from the prior dose calculation. Yes, and this is predicted to reduce the toxicity of radioactively labeled NeoBOMB1. ru.

[0057] Advantageously, radiolabeled GRPR antagonists are 177 It is labeled with Lu.

[0058] In a detailed embodiment of the above method, the cancers are prostate cancer, breast cancer, small cell lung cancer, and colon cancer. Gastrointestinal stromal tumors, gastrinomas, renal cell carcinomas, pancreatic gastrointestinal neuroendocrine tumors, esophageal squamous epithelial tumors Tumors, neuroblastomas, head and neck squamous cell carcinomas, and neoplasms-associated vascular structures that are GRPR-positive. The cancer is selected from ovarian, endometrial, and pancreatic tumors. In one embodiment, the cancer is prostate cancer or I have breast cancer.

[0059] According to one embodiment, a composition for use, comprising the pharmaceutical composition described in the previous section. be.

[0060] This disclosure also relates to a method for treating or preventing cancer, wherein the method is radiolabeled The process includes administering an effective amount of a composition containing a GRPR antagonist to a subject with cancer. Radiolabeled GRPR antagonists contain therapeutic efficacy between 2000 and 10000 MBq. It is administered to the subject in a specific amount.

[0061] Provided herein are methods for treating or preventing cancer, and these methods are provided herein. An effective amount of a composition containing a radiolabeled GRPR antagonist as defined in the specification, The process includes administering the drug to a subject having cancer. In some embodiments, the cancer is prostate cancer or I have breast cancer.

[0062] In some embodiments, a composition comprising a radiolabeled GRPR antagonist is used to treat cancer. When administered to a subject, it suppresses or delays tumor growth in that subject. , and / or can be reduced. In some embodiments, tumor growth is reduced in untreated patients. Compared to the patient, the delay is at least 50%, 60%, 70%, or 80%. In some embodiments, Tumor growth is delayed by at least 80% compared to untreated control patients. In this case, tumor growth was at least 50% compared to the predicted growth of an untreated tumor. The growth of the tumor is delayed by 0%, 70%, or 80%. In some aspects, tumor growth is delayed compared to the prognosis of an untreated tumor. Compared to the measured growth, it is delayed by at least 80%. Those skilled in the art can predict the growth rate of a tumor. However, epidemiological data, medical literature and reports on other knowledge in the field, tumor type Furthermore, they should be aware that this can be done based on measurements of tumor size, etc. ru.

[0063] In some embodiments, a composition comprising a radiolabeled GRPR antagonist is used to treat cancer. By administering it to a subject, the length of the subject's survival can be increased. In some aspects, the increase in survival is compared to untreated control patients. The increase in survival is compared to the predicted increase in survival of untreated subjects. In that configuration, the length of survival is at least three to four times longer compared to untreated control patients. , or increased fivefold. In some embodiments, the length of survival is compared to untreated control patients. The length increases by at least four times. In some embodiments, the length of survival is compared to untreated patients. Compared to the predicted lifespan of the elephant, the length increases by at least three, four, or five times. In some aspects, the length of survival is compared to the predicted length of survival of untreated subjects. The length increases by at least four times. In some embodiments, the length of survival is greater than that of an untreated control. Compared to the patient, at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or This increases by 3 years. In some aspects, the length of survival is shorter compared to untreated control patients. At the very least, it increases by one, two, or three months. In some aspects, the length of survival is affected by treatment. Compared to the predicted length of survival of subjects that do not undergo the procedure, at least 1 week, 2 weeks, 1 month, 2 months It increases by months, 3 months, 6 months, 1 year, 2 years, or 3 years. In some embodiments, the length of survival is Compared to the predicted length of survival for untreated subjects, at least 1 month, 2 months, or 3 months. It will increase by months.

[0064] In some embodiments, the amount of radiolabeled GRPR antagonist administered is the target In this case, the tumor control probability is 100%, so the amount is less than predicted for the subject. In some embodiments, the amount of radiolabeled GRPR antagonist administered is the target Because it has at least a 75% probability of tumor control, it is less than the amount predicted for the subject. In some embodiments, the amount of radiolabeled GRPR antagonist administered is the target To achieve a 50% tumor control probability, the amount used is less than the amount predicted for the subject. In some embodiments, the amount of radiolabeled GRPR antagonist administered is such that the subject is 25% To achieve tumor control probability, the amount is less than the predicted amount for the subject. Several aspects So, what is the amount of radiolabeled GRPR antagonist administered to ensure 10% tumor control in the target group? To achieve the rate, the amount is less than the amount predicted for the subject. In some embodiments, the dose is administered. The amount of radiolabeled GRPR antagonist used is such that the target has a 100% tumor control probability. Therefore, the amount is 25%, 30%, 40%, 50%, 60%, 70%, or 75% or less of the predicted amount for the subject. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is, For the elephant to have at least a 75% tumor control probability, 50% of the predicted amount for the subject, 60% The percentage is 70%, 75%, 80%, or 85% or less. In some embodiments, the administered radiolabeled The amount of GRPR-antagonist administered was such that the subject had at least a 50% chance of tumor control. The amount obtained for the subject is 60%, 65%, 70%, 75%, 80%, 85%, or 90% or less of the predicted amount. In some embodiments, the amount of radiolabeled GRPR antagonist administered is 25% of the target. The predicted amount for a subject to have a tumor control probability of 20%, 15%, 10%, or less than 5% In some embodiments, the amount of radiolabeled GRPR antagonist administered is The amount predicted for the subject is such that the subject has a 0% probability of tumor control. In this embodiment, the amount of radiolabeled GRPR antagonist administered is such that the target has 0% tumor It is a quantity predicted for the subject, possessing a control probability. [Examples]

[0065] (Example 1): 68 Screen of formulations for reducing the adhesion of NeoBOMB1 using Ga-NeoBOMB1 Ning During the development of the formulation kit, the inventors discovered that the peptide adheres to glass and plastic surfaces. I realized that I have a certain tendency to wear certain clothes.

[0066] This phenomenon is called nonspecific binding (NSB). Peptides are often larger than small molecules. This highlights the problem with uncharged peptides, particularly how uncharged peptides strongly adsorb to plastics. This is possible. These causes can be different, namely physical / chemical properties, van der Wat These are Ruhls interactions and ionic interactions.

[0067] Organic solvents can promote solubility and prevent adsorption. Ethanol, for example, is radiant. Used in drug injections to promote the solubility of highly lipophilic tracers or vials This can reduce adsorption to the membrane filter and syringe. Ethanol was rejected because it was not suitable for freeze-drying.

[0068] Human serum albumin (HSA) is also used as a stabilizer to prevent surface adsorption in many applications. Although used in protein-based formulations, this additive is unsuitable due to its thermal instability. It is not suitable. Another possible method is to use a surfactant (e.g., polysol). (Using Bate 20, Polysorbate 80, Pluronic F-68, Sorbitan Trioleate) there were.

[0069] The present inventors have found that ionic surfactants are, 68 Because interference can occur during Ga labeling, nonionic We focused on testing for surfactants.

[0070] Kolliphor HS15, Kolliphor K188, Tween 20, Tween 80, Polyvinylpyrrolidone K10 Nonionic tensioactives, such as those mentioned above, are used in solubilizing oral and injectable formulations. It is commercially available as an additive. The following table shows the initial results obtained with different tension activators. Summarize the test results.

[0071] Materials and methods: Labeling of NeoBOMB1 was performed by Castaldi et al. (Castaldi E, Muzio V, D'Angeli L, Fugazza L. 68 GaDOTATATE lyophilized ready to use kit for PET imaging in pancreatic cancer mur The ine model, based on the previously published kit method in J Nucl Med 2014; Vol. 55 (suppl 1): 1926) Based on.

[0072] Different surfactants were screened, and the adhesion percentage of the resulting aqueous solutions was used for dose calibration. After completely stopping the radioactively labeled solution, the total amount remaining in the vial was measured by a detector. The radioactivity was evaluated and determined. It was measured as a percentage before and after discontinuation of the sample. The difference between the total radioactivity levels directly correlates with the adhesion of peptides to the container stopper system. The results are summarized in Table 1.

[0073] [Table 1]

[0074] The best results regarding peptide adhesion were obtained using Kolliphor HS15 and Tween 20. The additives were further investigated to determine the final amount in the kit. The results obtained were radiochemical It was excellent in terms of target purity and peptide adhesion.

[0075] [Table 2]

[0076] The inventors have found that polysorbate (Tween 20) undergoes auto-oxidation, ethylene oxide subunit Cracks in the t and the presence of oxygen, metal ions, peroxides, or temperature rise are caused by these factors. Because it can perform hydrolysis of fatty acid ester bonds, we focus on Kolliphor HS15. Set.

[0077] (Example 2): 177Preclinical trials on the therapeutic efficacy of Lu-NeoBOMB1 Disclosed herein are: 177 Lu-NeoBOMB1 is used in three different dosages, and is a well-known GRPR- Therapy in animals xenotransplanted with the expressing prostate cancer cell lineage PC-3, 177 Treatment for Lu-NeoBOMB1 This is a model, non-limiting example of preclinical trials for efficacy. Furthermore, microclinical studies were conducted on small animals without tumors. In the loop, for the kidneys and pancreas 177 The effectiveness of Lu-NeoBOMB1 treatment, and the pathological tissue after treatment. It was tested using scientific methods.

[0078] Materials and methods radioactive label Dilute NeoBOMB1 (ADVANCED ACCELERATOR APPLICATIONS) (WO2014052471) in ultrapure water. The concentration and chemical purity were monitored using our proprietary titration method (Breeman WA, de Zanger RM). , Chan HS, de Blois E. Alternative method to determine specific activity of 177 L (U by HPLC. Curr Radiopharm. 2015; Vol. 8: pp. 119-122). To prevent peptide adhesion, release The irradiance is achieved by adding all the necessary additives, such as buffers, antioxidants, and tensile activators (Kolliph ( or HS15) containing peptides added to the vial 177 Lu100MBq / nmol). high speed liquid Chromatography was used to determine the radiochemical purity of methanol and 0.1% trifluor. The procedure was performed using a gradient of acetic acid. As mentioned above, instant thin-layer chromatography of silica gel was performed. Radioactive metal uptake (de Blois E, Chan) measured by thin-layer chromatography HS, Konijnenberg M, de Zanger R, Breeman WA. Effectiveness of quenchers to reduce e radiolysis of (111) In- or ( 177 )Lu-labelled methionine-containing regulatory pept ides. Maintaining radiochemical purity as measured by HPLC. Curr Top Med Chem.2 (2012; Vol. 12: 2677-2685) For SPECT / CT, as well as efficacy and toxicity tests, >6 The percentages were 7% and >90%.

[0079] Animal models, efficacy, and toxicity All animal testing is conducted by the Animal Welfare Committee of Erasmus Medical Center. The procedure was carried out in accordance with the requirements of the ITTEE and the approved guidelines. Inoculation medium (1 / 3 is matte) High-concentration Rigel (Corning) + 2 / 3 Hanks equilibrium salt solution (Thermofisher Scientific) 4 x 10 6 200 μL of PC-3 cells (American Type Culture Collection) were administered to male balb c nu / nu cells. The tumor cells were subcutaneously inoculated into the right shoulder of mice. Four weeks after tumor cell inoculation, the average tumor size was 543 ± 177 m². m 3 If this is reached, the animals will be divided into four groups, namely the control group (n=10) and the 1st to 3rd therapy groups (n per group). It was divided into 15 parts. 177 To determine the efficacy of Lu-NeoBOMB1, animals were subjected to isoflurane / O2 anesthesia. Under anesthesia, three mock injections (control group), 177 Lu-NeoBOMB1 3×30 MBq / 300 pmol (Group 1), 177 Lu-Ne oBOMB1 3×40 MBq / 400 pmol (Group 2) or 177 Lu-NeoBOMB1 3×60 MBq / 600 pmol (Group 3) were administered . The injections were administered intravenously and inoculated at one-week intervals.

[0080] To determine the therapeutic effect on pancreatic and kidney tissues, balb c nu / nu male mice without tumors were given the same treatment as the animals included in the efficacy test. At two different time points after the last therapeutic injection (12 weeks and 24 weeks p.i.), the animals were euthanized and pancreatic and kidney tissues were collected for pathological analysis.

[0081] In both tests, the body weight of the animals and / or the tumor size were measured biweekly. If the tumor size was ≧2000 mm 3 or a ≧20% decrease in the body weight of the animals was observed within 48 hours, the animals were excluded from this test. In the efficacy test, the animals were followed until the maximum allowable age reached 230 days .

[0082] SPECT / CT To quantify tumor uptake, SPECT / CT imaging was performed in a group of PC-3 xenograft animals (n = 2 per group) during follow-up . When the tumor sizes were all 477±53 mm 3 , the animals were injected with the same amount of peptide as the animals included in the efficacy and toxicity tests. Four hours and 24 hours after the first therapeutic injection, and four hours after the second and third therapeutic injections, whole-body SPECT / CT scans were performed. Performed on a hybrid SPECT / CT scanner (VECTor5, MILabs, Utrecht, The Netherlands). SPECT was performed at 40 bed positions over 30 minutes using a 2.0-mm pinhole collimator with a reported spatial resolution of 0.85 mm (Ivashchenko O, van der Have F, Goorden MC, Ra makers RM, Beekman FJ. Ultra-high-sensitivity submillimeter mouse SPECT. J Nucl Me d. 2015;56:470 - 475). SPECT images were reconstructed using photopeak windows 113 and 20 8 keV with background windows on both sides of the photopeak (width is 20% of the corresponding photopeak), and the SR-OSEM reconstruction method (Vaissier PE, Beekman FJ, Goorden MC. Similarity-regu lation of OS-EM for accelerated SPECT reconstruction. Phys Med Biol. 2016;61: 4300 - 4315), with a voxel size of 0.8 mm and registered to the CT data. A 3D Gaussian filter (1 mm fwhm) was applied after reconstruction . CT was performed with the following settings: 0.24 mA 3 , 50 kV, full rotation scan, 1 position. CT was reconstructed at 100 μm . 3

[0083] Pathological analysis Pancreas and kidney tissues collected for pathological analysis were fixed in formalin and embedded in paraffin . Hematoxylin and eosin staining was performed on 4-μm thick tissue sections using the Ventana Symphony™ H&E protocol (Ve ntana) to determine differences in tissue architecture between the four treatment groups In a total of four tissue sections, 50 μM of each organ was evaluated separately. Hematoxylin and eosin staining was evaluated by an experienced pathologist.

[0084] Dose measurement Using data obtained from previously published biodistribution and pharmacokinetic studies in 25 g body weight rats (Dalm SU, Bakker IL, de Blois E et al., Ga / 68 Ga / 177 Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology. J Nucl Med. 2017;58:293 - 299), and a RADAR realistic mouse model (Keenan MA, Stabin MG, Segars WP, Fernald MJ. RADAR realistic animal model series for dose assessment. J Nucl Med. 2010;51:47 1 - 476), the doses to tumors, pancreas, and kidneys were calculated when the animals were treated with Lu-NeoBOMB1 at 3 × 30 MBq / 300 pmol, 4 × 40 MBq / 400 pmol or 3 × 60 MBq / 600 pmol. The biodistribution data from the inventors' previously published paper (Dalm SU, Bakker IL, de Blois E et al., 177 Ga / Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology. J Nucl Med. 2017;58:293 - 299) were fitted to an exponential curve to define the time-activity curves in tumors and organs. et al., 68 Ga / 177 Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology. J Nucl Med. 2017 ;58:293 - 299) were fitted to an exponential curve to define the time-activity curves in tumors and organs. The biodistribution data from the inventors' previously published paper (Dalm SU, Bakker IL, de Blois E et al., Ga / 177Time integrated activity with respect to Lu es) 177 Lu decay curve (T 1 / 2 By integrating these superimposed exponential curves (=6.647d), the result is obtained. The absorbed dose per administered activity was determined by Keenan et al. (Keenan MA, Stabin MG, Segars) WP, Femald MJ. RADAR realistic animal model series for dose assessment. J Nucl M By multiplying by the organ S value obtained from (ed. 2010; Vol. 51: 471-476) or in the case of a tumor of 340 mg Spherical node S value (Stabin MG, Konijnenberg MW). Re-evaluation of absorbed fraction s for photons and electrons in spheres of various sizes.J Nucl Med.2000;4l volume:l This was obtained by using pages 49-160.

[0085] Tumor dosimetry is performed using a linear quadratic (LQ) model (Konijnenberg MW) based on tumor control probability (TCP). , Breeman WA, de Blois E et al., Therapeutic application of CCK2R-targeting PP-F11:in Influence of particle range, activity, and peptide amount. EJNMMI Res. 2014; Vol. 4: 47 The data (page number) was used to predict treatment outcomes.

[0086]

number

[0087] Nclonogens is the number of clonogenic (stem) cells within the tumor, and S(D,T) is the survival fraction of cells as a function of absorbed dose D and time T. The LQ model shows survival as a function of absorbed dose for tumor growth using the doubling time T

Equation

[0088] Tumor volume analysis The doubling time of the tumor was measured in the control group, and the exponential growth function over time was fitted to the tumor volume. This was determined by the following: In the therapy group, the interval with an exponential decrease in tumor volume was the lowest. The growth curve was adjusted to reflect the onset of regrowth after irradiation. The growth curve was adjusted for tumors (>2000mm). 3 ) is too large, average For mice where growth statistics could not be determined, we estimated beyond the censoring point. Tumor growth Delay time, maximum tumor size 2000 mm 3 The time required to reach this point was compared to the control group. The determination was made individually by comparing it with the average time that was determined.

[0089] statistics Prism software (version 5.01, GraphPad Software) was used for statistical analysis. A p-value > 0.05 was considered statistically significant. Tumor volume growth and The difference in delay time was analyzed using one-way ANOVA studies, including Bonferroni's multiple comparison study. We analyzed the curve fitting using Pearson R. 2 The fitting is done according to the least squares fitting method. We quantified the quality of Mari.

[0090] result SPECT / CT At most points in time, the average radioactive uptake quantified by SPECT / CT was highest in group 3. The group with the highest score was the second group, followed by the first group. However, the difference between the groups was not statistically significant. Figure 1A shows the results 4 hours and 24 hours after the first injection, and 4 hours after the second and third injections. The scans obtained for one animal from each group are shown. Quantified tumor uptake is illustrated in Figure 1B. .

[0091] 177 Lu-NeoBOMB1 Therapeutic Efficacy 177 Therapy with Lu-NeoBOMB1 has proven effective. In the control group, animals were The tumor size is 2000 mm 3 It reached the range of 20.3±5.9d, which is the same for Group 1, Group 2, and In the case of the first and third groups, the values ​​were 97±59d, 103±66d, and 95±26d, respectively (Figure 2A). Furthermore, the first group Two animals obtained from this group and one animal from the second group showed no tumor regrowth after complete remission. However, there was no significant difference in the time of tumor growth delay within the treatment group compared to the control group. The difference was highly statistical (P<0.0001).

[0092] Consistent with the above, animals in the treatment group had significantly better survival rates compared to the treatment group (P <0.001) (Figure 2B). Median survival was 19 for the control group, group 1, group 2, and group 3, respectively. The results were d, 82d, 89d, and 99d.

[0093] Five individuals (n=3 from group 2 and n=2 from group 3) were excluded from this study for the following reasons; one individual was excluded. Death was discovered after the first injection, and one animal had very small vein smears that disappeared within a few days of starting treatment. One of the animals had a tumor of a certain type, one had lost more than 10% of its body weight within 48 hours, and one had fluid retention in its abdomen. He maintained the condition. None of the mentioned events showed any signs related to treatment.

[0094] Renal and pancreatic toxicity Animals exposed to the toxin did not show a significant decrease in body weight over the follow-up period (Figure 3). The animals' body weight increased during the first week and remained relatively stable over time. (Control group) One of the individuals (ID:B) and one from the first group (ID:869) showed a decrease in body weight, which is due to 4 Less than 10% were found within 8 hours. Histopathological analysis of the pancreas showed no tissue damage or other abnormalities. There was none (Figure 4). Regarding the kidneys (Figure 5), a narrow area with lymphocyte infiltration was the final therapeutic injection. This was observed in the kidneys at 12 and 24 weeks post-injection. This was observed in control animals and treated animals. This was a case of kidney disease, and the findings were not related to the therapy. 24 weeks after the therapy, atrophy occurred. Shrinkage and fibrosis were not associated with the therapy and occurred in only one animal that received the lowest therapeutic dose. Observed in the kidneys of (ID:864). Animals obtained from the third group, which were euthanized 24 weeks after therapy. Mild chronic inflammatory responses were observed in the kidneys of two of the animals.

[0095] Dose measurement 177 Treatment with Lu-NeoBOMB1 3×30 MBq / 300 pmol, 3×40 MBq / 400 pmol, or 3×60 MBq / 600 pmol The radioactive doses to the tumor, pancreas, and kidney after treatment were estimated (see Table 3 below). (and). It was hypothesized that tumor and organ uptake were similar after each injection.

[0096] Table 3

Claims

1. A pharmaceutical composition, - The following formula: MC-SP [In the formula, M is a radioactive metal, and C is a chelating agent that binds to M; S is a spacer, covalently bonded between C and the N-terminus of P; P is a general formula: It is a GRP receptor peptide antagonist for Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is either absent or contains the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Th i) 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine Nin (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo- Tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all L- or Selected from the group consisting of D-isomers; Xaa2 is Gln, Asn, or His; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi); Xaa4 is Ala, Ser, or Val; Xaa5 is Val, Ser, or Thr; Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; Xaa7 is His or (3-methyl)histidine (3-Me)His; Z is selected from -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O-alkyl. Or, Z is, 【Chemistry 1】 (In the formula, X is NH (amide) or O (ester), and R1 and R2 are the same or different.) , proton, optionally substituted alkyl, optionally substituted alkylalkyl, Aryl, aryl ether, or alkyl-, halogen, hydroxyl or hydro (Selected from xyalkyl-substituted aryl or heteroaryl groups) Radiolabeled GRPR antagonists; and - A surfactant containing a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester. Aphrodisiacs A pharmaceutical composition containing the above.

2. P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH(CH 2 -CH(CH 3 ) 2 ) 2 The claim described in claim 1 is as follows: Pharmaceutical composition.

3. The aforementioned GRPR antagonist is given by equation (I): 【Chemistry 2】 [In the formula, M is a radioactive metal, preferably M is, 177 Lu, 68 [Selected from Ga] The pharmaceutical composition according to claim 1 or 2, wherein NeoBOMB1.

4. The aforementioned surfactant is defined by formula (III): 【Transformation 3】 [In the formula, n is between 3 and 1000, preferably between 5 and 500, more preferably between 10 and 50] 、 R is a fatty acid chain, preferably an aliphatic chain that may be substituted. A pharmaceutical composition according to any one of claims 1 to 3, comprising the compound.

5. The surfactant is polyethylene glycol 15-hydroxystearate and free ethyl A pharmaceutical composition according to any one of claims 1 to 4, comprising lenglycol.

6. The radiolabeled GRPR antagonist is present in a concentration of at least 100 MBq / mL, preferably 25 Any of claims 1 to 5, which is present at a concentration that provides volume radioactivity between 0 MBq / mL and 500 MBq / mL A pharmaceutical composition as described in any one of the items.

7. The surfactant is at least 5 μg / mL, preferably at least 25 μg / mL, and 50 μg A pharmaceutical composition according to any one of claims 1 to 6, present at a concentration between / mL and 1000 μg / mL thing.

8. The radiolabeled GRPR-antagonist is 177 Lu, 68 Ga or 111 labeled with In a pharmaceutical composition according to any one of claims 1 to 7.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is an aqueous solution.

10. The pharmaceutical composition is a solution for injection, according to any one of claims 1 to 9. Finished product.

11. A medical device according to any one of claims 1 to 10 for use in the treatment or prevention of cancer A pharmaceutical composition.

12. For use in vivo imaging, preferably PET and SPECT imaging, A pharmaceutical composition according to any one of claims 1 to 10.

13. A method for treating or preventing cancer in a subject that requires it, the method However, administering a therapeutically efficient amount of the composition according to any one of claims 1 to 10 to the subject. A method that includes doing something.

14. For in vivo imaging of tumors in subjects requiring it, particularly GRPR-positive tumors. A method for detecting a ulcer, wherein the method comprises an effective amount of any one of claims 1 to 10. Administering the composition described in the section to the subject, and the radioactive isotopes present in the compound This includes detecting signals derived from breakdown, thereby detecting GRPR-positive tumors. method.

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