Pharmaceutical compositions comprising radiolabeled GPRP antagonists and surfactants

Abstract

To provide an efficient treatment protocol for patients with cancer using a GRPR-antagonist.SOLUTION: The present disclosure relates to gastrin-releasing peptide receptor (GRPR) targeting radiopharmaceuticals and uses thereof. In particular, the present disclosure relates to a pharmaceutical composition comprising radiolabeled GRPR-antagonist and a surfactant. The present disclosure also relates to radiolabeled GRPR-antagonist for use in treating or preventing a cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to radiopharmaceuticals targeting the gastrin-releasing peptide receptor (GRPR) and their uses. In particular, the present disclosure relates to pharmaceutical compositions comprising a radiolabeled GRPR antagonist and a surfactant. The present disclosure also relates to radiolabeled GRPR antagonists for use in the treatment or prevention of cancer. [Background technology]

[0002] The gastrin-releasing peptide receptor (GRPR), also known as bombesin receptor subtype 2, is a G protein-coupled receptor expressed in various organs, including the gastrointestinal tract and pancreas (Guo M et al., Curr Opin Endocrinol Diabetes Obes. 2015; 22:3-8, 2; Gonzalez N et al., Curr Opin Enocrinol Diabetes Obes. 2008; 15:58-64). After binding of an appropriate ligand, GRPR is activated and induces multiple physiological processes, such as exocrine and endocrine regulation (Guo M et al., Curr Opin Endocrinol Diabetes Obes. 2015; 22:3-8, 2; Gonzalez N et al., Curr Opin Enocrinol Diabetes Obes. 2008; 15:58-64). Over the past few decades, GRPR expression has been reported in various cancer types, including prostate and breast cancer (Gugger M and Reubi JC. Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human breast. Am J Pathol. 1999;155:2067-2076; Markwalder R and Reubi JC. Cancer Res. 1999;59:1152-1159). Thus, GRPR has become an attractive target for receptor-mediated tumor imaging and therapy, such as peptide receptor scintigraphy and peptide receptor radionuclide therapy (Gonzalez N et al., Curr Opin Enocrinol Diabetes Obes. 2008;15:58-64).Following the successful use of radiolabeled somatostatin peptide analogs in neuroendocrine tumors for nuclear imaging and therapy (Brabander T et al., Front Horm Res. 2015; 44:73-87; Kwekkeboom DJ and Krenning EP. Hematol Oncol Clin North Am. 2016; 30:179-191), several radiolabeled GRPR radioligands have been synthesized and studied in preclinical and clinical trials, primarily in patients with prostate cancer. Examples of such peptide analogs include AMBA, the Demobesin series, and MP2653 (Yu Z et al., Curr Pharm Des. 2013; 19: 3329-3341; Lantry LE et al., J Nucl Med. 2006; 47: 1144-1152; Schroeder RP et al., Eur J Nucl Med Mol Imaging. 2010; 37: 1386-1396; Nock B et al., Eur J Nucl Med Mol Imaging. 2003; 30: 247-258; Mather SJ et al., Mol Imaging Biol. 2014; 16: 888-895). Recent studies have shown that GRPR antagonists are preferred over GRPR agonists (Mansi R et al., Eur J Nucl Med Mol Imaging. 2011; 38: 97-107; Cescato R et al., J Nucl Med. 2008; 49: 318-326). Compared with receptor agonists, antagonists often exhibit higher binding and favorable pharmacokinetics (Ginj M et al., Proc Natl Acad Sci USA. 2006; 103: 16436-16441). Clinical trials using radiolabeled GRPR agonists also reported unwanted side effects in patients caused by activation of the GRPR after the peptide binds to the receptor (Bodei L et al., [abstract], Eur J Nucl Med Mol Imaging. 2007; 34: S221).

[0003] It has recently been discovered that some GRPR-antagonists, such as NeoBOMB1, can be radiolabeled with different radionuclides and potentially used for imaging and treating GRPR-expressing cancers, including, but not limited to, prostate and breast cancer. However, only biodistribution studies have been reported so far, and no efficient treatment protocols or pharmaceutical compositions have been developed.

[0004] Therefore, in this context, it would be desirable to provide pharmaceutical compositions containing GRPR-antagonists that can be administered to patients. Furthermore, it would also be desirable to provide efficient treatment protocols for patients with cancer using GRPR-antagonists. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2014052471 [Non-patent literature]

[0006] [Non-Patent Document 1] Guo M et al., Curr Opin Endocrinol Diabetes Obes. 2015;22:3-8,2 [Non-patent document 2] Gonzalez N et al., Curr Opin Enocrinol Diabetes Obes. 2008;15:58-64 [Non-patent document 3] Gugger M and Reubi JC.Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human breast. Am J Pathol.1999;155:2067~2076 [Non-patent 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. 68GaDOTATATE lyophilized ready to use kit for PET imaging in pancreatic cancer murine model, J Nucl Med 2014;55 Vol(suppl 1):1926 [Non-licensed Document 19] Breeman WA, de Zanger RM, Chan HS, de Blois E. Alternative method to determine specific activity of 177Lu by HPLC. Curr Radiopharm. 2015; Volume 8: 119~122 [Non-licensed Document 20] de Blois E, Chan HS, Konijnenberg M, de Zanger R, Breeman WA. Effectiveness of quenchers to reduce radiolysis of (111)In- or (177)Lu-labelled methionine-containing regulatory peptides. Maintaining radiochemical purity as measured by HPLC. Curr Top Med Chem. 2012; 12 Vol: 2677~2685 [Non-licensed Document 21] Ivashchenko O, van der Have F, Goorden MC, Ramakers RM, Beekman FJ. Ultra-high-sensitivity submillimeter mouse SPECT.J Nucl Med. 2015; Volume 56: 470~475 [Non-licensed Document 22] Vaissier PE, Beekman FJ, Goorden MC. Similarity-regulation of OS-EM for accelerated SPECT reconstruction. Phys Med Biol. 2016; 61 Vol: 4300~4315 [Non-licensed Document 23] Dalm SU, Bakker IL, de Blois Eら, 68Ga / 177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology. J Nucl Med. 2017; 58 volumes: 293~299 pages [Non-licensed Document 24] Keenan MA, Stabin MG, Segars WP, Fernald MJ. RADAR realistic animal model series for dose assessment. J Nucl Med. 2010; Volume 51: 471~476 [Non-licensed Document 25] Stabin MG, Konijnenberg MW. Re-evaluation of absorbed fractions for photons and electrons in spheres of various sizes. J Nucl Med. 2000; 4l volume: 149~160 pages [Non-licensed Document 26] Konijnenberg MW, Breeman WA, de Blois E et al., Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount. EJNMMI Res. 20l4; vol. 4: p. 47 [Non-Patent Document 27] Carlson DJ, Stewart RD, Li XA, Jennings K, Wang JZ, Guerrero M. Comparison of in vitro and in vivo alpha / beta ratios for prostate cancer.Phys Med Biol.2004;49:4477~4491 [Non-patent document 28] Joiner M, Kogel Avd. Basic clinical radiobiology. 4th edition. London: Hodder Arnold;;2009. Summary of the Invention

[0007] In a first aspect, the present disclosure provides a compound of the formula: MC-SP [In the formula, M is a radiometal and C is a chelator that binds M; S is an optional spacer covalently linked between C and the N-terminus of P; P is a group of the general formula: is a GRP receptor peptide antagonist of Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is absent or selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all as the L- or D-isomer); 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] wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether, or an alkyl-, halogen, a hydroxyl- or hydroxyalkyl-substituted aryl or heteroaryl group; and - a surfactant comprising a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester The present invention relates to a pharmaceutical composition comprising:

[0008] In a second aspect, the present disclosure relates to a composition comprising a radiolabeled GRPR-antagonist for use in treating or preventing cancer in a subject, - the radiolabeled GRPR-antagonist has the formula: MC-SP [In the formula, M is a radiometal and C is a chelator that binds M; S is an optional spacer covalently linked between C and the N-terminus of P; P is a group of the general formula: is a GRP receptor peptide antagonist of Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is absent or selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all as the L- or D-isomer); 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] wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether, or an alkyl-, halogen, hydroxyl- or hydroxyalkyl-substituted aryl or heteroaryl group; - the radiolabeled GRPR-antagonist is administered to said subject in a therapeutically effective amount of between 2000 and 10000 MBq. [Brief explanation of the drawings]

[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 the tumor. Animals were injected with 30 MBq / 300 pmol (Group 1), 40 MBq / 400 pmol (Group 2), or 60 MBq / 600 pmol of 177Lu-NeoBOMB1. [Figure 1B] FIG. 1B shows quantified tumor uptake (n=2 per group) from the injections described in FIG. 1A. [Figure 2] Figure 2A shows estimated tumor size in untreated animals and animals treated with 177Lu-NeoBOMB1 at 3 × 30 MBq / 300 pmol (Group 1), 3 × 40 MBq / 400 pmol (Group 2), and 3 × 60 MBq / 600 pmol (Group 3). Figure 2B shows survival rates in untreated animals and animals treated with 177Lu-NeoBOMB1 at 3 × 30 MBq / 300 pmol (Group 1), 3 × 40 MBq / 400 pmol (Group 2), and 3 × 60 MBq / 600 pmol (Group 3). [Figure 3] Figure 3A shows the weight of animals before and after treatment for up to 12 weeks of treatment, and Figure 3B shows the weight of animals before and after treatment for up to 24 weeks of treatment. [Figure 4]Representative hematoxylin and eosin staining of pancreatic tissue from untreated and treated animals (177Lu-NeoBOMB1 3 x 30MBq / 300pmol (Group 1), 3 x 40MBq / 400pmol (Group 2), and 3 x 60MBq / 600pmol (Group 3)). [Figure 5] 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)). Circled areas indicate lesions with lymphocytic infiltration (IDs: D, 814, 861, 868, and 862) or atrophy and fibrosis (ID: 864). DETAILED DESCRIPTION OF THE INVENTION

[0010] definition The phrases "treatment" and "treating" include amelioration or cessation of a disease, disorder, or a symptom thereof.

[0011] The phrases "prevention of" and "preventing" include the avoidance of the onset of a disease, disorder, or symptoms thereof.

[0012] In agreement with the International System of Units, "MBq" is an abbreviation for the unit of radioactivity "megabecquerel."

[0013] As used herein, "PET" stands for positron emission tomography.

[0014] As used herein, "SPECT" stands for Single Photon Emission Computed Tomography.

[0015] As used herein, the term "effective amount" or "therapeutically effective amount" of a compound means an amount of a compound that elicits a biological or medical response in a subject, e.g., improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease.

[0016] As used herein, the term "substituted" or "optionally substituted" refers to any of a number of substituted or optionally substituted atoms ranging from 0 to the total number of open valences in the aromatic ring system, including halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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)R', -S(O)NR'R'', -NRSOR', -CN, -NO, -R', -N, -CH(Ph), fluoro(C1-C4)alkoxo, and fluoro(C1-C4)alkyl; R', R'', R''' and R'''' can be independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. When a compound of the present disclosure includes more than one R group, for example, when two or more of these groups are present, each of the R groups is independently selected, as are each R', R'', R''' and R'''' group.

[0017] As used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain alkyl functional group having from 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 its isomers (e.g., n-pentyl, isopentyl), and hexyl and its isomers (e.g., n-hexyl, isohexyl).

[0018] As used herein, the term "heteroaryl" refers to a polyunsaturated aromatic ring system containing 5 to 10 atoms, having a single ring or multiple aromatic rings fused or covalently linked together, wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O, and S. The nitrogen and sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized. Such rings can be fused to an aryl, cycloalkyl, or heterocyclyl ring. Non-limiting examples of such heteroaryls include furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl.

[0019] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group containing 6 to 10 ring atoms, having a single ring or multiple aromatic rings fused together, wherein at least one ring is aromatic. The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl, as defined herein) fused thereto. Suitable aryl groups include phenyl, naphthyl, and phenyl rings fused to a heterocyclyl, such as benzopyranyl, benzodioxolyl, benzodioxanyl, and the like.

[0020] As used herein, the term "halogen" means a fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I) group.

[0021] As used herein, the term "optionally substituted aliphatic chain" means an optionally substituted aliphatic chain having 4 to 36 carbon atoms, preferably 12 to 24 carbon atoms.

[0022] Radiolabeled GRPR-antagonists As used in the present invention, a GRPR-antagonist has the formula: MC-SP [In the formula, M is a radiometal and C is a chelator that binds M; S is an optional spacer covalently linked between C and the N-terminus of P; P is a group of the general formula: is a GRP receptor peptide antagonist of Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is absent or selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all as the L- or D-isomer); 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] wherein X is NH (amide) or O (ester), and R1 and R2 are the same or different and are selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether, or an alkyl-, halogen, hydroxyl- or hydroxyalkyl-substituted aryl or heteroaryl group.

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

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

[0025] In particular embodiments, C is [ka] is selected from the group consisting of:

[0026] According to one embodiment, S is a) The following formula: [ka] an aryl containing residue of: wherein PABA is p-aminobenzoic acid, PABZA is p-aminobenzylamine, PDA is phenylenediamine, and PAMBZA is (aminomethyl)benzylamine; b) The following formula: [ka] wherein DIG is diglycolic acid and IDA is iminodiacetic acid; c) PEG spacers of various chain lengths, in particular PEG spacer sele [ka] d) α- and β-amino acids, either single chains or homologous chains of various chain lengths or heterologous chains of various chain lengths, in particular [ka] GRP(1-18), GRP(14-18), GRP(13-18), BBN(1-5), or [Tyr4]BB(1-5); or e) A combination of a, b, c and d is selected from the group consisting of:

[0027] According to one embodiment, the GRPR antagonist has the formula: [ka] 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.

[0029] According to one embodiment, the radiolabeled GRPR-antagonist has formula (I): [ka] (M-DOTA-(p-aminobenzylamine-diglycolic acid)-[D-Phe 6 ,His-NH-CH[(CH2-CH(CH3)2]2 12 ,des-Leu 13 ,des-Met 14 ]BBN(6-14)); wherein M is a radioactive metal, preferably M is 177 Lu, 68 Ga and 111 In].

[0030] According to one embodiment, the radiolabeled GRPR-antagonist has formula (II): [ka] (M-N4(p-aminobenzylamine-diglycolic acid)-[D-Phe 6 , His-NH-CH[(CH2-CH(CH3)2]2 12 ,des-Leu 13 ,des-Met 14 ]BBN(6-l4));

[0039] Radiolabeled NeoBOMB2 of the formula:

[0040] wherein M is a radioactive metal.

[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, 166 H.O., 153 Sm,149 Pm, 151 Pm, 172 Tm, 121 Sn, 117m Sn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr, 225 Ac and 47 Preferably, M is selected from: 177 Lu, 68 Ga and 111 In is selected.

[0032] According to one embodiment, M is 177 In this case, the radiolabeled GRPR-antagonist can be used for radionuclide therapy. According to another embodiment, M is 68 In this case, the radiolabeled GRPR-antagonist can be used for PET. According to another embodiment, M is 111 In this case, a radiolabeled GRPR-antagonist can be used for SPECT.

[0033] Pharmaceutical Composition GRPR-antagonists tend to adhere to glass and plastic surfaces due to nonspecific binding (NSB), which poses a challenge for formulating pharmaceutical compositions. Several surfactants were tested to provide a stable composition. The inventors unexpectedly found that, among all the tested surfactants, a surfactant containing a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester produced the best results.

[0034] In a first aspect, the present disclosure relates to a pharmaceutical composition comprising a radiolabeled GRPR-antagonist as described herein and a surfactant comprising a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester. In one embodiment, the surfactant also comprises free ethylene glycol.

[0035] In one embodiment, the surfactant is of formula (III): [ka] wherein n is between 3 and 1000, preferably between 5 and 500, and more preferably between 10 and 50; R is a fatty acid chain, preferably an optionally substituted aliphatic chain.

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

[0037] The radiolabeled GRPR-antagonist may be present at a concentration exhibiting a volumetric radioactivity of at least 100 MBq / mL, preferably at least 250 MBq / mL. The radiolabeled GRPR-antagonist may be present at a concentration exhibiting a volumetric radioactivity comprised between 100 MBq / mL and 1000 MBq / mL, preferably between 250 MBq / mL and 500 MBq / mL.

[0038] The surfactant may be present in a concentration of at least 5 μg / mL, preferably at least 25 μg / mL, more preferably at least 50 μg / mL. The surfactant may be present in a concentration comprised between 5 μg / mL and 5000 μg / mL, preferably between 25 μg / mL and 2000 μg / mL, more preferably between 50 μg / mL and 1000 μg / mL.

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

[0040] In particular, the one or more additives may be selected from stabilizers against radiolytic degradation, buffers, sequestering agents and mixtures thereof.

[0041] As used herein, "radiolytic stabilizers" refers to stabilizers that protect organic molecules from radiolysis, e.g., gamma rays emitted from radionuclides break bonds between atoms of organic molecules, forming radicals that are then removed by stabilizers that prevent the radicals from undergoing any other chemical reactions that could result in unwanted, potentially ineffective, or even toxic molecules. Therefore, these stabilizers are also called "free radical scavengers," or simply "radical scavengers." Other alternative terms for these stabilizers are "radiation stability enhancers," "radiolytic stabilizers," or simply "quenchers."

[0042] As used herein, "sequestering agent" means a chelating agent suitable for binding free radionuclide metal ions in a formulation (that is not complexed with the radiolabeled peptide).

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

[0044] According to one embodiment, the pharmaceutical composition is an aqueous solution, for example an injectable formulation. According to a particular embodiment, 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 (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pp. 238-250 (1982) and SHP Handbook on Injectable Drugs, Trissel, 15th ed., pp. 622-630 (2009)).

[0046] The present disclosure also relates to a method of making a pharmaceutical composition comprising combining a radiolabeled GRPR-antagonist and a surfactant.

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

[0048] As used herein, the term "cancer" refers to cells capable of autonomous proliferation, i.e., an abnormal state or condition characterized by a rapid proliferation of cell growth. Hyperproliferative and neoplastic conditions can be classified as pathological, i.e., characterizing or constituting a disease state, or as non-pathological, i.e., deviating from normal but not associated with a disease state. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of invasive histopathological type or stage.

[0049] In particular embodiments, the cancer is selected from prostate cancer, breast cancer, small cell lung cancer, colon cancer, gastrointestinal stromal tumor, gastrinoma, renal cell carcinoma, gastrointestinal pancreatic neuroendocrine tumor, esophageal squamous cell tumor, neuroblastoma, squamous cell carcinoma of the head and neck, and ovarian, endometrial, and pancreatic tumors that exhibit neoplasia-associated vasculature that is GRPR. In one embodiment, the cancer is prostate cancer or breast cancer.

[0050] The present disclosure also relates to a pharmaceutical composition as described above for use in in vivo imaging, in particular for detecting GRPR-positive tumors in a subject in need thereof, preferably by PET and SPECT imaging.

[0051] The present disclosure also relates to a method for treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described above.

[0052] The present disclosure also relates to a method for in vivo imaging, comprising administering to a subject an effective amount of the pharmaceutical composition described above and detecting a signal derived from the decay of a radioisotope present in the compound.

[0053] Radiolabeled GRPR-antagonists for use in the treatment of cancer In a second aspect, the present disclosure also relates to a composition comprising a radiolabeled GRPR-antagonist for use in the treatment or prevention of cancer in a subject in need thereof, wherein the radiolabeled GRPR-antagonist is administered to said subject in a therapeutically effective amount comprised between 2000 and 10000 MBq.

[0054] In particular embodiments, a therapeutically effective amount of the composition is administered to the subject 2-8 times per treatment. For example, a patient may be administered 2-8 cycles of 2000-10000 MBq each intravenously of a radiolabeled GRPR antagonist, particularly 177 Treatment can be performed using Lu-NeoBOMB1.

[0055] In some embodiments, the subject is a mammal, such as, but not limited to, a rodent, canine, feline, or primate. In some embodiments, the subject is a human.

[0056] The present inventors have demonstrated that, as shown in animal models of cancer, 177Lu-NeoBOMB1 was found to be effective. Compared to untreated animals, the treated group had a significantly longer tumor growth delay and a significantly longer median survival time. In the non-limiting examples described herein, animals were 177 Animals were treated with 3 × 30 MBq / 300 pmol, 3 × 40 MBq / 400 pmol, or 3 × 60 MBq / 600 pmol of Lu-NeoBOMB1. Despite this, no significant differences in tumor growth delay time or median survival were found between treatment groups. This finding was unexpected because prior dosimetry calculations using a linear-quadratic model predicted differences in tumor control probability between treatment groups (tumor control probability: 0%, 75%, and 100% for animals treated with 3 × 30 MBq / 300 pmol, 3 × 40 MBq / 400 pmol, and 3 × 60 MBq / 600 pmol, respectively). Without being bound by any theory, this predicts that the dose required to treat patients should be much lower than predicted by prior dosimetry calculations, resulting in lower toxicity of radiolabeled NeoBOMB1.

[0057] Advantageously, the radiolabeled GRPR-antagonist is 177 It is labeled with Lu.

[0058] In particular embodiments of the above methods, the cancer is selected from prostate cancer, breast cancer, small cell lung cancer, colon cancer, gastrointestinal stromal tumor, gastrinoma, renal cell carcinoma, gastrointestinal pancreatic neuroendocrine tumor, esophageal squamous cell tumor, neuroblastoma, head and neck squamous cell carcinoma, and ovarian, endometrial, and pancreatic tumors that exhibit GRPR-positive neoplasia-associated vasculature. In one embodiment, the cancer is prostate cancer or breast cancer.

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

[0060] The present disclosure also relates to a method for treating or preventing cancer, the method comprising administering to a subject having cancer an effective amount of a composition comprising a radiolabeled GRPR-antagonist, wherein the radiolabeled GRPR-antagonist is administered to the subject in a therapeutically effective amount comprised between 2000 and 10000 MBq.

[0061] Provided herein are methods for treating or preventing cancer, the methods comprising administering to a subject having cancer an effective amount of a composition comprising a radiolabeled GRPR-antagonist, as defined herein. In some embodiments, the cancer is prostate cancer or breast cancer.

[0062] In some embodiments, administering a composition comprising a radiolabeled GRPR-antagonist to a subject with cancer can inhibit, delay, and / or reduce tumor growth in the subject. In some embodiments, tumor growth is delayed by at least 50%, 60%, 70%, or 80% compared to untreated control patients. In some embodiments, tumor growth is delayed by at least 80% compared to untreated control patients. In some embodiments, tumor growth is delayed by at least 50%, 60%, 70%, or 80% compared to the expected growth of a tumor without treatment. In some embodiments, tumor growth is delayed by at least 80% compared to the expected growth of a tumor without treatment. Those skilled in the art will recognize that predictions of tumor growth rate can be made based on epidemiological data, reports from the medical literature and other knowledge in the field, measurements of tumor type and tumor size, etc.

[0063] In some embodiments, administering a composition comprising a radiolabeled GRPR-antagonist to a subject with cancer can increase the subject's length of survival. In some embodiments, the increase in survival is compared to an untreated control patient. In some embodiments, the increase in survival is compared to the predicted increase in survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 3-fold, 4-fold, or 5-fold compared to an untreated control patient. In some embodiments, the length of survival is increased by at least 4-fold compared to an untreated control patient. In some embodiments, the length of survival is increased by at least 3-fold, 4-fold, or 5-fold compared to the predicted length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 4-fold compared to the predicted length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 3 years compared to an untreated control patient. In some embodiments, the length of survival is increased by at least 1 month, 2 months, or 3 months compared to untreated control patients. In some embodiments, the length of survival is increased by at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 3 years compared to the predicted length of survival of a subject without treatment. In some embodiments, the length of survival is increased by at least 1 month, 2 months, or 3 months compared to the predicted length of survival of a subject without treatment.

[0064] In some embodiments, the amount of radiolabeled GRPR-antagonist administered is less than would be expected for a subject for a 100% probability of tumor control in the subject. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is less than the amount predicted for a subject to have at least a 75% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is less than the amount predicted for a subject to achieve a 50% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is less than the amount predicted for a subject to achieve a 25% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is less than the amount predicted for a subject to achieve a 10% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is 25%, 30%, 40%, 50%, 60%, 70%, or 75% or less of the amount predicted for a subject to have a 100% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is 50%, 60%, 70%, 75%, 80%, or 85% or less of the amount predicted for a subject with at least a 75% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is 60%, 65%, 70%, 75%, 80%, 85%, or 90% or less of the amount predicted for a subject with at least a 50% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is the amount predicted for a subject with a tumor control probability of less than 25%, 20%, 15%, 10%, or 5%. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is the amount predicted for a subject with a 0% probability of tumor control. In some embodiments, the amount of radiolabeled GRPR-antagonist administered is the amount predicted for the subject for the subject to have a 0% probability of tumor control. [Example]

[0065] (Example 1): 68Screening of formulations to reduce adhesion of NeoBOMB1 using Ga-NeoBOMB1 During the development of the formulation kit, the inventors realized that peptides have a certain tendency to stick to glass and plastic surfaces.

[0066] This phenomenon is called nonspecific binding (NSB). Peptides often present a greater NSB problem than small molecules, and uncharged peptides in particular can strongly adsorb to plastics. The causes of this can be different: physical / chemical properties, van der Waals interactions, and ionic interactions.

[0067] Organic solvents can promote solubility and prevent adsorption. Ethanol, for example, can be used in radiopharmaceutical injections to promote solubility of highly lipophilic tracers or reduce adsorption to vials, membrane filters, and syringes. We rejected ethanol because it is not compatible with lyophilization.

[0068] Human serum albumin (HSA) is also used in many protein formulations as a stabilizer to prevent surface adsorption, but this additive is in a form that is not suitable due to its thermal instability. Another possible approach has been the use of surfactants (e.g., polysorbate 20, polysorbate 80, pluronic F-68, sorbitan trioleate).

[0069] The present inventors have found that the ionic surfactant is 68 We focused on testing non-ionic detergents because they may interfere with the labeling of Ga.

[0070] Non-ionic tensioactives such as Kolliphor HS15, Kolliphor K188, Tween 20, Tween 80, Polyvinylpyrrolidone K10 are commercially available as solubilizing additives in oral and injectable formulations. The following table summarizes the initial studies that have been carried out with different tensioactive agents.

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

[0072] Different surfactants were screened, and the percent adhesion of the resulting aqueous solutions was determined by assessing the total radioactivity remaining in the vial after complete discontinuation of the radiolabeled solution via dose calibrator measurements. The difference between the total radioactivity measured before and after discontinuation of the sample, expressed as a percentage, directly correlates with the adhesion of the peptide to the container closure system. These results are summarized in Table 1.

[0073] [Table 1]

[0074] The best results in terms of peptide attachment were obtained with Kolliphor HS15 and Tween 20. The two additives were further investigated to determine the final amounts in the kit. The results obtained were excellent in terms of radiochemical purity and peptide attachment.

[0075] [Table 2]

[0076] We focused on Kolliphor HS15 because polysorbate (Tween 20) is capable of autoxidation, cleavage at ethylene oxide subunits and hydrolysis of fatty acid ester bonds caused by the presence of oxygen, metal ions, peroxides or elevated temperature.

[0077] (Example 2): 177 Preclinical studies of the therapeutic efficacy of Lu-NeoBOMB1 Disclosed herein is a method for producing a medicament for the treatment of a pulmonary arthritis. 177 involving treatment of animals xenografted with the well-known GRPR-expressing prostate cancer cell line PC-3 with three different doses of Lu-NeoBOMB1. 177 This is an exemplary, non-limiting example of a preclinical study of the therapeutic efficacy of Lu-NeoBOMB1. Furthermore, in a small group of tumor-free animals, the efficacy of Lu-NeoBOMB1 on kidney and pancreas was demonstrated. 177 The effect of Lu-NeoBOMB1 treatment was examined by histopathological examination after treatment.

[0078] Materials and Methods radioactive label NeoBOMB1 (ADVANCED ACCELERATOR APPLICATIONS) (WO2014052471) was diluted in ultrapure water, and the concentration and chemical purity were monitored using a titration method developed in-house (Breeman WA, de Zanger RM, Chan HS, de Blois E. Alternative method to determine specific activity of 177 Lu by HPLC. Curr Radiopharm. 2015;8:119-122). To prevent peptide sticking, radioactivity was added to the vial containing the peptide, including all necessary additives, e.g., buffer, antioxidant, and tensioactivator (Kolliphor HS15). 177Lu 100 MBq / nmol). High-performance liquid chromatography was performed with a gradient of methanol and 0.1% trifluoroacetic acid to determine radiochemical purity. Radiometal incorporation was measured by instant thin-layer chromatography on silica gel as previously described (de Blois E, Chan HS, Konijnenberg M, de Zanger R, Breeman WA. Effectiveness of quenchers to reduce radiolysis of (111)In- or ( 177 ) Lu-labeled methionine-containing regulatory peptides. Maintaining radiochemical purity as measured by HPLC. Curr Top Med Chem. 2012;12:2677-2685) was >67% and >90% for SPECT / CT, and efficacy and toxicity studies, respectively.

[0079] Animal Models, Efficacy and Toxicity All animal studies met the requirements of the Animal Welfare Committee of the Erasmus Medical Center and were performed in accordance with accepted guidelines. 4 × 10 cells were cultured in a seeding medium (1 / 3 Matrigel High Concentration (Corning) + 2 / 3 Hank's Balanced Salt Solution (Thermofisher Scientific)). 6 200 μL of PC-3 cells (American Type Culture Collection) were subcutaneously inoculated into the right shoulder of male balb c nu / nu mice. Four weeks after tumor cell inoculation, the average tumor size was 543 ± 177 mm. 3 When the stool size reached 100 mg / kg, the animals were divided into four groups: a control group (n=10) and treatment groups 1-3 (n=15 per group). 177 To determine the efficacy of Lu-NeoBOMB1, animals were given three sham injections (control group), 177Lu-NeoBOMB1 3×30MBq / 300pmol (group 1), 177 Lu-NeoBOMB1 3 × 40 MBq / 400 pmol (Group 2) or 177 Lu-NeoBOMB1 3×60 MBq / 600 pmol (Group 3) was administered. The injections were administered intravenously, and the injections were spaced one week apart.

[0080] To determine the effects of treatment on pancreatic and renal tissues, tumor-free balb c nu / nu male mice received the same treatment as animals included in the efficacy study. At two different time points after the last therapeutic injection (12 and 24 weeks pi), animals were euthanized, and pancreatic and renal tissues were collected for pathological analysis.

[0081] In both studies, animal weights and / or tumor sizes were measured biweekly. 3 If the animal showed signs of aging or a loss of >20% of its body weight within 48 hours, the animal was removed from the study. In efficacy studies, animals were followed until they reached the maximum allowed age of 230 days.

[0082] SPECT / CT To quantify tumor uptake, SPECT / CT imaging was performed on additional groups of PC-3 xenografted animals (n=2 per group). Tumors were all 477±53 mm in size. 3If the dose was 0.01, the animals were injected with the same peptide dose as animals included in the efficacy and toxicity studies. Four and 24 hours after the first therapeutic injection, and 4 hours after the second and third therapeutic injections, whole-body SPECT / CT scans were performed with a hybrid SPECT / CT scanner (VECTor5, MILabs, Utrecht, The Netherlands). SPECT was performed over 30 minutes at 40 bed positions using a 2.0-mm pinhole collimator with a reported spatial resolution of 0.85 mm (Ivashchenko O, van der Have F, Goorden MC, Ramakers RM, Beekman FJ. Ultra-high-sensitivity submillimeter mouse SPECT. J Nucl Med. 2015;56:470-475). SPECT images were generated using photopeak windows of 113 and 208 keV with background windows on either side of the photopeak (widths 20% of the corresponding photopeak), and SR-OSEM reconstruction (Vaissier PE, Beekman FJ, Goorden MC. Similarity-regulation of OS-EM for accelerated SPECT reconstruction. Phys Med Biol. 2016;61:4300-4315), with a voxel size of 0.8 mm. 3 The reconstruction was performed using a 3D Gaussian filter (1 mm fwhm) and the CT data was registered. The reconstruction was performed with the following settings: 0.24 mA, 50 kV, circumferential scanning, 1 position. The CT was performed with a 100 μm 3 was reconstructed.

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

[0084] Dosimetry At a body weight of 25 g, data obtained from a previously published biodistribution and pharmacokinetic study (Dalm SU, Bakker IL, de Blois E, et al. 68 Ga / 177 Animals were treated with the RADAR realistic mouse model (Keenan MA, Stabin MG, Segars WP, Fernald MJ. RADAR realistic animal model series for dose assessment. J Nucl Med. 2010;51:471-476) with Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology. J Nucl Med. 2017;58:293-299). 177 The doses to the tumor, pancreas, and kidney were calculated for treatment with Lu-NeoBOMB1 3 x 30 MBq / 300 pmol, 4 x 40 MBq / 400 pmol, or 3 x 60 MBq / 600 pmol. 68 Ga / 177 Biodistribution data for 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 time-activity curves in tumors and organs. 177The time integrated activities for Lu are 177 Lu decay curve (T 1 / 2 The absorbed dose per administered activity was obtained by integrating these overlaid exponential curves (S = 6.647d). The absorbed dose per administered activity was obtained by multiplying by the organ S values ​​obtained from Keenan et al. (Keenan MA, Stabin MG, Segars WP, Femald MJ. RADAR realistic animal model series for dose assessment. J Nucl Med. 2010;51:471-476) or by using the spherical nodal S value for a 340 mg tumor (Stabin MG, Konijnenberg MW. Re-evaluation of absorbed fractions for photons and electrons in spheres of various sizes. J Nucl Med. 2000;41:149-160).

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

[0086]

number

[0087] N clonogens is the number of clonogenic (stem) cells in the tumor, and S(D,T) is the survival rate of the cells as a function of absorbed dose D and time T. The LQ model is

number

[0088] Tumor volume analysis Tumor doubling times were determined by fitting an exponential growth function to tumor volume over time in the control group. In the treatment group, intervals with exponential tumor volume decline were fitted with the onset of regrowth after the nadir time. Growth curves were plotted for tumors (>2000 mm). 3 Tumor growth lag time was estimated beyond the cutoff time point for mice where the tumor size was too large to determine mean growth statistics. 3 The time required to reach 100% was determined individually by comparing with the mean time found in the control group.

[0089] statistics Prism software (version 5.01, GraphPad Software) was used for statistical analysis. A P value of >0.05 was considered statistically significant. Differences in tumor volume growth and lag time for the four groups were analyzed using one-way ANOVA with Bonferroni's multiple comparison test. Curve fitting was performed using Pearson R 2 The goodness of fit was quantified by a least-squares fit according to

[0090] result SPECT / CT At most time points, mean radioactivity uptake quantified by SPECT / CT was highest in Group 3, followed by Groups 2 and 1. However, the differences between groups were not significant. Figure 1A shows scans of one animal from each group obtained 4 and 24 hours after the first injection and 4 hours after the second and third injections. Quantified tumor uptake is illustrated in Figure 1B.

[0091] 177 Lu-NeoBOMB1 treatment efficacy 177 Therapy with Lu-NeoBOMB1 proved effective. Animals in the control group had tumors measuring 2000 mm 3The tumor growth lag time reached 20.3 ± 5.9 days, which was 97 ± 59 days, 103 ± 66 days, and 95 ± 26 days for groups 1, 2, and 3, respectively (Figure 2A). Furthermore, two animals from group 1 and one animal from group 2 did not show any tumor regrowth after complete remission. However, there was no significant difference in tumor growth lag time within the treatment groups, and the difference with the control group was highly significant (P < 0.0001).

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

[0093] Five animals (n=3 from Group 2 and n=2 from Group 3) were excluded from the study for the following reasons: one was found dead after the first injection, one had a very small tumor at the start of therapy that disappeared within a few days, one had a weight loss of more than 10% within 48 h, and one had fluid retention in the abdomen. None of the events mentioned were treatment-related.

[0094] Kidney and pancreatic toxicity Animals included in the toxicity study did not show a significant loss of body weight over the follow-up period (Figure 3). Animal weight increased during the first week and remained relatively stable over time. One animal in the control group (ID: B) and one animal from group 1 (ID: 869) showed a loss of body weight, but this was less than 10% within 48 h. Histopathological analysis of the pancreas did not reveal any tissue damage or other abnormalities (Figure 4). Regarding the kidneys (Figure 5), small areas with lymphocytic infiltration were observed in the kidneys at 12 and 24 weeks after the final therapeutic injection. This was the case in the kidneys of both control and treated animals, indicating that this finding was not related to therapy. After 24 weeks of therapy, atrophy and fibrosis were observed in the kidneys of only one animal (ID: 864) receiving the lowest therapeutic dose, which is unlikely to be related to therapy. A mild chronic inflammatory response was observed in the kidneys of two animals from group 3 that were euthanized after 24 weeks of therapy.

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

[0096] [Table 3] The present invention includes the following aspects. <1> 1. A pharmaceutical composition comprising: - the following formula: MC-SP [In the formula, M is a radiometal and C is a chelator that binds M; S is an optional spacer covalently linked between C and the N-terminus of P; P is a group of the general formula: is a GRP receptor peptide antagonist of Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z; Xaa1 is absent or selected from the group consisting of the amino acid residues Asn, Thr, Phe, 3-(2-thienyl)alanine (Thi), 4-chlorophenylalanine (Cpa), α-naphthylalanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (oI-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all as the L- or D-isomer); 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 -NHOH, -NHNH 2 , -NH-alkyl, -N(alkyl)2, and -O-alkyl, or Z is

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Claims

1. 1. A pharmaceutical composition comprising: - stabilizers against radiolysis, Formula (I): 【Chemistry 1】 (Wherein M is 177 Lu) Compounds of the formula - a surfactant comprising a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester A pharmaceutical composition comprising:

2. The surfactant is represented by formula (III): 【Chemistry 2】 wherein n is between 10 and 50; R is a fatty acid chain) 2. The pharmaceutical composition of claim 1, comprising the compound of formula (I).

3. 10. The pharmaceutical composition of claim 1, wherein the surfactant comprises polyethylene glycol 15-hydroxystearate or polysorbate 20.

4. 4. The pharmaceutical composition of claim 3, wherein the surfactant comprises polyethylene glycol 15-hydroxystearate.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the compound of formula (I) is present in a concentration that provides a volumetric radioactivity of between 250 MBq / mL and 500 MBq / mL.

6. 6. The pharmaceutical composition of claim 1, wherein the surfactant is present in a concentration of at least 5 μg / mL.

7. 7. The pharmaceutical composition of claim 6, wherein the surfactant is present in a concentration between 50 μg / mL and 1000 μg / mL.

8. 8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an aqueous solution.

9. 9. A pharmaceutical composition according to any one of claims 1 to 8 for use in the treatment or prevention of cancer.

10. 1. A pharmaceutical composition comprising: - stabilizers against radiolysis, Formula (I): 【Transformation 3】 (Wherein M is 68 Ga) Compounds of the formula - a surfactant comprising a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester A pharmaceutical composition comprising:

11. The surfactant is represented by formula (III): 【Chemistry 4】 wherein n is between 10 and 50; R is a fatty acid chain) 11. The pharmaceutical composition of claim 10, comprising the compound of formula:

12. 11. The pharmaceutical composition of claim 10, wherein the surfactant comprises polyethylene glycol 15-hydroxystearate or polysorbate 20.

13. 13. The pharmaceutical composition of claim 12, wherein the surfactant comprises polyethylene glycol 15-hydroxystearate.

14. 14. The pharmaceutical composition according to any one of claims 10 to 13, wherein the compound of formula (I) is present in a concentration that provides a volumetric radioactivity of between 250 MBq / mL and 500 MBq / mL.

15. 15. The pharmaceutical composition of any one of claims 10 to 14, wherein the surfactant is present in a concentration of at least 5 μg / mL.

16. 16. The pharmaceutical composition of claim 15, wherein the surfactant is present in a concentration between 50 μg / mL and 1000 μg / mL.

17. 17. The pharmaceutical composition according to any one of claims 10 to 16, wherein the pharmaceutical composition is an aqueous solution.

18. 18. A pharmaceutical composition according to any one of claims 10 to 17 for use in in vivo imaging.

19. 20. A pharmaceutical composition according to any one of claims 10 to 18 for use in a method for in vivo imaging of tumors in a subject in need thereof, in particular for detecting GRPR-positive tumors, the method comprising administering an effective amount of the composition to the subject and detecting a signal derived from the decay of a radioactive isotope present in the compound, thereby detecting a GRPR-positive tumor.

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